ARRHYTHMIAS 22
Diagnosis wall via either handheld paddles or adhesive patches, or ‘internal’,
where a shock is delivered using a catheter inserted into the heart
A detailed history should be obtained, covering all of the symp- via a vein. DC cardioversion converts most tachycardias promptly
toms listed above. A characteristic of cardiac arrhythmias is their to sinus rhythm, but the recurrence rate is high. Catheter ablation
random onset. Symptoms that occur under speciic circumstances may cure many types of tachycardia and involves the delivery of
are less likely to be due to arrhythmia, but there are exceptions either radiofrequency or cryothermal energy via a catheter, result-
including certain uncommon types of VT, some cases of supraven- ing in the destruction of arrhythmogenic tissue by highly localised
tricular tachycardia (SVT) due to an accessory pathway, and vaso- heating or freezing, respectively.
vagal syncope (faints). Other key features of the history include:
• a history of cardiac disease; Supraventricular tachycardias
• a family history of heart disease and of sudden unexpected
Supraventricular tachycardias are tachycardias that arise from or
death; involve the atria.
• other diagnosed medical conditions;
• a full drug history, including over-the-counter medicines and Inappropriate sinus tachycardia
recreational drugs including alcohol. Although uncommon, inappropriate sinus tachycardia, that is, sinus
Physical examination is essential but often normal between tachycardia with no identiiable underlying cause, is one of the
episodes of arrhythmia. Mandatory investigation includes a more dificult arrhythmias to treat. The presenting symptom is usu-
12-lead ECG and an echocardiogram to detect structural heart ally palpitation, and the typical patient is a young, predominantly
disease. Other investigations for structural and ischaemic heart female, adult with no history of heart disease or other physical ill-
disease may be indicated at this stage with the aim of detecting ness. The 12-lead ECG shows sinus tachycardia and ambulatory
any underlying structural heart disease. If the history does not ECG monitoring demonstrates sinus tachycardia, but with diurnal
include sinister features such as syncope or a family history of variation in heart rate. Echocardiography is required to exclude
sudden unexpected death at a young age, and the resting 12-lead structural heart disease, and thyroid function and urinary catechol-
ECG and echocardiogram are normal, then the patient can be
reassured that they are extremely unlikely to have a serious heart amine excretion should be measured to detect thyrotoxicosis and
rhythm disturbance. The extent of further investigation will be phaeochromocytoma, respectively, as rare underlying causes of
dictated by how troublesome the symptoms are. sinus tachycardia. If treatment is required on symptomatic grounds,
The most certain way of reaching a irm diagnosis is a 12-lead β-blockers or verapamil are irst-line therapy. Ivabradine, a selec-
ECG recorded during the patient’s symptoms demonstrating tive ‘funny channel’ blocker, has been used in resistant cases but is
arrhythmia. Because many arrhythmias occur intermittently, some not currently licensed for this indication. These drugs are typically
form of ECG monitoring is often necessary. This may include a taken regularly in an attempt to control the heart rate and hence the
continuous ambulatory ECG (Holter) recording for up to 7 days at symptoms. Catheter ablation of the sinus node has been performed
a time if the symptoms occur frequently, or for less frequent symp- in highly symptomatic, drug-resistant, inappropriate sinus tachy-
toms an event recorder, which may store ECG strips automatically cardia, but with limited success and risks including symptomatic
if it detects an arrhythmia or if activated by the patient during their sinus bradycardia and phrenic nerve palsy.
symptoms. An insertable loop recorder may be implanted subcu-
taneously and is an ECG event recorder with a battery life of about Atrial flutter
3 years, making it a useful tool for the diagnosis of infrequent
arrhythmias. There are now attachments for mobile phones that Atrial lutter is a right atrial tachycardia with a re-entry circuit
turn them into single-lead ECG recorders, enabling patients with around the tricuspid valve annulus. The atrial rate is typically 300
suspected or actual arrhythmia to make high-quality recordings of per minute. The long refractory period of the AV node protects
their heart rhythm at any time, although the onset of the arrhyth- the ventricles from 1:1 conduction: In the presence of a healthy
mia is unlikely to be captured, which may limit their usefulness. AV node and the absence of AV node–modifying drugs, there is
usually 2:1 AV conduction resulting in a regular narrow-complex
Management tachycardia with a ventricular rate of 150 per minute.
Tachycardia Atrial lutter confers a risk of thromboembolism similar to that
of AF, and this risk should be managed in the same way as for AF
Tachycardia is conventionally deined as a resting heart rate greater (see later). Emergency management of atrial lutter is dictated
than 100 beats/min and can be classiied according to whether it by the clinical presentation but may include DC cardioversion
arises in or involves the atria (supraventricular tachycardias [SVTs]) or ventricular rate control with drugs that increase the refractory
or the ventricle (ventricular tachyarrhythmias). Management of period of the AV node such as β-blockers, verapamil, diltiazem,
tachycardia may involve the use of drugs, direct current (DC) car- or digoxin. DC cardioversion would be appropriate in the case of
dioversion, catheter ablation or implantable devices. DC cardio- signiicant haemodynamic compromise and might be considered
version is performed under either anaesthesia or sedation and may in a chronically anticoagulated patient or where the onset of the
be either ‘external’, where a shock is delivered across the chest arrhythmia is certain and is less than 48 hours. In other situations,
ventricular rate control with drugs would be appropriate.
385
22 THERAPEUTICS
I I
II 25 mm/s II 25 mm
10 mm/mV 10 mm
III 50~ 0.05–100 Hz III 50~
aVR aVR
aVL
aVL
aVF aVF
V1 V1
V2
V2
V3
V3
V4 V4
V5 V5
V6 V6
Fig. 22.7 A 12-lead electrocardiogram (ECG) recorded during the administration of intravenous
adenosine. The initial rhythm is atrial flutter with 2:1 conduction from atria to ventricles. The QRS
complexes obscure the atrial activity on the ECG. Adenosine does not terminate the atrial flutter but
causes temporary atrioventricular block, revealing the characteristic ‘sawtooth’ ECG morphology of
typical atrial flutter.
β-Blockers, verapamil, and digoxin may be given intrave- mechanism may be caused by abnormal automaticity, trig-
nously. β-Blockers or calcium channel blockers (CCBs) would gered activity or microreentry. Management is as described
usually be used as irst-line treatment, whereas the delayed onset for atrial lutter with three exceptions: (1) some focal atrial
of action of digoxin makes it less useful for rapid heart rate con- tachycardias terminate with adenosine; (2) the potential for
trol in an acute setting. Because the re-entry circuit is conined to class Ic antiarrhythmic drugs to slow tachycardia and result
the right atrium and does not involve the AV node, adenosine will in 1:1 AV conduction is lower than for atrial lutter; and
not terminate atrial lutter but will produce transient AV block, (3) catheter ablation of focal atrial tachycardia may be more
allowing the characteristic lutter waves to be seen on the ECG challenging than that of atrial lutter, but it is curative in a
(Fig. 22.7). majority of cases.
There is a limited role for antiarrhythmic drugs, whether used Junctional re-entry tachycardia
acutely to achieve chemical cardioversion or in the longer-term
to maintain sinus rhythm. Class Ic antiarrhythmic drugs such as The term supraventricular tachycardias is widely used to describe
lecainide or propafenone should be used only in conjunction junctional re-entry tachycardias, but it is a misnomer because it
with AV node–modifying drugs such as β-blockers, verapamil, implies any tachycardia arising from the atria. Junctional re-entry
diltiazem, or digoxin because they may otherwise cause slow- tachycardia is a more speciic term and may be preferable.
ing of the atrial lutter circuit and 1:1 conduction though the AV
node, which may be life-threatening. Sotalol and amiodarone Two mechanisms account for most junctional re-entry tachy-
have been used to restore and maintain sinus rhythm and have the cardias, and both involve a macroreentry circuit (Fig. 22.8). AV
advantage of helping to control the ventricular rate where rhythm nodal re-entry tachycardia (AVNRT) rotates around a circuit
control is incomplete. Catheter ablation of atrial lutter is highly including the AV node itself and the so-called AV nodal fast and
effective, safe, and is increasingly used in preference to long- slow pathways, which feed into the AV node. AV re-entry tachy-
term drug treatment. cardia (AVRT) comprises a re-entry circuit involving the atrial
myocardium, the AV node, the ventricular myocardium and an
Focal atrial tachycardia accessory pathway, a congenital abnormality providing a second
electrical connection between the atria and ventricles in addition
As its name implies, this relatively uncommon arrhythmia to the His bundle, thus forming a potential re-entry circuit.
results from the repetitive discharge of a focal source within
386 the atria or surrounding venous structures. The tachycardia Many accessory pathways conduct only retrogradely from the
ventricles to the atrium. In these cases, the ECG during sinus
ARRHYTHMIAS 22
SA node LA LA
AV node SA node
His bundle
RA RA
A AV node
I LV LV
His bundle
RV RV
B
Fig. 22.8 The re-entry circuits of (A) atrioventricular (AV) re-entry tachycardia (AVRT) and (B) AV nodal
re-entry tachycardia (AVNRT). (A) The AVRT circuit comprises atrial myocardium, the AV node and His
bundle, ventricular myocardium and an accessory pathway, a small strand of muscle providing a sec-
ond, abnormal, connection between atrium and ventricle, thus forming a potential re-entry circuit. The
accessory pathway itself is the target of catheter ablation. (B) The AVNRT circuit comprises ‘fast’ and
‘slow’ pathways feeding into the AV node itself. The slow pathway is the target of catheter ablation.
AV, Atrioventricular; LA, left atrium; LV, left ventricle; RA, right atrium; RV, right ventricle; SA, sinoatrial.
aVR V1 V4
II aVL V2 V5
III aVF V3 V6
II
Fig. 22.9 Electrocardiogram showing a Wolff–Parkinson–White pattern. The PR interval is short and
the QRS complex is abnormally broad, with a slurred upstroke or delta wave.
rhythm appears normal and the accessory pathway is described PR interval, because the conduction velocity of an accessory 387
pathway is usually faster than that of the AV node, and a delta
as ‘concealed’. Other accessory pathways conduct anterogradely wave, a slurred onset to the QRS complex that occurs because an
and retrogradely. In these cases, the ECG during sinus rhythm is accessory pathway inserts into the ventricular myocardium which
abnormal and is described as having a Wolff–Parkinson–White conducts more slowly than the His–Purkinje system.
pattern (Fig. 22.9). This abnormality is characterised by a short
22 THERAPEUTICS
Junctional re-entry tachycardias are characterised by a history Persistent: AF lasting more than 7 days or requiring cardioversion;
of discrete episodes of rapid regular palpitation that start and stop Longstanding persistent: continuous AF for more than 1 year; or
suddenly and occur without warning and apparently at random. Permanent: where a decision has been made not to attempt cure
The peak age range at which symptoms begin is from the mid-
teens to the mid-thirties, and the condition is more common in of persistent AF.
women. There are no symptoms between episodes, and cardiac
examination and investigation at these times are usually normal. AF may also be classiied as ‘valvular’ or ‘nonvalvular’. The
The diagnosis is usually made on the basis of the history, ideally term valvular AF is used for AF in the context of rheumatic valvular
conirmed by an ECG recorded during an episode showing a reg- disease (predominantly mitral stenosis) or prosthetic heart valves.
ular narrow-complex tachycardia with no discernible P waves or
P waves occurring in a 1:1 relationship with the QRS complexes. Stroke risk. Non-valvular AF is associated with a ivefold
increase in the risk of stroke. Most strokes complicating AF are
Acute treatment of junctional re-entry tachycardia aims to ter- ischaemic, as a result of embolism of thrombus that forms predomi-
minate the tachycardia by causing transient conduction block in
the AV node, an obligatory part of the re-entry circuit. Vagotonic nantly within the left atrial appendage due, at least in part, to sluggish
manoeuvres such as carotid sinus massage, a Valsalva manoeu- blood low within the ibrillating atria. Oral anticoagulants reduce
vre or eliciting the diving relex by immersion of the face in ice- stroke risk in AF by between 60% and 70% (Hart et al., 2007),
cold water may all result in a brief vagal discharge suficient to whereas antiplatelet drugs prescribed as monotherapy provide
block conduction in the AV node, terminating tachycardia. The little or no protection against stroke in this population and con-
same effect may be achieved with intravenous adenosine given fer a risk of intracranial bleeding similar to that seen with oral
as a rapid bolus injection in doses up to 12 mg. Intravenous vera- anticoagulants, especially in elderly patients.
pamil 5 mg as a rapid bolus injection is also a good alternative
where adenosine is contraindicated, for example, in patients with Guidelines for stroke risk management. Stroke risk man-
asthma. However, verapamil should not be used if the patient has agement in patients with atrial lutter and AF is the subject
been recently treated with β-blockers. of national and international guidelines (Camm et al., 2012;
National Institute for Health and Care Excellence [NICE],
Junctional re-entry tachycardia is often recurrent. There is a 2014). All patients presenting with AF (or atrial lutter) should
limited role for prophylactic drug treatment because this is gen- undergo assessment of their stroke risk. The type of AF (parox-
erally not a dangerous condition affecting young and otherwise ysmal, persistent, or permanent) does not appear substantially
healthy people. Among other factors, the eficacy, toxicity, and to inluence stroke risk, but there is strong evidence that stroke
acceptability of what may be long-term drug treatment requires risk in AF is determined by the entire stroke risk factor proile.
careful consideration. Options for prophylactic drug treatment
include β-blockers, verapamil, diltiazem, lecainide, and sotalol. Patients with valvular AF (i.e. rheumatic mitral valve disease
Particular importance should be given to discussion about the or a prosthetic heart valve) should be treated with a vitamin K
management of junctional re-entry tachycardia during pregnancy. antagonist (VKA) such as warfarin.
Catheter ablation is curative in one sitting in a majority of cases
and is widely regarded as preferable to long-term drug therapy For patients with non-valvular AF, stroke risk is currently
in this typically young and otherwise healthy group of patients. assessed by the CHA2DS2-VASc score (Table 22.1), which
ranges from 0 to 9. The risk of thromboembolism is directly
Atrial fibrillation
Table 22.1 The CHA2DS2-VASc score for the assessment
AF is the most common sustained arrhythmia, affecting about 1% of stroke risk in non-valvular atrial fibrillation
of the population. AF is rare before the age of 50 years, but its
prevalence approximately doubles with each decade thereafter Stroke risk factor CHA2DS2-VASc score
such that about 10% of those older than 80 years are affected. AF 1
is characterised by extremely rapid and uncoordinated electrical Congestive cardiac failure and/or
activity in the atria and variable conduction through the AV node, moderate-to-severely impaired left
resulting in irregular and usually rapid ventricular contraction. ventricular systolic function
The clinical importance of AF results from: Hypertension 1
1. symptoms including palpitation, reduced exercise capacity,
Age ≥75 years (2 points) 2
breathlessness and fatigue;
2. increased risk of thromboembolic stroke; Diabetes mellitus 1
3. exacerbation of heart failure through its direct haemodynamic
History of stroke, transient ischaemic 2
effect and by causing tachycardia-induced cardiomyopathy; attack or other thromboembolism
4. increased all-cause mortality (odds ratio 1.5 for men and 1.9
Arterial vascular disease (history of 1
for women). myocardial infarction, aortic atheroma
AF may be classiied as: or peripheral vascular disease)
Paroxysmal: self-limiting episodes of AF lasting no more than Age between 65 and 74 years 1
388 7 days;
Sex category (female) 1
Adapted from Lip et al. (2010a).
ARRHYTHMIAS 22
proportional to the CHA2DS2-VASc score (Fig. 22.10) international normalised ratio (INR) in the range 2.0–3.0.
(Olesen et al., 2011). Patients younger than 65 years with A sub-therapeutic INR increases substantially the risk of
non-valvular AF and no other stroke risk factors (including stroke or arterial thromboembolism. Conversely, a high INR
female patients) are considered to have a low enough stroke increases the risk of bleeding (Fig. 22.12). The approximate
risk that no stroke-preventative therapy is indicated. For all annual frequency of major and minor bleeding with VKAs
other patients, the CHA2DS2-VASc score should be calcu- is 3% and 10%, respectively. It may be difficult to maintain
lated, and those with a CHA2DS2-VASc score ≥1 should be an INR within the therapeutic range of 2.0–3.0, and indeed
considered for treatment with either a VKA or a non-VKA there is evidence from real-world studies that the INR may
oral anticoagulant (NOAC; also referred to as a direct oral be outside of this range for much of the time. Patients’ and
anticoagulant [DOAC]): a direct thrombin inhibitor such as doctors’ concerns about the use of VKAs have resulted in
dabigatran or one of the factor Xa inhibitors apixaban, rivar- their under-utilisation, particularly among elderly people,
oxaban and edoxaban. who are at the greatest risk of stroke. This concern has
led to the development of the NOACs (also referred to as
Antiplatelet agents are no longer recommended for stroke DOACs). The perceived advantages of the DOACs over VKAs
prevention in patients with AF. Dual antiplatelet therapy with include:
aspirin and clopidogrel has been shown to reduce stroke risk by 1. a predictable effect of the drugs upon coagulation such that
comparison with aspirin alone in patients with AF with mod-
erately high stroke risk considered unsuitable for treatment a standard dose is taken without the need for blood tests to
with an oral anticoagulant (ACTIVE Investigators et al., 2009), assess its effect,
but is associated with a signiicantly increased risk of internal
bleeding, and this combination is not recommended by current Table 22.2 The HAS-BLED score for calculation of the risk of
guidance. bleeding (Pisters et al., 2010)
Assessment of bleeding risk. The beneit of oral anticoagu- Hypertension (systolic blood pressure >160 mmHg) 1
lants in terms of stroke risk reduction in patients with AF is par-
tially offset by an increased risk of bleeding. Several bleeding Abnormal renal and/or liver function 1 or 2
risk scores have been proposed, among them the HAS-BLED
score (Table 22.2), which has been validated in the AF popula- Stroke 1
tion (Pisters et al., 2010) (Fig. 22.11).
Bleeding tendency or predisposition 1
The use of bleeding risk scores is not suficiently reined to
Labile international normalised ratios (if on warfarin, 1
allow accurate assessment of the anticipated net clinical bene- time in therapeutic range <60%)
it of anticoagulation in individuals with AF according to their Elderly (age >65 years, frail condition) 1
CHA2DS2-VASc score. However, it prompts consideration of the
risk of bleeding, modiication where possible of bleeding risk Drugs (antiplatelets, non-steroidal anti-inflammatories) 1 or 2
factors and perhaps intensiied monitoring. or alcohol excess/abuse
Choice of oral anticoagulant. VKAs, such as warfarin,
which inhibit the synthesis of clotting factors II, VII, IX
and X, have been the mainstay of oral anticoagulant treat-
ment for AF. The beneficial effect of VKAs is seen with an
Event rate (95% CI) of hospital admission
and death due to thromboembolism∗
per 100 person years
Bleeds per 100 patient-years
25 10
20 9
15 8
10 7
5 6
0 5
0123456789
CHA2DS2-VASc score 4
∗Ischaemic stroke, peripheral artery embolism and pulmonary 3
embolism, based upon 10 year follow-up.
Fig. 22.10 Hospital admission or death due to thromboembolism per 2
100 person-years as a function of CHA2DS2-VASc score, based upon
10-year follow-up. CI, Confidence interval. (Data from Olesen et al., 2011.) 1
0 123 4
0 HAS-BLED score
Fig. 22.11 Risk of major bleeding within 1 year as a function of the 389
HAS-BLED score. (Data are from Pisters et al., 2010.)
22 THERAPEUTICS
2. lower potential for interaction with other drugs,Odds ratio Each of the DOACs has been compared with warfarin in a
3. no dietary restrictions. prospective, randomised, multicentre clinical trial examining
both eficacy for stroke risk reduction and safety in patients with
The following are potential disadvantages of DOACs by com- AF and moderately increased stroke risk (Connolly et al., 2009;
parison with VKAs: Giugliano et al., 2013; Granger et al., 2011; Patel et al., 2011).
1. Assessing adherence may be problematic. The results are summarised in Table 22.4.
2. The DOACs are all to some extent renally excreted: Dose
Current European Society of Cardiology guidance (Kirchhof
reduction is necessary in patients with impaired renal func- et al., 2016) is that where an oral anticoagulant is indicated for
tion, and the drugs are contraindicated in those with severely stroke risk reduction in AF:
impaired renal function. • DOACs are recommended where there are dificulties in
3. The ability to achieve rapid reversal of the anticoagulant
effect of DOACs is a concern, although there is evidence that maintaining the INR within the therapeutic range with a
the intravenous administration of dried prothrombin com- VKA, where side effects are experienced with a VKA or
plex (factors II, VII, IX and X) may reverse the anticoagulant where a patient is unable or unwilling to undertake INR
of factor Xa inhibitors. Speciic reversal agents are becom- monitoring.
ing available: idarucizumab, a reversal agent for dabigatran, • DOACs should be considered rather than VKAs for most
received European Medicines Agency/U.S. Food and Drug patients with non-valvular AF based on their net clinical
Administration approval in the fourth quarter of 2015, and beneit.
reversal agents for factor Xa inhibitors are in development.
4. Some DOACs require twice-daily dosing, which may reduce Non-pharmacologic means of stroke risk reduction in atrial
adherence.
Characteristics of the DOACs are summarised in Table 22.3. ibrillation. A majority of intracardiac thrombi occurring in the
context of AF develop in the left atrial appendage. It is common
20 Ischaemic stroke1 practice to excise the left atrial appendage during surgical opera-
Intracranial bleeding2 tions on the mitral valve, because patients with mitral valve dis-
ease requiring surgery are at high risk of development of AF.
15 Left atrial appendage closure devices implanted percutaneously
obviate the need for long-term treatment with an oral anticoagu-
10 Therapeutic INR range lant and have been shown to provide protection against stroke
equivalent to that of warfarin in moderate-risk patients with AF.
5 The medium- to long-term beneit of these devices is partially
offset by a short-term risk of procedure-related complications.
1
Catheter ablation of AF may be curative. An important ques-
1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0 tion is whether successful catheter ablation reduces stroke risk
INR to the extent that it may no longer be necessary to take an oral
anticoagulant. The results of several retrospective/observa-
Fig. 22.12 The risk of stroke or intracranial bleeding according to tional studies suggest that this may indeed be the case (Bunch
the international normalised ratio (INR) in patients who are taking vita- et al., 2013). The methodological limitations of this type of
min K antagonists. 1Hylek et al. (1996); 2Fang et al. (2004). study are such that, pending the results of ongoing prospective
trials addressing this question, current guidelines recommend
Table 22.3 Pharmacokinetic and pharmacodynamic properties of non-vitamin K antagonist oral anticoagulants
Dabigatrana Apixabana,b Rivaroxabana,c Edoxaband,e
Mechanism of action Oral direct thrombin inhibitor Oral factor Xa Inhibitor Oral factor Xa inhibitor Oral factor Xa inhibitor
Bioavailability (%) 6 50 60–80 62
Plasma protein binding (%) 35 87 92–95 55
Time to peak levels (h) 0.5–2.0 3–4 2–4 1–2
Half-life (h) 12–14 12 5–13 10–14
Dosing
Non-valvular atrial fibrillation Twice daily Twice daily Once daily Once daily
390 aEriksson et al. (2009).
bBristol Myers Squibb-Pfizer (2017).
cBayer (2017).
dBounameaux and Camm (2014).
eDaiichi Sankyo UK Limited (2017).
ARRHYTHMIAS 22
Table 22.4 Summary of the results of prospective randomised trials comparing non-vitamin K antagonist oral anticoagulant drugs with
warfarin for stroke risk reduction in patients with non-valvular atrial fibrillation
Drug Dosage Trial outcome
Dabigatrana
150 mg twice a day Efficacy: both doses non-inferior to warfarin, higher dose superior to warfarin in
110 mg twice a day preventing stroke and systemic embolism
Safety: lower dose less major bleeding than warfarin, both doses less intracranial
haemorrhage compared with warfarin
Rivaroxabanb 20 mg once a day Efficacy: non-inferior to warfarin
15 mg once a day Safety: non-inferior to warfarin and less intracranial haemorrhage compared with
warfarin
Apixabanc 5 mg twice a day Efficacy: superior to warfarin for stroke risk reduction and all-cause mortality
2.5 mg twice a day Safety: less major bleeding or intracranial haemorrhage compared with warfarin
Edoxaband 60 mg once a day Efficacy: both doses non-inferior to warfarin
30 mg once a day Safety: less major bleeding or intracranial haemorrhage compared with warfarin
aConnolly et al. (2009).
bPatel et al. (2011).
cGranger et al. (2011).
dGiugliano et al. (2013).
the continuation of oral anticoagulants following catheter If DC cardioversion is deemed inappropriate, rapid ventricular 391
ablation of AF according to the CHA2DS2-VASc score (Camm rate control may be achieved with intravenous β-blockers, vera-
et al., 2012). pamil or digoxin.
Duration of treatment with oral anticoagulants. In trials Long-term management of atrial ibrillation. There has
comparing different drug-based treatment strategies for AF, a been considerable debate about the pros and cons of a rate-control
majority of strokes occurred in patients who had been consid-
ered to have good heart rhythm control and whose oral antico- strategy focusing on achieving adequate control of the ventricular
agulants had therefore been stopped (Sherman et al., 2005). It is rate with drugs modifying the AV node versus a rhythm-control
known that asymptomatic AF is commonplace, even in patients strategy, in which an attempt is made to restore and maintain sinus
who also have symptomatic episodes of AF. Furthermore, the rhythm with antiarrhythmic drugs with or without DC cardiover-
presence and prevalence of AF may be underestimated by many sion. These strategies have been compared in several large-scale
detection strategies. For these and other reasons it is rarely prospective randomised trials, which have failed to demonstrate
appropriate to discontinue oral anticoagulant treatment in those an advantage to a rhythm-control strategy. Sinus rhythm has been
patients with a CHA2DS2-VASc score ≥1. associated with a 47% reduction in all-cause mortality, although
this beneit was offset by a 49% increase in mortality associated
Emergency management of atrial ibrillation. AF associ- with the use of antiarrhythmic drugs (AFFIRM Investigators,
ated with unstable angina, heart failure or hypotension requires 2004). In that study, a wide variety of antiarrhythmic drugs was
emergency treatment. In most cases, the treatment of choice is used at the discretion of the investigator. These included several
DC cardioversion. Concerns about thromboembolism as the class I antiarrhythmic drugs, sotalol and amiodarone. A rhythm-
heart returns to sinus rhythm are valid but should not delay control strategy may be more appropriate in (1) younger patients,
emergency treatment. Immediate DC cardioversion is appro- (2) those with paroxysmal AF, (3) those with AF associated with
priate when the onset of AF is clearly identiied as within 48 heart failure, and (4) patients who remain symptomatic despite
hours of presentation or when the patient is already taking an adequate ventricular rate control.
oral anticoagulant with, in the case of warfarin, a therapeutic
INR for at least 4 weeks. If facilities permit, a transoesopha- Ventricular rate control. The mainstay of a ventricular rate-
geal echocardiogram may be performed in patients not already control strategy is the use of drugs that prolong the AV nodal
receiving an oral anticoagulant to exclude intracardiac throm- refractory period, thus reducing the ventricular rate. β-Blockers
bus. Heparin should then be given immediately and contin- or CCBs (verapamil or diltiazem) are generally effective both
ued until the patient is established on an oral anticoagulant. A at rest and on exertion, although a combination of these drugs
DOAC would be an attractive choice in this situation because is occasionally necessary. Digoxin may control the ventricular
of the rapid onset of action of this class of drugs. Anticoagulant rate at rest but is less successful at controlling the rate during
therapy should be continued for at least 3 months following exertion, and therefore should only be considered in patients
cardioversion because the complete return of effective contrac-
tion of the atrial musculature may take several weeks following with non-paroxysmal AF who do no or little physical exercise.
the restoration of sinus rhythm. The need for long-term stroke Where ventricular rate control cannot be achieved with drugs,
prophylaxis is guided thereafter by the CHA2DS2-VASc score. catheter ablation of the AV node in combination with perma-
nent pacemaker implantation can provide excellent symptom
relief. The adverse effects of right ventricular apical pacing may
22 THERAPEUTICS
offset some of the beneit of a slower ventricular rate and regular in frequency and duration until persistent AF supervenes. This
rhythm; therefore, biventricular pacing may be more appropri- progression appears to occur as a result of atrial remodelling, a
ate in this situation. complex and incompletely understood process involving elec-
trical and structural changes in the whole atrial myocardium
Rhythm control. Rhythm control can be considered in terms of predisposing to the development of AF independent of the pul-
either restoration or maintenance of sinus rhythm. The most rapid and monary veins. Catheter ablation strategies for persistent AF are
effective means of restoring sinus rhythm is DC cardioversion. Where more complex than those for paroxysmal AF with a correspond-
AF is of short duration, well-tolerated and not associated with struc- ingly higher rate of repeat procedures and a lower overall success
tural heart disease, class IC antiarrhythmic drugs such as lecainide rate. For all of these reasons, drug therapy remains the irst-line
and class III drugs such as amiodarone may be used intravenously treatment of AF, with catheter ablation reserved for patients with
to achieve chemical cardioversion. Stroke risk should be managed symptomatic AF that cannot be managed satisfactorily with drugs
in the same way as described for the emergency management of AF. and whose symptoms trouble them enough to undergo ablation.
Although sinus rhythm can be restored in most patients with Ventricular tachyarrhythmias
DC cardioversion and/or antiarrhythmic drugs, most patients
will revert to AF without further treatment. The SAFE-T trial Ventricular tachycardia
examined 665 patients with AF of at least 72 hours’ duration.
Sinus rhythm was restored with antiarrhythmic drugs (sotalol VT is a rapid, abnormal heart rhythm that originates in the ventri-
or amiodarone) or placebo, supplemented where necessary by cles. VT may present with palpitation, chest pain, breathlessness,
DC cardioversion (Singh et al., 2005). Patients were then main- presyncope, syncope or sudden cardiac death (death occurring
tained on placebo, sotalol or amiodarone. By 2 years, that prob- suddenly and unexpectedly within 1 hour of the onset of symp-
ability of remaining in sinus rhythm was 10% (placebo), 30% toms from a presumed cardiac cause). It is clinically useful to
(sotalol) and 50% (amiodarone). Another similar study (Roy subdivide VT in the following ways: VT complicating structural
et al., 2000) demonstrated equivalent eficacy of sotalol and the heart disease and ‘normal heart’ VT.
class Ic antiarrhythmic drug propafenone in the maintenance
of sinus rhythm (40% at 2 years) and conirmed the superiority Ventricular tachycardia complicating structural heart
of amiodarone (60%). Most heart rhythm specialists consider disease. Most VT occurs in patients with signiicant structural
that the toxicity of amiodarone precludes its long-term use for heart disease. The predominant cause is healed myocardial
the management of AF. It was hoped that dronedarone would infarction, but other important causes include hypertensive and
provide eficacy similar to amiodarone, but it has been shown valvular heart disease and a variety of cardiomyopathies includ-
to be less effective, although it has far fewer side effects and is ing dilated cardiomyopathy, hypertrophic cardiomyopathy, or
not used widely. In practice, for long-term treatment, lecainide arrhythmogenic right ventricular cardiomyopathy. VT of this
tends to be used in younger patients with structurally normal type is usually due to re-entry. Scarring of ventricular myocar-
hearts and with no evidence of cardiac conduction system dis- dium creates the central obstacle around which potential re-entry
ease. Sotalol is preferred in patients with hypertensive or isch- circuits develop forming the VT ‘substrate’. In this setting, a
aemic heart disease, and amiodarone is generally reserved for single ventricular premature beat, the VT ‘trigger’, may induce
elderly patients in whom there may be fewer concerns about the VT. The importance of VT complicating structural heart disease
is that there is a high chance of the VT recurring, and patients are
side effects of long-term amiodarone (Kirchhof et al., 2016). at substantially increased risk of sudden cardiac death.
Modern strategies for curative catheter ablation of AF followed
‘Normal heart’ ventricular tachycardia. These uncommon
the discovery in 1998 that paroxysmal AF is due, in most cases, VTs occur in the context of a structurally normal heart and a nor-
to rapid iring by the musculature surrounding the pulmonary mal ECG in sinus rhythm and are exempliied by right ventricular
veins close to their junctions with the left atrium. The cornerstone outlow tract (RVOT) tachycardia and fascicular tachycardia. The
of most current ablation strategies for paroxysmal AF is com- importance of recognising these VTs is that unlike VT associated
plete electrical isolation of all four pulmonary veins from the left with structural heart disease, they are associated with a normal
atrium, using either radiofrequency ablation (cautery) or cryo- prognosis, may be managed successfully with drugs (β-blockers,
ablation to ablate in rings around the pairs of ipsilateral veins. verapamil or lecainide for RVOT tachycardia, verapamil for fas-
Catheter ablation can cure a majority of paroxysmal AF but needs cicular tachycardia) and are curable by catheter ablation.
to be repeated in 20–25% of patients and carries risk, including
stroke (2–3/1000) and pericardial effusion (1–2/100). Catheter Ventricular fibrillation
ablation has been shown to be superior to antiarrhythmic drug
therapy in maintaining sinus rhythm and improving symptoms Ventricular ibrillation (VF) comprises rapid and totally disorgan-
and quality of life. Catheter ablation has also been shown in non- ised electrical activity in the ventricles such that effective con-
randomised studies to improve left ventricular ejection fraction traction ceases and results in sudden death unless sinus rhythm is
and heart failure symptoms. The CASTLE-AF study (Marrouche restored either spontaneously or by deibrillation. Acute myocar-
et al., 2018) was the irst to demonstrate that catheter ablation is dial ischaemia and infarction are probably responsible for most
associated with a reduction in mortality by comparison with stan- VF, although virtually any structural heart disease may also be
complicated by VF. Other cases occur in the context of a group of
dard medical therapy, in patients with severely impaired left ven- conditions known as channelopathies.
tricular systolic function and heart failure symptoms. No beneit
has been convincingly demonstrated in terms of reduced stroke
392 risk. The natural history of AF is for episodes of AF to increase
ARRHYTHMIAS 22
Channelopathies. Channelopathies are a group of inherited 300 mg over 20–60 minutes followed by 900 mg over the next
conditions characterised by abnormal function of the protein 24 hours. Amiodarone must be given via a central vein because
channels present in the cardiac myocyte cell membrane that it can cause thrombophlebitis when given peripherally and
regulate the low of ions responsible for generating the resting limb-threatening soft tissue damage if extravasation occurs.
transmembrane potential and the action potential. These include
the long QT syndromes, short QT syndrome, early repolarisation Ongoing management of ventricular arrhythmias
syndrome, Brugada syndrome and catecholaminergic polymor-
phic VT. A detailed description of these conditions is beyond the Once stabilised, patients presenting with VT or VF should remain
scope of this chapter, but there are certain key points: in hospital and their management should be discussed at an
• With the exception of catecholaminergic polymorphic VT, early stage with a specialist cardiac electrophysiology service.
Investigations should be performed to establish the nature and
each is associated with characteristic abnormalities of the rest- extent of underlying heart disease, with emphasis on detecting
ing ECG in sinus rhythm. structural heart disease, coronary artery disease, inducible myo-
• Each may be complicated by ventricular tachyarrhythmias
and sudden cardiac death. cardial ischaemia and consideration of channelopathies in those
• β-Blockers reduce the likelihood of arrhythmia in long QT
syndromes and catecholaminergic polymorphic VT. with structurally normal hearts.
• Many drugs lengthen the QT interval (Box 22.1) and are Most patients with ischaemic heart disease should be treated
contraindicated in patients with long QT syndromes. A list
of drugs known to prolong the QT interval can be found at with aspirin, statins, angiotensin-converting enzyme (ACE)
http://www.crediblemeds.org. inhibitors or angiotensin II receptor antagonists and β-blockers.
• Class I antiarrhythmic drugs and a variety of other drugs β-Blockers and ACE inhibitors reduce somewhat the risk of
are contraindicated in Brugada syndrome. A list of drugs to sudden cardiac death. Although these patients remain at high
avoid in the Brugada syndrome can be found at http://www. risk of sudden cardiac death because of recurrent ventricular
brugadadrugs.org. tachyarrhythmias, there is no role for the routine use of antiar-
• Most patients with these conditions who experience syncope
or cardiac arrest or who develop spontaneous ventricular rhythmic drugs. In patients with complex ventricular ectopy and
arrhythmias will be considered for an implantable cardio- impaired left ventricular systolic function following acute myo-
verter-deibrillator (ICD). cardial infarction, class Ic antiarrhythmic drugs including le-
cainide were shown in the Cardiac Arrhythmia Suppression Trial
Emergency management of ventricular arrhythmias (CAST) (Echt et al., 1991) to increase mortality, whereas in other
high-risk groups amiodarone has been shown to have no effect
VF and pulseless VT should be managed according to Resusci- on all-cause mortality (Cairns et al., 1997; Julian et al., 1997).
tation Council (UK) guidelines for advanced life support, which All patients should be considered for an ICD. These devices have
are updated periodically and can be found at http://www.resus. been shown to improve prognosis following:
org.uk. • cardiac arrest due to VT or VF in the absence of a reversible
VT associated with a pulse is also the subject of guide- underlying cause,
lines by the Resuscitation Council (UK) (http://www.resus. • VT associated with syncope or signiicant haemodynamic
org.uk). If the patient is hypotensive in a low cardiac output
state or has heart failure, the correct treatment is prompt DC compromise,
cardioversion. If none of these features are present, chemical
cardioversion may be attempted with intravenous amiodarone • VT with a left ventricular ejection fraction of less than 35%.
Although ICDs treat further episodes of VT and VF, they do
Box 22.1 Drugs associated with prolonged QT intervals
not prevent these arrhythmias from recurring and resulting in
Inhalational agents: halothane, isoflurane device therapies including shocks that are psychologically trau-
Macrolide antibiotics: erythromycin, clarithromycin matic and lead to premature battery depletion. In the case of fre-
Halofantrine quently recurring ventricular arrhythmias, patients should be on
Lithium the maximum tolerated dose of a β-blocker, and there is a role in
Fosphenytoin this situation for antiarrhythmic drugs including amiodarone and
Mizolastine mexiletine (mexiletine has a European license and is available by
Phenothiazines special order in the UK). Catheter ablation of VT is an important
Pentamidine adjunctive treatment.
Sertindole
Antihistamines: terfenadine, astemizole, mizolastine Bradycardia 393
Antipsychotics: haloperidol, droperidol, pimozide
Tricyclic antidepressants: amitriptyline, imipramine Bradycardia is conventionally deined as a resting heart rate
Class IA or III antiarrhythmics of less than 60 per minute when awake or 50 per minute when
asleep. Bradycardia can be classiied as sinus bradycardia, where
Adapted from Crouch et al. (2003). the sinus node discharges too slowly, or AV block (‘heart block’),
where conduction between the atria and ventricles is impaired.
AV block may be subdivided into three classes:
First degree. Every P wave conducts to the ventricles but takes
longer than normal to do so. The PR interval on the ECG is
22 THERAPEUTICS
prolonged to greater than 200 ms (one large square on a stan- effects at a cellular level, using the Vaughan–Williams classii-
dard ECG recorded at 25 mm/s). cation (Vaughan-Williams, 1970). Alternatively, antiarrhythmic
Second degree. Some, but not all, P waves conduct to the ven- drugs may be classiied according to their main sites of action
tricles. Progressive PR interval prolongation followed by within the heart.
a non-conducted P wave is referred to as Mobitz type I or
Wenckebach heart block and implies block occurring in the AV Vaughan–Williams classification
node. Mobitz type II heart block is the term used when a non-
conducted P wave is not preceded by progressive PR interval All antiarrhythmic drugs act by altering the movement of elec-
prolongation and implies block occurring in the conducting trolytes across the myocardial cell membrane. The Vaughan–
system below the level of the AV node. Williams classiication groups drugs according to their ability
Third degree (‘complete heart block’). No P waves conduct to to block the movement of one or more of these ions across the
the ventricles. myocardial cell membrane (Vaughan-Williams, 1970). Most
drugs have several modes of action, and their effectiveness as
Bradycardia may be due to intrinsic cardiac disease or second- antiarrhythmic agents depends upon the summation of these
ary to non-cardiac disease or drugs. In many cases, bradycar- effects. The effect of the different drug classes on the various
dia due to intrinsic cardiac disease is idiopathic, that is, occurs phases of the action potential are shown in Table 22.5. The choice
without other identiiable heart disease. Bradycardia may also of which drug to use is based upon the origin of the arrhyth-
complicate acute myocardial infarction or virtually any form of mia, regardless of its pattern. However, the preference of one
structural heart disease and is also common following cardiac class over another may vary, depending on a clinician’s experi-
surgery. Non-cardiac causes of bradycardia include neurocardio- ence with particular drugs, on the presentation of the arrhyth-
genic (‘vasovagal’) syncope (faints), hypothyroidism, hyperka- mia and on patient characteristics. Such factors also govern
laemia, hypothermia and raised intracranial pressure. Complete the choice of drug within a class. The drug chosen should have
heart block may occur as a complication of Lyme disease (tick- the dosing schedule and adverse effect proile that best suit the
borne borreliosis). Drugs commonly associated with bradycardia patient or inconvenience them least (see Tables 22.6 and 22.7).
include β-blockers, verapamil, diltiazem, digoxin and antiar- Thus, for example, a patient with glaucoma or prostatism
rhythmic drugs of any class. should not be given disopyramide, which possesses marked
anticholinergic properties, and a patient with obstructive air-
The management of bradycardia is as follows: ways disease should preferably not be prescribed a β-blocker
• Treat underlying medical conditions. (class II), although if considered essential they could have a
• Consider stopping or reducing the dose of causative drugs. cardio-selective agent.
• Consider temporary or permanent pacemaker implantation.
The pharmacokinetic proiles of selected antiarrhythmic drugs
Permanent pacemaker implantation is indicated for symptom- are presented in Table 22.8.
atic bradycardia as a result of sinus bradycardia or AV block,
or on prognostic grounds for Mobitz type 2 second-degree or Class I antiarrhythmic drugs
third-degree AV block.
In an emergency situation, drugs may be used in an attempt to Class I antiarrhythmic drugs block sodium channels and there-
support the heart rate until transvenous pacing can be established. fore inhibit the inward sodium current INa, responsible for the
The most useful drugs in this situation are atropine in 500-micro- upstroke of the action potential in cells other than those of
gram boluses up to a total of 3 mg, adrenaline infused at a rate the sinoatrial and AV nodes. The result of INa inhibition is to
of 2–10 micrograms/min or isoprenaline 1–10 micrograms/min, slow conduction velocity, which should promote re-entry, and
titrated against heart rate. External pacing is another useful mea- thus be proarrhythmic. The antiarrhythmic effect of class I
sure until transvenous pacing can be established. More detailed
guidance on the emergency management of bradycardia may be Table 22.5 Effect of different drug classes on phases of action
viewed at http://www.resus.org.uk. potential
Drug therapy Dominant ion Drug class Effect
Phase movement
Antiarrhythmic drug therapy is used to control the frequency and IA Block ++
severity of arrhythmias, with the aim of maintaining sinus rhythm 0 Sodium inward IB Block +
where possible. Although antiarrhythmic drug treatment has been IC Block +++
the mainstay of arrhythmia treatment, many of these drugs have
limited eficacy and important toxicity. Many arrhythmias are 2 Calcium inward IV Block
now curable by catheter ablation. Implantable devices such as
permanent pacemakers and ICDs have assumed an increasingly 3 Potassium outward III Marked slowing
important role in the treatment of arrhythmias, and in many cases,
antiarrhythmic drugs have an adjunctive role. Antiarrhythmic 4 Sodium inward, I, II, IV Slows
394 drugs can be grouped according to their electrophysiological
potassium outward
ARRHYTHMIAS 22
Table 22.6 Adverse effects of antiarrhythmic drugs (class I)
Drug Cardiac Non-cardiac Caution or avoid in
Disopyramide Glaucoma, prostatism, hypotension
Torsade de pointes Anticholinergic (urinary retention,
Myodepressant constipation, dry mouth, blurred vision) Myasthenia gravis, slow acetylators
(increased risk of lupus)
Procainamide Lupus, nausea, diarrhoea Myasthenia gravis
Quinidine Torsade de pointes Diarrhoea, nausea, tinnitus, headache, Liver failure (reduce dose)
Vasodilation (i.v.) deafness, confusion, visual disturbances, Second- or third-degree heart block
blood dyscrasias Not recommended if any cardiac
Lidocaine (lignocaine) Proarrhythmic dysfunction
Mexiletine Convulsions in overdose, paraesthesiae
Flecainide Not recommended if any cardiac
Nausea, paraesthesiae dysfunction
Paraesthesiae, tremor
Propafenone Myodepressant Gastro-intestinal disturbances
Proarrhythmic
Myodepressant
Table 22.7 Adverse effects of antiarrhythmic drugs (classes II–IV)
Drug Cardiac Non-cardiac Caution or avoid in
β-Blockers (general)
Myodepressant Bronchoconstriction (β2) Asthma, COPD, Raynaud’s disease,
Heart block Vasoconstriction diabetes mellitus, depression
Hallucinations/vivid dreams (greater with
more lipophilic agents)
Decreased renal blood flow
Changes in serum lipid profile
Drowsiness, fatigue
Dofetilide Torsade de pointes Combination with disopyramide or
amiodarone or drugs in Table 22.5
Amiodarone Torsade de pointes Hyperthyroidism/hypothyroidism, pneu- Thyroid disease, liver dysfunction, lung
monitis, myopathy, neuropathy, hepatitis, disease (e.g. pneumonectomy)
corneal deposits, photosensitivity
Bretylium Hypotension Initial sympathomimetic response,
nausea
Verapamil Heart block Constipation, headaches, flushing, ankle Myasthenia gravis
oedema, light-headedness
Adenosine Heart block Bronchoconstriction, flushing, chest pain Asthma, COPD, combination with
dipyridamole
Decompensated heart failure, patients
with a history of convulsions/seizures
or recent heart transplant (<1 year)
COPD, Chronic obstructive pulmonary disease.
395
22 THERAPEUTICS
Table 22.8 Pharmacokinetics of selected antiarrhythmics
Amiodarone Oral absorption Protein binding (%) Elimination, metabolism, half-life (therapeutic
Slow, variable >95 range if recommended to be measured)
Extensive metabolism, very variable rate, t½ 2 days
initially increasing to 40–60 days
Bretylium Intravenous/intramuscular only Unbound Renal, t½ 5–10 h
Digoxin Variable, 70% 25
Diltiazem 40% absorbed 80 70% renal, variable, t½ 36 h (0.8–2 ng/mL)
Disopyramide Rapid, >80% 30–90
Flecainide Complete, slow 40 Hepatic, t½ 3 h
Lidocaine Intravenous/intramuscular only 60–80
50% renal, 15% bile, active metabolite, t½ 4–10 h
30% renal, t½ 20 h
10% renal, rapid hepatic metabolism to central ner-
vous system–toxic products, t½ 8–100 min increases
with duration of dosing
Mexiletine >90% 60–70 10% renal, t½ 10–12 h, hepatic metabolites mostly
inactive
Procainamide Rapid, >75% 15–20 50% renal, 25–40% converted to N-acetylprocain-
amide (active, t½ 6 h), procainamide t½ 2.5–4.5 h
Propafenone Complete, rapid >95 Extensive first-pass metabolism, capacity-limited,
t½ 2–12 h
Quinidine Rapid, >80% 80–90 Mixed renal and hepatic, t½ 6 h
Verapamil Rapid, >90% 90 Hepatic, t½ 4–12 h, marked first-pass effect
All values quoted are subject to marked interindividual variability. Most therapeutic ranges are poorly defined. Oral absorption does not account for drug lost by
first-pass hepatic metabolism. Rapid absorption indicates a peak plasma concentration in less than 2 hours.
t½, Elimination half-life at normal renal function.
drugs is attributed to critical depression of conduction in Class Ib antiarrhythmic drugs. Class Ib drugs (lidocaine,
already slowly conducting areas such as the diastolic pathway mexiletine) are the weakest sodium channel blockers, producing
little change in the QRS duration in normal cardiac tissue, and
of re-entry circuits associated with structural heart disease, also have no signiicant effect on repolarisation.
resulting in conduction block and abolishing or preventing re- Lidocaine is occasionally used in the treatment of VT, par-
entry. The properties of class I antiarrhythmic drugs fall into ticularly when VT occurs in patients already taking amiodarone
three subgroups: class Ia, class Ib and class Ic antiarrhythmic and β-blockers. Lidocaine acts preferentially on ischaemic myo-
drugs. cardium and is more effective in the presence of a high external
potassium concentration. Therefore, hypokalaemia must be cor-
Class Ia antiarrhythmic drugs. Drugs in this class (quini- rected for maximum eficacy. Lidocaine has no value in treating
dine, disopyramide and procainamide) have an intermediate supraventricular tachyarrhythmias.
inhibitory effect on the inward sodium current INa, generally caus-
ing signiicant slowing of conduction only at faster heart rates. Mexiletine may be administered intravenously or orally to con-
Class Ia drugs also inhibit the rapid component of the delayed trol VT. Frequent gastro-intestinal and central nervous system
rectiier current IKr, resulting in prolongation of the cardiac (CNS) side effects (dizziness, light-headedness, tremor, nervous-
action potential and hence effective refractory period. This prop- ness, dificulty with coordination) limit the dose and possible
erty is responsible for a propensity to cause Torsade de pointes. therapeutic beneit.
Both quinidine and disopyramide additionally block muscarinic
cholinoceptors, which may contribute to their eficacy for the Class Ic antiarrhythmic drugs. Class Ic antiarrhythmic
treatment of arrhythmias in which the parasympathetic nervous drugs (lecainide, propafenone) inhibit the inward sodium cur-
system plays a role, such as AF. rent INa with a slow time-constant for recovery, leading to marked
slowing of conduction, which is most prominent in depolarised
Class Ia antiarrhythmic drugs have been used for the treatment tissue. They also inhibit the ultra-rapid (IKur) and rapid (IKr)
of a variety of atrial and ventricular arrhythmias but are now components of the delayed rectiier outward potassium current,
prolonging the cardiac action potential and hence increasing
rarely used because of their proarrhythmic and non-cardiac side
396 effects and potential for drug interactions.
ARRHYTHMIAS 22
the effective refractory period. This action is more prominent at noradrenaline for occupation of β-adrenoceptors and therefore
higher heart rates (‘use dependency’), which may help to explain
the eficacy of these drugs for the treatment of AF. Propafenone reduce the sinus rate, slow conduction, and increase refractory
is also a β-adrenoceptor antagonist.
period in the AV node; have a negative inotropic effect; and
Class Ic agents are potent antiarrhythmics used largely in the slightly prolong cardiac action potential and effective refrac-
control of paroxysmal supraventricular and ventricular tachyar- tory period. The latter effect is probably clinically unimportant.
rhythmias resistant to other drugs, although they have acquired Although some of the antiarrhythmic effects of β-blockers may
a particularly bad reputation as a result of the proarrhythmic be explained in terms of their acute effects on transmembrane
effects seen in the CAST (Echt et al., 1991) and the Cardiac currents, the effects of adrenergic stimulation, and hence those
Arrest Study Hamburg (CASH) (Kuck et al., 2000) studies. of β-blockers, are complex, differ between acute and chronic
Faster heart rates, increased sympathetic activity, and diseased stimulation, and are modiied by a variety of disease states.
or ischaemic myocardium all contribute to the proarrhythmic Furthermore, although many of the effects of β-blockers are
as a direct result of changes in transmembrane currents, others
effects of these drugs. This has led to these drugs being con- result from changes in heart rate: for example, APD and effec-
traindicated in patients with structural heart disease because tive refractory period are inversely proportional to heart rate.
poor systolic function exaggerates the proarrhythmic effects. β-Blockers licensed for the treatment of arrhythmias include
However, lecainide is effective for the treatment of both supra- propranolol, acebutolol, atenolol, esmolol, metoprolol and sotalol.
ventricular and ventricular arrhythmias in patients without The antiarrhythmic activity of the various β-blockers is reasonably
structural heart disease and is moderately successful for main- uniform, the critical property being β1-adrenoreceptor blockade.
Atenolol, metoprolol, propranolol and esmolol are available for
tenance of sinus rhythm after cardioversion of AF. Propafenone intravenous use. Esmolol, a selective β1-adrenoreceptor antag-
has mild β-blocking properties, especially in higher doses, so onist, has a half-life of 9 minutes with full recovery from its
it should be avoided in patients with reversible obstructive air- β-blockade properties within 30 minutes. Esmolol is quickly
ways disease. metabolised in red blood cells, independent of renal and hepatic
Class II antiarrhythmic drugs: β-adrenoreceptor function, and due to its short half-life can be useful in situations
antagonists (β-blockers)
where there are relative contraindications or concerns about the
β-Adrenoceptors are widely distributed throughout the atrial use of a β-blocker. Sotalol has some class III activity, as well as
and ventricular myocardium, with particularly high concentra- class II effects.
tions in the sinoatrial and AV nodes. β1-Adrenoceptors account
for 70–80% of the total, and β2-adrenoceptors a majority of the The use of β-blockers is somewhat constrained by their adverse
remainder. Stimulation of β1-adrenoceptors by binding of adrena- effects. β2-Adrenoreceptors on bronchial smooth muscle are
line or noradrenaline activates a Gs protein, which in turn acti- tonically activated by circulating catecholamines to cause bron-
vates adenylyl cyclase, which catalyses the formation of cAMP chodilation. β-Blockers can, therefore, cause bronchoconstric-
from adenosine triphosphate (ATP) (Fig. 22.13). tion and are contraindicated in patients with asthma, and should
cAMP increases the inward current If, which increases the be used with caution in chronic obstructive pulmonary disease.
pacemaker rate, INa, which increases conduction velocity in tis- β2-Adrenoreceptors are also found on vascular smooth muscle
sue with an action potential upstroke carried by that current, and are tonically activated by circulating catecholamines to
and ICa,L, which is responsible for a positive inotropic effect, cause vasodilatation. β-Blockers may, therefore, cause vasocon-
and increases the conduction velocity and reduces the refrac- striction and exacerbate the symptoms of peripheral vascular
tory period in the AV node. cAMP also increases the repola- disease.
rising current IKs, which shortens APD and hence effective
refractory period. β-Blockers compete with adrenaline and Cardiac adverse effects of β-blockers include sinus brady-
cardia, exacerbation of AV conduction block, reduced exercise
If capacity, and exacerbation of acute heart failure. In patients with
chronic, stable heart failure due to mild-to-moderate LV systolic
INa dysfunction and already treated by ACE inhibitors and diuret-
ics, however, β-blockers improve both symptoms and progno-
AC + + ICa, L sis. Other adverse effects of β-blockers include nightmares and
+ cAMP + IKs impotence.
β1 Gs + β-Blockers vary in their lipid solubility. Agents such as pro-
ATP pranolol and carvedilol are highly lipid-soluble, whereas others
such as atenolol and nadolol are more hydrophilic. Lipid solubil-
Fig. 22.13 Principal mechanisms of antiarrhythmic action of β- ity determines the degree of drug penetration into the CNS and the
adrenoreceptor antagonists. utility of haemodialysis or haemoiltration. High lipid solubility
AC, adenylyl cyclase; ATP, adenosine triphosphate; cAMP, cyclic aden- is associated with a larger volume of distribution and better CNS
osine monophosphate. penetration. Lipophilic β-blockers are primarily metabolised by
the liver. Conversely, hydrophilic β-blockers have a small vol-
ume of distribution and are eliminated essentially unchanged by
the kidneys; this property allows hydrophilic β-blockers to be
removed by haemodialysis.
397
22 THERAPEUTICS
Class III antiarrhythmic drugs the absorption of oral amiodarone is very slow, taking up to
15 hours. The combination of a relatively fast elimination and a
Class III antiarrhythmic drugs inhibit the delayed rectiier cur- poor rate of absorption could lead to a signiicant fall in serum
rent IK, which prolongs cardiac APD and hence effective refrac- amiodarone levels if intravenous therapy is stopped abruptly
tory period. Most clinically important arrhythmias are as a result when oral therapy is initiated, with the period of maximum risk
of re-entry. For re-entry to sustain, the activation wavefront being the irst 24 hours of oral therapy. It is therefore advis-
must continuously meet electrically excitable tissue as it pro- able to phase out intravenous therapy gradually and allow
an intravenous/oral overlap period of at least 24 hours. Once
gresses around the re-entry circuit, the so-called excitable gap. amiodarone has reached saturation, amiodarone is eliminated
Prolongation of the effective refractory period by a class III anti-
arrhythmic drug reduces or even abolishes the excitable gap, thus very slowly, with a half-life of about 25–110 days. Because of
reducing the likelihood of sustained re-entry. the long terminal half-life of amiodarone, there is a potential
for drug interactions to occur several weeks (or even months)
Class III drugs include sotalol, dofetilide, amiodarone and after treatment with it has been stopped. Common interactions
dronedarone. Sotalol and dofetilide selectively inhibit the rapid include antibacterials, other antiarrhythmics, lipid-regulating
component of the delayed rectiier current IKr, whereas amio- drugs and digoxin.
darone and dronedarone are less speciic, also inhibiting the
slow component IKs. Selective IKr inhibitors are more effective Amiodarone has been associated with toxicity involving the
at slower heart rates, a phenomenon termed reverse use depen- lungs, thyroid gland, liver, eyes, skin and peripheral nerves. The
dence. It is this property that predisposes to the development incidence of most adverse effects is related to total amiodarone
of Torsade de pointes, a polymorphic VT that may be life- exposure (i.e. dosage and duration of treatment). Therefore, prac-
threatening. The development of Torsade de pointes is attrib- titioners must consider carefully the risk–beneit ratio of the use
uted to a combination of triggered activity as a result of EADs of amiodarone in each patient, use the lowest possible dose of
and increased transmural dispersion of repolarisation within the
amiodarone, monitor for adverse effects and, if possible, discon-
ventricles because action potential prolongation is not uniform tinue treatment if adverse effects occur.
across the ventricular wall. Hypokalaemia, hypomagnesaemia
or bradycardia increase the likelihood of Torsade de pointes; Corneal microdeposits (reversible on withdrawal of treat-
therefore, sotalol, with marked class II activity, may be uniquely ment) develop in nearly all adult patients given prolonged ami-
arrhythmogenic. odarone; these rarely interfere with vision, but drivers may be
dazzled by headlights at night. However, if vision is impaired
Amiodarone is a potent antiarrhythmic drug with additional or if optic neuritis or optic neuropathy occur, amiodarone must
class I, II and IV activity that is effective in treating a wide vari-
ety of atrial and ventricular arrhythmias, but its use is constrained be stopped to prevent blindness. Long-term administration of
by complex pharmacokinetics and concern about toxicity. Many amiodarone is associated with a blue-grey discoloration of the
heart rhythm specialists would consider that the side effect proile skin. This is more commonly seen in individuals with lighter
of amiodarone precludes its use for the long-term treatment of skin tones. The discoloration may revert upon cessation of the
atrial arrhythmias. Amiodarone may be extremely effective in the drug. However, the skin colour may not return completely to
emergency treatment of VT and VF, especially where recurrent. normal.
Amiodarone may also reduce the likelihood of recurrent ven-
tricular arrhythmias when taken on a long-term basis but confers Individuals who are taking amiodarone may become more sen-
no prognostic beneit and should be considered as an adjunct to sitive to the harmful effects of ultraviolet A (UV-A) light. Using
treatment with an ICD. sunblock that also blocks UV-A rays appears to prevent this side
effect. Amiodarone contains iodine and can cause disorders of
When rapid control of an arrhythmia is needed, the intrave- thyroid function. Both hypothyroidism and hyperthyroidism may
nous route is preferred, with 300 mg given over 30–60 minutes occur. Clinical assessment alone is unreliable, and laboratory
followed by 900 mg over 23–24 hours, administered through a tests should be performed before treatment and every 6 months
central vein. Higher loading doses may cause hypotension. A including tri-iodothyronine (T3), T4 and thyroid stimulating hor-
concurrent oral loading regimen of up to 2400 mg daily in two mone (TSH). A raised T3 and T4 with a very low or undetectable
to four divided doses is usually given for 7–14 days and then TSH concentration suggests the development of thyrotoxico-
reduced to a maintenance dosage of 200 mg daily or less. sis. Amiodarone-associated thyrotoxicosis may be refractory to
treatment, and amiodarone should usually be withdrawn, at least
During the early stages of therapy with amiodarone (whether
intravenous or oral), the kinetics of the drug are different from temporarily, to help achieve control, although treatment with car-
those after chronic administration. Amiodarone is highly lipid- bimazole is often required. Hypothyroidism can be treated safely
soluble and thus has a very large volume of distribution. As the with replacement therapy without the need to withdraw amioda-
slowly equilibrating tissue stores are penetrated to a minimal
extent during the early days of therapy, the effective elimina- rone if amiodarone is considered essential. Amiodarone is also
tion half-life (t½) is initially dependent upon a more rapidly associated with hepatotoxicity, and treatment should be discon-
exchanging compartment, with a half-life of 10–17 hours, sub-
stantially shorter than the half-life seen during chronic adminis- tinued if severe liver function abnormalities or clinical signs of
tration. The short half-life becomes important during the acute liver disease develop.
phase and any intravenous to oral changeover period because
398 The most serious adverse effect of amiodarone therapy is pul-
monary toxicity, typically acute pneumonitis or more insidious
pulmonary ibrosis. Although acute pneumonitis may respond to
corticosteroids, pulmonary ibrosis is largely irreversible.
ARRHYTHMIAS 22
Class IV antiarrhythmic drugs (calcium channel A1 – + β1
blockers) + Gs Gi AC cAMP +
CCBs bind to and inhibit voltage-gated transmembrane calcium ATP ATP
channels carrying an inward current ICa,L. This current is respon-
sible for phase 0 depolarisation of the action potential in the IKAdo If
sinoatrial and AV nodes. CCBs reduce the sinus rate and reduce
conduction velocity and increase the effective refractory period Fig. 22.14 Principal mechanisms of antiarrhythmic action of adeno-
of the AV node. By reducing calcium entry, CCBs have a negative sine.
inotropic effect. L-type calcium channels are also present in vas- AC, adenylyl cyclase; ATP, adenosine triphosphate; cAMP, cyclic aden-
cular smooth muscle, and CCBs therefore cause vasodilatation. osine monophosphate.
In vivo, dihydropyridine CCBs such as nifedipine and amlodip-
ine are relatively selective for vascular smooth muscle, with only Adenosine
minor cardiac effects, whereas phenylalkylamine (verapamil)
and benzothiazepine (diltiazem) CCBs are considerably more The electrophysiological effects of adenosine are mediated by
cardioselective. A1 adenosine receptors in the cell membrane of atrial, sinoatrial
and AV nodal, but not ventricular, myocytes. Binding of adenos-
Verapamil possesses a chiral carbon and is marketed as a ine to the A1 receptor activates a G protein that in turn activates
racemic mixture of R- and S-stereoisomers. In humans, both an outward potassium current IKAdo, resulting in hyperpolarisa-
isomers share qualitatively similar negative chronotropic and tion, and inhibits the pacemaker current If and an inward calcium
dromotropic effects on the sinoatrial and AV nodes, respec- current ICa. Activation of A1 receptors also has indirect electro-
tively, but the S-stereoisomer is 10–20 times more potent than physiological effects mediated by an inhibitory G protein, which
the R with respect to these effects. Hence the S-stereoisomer inhibits production of cAMP by adenylyl cyclase, thus opposing
determines the negative chronotropic and dromotropic effects of the action of catecholamines (Fig. 22.14). The effects of these
verapamil, whereas the R-stereoisomer is of minor importance. actions are a reduction in the iring rate of cells with pacemaker
activity (negative chronotropic effect), a reduction in conduction
Verapamil also undergoes extensive stereoselective irst-pass velocity in the AV node (negative dromotropic effect) manifest as
hepatic metabolism. S-verapamil is more rapidly metabolised varying degrees of AV block, and a shortening of atrial effective
than R-verapamil after oral administration, resulting in a lower refractory period, occasionally manifest as the development of
bioavailability of the S-stereoisomer and a proportionally higher AF following the administration of adenosine.
concentration of the R-stereoisomer in the systemic circulation
(20% and 50%, respectively). However, because Cmax is higher The ultra-short duration of action (<10 seconds) of intrave-
with the immediate-release formulation and S-verapamil is nous adenosine makes it very suitable as a diagnostic aid and for
10–20 times more potent than R-verapamil, it is unsurprising that interrupting supraventricular arrhythmias in which the AV node
this difference is also clinically signiicant. With the immediate- is part of the re-entry pathway. Adenosine is, however, a bron-
release formulation, a plot of PR-interval change versus time has choconstrictor and causes dyspnoea, lushing, chest pain and fur-
the same shape as the concentration–time curve. The extended- ther transient arrhythmias in a high proportion of patients, and its
release formulation does not have the same concentration–time metabolism is inhibited by dipyridamole, a vasodilator drug that
effect relationship. This has been attributed to the difference in blocks adenosine uptake by cells, thereby reducing the metabo-
oral input rates, to the concentration-related saturable irst-pass lism of adenosine.
hepatic metabolism, or both.
Ivabradine
Because the formulation of verapamil may play a role in the
drug’s complex pharmacokinetics and eficacy, one formulation Ivabradine is a selective inhibitor of the If current that plays an
of verapamil cannot be safely substituted for another. Immediate- important role in pacemaker activity in cells of the cardiac con-
release preparations are preferred to maximise bioavailability of duction system. If is an inward depolarising current of sodium
the S-stereoisomer. and potassium via speciic membrane channels that are activated
by hyperpolarisation. Predominantly as a result of If, the trans-
Class IV antiarrhythmic drugs should be avoided in sick sinus membrane potential in cells of the sinoatrial node becomes pro-
syndrome or second- or third-degree heart block unless the patient
has a permanent pacemaker. Combined therapy with a CCB and gressively less negative until the threshold potential for action
β-blocker should be instituted with caution because of the risk of potential generation is reached. The magnitude of If is increased
excessive AV block, and should be used where only where mono- by cAMP. The sinoatrial node is innervated by both sympathetic
therapy is insuficient to control ventricular rate during atrial lut- and parasympathetic (the vagus) nerves. Binding of catechol-
ter or ibrillation. Verapamil causes greater arterial vasodilation amines to β-adrenoceptors stimulates the production of cAMP
than diltiazem and may be especially useful in patients with hyper- and hence increases the rate of discharge of the sinoatrial node.
tension or angina. Both agents have a negative inotropic effect and Binding of acetylcholine to muscarinic cholinoceptors has the
are thus contraindicated in heart failure. Adverse effects are mostly
predictable and include ankle oedema, lushing, dizziness, light-
headedness and headache. Constipation is common in patients
receiving verapamil, whereas a rash is common with diltiazem.
399
22 THERAPEUTICS
– Achm If Table 22.9 Interactions involving digoxin
Iv
Effect Offending agent or condition
AC + Serum level increased by Amiodarone, verapamil, diltiazem,
+ cAMP quinidine, propafenone, clarithromy-
β1 ATP cin, broad-spectrum antibiotics (eryth-
romycin, tetracyclines), decreased
Fig.22.15 Principalmechanismsofantiarrhythmicactionofivabradine. renal blood flow (β-blockers, non-
AC, Adenylyl cyclase; ATP, adenosine triphosphate; cAMP, cyclic aden- steroidal anti-inflammatory drugs),
osine monophosphate. renal failure, heart failure
opposite effect (Fig. 22.15). Ivabradine selectively blocks If Serum level decreased Colestyramine, sulfasalazine, neomy-
channels, resulting in a dose-dependent reduction in the slope of by cin, rifampicin, antacids, improved
diastolic depolarisation in cells of the sinoatrial node, and hence renal blood flow (vasodilators), levo-
a reduction in the sinus rate. Ivabradine exhibits use dependence, thyroxine (thyroxine)
which means its effect is more pronounced at higher heart rates.
Ivabradine was developed as an antianginal drug and is also used Therapeutic Hypokalaemia, hypercalcaemia,
in patients with chronic heart failure associated with sinus tachy- effect increased by hypomagnesaemia, antiarrhythmic
cardia. It has been used for the treatment of inappropriate sinus classes IA, II and IV, diuretics that
tachycardia, although it is not currently licensed in the UK for cause hypokalaemia, corticosteroids,
that indication. myxoedema, hypoxia (acute or
chronic), acute myocardial ischaemia
or myocarditis
Therapeutic effect Hyperkalaemia, hypocalcaemia,
decreased by thyrotoxicosis
Digoxin predominantly by the kidney (70% renal elimination in normal
renal function), renal function is the most important determi-
The therapeutic effect of digoxin results from central and periph- nant of the daily digoxin dosage. Importantly, in severe renal
eral augmentation of vagal tone, manifest as reduced conduc- insuficiency, there is also a decrease in the volume of distri-
tion velocity and prolonged effective refractory period of the AV bution of digoxin; therefore, lower loading doses should be
node. The latter property has the effect of reducing the ventricular used.
rate during atrial tachyarrhythmias. The effect of digoxin is most
pronounced under conditions of vagal predominance (i.e. rest and Both the therapeutic and toxic effects of digoxin are potentiated
sleep), whereas the drug is relatively ineffective during condi- by hypokalaemia and hypercalcaemia. There are also numerous
tions of sympathetic predominance, such as exercise or AF of drug interactions (Table 22.9), some of which are pharmacoki-
acute onset. netic and some of which are pharmacological.
Digoxin also directly inhibits the transmembrane Na+-K+- The occurrence of adverse drug reactions is common, because
ATPase exchange pump. As a result there is a tendency for of the narrow therapeutic index of digoxin. Adverse effects are
intracellular sodium concentration to increase, which in turn concentration dependent and are rare when serum digoxin con-
activates a Na+-Ca2+ exchange pump, which extrudes sodium centration is less than 0.8 micrograms/L. Common adverse
in exchange for calcium, increasing intracellular calcium con- effects include loss of appetite, nausea, vomiting and diarrhoea
centration. The latter is responsible for the positive inotropic as gastro-intestinal motility increases. Other common effects
effect of digoxin but also, in overdose, for intracellular cal- are blurred vision, visual disturbances (yellow-green halos and
cium overload, resulting in DADs, which may lead to trig- problems with colour perception), confusion and drowsiness.
gered activity. The often described adverse effect of digoxin, xanthopsia, the
disturbance of colour vision (mostly yellow and green colour),
Digoxin is not indicated for the treatment of paroxysmal AF is rarely seen.
because it has no direct antiarrhythmic effect and neither termi-
Patient care
nates an episode of AF nor reduces the likelihood of further epi-
sodes of AF occurring. Furthermore, digoxin has limited eficacy Patients with cardiac arrhythmia may experience considerable
for ventricular rate control at the start of an episode of AF, where anxiety related to their condition. The symptoms typically occur
sympathetic nervous system activity is often high. unpredictably, may be extremely unpleasant and may result in the
need for urgent medical attention. Many patients are worried that
The long half-life of digoxin (about 36 hours) warrants spe- their condition may be life-threatening, whereas others present-
cial consideration when treating arrhythmias as several days ing with arrhythmia are found to have prognostically important
of constant dosing would be required to reach steady-state.
Therefore, loading doses of up to 1.5 mg may be used rapidly
to increase digoxin serum levels. Digoxin is given once daily
thereafter, usually in 125- or 250-microgram doses, and has a
narrow therapeutic window with the ideal blood concentration
400 regarded as 1–2 micrograms/L. Because digoxin is excreted
ARRHYTHMIAS 22
Table 22.10 Common therapeutic problems in the management of arrhythmias
Problem Comment
All antiarrhythmics are proarrhythmic
Prevention is better than cure. Minimise the requirement for drugs by careful attention
to precipitating factors. Consider use of pacemakers or non-pharmacological therapies
if appropriate.
Nausea and vomiting with blurred vision and These are symptoms and signs of digoxin toxicity noting digoxin has a narrow thera-
visual discolouration on digoxin peutic range. Poor renal function may have also contributed.
β-Blockers are generally contraindicated in Consider verapamil or diltiazem.
bronchial and peripheral vascular disease
Calcium channel blockers–induced constipation If it occurs, give regular osmotic laxatives.
Torsade de pointes may be precipitated by Patients should remind members of healthcare team that they are taking antiarrhythmic
taking other medication with amiodarone or drugs; also consider electrolyte disturbance such as hypokalaemia.
disopyramide
Patients experiencing myopathy Healthcare professionals involved in screening prescriptions for antiarrhythmics should
be aware of the clinically relevant interactions and how to manage these. Patients who
are taking statins will need regular monitoring for signs of myopathy, particularly those
receiving high-intensity statin therapy.
Patient with severe asthma admitted with Adenosine is contraindicated because of the risk of bronchospasm. Verapamil is a suit-
supraventricular tachycardia able alternative.
Amiodarone is commonly associated with Warn all patients to stay covered up when outdoors, use sun block or stay indoors.
an increased tendency to sunburn
Acutely treated patient with atrial fibrillation Although amiodarone has a long terminal half-life once saturated, amiodarone has
cardioverted initially with i.v. amiodarone,
but on converting to oral therapy, reverted a very large volume of distribution, and because tissue stores are penetrated to a
back to atrial fibrillation
minimal extent during the early days of therapy, the effective elimination half-life (t½) is
initially dependent upon a more rapidly exchanging compartment, with a t½ of
10–17 h, substantially shorter than the t½ seen during chronic administration. The
shorter t½ becomes important during the acute phase and any intravenous to oral
changeover period because the absorption of oral amiodarone is very slow, taking up
to 15 h. The combination of a relatively fast elimination and a poor rate of absorption
could lead to a significant fall in serum amiodarone levels if intravenous therapy is
stopped abruptly when oral therapy is initiated, with the period of maximum risk being
the first 24 h of oral therapy. It is, therefore, advisable to phase out intravenous therapy
gradually and allow an intravenous/oral overlap period of at least 24 h.
underlying heart disease. The diagnosis of an inherited cardiac Examples of some common therapeutic problems that may
condition also raises concern for potentially affected relatives. occur during the management of arrhythmias are set out in
An individual’s anxiety may be exacerbated by the fact that most Table 22.10.
antiarrhythmic drugs work in only a proportion of patients, and
several treatment options may be tried before the most appropri- Case studies
ate one is identiied.
Case 22.1
Many patients therefore require considerable reassurance.
The patient’s family and friends may need to be advised on Ms AJ, a 25-year-old woman, presents to the hospital emer-
what to do in the event of an acute arrhythmia. Patients should gency department with a 2-hour history of palpitation and chest
give informed consent for all interventions, and prescrib- tightness. She has experienced several similar episodes in the
ers must be prepared that a patient’s views on the use of a past, all of which have started abruptly at rest and consisted of
medicine may differ from their own. Prescribers should seek rapid, regular palpitations. Previous episodes have all stopped
and respect patients’ views on treatment choices, rather than after a few minutes and between events she has been entirely
assume all patients are the same or that they will always agree well. Ms AJ has no history of heart disease or other ongoing
with their own views.
401
22 THERAPEUTICS
medical problems and is on no regular drug treatment. She 2. If Mr DS was to continue amiodarone therapy longer-term, then
drinks alcohol within recommended weekly limits and takes the following monitoring would be appropriate:
no other recreational drugs. On examination Ms AJ is anxious,
has a slightly cool periphery, her pulse is 190 beats/min and Chest X-ray: pulmonary Baseline and if symptoms present
regular, and blood pressure is 130/90 mmHg. The remainder of Thyroid function test Baseline and every 3–6 months
the examination is unremarkable. A 12-lead ECG demonstrates Liver function tests Baseline and every 3–6 months
a regular narrow-complex tachycardia with no discernible Eye examination Baseline and every 12 months
P waves. ECG Baseline and as required
Clinical evaluation Baseline and every 3 months
Question
What is the most likely diagnosis, and how should Ms AJ be man- Case 22.3
aged?
Mr SB is 77 years of age. He attends the hospital emergency
Answer department with worsening shortness of breath. His medical his-
tory includes a myocardial infarction 10 years ago which left him
Ms AJ has the signs and symptoms of SVT. Non-pharmacological with left ventricular dysfunction (ejection fraction <40%). He also
means of restoring sinus rhythm include carotid sinus massage, sub- has hypertension. Mr SB’s current medication is:
jecting the patient to the Valsalva manoeuvre or eliciting the diving • bisoprolol 2.5 mg daily,
reflex by immersion of the face in ice-cold water. Either approach • ramipril 5 mg daily,
should result in a brief vagal discharge sufficient to block conduction • aspirin 75 mg daily,
in the AV node and terminate the tachycardia. If these manoeuvres • furosemide 80 mg each morning,
are unsuccessful, intravenous adenosine can be given in doses of • atorvastatin 40mg daily.
up to 12 mg as a rapid bolus injection followed quickly by a saline
flush. Intravenous verapamil 5 mg may also be administered as a His heart rate is 65 beats/min and irregular, and he has a blood
rapid bolus injection and is a good alternative where adenosine is pressure of 160/85 mmHg. Mr SB’s ECG shows AF. It was decided
contraindicated. to control his AF with an increased dose of bisoprolol.
Case 22.2 Questions
Mr DS was admitted to hospital for an emergency laparotomy 1. What drug is most appropriate for stroke prevention in Mr SB?
for a perforated gut. He has a history of paroxysmal AF for 2. Should anticoagulation be initiated along with aspirin or in place
which he has recently been started on amiodarone 200 mg once
daily. of it?
Following the laparotomy Mr DS has new-onset AF that the Answers
medical team would like to treat pharmacologically. His only other
current medication is thromboprophylaxis with enoxaparin 20 mg 1. All patients presenting with AF (or atrial flutter) should undergo
once daily. assessment of their risk of stroke. Although various risk-stratifica-
tion schemes exist, the CHA2DS2-VASc score is widely used. For
Questions Mr SB the following is determined: Congestive cardiac failure 1;
Hypertension 1; Age older than 75 years 2; Diabetes mellitus 0;
1. What treatment plan would you initially suggest for Mr DS? Stroke 0; Vascular disease 1; Sex category 0. Given that Mr SB
2. What longer-term monitoring would be appropriate for Mr DS if has a CHA2DS2-VASc score of 5, this suggests an annual stroke
risk of 6.7% if no therapy is prescribed (Lip et al., 2010b). This
he was to remain taking amiodarone? risk will reduce to 5.4% if he is prescribed aspirin, or 2.2% if he
is prescribed an anticoagulant. Assuming no contraindications or
Answers concerns, anticoagulation should be prescribed.
1. If Mr DS has any electrolyte abnormalities, these should be 2. In patients with stable vascular disease, such as those with no
corrected. If he remains in AF he should be prescribed amio- acute ischaemic events or percutaneous coronary intervention/
darone by i.v. infusion, because acutely amiodarone can be stent procedure in the preceding year, anticoagulation mono-
effective in cardioversion. The reduced dose of enoxaparin is therapy should be used (Kirchhof et al., 2016). There is no need
because Mr DS is a post-surgical patient and at high risk of for concomitant aspirin, which could increase the risk of a major
bleeding. bleed. Therefore, concomitant antiplatelet therapy should not be
Mr DS cardioverts back to sinus rhythm following a bolus dose of prescribed for Mr SB. In patients with AF treated for acute coro-
300 mg amiodarone. The plan is to maintain him on amiodarone nary syndrome, and in those receiving a coronary stent, the doc-
for a short period, for example, a week (600 mg daily) to try to tor may consider a combination of an anticoagulant and aspirin
keep him in sinus rhythm, with a view to stopping if he is main- (Kirchhof et al., 2016); however, it should be noted that such a
tained back in sinus rhythm during this period. combination will significantly increase the risk of a major bleed.
Optimising the modifiable risk factors in HAS-BLED (e.g. blood
pressure) will help minimise the risk of bleeding if a decision is
taken to prescribe aspirin and an anticoagulant together.
402
ARRHYTHMIAS 22
References Hylek, E.M., Skates, S.J., Sheehan, M.A., et al., 1996. An analysis of the
lowest effective intensity of prophylactic anticoagulation for patients with
ACTIVE Investigators, Connolly, S.J., Pogue, J., et al., 2009. Effect of nonrheumatic atrial ibrillation. N. Engl. J. Med. 335, 540–546.
clopidogrel added to aspirin in patients with atrial ibrillation. N. Engl. J.
Med. 360, 2066–2078. Julian, D.G., Camm, A.J., Frangin, G., et al., 1997. Randomised trial of
effect of amiodarone on mortality in patient with left ventricular dysfunc-
AFFIRM Investigators, 2004. Relationship between sinus rhythm, treatment, tion after recent myocardial infarction: EMIAT. European Myocardial
and survival in the atrial ibrillation follow-up investigation of rhythm Infarct Amiodarone Trial Investigators. Lancet 349, 667–674.
management (AFFIRM) study. Circulation 109, 1509–1513.
Kirchhof, P., Benussi, S., Kotecha, D., et al., 2016. 2016 ESC guidelines
Bayer, 2017. Xarelto: summary of product characteristics. Available at: http: for the management of atrial ibrillation developed in collaboration with
//www.medicines.org.uk/emc/medicine/21265. EACTS. Eur. Heart J. 37, 2893–2962.
Bounameaux, H., Camm, A.J., 2014. Edoxaban: an update on the new oral Kuck, K., Cappato, R., Siebels, J., et al., 2000. Randomized comparison of
direct factor Xa inhibitor. Drugs 74, 1209–1231. antiarrhythmic drug therapy with implantable deibrillators in patients
resuscitated from cardiac arrest. Circulation 102, 748–754.
Bristol Myers Squibb-Pizer, 2017. Eliquis: summary of product characteristics.
Available at: http://www.medicines.org.uk/emc/medicine/24988. Lip, G.Y., Nieuwlaat, R., Pisters, R., et al., 2010a. Reining clinical risk
stratiication for predicting stroke and thromboembolism in atrial ibrilla-
Bunch, T.J., May, H.T., Blair, T.L., et al., 2013. Atrial ibrillation patients tion using a novel risk factor-based approach: the Euro Heart Survey on
have long-term stroke rates similar to patients without atrial ibrillation Atrial Fibrillation. Chest 137, 263–272.
regardless of CHADS2 score. Heart Rhythm 10, 1272–1277.
Lip, G.Y.H., Frison, L., Halperin, J.L., et al., 2010b. Identifying patients at
Cairns, J.A., Connolly, S.J., Roberts, R., et al., 1997. Randomised trial of high risk of stroke despite anticoagulation. A comparison of contempo-
outcome after myocardial infarction in patients with frequent or repetitive rary stroke risk stratiication schemes in an anticoagulated atrial ibrilla-
ventricular premature depolarisations: CAMIAT Canadian Amiodarone Myo- tion cohort. Stroke 41, 2731–2738.
cardial Infarction Arrhythmia Trial Investigators. Lancet 349, 675–682.
Marrouche, N.F., Brachmann, J., Andresen, D., et al., 2018. Catheter
Camm, A.J., Lip, G.Y.H., De Caterina, R., et al., 2012. Focused update of ablation for atrial ibrillation with heart failure. N Engl. J. Med. 378,
the ESC guidelines for the management of atrial ibrillation. Eur. Heart J. 417–427.
33, 2719–2747.
National Institute for Health and Care Excellence (NICE), 2014. Atrial
Connolly, S.J., Ezekowitz, M.D., Yusuf, S., et al., 2009. Dabigatran versus war- ibrillation: management. Clinical Guideline (CG180), London, NICE.
farin in patients with atrial ibrillation. N. Engl. J. Med. 361, 1139–1151. Available at: https://www.nice.org.uk/guidance/cg180.
Crouch, M.A., Limon, L., Cassano, A.T., 2003. Drug-related QT interval Olesen, J.B., Lip, G.Y., Hansen, M.L., et al., 2011. Validation of risk strati-
prolongation: drugs associated with QT prolongation. Pharmacotherapy ication schemes for predicting stroke and thromboembolism in patients
23, 802–805. with atrial ibrillation: nationwide cohort study. Br. Med. J. 342, d1124.
Daiichi Sankyo UK Limited, 2017. Lixiana: summary of product character- Patel, M.R., Mahaffey, K.W., Garg, J., et al., 2011. Rivaroxaban versus war-
istics. Available at: http://www.medicines.org.uk/emc/medicine/30513. farin in nonvalvular atrial ibrillation. N. Engl. J. Med. 365, 883–891.
Echt, D.S., Liebson, P.R., Mitchell, L.B., et al., 1991. Mortality and morbidity Pisters, R., Lane, D.A., Nieuwlaat, R., et al., 2010. A novel user-
in patients receiving encainide, lecainide, or placebo: the Cardiac Arrhyth- friendly score (HAS-BLED) to assess 1-year risk of major bleeding
mia Suppression Trial. N. Engl. J. Med. 324, 781–788. in patients with atrial fibrillation: the Euro Heart Survey. Chest 138,
1093–1100.
Eriksson, B.I., Quinlan, D.J., Weitz, J.I., 2009. Comparative pharmaco-
dynamics and pharmacokinetics of oral direct thrombin and factor Xa Roy, D., Talajic, M., Doran, P., 2000. Amiodarone to prevent recurrence of
inhibitors in development. Clin. Pharmacokinet. 48, 1–22. atrial ibrillation. N. Engl. J. Med. 342, 913–920.
Fang, M.C., Chang, Y., Hylek, E.M., et al., 2004. Advanced age, antico- Sherman, D.G., Kim, S.G., Boop, B.S., et al., 2005. Occurrence and charac-
agulation intensity, and risk of intracranial haemorrhage among patients teristics of stroke events in the atrial ibrillation follow-up investigation
taking warfarin for atrial ibrillation. Ann. Intern. Med. 141, 745–752. of sinus rhythm management (AFFIRM) study. Arch Intern Med. 165,
1185–1191.
Giugliano, R.P., Ruff, C.T., Braunwald, E., et al., 2013. Edoxaban versus
warfarin in patients with atrial ibrillation. N. Engl. J. Med. 369, Singh, B.N., Singh, S.N., Reda, D.J., 2005. Amiodarone versus sotalol for
2093–2104. atrial ibrillation. N. Engl. J. Med. 352, 1861–1872.
Granger, C.B., Alexander, J.H., McMurray, J.J.V., et al., 2011. Apixaban versus Vaughan-Williams, E.M., 1970. The experimental basis for the choice of an
warfarin in patients with atrial ibrillation. N. Engl. J. Med. 365, 981–992. anti-arrhythmic drug. Adv. Cardiol. 4, 275–289.
Hart, R.G., Benavente, O., McBride, R., et al., 2007. Meta-analysis: an-
tithrombotic therapy to prevent stroke in patients who have nonvalvular
atrial ibrillation. Ann. Intern. Med. 146, 857–867.
Further reading Lip, G., Nieuwlaat, R., Pisters, R., et al., 2010. Reining clinical risk strati-
ication for predicting stroke and thromboembolism in atrial ibrillation
Billman, G.E. (Ed.), 2010. Novel therapeutic targets for antiarrhythmic using a novel risk factor based approach: the Euro Heart Survey on Atrial
drugs. Wiley, Hoboken. Fibrillation. Chest 137, 263–272.
Fogoros, R.N., 2007. Antiarryhthmic Drugs: A Practical Guide, second ed.
Wiley-Blackwell, Oxford.
Useful websites UK Resuscitation Council website, with guidance on the management of
peri-arrest tachy and bradyarrhythmias: http://www.resus.org.uk
Current list of drugs known to cause QT interval prolongation:
http://www.crediblemeds.org European Society of Cardiology: https://www.escardio.org/
American Heart Association: http://www.heart.org
Current list of drugs to avoid in patients with Brugada syndrome:
http://www.brugadadrugs.org
403
THERAPEUTICS
23 Thrombosis
Philip A. Routledge, Hamsaraj Shetty and Simon J. Wilkins
404 Key points • Acute myocardial infarction is the commonest form of arterial
thrombosis.
Venous thromboembolism
• Venous thromboembolism (VTE) is the development of a • Arterial thromboembolism affecting the cerebral circulation
results in either transient ischaemic attacks (TIAs) or, in more
‘thrombus’, principally containing fibrin and red blood cells, in severe cases, cerebral infarction (stroke).
the venous circulation. This most often occurs as a deep vein
thrombosis (DVT) in the deep, as distinct from the superficial, • Arterial thrombosis is the development of a ‘thrombus’ consist-
veins of the legs. ing of platelets, fibrin, red blood cells and white blood cells in
the systemic circulation.
• If part of a thrombus in the venous circulation breaks off and
enters the right heart, it may become lodged in the pulmonary • An embolus may result in peripheral arterial occlusion, either
arterial circulation, causing pulmonary embolism (PE). in the lower limbs or in the cerebral circulation (where it may
cause thromboembolic stroke).
• Combinations of sluggish blood flow and hypercoagulability
are the most common causes of VTE. Vascular injury is also a Venous thromboembolism
recognised causative factor.
Epidemiology
• Treatment of VTE involves the use of anticoagulants and, in
severe cases, thrombolytic drugs. Venous thromboembolism (VTE) is common, with an incidence
of 2–5%. Deep vein thrombosis (DVT) may result in not only
• Anticoagulant therapy often involves an immediate-acting pulmonary embolism (PE) but also subsequent morbidity as a
agent, such as heparin, followed by maintenance treatment result of the post-phlebitic limb. Thrombosis and thromboembo-
with an oral anticoagulant, such as warfarin. lism are the most common direct cause of maternal death in the
UK (Knight et al., 2016). Thromboembolism appears to increase
• Another option is the use of a direct oral anticoagulant in prevalence past the age of 50 years, and the diagnosis is more
(DOAC), also sometimes known as a non–vitamin K antagonist often missed in this age group.
oral anticoagulant/novel oral anticoagulant (NOAC), with a
marketing authorisation for such use. The use of heparin in Aetiology
the early stages is not necessary with all of the DOACs, but
requirements change, and thus product literature should be VTE occurs primarily due to a combination of stagnation of
consulted. blood low and hypercoagulability. Vascular injury is also a rec-
ognised causative factor but is not necessary for the development
• Unfractionated heparins increase the rate of interaction of of venous thrombosis. In VTE, the structure of the thrombus
thrombin with antithrombin III 1000-fold and prevent the pro- is different from that in arterial thromboembolism. In the for-
duction of fibrin from fibrinogen. mer, platelets seem to be uniformly distributed through a mesh
of ibrin and other blood cell components, whereas in arterial
• Low-molecular-weight heparins inactivate factor Xa, have a thromboembolism the white platelet ‘head’ is more prominent,
longer half-life and produce a more predictable response than and it appears to play a much more important initiatory role in
unfractionated heparins. thrombus.
• Warfarin is the most widely used coumarin because of potency, Sluggishness of blood low may be related to bed rest, sur-
reliable bioavailability and an intermediate half-life of elimina- gery or reduced cardiac output, for example, in heart failure.
tion (36 hours). Factors increasing the risk of hypercoagulability include sur-
gery, pregnancy, oestrogen administration, malignancy, myo-
• Warfarin consists of an equal mixture of two enantiomers, (R)- cardial infarction and several acquired or inherited disorders of
and (S)-warfarins, that have different anticoagulant potencies coagulation (for further detail on genetic factors, see Rosendaal
and routes of metabolism. The latter enantiomer is a much and Reitsma [2009]).
more potent anticoagulant.
• DOACs currently available include dabigatran etexilate, a
direct thrombin (factor IIa) inhibitor, and apixaban, edoxaban
and rivaroxaban, which are direct inhibitors of activated
factor Xa.
Arterial thromboembolism
• Arterial thromboembolism is normally associated with vascular
injury and hypercoagulability.
THROMBOSIS 23
Protein C deficiency Prothrombin G20210A mutation
Protein C deiciency is inherited through autosomal-dominant A mutation in part of the prothrombin gene (prothrombin
transmission and has a prevalence of 0.2–0.5% in the general G20210A) results in increased prothrombin concentrations and
population (Bauer et al., 2017). Such patients are at increased an increased risk of venous thrombosis by three- to fourfold over
risk not only for VTE but also for warfarin-induced skin necro- controls (Bauer et al., 2017).
sis, which occurs because protein C (and its closely related co-
factor, protein S) is a vitamin K–dependent antithrombotic factor Fibrinogen gamma 10034T
that can be further suppressed by the administration of warfarin.
Thrombosis in the small vessels of the skin may occur if large Approximately 6% of individuals carry this variant gene, which
loading (induction) doses of warfarin are given to such patients increases thrombotic risk approximately twofold (Rosendaal, 2009).
when the suppression of the antithrombotic effects of these fac-
tors occurs before the antithrombotic effects of blockade of vita- Oestrogens
min K–dependent clotting factor (II, VII, IX and X) production
has occurred. The prevalence of protein C deiciency in individu- Oestrogens increase the circulating concentrations of clotting
als who have had a VTE is 2–5% (Bauer et al., 2017). factors I, II, VII, VIII, IX and X and reduce ibrinolytic activity.
They also depress the concentrations of antithrombin III, which
Protein S deficiency is protective against thrombosis. This effect is dose related, and
venous thrombosis was more often seen with contraceptive pills
Protein S deiciency is probably even rarer than protein C dei- containing high (50 micrograms) oestrogen than with the present
ciency; the prevalence in the general population is unknown lower-dose preparations (Rosendaal, 2009). Hormone replace-
(Bauer et al., 2017). The familial form, inherited in an autosomal- ment therapy, pregnancy and the puerperium (up to 6 weeks
dominant fashion, is a high-risk state, accounting for VTE in some after delivery) are also recognised risk factors for VTE (National
individuals. The prevalence of protein S deiciency in individuals Institute for Health and Care Excellence [NICE], 2015a).
who have had a VTE is reported to be 1% (Bauer et al., 2017).
Malignancy
Factor V Leiden
VTE is more common in malignancy, and the risk may be up to
The presence of factor V Leiden, a point mutation in the factor ivefold greater than in those without malignancy. Although irst
V gene, causes the activated factor V molecule to be resistant described in association with carcinoma of the pancreas, all solid
to deactivation by activated protein C (APC). This defect may tumours seem to be associated with this problem. The absolute
have a prevalence of 4–5% in Caucasian populations (Bauer risk seems to be related to the type of tumour and its stage and
et al., 2017) and higher in patients with thromboembolic disease, treatment with chemotherapy. The exact mechanisms responsible
and it may in itself be of little consequence until there is another for the increased risk of VTE in malignancy are not known but
risk factor, such as immobility or use of the contraceptive pill. In may be related to the expression of tissue factor or factor X acti-
these circumstances, the combination of risks may be responsible vators (Elyamany et al., 2014).
for the increased predisposition to thromboembolism in a high
proportion of affected individuals. Surgery
Antithrombin III deficiency The increased risk of VTE in surgery is related, in part, to stag- 405
nation of venous blood in the calves during the operation and
Antithrombin III deiciency is a rare autosomal-dominant inher- recovery. Tissue trauma may also play a role because VTE
ited abnormality associated with a reduced plasma concentration appears to be more common in operations that involve marked
of this protein. The defect may not result in clinical problems tissue damage, such as orthopaedic surgery. This may in turn be
until pregnancy or until patients enter their fourth decade, when related to release of tissue thromboplastin and to reduced ibri-
venous and, to a lesser extent, arterial thrombosis becomes more nolytic activity. The most important risk factors associated with
common. Nevertheless, its prevalence in individuals with VTE VTE after surgery are duration of anaesthesia and procedure of
has been estimated to be between 1% and 7% (Bauer et al., 2017). more than 90 minutes (or 60 minutes if surgery involves lower
limbs or pelvis), acute surgical admission with an inlammatory
Lupus anticoagulant or intra-abdominal condition and expected signiicant reduction
in mobility (NICE, 2015a). Other patient-related risk factors
Lupus anticoagulant, an antibody against phospholipid, is so for VTE include age older than 60 years, dehydration, known
named because it increases the clotting time in blood when mea- thrombophilias, obesity (body mass index >30 kg/m2), one or
sured by some standard coagulation tests. Patients affected are more signiicant comorbidities, personal history or irst-degree
more prone to thromboembolism. It is also found in the primary relative with previous VTE, use of hormone replacement therapy
antiphospholipid syndrome (PAPS), where it may signify an or oestrogen-containing contraceptives and varicose veins with
increased risk of venous and arterial thrombosis and for recur- associated phlebitis. These will add to the risk, if present, but are
rent miscarriage (Derksen et al., 2001). also independent risk factors.
23 THERAPEUTICS
Clinical manifestations Table 23.1 Two-level deep vein thrombosis Wells score
DVT occurs commonly in the veins of the lower limbs and pelvis. Clinical feature Points
In some patients, there may not be any local symptoms or signs, and 1
the onset of PE may be the irst evidence of the presence of VTE. In Active cancer (treatment ongoing, within 6 months,
other cases, patients classically present with pain involving the calf or palliative)
or thigh, associated with swelling, redness of the overlying skin
and increased warmth. In a large DVT that prevents venous return, Paralysis, paresis or recent plaster immobilisation of 1
the leg may become discoloured and oedematous. Massive venous the lower extremities
thrombus can occasionally result in gangrene, although this occurs
very rarely now that effective drug therapies are available. Recently bedridden for 3 days or more or major 1
surgery within 12 weeks requiring general or regional
PE may occur in the absence of clinical signs of venous thrombo- anaesthesia
sis. It may be very dificult to diagnose because of the non-speciicity
of symptoms and signs. Clinical diagnosis is often made because Localised tenderness along the distribution of the 1
of the presence of associated risk factors. Obstruction with a large deep venous system
embolus of a major pulmonary artery may result in acute massive
PE, presenting with sudden shortness of breath and dull central chest Entire leg swollen 1
pain, together with marked haemodynamic disturbance, for example,
severe hypotension and right ventricular failure, sometimes resulting Calf swelling at least 3 cm larger than asymptomatic 1
in death due to acute circulatory failure unless rapidly treated. side
Acute submassive PE occurs when less than 50% of the pul- Pitting oedema confined to the symptomatic leg 1
monary circulation is occluded by embolus, and the embolus nor-
mally lodges in a more distal branch of the pulmonary artery. It Collateral superficial veins (non-varicose) 1
may result in some shortness of breath, but if the lung normally
supplied by that branch of the pulmonary artery becomes necrotic, Previously documented DVT 1
pulmonary infarction results, with pleuritic pain and haemoptysis
(coughing up blood), and there may be a pleural ‘rub’ (a sound like An alternative diagnosis is at least as likely as DVT −2
Velcro being torn apart when the patient breathes in) as a result of Clinical probability simplified score
inlammation of the lung. Patients may, rarely, develop recurrent
thromboembolism. This may not result in immediate symptoms or DVT – likely 2 points
signs, but the patient may present with increasing breathlessness or more
and signs of pulmonary hypertension (right ventricular hypertro-
phy) and, if untreated, progressive respiratory failure. DVT – unlikely 1 point
or less
Investigations DVT, Deep vein thrombosis.
Adapted from Wells et al. (2003) and NICE (2015b).
Deep vein thrombosis
Ultrasound. Ultrasound is a non-invasive alternative to
A DVT is the most common cause of pain, swelling and tender- venography that does not involve exposure to ionising radiation
ness within the leg, although other conditions, such as a Baker’s or potentially allergenic contrast media. It is now the initial inves-
cyst (which involves rupture of the posterior aspect of the syno- tigation of choice in clinically suspected DVT, although it is less
vial capsule of the knee), may mimic it. The two-level DVT sensitive for below-knee and isolated pelvic deep vein thrombosis.
Wells score is advocated as a helpful initial clinical screening test
to ascertain whether DVT is likely or unlikely (NICE, 2015b). Venography. Venography involves injection of radio-opaque
The clinical scoring tool for this approach is shown in Table 23.1. contrast medium, normally into a vein on the top of the foot, and
subsequent radiography of the venous system. Although speciic,
A DVT Wells Score of 2 points or more means that a DVT it is also invasive.
is classiied as likely. If this is the case, a proximal leg vein
ultrasound scan should be carried out within 4 hours of being Magnetic resonance imaging. Magnetic resonance imaging
requested, and if the result is negative, a D-dimer test should be (MRI) is also non-invasive and avoids radiation exposure. When
performed (D-dimer is a product formed in the body when blood used with direct thrombus imaging (DTI), which detects methae-
is broken down). If a proximal leg vein ultrasound scan cannot be moglobin in the clot, MRI DTI is sensitive and speciic, even with
carried out within 4 hours, a D-dimer test should be performed below-knee and isolated pelvic deep vein thrombosis. However,
and an interim 24-hour dose of a parenteral anticoagulant given it is not widely clinically available, and ultrasound remains the
while waiting for the proximal leg vein ultrasound scan to be car- primary initial investigation.
ried out within 24 hours. The NICE (2015b) guidance also rec-
ommends that the proximal leg vein ultrasound scan should be Pulmonary embolism
repeated 6–8 days later for all patients with a positive D-dimer
406 test and a negative proximal leg vein ultrasound scan. If PE is suspected, and the two-level PE Wells Score indi-
cates that PE is likely (more than 4 points using the two-level
THROMBOSIS 23
Table 23.2 Two-level pulmonary embolism Wells Score as an alternative to CTPA in patients who are allergic to contrast
media, or who have renal impairment or whose risk from irradia-
Clinical feature Points tion is considered to be high, because total radiation exposure is
3 lower than with CTPA (NICE, 2015b).
Clinical signs and symptoms of DVT (minimum of
leg swelling and pain with palpation of the deep Other indings. Other indings occur in PE, such as changes in
veins) the chest radiograph, for example, a raised right hemidiaphragm
as a result of the loss of lung volume (PE more commonly affects
An alternative diagnosis is less likely than PE 3 the right than the left lung). Hypoxia is also seen, and the larger
the PE, the worse this is. The electrocardiogram may show signs
Heart rate >100 beats/min 1.5 of right ventricular strain. The echocardiogram may show right
ventricular overload and dysfunction in massive PE. However,
Immobilisation for more than 3 days or surgery in 1.5 all these changes are relatively nonspeciic and do not obviate the
the previous 4 weeks need for the speciic tests mentioned previously.
Previous DVT/PE 1.5 Treatment
Haemoptysis 1 The aim of treatment of venous thrombosis is to allow normal
circulation in the limbs and, wherever possible, to prevent dam-
Malignancy (on treatment, treated in the last 1 age to the valves of the veins, thus reducing the risk of the swol-
6 months, or palliative) len post-phlebitic limb. Secondly, it is important to try to prevent
associated PE and also the recurrence of either venous thrombo-
Clinical probability simplified scores sis or PE in the risk period after the initial episode.
PE – likely More than In acute massive PE, the initial priority is to correct the circula-
4 points tory defect that has caused the haemodynamic upset, and in these
circumstances, rapid removal of the obstruction using thrombo-
PE – unlikely 4 points or lytic drugs or surgical removal of the embolus may be necessary.
less In acute submassive PE, the goal of treatment is to prevent further
DVT, Deep vein thrombosis; PE, pulmonary embolism. episodes, particularly of the more serious acute massive PE. In
Adapted from Wells et al. (2000). both DVT and PE, a search must be made for underlying risk fac-
tors, such as carcinoma, and particularly in those with repeated
PE Wells Score; Table 23.2), either an immediate computed episodes of VTE.
tomography pulmonary angiogram (CTPA) should be per-
formed or immediate interim parenteral anticoagulant therapy The treatment of VTE consists of the use of anticoagulants
initiated, followed by a CTPA, if a CTPA cannot be carried and, in severe cases, thrombolytic drugs. Anticoagulant therapy
out immediately. A proximal leg vein ultrasound scan should involves the use of immediate-acting agents (particularly hepa-
be considered if the CTPA is negative and DVT is suspected rin) and oral anticoagulants, the commonest of which is warfarin,
(NICE, 2015b). but direct oral anticoagulant (DOACs) are also an option as alter-
natives. Anticoagulation may be necessary for some time after
Computed tomography pulmonary angiogram. CTPA is a the initial event, depending on the persistence of risk factors for
minimally invasive test that has now largely superseded pulmo- recurrent thromboembolism.
nary angiography as the most speciic test in the diagnosis of PE.
It involves the intravenous administration of iodine-containing Prophylaxis
contrast media to allow sophisticated radiographic imaging to
detect whether blood is lowing to all parts of the lungs or whether Prevention of initial episodes of VTE in those at risk is clearly of
a PE is causing blockage in the pulmonary arterial vasculature. great importance. It has been estimated that around 25,000 peo-
ple in the UK die from preventable hospital-acquired VTE annu-
Ventilation–perfusion scanning. Ventilation–perfusion scan- ally, including patients admitted to hospital for medical care and
ning involves the injection of a radiolabelled substance into the surgery (House of Commons Health Committee, 2005). There
vein and measurement of perfusion via the pulmonary circula- is also widespread evidence of inconsistent use of prophylactic
tion, using a scintillation counter. This is often combined with measures for VTE in hospital patients, including mechanical and
a ventilation scan in which radiolabelled gas, normally xenon, pharmacological means of VTE prophylaxis. Some of the medi-
is inhaled by the patient. PE classically results in an area of cines described in the following sections contribute to those phar-
under- or non-perfusion of a part of the lung that, nevertheless, macological measures. Guidelines on reducing the risk of VTE in
because the airways are patent, ventilates normally. This pattern patients admitted to hospital are available (NICE, 2015a).
is called ventilation–perfusion mismatch and is a speciic sign
of PE. The preferred technique is a ventilation/perfusion single- Heparins
photon emission computed tomography (V/Q SPECT) scan. If a
V/Q SPECT scan is not available, a V/Q planar scan is an alterna- Conventional or unfractionated heparin (UFH) is a heterogeneous
tive, although it has lower sensitivity and speciicity. NICE rec- mixture of large mucopolysaccharide molecules ranging widely 407
ommends that ventilation-perfusion scanning can be considered
23 THERAPEUTICS
in molecular weight between 3000 and 30,000, with immediate Box 23.1 Guidelines to control unfractionated heparin
anticoagulant properties. It acts by increasing the rate of the inter- treatment
action of thrombin with antithrombin III by a factor of 1000. It,
thus, prevents the production of ibrin (factor I) from ibrinogen. Loading dose
Heparin also inhibits the production of activated clotting factors 5000 IU over 5 min
IX, X, XI and XII, and these effects occur at concentrations lower
than its effects on thrombin. Infusion
Start at 1400 IU/h (e.g. 8400 IU in 100 mL of normal saline over
Unlike UFH, low-molecular-weight heparins (LMWHs) con- 6 h). Check after 6 h.
tain polysaccharide chains ranging in molecular weight between Adjust dose according to ratio of the KCCT to the control value
4000 and 6000. Whereas UFH produces its anticoagulant effect using the following values
by inhibiting both thrombin and factor Xa, LMWHs predomi-
nantly inactivate only factor Xa. In addition, unlike UFH, they KCCT ratio Infusion rate change
inactivate platelet-bound factor Xa and resist inhibition by
platelet factor 4 (PF4), which is released during coagulation. >7.0 Discontinue for 30 min to 1 h and reduce by
Dalteparin, enoxaparin and tinzaparin are LMWHs with similar
eficacy and adverse effects. >500 IU/h
Because UFH and LMWHs all consist of high-molecular- >5.0 Reduce by 500 IU/h
weight molecules that are highly ionised (heparin is the strongest
organic acid found naturally in the body), they are not absorbed 4.1–5.0 Reduce by 300 IU/h
via the gastro-intestinal tract and must be given by intravenous
infusion or deep subcutaneous (never intramuscular) injection. 3.1–4.0 Reduce by 100 IU/h
UFH is highly protein bound, and it appears to be restricted to the
intravascular space, with a consequently low volume of distribu- 2.6–3.0 Reduce by 50 IU/h
tion. It does not cross the placenta and does not appear in breast
milk. Its pharmacokinetics are complex, but it appears to have 1.5–2.5 No change
a dose-dependent increase in half-life. The half-life is normally
about 60 minutes but is shorter in patients with PE. It is removed 1.2–1.4 Increase by 200 IU/h
from the body by metabolism, possibly in the reticuloendothelial
cells of the liver, and by renal excretion. The latter seems to be <1.2 Increase by 400 IU/h
more important after high doses of the compound.
After each dose change, wait 10 h before next KCCT estima-
LMWHs have a number of potentially desirable pharmaco-
kinetic features compared with UFH. They are predominantly tion unless KCCT >5, when more frequent (e.g. 4-hourly) estima-
excreted renally and have longer and more predictable half-lives
than UFH and so have a more predictable dose response than UFH. tion is advisable. Developed using Diogen (Bell and Alton); local
They can, therefore, be given once or, at the most, twice daily in a
ixed dose, sometimes based on the patient’s body weight, without validation may be necessary.
the need for laboratory monitoring, except for patients given treat-
ment doses and those at a high risk of bleeding. KCCT, Kaolin–cephalin clotting time.
Modified from Fennerty et al. (1986).
The major adverse effect of all heparins is haemorrhage, which
is more common in patients with severe heart or liver disease, Heparins, particularly UFH, may also cause thrombocytope-
renal disease, general debility and in women older than 60 years. nia (low platelet count). This may occur in two forms. The irst
The risk of haemorrhage is increased in those with prolonged occurs 3–5 days after treatment and does not normally result
clotting times and in those given UFH by intermittent intravenous in complications. The second type of thrombocytopenia occurs
bolus rather than by continuous intravenous administration. UFH after about 6 days of treatment and often results in much more
is monitored by derivatives of the activated partial thromboplas- profound decreases in platelet count and an increased risk of
tin time (APTT), for example, the kaolin–cephalin clotting time thromboembolism. LMWHs are thought to be less likely to cause
(KCCT); in those patients with a KCCT three times greater than thrombocytopenia, but this complication has been reported,
control, there is an eightfold increase in the risk of haemorrhage. including in individuals who had previously developed throm-
The therapeutic range for the KCCT during UFH therapy, there- bocytopenia after UFH. For these reasons, patients should have
fore, appears to be between 1.5 and 2.5 times the control values. a platelet count on the day of starting UFH, and alternate-day
Rapid reversal of the effect of UFH can be achieved using prot- platelet counts should be performed from days 4–14 thereafter.
amine sulphate, but this is rarely necessary because of its short For patients on LMWH, platelet counts should be performed at
duration of action. LMWHs may produce fewer haemorrhagic 2- to 4-day intervals from days 4–14 (Keeling et al., 2006). If
complications, and at the doses normally used for treatment, they the platelet count falls by 50% and/or the patient develops new
do not signiicantly affect coagulation tests, so routine monitor- thrombosis or skin allergy during this period, heparin-induced
ing is not necessary (Baglin et al., 2006). Protamine sulfate can thrombocytopenia (HIT) should be considered; if HIT is strongly
inhibit the prolongation in clotting time induced by LWMHs, but suspected or conirmed, heparin should be stopped and an alter-
408 does not fully inhibit their anti-factor Xa activity. native agent such as a heparinoid or hirudin commenced.
Heparin-induced osteoporosis is rare but may occur when the
drug is used during pregnancy and may be dose related. The exact
mechanism is unknown. Other adverse effects of heparin are alo-
pecia, urticaria and anaphylaxis, but these are also rare.
It has been shown that there is a nonlinear relationship between
the dose of UFH infused and the KCCT. This means that dis-
proportionate adjustments in dose are required depending on
the KCCT if under- or overdosing is to be avoided (Box 23.1).
Because the half-life of UFH is 1 hour, it would take 5 hours (ive
half-lives of the drug) to reach a steady state. A loading dose is
therefore administered to reduce the time to achieve adequate
anticoagulation. UFH in full dose can also be given by repeated
THROMBOSIS 23
subcutaneous injection, and in these circumstances the calcium of these is not necessary. It has to be given parenterally. It is used
salt appears to be less painful than the sodium salt. Opinions differ for prophylaxis of VTE in high-risk situations and for treatment
as to whether the subcutaneous or intravenous route is preferable. of acute DVT and treatment of acute PE, except in haemody-
The subcutaneous route may take longer to reach effective plasma namically unstable patients or patients who require thrombolysis
heparin concentrations but avoids the need for infusion devices. or pulmonary embolectomy. It also has an indication for the treat-
ment of unstable angina or non-ST-segment-elevation myocardial
Use of a LMWH or fondaparinux is recommended in the imme- infarction (NSTEMI) and for the treatment of ST-segment-
diate stages of proximal DVT and PE. UFH may be considered elevation myocardial infarction (STEMI). Haemorrhage is the
for use, with appropriate monitoring and care, in patients with most important adverse effect.
severe renal impairment, at increased risk of bleeding or with
haemodynamic instability. LMWH, UFH or fondaparinux should Oral anticoagulants
be administered with warfarin for at least 5 days or until the
international normalised ratio (INR) has been in the therapeutic Warfarin. Although it is not the only coumarin anticoagulant 409
range for 2 successive days, whichever is the longer. Monitoring, available, warfarin is by far the most widely used drug in this
as detailed previously, is essential to avoid the complications of group because of its potency, duration of action and more reliable
HIT. Patients with previous exposure to heparin within the past bioavailability. When given by mouth, warfarin is completely
100 days should also have a platelet count performed before the and rapidly absorbed, although food decreases the rate (but not
second dose of heparin is administered (Winter et al., 2005). the extent) of absorption. It is extremely highly plasma-protein
Requirements with DOACs differ, and not all require cover with bound (99%) and, therefore, has a small volume of distribution
a parenteral anticoagulant when used to treat a VTE. (7–14 L). It consists of an equal mixture of two enantiomers, (R)-
and (S)-warfarins. They have different anticoagulant potencies
Heparinoids and routes of metabolism.
Danaparoid is a heparinoid that is licensed for prophylaxis of Both enantiomers of warfarin act by inducing a functional
DVT in patients undergoing general or orthopaedic surgery. It deiciency of vitamin K and thereby prevent the normal car-
is a mixture of the low-molecular-weight sulphated glycosami- boxylation of the glutamic acid residues of the amino-terminal
noglycuronans: heparin sulphate, dermatan sulphate and a small ends of clotting factors II, VII, IX and X. This renders the clot-
amount of chondroitin sulphate. It acts by inhibiting factor Xa ting factors unable to cross-link with calcium and thereby bind
and, like LMWHs, is given by subcutaneous injection. It nor- to phospholipid-containing membranes. Warfarin prevents the
mally has a low cross-reactivity rate with heparin-associated anti- reduction of vitamin K epoxide to vitamin K by epoxide reduc-
platelet antibodies, and if this is not present, it can be used in the tase. (S)-warfarin appears to be at least ive times more potent
treatment of individuals who develop HIT but still need ongoing in this regard than (R)-warfarin. Because warfarin does not have
anticoagulation. It is administered intravenously, with monitoring any effect on already carboxylated clotting factors, the delay in
of anti-Xa activity only required in those at high risk of bleeding, onset of the anticoagulant effect of warfarin is dependent on the
for example, in renal insuficiency. It should be avoided in severe rate of clearance of the fully carboxylated factors already syn-
renal insuficiency and severe hepatic insuficiency. thesised. The half-life of removal of factor VII is approximately
6 hours, that of factor IX is 24 hours, that of factor X is 36
Hirudins hours and that of factor II is 50 hours. Some of the variability
in response to warfarin may be related to genetic variations in
Lepirudin, a recombinant hirudin, is licensed for anticoagulation the gene encoding the vitamin K epoxide reductase multiprotein
in patients with type II (immune) HIT who require parenteral anti- complex (VKORC1 gene).
thrombotic treatment. The dose of lepirudin is adjusted according
to the APTT, and it is given intravenously by infusion. The risk of The effect of warfarin is monitored using the one-stage pro-
haemorrhage is greater in those with poor renal function. Severe thrombin time, for example, the INR. This test is sensitive chiely
anaphylaxis occurs rarely in association with lepirudin treatment to factors VII, II and X (and to a lesser extent factor V, which is
and is more common in previously exposed patients (Keeling not a vitamin K–dependent clotting factor). However, factor VII
et al., 2006). Bivalirudin is an analogue of hirudin but acts as is the most important factor in the extrinsic pathway of clotting.
a direct thrombin inhibitor. It is licensed for anticoagulation in The optimum therapeutic range for the INR differs depending
patients undergoing percutaneous coronary intervention (PCI). on the clinical indication because the lowest INR consistent with
It has to be administered parenterally, and the activated clotting therapeutic eficacy is the best in reducing the risk of haemor-
time (ACT) is used to assess its activity. Haemorrhage is also an rhage. Examples of therapeutic ranges recommended for various
important adverse effect of this agent. indications are given in Table 23.3 (Keeling et al., 2011).
Fondaparinux Warfarin is metabolised by the liver via the cytochrome P450
system. Only very small amounts of the drug appear unchanged
Fondaparinux sodium is a synthetic pentasaccharide that binds to in the urine. The average clearance is 4.5 L/day, and the half-
antithrombin III, thus inhibiting factor Xa but without effect on life ranges from 20 to 60 hours (mean 40 hours). It thus takes
factor IIa. Therefore, at doses normally used for treatment, it does approximately 1 week (around ive half-lives) for the steady
not signiicantly affect coagulation tests, and routine monitoring state to be achieved after warfarin has been initiated. The
enantiomers of warfarin are metabolised stereo-speciically,
(R)-warfarin being mainly reduced at the acetyl side chain into
23 THERAPEUTICS
Table 23.3 Recommended target INRs for different conditions Table 23.4 Some clinically important drug interactions with
warfarin
Indication Target INR Interacting drug Effect Probable
Pulmonary embolus (first episode) 2.5 mechanism(s)
Carbamazepine Reduced
Proximal deep vein thrombosis (first episode) 2.5 Rifampicin anticoagulant Induction of warfarin
St John’s wort effect metabolism
Recurrence of venous thromboembolism while 3.5
on warfarin therapy (and INR >2.0)
Antiphospholipid syndrome 2.5 Oral contraceptives, Reduced Pharmacodynamic
oestrogens and anticoagulant antagonism of
progestogens effect anticoagulant effect
Vitamin K (e.g. in some
Non-rheumatic atrial fibrillation 2.5 enteral feeds)
Atrial fibrillation associated with mitral stenosis 2.5
or regurgitation
Amiodarone Increased Inhibition of warfarin
Cimetidine anticoagulant metabolism
Ciprofloxacin effect
Cardioversion 2.5 Clarithromycin
Erythromycin
Mechanical prosthetic heart valve (depends on prosthesis throm- Fibrates
bogenicity; consult full guideline) Fluconazole
Bioprosthetic valve (depends on valve affected and associated Fluvastatin
risk factors; consult full guideline) Itraconazole
Ketoconazole
INR, International normalised ratio. Leflunomide
Adapted from Keeling et al. (2011); consult the full guideline for further Metronidazole
information. Miconazole
Norfloxacin
secondary warfarin alcohols, whereas (S)-warfarin is predomi- Ofloxacin
nantly metabolised at the coumarin ring to hydroxywarfarin. Paracetamol
The clearance of warfarin may be reduced in liver disease and Rosuvastatin
during the administration of a variety of drugs known to inhibit Sulfinpyrazone
either the (S) or (R), or both, enantiomers. The number of possi- Sulfamethoxazole
ble interactions and the potential severity of their outcome mean Trimethoprim
that it is essential not to prescribe any medicine concomitantly
with warfarin until a thorough check on all possible interactions Danazol Increased Pharmacodynamic
has been undertaken. The British National Formulary (BNF) Tamoxifen anticoagulant potentiation of
contains comprehensive information on possible interactions effect anticoagulant effect
between warfarin and other medicines. It is advised that the
BNF is always consulted before the use of any other medication Cranberry juice Increased Mechanism unknown
with warfarin. Some examples of signiicant interactions with anticoagulant
warfarin are provided in Table 23.4. effect
Renal function is thought to have little effect on the pharma- NSAIDs (including aspi- Increased risk Additive effects on
cokinetics of, or anticoagulant response to, warfarin. Some of rin at all doses) of bleeding coagulation
the variability in warfarin dose requirement is related to genetic Clopidogrel Haemostasis
polymorphisms of the cytochrome (CYP2C9) mediating the rate
of hepatic metabolism of (S)-warfarin. Individuals with the vari- NSAIDs, Non-steroidal anti-inflammatory drugs.
ant isoform (either heterozygotes or in particular homozygotes)
metabolise this more active enantiomer more slowly and so Skin reactions to warfarin may also occur but are rare. The
require lower doses. most serious skin reaction is warfarin-induced skin necrosis,
which may occur over areas of adipose tissue such as the breasts,
The major adverse effect of warfarin is haemorrhage, which buttocks or thighs, especially in women, and is related to relative
often occurs at the site of a predisposing abnormality, such as an deiciency of protein C or S. This is important because these dei-
ulcer or a tumour. The risk of bleeding is increased by exces- ciencies result in an increased risk of thrombosis, and therefore
sive anticoagulation, although this may not need to be pres- warfarin may more often be used in such subjects. Preventing
ent for severe haemorrhage to occur. Close monitoring of the excessive anticoagulation in the initial stages of induction of
degree of anticoagulation of warfarin is, therefore, important, therapy may reduce the severity of the reaction. A dosing sched-
and guidelines for reversal of excessive anticoagulation are ule which helps achieve this is shown in Table 23.5.
shown in Box 23.2.
Warfarin may also be teratogenic, producing in some instances
It is also important to reduce the duration of therapy of the drug a condition called chondrodysplasia punctata. This is associated
410 to the minimum effective period to reduce the period of risk. with ‘punched-out’ lesions at sites of ossiication, particularly of
THROMBOSIS 23
Box 23.2 Recommendations for management of bleeding and Table 23.5 Suggested warfarin induction schedule
excessive anticoagulation in patients receiving warfarin
Day INR Warfarin dose (mg)
• Major bleeding – stop warfarin sodium; give phytomenadione First <1.4
(vitamin K1) 5 mg by slow intravenous injection; give dried 10 (5 may be more appropriate for
prothrombin complex (factors II, VII, IX and X) 25–50 units/kg; the elderly and those with low body
if dried prothrombin complex unavailable, fresh frozen plasma weight, liver disease, cardiac failure or
15 mL/kg can be given but is less effective; recombinant fac- at high risk of bleeding)
tor VIIa is not recommended for emergency anticoagulation
reversal. Second <1.8 10
• INR >8.0, minor bleeding – stop warfarin sodium; give phy- 1.8 1
tomenadione (vitamin K1) 1–3 mg by slow intravenous injec-
tion; repeat dose of phytomenadione if INR is still too high >1.8 0.5
after 24 h; restart warfarin sodium when INR <5.0.
Third <2.0 10
• INR >8.0, no bleeding – stop warfarin sodium; give phytom-
enadione (vitamin K1) 1–5 mg by mouth using the intravenous 2.0–2.1 5
preparation orally (unlicensed use); repeat dose of phytome-
nadione if INR is still too high after 24 h; restart warfarin when 2.2–2.3 4.5
INR <5.0.
2.4–2.5 4
• INR 5.0–8.0, minor bleeding – stop warfarin sodium; give
phytomenadione (vitamin K1) 1–3 mg by slow intravenous 2.6–2.7 3.5
injection; restart warfarin sodium when INR <5.0.
2.8–2.9 3
• INR 5.0–8.0, no bleeding – withhold 1 or 2 doses of warfarin
sodium and reduce subsequent maintenance dose. 3.0–3.1 2.5
• Unexpected bleeding at therapeutic levels – always investi- 3.2–3.3 2
gate the possibility of an underlying cause (e.g. unsuspected
renal or gastro-intestinal tract pathology). 3.4 1.5
INR, International normalised ratio. 3.5 1
Based on Keeling et al. (2011), and adapted from information within the
British National Formulary 2018. 3.6–4.0 0.5
the long bones but also of the facial bones, and may be associated >4.0 0 (predicted maintenance dose)
with the absence of the spleen. Although it has been associated
predominantly with warfarin anticoagulation during the irst tri- Fourth <1.4 >8
mester of pregnancy, other abnormalities, including cranial nerve
palsies, hydrocephalus and microcephaly, have been reported at 1.4 8
later stages of pregnancy if the child is exposed.
1.5 7.5
Other coumarin anticoagulants are available. Acenocoumarol
(nicoumalone) has a much shorter duration of action than warfa- 1.6–1.7 7
rin, and phenindione may be associated with a higher incidence of
non-haemorrhagic adverse effects. In the vast majority of cases, 1.8 6.5
these drugs have not been shown to have any clear beneits over
warfarin, but they may be used occasionally where a patient does 1.9 6
not tolerate warfarin. It is now the case that a patient who does
not tolerate warfarin would be more likely to receive a DOAC 2.0–2.1 5.5
rather than another vitamin-K antagonist instead.
2.2–2.3 5
The necessary duration of anticoagulation in venous thrombo-
sis and pulmonary embolus is still uncertain. On the basis of the 2.4–2.6 4.5
available evidence, therapy may be required for approximately
6 months after the irst DVT or PE. It may be possible to reduce 2.7–3.0 4
the duration of therapy in patients who have had a postoperative
episode because it is likely that the risk factor has been reversed 3.1–3.5 3.5
(unless immobility continues). In patients with a second episode,
therapy may be required for even longer, and in patients with 3.6–4.0 3
more than two episodes, lifelong treatment may be necessary to
reduce the risk of recurrence (Keeling et al., 2011). 4.1–4.5 Miss out next day’s dose, then give 2 mg
Direct acting oral anticoagulants. DOACs (e.g. apixaban, >4.5 Miss out 2 days’ doses, then give 1 mg
dabigatran, edoxaban and rivaroxaban) are highly effective
agents, but like all anticoagulants, they can cause potentially life- INR, International normalised ratio. 411
threatening bleeding in some patients. The various DOACs have Modified from Fennerty et al. (1984).
23 THERAPEUTICS
different marketing authorisations for use in different indications, Dabigatran. Dabigatran is an orally active inhibitor of both
and because these are relatively new agents, their authorisations free and clot-bound thrombin (Wittkowsky, 2010). It has a rapid
are subject to regular change. Product literature and/or the BNF onset of action. Dabigatran etexilate is a prodrug which is hydro-
should be consulted before use to ensure that an appropriate agent lysed to active dabigatran in the liver. Because 80% of activated
is selected for the indication. dabigatran is excreted unchanged through the kidneys, it should
be avoided in patients with severe renal impairment (creatinine
Although DOACs interact with fewer drugs than vitamin-K clearance <30 mL/min), and the dose should be reduced in mod-
antagonists such as warfarin, some potentially signiicant interac- erate renal impairment (creatinine clearance 30–50 mL/min).
tions do occur. All of the available agents appear to be substrates Dabigatran is a substrate for the transport protein p-GP, which
for p-glycoprotein (p-GP), and so various inhibitors or inducers facilitates renal elimination of certain drugs. Amiodarone, an
of this system will respectively increase or decrease the effect inhibitor of p-GP, reduces the clearance of dabigatran, and so
of the DOACs to different extents. A DOAC dose reduction is doses should be reduced in patients who are on concurrent treat-
advised when certain other medicines are co-prescribed and some ment with amiodarone. In patients who are on strong p-GP inhib-
are contraindicated in combination. As with warfarin, the BNF itors, such as verapamil and clarithromycin, dabigatran should
should be consulted before the co-administration of any other be used with caution, and it should not be used together with
medicine with a DOAC. quinidine. Drugs such as rifampicin and St John’s wort, which are
potent p-GP inducers, may potentially reduce its eficacy.
The relatively short half-lives of the DOACs means adherence
to treatment is essential for them to be optimally effective. They Rivaroxaban. Rivaroxaban is an orally active inhibitor of
are not, therefore, a panacea for a patient who is nonadherent to both the ‘free’ and prothrombinase complex-bound forms of acti-
warfarin or other medicines. vated factor X (Xa) (Wittkowsky, 2010). Two-thirds of the dose
is metabolised, principally by CYP450 enzymes, and the remain-
There is sometimes a perception that there is no requirement ing third is excreted unchanged in the urine. It should also be
for biochemical or physiological monitoring with DOACs. It is used with caution in patients with creatinine clearance less than
true that no routine anticoagulant monitoring is required; indeed, 30 mL/min (severe renal impairment) and is contraindicated in
this is not currently possible. However, there is a requirement to those with creatinine clearance less than 15 mL/min.
assess renal function before initiation and periodically thereafter,
particularly where a decline in renal function is suspected, and Like dabigatran, rivaroxaban also appears to be a p-GP sub-
also to monitor for signs of suspected bleeding or anaemia. strate, and it should be used with caution when prescribed
concomitantly with p-GP inhibitors and potent p-GP inducers.
The DOACs have been shown in clinical trials to be gener- Several CYP3A4 inhibitors and inducers have also been shown
ally safe for use without routine anticoagulant monitoring; how- to affect its metabolism. Some CYP3A4 inhibitors signiicantly
ever, arguments for and against laboratory monitoring have been increase the area-under-the-curve (AUC) of rivaroxaban, partic-
published (Kitchen et al., 2014). The absence of such monitor- ularly ketoconazole and other azole-antimycotics, such as itra-
ing may be a disadvantage in some cases, as it is not possible conazole, voriconazole and posaconazole and also HIV protease
to identify signs of sub-therapeutic or supra-therapeutic plasma inhibitors such as ritonavir. Therefore, the use of rivaroxaban is
levels until a thromboembolism or haemorrhage occurs. Further not recommended in patients receiving concomitant systemic
information on the effects of DOACs on laboratory measures of treatment with these agents. The CYP3A4 inducer rifampicin
anticoagulation can be found in the relevant British Society for (and possibly other inducers of this cytochrome) reduces the
Haematology guideline (Kitchen et al., 2014). AUC for rivaroxaban.
When considering the use of a DOAC, it is advised that the Apixaban. Apixaban is an orally active direct inhibitor
Cockroft–Gault formula is used to calculate an accurate creati- of activated factor X (factor Xa). Around 30% of the dose is
nine clearance before initiation. Dose reductions are advised with excreted unchanged in urine. The normal elimination half-life
DOACs at different levels of renal impairment, and they are also is around 12 hours, but this is prolonged in renal dysfunction.
contraindicated at different levels of impairment. This is some- It is not recommended if the creatinine clearance is less than
times dependent on the indication for which they are prescribed. 15 mL/min. The dose should be reduced if the eGFR is between
In patients with moderate to severe renal impairment, a drug 15 and 29 mL/min/1.73 m2, or if serum-creatinine ≥133 mmol/L
which is not predominantly renally excreted, with a marketing and the patient’s age is ≥80 years or the patient’s body weight
authorisation for this use, should be used. Some further infor- is ≤60 kg.
mation is given in the following sections, but again, the product
literature and/or the BNF should also be consulted. Like dabigatran and rivaroxaban, apixaban also appears to be
a p-GP substrate, and so it should be used with caution when
Haemorrhage is the major adverse effect of the DOACs, and prescribed concomitantly with p-GP inhibitors and potent p-GP
patients should be advised to seek urgent medical attention if they inducers.
notice signs of bleeding. Idarucizumab, a monoclonal antibody
fragment, is licenced in the UK for reversal of the anticoagulant Edoxaban. Edoxaban is also an orally active direct inhibitor
effect of dabigatran (NICE, 2016). It binds to both free and throm- of activated factor X (factor Xa). Around 50% of the clearance
bin-bound dabigatran, reversing the anticoagulant effect within of the drug is via the kidney as unchanged drug in the urine, the
minutes. Andexanet alfa, which is a recombinant modiied human remainder being cleared by metabolism and biliary or intestinal
factor Xa decoy protein, has been shown to reverse the anticoagu- excretion. The terminal elimination half-life of edoxaban fol-
lant effects of apixaban and rivaroxaban (Connolly et al., 2016). It lowing oral administration in health is around 10–14 hours. The
does not yet have a marketing authorisation in the UK.
412
THROMBOSIS 23
manufacturer advises a reduction in edoxaban dose in moderate acute myocardial infarction. In this clinical situation, reteplase
to severe renal impairment and to avoid using the medicine in is administered as an intravenous bolus, followed by a second
end-stage renal disease or in dialysis. bolus 30 minutes later (double bolus), and tenecteplase is given
as a single intravenous bolus. They, therefore, have the advantage
Edoxaban is a substrate of p-GP, and co-administration of of convenience of administration compared with alteplase, and
potent inhibitors like ciclosporin, dronedarone, erythromycin, they are the preferred option in pre-hospital settings, particularly
ketoconazole, quinidine or verapamil increases edoxaban expo- when administered by paramedics (NICE, 2002).
sure, necessitating a recommended reduction in dose.
Urokinase. Urokinase, like alteplase and streptokinase, can
Fibrinolytic drugs be used for the treatment of DVT and PE. It is also licensed to
restore patency in intravenous catheters and cannulas blocked by
Thrombolytic therapy is used in life-threatening acute massive ibrin thrombi.
PE. It has been used in DVT, particularly in those patients where
a large amount of clot exists and venous valvular damage is Patient care
likely. However, ibrinolytic drugs are potentially more danger-
ous than anticoagulant drugs, and evidence is not available in Patients taking oral anticoagulants should be given full informa-
situations other than acute massive embolism to show a sustained tion on what to do in case of problems and what circumstances
beneit from their use. and drugs to avoid. An anticoagulant card with previous INR val-
ues and doses should also be provided to those taking warfarin,
Streptokinase. Streptokinase was the irst agent available and patients should be told of the colour codes for the different
in this class. It was produced from streptococci and is a large strengths of warfarin tablets and advised to carry their treatment
protein that binds to and activates plasminogen, thus encourag- card at all times. Similarly, patients taking a DOAC should be
ing the breakdown of formed ibrin to ibrinogen degradation provided with an appropriate anticoagulant card for their treat-
products. It also acts on the circulating ibrinogen to produce a ment. The likely duration of any anticoagulant therapy should
degree of systemic anticoagulation. Because it is a large protein be made clear to the patient to avoid unnecessary and poten-
molecule, it cannot be administered orally and has to be given tially dangerous prolongations of treatment. Patients who have
by intravenous infusion. The half-life of removal from the body received a ibrinolytic agent should also carry a card identifying
is 30 minutes. It is cleared chiely by the reticuloendothelial the drug given and the date of administration.
system in the liver.
Arterial thromboembolism
Its major adverse effect is to increase the risk of haemor-
rhage, but it may also be antigenic and produce an anaphylactic Acute myocardial infarction is the commonest clinical presen-
reaction. It may also cause hypotension during infusion, and in tation of acute arterial thrombosis. Stroke is commonly caused
some patients, particularly those who have been administered by atherothromboembolism from the great vessels or embolism
the drug within the previous 12 months, a relative resistance to arising from the heart (approximately 80% of strokes). These two
the drug may occur. Thrombolytic therapy is contraindicated in conditions are discussed elsewhere. Peripheral arterial thrombo-
patients who have had major surgery or with active bleeding sis or thromboembolism may also occur, most often in the lower
sites in the gastro-intestinal or genitourinary tract; those who limb. Antiplatelet drugs are often used for prophylaxis, but surgi-
have a history of stroke, renal or liver disease; and those with cal embolectomy and/or ibrinolytic therapy may be needed for
hypertension. It should also be avoided during pregnancy and treatment of acute thrombotic or thromboembolic events to avoid
the postpartum period. consequent ischaemic damage.
Alteplase. Tissue plasminogen activator (rt-PA) or alteplase Aetiology
was developed using recombinant DNA technology. Although
this agent is much more expensive than streptokinase, it can be Arterial thromboembolism is normally associated with vascular
used in those situations where streptokinase may be less effec- injury and hypercoagulability. Vascular injury is most often due
tive because of development of antibodies, for example, within 1 to atheroma, itself aggravated by smoking, hypertension, hyper-
year of previous streptokinase use or where allergy to streptoki- lipidaemia or diabetes mellitus. Although the exact mechanism is
nase has previously occurred. Alteplase produces a lesser degree not clear, it is thought that platelet aggregation may be induced
of systemic anticoagulation because it is more active against by the shear stresses caused by the stenosis of an atherosclerotic
plasminogen associated with the clot; immediate use of hepa- vessel. This thrombotic material may embolise to cause occlusion
rin subsequently is necessary to prevent recurrence of throm- further downstream. Hypercoagulability is also a risk factor. It
bosis. Alteplase is also used for acute ischaemic stroke, where may be associated with increased plasma ibrinogen levels and an
its prompt use may improve outcome in carefully selected indi- increase in circulating cellular components, for example, polycy-
viduals in whom cerebral haemorrhage has been excluded using thaemia or thrombocythaemia. As mentioned earlier, the throm-
appropriate imaging techniques (NICE, 2012). Currently, it is the bus formed in the artery contains a much larger proportion of
only thrombolytic licensed for this indication (see discussion of
arterial thromboembolism).
Reteplase and tenecteplase. Reteplase and tenecteplase are
also ibrin-speciic agents, and so heparin is required to prevent
rebound thrombosis. They are indicated for the treatment of
413
23 THERAPEUTICS
platelets, possibly relecting the fact that other blood components and irreversibly inhibiting the binding of adenosine diphosphate
that are not as readily adherent may be dissipated by the higher (ADP) to its platelet receptor, thus preventing the ADP-mediated
low rates in the arterial circulation. Oestrogens, by the mecha- activation of the glycoprotein IIb/IIIa receptor for the life of the
nisms described earlier, are likely to increase the risk of arterial platelet. It is an orally active prodrug and is given once daily for the
and venous thrombosis. Hyperlipidaemia may also increase the reduction of atherosclerotic events in those with pre-existing ath-
risk of hypercoagulability, as well as enhance thrombotic risk erosclerotic disease. In this respect, it may be a useful alternative
through its role in the progression of atheroma and vascular injury. to aspirin in aspirin-allergic subjects, but haemorrhage occurs with
the same frequency as aspirin, and thrombocytopenia (sometimes
Treatment and prevention severe) may be commoner than with aspirin therapy. Activation
to its active metabolite may be subject to a genetic polymorphism
Aspirin of CYP450 2C19 and may also be reduced by the proton pump
inhibitor omeprazole or esomeprazole, so the use of alternative
Aspirin (acetylsalicylic acid) is a potent inhibitor of the enzyme gastroprotective agents may need to be considered if required.
cyclo-oxygenase, which catalyses the production of prostaglan-
dins. It reduces the production of a pro-aggregatory prostaglan- Clopidogrel is licensed in the UK for the prevention of ath-
din, thromboxane A2, in the platelet, an effect that lasts for the erothrombotic events (myocardial infarction, ischaemic stroke,
life of the platelet. established peripheral arterial disease, and acute coronary syn-
drome in combination with aspirin) and the prevention of ath-
Aspirin is well absorbed after oral administration. It is rapidly erothrombotic and thromboembolic events in atrial ibrillation
metabolised by esterases in the blood and liver (so that its half- (Consilient Health, 2017).
life is only 15–20 minutes) to salicylic acid and other metabolites
that are excreted in the urine. In the doses used in prophylaxis Prasugrel
against thromboembolism, aspirin is largely metabolised by the
liver, but in overdose, urinary excretion of salicylate becomes a Prasugrel inhibits platelet activation and aggregation. It is a pro-
limiting factor in drug elimination. drug whose active metabolite irreversibly binds to P2Y12 class
of ADP receptors on platelets. This prevents activation of the
The major adverse effect of aspirin is gastro-intestinal irritation GPIIb/IIIa receptor complex and thus causes inhibition of ADP-
and bleeding. This problem is much more common with higher mediated platelet activation and aggregation. In combination
doses of aspirin (300 mg or more) that were once used in the pre- with aspirin, it is recommended by NICE as an option, within its
vention of arterial thromboembolism but are less common with the marketing authorisation, for preventing atherothrombotic events
doses (e.g. 75 mg) now used. Concomitant use of ulcer-healing in adults with acute coronary syndrome (unstable angina [UA],
drugs, particularly proton pump inhibitors, can reduce the risk of NSTEMI or STEMI) having primary or delayed percutaneous
peptic ulceration induced by non-steroidal anti-inlammatory drug coronary intervention (NICE, 2014).
(NSAID) use in patients susceptible to the problem (NICE, 2015c).
There is also little evidence that buffered or enteric-coated prepara- Ticagrelor
tions of aspirin are safer in this respect. However, the vast majority
of patients tolerate low-dose aspirin well, and it is normally given Like prasugrel and clopidogrel, ticagrelor blocks ADP receptors
as a single oral dose of soluble aspirin. Aspirin may also, rarely, of subtype P2Y12. However, unlike the other antiplatelet drugs,
induce asthma, particularly in patients with co-existing reversible it has a binding site different from ADP (it is an allosteric antago-
airway obstruction. Other patients have a form of aspirin hyper- nist), and the blockade is therefore reversible. It is an active drug
sensitivity that may result in urticaria and/or angioedema. In this in its own right and does not require activation by metabolism.
situation, there may be cross-reactivity with other NSAIDs. Ticagrelor in combination with low-dose aspirin is recommended
for up to 12 months as a treatment option in adults with acute
Haemorrhagic stroke is a rare but very serious complication of coronary syndromes (NICE, 2011).
therapy with aspirin (and with other antiplatelet agents). Aspirin
must not be given to children or people younger than 16 years Dipyridamole
because of the risk of the rare but life-threatening possibility of
Reye’s syndrome, which may cause liver and renal failure. Dipyridamole is prescribed as an adjunct to oral anticoagulation
for prophylaxis of thromboembolism associated with prosthetic
Aspirin is an established treatment for the secondary preven- heart valves. Dipyridamole modiied-release preparations 200 mg
tion of cardiovascular events. However, a review of its use for twice a day may be used in combination with aspirin 75 mg
primary prevention found that the risks and beneits are more daily for long-term vascular prevention in people with ischaemic
inely balanced than previously thought, and low-dose aspirin stroke or TIA without paroxysmal or permanent atrial ibrillation,
is no longer routinely recommended for this indication, even in but only if clopidogrel 75 mg daily cannot be used (Bowen et al.,
high-risk patients such as those with diabetes or hypertension 2016). If clopidogrel and aspirin cannot be tolerated or are con-
(Anon., 2009). It should also be noted that it does not have a traindicated, then modiied-release dipyridamole 200 mg twice a
marketing authorisation for such use. day would be used by itself.
Clopidogrel Dipyridamole is a phosphodiesterase inhibitor and, thus, ele-
vates concentrations of cyclic AMP. It may also block the uptake
Clopidogrel is a prodrug that is metabolised in part to an active
414 thiol derivative. The latter inhibits platelet aggregation by rapidly
THROMBOSIS 23
of adenosine by erythrocytes and other cells. Adverse effects Case 23.2
include headache (to which tolerance may gradually develop)
gastro-intestinal problems, lushing and hypotension. A patient, Mr FG, receiving heparin for 7 days for extensive VTE
develops arterial thrombosis.
Glycoprotein IIb/IIIa inhibitors
Question
Glycoprotein IIb/IIIa inhibitors prevent platelet aggregation by
blocking the binding of ibrinogen to receptors on platelets. What would you suspect in this situation, and what should be done?
Abciximab. Abciximab is a monoclonal antibody which binds Answer
to coronary glycoprotein IIb/IIIa receptors and to other related
sites. It is recommended as an adjunct to heparin and aspirin for The rare but serious heparin-induced thrombocytopenia (HIT) may
the prevention of ischaemic complications in high-risk patients be responsible. The platelet count should be measured immedi-
undergoing percutaneous transluminal coronary intervention ately, and if HIT is strongly suspected or confirmed, the heparin
(NICE, 2010). Abciximab should be used once only to avoid fur- should be discontinued. An alternative anticoagulant should be
ther risk of thrombocytopenia. started at full dose whilst specific confirmatory tests are being per-
formed, unless there are significant contraindications. Danaparoid
Eptiibatide and tiroiban. Eptiibatide and tiroiban also and lepirudin may be considered as alternative anticoagulants in
inhibit glycoprotein IIb/IIIa receptors; they are licensed for use these circumstances.
with heparin and aspirin to prevent early myocardial infarction in
patients with unstable angina or NSTEMI. Case 23.3
Abciximab, eptiibatide and tiroiban all have to be adminis- Mr MT, admitted to an acute hospital with suspected myocardial
tered parenterally and should be used by specialist clinicians only infarction, says that he had a myocardial infarction 4 years ago
(NICE, 2010). and was treated with a drug to ‘dissolve the clot in the coronary
artery’. The chest pain started 4 hours earlier, and his electrocar-
Patient care diogram shows ST-segment elevation in the anterior leads.
Aspirin is normally well tolerated at the doses used for stroke Question
prevention. However, it should not be given to patients with a his-
tory of gastro-intestinal ulceration. Because it may induce bron- What relevance may Mr MT’s previous treatment, present history and
chospasm in susceptible individuals, it should be used cautiously findings have to his management on this occasion?
in such circumstances. It is best tolerated if taken once daily as
soluble aspirin after food. Answer
Case studies Thrombolytic drugs are indicated for any patient with acute myo-
cardial infarction, provided the likely benefits outweigh the possible
Case 23.1 risks. Trials have shown that the benefit is greatest in those with elec-
trocardiogram (ECG) changes that include ST-segment elevation,
Mr AJ, a 75-year-old patient receiving warfarin to prevent DVT, especially in those with anterior infarction, and in patients with bundle
comes to the clinic with an INR of 12, despite taking the same branch block. The patient has received a thrombolytic, possibly strep-
dose of the drug. There is no evidence of bleeding. He was previ- tokinase, in the past. Mr MT should be asked if he was given a card
ously well controlled on warfarin. to carry with him with the identity of the therapy he was given. If
the prior treatment was with streptokinase or anistreplase (no longer
Question available), prolonged persistence of antibodies to streptokinase may
reduce the effectiveness of subsequent treatment. Therefore, strep-
What should be done? tokinase should not be used again beyond 4 days of first adminis-
tration of streptokinase (or anistreplase), and urgent consideration
Answer should be given to the use of an alternative thrombolytic agent such
as alteplase, reteplase or tenecteplase.
Because Mr AJ’s INR is more than 8 (even if there is no bleeding),
the national guidelines recommend that warfarin be stopped (Keeling Case 23.4
et al., 2011). The patient should then be given phytomenadione (vita-
min K1) 1–5 mg by mouth using the intravenous preparation orally (unli- A 64-year-old male patient, Mr TS, is to be prescribed aspirin ther-
censed use). The dose of phytomenadione should be repeated if the apy following an acute myocardial infarction.
INR is still too high after 24 hours. However, a single dose often helps
the INR return to close to the target level at 24 hours without causing Question
warfarin resistance subsequently. The warfarin can be restarted when
the INR is less than 5.0. A search for clinical conditions or drugs which What questions should you ask Mr TS before starting treatment with
might cause warfarin sensitivity should also be made. Measurement of
plasma warfarin concentration may help in difficult cases. aspirin? 415
23 THERAPEUTICS
Answer rise above 1.4 even when her warfarin dose is increased to 20 mg
daily.
Mr TS should be asked if he has had aspirin before and, if so, whether
he tolerated it. Caution is necessary in elderly patients, in those with Question
uncontrolled hypertension and in patients taking other drugs that
increase the risk of bleeding. Caution is also required in those with a What can be done to find the cause of the resistance?
previous history of peptic ulceration, and some manufacturers advise
avoidance in such circumstances; active peptic ulceration is a defi- Answer
nite contraindication. Other contraindications include severe hepatic
impairment, severe renal failure, haemophilia and other bleeding dis- Mrs BC should be asked about any new medications which might have
orders. Aspirin may induce bronchospasm or angioedema in suscep- been introduced recently, including over-the-counter and herbal prep-
tible individuals, for example, in asthmatics, and caution should be arations. Some proprietary medicines may contain vitamin K, which
exercised in these circumstances. could cause resistance by pharmacodynamic mechanisms. Other medi-
cines, including the herbal medicine St John’s wort, might induce warfa-
Case 23.5 rin metabolism and result in resistance as a result of a pharmacokinetic
interaction (see Table 23.4). One other cause of apparent resistance to
Mrs BC, a 56-year-old woman on warfarin therapy for atrial fibrilla- warfarin is poor adherence, and this should, therefore, be considered.
tion with mitral stenosis, appears to become resistant to warfarin Supervised administration of the dose and/or measurement of plasma
after previously good control on 5 mg daily. Her INR does not warfarin concentrations may be of value if this is suspected.
References
416 Anon, 2009. Aspirin for primary prevention of cardiovascular disease? National Institute for Health and Care Excellence (NICE), 2010. Guidance
Drugs Therapeut. Bull. 47, 122–125. on the use of glycoprotein IIb/IIIa inhibitors in the treatment of acute
coronary syndromes. Technology Appraisal 47 NICE, London. Available
Baglin, T., Barrowcliffe, T.W., Cohen, A., et al., 2006. British Committee at: http://www.nice.org.uk/guidance/ta47/.
for Standards in Haematology, guidelines on the use and monitoring of
heparin. Br. J. Haematol. 133 19–34. National Institute for Health and Care Excellence (NICE), 2011. Ticagrelor
for the treatment of acute coronary syndromes. Technology Appraisal
Bauer, K.A., Leung, L.L.K., Tirnauer, J.S., 2017. Protein C deiciency. UpTo- Guidance TA236. NICE, London. Available at https://www.nice.org.uk/g
Date. Available at: https://www.uptodate.com/contents/protein-c-deiciency. uidance/ta236/.
Bowen, A., James, M., Young, G., 2016. Intercollegiate Stroke Working National Institute for Health and Care Excellence (NICE), 2012.
Party, national clinical guideline for stroke. Royal College of Physicians, Alteplase for treating acute ischaemic stroke. Technology Appraisal
London. Available at: https://www.strokeaudit.org/SupportFiles/Docum- TA264. NICE, London. Available at: https://www.nice.org.uk/
ents/Guidelines/2016-National-Clinical-Guideline-for-Stroke-5t-(1).aspx. guidance/ta264/.
Connolly, S.J., Milling, T.J., Eikelboom, J.W., et al., 2016. Andexanet alfa National Institute for Health and Care Excellence (NICE), 2014. Prasugrel
for acute major bleeding associated with factor Xa inhibitors. New Engl. with percutaneous coronary intervention for treating acute coronary
J. Med. 375, 1131–1141. syndromes. Technology Appraisal TA317. NICE, London. Available at:
http://www.nice.org.uk/ta317.
Consilient Health, 2017. Summary of product characteristics clopidogrel.
Available at: https://www.medicines.org.uk/emc/medicine/24979. National Institute for Health and Care Excellence (NICE), 2015a. Reducing
the risk of venous thromboembolism (deep vein thrombosis and pulmo-
Derksen, R.H.W.M., de Groot, P.G., Nieuwenhuis, H.K., et al., 2001. How nary embolism) in patients admitted to hospital. Clinical Guideline 92.
to treat women with antiphospholipid antibodies in pregnancy? Ann. NICE, London. Available at: http://www.nice.org.uk/guidance/cg92.
Rheum. Dis. 60, 1–3.
National Institute for Health and Care Excellence (NICE), 2015b. Venous
Elyamany, G., Alzahrani, A.M., Bukhary, E., 2014. Cancer-associated thromboembolic diseases: diagnosis, management and thrombophilia test-
thrombosis: an overview. Clin. Med. Insights Oncol. 8, 129–137. ing. NICE, London. Available at: https://www.nice.org.uk/guidance/CG144.
Fennerty, A., Dolben, J., Thomas, P., et al., 1984. Flexible induction dose regimen National Institute for Health and Care Excellence (NICE), 2015c. Clinical
for warfarin and prediction of maintenance dose. Br. Med. J. 288, 1268–1270. knowledge summaries. Antiplatelet treatment. Available at: https://cks.
nice.org.uk/antiplatelet-treatment#!scenario:1.
Fennerty, A.G., Renowden, S., Scolding, N., et al., 1986. Guidelines for the
control of heparin treatment. Br. Med. J. 292, 579–580. National Institute for Health and Care Excellence (NICE), 2016. Reversal of
the anticoagulant effect of dabigatran: idarucizumab. Evidence summary
House of Commons Health Committee, 2005. The prevention of venous [ESNM 73]. NICE, London. Available at: https://www.nice.org.uk/advice
thromboembolism in hospitalised patients. The Stationery Ofice, London. /esnm73/chapter/Key-points-from-the-evidence.
Keeling, D., Baglin, T., Tait, C., et al., 2011. For British Committee for Rosendaal, F.R., 2009. In: Van Beek, E.J.R., Büller, H.R., Oudkerk, M.
Standards in Haematology, guidelines on oral anticoagulation with warfa- (Eds.), Deep Vein Thrombosis and Pulmonary Embolism. Wiley-Black-
rin: fourth edition. Br. J. Haematol. 154, 311–324. well, Chichester.
Keeling, D., Davidson, S., Watson, H., 2006. Haemostasis and Thrombosis Task Rosendaal, F.R., Reitsma, P.H., 2009. Genetics of venous thrombosis. J.
Force of the British Committee for Standards in Haematology, the manage- Thromb. Haemostasis. 7 (Suppl. 1), 301–304.
ment of heparin induced thrombocytopenia. Br. J. Haematol. 133, 259–269.
Wells PS, Anderson DR, Rodger M, et al., 2000. Derivation of a Sim-
Kitchen, S., Gray, E., Mackie, I., 2014. Measurement of non-coumarin antico- ple Clinical Model to Categorize Patients Probability of Pulmonary
agulants and their effects on tests of haemostasis. Guidance from the British Embolism: Increasing the Models Utility with the SimpliRED D-dimer.
Committee for Standards in Haematology. Br. J. Haematol. 166, 830–841. Thromb. Haemost. 83, 416–420.
Knight, M., Nair, M., Tuffnell, D., et al. (Eds.), for MBRRACE-UK, 2016. Wells, P.S., Anderson, D.R., Rodger, M., et al., 2003. Evaluation of D-dimer
Saving lives, improving mothers’ care surveillance of maternal deaths in in the diagnosis of suspected deep-vein thrombosis. New Engl. J. Med.
the UK 2012–14 and lessons learned to inform maternity care from the 349, 1227–1235.
UK and Ireland Conidential Enquiries into Maternal Deaths and Morbid-
ity 2009–14. National Perinatal Epidemiology Unit, Oxford. Available at: Winter, M., Keeling, D., Sharpen, F., et al., 2005. Procedures for the out-
https://www.npeu.ox.ac.uk/downloads/iles/mbrrace-uk/reports/MBRRA patient management of patients with deep vein thrombosis. Clin. Lab.
CE-UK%20Maternal%20Report%202016%20-%20website.pdf Haematol. 27, 61–66.
National Institute for Health and Care Excellence (NICE), 2002. Guidance Wittkowsky, A.K., 2010. New oral anticoagulants: a practical guide for
on the use of drugs for early thrombolysis in the treatment of acute myo- clinicians. J. Thromb. Thrombolysis. 29, 182–191.
cardial infarction. Technology Appraisal 52. NICE, London. Available at:
http://www.nice.org.uk/guidance/ta52.
THROMBOSIS 23
Further reading
Kesieme, E., Kesieme, C., Jebbin, N., et al., 2011. Deep vein thrombosis: a
clinical review. J. Blood Med. 2, 59–69.
Useful website
Thrombosis UK: http://www.thrombosisuk.org.
417
THERAPEUTICS
24 Dyslipidaemia
Helen Williams
Key points cholesterol (HDL-C) confers protection against CVD, with the
risk reducing as HDL-C increases. It is, therefore, clear that the
• Elevated concentrations of total cholesterol (TC) and low- term hyperlipidaemia, which was formerly used to describe dis-
density lipoprotein cholesterol (LDL-C) increase the risk of orders of lipoprotein metabolism, is inappropriate. It is more
cardiovascular disease (CVD), whereas high-density lipoprotein appropriate to use the term dyslipidaemia, which encompasses
cholesterol (HDL-C) confers protection. both abnormally high levels of speciic lipoproteins, for exam-
ple, LDL-C, and abnormally low levels of other lipoproteins, for
• Two-thirds of the UK adult population has a serum TC greater example, HDL-C, as well as disorders in the composition of the
than 5 mmol/L. The average TC concentration is 5.6 mmol/L. various lipoprotein particles. It is particularly appropriate when
considering the individual at risk of CVD with a normal or high
• Dyslipidaemia may develop secondary to disorders such as dia- TC and low HDL-C (TC:HDL-C ratio).
betes mellitus, hypothyroidism, chronic renal failure, nephrotic
syndrome, obesity, high alcohol intake and some drugs. Epidemiology
• Understanding and managing dyslipidaemia is of particular Lipid and lipoprotein concentrations vary among different popu-
importance to reduce cardiovascular (CV) events in patients lations, with countries consuming a Western type of diet gener-
with or at risk of CV disease, but dyslipidaemia can also ally having higher TC and LDL-C levels than those where regular
predispose patients to other disorders; for example, severe consumption of saturated fat is low. The UK’s cholesterol level
hypertriglyceridaemia (>10 mmol/L) is responsible for up to 4% is ninth highest in the world, slightly less than 5.5 mmol/L.
of cases of acute pancreatitis. However, UK men and women have both shown one of the larg-
est drops in cholesterol in all high-income countries, from 6.2
• Androgens, β-blockers, ciclosporin, oral contraceptives, diuret- to 5.4 mmol/L (Farzadfar et al., 2011). In contrast, in China and
ics, glucocorticoids and vitamin A derivatives are examples of Japan, the average is reading is less than 5 mmol/L (Research
drugs that can have an adverse effect on the lipid profile. Committee on Serum Lipid Level Survey 1990 in Japan, 1996;
Yang et al., 2012).
• There are five main classes of lipid-lowering agents: statins,
fibrates, resins, nicotinic acid derivatives and absorption block- The ideal serum lipid proile is unknown and varies between
ers. More recently, proprotein convertase subtilisin/kexin type 9 different populations, even across Europe, and also within a
inhibitors have been introduced. given population. Until recently, calculated LDL-C level was
a key target for lipid lowering and monitoring, but in 2014 the
• Statins are the drugs of choice in the treatment of primary National Institute for Health and Care Excellence (NICE) recom-
prevention and secondary prevention of CVD. mended the use of non-high-density lipoprotein cholesterol (non-
HDL-C) rather than LDL-C. Non-HDL-C is TC minus HDL-C.
• The aim of treatment in primary prevention (≥10% risk of CVD LDL-C is not directly measured; it requires a calculation using
over 10 years) is to reduce overall CV risk by treatment with a a fasting sample and for the triglyceride levels to be less than
high-intensity statin, such as atorvastatin 20 mg. No specific 4.5 mmol/L (NICE, 2014). Measurement of non-HDL-C does not
target treatment levels are recommended in primary preven- require either of these. Non-HDL-C represents the total of cho-
tion, although a 40% or more drop in non-HDL-C should be lesterol circulating on apoprotein B (apoB) particles, that is, both
used as a marker of adherence. LDL and triglyceride-rich lipoproteins, and represents the main
atherogenic particles. A desirable value is less than 3 mmol/L.
• In secondary prevention, treatment should be started with a
high dose of a high-intensity statin, such as atorvastatin 80 mg The values presented in Table 24.1 represent what might be
daily. No specific target treatment levels are recommended in considered as an optimal lipid proile in the UK. Speciic target
secondary prevention, although a 40% or more decline in non- levels for patients receiving treatment for primary or secondary
HDL-C should be used as a marker of adherence.
Disorders of lipoprotein metabolism together with high-fat diets,
obesity and physical inactivity have all contributed to the current
epidemic of atherosclerotic disease seen in developed countries.
Disorders of lipoprotein metabolism that result in elevated serum
concentrations of total cholesterol (TC) and low-density lipopro-
tein cholesterol (LDL-C) increase the risk of development of car-
418 diovascular disease (CVD). In contrast, high-density lipoprotein
DYSLIPIDAEMIA 24
Table 24.1 Optimal serum lipid profile ingested lipids; and B-100, which is found in endogenously
secreted VLDL-C and associated with the transport of lipids from
Total cholesterol <4.0 mmol/L the liver (Fig. 24.1).
Low-density lipoprotein cholesterol <2.0 mmol/L When dietary cholesterol and triglycerides are absorbed from
the intestine they are transported in the intestinal lymphatics as
Triglyceride <1.7 mmol/L (fasting) chylomicrons. These are the largest of the lipoprotein particles
of which triglycerides normally constitute approximately 80% of
High-density lipoprotein cholesterol >1.0 mmol/L in men the lipid core. The chylomicrons pass through blood capillaries in
>1.2 mmol/L in women adipose tissue and skeletal muscle, where the enzyme lipoprotein
lipase is located, bound to the endothelium. Lipoprotein lipase is
prevention of CVD are no longer recommended by NICE (2014); activated by apoC-II on the surface of the chylomicron. The lipase
they state that a 40% reduction in non-HDL-C from pretreatment catalyses the breakdown of the triglyceride in the chylomicron to
baseline is an indication of adherence to treatment. free fatty acid and glycerol, which then enter adipose tissue and
muscle. The cholesterol-rich chylomicron remnant is taken up by
Despite a 50% reduction in the death rate from CVD over receptors on hepatocyte membranes, and in this way dietary cho-
the past 25 years, CVD remains the leading cause of death in lesterol is delivered to the liver and cleared from the circulation.
the UK (NICE, 2014). The death rate from CVD is threefold
higher in males than females, but because women live longer VLDL-C is formed in the liver and transports triglycerides,
and are at increased risk of stroke after the age of 75 years, which again make up approximately 80% of its lipid core, to the
their lifetime risk of disease is greater (NICE, 2014). Death periphery. The triglyceride content of VLDL-C is removed by
from CVD is responsible for one quarter of premature deaths lipoprotein lipase in a similar manner to that described earlier
in men and 17% of premature deaths in women (British Heart for chylomicrons, and forms IDL-C particles. The core of IDL-C
Foundation, 2015). The higher the levels of TC in an individ- particles is roughly 50% triglyceride and 50% cholesterol esters,
ual, the greater is the chance of development of CVD. For an acquired from HDL-C under the inluence of the enzyme leci-
individual, there appears to be no level below which a further thin-cholesterol acyltransferase (LCAT). Approximately 50% of
reduction of TC or LDL-C is not associated with a lower risk the body’s IDL particles are cleared from serum by the liver. The
of CVD. other 50% of IDL-C are further hydrolysed and modiied to lose
triglyceride and apoE1, and become LDL-C particles. LDL-C is
Population-based approaches to vascular screening have the the major cholesterol-carrying particle in serum.
potential to provide signiicant health gain for society because
most deaths from CVD occur in individuals who are not yet LDL-C provides cholesterol, an essential component of cell
identiied as at increased risk. Moreover, a small reduction in membranes, bile acid and a precursor of steroid hormones to
average population levels of TC and LDL-C/non-HDL-C can those cells that require it. LDL-C is also the main lipoprotein
potentially prevent many deaths. In England, the NHS Health involved in atherogenesis, although it appears to take on this role
Checks scheme was introduced in 2009 for everyone between only after it has been modiied by oxidation. For reasons that are
40 and 74 years of age to receive a free health check every 5 not totally clear, the arterial endothelium becomes permeable to
years; this health check includes measurement of TC and the the lipoprotein. Monocytes migrate through the permeable endo-
TC:HDL-C ratio and a calculation of cardiovascular (CV) risk. thelium and engulf the lipoprotein, resulting in the formation of
The intention is that individuals are given the necessary infor- lipid-laden macrophages that have a key role in the subsequent
mation about their health to make changes to lifestyle and avoid development of atherosclerosis. The aim of treatment in dyslipi-
preventable disease. daemia is normally to reduce concentrations of LDL-C (and con-
sequently atherogenesis), and thus reduce TC at the same time.
Lipid transport and lipoprotein
metabolism Non-HDL cholesterol (TC minus HDL-C) is a measure of all
the ‘bad elements’ of the lipid proile and is now used in prefer-
The clinically important lipids in the blood (unesteriied and ence to LDL-C, because it can be calculated without the need to
esteriied cholesterol and triglycerides) are not readily solu- take a fasting blood sample and is not affected by the presence of
ble in serum and are rendered miscible by incorporation into high triglyceride levels.
lipoproteins. There are six main classes of lipoproteins: chy-
lomicrons, chylomicron remnants, very low-density lipopro- Whereas VLDL-C and LDL-C are considered the ‘bad’ lipo-
teins (VLDL), intermediate-density lipoproteins (IDL), LDL proteins, HDL-C is often considered to be the ‘good’ antiath-
and HDL. erogenic lipoprotein. In general, about 65% of TC is carried in
LDL-C and about 25% in HDL.
The protein components of lipoproteins are known as apopro-
teins (apo), of which apoA-I, apoE, apoC and apoB are perhaps High-density lipoprotein 419
the most important. ApoB exists in two forms: B-48, which is
present in chylomicrons and associated with the transport of HDL-C is formed from the unesteriied cholesterol and phos-
pholipid removed from peripheral tissues and the surface of tri-
glyceride-rich proteins. The major structural protein is apoA-I.
HDL-C mediates the return of lipoprotein and cholesterol from
peripheral tissues to the liver for excretion in a process known as
reverse cholesterol transport.
24 THERAPEUTICS
Exogenous pathway Endogenous pathway
Chylomicron transport of dietary fat and cholesterol VLDL-C and HDL-C metabolism in plasma
Dietary fat and Bile acids + cholesterol
cholesterol
LDL LDL-C LDL
receptor B-100 receptor
Intestine Remnant Liver Extrahepatic
receptor tissues
LDL
receptor
Chylomicrons Chylomicron VLDL-C IDL-C HDL-C
remnants
E E CII A-I A-II
CII E B-48 CI B-100 E B-100
B-48
Plasma
LCAT
Capillaries Capillaries
Lipoprotein Free fatty acids Lipoprotein
lipase lipase Free fatty acids
Adipose tissue Adipose tissue
and muscle and muscle
Fig. 24.1 Schematic representation of lipoprotein metabolism in plasma. Dietary cholesterol and
fat are transported in the exogenous pathway. Cholesterol produced in the liver is transported in the
endogenous pathway.
HDL-C, High-density lipoprotein cholesterol; IDL-C, intermediate-density lipoprotein cholesterol;
LCAT, lecithin-cholesterol acyltransferase; LDL-C, low-density lipoprotein cholesterol; VLDL-C, very
low-density lipoprotein cholesterol.
Reverse cholesterol transport pathway ester content (and potentially some free cholesterol) of mature
HDL particles is taken up primarily by a selective uptake process
The reverse cholesterol transport pathway (Fig. 24.2) controls the involving the hepatic scavenger receptor B1; and (2) an indirect
formation, conversion, transformation and degradation of HDL-C pathway (dotted blue lines in Fig. 24.2) in which cholesteryl
and is the target site for a number of drugs (Chapman et al., 2010). ester originating in HDL is deviated to potentially atherogenic
VLDL, IDL and LDL particles by cholesteryl ester transfer pro-
The reverse cholesterol transport system involves lipoprotein- tein. Both the cholesteryl ester and free cholesterol content of
mediated transport of cholesterol from peripheral, extrahepatic these particles are taken up by the liver, predominantly via the
tissues and arterial tissue (potentially including cholesterol- LDL receptor, which binds their apoB100 component. This latter
loaded foam cell macrophages of the atherosclerotic plaque) to pathway may represent up to 70% of cholesteryl ester delivered
the liver for excretion, either in the form of biliary cholesterol to the liver per day. The hepatic LDL receptor is also responsible
or bile acids. The ATP-binding cassette transporters, ABCA1 and for the direct uptake of HDL particles containing apoE; apoE may
ABCG1, and the scavenger receptor B1 are all implicated in cellu- be present as a component of both HDL2 and HDL3 particles,
lar cholesterol eflux mechanisms to speciic apoA-1/HDL accep- and may be derived either by transfer from triglyceride-rich lipo-
tors. The progressive action of lecithin cholesterol acyltransferase proteins or from tissue sources (principally liver and monocyte-
(LCAT) on free cholesterol in lipid-poor, apolipoprotein A-I- macrophages). Whereas HDL uptake by the LDL receptor results
containing nascent HDLs, including pre-β-HDL, gives rise to the primarily in lysosomal-mediated degradation of both lipids and
formation of a spectrum of mature, spherical HDLs with a neutral apolipoproteins, interaction of HDL with scavenger receptor B1
lipid core of cholesteryl ester and triglyceride. Mature HDLs con- regenerates lipid-poor apoA-I and cholesterol-depleted HDL,
sist of two major subclasses, large cholesteryl ester-rich HDL2 both of which may re-enter the HDL/apoA-I cycle.
and small cholesteryl ester-poor, protein-rich HDL3 particles; the
latter represent the intravascular precursors of HDL2. The reverse From this description it is evident that HDL-C plays a major
cholesterol transport system involves two key pathways: (1) the role in maintaining cholesterol homeostasis in the body. As a
420 direct pathway (blue lines in Fig. 24.2), in which the cholesteryl
DYSLIPIDAEMIA 24
Peripheral cells + macrophages
FC+PL FC FC
ABCA1 ABCG1 SR–B1
Liver Intestine
apoA–I FC+PL
apoA–I ABCA1
FC+PL
FC
FC
HL
Lipid-poor Pre β HDL LCAT
apoA–I PL LCAT
CE/TG
FC+PL ABCA1 FC PL CE/TG HDL2 CE/TG
HDL3 HDL2
LCAT
Cholesterol–depleted HDL CE
Bile SR–B1 FC+CE CETP
bile HDL–R
LDL–R CE+FC TG apoB–
FC+ acids lipoproteins
(VLDL,IDL,
Excretion LDL)
ABDA1 = ATP binding cassette transporter A1; ABDG1 = ATP binding casssette transporter G1; CE = cholesterol ester; CETP = cholesteryl
ester transfer protein; FC = free cholesterol; HDL–R = holo HDL receptor; HL = hepatic lipase; LCAT = lecithin cholesterol acyltransferase;
LPL = lipoprotein lipase; PL = phospholipids; SR–B1 = hepatic scavenger receptor B1; TG = triglycerides
Fig. 24.2 Pathways of reverse cholesterol transport in human. (Chapman et al., 2010, with kind per-
mission from Oxford University Press, Oxford.)
consequence it is considered desirable to maintain both levels mellitus. Many individuals have a mixed dyslipidaemia that
of the protective HDL-C and the integrity of the reverse cho- includes elevated levels of triglycerides and LDL-C, but a reduc-
lesterol transport pathway. Low levels of HDL-C are found tion of LDL-C normally remains the primary focus of treatment.
in 17% of men and 5% of women, and may be a risk factor A recent analysis, in more than 73,000 individuals, of a genetic
for atherogenesis that is comparable in importance to elevated variant that regulates triglyceride concentrations has demon-
levels of LDL-C. Drugs that reduce HDL-C levels are con- strated a causal association between triglycerides and coronary
sidered to have an undesirable effect on lipid metabolism and heart disease (CHD) (Triglyceride Coronary Disease Genetics
increase the risk of development of CVD. Examples of drugs Consortium and Emerging Risk Factors Collaboration, 2010).
that can lower HDL-C include some progestins, anabolic ste-
roids, danazol, β-blockers and irst-generation antipsychotics Aetiology 421
(Herink and Ito, 2015).
Primary dyslipidaemia
Triglycerides
Up to 60% of the variability in cholesterol fasting lipids may be
The role of hypertriglyceridaemia as an independent risk factor genetically determined, although expression is often inluenced
for atherosclerotic CVD is unclear because triglyceride levels are by interaction with environmental factors. The common familial
confounded by an association with low HDL-C, hypertension, (genetic) disorders can be classiied as:
diabetes and obesity, and a synergistic effect with LDL-C and/ • the primary hypercholesterolaemias such as familial hyper-
or low HDL-C. An isolated elevation of triglyceride may be the
consequence of a primary disorder of lipid metabolism; it may cholesterolaemias (FHs) in which LDL-C is raised;
be secondary to the use of medicines such as oestrogens, prote- • the primary mixed (combined) hyperlipidaemias in which
ase inhibitors, retinoids, corticosteroids, some immunosuppres-
sants and some antipsychotics (Herink and Ito, 2015); or it may both LDL-C and triglycerides are raised; or
be a component of the metabolic syndrome or type 2 diabetes • the primary hypertriglyceridaemias such as type III hyperlipo-
proteinaemia, familial lipoprotein lipase deiciency and famil-
ial apoC-II deiciency.
24 THERAPEUTICS
Box 24.1 Simon Broome criteria indicating familial In contrast with the heterozygous form, homozygous FH is rare
hypercholesterolaemia (NICE, 2008a) (1–2 per 1 million individuals) and is associated with an absence
of LDL receptors and almost absolute inability to clear LDL-C. In
Definite FH is defined as: these individuals, involvement of the aorta is evident by puberty
1. TC >6.7 mmol/L or LDL cholesterol >4.0 mmol/L in a child and usually accompanied by cutaneous and tendon xanthomas.
Myocardial infarction (MI) has been reported in homozygous
<16 years old, or TC >7.5 mmol/L or LDL cholesterol >4.9 children younger than 5 years (Dumić et al., 2007; Gautschi et al.,
mmol/L in an adult (levels are either pretreatment or highest 2012; Widhalm et al., 2011). Up to the 1980s, sudden death from
on treatment.) acute coronary insuficiency before the age of 20 years was normal.
PLUS
2. Tendon xanthomas in patient, or in first-degree relative (par- Familial combined hyperlipidaemia
ent, sibling, child), or in second-degree relative (grandparent,
uncle, aunt) Familial combined hyperlipidaemia has a prevalence of 1 in
OR 50–200 and is associated with excessive synthesis of VLDL-C
3. DNA-based evidence of an LDL receptor mutation or familial (Gaddi et al., 2007). In addition to increases in triglyceride and
defective apoB-100 LDL-C levels, patients also typically have raised levels of apoB
and elevated levels of small, dense LDL particles. It is associated
Possible FH is defined as: with an increased risk of atherosclerosis and occurs in approxi-
Above criteria PLUS one of the following: mately 10% of patients who present with CHD before the age of
• Family history of myocardial infarction: <50 years of age in 60 years (Gaddi et al., 2007).
second-degree relative or <60 years in first-degree relative Familial type III hyperlipoproteinaemia
• Family history of raised cholesterol: >7.5 mmol/L in adult first-
Familial type III hyperlipoproteinaemia has an incidence of 1 in
or second-degree relative or >6.7 mmol/L in child or sibling 5000–10,000 (National Organization of Rare Disorder, 2005). It
<16 years of age is characterised by the accumulation of chylomicron and VLDL
remnants that fail to get cleared at a normal rate by hepatic recep-
DNA, Deoxyribonucleic acid; LDL-C, low-density lipoprotein cholesterol; tors because of the presence of less active polymorphic forms of
TC, total cholesterol. apoE. Triglycerides and TC are both elevated and accompanied
by corneal arcus, xanthelasma, tuberoeruptive xanthomas (groups
Familial hypercholesterolaemia of lat or yellowish raised nodules on the skin over joints, espe-
cially the elbows and knees), and palmar striae (yellow raised
Heterozygous FH is an inherited metabolic disease, which NICE streaks across the palms of the hand). The disorder predisposes to
estimates to affect approximately 1 in 500 of the population (110,000 premature atherosclerosis.
individuals in England and Wales) (NICE, 2008a). However, more
recent data suggest a higher prevalence, with a Danish study of Familial lipoprotein lipase deficiency
more than 69,000 people detecting a prevalence of 1 in 137 (Benn
et al., 2012). FH is caused by a range of mutations, which vary Familial lipoprotein lipase deiciency is characterised by marked
from family to family, in genes for the pathway that clear LDL-C hypertriglyceridaemia and chylomicronaemia, and usually pres-
from the blood. The most common mutation affects the LDL recep- ents in childhood. It has an incidence of 1 per 1 million individuals
tor gene. Given the key role of LDL receptors in the catabolism of (Gotoda et al., 1991) and is due to a deiciency of the extrahepatic
LDL-C, patients with FH may have serum levels of LDL-C two enzyme lipoprotein lipase, which results in a failure of lipolysis and
to three times higher than the general population. It is important the accumulation of chylomicrons in plasma. The affected patient
to identify these individuals from birth and initiate treatment early presents with recurrent episodes of abdominal pain, eruptive xan-
in life; otherwise, they will be exposed to high concentrations of thomas, lipaemia retinalis (retinal deposition of lipid) and enlarged
LDL-C and will suffer the consequences. FH is transmitted as a spleen. This disorder is not associated with an increased susceptibil-
dominant gene, with siblings and children of a parent with FH hav- ity to atherosclerosis; the major complication is acute pancreatitis.
ing a 50% risk of inheriting it. It is important to suspect FH in
people who present with TC greater than 7.5 mmol/L, particularly Familial apolipoprotein C-II deficiency
where there is evidence of premature CV disease within the fam-
ily (NICE, 2014). The clinical criteria that indicate FH are listed In the heterozygous state, familial apoC-II deiciency is associ-
in Box 24.1. Guidance on diagnosis, identifying affected relatives, ated with reduced levels of apoC-II, the activator of lipoprotein
and management are available, but it is important to seek specialist lipase. Typically, levels of apoC-II are 50–80% of normal. This
advice for this group of high-risk patients (NICE, 2008a). level of activity can maintain normal lipid levels. In the rare
homozygous state, there is an absence of apolipoprotein C-II and
In patients with heterozygous FH, CVD presents about 20 despite normal levels of lipoprotein lipase, it cannot be activated.
years earlier than in the general population, with some individu- Consequently, homozygotes have triglyceride levels from 15 to
als, particularly men, dying of atherosclerotic heart disease often greater than 100 mmol/L (normal range <1.7 mmol/L) and may
before the age of 40 years. The adult heterozygote typically
exhibits the signs of cholesterol deposition such as corneal arcus
(crescentic deposition of lipids in the cornea), tendon xanthoma
(yellow papules or nodules of lipids deposited in tendons) and
xanthelasma (yellow plaques or nodules of lipids deposited on
422 eyelids) in their third decade.
DYSLIPIDAEMIA 24
Box 24.2 Examples of disorders known to adversely affect the Table 24.2 Typical effects of selected drugs on lipoprotein
lipid profile levels
• Anorexia nervosa Drug VLDL-C LDL-C HDL-C
• Bulimia Alcohol ↑ 0 ↑
• Type 1 diabetes
• Type 2 diabetes Androgens, testosterone ↑ ↑↓
• Hypothyroidism
• Pregnancy Angiotensin-converting 0 00
• Inappropriate diet enzyme inhibitors
• Alcohol abuse
• Chronic renal failure β-Blockers ↑ 0↓
• Nephrotic syndrome
• Renal transplantation Calcium channel blockers 0 00
• Cardiac transplantation
• Hepatocellular disease Ciclosporin ↑ ↑↑
• Cholestasis
• Myeloma Oestrogens, oestradiol ↑ ↓↓
experience development of acute pancreatitis. Premature athero- Glucocorticoids ↑ 0↑
sclerosis is unusual but has been described.
Isotretinoin ↑ 0↓
Lipoprotein(a)
Progestins ↓ ↑↓
There are many other familial disorders of lipid metabolism in
addition to those mentioned earlier, but most are rare. However, a Protease inhibitors ↑ 00
raised level of lipoprotein(a), otherwise known as Lp(a), appears
to be a genetically inherited determinant of CVD. Lp(a) is an Sertraline ↑ ↑0
LDL-like particle synthesised by the liver and irst described more
than 40 years ago. It is found in the serum of virtually everyone Tacrolimus ↑ ↑↑
in a wide concentration range (0.01–2 g/L), with up to 70% of the
variation in concentration being genetically determined. The con- Thiazide diuretics ↑ ↑↓
centration of Lp(a) is not normally distributed, and the contribu-
tion of inheritance to circulating Lp(a) levels is more pronounced Valproate ↑ 0↓
than for any other lipoprotein or apoprotein. A parental history
of early-onset CVD is associated with raised concentrations of Effect seen may vary depending on dose, duration of exposure, and drugs
Lp(a), and these appear to play a role in both atherogenesis and within same class.
thrombosis. An important component of Lp(a) is apo(a), which ↓, Reduction; ↑, increase; 0, no change; HDL-C, high-density lipoproteins
is structurally and functionally similar to plasminogen and may cholesterol; LDL-C, low-density lipoproteins cholesterol; VLDL-C, very low-
competitively bind to ibrin and impair ibrinolysis. density lipoproteins cholesterol.
Concentrations of Lp(a) greater than 0.3 g/L occur in about one does not resolve the other. There are, however, two notable
20% of Caucasians (von Depka et al., 2000) and increase the risk exceptions to the rule with this example: nicotinic acid and feno-
of coronary atherosclerosis and stroke. Under a wide range of ibrate. Both drugs reduce triglyceride levels, but nicotinic acid
circumstances, there are continuous, independent, and modest increases urate levels, whereas fenoibrate reduces them by an
associations of Lp(a) concentration with the risk of CHD and independent uricosuric effect.
stroke (Erqou et al., 2009).
Some of the more common disorders that cause secondary dys-
Secondary dyslipidaemia
lipidaemias include the following.
Dyslipidaemias that occur secondary to a number of disorders
(Box 24.2), dietary indiscretion, or as a side effect of drug ther- Diabetes mellitus
apy (Table 24.2) account for up to 40% of all dyslipidaemias.
Fortunately, the lipid abnormalities in secondary dyslipidaemia Premature atherosclerotic disease is the main cause of reduced 423
can often be corrected if the underlying disorder is treated, effec- life expectancy in patients with diabetes. The atherosclerotic dis-
tive dietary advice implemented, or the offending drug withdrawn. ease is often widespread, and complications such as plaque rup-
ture and thrombotic occlusion occur more often and at a younger
On occasion, a disorder may be associated with dyslipidaemia, age. The prevalence of CHD is up to four times higher among
but not the cause of it. For example, hyperuricaemia (gout) and patients with diabetes, with more than 80% likely to die of a CV
hypertriglyceridaemia co-exist (Emmerson, 1998). In this par- event (Haffner et al., 1998; Malmberg et al., 2000). LDL levels
ticular example, neither is the cause of the other, and treatment of are a stronger predictor of CV risk in patients with diabetes than
blood glucose control or blood pressure.
Type 1 diabetes. In patients with type 1 diabetes, HDL-C may
appear high, but for reasons which are unclear it does not impart
24 THERAPEUTICS
the same degree of protection against CVD as in those without Obesity
diabetes. It is, therefore, not appropriate to use CV risk predic-
tion charts that utilise the TC:HDL-C ratio in patients with type 1 Chronic, excessive intake of calories leads to increased concen-
diabetes. Patients with type 1 diabetes have a twofold to threefold trations of triglycerides and reduced HDL-C. Obesity per se can
increased risk of development of CVD. NICE (2014) recom- exacerbate any underlying primary dyslipidaemia. Individuals
mends that people with type 1 diabetes should be considered for with central obesity appear to be at particular risk of what has
treatment with a statin if they are more than 40 years old or have become known as the metabolic or DROP (dyslipidaemia, insu-
had type 1 diabetes for more than 10 years, or have evidence of lin resistance, obesity and high blood pressure) syndrome which
kidney disease or other CVD risk factors. represents a cluster of risk factors. Obesity and sedentary life-
style coupled with inappropriate diet and genetic factors interact
Type 2 diabetes. Patients with type 2 diabetes typically have to produce the syndrome (Kolovou et al., 2005).
increased triglycerides and decreased HDL-C. Levels of TC may
be similar to those found in individuals without diabetes, but the Alcohol
patient with type 2 diabetes often has increased levels of highly
atherogenic small, dense LDL particles. In the heavy drinker, the high-calorie content of beer and wine
may be a cause of obesity with its associated adverse effect on the
Individuals with type 2 diabetes and older than 40 years, but lipid proile. In addition, alcohol increases hepatic triglyceride
without CVD, are often considered to have the same CV risk as synthesis, which in turn produces hypertriglyceridaemia.
patients without diabetes who have survived an MI. This assump-
tion is generally appropriate but inluenced by patient age, dura- Light-to-moderate drinkers (1–3 units/day) have a lower inci-
tion of diabetes and gender, and it holds better for women than dence of CVD and associated mortality than those who do not
men. This probably occurs because the impact of type 2 diabetes drink. This protective effect is probably due to an increase in
is more marked in women than men. In previous NICE (2008b) HDL-C and appears independent of the type of alcohol. Men and
guidance, the criteria for at risk was age older than 40 years but women should be advised to limit their alcohol intake to 2–3 units/
with one other risk factor present, for example, hypertension, day with a maximum intake of 14 units/week. Everyone should be
obesity, smoker, etc. NICE (2014) now recommends CV risk advised not to binge drink and aim to have two or more alcohol-
assessment using QRisk2 for individuals with type 2 diabetes to free days a week (Department of Health, 2016).
assess whether a statin should be considered.
Hypothyroidism Drugs
Abnormalities of serum lipid and lipoprotein levels are common A number of drugs can adversely affect serum lipid and lipopro-
in patients with untreated hypothyroidism. Hypothyroidism may tein concentrations (see Table 24.2).
elevate LDL-C because of reduced LDL receptor activity, and it
frequently causes hypertriglyceridaemia and an associated reduc- Antihypertensive agents. Hypertension is a major risk fac-
tion in HDL-C as a result of reduced lipoprotein lipase activity. tor for atherosclerosis, and the beneicial effects of lowering
Remnants of chylomicrons and VLDL-C may also accumulate. blood pressure are well recognised. It is, however, a concern that,
However, once adequate thyroid replacement has been initiated although treatment of patients with some antihypertensives has
the dyslipidaemia should resolve. reduced the incidence of cerebrovascular accidents and renal fail-
ure, there has been no major impact in reducing the incidence of
Chronic renal failure CHD. It has been suggested that some of these antihypertensive
agents have an adverse effect on lipids and lipoproteins that over-
Dyslipidaemia is frequently seen in patients with renal failure in ride any beneicial reduction of blood pressure.
the predialysis phase, during haemodialysis, or when undergoing
chronic ambulatory peritoneal dialysis. The hypertriglyceridae- Diuretics. Thiazide and loop diuretics increase VLDL-C
mia that most commonly occurs is associated with reduced lipo- and LDL-C by mechanisms that are not completely under-
protein lipase activity and often persists despite starting chronic stood. Whether these adverse effects are dose dependent is also
maintenance renal dialysis. NICE (2014) recommends that peo- unclear. Use of a thiazide for less than 1 year has been reported
ple with chronic kidney disease and an estimate of glomerular to increase TC by up to 7% with no change in HDL-C (Ames,
iltration rate less than 60 mL/min/1.73 m2 and/or albuminuria 1988). However, short-term changes in lipids do not occur with
should be considered for a statin. the low doses in current use and in the longer-term there is little
effect on TC levels.
Nephrotic syndrome
β-Blockers. The effects of β-blockers on lipoprotein metabo-
In patients with the nephrotic syndrome, dyslipidaemia appears lism are relected in an increase in serum triglyceride concentra-
to be caused by an increased production of apoB-100 and associ- tions, a decrease in HDL-C, but with no discernible effect on
ated VLDL-C along with increased hepatic synthesis of LDL-C LDL-C (Herink and Ito, 2015). β-Blockers with intrinsic sympa-
and a reduction in HDL-C. The necessary use of glucocorticoids thomimetic activity appear to have little or no effect on VLDL-C
in patients with the nephrotic syndrome may exacerbate underly- or HDL-C. Pindolol has intrinsic sympathomimetic activity but
424 ing lipoprotein abnormality. is rarely used as an antihypertensive agent because it may exac-
erbate angina. Alternatively, the combined α- and β-blocking
effect of labetalol may be of use because it would appear to have
a negligible effect on the lipid proile.
DYSLIPIDAEMIA 24
Overall, the need to use a diuretic or a β-blocker must be Hepatic microsomal enzyme inducers. Drugs such as car-
balanced against patient considerations. A patient in heart fail- bamazepine, phenytoin, phenobarbital, rifampicin and griseo-
ure should receive a diuretic if indicated regardless of the lipid fulvin increase hepatic microsomal enzyme activity and can also
proile. Likewise, the patient with heart failure may also beneit increase serum HDL-C. The administration of these drugs may
from a β-blocker such as bisoprolol or carvedilol. Patients who also give rise to a slight increase in LDL-C and VLDL-C. The
have had an MI should be considered for the protective effect of overall effect is one of a favourable increase in the TC:HDL-C
a β-blocker, and again the beneits of use will normally override ratio.
any adverse effects on the lipid proile.
Cardiovascular risk assessment
If an antihypertensive agent without adverse effects on lipo-
proteins is required, angiotensin-converting enzyme (ACE) Primary prevention
inhibitors, angiotensin II receptor antagonists, calcium channel
blockers, or α-adrenoceptor blockers can be used. It is recommended that CV risk assessment is carried out every
5 years for all adults from the age of 40 years, with no history of
Oral contraceptives. Oral contraceptives that contain an oes- CVD or diabetes, and not receiving treatment for raised blood
trogen and a progestogen provide the most effective contracep- pressure or dyslipidaemia. A number of CVD risk calculators
tive preparations for general use and have been well studied with are available, including QRisk (UK and recommended by NICE;
respect to their harmful effects. https://www.qrisk.org/), SCORE (Europe; https://www.escardio.
org/Education/Practice-Tools/CVD-prevention-toolbox/SCORE-
Oestrogens and progestogens both possess mineralocorti- Risk-Charts#), Joint British Socities-3 (JBS-3; http://www.
coid and glucocorticoid properties that predispose to hyperten- jbs3risk.com) and ASSIGN (Scotland; http://assign-score.com).
sion and diabetes mellitus, respectively. However, the effects
of the two hormones on lipoproteins are different. Oestrogens QRisk2
cause a slight increase in hepatic production of VLDL-C and
HDL-C, and reduce serum LDL-C levels. In contrast, progesto- QRisk2 is based on a database, established in 2003, of anonymised 425
gens increase LDL-C and reduce serum HDL-C and VLDL-C
(Herink and Ito, 2015). UK primary care patients. It contains more than 20 million sets
of encrypted patient records. A cohort of 1.28 million patients
The speciic effect of the oestrogen or progestogen varies without evidence of diabetes mellitus or CVD was identiied and
with the actual dose and chemical entity used. Ethinyloestradiol followed up for more than 5 years looking for the irst develop-
at a dose of 30–35 micrograms or fewer would appear to cre- ment of CVD as an endpoint (Hippisley-Cox et al., 2007).
ate few problems with lipid metabolism (Herink and Ito,
2015), while norethisterone is one of the more favourable pro- The following parameters, with any missing values calcu-
gestogens even though it may cause a pronounced decrease in lated by a complex averaging procedure, are used to calculate a
HDL-C. patient’s CV risk:
• patient age (35–84 years)
Corticosteroids. The effect of glucocorticoid administra- • patient sex
tion on lipid levels has been studied in patients treated with • smoking status
steroids for asthma, rheumatoid arthritis and connective tis-
sue disorders. Administration of a glucocorticoid such as • family history of heart disease aged less than 60 years
prednisolone has been shown to increase TC and triglycerides • existing treatment with blood pressure agent
by elevating LDL-C and, less consistently, VLDL-C (Herink • postcode (postcode is linked to Townsend score measure of
and Ito, 2015). The changes are generally more pronounced in
women. Alternate-day therapy with glucocorticoids has been deprivation)
suggested to reduce the adverse effect on lipoprotein levels in • body mass index (BMI) (height and weight)
some patients. • systolic blood pressure (use current, not pretreatment, value)
Ciclosporin. Ciclosporin is primarily used to prevent tis- • TC and HDL-C
sue rejection in recipients of renal, hepatic and cardiac trans-
plants. Its use has been associated with increased LDL-C • self-assigned ethnicity (not nationality)
levels, hypertension and glucose intolerance (Herink and Ito,
2015). These adverse effects are often exacerbated by the con- • rheumatoid arthritis
current administration of glucocorticoids. The combined use
of ciclosporin and glucocorticoid contributes to the adverse • chronic kidney disease
lipid proile seen in transplant patients. Unfortunately, the • atrial ibrillation
administration of a statin to patients treated with ciclosporin The QRisk2 risk assessment tool should be used to assess CVD
increases the incidence of myositis, rhabdomyolysis (dissolu-
tion of muscle associated with excretion of myoglobin in the risk of the primary prevention of CVD in people up to and
urine) and renal failure. Use of a statin is, therefore, contra- including age 84 years. It calculates the risk of an individual hav-
indicated in patients who are receiving ciclosporin. Similar ing a heart attack or stroke in the next 10 years. Patients with a
interactions between statins and other drugs used to prevent CV risk ≥10% over 10 years are considered to be at suficient
tissue rejection, including tacrolimus and sirolimus, have been risk to warrant lipid-lowering therapy according to current NICE
reported, and hence concomitant use is not recommended
(Wiggins et al., 2016). (2014) guidelines, although recommendations as to when to
intervene with medication vary internationally. It should be noted
that although NICE (2014) recommends using the tool for people
with type 2 diabetes, it does not recommend using it for patients
with type 1 diabetes.
24 THERAPEUTICS
Other risk assessment tools Box 24.3 Lifestyle targets
Framingham. Up to 2008, risk charts and calculators based • Do not smoke.
on Framingham data were the most widely used and researched • Maintain ideal body weight (BMI 20–25 kg/m2).
approach for calculating CV risk and are the data on which the • Avoid central obesity.
risk charts discussed earlier are based. • Reduce total dietary intake of fat to ≤30% of total energy intake.
• Reduce intake of saturated fats to ≤7% of total fat intake.
ASSIGN. ASSIGN is a risk calculator based on data from a • Reduce intake of dietary cholesterol to <300 mg/day.
Scottish population and includes many of the variables utilised • Replace saturated fats by an increased intake of monounsatu-
in the Framingham-based model. It also takes into account social
status, determined by postcode of residence in Scotland, and fam- rated fats.
ily history of CVD (Woodward et al., 2007). • Increase intake of fresh fruit and vegetables to at least five
SCORE. The European SCORE risk charts were developed portions per day.
from a large dataset tested thoroughly on European data. It oper- • Regularly eat fish and other sources of omega-3 fatty acids (at
ates with hard, reproducible endpoints (CVD death), and risk of
CHD and stroke death can be derived separately. The SCORE risk least two portions of fish each week).
function can be calibrated to each country’s national mortality sta- • Choose whole-grain varieties of starchy food.
tistics. The SCORE database was developed through combining • Reduce intake of sugar and food products that contain refined
results from 12 European cohort studies with 250,000 patients’
data equating to 3 million person-years of observation and 7000 sugars including fructose.
fatal CV events recorded (European Society of Cardiology, 2017). • Eat at least four to five portions of unsalted nuts, seeds and
Secondary prevention legumes per week.
• Limit alcohol intake to <14 units/week (men and women).
Patients with CVD and levels of TC greater than 4 mmol/L and • Restrict intake of salt to <100 mmol/day (<6 g of sodium
LDL-C greater than 2 mmol/L are those most likely to beneit
from treatment with lipid-lowering agents. Typical of individuals chloride or <2.4 g sodium/day).
who fall into this category are patients with a history of angina, • Undertake regular aerobic exercise, aiming for 150 min of
MI, acute coronary syndrome (ACS), coronary artery bypass
grafting, coronary angioplasty, or cardiac transplantation, as well moderate-intensity aerobic activity or 75 min of vigorous-
as patients with evidence of atherosclerotic disease in other vas- intensity aerobic activity per week.
cular beds, such as patients post-stroke or transient ischaemic • Avoid excess intake of coffee or other caffeine-rich products.
attack, and those with peripheral arterial disease.
an MI. In the case of the latter, samples drawn within 24 hours of
As in the situation with primary prevention outlined earlier, infarct onset will relect the preinfarction state. In general, mea-
if an individual is to receive a lipid-lowering agent as part of a surement should be deferred for 2 weeks after a minor illness and
secondary prevention strategy, the possibility of a familial dys- for 3 months after an MI, serious illness or pregnancy.
lipidaemia and the need to assess other family members must not
be overlooked (NICE, 2008b, 2014). Once the TC and HDL-C are known, non-HDL-C can be cal-
culated as follows:
Treatment
Non-HDL-C = TC – HDL-C
Lipid profile
If the TC, HDL-C and triglyceride values are known, then the
When a decision has been made to determine an individual’s lipid value for LDL-C can be calculated using the Friedewald equation:
proile, a random serum TC and HDL-C, from which non-HDL-C
levels can be calculated, will often sufice. If a subsequent deci- LDL-C = (total cholesterol − HDL-C)
sion is made to commence treatment and monitor outcome, a − (0.45 × triglyceride) mmol/L
more detailed proile may be obtained, although it may not be
essential if non-HDL-C is used for monitoring. Treatment should The Friedewald equation should not be used in non-fasting
not be initiated on the basis of a single random sample. individuals, it is less reliable in individuals with diabetes, and it
is not valid if the serum triglyceride concentration is greater than
Serum concentrations of triglycerides increase after the inges- 4.5 mmol/L.
tion of a meal and, therefore, if a full lipid proile is to be obtained,
patients must fast for 12–15 hours before they can be measured. Lifestyle
Patients must also be seated for at least 5 minutes before drawing a
blood sample. TC level and HDL are little affected by food intake, When a decision is made to start treatment with a lipid-lower-
and this is, therefore, not a consideration if only these are to be ing agent, other risk factors must also be tackled as appropriate,
measured. However, it is important that whatever is being mea- such as smoking, obesity, high alcohol intake and lack of exer-
sured relects a steady-state value. For example, during periods cise (Box 24.3). Underlying disorders such as diabetes mellitus
426 of weight loss, lipid concentrations decline as they do following and hypertension should be treated as appropriate. Issues around
body weight, diet and exercise will be briely covered in the fol-
lowing sections.
Body weight and waist measurement
The overweight patient is at increased risk of atherosclerotic
disease and typically has elevated levels of serum triglycerides,
DYSLIPIDAEMIA 24
raised LDL-C and a low HDL-C. This adverse lipid proile is at baseline in 1980. During the 16-year follow-up, a signii- 427
often compounded by the presence of hypertension and raised cant inverse association between ish intake and incidence of
blood glucose, that is, the metabolic syndrome. A reduction in CHD was observed. The Lyon Heart Study (de Lorgeril et al.,
body weight will generally improve the lipid proile and reduce 1999) was an intervention trial involving 605 survivors of
overall CV risk. irst MI, of whom 303 were randomised to be control patients
and 302 were advised to adopt a Mediterranean-style diet,
It is useful to classify the extent to which an individual is over- including use of margarine with higher levels of linoleic acid
weight by calculating their BMI. The BMI (kg/m2) in all but the and α-linoleic acid (ALA) than olive oil. In the experimental
most muscular individual gives a clinical measure of adiposity. group the relative risk of MI-caused death was 0.44 and that of
• BMI 18.5: underweight cardiac death and nonfatal MI was 0.28, whereas other clinical
• BMI 18.6–24.9: ideal events such as unstable angina, heart failure and stroke were
• BMI 25–29.9: overweight also less frequently observed.
• BMI 30–40: obese
• BMI >40: morbidly obese Consumption of omega-3 fatty acids decreases triglyceride
levels but has little effect on LDL-C or HDL-C. The proposed
The distribution of body fat is also recognised as a factor that mechanisms are thought to involve the omega-3 fatty acids and
inluences CVD risk. Measurement of waist circumference is their antiarrhythmic properties, ability to reduce blood pressure
perhaps the most accurate indicator of central obesity and cor- and heart rate, lower triglyceride levels, stimulate endothelial-
relates well with CVD risk. Target waist circumference should derived nitric oxide, increase insulin sensitivity, decrease platelet
be less than 102 cm in white Caucasian men, less than 88 cm in aggregation and decrease proinlammatory eicosanoids. There
white Caucasian women, less than 90 cm in Asian men and less would appear to be beneits in consuming at least two portions
than 80 cm in Asian women (World Health Organization, 2011). (portion = 140 g) of ish per week, including a portion of oily ish,
particularly in those who have had an MI. Pregnant women are
Diet advised to limit their intake of oily ish to two portions per week
because of the potential accumulation of low-level pollutants in
Diet modiication should always be encouraged in a patient with the ish.
dyslipidaemia, but it is rarely successful alone in bringing about
a signiicant improvement in the lipid proile. Reduction or modi- Trans fats. Trans fats are unsaturated fatty acids with at least
ication of dietary fat intake has shown variable results on CV one double bond in the trans coniguration. They are formed
morbidity and mortality. Systematic review of dietary interven- when vegetable oils are hydrogenated to convert them into semi-
tions to lower cholesterol in community settings indicates that solid fats that can be incorporated into margarines or used in
mean reductions in TC of up to 6% can be achieved, although commercial manufacturing processes. Trans fats are typically
there is a wide variation in response to diet between individuals found in deep-fried fast foods, bakery products, packaged snack
(Tang et al., 1998). The overall picture is that patients with dys- foods, margarines and crackers. When the caloriic equivalent of
lipidaemia should receive dietary advice, and a small number of saturated fats, cis unsaturated fats and trans fats are consumed,
those who adhere to the advice will experience a decline in TC. trans fats raise LDL-C, reduce HDL-C and increase the ratio
of TC:HDL-C. In addition to these harmful effects, trans fats
There is a common misconception that a healthy diet is one also increase the blood levels of triglycerides, increase levels of
that is low in cholesterol. However, generally it is the saturated Lp(a) and reduce the particle size of LDL-C, all of which further
fat content that is important, although many components of a increase the risk of CHD. It is, therefore, necessary to reduce the
healthy diet are not related to fat content. For example, the low dietary intake of trans fatty acids to less than 0.5% of total energy
incidence of CVD in those who consume a Mediterranean-type intake, and this has led to calls for a complete ban on trans fats
diet suggests an increased intake of fruit and vegetables is also in foods.
important. The typical Mediterranean diet has an abundance of
plant food (fruit, vegetables, breads, cereals, potatoes, beans, nuts Stanol esters and plant sterols. The availability of marga-
and seeds), minimally processed, seasonally fresh and locally rines and other foods enriched with plant sterols or stanol esters
grown; fresh fruit as the typical daily dessert, with sweets con- appears to increase the likelihood that LDL-C can be reduced by
taining concentrated sugars or honey consumed a few times per dietary change. Both stanol esters and plant sterols at a maxi-
week; olive oil as the principal source of fat; dairy products (prin- mum effective dose of 2 g/day inhibit cholesterol absorption
cipally cheese and yoghurt) consumed daily in low-to-moderate from the gastro-intestinal tract and reduce LDL-C by an aver-
amounts; 0–4 eggs consumed weekly; and red meat consumed in age of 10%. They compete with cholesterol for incorporation
low-to-moderate amounts. This diet is low in saturated fat (<8% into mixed micelles, thereby impairing its absorption from the
of energy) and varies in total fat content from less than 25% to intestine. However, as with other dietary changes, the reduction
greater than 35% of energy. seen varies between individuals and is probably dependent on
the initial cholesterol level and the total amount of stenol esters
Fish. Regular consumption of the long-chain omega-3 and/or plant sterols ingested. There is currently no evidence that
fatty acids, principally eicosapentaenoic acid and docosa- ingestion lowers the risk of CV events, and as a result they are
hexaenoic acid, typically found in fatty ish and ish oils, has not recommended by NICE (2014).
been linked to the low levels of CHD seen in Inuits (Eskimos).
Hu et al. (2002) studied a group of 84,688 women enrolled Antioxidants. Antioxidants occur naturally in fruit and vege-
in the Nurses’ Health Study, all of whom were registered tables and are important components of a healthy diet. Their con-
nurses aged 30–55 years and were free from CVD and cancer sumption is thought to be beneicial in reducing the formation of
24 THERAPEUTICS
atherogenic, oxidised LDL-C. Primary and secondary prevention Primary prevention
trials with antioxidant vitamin supplements, however, have not
been encouraging. Neither vitamin E nor β-carotene supplements In primary prevention, dyslipidaemia should not be treated in
would appear to reduce the risk of CHD but likewise have not isolation, and management must be embarked upon with clear
been shown to be harmful. goals. In addition to lifestyle advice, this will not only address
management of dyslipidaemia, but will also seek to optimise use
Salt. Dietary salt (sodium) has an adverse effect on blood of antihypertensive agents and other CV protective therapies, and
pressure and, therefore, a potential impact on CHD and stroke. It achieve tight blood glucose control as appropriate. In patients
is recommended that the average adult intake of sodium should without evidence of arterial disease, statin treatment must be
be reduced from approximately 150 mmol (9 g) to 100 mmol considered if the risk of CVD is ≥10% over 10 years (NICE,
(6 g) of salt or even lower. This intake can be reduced by con- 2014). Although some dispute the beneit of statins in primary
suming fewer processed foods, avoiding many ready meals and prevention (Kausik et al., 2010), treatment will normally include:
not adding salt to food during cooking and at the table. • a lipid-lowering agent such as atorvastatin 20 mg/day (or
Exercise alternative) with an aim of a 40% decline in non-HDL-C from
baseline to indicate adherence to treatment (NICE, 2014);
Moderate amounts of aerobic exercise (brisk walking, jogging, • personalised information on modiiable risk factors including
swimming, cycling) on a regular basis have a desirable effect on physical activity, diet, alcohol intake, weight and tight control
the lipid proile of an individual. These beneicial effects have of diabetes;
been demonstrated within 2 months in middle-aged men exer- • advice to stop smoking; and
cising for 30 minutes, three times a week. Current advice from • advice (and treatment if appropriate) to achieve blood pres-
NICE (2014) is to advise people at high risk of or with CVD to sure below 140 mmHg systolic and 90 mmHg diastolic.
do the following every week: Some consider an isolated raised TC:HDL ratio greater than 6.5 war-
• at least 150 minutes of moderate-intensity aerobic activity, or rants treatment regardless of the risk assessment outcome, but this
• 75 minutes of vigorous-intensity aerobic activity or a mix of approach has received little support in national treatment guidelines.
For primary prevention in patients with type 1 diabetes who are
moderate and vigorous aerobic activity. more than 40 years old or have had type 1 diabetes for more than
People are also advised to do muscle strengthening activities 10 years or have established nephropathy or other CVD risk fac-
on 2 or more days a week that work all major muscle groups tors, atorvastatin 20 mg daily should be offered and lifestyle mod-
(legs, hips, back, abdomen, chest, shoulders and arms). If people iications made (NICE, 2014). Patients with type 2 diabetes who
cannot perform moderate-intensity physical activity because of have a risk of CVD of ≥10% over 10 years should be offered
comorbidity, medical conditions or personal circumstances, then atorvastatin 20 mg daily for primary prevention (NICE, 2014).
they need to exercise at their maximum safe capacity.
Exercise per se probably has little effect on TC levels in the Secondary prevention
absence of a reduction in body weight, body fat or dietary fat.
Perhaps the most important effect of regular exercise is to raise In individuals diagnosed with CVD or other occlusive arterial
levels of HDL-C in a dose-dependent manner according to energy disease, treatment should include:
expenditure. • a lipid-lowering agent such as atorvastatin 80 mg/day (or
Overall, comprehensive dietary and lifestyle changes (stopping alternative) with an aim of a 40% decline in non-HDL-C from
smoking, stress management training and moderate exercise) can baseline to indicate adherence to treatment (NICE, 2014);
bring about regression of coronary atherosclerosis. Unfortunately, • advice to stop smoking;
many ind it dificult to attain or sustain the necessary changes. In • personalised information on modiiable risk factors including
others, dietary and lifestyle changes alone will never be adequate physical activity, diet, alcohol intake, weight and diabetes;
or will not bring about the necessary improvement in lipid pro- • advice and treatment to achieve blood pressure at least below
ile quickly enough. As a consequence, the use of lipid-lowering 140 mmHg systolic and 90 mmHg diastolic;
drugs is widespread. • tight control of blood pressure and glucose in those with
diabetes;
Drugs • low-dose aspirin (75 mg daily) or clopidogrel (75 mg daily);
• ACE inhibitors in selected groups, speciically those with left
If an individual is found to be at risk of CVD (primary pre- ventricular dysfunction, diabetes, chronic kidney disease or
vention), including people with type 2 diabetes, then all other nephropathy;
modiiable risk factors should be addressed, including dietary • β-blocker for those who have had an MI and in those with
and lifestyle changes, before statin therapy is offered. CV risk heart failure; and
assessment should then be repeated using QRisk2, and if the CV • anticoagulant therapy for those with atrial ibrillation and
risk remains high, drug therapy in the form of a statin should be additional stroke risk factors.
offered. In an individual who requires treatment for secondary
prevention, a delay of several months in starting treatment is not In patients with chronic kidney disease, atorvastatin 20 mg
appropriate and treatment will normally be commenced immedi- daily should be offered for primary or secondary prevention of
428 ately with a lipid-lowering agent. CVD (NICE, 2014).
DYSLIPIDAEMIA 24
Lipid-lowering therapy Table 24.3 Relative potency of statins
Five well-established classes of lipid-lowering agents are % Reduction in low-density lipoprotein cholesterol
available:
• statins Dosage 5 10 20 40 80
• cholesterol absorption inhibitors (mg/day) 33
• ibrates –– 21 27
• bile acid binding agents Fluvastatin
• nicotinic acid and derivatives
Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors Pravastatin – 20 24 29 –
have recently been introduced for use in selected indications.
Simvastatin – 27 32 37 42a
Agents such as soluble ibre and ish oils have also been used to
reduce lipid levels. The choice of lipid-lowering agent depends on Atorvastatin – 37 43 49 55
the underlying dyslipidaemia, the response required and patient
acceptability. The various groups of drugs available have differ- Rosuvastatin 38 43 48 53 –
ent mechanisms of action and variable eficacy depending on the
lipid proile of an individual. Statins are currently the drugs of aThe Medicines and Healthcare products Regulatory Agency advises that
choice in the majority of patients with dyslipidaemia due to the because there is an increased risk of myopathy associated with high-dosage
overwhelming evidence that treatment with these agents reduces 80 mg/day simvastatin, this dosage should be considered only in patients
CV events. with severe hypercholesterolaemia and high risk of cardiovascular complica-
tions who have not achieved their treatment goals on lower doses, when the
Statins benefits are expected to outweigh the potential risks.
Adapted from NICE (2014).
The discovery of a class of drugs, the statins, which selectively
inhibit 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG- reductions in LDL-C safely produce deinite further reductions 429
CoA reductase) was a signiicant advance in the treatment of dys- in the incidence of heart attack, of revascularisation and of
lipidaemia. Their primary site of action is the inhibition of HMG- ischaemic stroke, with each 1.0 mmol/L reduction reducing the
CoA reductase in the liver and the subsequent inhibition of the annual rate of these major vascular events by just more than a
formation of mevalonic acid, the rate-limiting step in the biosyn- ifth. There was no evidence of any threshold within the choles-
thesis of cholesterol. This results in a reduction in intracellular terol range studied suggesting that reduction of LDL-C by 2–3
levels of cholesterol, an increase in expression of hepatic LDL mmol/L would reduce risk by about 40–50%.
receptor, and enhanced receptor-mediated catabolism and clear-
ance of LDL-C from serum. Production of VLDL-C, the precur- There is much debate around the statin of choice. Atorvastatin
sor of LDL-C, is also reduced. The overall effect is a reduction is currently the preferred agent because of its low cost, safety pro-
in TC, LDL-C, VLDL-C and triglycerides with an increase in ile and evidence of eficacy. Of paramount importance is the need
HDL-C. The reduction in LDL-C occurs in a dose-dependent to identify patients who need treatment and ensure they receive
manner, with a lesser and dose-independent effect on VLDL-C an appropriate, effective dose of a statin and adhere to treat-
and triglycerides. ment. Despite overwhelming evidence of beneit, effectiveness
is frequently compromised by poor adherence and persistence.
Simvastatin was the irst member of the group to be marketed For example, Helin-Salmivaara et al. (2008) studied persistence
in the UK, and it was followed by pravastatin, luvastatin, atorv- with therapy in more than 18,000 new statin users and reported
astatin, cerivastatin and rosuvastatin. Cerivastatin was withdrawn 1-year persistence rate of 73% and 10-year persistence rate of
from the market in 2001 because of an observed increased risk 44%. Thirteen percent of patients stopped taking the statin after
of fatal rhabdomyolysis. Lovastatin is available in the USA and the irst prescription. Patient factors that inluence this include
pitavastatin is available in Japan since 2003. The relative poten- perception of risk, side effects of medication, expected treatment
cies of the statins available in the UK are shown in Table 24.3. duration and socio-demographic factors.
The eficacy of statins has been demonstrated in a number of Rosuvastatin is the most potent of the statins, with evidence
landmark randomised placebo-controlled trials and evaluated by of impact on morbidity and mortality (see Table 24.3) (Ridker
meta-analysis (Cholesterol Treatment Trialists, 2012). A greater et al., 2008). It is normally reserved for those individuals who
absolute beneit was seen in those trials that involved estab- have had an inadequate response to their irst-line statin or fail-
lished CVD, that is, secondary prevention studies, compared ure to tolerate other statins. There remains concern about its
with those that involved individuals without established CVD, safety proile, rhabdomyolysis in particular, when used at the
that is, primary prevention studies. Statins are currently the lipid- higher dosage of 40 mg/day. It is recommended that this dosage
lowering agents of choice in both primary and secondary pre- should be used only under specialist supervision in individuals
vention of CVD. Over time there has been a shift towards more with severe FH and at high CV risk. In patients of Asian origin
intensive lipid lowering, with the Cholesterol Treatment Trialist (Japanese, Chinese, Filipino, Vietnamese, Korean and Indian),
Collaboration (2010) undertaking a meta-analysis of 26 trials the maximum dose should not exceed 20 mg/day because of their
including more than 170,000 participants, concluding further increased predisposition to myopathy and rhabdomyolysis.
All the statins require the presence of LDL receptors for their
optimum clinical effect, and consequently they are less effec-
tive in patients with heterozygous FH because of the reduced
24 THERAPEUTICS
number of LDL receptors. However, even in the homozygous Table 24.4 Examples of drug interactions involving statins and
patient where there are no LDL receptors, they can bring about the cytochrome P450 enzyme pathway
some reduction of serum cholesterol, although the mechanism is
unclear. CYP 450 isoenzyme Inducers Inhibitors
Adverse effects CYP3A4 Phenytoin Ketoconazole
Atorvastatin Barbiturate Itraconazole
Many side effects appear mild and transient. The commonest Lovastatin Rifampicin Fluconazole
include gastro-intestinal symptoms, altered liver function tests Simvastatin Dexamethasone Erythromycin
and muscle aches. Less common are elevation of liver transami- Cyclophosphamide Clarithromycin
nase levels in excess of three times the upper limit of normal, Carbamazepine Tricyclic antidepressants
hepatitis, rash, headache, insomnia, nightmares, vivid dreams Omeprazole Nefazodone
and dificulty concentrating. Venlafaxine
Fluoxetine
Myopathy (unexplained muscle soreness or weakness) leading Sertraline
to myoglobulinuria secondary to rhabdomyolysis is also a rare Ciclosporin
but serious potential adverse effect of all the statins that can occur Tacrolimus
at any dose. The risk of myopathy is increased: Diltiazem
• when there are underlying muscle disorders, a family history Verapamil
Protease inhibitors
of muscle disorders, renal impairment, untreated hypothyroid- Midazolam
ism, alcohol abuse, or the recipient is aged over 65 years or Corticosteroids
female; Grapefruit juice
• where statins are co-prescribed with other lipid-lowering Tamoxifen
drugs, for example, ibrates or nicotinic acid; Amiodarone
• when there is a history of myopathy with another lipid-lower-
ing drug or statin; or CYP2C9 Rifampicin Ketoconazole
• where there is co-prescription of simvastatin or atorvastatin Fluvastatin Phenobarbitone Fluconazole
with drugs that inhibit cytochrome P450 3A4 (CYP3A4). Phenytoin Sulfaphenazole
The statins are a heterogeneous group metabolised by differ-
ent cytochrome P450 (CYP450) isoenzymes. Simvastatin, ator- protein have been used to identify individuals at risk of plaque
vastatin and lovastatin are metabolised by CYP3A4, luvastatin rupture and consequent MI and stroke. Statins can reduce levels
is metabolised by CYP2C9, and pravastatin and rosuvastatin are of C-reactive protein.
eliminated by other metabolic routes and less subject to interac-
tions with CYP450 isoenzymes than other members of the fam- An important aspect of vascular endothelium dysfunction is the
ily. Nevertheless, caution is still required because a 5- to 23-fold impaired synthesis, release and activity of endothelial-derived
increase in pravastatin bioavailability has been reported with nitric oxide, an important and early marker of atherosclerosis.
ciclosporin. Simvastatin and atorvastatin do not alter the activ- After the administration of a statin, one of the earliest effects
ity of CYP3A4 themselves, but their serum levels are increased observed (within 3 days) is an increased endothelial nitric oxide
by known inhibitors of CYP3A4 (Table 24.4). Advice has been release, thereby mediating an improvement in vasodilation of the
published on drug interactions with simvastatin (Medicines and endothelium.
Healthcare products Regulatory Agency, 2012) (Table 24.5).
For some, although it has been thought that part of the benei-
Pleiotropic properties cial effect of statins on CVD could be attributed to an effect on
blood coagulation, it is now evident that statins, amongst their
Although the effect of statins on the lipid proile contributes many actions, decrease platelet activation and activity, reduce
to their beneicial outcome in reducing morbidity and mortal- prothrombin activation, factor Va generation, ibrinogen cleavage
ity from CVD, other mechanisms, known as pleiotropic effects, and factor XIII activation, and increase factor Va inactivation.
may also play a part. These effects include plaque stabilisation,
inhibition of thrombus formation, reduced serum viscosity, Over-the-counter sale
and anti-inlammatory and antioxidant activity. These pleio-
tropic properties, that is, cholesterol-independent effects, are Low-dose (10 mg) simvastatin can be purchased from commu-
far reaching and reveal a clinical impact beyond a process of nity pharmacies in the UK to treat individuals at moderate CV
reducing TC. For example, lowering TC produces only mod- risk. Men aged 55–70 years with or without risk factors and men
est reductions of a ixed, atherosclerotic, luminal stenosis but aged 45–54 years or women aged 55–70 years with at least one
results in a qualitative change of the plaque and helps stabilise risk factor (smoker, obese, family history of premature CHD or of
it. This protects the plaque from rupturing and triggering further South Asian origin) are eligible for treatment. Simvastatin cannot
coronary events. be sold to individuals who have CVD, diabetes or familial dys-
lipidaemia, or are taking lipid-lowering agents or medication that
Inlammation is thought to play a prominent part in the devel- may interact with simvastatin. The rationale for over-the-counter
430 opment of atherosclerosis, and increased levels of C-reactive
DYSLIPIDAEMIA 24
Table 24.5 Advice on drug interactions with simvastatin is limited by intolerance and a change to an alternative statin is
being considered (NICE, 2016a).
Avoid with simvastatin as HIV protease inhibitors
contraindicated Azole antifungals Ezetimibe use has been limited because of a lack of CV out-
Erythromycin, clarithromycin, comes data. The IMPROVE-IT study (Cannon et al., 2015) dem-
onstrated that the addition of ezetimibe to simvastatin 40 mg
telithromycin in 18,144 patients following an ACS reduced the primary end-
Nefazodone point, a composite of CV death, MI, unstable angina requiring
Ciclosporin rehospitalisation, coronary revascularisation or stroke, by 6.4%
Danazol (absolute risk reduction 2% over 7 years) when compared with
Gemfibrozil patients who received simvastatin alone. As a result, ezetimibe
is now licensed to reduce the risk of CV events in patients with
Do not exceed a dose of Other fibrates (except fenofi- CHD and a history of ACS when added to ongoing statin therapy
simvastatin 10 mg daily brate) or initiated concomitantly with a statin.
Do not exceed a dose of Amiodarone Ezetimibe should be prescribed at a dosage of 10 mg daily and
simvastatin 20 mg daily Amlodipine can be taken at any time of the day, with or without food. Ezetimibe
Verapamil is contraindicated in patients who have a hypersensitivity to the
Diltiazem active substance or excipients, are pregnant or lactating and, if co-
administered with a statin, in patients with active liver disease or
Avoid when taking simvastatin Grapefruit juice unexplained persistent elevations in serum transaminases.
Adapted from Medicines and Healthcare products Regulatory Agency (2012).
sale is to reduce the risk of a irst major coronary event in adults Fibrates 431
at moderate risk, but sales have been low. Moreover, the evidence
base to support the use of 10 mg simvastatin and achieve long- The use of ibrates has waned over the last 10–15 years because
term CV beneit is limited. of lack of eficacy data compared with the statins. However, some
agents from this class, such as bezaibrate and fenoibrate, are still
Patient counselling used in selected patients. Members of this group include bezai-
brate, ciproibrate, fenoibrate and gemibrozil. They are thought
In patients who are receiving a statin, a once-daily regimen to act by binding to peroxisome proliferator-activated receptor α
involving an evening dose is often preferred. Several of the on hepatocytes. This then leads to changes in the expression of
statins (luvastatin, pravastatin, simvastatin) are claimed to be genes involved in lipoprotein metabolism. Consequently, ibrates
more effective when given as a single dose in the evening com- reduce triglyceride and, to a lesser extent, LDL-C levels, while
pared with a similar dose administered in the morning. This has increasing HDL-C. Fibrates take 2–5 days to have a measurable
been attributed to the fact that cholesterol biosynthesis reaches
peak activity at night. However, atorvastatin and rosuvastatin effect on VLDL-C, with their optimum effect present after 4
may be taken in the morning or evening with similar eficacy.
A reduction in TC and LDL-C is usually seen with all statins weeks. In addition to their effects on serum lipids and lipopro-
within 2 weeks, with a maximum response occurring by week 4 teins, the ibrates may also have a beneicial effect on the ibri-
and maintained thereafter during continued therapy. nolytic and clotting mechanisms. The ibrates also produce an
improvement in glucose tolerance, although bezaibrate probably
Cholesterol absorption inhibitors has the most marked effect.
Ezetimibe is a 2-azetidinone derivative that interacts with a In the patient with elevated triglycerides and gout, only feno-
putative cholesterol transporter in the intestinal brush-border ibrate has been reported to have a sustained uricosuric effect on
membrane and thereby blocks cholesterol re-absorption from chronic administration. Overall, there appears little to differenti-
the gastro-intestinal tract. It can reduce LDL-C by 15–20%
when added to diet. Ezetimibe also brings about a small increase ate members of the group with regard to their effect on the lipid
in HDL-C and a reduction in triglycerides. When added to a proile, with fenoibrate and ciproibrate being the most potent
statin, ezetimibe lowers LDL-C by approximately 20% over members of the group.
and above that achieved by statin therapy alone (Kastelein
et al., 2008). In patients with diabetes, the typical picture of dyslipidaemia
Ezetimibe monotherapy is recommended by NICE (2016a) for is one of raised triglycerides, reduced HDL-C and near-normal
the treatment of primary hypercholesterolaemia in patients where LDL-C. Despite the effect of ibrates to reduce triglycerides and
initial statin therapy is contraindicated or not tolerated. Ezetimibe increase HDL-C, statins are irst-line lipid-lowering agent in
plus statin therapy is recommended for the treatment of primary most guidelines because of a lack of clear evidence that ibrates
hypercholesterolaemia where the TC or LDL-C is not controlled, prevent CVD in diabetes. Early data for ibrate monotherapy in
either after dose optimisation of statin therapy or where the dose primary and secondary prevention studies did show promise with
a signiicant reduction in coronary events and stroke, and even a
modest impact on CV mortality (Frick et al., 1987; Rubins et al.,
1999). It was hoped that a 5-year study of fenoibrate in individu-
als with type 2 diabetes (Keech et al., 2005) would clarify the
issue. However, in the inal analysis the results provided little
convincing evidence to change from recommending a statin,
although they did conirm the safety of using a combination of a
24 THERAPEUTICS
Table 24.6 Typical drug interactions involving bile acid binding agents and fibratesa
Drug group Interacting drug Comment
Bile acid binding agents
Colestyramine/colestipol All medication should be taken 1 h before or at least 4 h after colestyr-
amine/colestipol to reduce absorption caused by binding in the gut
Acarbose Hypoglycaemia enhanced by colestyramine
Digoxin Absorption reduced
Diuretics Absorption reduced
Levothyroxine Absorption reduced
Mycophenolate mofetil Absorption reduced
Paracetamol Absorption reduced
Raloxifene Absorption reduced
Valproate Absorption reduced
Statins Absorption reduced
Vancomycin Effect of oral vancomycin antagonised by colestyramine
Warfarin Increased anticoagulant effect due to depletion of vitamin K or reduced
anticoagulant effect due to binding or warfarin in gut
Colesevelam All medication should be taken at least 4 h before or 4 h after colesevelam
to reduce absorption caused by binding in the gut
Ciclosporin Absorption reduced
Digoxin Absorption unchanged
Glyburide Absorption reduced
Levothyroxine Absorption reduced
Oral contraceptive Absorption reduced
Statins Absorption unchanged
Valproate Absorption unchanged
Warfarin Absorption unchanged
Increased anticoagulant possible because of depletion of vitamin K
Fibrates Antidiabetic agents Improvement in glucose tolerance
Ciclosporin Increased risk of renal impairment
Colestyramine/colestipol Reduced bioavailability of fibrate if taken concomitantly
Statin Increased risk of myopathy
Warfarin Increased anticoagulant effect
aAbsorption studies involve concomitant administration.
statin and fenoibrate. In contrast, gemibrozil should not be used Adverse effects
with a statin. Similarly, the ACCORD study (ACCORD Study
Group, 2010) compared combination statin plus ibrate therapy Overall, the side effects of ibrates are mild and vary between
with statin alone in patients with type 2 diabetes and concluded members of the group. Their apparent propensity to increase the
that the combination of fenoibrate and simvastatin did not reduce cholesterol saturation index of bile renders them unsuitable for
the rate of fatal CV events, nonfatal MI or nonfatal stroke, as patients with gallbladder disease. Gastro-intestinal symptoms such
as nausea and abdominal pain are common but transient, and often
compared with simvastatin alone. resolve after a few days of treatment. Myositis has been described
Overall, ibrates should not be used irst line to reduce lipid and is associated with muscle pain, unusual tiredness or weakness.
The mechanism is unclear, but it is thought that ibrates may have a
levels in either primary or secondary prevention of CVD (NICE, direct toxic action on muscle cells in susceptible individuals.
2014). Fibrates may be considered irst line in patients with iso-
lated severe hypertriglyceridaemia, especially in individuals with Fibrates have been implicated in a number of drug interac-
tions (Table 24.6), of which two in particular are potentially
triglyceride levels greater than 10 mmol/L where there is a risk serious. Fibrates are known to signiicantly increase the effect of
of acute pancreatitis (Fortson et al., 1995). In those with mixed anticoagulants, while concurrent use with a statin is associated
hyperlipidaemia, ibrates may be considered when a statin or with an increased risk of myositis and, rarely, rhabdomyolysis.
432 other agent is contraindicated or not tolerated, or as an add-on
therapy where monotherapy is ineffective.
DYSLIPIDAEMIA 24
Concurrent use of cerivastatin and gemibrozil was noted to (see Table 24.6). Whether these absorption-type interactions are
cause rhabdomyolysis, and this contributed to the withdrawal of qualitatively and quantitatively similar between the different
cerivastatin from clinical use in 2001. agents is unclear, and the picture is confused when the absorption
of a given drug is known to interact with one bile acid binding
Bile acid binding agents agent but has not been tested with other members of the group.
The three bile acid binding agents in current use are colestyramine, Long-term use of bile acid binding agents may also interfere
colestipol and colesevelam. Both colestyramine and colestipol with the absorption of fat-soluble vitamins, and supplementation
were formerly considered irst-line agents in the management of with vitamins A, D and K is recommended.
patients with FH but now have limited use. Colesevelam is the
most recent of the bile acid binding agents to receive marketing Patient counselling
authorisation (in 2004) and consequently has never had a irst-
line indication. Each of the bile acid binding agents reduce TC Palatability is often a major problem with the bile acid binding
and increase triglyceride levels. agents, and patients need to be well motivated and prepared for
the problems they may encounter.
Following oral administration, neither colestyramine, colesti-
pol nor colesevelam is absorbed from the gut. They bind bile Both colestyramine and colestipol are available in an orange
acids in the intestine, prevent reabsorption and produce an insol- lavour and/or as a low-sugar (aspartame-containing) powder.
uble complex that is excreted in the faeces. The depletion of bile Colestipol is without taste and is odourless. Each sachet of cole-
acids results in an increase in hepatic synthesis of bile acids from styramine or colestipol should be added to at least 150 or 100 mL
cholesterol. The depletion of hepatic cholesterol upregulates the of liquid, respectively, and stirred vigorously to avoid the powder
hepatic enzyme 7-α-hydroxylase which increases the conversion clumping. The powder does not dissolve but disperses in the chosen
of cholesterol to bile acids. This increases LDL receptor activity liquid, which may be water, fruit juice, skimmed milk or non-car-
in the liver and removes LDL-C from the blood. Hepatic VLDL-C bonated beverage. Both may also be taken in soups, with cereals and
synthesis also increases, and it is this which accounts for the raised with pulpy fruits with high moisture content, such as apple sauce.
serum triglycerides. There is little evidence that bile acid binders
reduce the risk of CV events, and therefore they are not recom- All patients who are receiving a bile acid binding agent should
mended for use for primary or secondary prevention of CVD be advised that reduced absorption with co-administered drugs
(NICE, 2014). This class should only be considered for use by should be anticipated. Medication that has to be taken should be
specialists as adjunctive therapy where irst-line therapies for the administered 1 hour before (at least 4 hours for colesevelam) or at
management of dyslipidaemia are contraindicated or ineffective. least 4 hours after the bile acid binding agent. As a consequence,
for individuals receiving multiple-drug therapy, bile acid binding
Colestyramine has a starting dosage of one 4-g sachet twice a agents may not be appropriate for this reason alone.
day. Over a 3- to 4-week period the dosage should normally be
built up to 12–24 g daily taken in water or a suitable liquid as a Nicotinic acid and derivatives 433
single dose, or up to four divided doses each day. Occasionally,
36 g/day may be required, although the beneits of increasing the Nicotinic acid in pharmacological doses (1.5–6 g) lowers serum
dose above 16 g/day are offset by gastro-intestinal disturbances LDL-C, TC, VLDL-C, apolipoprotein B, triglycerides and Lp(a),
and poor patient adherence. and increases levels of HDL-C (particularly the beneicial HDL3
subfraction). While nicotinic acid and its derivatives may have
Colestipol is also available in a granular formulation and can beneicial effects on the lipid proile and did hold promise in terms
be mixed with an appropriate liquid at a dose of 5 g once or twice of reducing CV events, these products have been withdrawn from
daily. This dose can be increased every 1–2 months to a maxi- the market in the UK due to safety concerns (European Medicines
mum of 30 g in a single- or twice-daily regimen. Agency, 2014), following a meta-analysis indicating increased risk
of diabetes, myositis and infection. Only patients under the man-
Colesevelam is up to six times as potent as the other bile acid agement of a lipid specialist should be prescribed nicotinic acid or
binding agents, probably because of a greater binding to glyco- nicotinic acid derivatives in line with NICE guidance for FH, with
cholic acid. Whether this translates into better clinical outcomes supplies imported on a named patient basis (NICE, 2008a).
or more, or less, problems with drugs administered concurrently is
unclear. Colesevelam is administered as a 625 mg tablet to a maxi- The commonest side effect of nicotinic acid is lushing
mum dosage of 4.375 g/day (7 tablets). There is limited evidence which is most prominent in the head, neck and upper torso and
to suggest it may achieve a higher adherence than colestyramine occurs in more than 90% of patients. It is cited as the major
or colestipol. It can be taken as a single- or twice-daily regimen. reason for discontinuation of treatment in 25–40% of patients.
A number of strategies have been devised to overcome this,
Adverse effects including co-administration of a cyclo-oxygenase inhibitor
such as aspirin. Other strategies include regular consistent
With all three agents, side effects are more likely to occur dosing, the use of extended-release formulations, patient edu-
with high doses and in patients older than 60 years. Bloating, cation, dosing with meals or at bedtime, and the avoidance of
latulence, heartburn and constipation are common complaints. alcohol, hot beverages, spicy foods, and hot baths or showers
Constipation is the major subjective side effect, and although close to or after dosing. Less common side effects of nicotinic
usually mild and transient, it may be severe. acid include postural hypotension, diarrhoea, exacerbation of
peptic ulcers, hepatic dysfunction, gout and increased blood
Colestyramine, colestipol and colesevelam are known to inter- glucose levels.
act with many drugs primarily by interfering with absorption
24 THERAPEUTICS
Fish oils excipients. In the trials to date, both drugs have been well tol-
erated with the most common side effects being symptoms of
Fish oil preparations rich in omega-3 fatty acids have been inluenza, nasopharyngitis, upper respiratory tract infection, rash,
shown to markedly reduce serum triglyceride levels by decreas- nausea, backache, arthralgia and injection-site reactions.
ing VLDL-C synthesis, although little change has been observed
in LDL-C or HDL-C levels. The effect is, however, inconsistent, Drugs in development
and signiicant increases in LDL-C have also been reported to
accompany the use of ish oils. Available commercial products Cholesterol ester transfer protein inhibitors
contain omega-3-acid ethyl esters (Omacor) and omega-3-marine
triglycerides (Maxepa). Either can be used as an alternative to a Low levels of cholesterol ester transfer protein (CETP) are asso-
ibrate or in combination with a statin to manage hypertriglyceri- ciated with increased levels of HDL-C and reduced CV risk.
daemia. However, they are not recommended by NICE (2014) for CETP transfers cholesterol from HDL-C to LDL-C and VLDL-C,
use in the primary or secondary prevention of CVD. thereby altering the HDL-C:LDL-C ratio in a potentially unfavour-
able manner. In epidemiological studies, higher circulating levels
Soluble fibre of HDL have been associated with reduced CV events, hence the
CETP inhibitors were thought to be a promising therapeutic option.
Preparations that contain soluble ibre, such as ispaghula husk, However, of the original four CETP inhibitors in development, three
have been shown to reduce lipid levels. The ibre is thought to have been abandoned because of increased mortality (torcetrapib)
bind bile acids in the gut and increase the conversion of choles- or lack of impact on CV events despite adequate HDL increases
terol to bile acids in the liver. However, their role in the manage- (dalcetrapib and evacetrapib). Recently announced results of the
ment of dyslipidaemia is unclear, and they are much less effective REVEAL study of anacetrapib indicate a modest reduction in CV
than statins in reducing TC and LDL-C. events when added to intensive statin therapy, with no major safety
signals (Bowman et al., 2017). Whether this will result in a change
Proprotein convertase subtilisin/kexin type 9 to clinical practice in the future remains to be seen.
inhibitors
Other options
Key to the removal of LDL cholesterol from the circulation is
the LDL receptor PCSK9, a secreted protease that has a role in Low-density lipoprotein apheresis
controlling the number of LDL receptors available by binding
LDL-C receptors and preventing them from being expressed on Lipoprotein apheresis is a treatment option used in patients with
the cell surface. High levels of PCSK9 suppress LDL-C receptor severe treatment-resistant hypercholesterolaemia. Currently
activity, reducing the number of available receptors, and result in approximately 70 patients are receiving apheresis treatment in
raised circulating cholesterol. Inhibition of PCSK9 will facilitate England and Wales. Lipoprotein apheresis removes LDL-C,
increased LDL-C receptor activity through increased number of Lp(a) and triglycerides from the plasma. Treatment can lower
receptors, and hence lower circulating cholesterol levels. LDL-C by upwards of 75%, but the effect is transient, and hence
treatment needs to be repeated at regular intervals (Thompson
Alirocumab and evolocumab, both monoclonal antibody et al., 1995). The eficacy and superiority of lipoprotein apher-
PCSK9 inhibitors, have recently been licensed as options in the esis in comparison with standard lipid-lowering therapies is well
management of primary FH and non-FH. In the studies to date, established; however, there is still uncertainty regarding the abil-
evolocumab with or without background statin therapy has been ity of lipoprotein apheresis to promote atherosclerotic plaque
shown to reduce LDL-L levels between 55% and 75% compared regression, because its effects are only transient. Furthermore,
with placebo, and by up to 50% more than ezetimibe (Raal et al., although LDL apheresis is a highly effective treatment, its uptake
2015; Robinson et al., 2014; Stroes et al., 2014). Across ive clini- and application are somewhat restricted because of its limited
cal trials involving 2476 patients with FH receiving optimal statin availability at specialist centres only and the need for repeated
therapy, the average reduction in LDL-C with alirocumab ranged treatments on a weekly or twice-weekly basis.
from 36% to 59%, compared with placebo (U.S. Food and Drug
Administration, 2015). The irst CV outcomes study investigated NICE (2008a) recommends that apheresis is considered for the
the impact of evolocumab in addition to statins in patients with management of people with clinical homozygous FH and also
atherosclerotic coronary disease (Sabatine et al., 2017). Over 2.2 for those with heterozygous FH in exceptional circumstances, for
years of follow-up, the addition of evolocumab to statin therapy example, progressive, symptomatic CHD despite maximal oral
demonstrated a signiicant reduction in CV events: 9.8% versus lipid-lowering therapy and optimal medical-surgical intervention.
11.3% for statins alone with an absolute risk reduction of 1.5%.
Lomitapide
Currently, these drugs are recommended by NICE as an option
for the treatment of primary hypercholesterolaemia or mixed Lomitapide inhibits microsomal triglyceride transfer protein which
dyslipidaemia provided a set of usage criteria are met, includ- plays a major role in the assembly and secretion of the lipopro-
ing minimum baseline LDL levels before initiation of treatment teins in the intestine and liver. As a result, lomitapide inhibits the
(NICE, 2016b, 2016c). synthesis of triglyceride-rich chylomicrons in the intestine and
VLDL (the precursor of LDL) in the liver. This results in an overall
Both drugs are administered by subcutaneous injection and reduction in circulating cholesterol. Lomitapide has been studied
434 require storage in a refrigerator. Both are contraindicated in
patients with known hypersensitivity to the active ingredient or
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Clinical Pharmacy and Therapeutics - Book 1
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