Cardio Diabetes_2017 book

378 Mechanical Circulatory Support for
Advanced Heart Failure

(40-50% ofpatients) or 2 (25-35% of patients) and, as reduce intracardiac filling pressures (there by reduc-
consequence, the long-term survival was marginal. ing congestion and/or pulmonary edema), reduce
Most of the mortality occurred during the initial hos- ventricular volumes, wall stress, and myocardial oxy-
pitalization for assist device surgery, closely related gen consumption;and augment myocardial perfusion
to the degree of organ compromise and urgency at by increasing coronary blood flow(theoretically also
the time of implantation, which might have been as- limiting the infarct size in the setting of myocardial
sociated with irreversible organ dysfunction. infarction).Each of the currently available devices is
designed to tackle the entire equation (i.e. circulatory
These observations have led the heart failure com- support, ventricular unloading, myocardial perfusion)
munity to begin using temporary(acute) mechanical but primarily address specific aspects of that equa-
circulatory support devices in order to stabilize high- tion.
risk patients (profiles 1-2) and downshift the risks of
a durable assist devices implantinto defined popula- The temporary mechanical circulatory support devic-
tions with lower post-operative morbidity (e.g. profiles es can be largely divided into pulsatile and non-pul-
3-4)leading to better survival. Indeed, the most recent satile devices. The pulsatile device that has been
data from INTERMACS have shown that this strate- used since 1960s is the intra-aortic balloon pump
gy yields 80% one-year and 48% 5-year survival in that primarily functions to augment the diastolic
the current era, starting to approach the survival af- pressure and, as a result, increase coronary per-
ter heart transplantation in individuals older than 60 fusion. The ventricular unloading aspect of the in-
years of age (87% one-year and 69% 5-year survival). tra-aortic balloon pump (counter pulsation) relies on
Finally, theresults from the recently completed Risk an intact ventricular-vascular coupling and may be
Assessment and Comparative Effectivenessof Left diminished in patients with sicker left ventricles. The
Ventricular Assist Device and Medical Management third part of the equation (i.e. circulatory support) re-
in Ambulatory HeartFailure Patients (ROADMAP) tri- lies on the augmented mean arterial pressure that is
al have shown that in carefully selected profile 4-7 driven primarily by the augmented diastolic pressure.
patients, the 1 and 2 year survival were greater than Its usefulness is limited to patients in the early shock
continuing optimal medical therapy (80% vs. 63% for phase or in patients with active ischemia or ischemic
one-year, and 70% vs. 43% for two year survival in ventricular arrhythmias.The continuous flow devices
theventricular assist device and optimal medical ther- can be further divided into axial or centrifugal flowde-
apy groups, respectively). vices. The axial flow pumps that currently exist are
the Impella axial flow catheters(2.5 L, CP and 5 L) that
Acute (Temporary) Mechanical Circulatory use a rotodynamic pump and work by taking blood
Support Devices from the left ventricle and directly ejecting it into the
aorta. Axial flowdevices will effectively increase mean
These devices are used primarily in patients needing arterial pressure and directly unload the leftventricle,
high-risk percutaneous coronary interventions, or in thereby reducing ventricular pressure. As a result of
post-cardiotomy failure to wean from the cardiopul- the increased meanaortic pressure and lower ven-
monarybypass, or in cardiogenic shock. Cardiogenic tricular pressure, the transmyocardial perfusion gra-
shock occurs secondary to acute left or right ventric- dient changes and coronary perfusion will increase.
ular systolic dysfunction, acute (on chronic) aortic or The centrifugal flow pumps are extracorporeal and
mitral valvular disease, and vasodilator abnormalities include the TandemHeartdevice and veno-arterial ex-
in patients with acute myocardial infarction, out-of tracorporeal membrane oxygenation (VA ECMO). In
hospital cardiacarrest, and worsening chronic heart the Tandem Heart configuration for left ventricular
failure. In clinical practice, patients with cardiogenic support, blood is taken out of the left atrium (via a
shock represent a spectrum of disease that can be trans-septal catheter) and delivered into the systemic
classified as early shock,shock, and severe shock, circulationto the iliac artery. In the VA ECMO configu-
depending on the level of blood pressure, heart rate, ration, blood is taken from the right atrium, oxygenat-
intracardiac filling pressures, cardiac output, tissue ed, and delivered to the iliac artery into the systemic
perfusion (lactate, urine output) and need for vaso- circulation.The hemodynamic effect between these
active medications. Potential benefits of temporary two devices is very different. The Tandem Heart will
mechanical circulatory support devices in this set- effectively address all three components of the equa-
ting include the ability to provide circulatory support tion byunloading the left ventricle, by reducing left
(thereby maintaining vital organ perfusion and pre- atrial volume (reducing left ventricular preload), and
venting systemic shock syndrome); provide ventric- by increasing mean arterial pressure, which leads to
ular unloading (left, right, biventricular) in order to increase in the coronary perfusion pressure. The VA

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Cardio Diabetes Medicine 2017 379

ECMO system is distinct from all the other devices by 80 and 50%, and marked improvement in symptoms
very effectively providing circulatory support (mean and quality of life. While the traditional indications for
arterialpressure will increase). However, by directly implantation were divided into bridge to transplanta-
transferring venous blood intothe systemic circula- tion, bridge to decision and destination therapy, the-
tion, afterload goes up and the left ventricle has to improved reliability of today’s devices and the lack
work harder. As such, VA ECMO in isolation will not of available organs for transplantationhas led to a
unload the left ventricle and would need the addi- paradigm shift where future device will be designed/
tion of pharmacological (e.g. inotropes), mechanical tested for short or long term use, without a transplant
(e.g.intra-aortic balloon pump, Impella) or surgical (e.g. associated label.
direct left atrial or ventricularvent) unloading. In addi-
tion, there are limited data to understand the effect First generation positive displacement pulsatile de-
of VAECMO on coronary perfusion pressure.A clear vices (e.g. Thoratec HeartMateXVE, Novacor LVAS)
understanding of each device strengths and weak- used a diaphragm and unidirectional valves to mimic
ness is crucial,since the complications are not trivial. the pulsatile cardiac cycle through diastolic filling and
Patients are kept on support until end organ function systolic emptying of the pump.The use of HeartMate
has improved and a decision of weaning for recovery XVE in the Randomized Evaluation of Mechanical As-
or proceeding to permanent support is achieved, or sistance for the Treatment of Congestive Heart Fail-
palliative withdrawal is instituted. ure (REMATCH) trial opened the door for mechanical
circulatory support for long-term use in transplant
The initial approach is to quickly achieve normal in eligible patients (“destination therapy”). However,
perfusion (mean arterial pressure above 65 mmHg, due to their size, adverse events and limited dura-
lactate level below 2 mmol/L),while maintaining the bility (18-24 months), their use was very limited and
acid base equilibrium (pH 7.3-7.4), adequate tissue these pumps were eventually discontinued in mid to
oxygenation(hematocrit above 30 %), and urine out- late 2000s.
put (greater than 1.5-2 mL/kg/h). All patients should
be anticoagulated with intravenous heparin, targeting Second and third generation continuous flow pumps
partial thromboplastin time of 45-60 s or unfraction- are smaller, enjoy simpler implantation, and have
ated heparin level of 0.3-0.5 U/mL. When hemo- more limited blood contacting area with fewer mov-
dynamicsimprove (right atrial pressure below 10-12 ing parts and without valves, air vents and com-
mmHg, pulmonary capillary wedge pressures below pliance chambers, leading to longer durability and
20 mmHg), echocardiography guided weaning ofthe reduced risks for thromboembolism, infection, and
support is attempted. The amount of support should malfunction. They use a permanent magnetic field
gradually be decreased (from full support of4-5 L to designed to rapidly spin a single impeller supported
minimal support of 1-1.5 L), while paying attention to by mechanical,hydrodynamic (using a layer of blood
left ventricular size,severity of mitral regurgitation, – blood bearing – to lift the rotor) or magnetic bear-
right ventricular function (fractional area change, ings (using magnetic bearings to levitate the rotor).
freewall s’) and hemodynamics (mean arterial pres- Second-generation axial pumps have the impeller
sure, right atrial pressure and pulmonary capillary outflow directed parallel to the axis of rotation with
wedge pressures). If the weaning is successful, the the rotor spinning on mechanical (Abbott HeartMate
temporary mechanical circulatory support is removed II,Jarvik 2000, Reliant Heart HeartAssist 5) or con-
and patients are bridged via inotropes to oral heart tact-free bearings (Berlin Heart Incor). Third-gener-
failure therapies. If the weaning is unsuccessful, the ation centrifugal pumps have the impeller outflow
patients are then implanted with durable ventricu- perpendicularto the axis of rotation (Medtronic Heart-
larassist devices. Ware Ventricular Assist Device [HVAD] and Abbott
HeartMate III) or use a mixed design, where blood
Durable (Permanent) Mechanical Circulatory flows along the axis of rotation but exits perpendicu-
Support Devices lar to the inflow (Medtronic HeartWare miniatureven-
tricular assist device [MVAD]).
Durable ventricular assist devices are evolving into
an effective and reasonably cost-effective therapy Underlying Physiologic Principles of
for a growing population of patients with advanced Continuous Flow Devices
heart failure.They provide significant left ventricular
unloading and increased cardiac output and improve The pump blood flow is directly proportional to the
end-organ function. Patients supported with ventric- rotor speed and inversely proportional to the pres-
ular assist device enjoy one and 5-year survival of sure differential across the pump (i.e. head pressure,
the pressure difference between the left ventricle and

Cardio Diabetes Medicine

380 Mechanical Circulatory Support for
Advanced Heart Failure

aorta). However, the axial and centrifugal pumps to heart-kidney transplantation), biopsy proven liver
differ in their hydrodynamic performance, as char- cirrhosis,active or recent history (within 3 months)
acterized by the relation between flowrate and head of heparin induced thrombocytopenia, irreversible
pressure. Axial flow pumps have a steep and inverse- cognitive dysfunction (as established by formal neu-
linear relationship between flow and head pressure, rocognitive testing) andmarked frailty. Patients are
while in centrifugal pumps this relationshipis flatter also deemed to not be good candidates for implan-
and more susceptible to head pressure changes tationif they lack social support or have a recent or
(i.e., more sensitive topre-load and afterload). Due to active history of significant alcoholor illicit substance
these hydrodynamic characteristics, with the same use. Older patients (older than 80 years) or morbidly
change in pressure, centrifugal pumps generate larg- obesepatients (body mass index above 45 kg/m2)
er changes in flow and yield more pulsatile wave- should be evaluated on case-by-case basis.
forms, more accurate flow estimation, and have a
lower risk of suction events (insetting of dehydration, Current Clinical Results with Continuous
arrhythmias, or right ventricular failure), but are more Flow Pumps
dependenton the loading conditions when compared
with axial flow pumps. Several modern trials with ventricular assist devices
have been presented in the lastdecade, with one-year
Patient Selection survival ranging from 68% (in the initial Abbott Heart-
Mate II bridge to transplant and destination therapy
The patients most likely to benefit from long-term trials and Medtronic HVAD destination therapy trial)
use of ventricular assist devices are patients with ad- to 86% (Medtronic HVAD bridge to transplant trial,
vanced heart failure,preferably INTERMACS profiles Abbott HeartMate II post approval studies). Asdis-
3-4, where the surgical risk of implantation is fairly cussed before, patients with INTERMACS profiles
small (in-hospital mortality less than 3-5 %). Patients 3-7 had better survival,slightly greater than 90% at
with INTERMACSprofiles 1-2 should be bridged with one year.
temporary mechanical circulatory supportdevices
and their end-organ function and nutritional status The use of ventricular assist devices has been ham-
improved significantly or normalized in order to de- pered by the relatively high probability of device re-
crease the surgical mortality and morbidity associat- lated adverse events (rates per 100 patient-months):
ed withthe durable ventricular assist devices implant. bleeding– mainly gastrointestinal (early [within first
Ideal candidates are patients with large left ventri- 90 days post implant] of 19.6 andlate [90 days to
cles, relatively preserved rightventricular function, 24 months post implant] of 3.25); infections – mainly
elevated left ventricular filling pressures and low driveline infections (early of 16.95 and late of 4.06),
cardiac output,with competent aortic valve, without strokes (early of 4.64 and late of 1.21); and pump
history of gastrointestinal bleeding, compliant,with thrombosis or mechanical failure (early of 2.79 and
adequate social support, and with few extracardiac late of 1.53). In addition, significant right heart failure
comorbidities that could limit the long-term benefit of can occur in up to 30% of patients,and 5-10 % require
ventricular assist devices. Carefully selected patients insertion of a temporary or permanent right ventric-
with restrictive cardiomyopathy, incessant ventricular ular assist device. Up to 30% of patients will develop
tachycardia or congenital heart disease could also over time aortic insufficiency,which may be related
benefit from ventricular assist device implantation. to the degree of opening allowed by the ongoing
ventricular assist device settings. The hospitalization
The absolute medical contraindications to implanta- rates for device related complications are high,with
tion include recent stroke (within 3 months), active reportedly up to 70% of patients being hospitalized
systemic infection, uncorrectable peripheralvascular at least once during thefirst year on support. Howev-
disease or aortic disease, severe irreversible lung dis- er, as shown in the ROADMAP trial, the implantation
ease (forced expiratory volume in first second less of less sick patients, may lead to lower complication
than 1 L or diffusing capacity of the lungs for car- rates and allow for betterhospital free survival.
bonmonoxide less than 35 % of predicted values),
severe cardiac cachexia (body massindex below 19 In Hospital Management
kg/m2, serum albumin level below 2.5 g/dL, or se-
rum pre-albuminlevel below 15 mg/dL), end stage Once the patient is deemed to be a suitable candi-
renal disease on dialysis or with high likelihood of date for ventricular assist device implantation, preop-
needing dialysis post implant (e.g. creatinine above erative optimization using a multi-systems approach
3 mg/dL, unless the patient is considered as bridge prepares the patient for thebest chance of a suc-
cessful outcome. Although several risk scores have

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Cardio Diabetes Medicine 2017 381

been proposed,there are currently no validated risk therisk for right ventricular ischemia if the mean ar-
prediction models to identify patients athighest risk terial pressure is below 65-70 mmHg.
for perioperative complications for ventricular assist
device implant.All efforts should be made to ensure Poor nutritional state is associated with a high risk
that all patients go into surgery with optimalorgan of post-operative complications,including infections,
functions, irrespective of its baseline state. poor healing, poor functional recovery and prolonged
length of stay. Patients with cardiac cachexia should
Pre-operative Optimization receive intensive nutritional optimization with high
caloric oral supplements, enteral feedings orparen-
The use of inotropes, vasopressors and temporary- teral nutrition in order to boost nutritional status on
mechanical circulatory support devices can improve the short term (e.g. few dayspre-op) and achieve a
renal blood flow, while judicious decongestion with pre-operative albumin and pre-albuminvalues of
combination of intravenous diuretics, aquaretics or above 3 mg/dL and 15 mg/dL, respectively.
ultrafiltration will reduce the central and renal venous
pressures. All attempts should be made to improve Intra-operative Management
renal function to pre-operative creatinine and blood
urea nitrogen values of less than 2 mg/dL and 50 The intraoperative period is the most critical time oft-
mg/dL, respectively. Hepatic dysfunction in heart he implant and proper anesthetic techniques, hemo-
failure is a result of circulatory shock from acute dynamic management and surgical techniques are
decompensation and persistently high right atrial key to a successful outcome. The right ventricle is
pressures in the setting of venous congestion and particularly vulnerable during the implant procedure.
poor rightventricular function.Hepatic dysfunction Right coronary artery hypoperfusion from hypoten-
can lead to coagulation abnormalities and increased sion or air emboli should be avoided. Vasopres-
risk ofbleeding in patients undergoing ventricular sors (or vasodilators as needed)should be used to
assist device implantation. Those with acute heart maintain a mean arterial pressure of 70-75 mmHg
failure decompensation and elevations of transam- during the implant procedure. Inotropes should be
inases or bilirubin should receive aggressive therapy used to maintain a good contractile function and
with diuresis, inotropes, and temporary mechanical intravenous diuretics or ultrafiltration should be
circulatory support devices as necessary to improve used to maintain euvolemia.Judicious blood prod-
hepatic function prior to implantation, to pre-opera- uct and fluid management is key in order to prevent
tive transaminases and bilirubin values of lessthan right ventricular volume overload and dysfunction.
100 IU/L and 2 mg/dL, respectively. During surgical implantation, the ventricular assist
device inflow cannula should be placed parallel to
Right ventricular dysfunction is common in advanced the septum directed towards the mitral valve, away
heart failure patients andis consequence of pulmo- from the free wall. This should be verified by transe-
nary venous hypertension from chronically elevated sophageal echocardiography. Correct inflow cannula
leftventricular filling pressures, valvular pathology, or placement will minimize thechance of suction events.
a combination of these processes. All patients with For patients where lateral thoracotomy is used for
right ventricular dysfunction (more than mild) should implantation,sufficient surgical space should be
be admitted to the hospital prior the implant surgery available for a good visualization of the coring area
and are optimized by receiving inotropes (e.g. dobu- and inflow cannula implantation. The outflow graft
tamine or milrinone) and/or temporary mechanical should be positioned to the right of sternal midline
circulatory support devices in order to increase the and avoid compression of right ventricle. Minimizing
cardiac index above 2.2 L/min/m2. In addition,all total cardiopulmonary bypass time may reduce the
patients should receive intravenous diuretics or ul- unfavorable extracorporeal-induced trauma of blood
trafiltration in order to achieve a preoperative central elements and the chance of bleeding. At the sepa-
venous pressure <10 mmHg. Patients with pulmonary ration from cardiopulmonary bypass, pulmonary va-
vascularresistance above five Wood units and mod- sodilation therapy with inhaled nitric oxide shouldbe
erate to severe right ventricular dysfunction should initiated prior to separation from bypass in order to
receive sildenafil or inhaled nitric oxide in order to provide the most favorable conditions for the right
decreasethe pulmonary vascular resistance and en- heart. Inotropic therapy should be continued or initi-
hance the right ventricular function pre-operatively. ated and volume management should be maintained.
Finally, low dose vasopressors (e.g. vasopressin, nor- Sequential atrio-ventricular pacing can enhance right
epinephrine) can be used to increase the perfusion ventricular function and should be attempted if brad-
pressure to the right coronary artery and minimize yarrhythmias exist.

Cardio Diabetes Medicine

382 Mechanical Circulatory Support for
Advanced Heart Failure

Post-operative Management flows and loss of pulsatility). If needed, intravenous
inotropes could be used for an extended period of
The primary objective of early post-operativeman- time. All sustained atrial and ventricular arrhythmias
agement is to support organ recovery and to avoid should be treated with anti arrhythmic agents and
multi-system organ failure through optimization of synchronized cardioversion should be used in refrac-
organ perfusion. Invasive monitoring of the patient tory cases.
for the first 48-72 hrs is used in order to ensure ad-
equate optimization of hemodynamic support. Pump A comprehensive transthoracic echocardiogram
speed should be adjusted to maintain an output that should be obtained prior to discharge toevaluate
provides the patient with adequate cardiac output ventricular size and function, cannula position and
while avoiding left ventricular suction and septum flow, aortic valve opening,tricuspid valve regurgita-
deviation to the left. A low pump output should trig- tion and perform a ramp test to determine the best-
ger evaluationfor hypovolemia (e.g. bleeding), tam- pump speed that unloads the left ventricle without
ponade, right heart failure, and in rarecases, inflow inducing right ventriculardys function.
or outflow cannula obstruction. Surgical bleeding
that occurs despite correction of coagulopathies will Long-Term Management
require that the patient be returned promptly to the
operating room to identify the source. Uncontrolled After implantation of the ventricular assist device
bleeding should always be surgically evaluated. and discharge from the index hospitalization, the
clinician is faced with the challenge of caring for the
Intravenous heparin is started 24 hrsafter the surgi- patient in the outpatient setting. This phase of care
cal bleeding is controlled and the anticoagulation is may last years and the clinical concernsmay evolve
gradually increased (increasing partial thromboplas- (e.g. moving from rehabilitation in the early period to
tin time targets by 10-15 s every other day to a goal of preventing ortreating comorbid conditions over time).
55-65 s), and warfarin started when the chest tubes Patients can be followed at the implant center or in
have been removed. Aspirin 81 mg is started when coordination with the referring cardiologist (“shared
the platelet count has rebounded (usually 2-3 days care”). If a shared care approach is used, manage-
postoperatively). ment guidelines should be distributed to the referring
cardiologist to ensure a uniform approach and long-
The impact of the ventricular assist device on right term success.
ventricular function can be both beneficial and det-
rimental. The beneficial effects are realized through Patients can be seen in the outpatient clinic weekly
unloading the left ventricle and decreasing filling or biweekly for the first 30 days post discharge, then
pressures, thereby reducing right ventricular after- at 1 month and every 3 months afterwards. A panel
load. The potential detrimental effects include an in- of laboratory values (basic chemistry, complete blood
crease in rightventricular preload from the normalized count, lactate dehydrogenase, plasma free hemoglo-
cardiac support, and the septal shift observed with bin, international normalized ratio [INR],natriuretic
unloading the left ventricle. With lower left ventricu- peptide) can be obtained with every clinic visit and
lar filling pressures, the septum will tend to shift to monthly after the 1-month clinic visit.
the left and decrease the septal contribution toright
ventricular output. Pump speed should be maintained All patients should be maintained on oral anticoagu-
to achieve an optimal balance between an adequate lation with a combination of warfarin(target INR 2-2.5)
cardiac output and avoidance of right ventricular dys- and aspirin 81 mg daily. The INR target is lowered
function. to 1.8-2.2 for patients with evidence of gastrointesti-
nal bleeding or individuals older than age 70 years
Weaning of inotropic support should be initiated at high risk for bleeding. Blood pressure control is
once the patient is euvolemic and is clinically guid- key to preventing strokes in patients on ventricular
ed by the physical examination with close monitoring assist devices. In patients with pulsatile hemody-
of device parameters. As inotropes are weaned, the namics (pulse pressure more than 20 mmHg), one
clinician should evaluate for evidence of right ventric- should target a systolic blood pressure below 90-100
ular dysfunction including: increasing edema; eleva- mmHg while inpatients with non-pulsatile physiology
tion in jugular venous pressure above 12-15 mmHg; one should achieve mean arterial pressures of70-
low cardiac output (mean arterialpressure below 60 80 mmHg. Traditional neurohormonal antagonists
mmHg, poor urine output, decrease central venous (angiotensin convertingenzyme inhibitors, angioten-
saturation);end organ dysfunction (renal or liver fail- sin receptor blockers, mineralocorticoid receptoran-
ure); and change in pump parameters(decrease in tagonists, hydralazine) should be used as first line

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Cardio Diabetes Medicine 2017 383

therapy, and beta-blockers only in patients without Management of Infections
evidence of significant right ventricular failure.
The most common pathogens in ventricular assist de-
Driveline management is an important part of the vice-related infections are Staphylococcus and Pseu-
long-term care. Use a thoracic driveline exit site and domonas and the most common site of infections
driveline dressings changed every third day are key is the percutaneous driveline exit site. One should
to prevent infections. If trauma to driveline exists site have a low threshold for blood culture collection to
occurs (e.g. dropping the controller, pulling the drive- evaluate for an occult bloodstream infection and
line during physical activities),patients remotely send patients should be aggressively treated with empiric
a picture of their exit site, and if erythema or early- antibiotics after blood cultures are obtained. Empiric
infection are identified, patients are promptly started therapy with cephalexin 500 mg oral every 6 hrs for
on oral antibiotics. 10 days, or doxycycline 100 mg oral every12 hrs for
10 days in patients with a history of/colonized with
All patients are optimized on neurohormonal antago- methicillin resistant Staphylococcus Aureus can be
nists for treatment of heartfailure, to the highest tol- used. The antibiotics are modified accordingly based
erated doses. Transthoracic echocardiography should on culture data. If the initial treatment has not led to
be used periodically(at 30 days, 3 months, then year- resolution of the superficial driveline infection, a 48-
ly) to optimize the ventricular assist device speed. In 72 hrs course of intravenous antibiotics can be used,
setting of recurrent heart failure, cardiac catheteriza- followed by longer oral antibiotic course (14-28 days).
tion in conjunction with echocardiography should be For recurrent superficial driveline infections, patients
used to assess and optimize the device function. should receive lifetime suppressive coverage. Deep
driveline infections are treated with intravenous van-
Atrial and ventricular arrhythmias should be con- comycin 15-20 mg/kg mg every 8-12 hrs and pipera-
trolled, using specific anti-arrhythmicdrugs (e.g. cillin/tazobactam4.5 g every 6 hrs for a minimum of 14
dofetilide, amiodarone, mexiletine) or cardioversion. days. Consideration for surgical exploration,debride-
The cardiac implantable electric devices should be ment and vacuum assisted closure system should be
interrogated every 3 months, at the time of the clinic given early for deep driveline infections.
visit, in order to correlate potential ventricular assist
device malfunction with concomitant arrhythmias. Management of Atrial and Ventricular
Arrhythmias
Management of Gastrointestinal Bleeding
In patients who develop symptomatic or sustained
After hospital discharge, the most common cause ventricular arrhythmias the hemodynamics should
of bleeding is the gastrointestinaltract. The reasons be optimized with medical therapy and pump op-
for this common complication are likely related to timization. Additional medical therapy consists of
the use of antithrombotictherapy, acquired von Wil- beta-blockers (irrespective of the right ventricu-
lebrand factor deficiency, acquired impairedplatelet lar function)and anti arrhythmic agents (including
aggregation, and intestinal angiodysplasia related to amiodarone, mexiletine, and sotalol).For patients
continuous flow technology. During the first bleeding with refractory ventricular tachycardia, catheter ab-
episode the gastrointestinaltract should be explored lation is an option. Atrial arrhythmias are common
in detail (upper endoscopy, colonoscopy, capsule in patients on ventricular assist device support and
endoscopy and doubleballoon enteroscopy) and the persistent atrial fibrillation has been associated with
identified lesions should be treated. If no lesions are worse right ventricular function and impaired func-
identified or if the bleeding is recurrent, further inves- tional capacity. Rhythm control strategies should be
tigations are not performed and patients should be used in these patients, and the INR goal should be
transfused to a hematocrit above 30%. Intravenous increasedto 2.5-3 in order to prevent microemboliza-
or oral iron supplements can be used, but erythro- tion.Rarely, if needed, catheter ablation can be used.
poietin-stimulating agents should be used, as they
have been associated with thrombotic complications Management of de Novo Aortic Insufficiency
in patients with ventricular assist devices. In patients
with recurrent bleeding or significant need for trans- Aortic valve insufficiency can develop denovo or un-
fusion, octreotide (monthly injectionsof long acting derlying aortic valve pathology may be exacerbated
octreotide) and/or oral thalidomide have been used after ventricular device implantation. In order to pre-
with good results. ventit, the valve should be replaced at the time of
implant if there is more than mild regurgitation.The
de novo occurrence of aortic insufficiency is more

Cardio Diabetes Medicine

384 Mechanical Circulatory Support for
Advanced Heart Failure

common with continuous-flowpumps and occurs due setting of hemorrhagic stroke, intracranial hemor-
to commissural fusion associated with reduced rates rhage, and subdural hemorrhage. Anticoagulation
of aortic valve opening. Medical management of aor- should be reversed immediately with prothrombin
tic insufficiency includes aggressive blood pressure factor concentrates or fresh frozen plasma.Warfa-
management to reduce the pressure gradientbetween rin and antiplatelet agents typically continue to be
the aorta and left ventricles. While percutaneous clo- withheld until the source ofthe hemorrhage has been
sure of the aortic valveand transcatheter aortic valve addressed or, if a source has not been identified,
replacement have been reported the best long term until the bleeding subsides and the affected area is
solution is surgical replacement. determined to be small enough to not bleed again.
In the setting of ischemic stroke, antihypertensive
Management of Pump Thrombosis and medications should be with held to allow for a high-
Pump Malfunction er systemic pressure (mean arterial pressure of 80-
90 mmHgor recovery of some pulsatility) to improve
Continuous flow devices are more likely to fail due to perfusion to the affected brain areas. In the setting
pump thrombosis rather than mechanical pump fail- of hemorrhagic stroke, intracranial hemorrhage, and
ure. In the vast majority of cases, pump thrombosis subdural hemorrhage,the blood pressure targets are
isdue to poor surgical pump or outflow graft position- lower. If the patient recovers, warfarin and aspirin are
ing, and/or suboptimal long-term anticoagulation. reinstituted upon discharge. All patients are provided
Typical presentations for pump thrombosis range with intensive in patient physical and occupational
from asymptomatic rise in plasma free hemoglobin therapy with the goal of discharging the patient to a
or lactate dehydrogenase, to hemolysis with hemo- stroke rehabilitation center to maximize their func-
globinuria, or to frank heart failure symptoms, asso- tional recovery.
ciated with ventricular assist device flow and power
elevations. Initial management strategies focus on Conclusions
patient stabilization and consideration of emergent
surgical interventions or thrombolytic agents, espe- Mechanical circulatory support devices represent a
cially in Medtronic HVAD pumps, which seem to be significant advancement in the field of heart failure.
more amenable to medical management. For these Device technology continues to evolve rapidly and
patients, low doses of tissue plasminogen activator patient survival is improving, both for those with car-
has been used in a dose of 10 mg intravenousas bo- diogenic shock and for those with chronic advanced-
lus, followed by an infusion of 10 mg over an hour, heart failure. Better patient selection, surgical tech-
with high dose unfractionated heparin (partial throm- niques and post-operative and long-term manage-
boplastin time of 70-80 s). If successful(normaliza- ment can minimize the device-related complications
tion of pump power and a decrease of lactate dehy- and allow more patients to benefit from this therapy.
drogenase levelsbelow 400 U/L), aggressive chronic It is likely than within a decade advanced heart failure
therapy should be used to prevent further thrombosis patients will benefit from a completely implantable
(INR 2.5-3). In patients with hemolysis refractory to assist device that will replace heart transplantation
intensification of antithrombotic therapy early device as the treatment of choice for advance heart failure.
exchange should be considered in order to minimize This device will provide full support, including phys-
the risk of stroke and death. iologic optimization (i.e. during exercise), will be im-
planted via a minimally invasive surgery, will enjoy
Management of Neurological Events limited complications rate, will be remotely monitored
and accessed, and will do so within cost effective
Neurological events (strokes) are relatively frequent parameters.
in patients with ventricular assist devices, with a
higher proportion of patients supported by Medtron-
ic HVADhaving hemorrhagic strokes compared to
patients supported by Abbott HeartMate II devices
(10% vs. 5%). Data from recent clinical trials havesh-
own that these events are likely due to uncontrolled
blood pressure. Ischemic strokes are equally fre-
quently seen in the two devices (5%) and are due
to suboptimal anticoagulation. All patients present-
ing with a neurological event should be hospitalized
and warfarin and antiplatelet agents withheld in the

GCDC 2017

Cardio Diabetes Medicine 2017 385

Table 1 Critical Cardiogenic Shock Patients with life-threatening hypotension despite rapidly
(“crash and burn”) escalating inotropic support, critical organ hypoperfusion,
Profile 1 often confirmed by worsening acidosis and/or lactate lev-
Profile 2 els.
Profile 3
Profile 4 Progressive Decline (“sliding Patient with declining function despite intravenous inotro-

Profile 5 on inotropes”) pic support; may be manifested by worsening renal func-

Profile 6 tion, nutritional depletion, or inability to restore volume

Profile 7 balance. Also describes declining status in patients unable

to tolerate inotropic therapy.

Stable but Inotrope Depen- Patient with stable blood pressure, organ function, nutri-
dent (“dependent stability”) tion, and symptoms on continuous intravenous inotropic

support (or a temporary circulatory support device or both),
but demonstrating repeated failure to wean from support
because of recurrent symptomatic hypotension or renal
dysfunction.

Resting Symptoms (“frequent Patient can be stabilized close to normal volume status

flyer”) but experiences daily symptoms of congestion at rest or

during activities of daily living. Doses of diuretics generally

fluctuate at very high levels. More intensive management

and surveillance strategies should be considered, which

may in some cases reveal poor compliance that would

compromise outcomes with any therapy. Some patients

may shuttle between profiles 4 and 5.

Exertion Intolerant (“house- Comfortable at rest and with activities of daily living but

bound”) unable to engage in any other activity, living predominantly

within the house. Patients are comfortable at rest without

congestive symptoms, but may have underlying refractory

elevated volume status, often with renal dysfunction. If un-

derlying nutritional status and organ function are marginal,

patient may be more at risk than in profile 4 and require

definitive intervention.

Exertion Limited (“walking Patient without evidence of fluid overload is comfortable
wounded”) at rest, and with activities of daily living and minor ac-
tivities outside the home, but fatigues after few minutes
of any meaningful activity. Attribution to cardiac limitation
requires careful measurement of peak VO2, in some cas-
es with hemodynamic monitoring to confirm severity of
cardiac impairment.

Advanced New York Heart A placeholder for more precise specification in future, this
Association functional class level includes patients who are without current or recent
III episodes of unstable fluid balance, living comfortably with

meaningful activity limited to mild physical exertion.

Cardio Diabetes Medicine

386 Mechanical Circulatory Support for
Advanced Heart Failure

Future directions:

• Design of hemocompatible surfaces will alleviate the need for anticoagulation and
minimize the risk of bleeding, pump thrombosis and stroke.

• Modulation of pulsatility in newer ventricular assist devices will likely decrease the
complications related to gastrointestinal bleeding or aortic valve insufficiency.

• Pump speed modulation will be used for antithrombotic cycling to prevent pump
thrombosis.

• In the future, speed modulation algorithms will respond to specific physiological
demands, such as those related to exercise and remote monitoring will be able to
control the pump.

• The advent of transcutaneous energy transfer will allow the development of
completely implantable devices, with improved quality of life and marked decrease
in the risk for infections.

• Newer devices will be miniaturized and will allow for smaller surgical or
transcatheter implantation.

• Similarly to cardiac implantable electric devices, remote monitoring will allow for
real time assessment of pump function.

• Ventricular assist devices will be used as platforms allowing concomitant
administration of full dose neurohormonal blockade and intramyocardial injections
of stem cells that will lead to myocardial recovery.

References:

1. Mozaffarian D, Benjamin EJ, Go AS, et al.; American Heart Association
Statistics Committee and Stroke Statistics Subcommittee. Executive Sum-
mary: Heart Disease and Stroke Statistics - 2016 Update: A Report From
the American Heart Association. Circulation. 2016; 133: 447-454.

2. Mehra MR, Canter CE, Hannan MM, et al. The 2016 International Society
for Heart Lung Transplantation listing criteria for heart transplantation: A
10-year update. J Heart Lung Transplant. 2016; 35: 1-23.

3. Fang JC, Ewald GA, Allen LA, et al. Advanced (stage D) heart failure: a
statement from the Heart Failure Society of America Guidelines commit-
tee. J Cardiac Fail. 2015; 21: 519-534.

4. Stevenson LW, Pagani FD, Young JB, et al. INTERMACS profiles of ad-
vanced heart failure: the current picture. J Heart Lung Transplant. 2009;
28: 535-541.

5. Kirklin JK, Naftel DC, Pagani FD, et al. Seventh INTERMACS annual re-
port: 15,000 patients and counting. J Heart Lung Transplant. 2015; 34:
1495-1504.

6. Estep JD, Starling RC, Horstmanshof DA, et al. Risk assessment and
comparative effectiveness of left ventricular assist device and medical man-
agement in ambulatory heart failure patients: results from the ROADMAP
study. J Am CollCardiol. 2015; 66: 1747-1761.

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Cardio Diabetes Medicine 2017 387

05. Invasive Procedure

1. Role of Percutaneous Intervention in Cardiovascular Diseases in Diabetes -
Prof. R.s. Hariharan

2. Percutaneous Coronary Intervention in the Management of Multi-Vessel CAD in Diabetics-
Is there Still a Role after Freedom Trial - Dr. Puvi Seshiah

3. Percutaneous Heart Repair- Can We Replace Open Heart Surgery - Dr. Puvi Seshiah

Cardio Diabetes Medicine

388 Role of Percutaneous Intervention in
Cardiovascular Diseases in Diabetes

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Cardio Diabetes Medicine 2017 389

Role of Percutaneous Intervention in
Cardiovascular Diseases in Diabetes

Prof. R.S. HARIHARAN. MD DR. R. H. SUNDAR. MD, DNB (Cardiology),

Director, Director, Cardiology
Hariharan Institute of Diabetes & Hariharan Diabetes& Heart care Hosp.Pvt.
Hariharan Diabetes & Heart Care Hospital (P) Ltd., Nanganallur, Chennai

Nanganallur, Chennai – 600 061.

Abstract that the commonest cause of death in diabetics is
cardiovascular in origin.
Cardiovascular diseases contribute to the increased
morbidity and mortality in Diabetes. During the past 2. Diabetes involves the arterial tree from head to
nearly two decades, primary prevention strategies toe irrespective of the vessel size. This involvement
and pharmacological approaches in the form of life results in more aggressive disease in diabetics than
style modification, cessation of smoking, physical their non-diabetic counterparts. Hence the need for
exercise, statins, nitrates and aspirin have been aggressive approach in the treatment of this epidem-
well addressed. The last decade is a witness to ic with newer technologies.
the emergence of percutaneous intervention as
an effective complementary treatment to surgical 3. Percutaneous intervention has made rapid strides
intervention in cardiovascular diseases in patients with in the past decade with the availability of modern
or without diabetes. It is the purpose of this presentation catheterization laboratories and newer hard- wares
to highlight the role of percutaneous intervention in permitting one to treat these vascular diseases with-
cardiovascular diseases in diabetes. out recourse to surgical intervention in a significant
number of patients.
Text
4. Percutaneous intervention has two important roles:
1. Diabetes is well – known as a metabolic-cum-
vascular disease. Its vascular complications are both * Diagnosis of the obstructive arterial disease
micro-vascular and macrovascular. The micro-vascular
complications of retinopathy and nephropathy, which * Treatment of the obstructive arterial disease
are specific for Diabetes develop at a higher glucose
threshold (viz 2 hour OGTT value of > 200mg%) than 5. The role of percutaneous intervention in the diag-
the macrovascular complications. The macrovascular nosis of cardiovascular diseases in diabetics:
complications that occur also in non-diabetics, occur at
a lower blood glucose threshold, (viz < 200mg%) than (i) Coronary angiogram helps not only to delineate
the microvascular complications in diabetics. Further, the Nature and extent of altherosclerotic coronary
their prevalence, incidence, distribution and severity artery disease, but also helps in the differential di-
are more in diabetics compared to non- diabetics. Even agnosis of cardiac failure in diabetics. In diabetics
though one is presenting with features of cardiac failure, a
normal coronary angiogram points to a diagnosis
concerned about the specific diabetic microangio- of diabetic cardiomyopathy, while the presence of
pathic complications of Diabetes, diabetics often obstructive coronary artery disease points to a diag-
succumb to macroangiopathic complications. This nosis of ischaemic cardiomyopathy. It further guides
was perhaps responsible for Miles Fisher to state in those with obstructive coronary artery disease as
that Diabetes should be defined as “a disease of to whether revascularisation is possible and, if so,
premature cardiovascular death due to chronic hy- should it be by percutaneous angioplasty or coronary
perglycaemia, and may also be associated with blind- artery bypass surgery.
ness and renal failure.” This vididly describes the fact
(ii) Likewise peripheral angiogram is extremely use-

Cardio Diabetes Medicine

390 Role of Percutaneous Intervention in
Cardiovascular Diseases in Diabetes

ful in guiding the appropriate treatment modalities in diseases of the aorta, carotid artery disease, subcla-
diabetics with foot lesion. vian artery disease, etc can also be treated percuta-
neously whenever required.
(iii) Similarly, from time to time renal angiogram helps
to diagnose renal artery stenosis as the cause of re- (d) Venous interventions in chronic kidney
sistant hypertension and recurrent cardiac failure due disease
to accelerated hypertension.
(CKD) patients undergoing dialysis is yet another
6. Role of percutaneous intervention in the manage- area where percutaneous therapies play a role in
ment of Cardiovascular diseases in diabetics: preventing arterio-venous fistula failures and treating
central venous occlusions.
Percutaneous intervention is very useful in several
clinical situations in the management of cardiovas- 7. Thus percutaneous intervention plays a signifi-
cular diseases in diabetics. They include: cant role in the management of various forms of
cardio-vascular diseases in the diabetes. The lecture
(a) Coronary artery disease: would illustrate the benefits of percutaneous inter-
vention based on our experience over the past 5
Coronary artery disease is perhaps the single largest years and stress the need for more awareness about
contributor to the morbidity and mortality amongst this specialised area of Diabetes Care
cardio-vascular diseases in diabetics. Primary angio-
plasty for acute myocardial infarction in general and and its greater application in clinical practice.
in diabetics in particular has shown significant mor-
tality benefit, preservation of left ventricular Summary

function and shortening of hospital stay in all the * Macrovascular disease is the leading causes of
major land mark trials. The same is true for other morbidity and mortality in diabetes.
forms of acute coronary syndromes. The debate be-
tween multi-vessel percutenous transluminal coro- * Coronary artery disease, peripheral arterial disease
nary angioplasty (PTCA) and coronary artery bypass and arterio-venous fistula failure contribute signifi-
graft (CABG) for stable angina is going on for more cantly to the burden in diabetics.
than a decade. However, with the availability of third
generation drug-eluting stents there is now data to * Apart from medical line of management, only sur-
show that multi-vessel PTCA in diabetics is non-in- gical management of these conditions was hitherto
ferior to CABG. This assumes greater significance in available.
our country today after the standardization of the
cost of stents. * Now, percutaneous intervention in atherosclerotic
disease of the coronaries, peripheral arteries and oth-
(b) Peripheral arterial disease: er macrovessels with high success rates has opened
up new vistas in their management.
Next to coronary artery disease, atherosclerotic pe-
ripheral arterial disease contributes significantly to * More awareness and greater application in clinical
the morbidity and mortality in diabetics. Indeed it is practice of percutaneous intervention as a special-
largely under - diagnosed and undertreated com- ised area of Diabetes Care needs to be stressed.
pared to atherosclerotic coronary artery disease.
Atherosclerotic diseases of lower limb arteries from
iliac to tibial arteries can be successfully treated per-
cutaneously to heal ischaemic ulcers and save limbs
threatened by

acute limb ischaemia can also be salvaged by percu-
taneous means. Lower limb interventions pose par-
ticular challenge to interventionists due to difficulty
in hardware selection and complexity of the anatomy
of the lesion.

(c)Renal artery disease

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Cardio Diabetes Medicine 2017 391

Percutaneous Coronary Intervention in The Man-
agement of Multi-Vessel CAD in Diabetics - is
There Still A Role After Freedom Trial

Dr. Puvi Seshiah, MD, FACC, FSCAI, FRCP (G)

Director, structural Heart Program,
TriHealth Heart Institute, Cincinnati

Abstract and EASD guidelines prescribe HbA1C < 7% in most
patients.
Diabetes is a systemic vascular disease character-
ized by hyperglycemia, dyslipidemia and end- organ BP control is consistently correlated with CV events.
damage. Macrovascular disease presents clinically as In the UKPDS, BP control was twice as effective as
myocardial infarction, stroke and peripheral vascular glucose control in diabetic endpoints but all cause
disease. Diabetes is a unique cardiovascular risk fac- mortality and MI did not differ. In the ABCD trial dia-
tor that should be treated differently from other risk stolic BP < 75 mmHg decreased CVD events. VADT
factors. Current guidelines recommend that patients trial showed DBP < 70 mmHg increased mortality.
with diabetes be treated as having a CAD equivalent. ACCORD- BP trial did not show a difference in SBP <
120 and SBP <140 mmHg. JNC-7 recommended target
Atherosclerosis is accelerated in diabetes predis- for Diabetics is < 130/<80 mmHg.
posing patients with diabetes to a 2 to4 fold lifetime
increase in CAD, with 75% of patients with diabetes * Current guidelines recommend high dose statins –
dying of a cardiovascular cause. Diabetics have a atorvastatin 80mg or rosuvastatin 40mg in patients
substantially higher incidence of multi-vessel disease with diabetes.
and a greater plaque burden at presentation, with the
extent and severity of CAD * Aspirin 75mg-162mg/day is uniformly recommend-
ed.
proportional to the duration of diabetes.
* Clopidogreluse was studied in the CHARISMA(4) tri-
Management of CAD in patients with diabetes pres- al ( ~80% Diabetics) and clopidogrel plus aspirin was
ents a unique challenge due to the extensive disease not significantly more effective than aspirin alone in
– multivessel and complex coronary lesions. Multiple reducing the rate of myocardial infarction, stroke, or
trials have tried to address the problem of treatment death from cardiovascular causes.
of multi-vessel CAD and the effect of diabetes. Man-
agement of these patients is indeed complex and * In patients with prior MI however Ticagrelor plus
may need a multi-disciplinary team approach. In this aspirin decreased death, MI and stroke rates in the
chapter we will highlight management strategies for PEGASYS(5) trial ( ~ 30% Diabetics)
diabetics with CAD.
* ACE inhibitors and Beta blockers have shown to
Contemporary Optimal Medical therapy decrease CV mortality and morbidity.
(OMT) in patients with CAD
* In patients with diabetes, newer therapies such
Glycemic control in diabetes over a long term may as sodium-glucose transporter-2 inhibitors and glu-
help reduce CV endpoints and mortality. Recent tri- cagon-like peptide-1 receptor agonists have been
als- ACCORD(1), ADVANCE(2) and VADT(3) failed to shown to reduce the risk of cardiovascular outcomes.
show any mortality benefit from aggressive glycemic However these have not been studied as a strategy
control (HbA1C < 6%) and indeed in the ACCORD trial of OMT in CAD in DM.
there was a 22% increase in total mortality with in-
tensive therapy driven by CV mortality. Current ADA * Achieving multiple risk factor (RF) goals through

Cardio Diabetes Medicine

392 Percutaneous Coronary Intervention in The Management of Multi-Vessel CAD

in Diabetics - is There Still A Role After Freedom Trial

protocol-guided intensive medical therapy is feasible
and improves outcomes in type 2 diabetes mellitus.
In a nonrandomized analysis of survival/cardio-
vascular events and control of 6 RFs (no smoking,
non-high-density lipoprotein cholesterol <130 mg/
dl, triglycerides <150 mg/dl, blood pressure [systol-
ic <130 mm Hg; diastolic <80 mm Hg], glycosylated
hemoglobin <7%) in BARI 2D(6) trial, there was a 2
fold decrease in death rate in patients with all 6 risk
factors in the optimal range compared to patients
with 0 to 2 RFs in control.

Figure 2: CT angiography showing Left internal mam-
mary artery graft to the distal LAD and a Saphenous
venous graft to the distal RCA. The Proximal RCA
and LAD are diffusely diseased with heavy plaque
burden.

Figure 1: Reduction in MACE with control of risk fac-
tors.

How CABG differs from PCI Figure 3 : CT angiography showing proximal LAD
stent with extensive ulcerated complex plaque distal
Bypass grafts from the Aorta and the mammary to the stent
arteries are anastomosed to distal, usually healthy
portion of coronary arteries. Vulnerable plaque is Contemporary surgical practices – Off-pump CABG
common in the proximal portions of coronary ar- have not shown to be superior to on-pump CABG in
teries and this increases the lifetime risk of future terms of clinical outcomes. Recent trials- ROOBY(7),
myocardial infarctions. The underlying rationale is CORONARY(8) and GOPCABE(9).
that the bypass graft will confer longer-term protec-
tion (for the lifespan of the graft) by preventing the All three trials showed similar prevalence of death,
clinical consequences of plaque rupture/myocardial stroke, and acute renal failure at 30 days among pa-
infarction, compared with a stent which would treat tients who underwent off-pump CABG and those who
the obstructive lesion alone. Atherosclerotic process underwent on-pump CABG. However trials showed
is diffuse and disease typically progresses distal to that patients who underwent off-pump CABG had
the stented segment. Hence patients who undergo fewer bypass grafts than those who underwent on-
PCI are not “protected” by plaque rupture that occurs pump CABG, a finding that suggests more incom-
distal to the stents. plete revascularization. In addition, both the CORO-
NARY and GOPCABE trials showed a higher preva-
lence of repeat revascularization at 30 days among
patients who underwent off-pump CABG than among
those who underwent on-pump CABG, a finding that
suggests less effective revascularization.

In the 5 yr follow up of the ROOBY trial the rate of
death at 5 years was 15.2% in the off-pump group

GCDC 2017

Cardio Diabetes Medicine 2017 393

versus 11.9% in the on-pump group (P=0.02). The rate elective PCI should receive 2nd or 3rd generation Drug
of major adverse cardiovascular events at 5 years eluting stents preferably Everolimus based stents.
was 31.0% in the off-pump group versus 27.1% in the Duration of DAPT in diabetics will need to managed
on-pump group (P=0.046). For the 5-year secondary on the basis of risk benefit ratio. The DAPT score
outcomes, no significant differences were observed: can help with this analysis. Usually diabetics have
for nonfatal myocardial infarction, for death from more extensive disease and benefit from longer term
cardiac causes, for repeat revascularization, and for DAPT.
repeat CABG.
Syntax score
PCI for treatment of CAD
Syntax score was an anatomic score designed to
The development of the first-generation DES (siro- objectively assess extent and complexity of CAD.
limus and paclitaxel) was a major breakthrough in This was initially done to help with randomization
PCI, especially in patients with Diabetes. it reduced of complex CAD patients for trials. It is an angio-
the incidence of restenosis in comparison to BMS. graphic tool to grade CAD complexity. The concept
In fact, a meta-analysis of 35 trials(10) showed that of SYNTAX score was prospectively validated in the
first-generation DES decreased target lesion revas- SYNTAX (14)trial. Using tertiles of the anatomic SYN-
cularization (TLR) when compared with BMS. Never- TAX score (low  <23, intermediate  23  to 32, high  ≥33)
theless, no difference in overall mortality, MI or stent in SYNTAX trial, patients were randomized to CABG
thrombosis was shown. Safer stent technology led versus multi-vessel PCI. Outcomes varied based on
to the development of the second-generation DES. the SYNTAX score.

A meta-analysis of 42 trials published in 2012 (12) SYNTAX score can be calculated using an online
analyzed five stent types – BMS, first-generation DES tool- www.syntaxscore.com.
and second-generation DES – in 10,714 patients with
diabetes (with 22,844 patient years of follow-up). In Trials comparing CABG to PCI in CAD
this study, all DES were associated with a significant
reduction in TVR (37% to 69%) when compared with Multiple randomized trials have addressed the issue
BMS; however, the efficacy varied with the type of of CABG vs PCI for revascularization of multi-vessel
DES. EES was found to be the most efficacious and coronary artery disease in patients with diabetes mel-
safe stent and it had the highest probability of being litus. While the debate over whether CABG or PCI is
associated with the lowest rate of TVR, MI and any the preferred mode of revascularization in diabetics
stent thrombosis. as lingered on, the value of revascularization over
(optimum medical therapy) OMT in patients with
The recent publication of the results of the TUXEDO stable CAD has itself been questioned. In the BARI
trial (13)”container-title”:”The New England journal 2D (Bypass Angioplasty Revascularization Investiga-
of medicine”,”page”:”1709-1719”,”volume”:”373”,”is- tion 2 Diabetes) study, a strategy of revasculariza-
sue”:”18”,”abstract”:”BACKGROUND: The choice of tion (CABG or PCI) + OMT was no better than OMT
drug-eluting stent in the treatment of patients with to reduce the risk of death or major cardiovascular
diabetes mellitus and coronary artery disease who events (MACE) (death, MI, or stroke). Similarly, in
are undergoing percutaneous coronary intervention the COURAGE trial, PCI did not reduce the risk of
(PCIgave some more insight in this context. In this death or MI, even in those with diabetes. However,
study, 1,788 patients with DM were randomized to in the BARI 2D trial, CABG reduced MACE over OMT,
receive PES (889 patients) or EES (899 patients). The mainly driven by a significant reduction in MI (7.4% vs.
primary endpoint was TVF (defined as a composite 14.6%), but not mortality (14.0% vs. 16.9%). Despite this,
of cardiac death, target vessel MI or ischemia-driv- the 2014 American College of Cardiology/American
en TVR). At one year, PES did not meet the criterion Heart Association stable ischemic heart disease
for non-inferiority to EES with respect to the primary guidelines recommend OMT, even in patients with
endpoint (5.6% vs. 2.9%; p=0.38 for non-inferiority). In diabetes, and revascularization is recommended only
addition, there was a significantly higher 1-year rate in patients whose symptoms compromise quality of
in the PES group of spontaneous MI (3.2% vs. 1.2%; life, despite OMT.
p=0.0004), stent thrombosis (2.1% vs. 0.4%; p=0.002),
TVR (3.4% vs. 1.2%; p=0.002), and TLR (3.4% vs. 1.2%; It must be highlighted that a considerable proportion
p=0.002). of patients who crossed over from OMT alone to re-
vascularization in the COURAGE (33%) and BARI 2D
In current practice, patients with DM who undergo (42%) trials makes it harder to consider OMT alone
as a treatment option, but more appropriately OMT

Cardio Diabetes Medicine

394 Percutaneous Coronary Intervention in The Management of Multi-Vessel CAD

in Diabetics - is There Still A Role After Freedom Trial

should be an initial strategy, with revascularization in rates of both myocardial infarction (P<0.001) and
needed in 1 out of every 2 or 3 patients. death from any cause (P=0.049). Stroke was more
frequent in the CABG group, with 5-year rates of
SYNTAX trial(14)randomly assigned 1800 patients 2.4% in the PCI group and 5.2% in the CABG group
with three-vessel or left main coronary artery disease (P=0.03).   There was increased all-cause mortality in
to undergo CABG or PCI (in a 1:1 ratio). For all these the PCI group (P=0.049), with 5-year rates of 16.3% in
patients, the local cardiac surgeon and intervention- the PCI group versus 10.9% in the CABG group, for an
al cardiologist determined that equivalent anatomi- absolute difference of 5.4 percentage points.
cal revascularization could be achieved with either
treatment.Rates of major adverse cardiac or cere- In patients with a low SYNTAX score (i.e., ≤22),
brovascular events at 12 months were significantly there was a minimal difference in long-term clini-
higher in the PCI group (17.8%, vs. 12.4% for CABG; cal outcomes between cardiac surgery and PCI with
P=0.002), in large part because of an increased rate first-generation drug-eluting stents.
of repeat revascularization (13.5% vs. 5.9%, P<0.001).
At 12 months, the rates of death and myocardial in- BEST Trial(16)randomized multi-vessel CAD patients
farction were similar between the two groups. How- to CABG vs PCI with 2nd generation Everolimus stents.
ever stroke was significantly more likely to occur with 40% of these patients had diabetes.During long-term
CABG (2.2%, vs. 0.6% with PCI; P=0.003). follow-up, the primary end point occurred more fre-
quently in the PCI group than in the CABG group
Patients were categorized into low (<22), intermediate (15.3% vs. 10.6%; hazard ratio, 1.47; 95% CI, 1.01 to 2.13;
(23-32) and high (>33) score based on their coronary P=0.04). This difference was attributed largely to the
anatomy.In the CABG group, the binary 12-month preponderance of events of any repeat revasculariza-
rates of major adverse cardiac or cerebrovascular tion in the PCI group. Importantly rate of Death, stroke
events were similar among patients with low SYN- or MI did not defer between the two groups.  Among
TAX scores (0 to 22, 14.7%) to those with interme- patients with diabetes, the rate of the primary end
diate scores (23 to 32, 12.0%), and those with high point was significantly higher among those assigned
scores (≥33, 10.9%). In contrast, in the PCI group, the to PCI than among those assigned to CABG (19.2%
rate of major adverse cardiac or cerebrovascular vs. 9.1%, P=0.007)
events was significantly increased among patients
with high SYNTAX scores (23.4%) as compared with Revascularization of patients with Diabetes
those with low scores (13.6%) or intermediate scores
(16.7%) (P=0.002 for high vs. low scores; P=0.04 for Taken altogether treatment of DM patients with MVD
high vs. intermediate scores) and SYNTAX score > 23 remains in the domain of
cardiac surgery as primary treatment.
At 5 years the overall adverse-event rate was low-
er with CABG (27%) than with PCI (37%;  P<0.001). It perhaps is not unreasonable to offer CABG as the
However, neither all-cause mortality nor stroke rate primary revascularization modality when a patient
differed significantly between the two groups. The with DM develops 3 VD based on the FREEDOM tri-
rates of MI and repeat revascularization were higher al. Strategy of offering patients with Diabetes CABG
with PCI than with CABG (9.7% vs. 3.8% and 26% vs. early particularly when there is limited plaque burden,
14%, respectively).In patients with SYNTAX scores ≥33, runs the risk of grafts failing in the long term. On the
the overall adverse-event rate was 27% with CABG other hand if CABG is offered too late, perioperative
and 44% with PCI, including a statistically significant risks increase due to co-morbidities and too diffuse
absolute increase in all-cause mortality of about 8% CAD will preclude graft placement, thereby losing the
with PCI. mortality benefit of CABG over PCI.

Only about 25% of the patients enrolled were medi- In addition to anatomical disease and clinical fac-
cally treated Diabetics. tors, some non-clinical factors may influence choice
of therapy. For example- socio-economic status, pa-
FREEDOM trial (15)coronary-artery bypass grafting tientswishes, operator skill, cultural acceptance and
(CABG randomnly assigned patients with diabetes resource availablilty.
and multivessel coronary artery disease to undergo
either PCI with first generation drug-eluting stents Multi-disciplinary team approach to management of
or CABG.  The primary outcome occurred more fre- these complex patients while inconvenient may help
quently in the PCI group (P=0.005), with 5-year rates management of these patients.
of 26.6% in the PCI group and 18.7% in the CABG
group. The benefit of CABG was driven by differences

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Cardio Diabetes Medicine 2017 395

Figure 4 : Adopted from Serruys et al (17). The Heart 6. Bittner V, Bertolet M, Barraza Felix R, Farkouh ME, Goldberg S, Ramana-
Team and Decision-Making in Complex Coronary than KB, et al. Comprehensive Cardiovascular Risk Factor Control Improves
Artery Disease. The complex interaction among an- Survival: The BARI 2D Trial. J Am CollCardiol. 2015 Aug 18;66(7):765–73.
atomic complexity, clinical factors/comorbidities,
patient wishes, and local resources the heart team 7. Shroyer AL, Hattler B, Wagner TH, Collins JF, Baltz JH, Quin JA, et al.
needs to consider in decision-making in patients with Five-Year Outcomes after On-Pump and Off-Pump Coronary-Artery Bypass.
complex coronary artery disease. N Engl J Med. 2017 Aug 16;377(7):623–32.

Conclusion 8. Lamy A, Devereaux PJ, Prabhakaran D, Taggart DP, Hu S, Straka Z, et al.
Five-Year Outcomes after Off-Pump or On-Pump Coronary-Artery Bypass
Diabetics with CAD have extensive disease and have Grafting. N Engl J Med. 2016 Oct 23;375(24):2359–68.
higher morbidity and mortality related to CV events.
Optimal medical therapy with control of 6 RFs (no 9. Diegeler A, Börgermann J, Kappert U, Breuer M, Böning A, Ursulescu A,
smoking, non-high-density lipoprotein cholester- et al. Off-Pump versus On-Pump Coronary-Artery Bypass Grafting in Elderly
ol <130 mg/dl, triglycerides <150 mg/dl, blood pres- Patients. N Engl J Med. 2013 Mar 11;368(13):1189–98.
sure [systolic <130 mm Hg; diastolic <80 mm Hg],
glycosylated hemoglobin <7%) decreased mortality. 10. Stettler C, Allemann S, Wandel S, Kastrati A, Morice MC, Schomig A, et
In patients with continued symptoms revasculariza- al. Drug eluting and bare metal stents in people with and without dia-
tion with CABG or PCI should be considered using a betes: collaborative network meta-analysis. England; 2008 Aug p. a1331.
multi-disciplinary approach. Several non-clinical fac-
tors influence the choice of therapy for these patients 11. Kufner S, de Waha A, Tomai F, Park S-W, Lee S-W, Lim D-S, et al. A
and should be considered on an individualized basis. meta-analysis of specifically designed randomized trials of sirolimus-eluting
versus paclitaxel-eluting stents in diabetic patients with coronary artery
disease. Am Heart J. 2011 Oct;162(4):740–7.

12. Bangalore S, Kumar S, Fusaro M, Amoroso N, Kirtane AJ, Byrne RA, et al.
Outcomes with various drug eluting or bare metal stents in patients with
diabetes mellitus: mixed treatment comparison analysis of 22,844 patient
years of follow-up from randomised trials. BMJ. 2012 Aug 10;345:e5170.

13. Kaul U, Bangalore S, Seth A, Arambam P, Abhaichand RK, Patel TM, et al.
Paclitaxel-Eluting versus Everolimus-Eluting Coronary Stents in Diabetes.
N Engl J Med. 2015 Oct 29;373(18):1709–19.

14. Serruys PW, Morice M-C, Kappetein AP, Colombo A, Holmes DR, Mack MJ,
et al. Percutaneous Coronary Intervention versus Coronary-Artery Bypass
Grafting for Severe Coronary Artery Disease. N Engl J Med. 2009 Mar
5;360(10):961–72.

15. Farkouh ME, Domanski M, Sleeper LA, Siami FS, Dangas G, Mack M, et
al. Strategies for multivessel revascularization in patients with diabetes.
N Engl J Med. 2012 Dec 20;367(25):2375–84.

16. Park S-J, Ahn J-M, Kim Y-H, Park D-W, Yun S-C, Lee J-Y, et al. Trial of
Everolimus-Eluting Stents or Bypass Surgery for Coronary Disease. N Engl
J Med. 2015 Mar 16;372(13):1204–12.

17. Serruys PW, Farooq V. Cherry-Picking Historical Data to Legitimize Con-
temporary Practice. J Am CollCardiol. 2017 Jan 23;69(4):404.

References:

1. Effects of Intensive Glucose Lowering in Type 2 Diabetes. N Engl J Med.
2008 Jun 12;358(24):2545–59.

2. Intensive Blood Glucose Control and Vascular Outcomes in Patients with
Type 2 Diabetes. N Engl J Med. 2008 Jun 12;358(24):2560–72.

3. Duckworth W, Abraira C, Moritz T, Reda D, Emanuele N, Reaven PD, et
al. Glucose Control and Vascular Complications in Veterans with Type 2
Diabetes. N Engl J Med. 2009 Jan 8;360(2):129–39.

4. Bhatt DL, Fox KAA, Hacke W, Berger PB, Black HR, Boden WE, et al.
Clopidogrel and Aspirin versus Aspirin Alone for the Prevention of Athero-
thrombotic Events. N Engl J Med. 2006 Apr 20;354(16):1706–17.

5. Bonaca MP, Bhatt DL, Cohen M, Steg PG, Storey RF, Jensen EC, et al.
Long-Term Use of Ticagrelor in Patients with Prior Myocardial Infarction.
N Engl J Med. 2015 Mar 14;372(19):1791–800.

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396 Cardio Diabetes Medicine 2017

Percutaneous Heart Repair- Can We Replace
Open Heart Surgery

Dr.Puvi Seshiah, MD, FACC, FSCAI, FRCP (G)

Director, structural Heart Program,
TriHealth Heart Institute, Cincinnati

Coronary angioplasty was the first percutaneous Figure 1: Andersen Valve
therapy that revolutionized minimally invasive thera- Several transcatheter valve companies have brought
pies for heart disease. 2017 is the 40th year anniversa- innovations to improve deliverability and safety of the
ry of the first PTCA performed in man. In 1984 the first procedure. Design changes to deal with paravalvular
mitral balloon valvuloplasty was described by Inoue leak and smaller delivery catheters which have led to
followed by aortic valvuloplasty by Dr. Alain Cribier. improved outcomes.
This soon led to the first aortic valve implant in a pig
by Dr. Hening Andersen in 1989. First human implant Figure 2: Several design advancement in TAVR valves.
of catheter based valve was done in 2000 – RV to PA Corevalve and Sapien.
conduit by Dr. Bonhoeffer.Percutaneous valve thera-
pies have evolved since the first transcatheter aortic
valve implant in 2002. The therapy has changed how
we approach and treat valve disease. Advances in
catheter based technology have led to therapies for
all of the valves.

This chapter will explore the different valve therapies
that can possibly replace open surgical valve repair/
replacement.

History of Transcatheter Valve Therapy

Hening Rud Andersen was training as an interven-
tional cardiologist in 1989 and was inspired by a pre-
sentation of coronary artery stents. He built a valve
himself bending wires to create a stent and buying
pig hearts from the local butcher shop for the aortic
valves. He then built a transcatheter delivery device
inspired by the Cribier-Letac balloon catheter pio-
neered in France during the 1980s for balloon aortic
valvuloplasty (BAV) by Alain Cribier MD. From con-
ception to proof-of-concept took Andersen just 75
days.

On May 1st, 1989, he implanted the valve in a pig and
it survived. His patent was sold to a company that led
to the FIM implant in 2002 by Dr. Cribier in France
via a transeptal approach. (1)

GCDC 2017

Percutaneous Heart Repair - 397
Can We Replace Open Heart Surgery

Figure 3: Design changes have resulted in smaller A (2)(n = 699) for high-risk surgical patients (Society
delivery catheters. of Thoracic Surgeons score >10%, surgeon assessed
risk of mortality >15%) and PARTNER B(3) (n = 358,
Transcatheter Aortic Valve Replacemement patients inoperable by assessment of 2 surgeons).
PARTNER A patients were divided into femoral ar-
The original TAVR valve from Sapien was deployed in tery access transcatheter aortic valve replacement or
an antegrade approach using a transeptal approach none (n = 207), and then randomized to open aortic
due to the large size of the device and catheter. valve replacement (n = 351) or device (n = 348). Inclu-
Refinements in the valve and delivery system led to a sion criteria included valve area <0.8 cm(2), gradient
retrograde transfemoral, subclavian or direct thoracic >40 mm Hg or peak >64 mm Hg, and survival >1 year.
approach or antegrade transapical approach. Today The end point of the study was 1-year mortality.
majority of TAVR are done femorally > 80%.
It tried to answer two questions: 1. Was TAVR equiv-
Figure 4: A: Edwards Sapien Valve Deployment B: alent to surgical AVR (PARTNER A)
Medtronic Transfemoral Corevalve Deployment C:
Sapien Transapical deployment. 2. Was TAVR better then medical therapy for inoper-
able aortic stenosis (PARTNER B)
Trials of Transcatheter Aortic Valve
Replacement (TAVR) Thirty-day mortality for PARTNER A was 3.4% for tran-
scatheter aortic valve replacement and 6.5% for aor-
There are several TAVR valves that have been ap- tic valve replacement; 1-year mortality was 24.2% and
proved for use in aortic stenosis. The most commonly 26.8%, respectively (P = .001 for noninferiority). The re-
used valves are the Edwards Sapien S3 valve (60% ) spective prevalence of stroke was 3.8% and 2.1% (P =
and the Medtronic Corevalve Evolut (30%). .2), although for all neurologic events, the difference
The first major randomized trial that led to the FDA between transcatheter aortic valve replacement and
approval was the PARTNER Trial. This was a prospec- aortic valve replacement was significant (P = .04), in-
tive, randomized trial designed with 2 arms: PARTNER cluding 4.6% for femoral artery access transcatheter
aortic valve replacement versus 1.4% for open aortic
valve replacement (P = .05)

For PARTNER B--transcatheter aortic valve replace-
ment versus medical treatment-30-day mortality was
5.0% versus 2.8% (P = .41), and at 1 year, mortality was
30.7% versus 50.7% (P < .001), respectively.

Similar results were seen in the Corevalve trials.

So, in High risk and inoperable patients, TAVR has
replaced surgery.

PARTNER 2(4)randomly assigned 2032 intermedi-
ate-risk patients with severe aortic stenosis, at 57
centers, to undergo either TAVR or surgical replace-
ment. The primary end point was death from any
cause or disabling stroke at 2 years.

Non-inferiority was met at 2-year follow-up, with the
primary endpoint (composite mortality or disabling
stroke) occurring in 19.3% of TAVR versus 21.1% of
SAVR patients (P = .25). Patients were considered in-
termediate risk (mean STS score, 5.8%), and 76.3%
of TAVR recipients were treated via the femoral ap-
proach.

In the femoral access cohort, TAVR resulted in lower
mortality from any cause or disabling stroke com-
pared with SAVR (P = .04)

So, in Medium risk patients TAVR has replaced sur-

Cardio Diabetes Medicine

398 Cardio Diabetes Medicine 2017

gery also.

PARTNER 3 And Corevalve Low risk Trial are eval-

uating TAVR vs Surgery in low risk patients. NO-

TION(5)”container-title”:”Journal of the American Col-

lege of Cardiology”,”page”:”2184”,”volume”:”65”,”is-

sue”:”20”,”abstract”:”Background Transcatheter

aortic valve replacement (TAVRTrial randomized 280

patients- Mean age was 79.1 years, and 81.8% were

considered low-risk patients, STS < 4%. In the inten-

tion-to-treat population, no significant difference in

the primary endpoint was found (13.1% vs. 16.3%; p =

0.43 for superiority)

In the near future, all patients with degenerative aor-
tic stenosis will undergo TAVR and not surgery.

Figure 5: Growth of TAVR vs Surgical AVR in the US

Transcatheter Mitral Valve Repair / Figure 6: Mitraclip for MV repair.
Replacement (TMVR)
Mitral valve repair devices that have received CE Mark
TMV repair has been slower to grow than TAVR due include the Abbott Mitraclip, Mitralign and Edwards
to the complexity of the mitral valve and its function Cardioband. Mitraclip was first implanted in 2003
in relation to the Left ventricle. Mitral valve regurgi- and has been used to most with worldwide use in >
tation can be primary or secondary.Primary etiology 45000 patients.
involves degeneration of the MV apparatus. Second-
ary etiology is due to LV dysfunction and annular dil- Currently in the US this is approved for Primary MR
atation. This makes treatment of mitral valve defects only however data is encouraging in patients with
more complex as there is no single solution that will secondary MR.
work for all the etiologies.
EVEREST II(6) randomized 279 patients with moder-
ate to severe (3+ or 4+) MR and high surgical risk in a
2:1 fashion to either percutaneous (n = 184) or surgical
(n = 95) treatment. The primary outcome was freedom
from a composite of death, repeat mitral surgery, or
3+ or 4+ MR. At 5 years, this occurred in 44.2% of
MitraClip patients vs 64.3% of surgical patients (P =
0.01). Mortality was not different between groups.
The composite outcome was driven by higher rates
of moderate-to-severe MR (12.3% vs 1.8%; P = 0.02)
and mitral surgery (27.9% vs 8.9%; P = 0.03) in the
percutaneous group. Looking at the data over time,
however, the majority (78%) of mitral surgeries oc-

GCDC 2017

Percutaneous Heart Repair - 399
Can We Replace Open Heart Surgery

curred during the first 6 months. Between 6 months recently.
and 5 years, however, there was no difference be-
tween the percutaneous and surgical groups in the Figure 8: Mitral Valve-in-valve Transapical approach.
incidence of surgery for mitral dysfunction. Surgery
was more effective than MitraClip in terms of free- Transcatheter Pulmonary Valve Implantation
dom from MR and repeat mitral surgery. MitraClip is
not a replacement for surgery, but rather is a viable Percutaneous pulmonic valve implantation (PPVI) was
option for selected patients who are thought to be at developed as a nonsurgical treatment for patients
prohibitive surgical risk. with right ventricular outflow tract (RVOT) dysfunc-
tion. PPVI devices are intended for use in a dysfunc-
A propensity-matched comparison of EVEREST II tional (stenotic or regurgitant) right ventricle-to-pul-
HRR/REALISM patients and high-risk Duke Echo- monary artery conduit. PPVI is intended to extend
cardiography Laboratory Database patients man- the lifetime of a right ventricle-to-pulmonary artery
aged nonsurgically suggested a survival benefit with conduit and hence reduce the total number of open-
MitraClip therapy at 12 months (relative risk, 0.64; heart surgeries required over a patient’s lifetime.
P = .013). Similarly, a propensity-matched cohort of Some centers have extended the application of PPVI
120 patients with cardiomyopathy and functional MR to treat patients with tetralogy of Fallot without a con-
showed improved rates of hospital readmission and duit and to treat patients with tetralogy of Fallot with
overall survival when MitraClip therapy was com- failing pulmonic bioprosthetic valves.
pared to optimal medical therapy. The Medtronic Melody Transcatheter Pulmonary
Valve is available in two sizes (20 and 22).(8) The
Mitral Valve Replacement experience remains at an 20 mm valve can be implanted with a diameter of
early stage. There have been important challenges 18 or 20 mm balloon and the 22 mm valve with an
in the development of this technology, including 18, 20, or 22 mm delivery system or 22. The Melo-
the complexity of the mitral valve anatomy involv- dy valve consists of a 34 mm bare metal Cheatham
ing a saddle oval shape, the subvalvular apparatus, platinum stent (NuMED CP Stent CP8Z34) into which
the interaction with the left ventricular outflow tract a Medtronic Contegra bovine jugular venous valve is
(LVOT) and the aortic valve, as well as the large size hand-sewn. The valve is crimped onto a designat-
of transcatheter MVR devices and large catheters for ed double balloon delivery system requiring a 22 F
implantation. sheath.
The Edwards SAPIEN Pulmonic Transcatheter Heart
Figure 7: A: Sapien S 3 Valve B. CardiaQ Valve C. Valve is available in three sizes, 23, 26, and 29 mm.
Medtronic Intrepid D. Abbott Tendyne Valve

Patients with failed surgical mitral bioprostheses or
rings have been treated with the off-label use of stan-
dard aortic transcatheter heart valve devices(7). The
pre-existing circular frame provided by a surgical bi-
oprosthesis and some surgical rings can be used as
a landing zone and provide anchoring for a balloon
expandable or newer aortic transcatheter heart valve
devices. This technique has been used in patients
with severe Mitral annular calcification. Transcathe-
ter mitral valve-in-valve and valve-in-ring have been
successfully performed and has been FDA approved

Cardio Diabetes Medicine

400 Cardio Diabetes Medicine 2017

Transcatheter Tricuspid Valve Repair/
Replacement

The current transcatheter approaches for treating TR
can be grouped by mechanism of action, including
annuloplasty systems, coaptation devices, leaflet de-
vices, caval valve implantation, and tricuspid valve re-
placement. All of the devices are in the early phases
of development in the TR space, and only one has
completed an early feasibility trial. Despite this, there
is significant excitement regarding the potential ben-
efits of these therapies.

Conclusion

Percutaneous devices have rapidly progressed from
closure of simple cardiac defects (ASD, VSD) to more
complex repair of cardiac valves. In some cases they
have begun to replace surgery as the initial means of
repair. With advances in transcatheter valves, surgery
may become obsolete.

References

1. Cribier A, Eltchaninoff H, Bash A, Borenstein N, Tron C, Bauer F, et al.
Percutaneous transcatheter implantation of an aortic valve prosthesis for
calcific aortic stenosis: first human case description. Circulation. 2002
Dec 10;106(24):3006–8.

2. Leon MB, Smith CR, Mack M, Miller DC, Moses JW, Svensson LG, et al.
Transcatheter Aortic-Valve Implantation for Aortic Stenosis in Patients Who
Cannot Undergo Surgery. N Engl J Med. 2010 Sep 22;363(17):1597–607.

3. Smith CR, Leon MB, Mack MJ, Miller DC, Moses JW, Svensson LG, et
al. Transcatheter versus Surgical Aortic-Valve Replacement in High-Risk
Patients. N Engl J Med. 2011 Jun 5;364(23):2187–98.

4. Leon MB, Smith CR, Mack MJ, Makkar RR, Svensson LG, Kodali SK, et al.
Transcatheter or Surgical Aortic-Valve Replacement in Intermediate-Risk
Patients. N Engl J Med. 2016 Apr 2;374(17):1609–20.

5. Thyregod HGH, Steinbrüchel DA, Ihlemann N, Nissen H, Kjeldsen BJ,
Petursson P, et al. Transcatheter Versus Surgical Aortic Valve Replacement
in Patients With Severe Aortic Valve Stenosis. J Am Coll Cardiol. 2015
May 26;65(20):2184.

6. Feldman T, Foster E, Glower DD, Kar S, Rinaldi MJ, Fail PS, et al. Percu-
taneous Repair or Surgery for Mitral Regurgitation. N Engl J Med. 2011
Apr 4;364(15):1395–406.

7. Cheung A, Webb JG, Barbanti M, Freeman M, Binder RK, Thompson C,
et al. 5-Year Experience With Transcatheter Transapical Mitral Valve-in-
Valve Implantation for Bioprosthetic Valve Dysfunction. J Am Coll Cardiol.
2013 Apr 30;61(17):1759.

8. McElhinney DB, Hellenbrand WE, Zahn EM, Jones TK, Cheatham JP,
Lock JE, et al. Short- and medium-term outcomes after transcatheter
pulmonary valve placement in the expanded multicenter US melody valve
trial. Circulation. 2010 Aug 3;122(5):507–

GCDC 2017

Cardio Diabetes Medicine 2017 401

06. Therapeutics Options

1 Real World Effect of Type 2 Diabetes Therapies on HbA1c and Weight - Dr. Kevin Shotliff
2 Raising the Standard of Care in Cardiodiabetes Post Graduate Diploma in Cardiodia-

betes -Professor Ram Dhillon
3 DM Management in Special Situations – - Prof. (Dr.) Sandeep Bansal
4 Cardiac Emergencies in Diabetes Mellitus - Dr. Arvinth Soundarrajan
5 Don’t Let Diabetes Pull Down our Foot - Prof. Dr. J. A.jayalal
6 Glycemic Control- How Tight it Should Be? - Dr. Janani Karthik
7 New Armamentarium in Combined dyslipidemia Management – Current Evidences -

Dr Sudhir Mehta
8 Cardiovascular Outcomes with Antihyperglycemic Therapy: Past , Present And Future

Impact on Practice - Dr. V. Balachandran
9 Obesity- Pharmacotherapy - Dr. Rakesh Kumar Sahay
10 Bariatric Surgery In Diabesity : What is Endocrinologist’s Perspective? - Dr. S. Murthy
11 Idnetifying the Right Patients Who Benefits from AICD Implantation - Dr. Raja Selvaraj
12 Heart Failure: Drug Therapies and Revascularization Strategies - Dr Abraham Oomman
13 When to Use ? When Not to Use ? - Antiplatelets - Prof. A.S. Mohan
14 Nutrient Manipulation for Obesity , Metabolic Syndrome and Diabetes -

Dr. Sethuramashankaran
15 Cardio Vascular Safety of Antidiabetic Drugs –Do we know Enough? - Dr. S. Saravanan
16 NAFLD And CVD - Importance and Therapies - Dr. R. Ramasubramanian
17 Foot Care in Type 2 Diabetes - Dr.Vijay Viswanathan
18 Newer Guidelines on Cardiac Arrest in Nutshell - Dr. S. Senthilkumaran
19 Stable Ischaemic Heart Disease in Diabetics: Medical Therapy vs Revascularization -

Dr. Gurpreet S Wander
20 New Lipid Lowering Therapies - Dr. Devaki Nair
21 Drugs on Pipeline For Management of Diabetes- An Overview - Dr .P. Rajavel Murugan
22 Hyperglycemia & Glycemic Control In ICU - Prof. Dr. S. Arulrhaj
23 Stroke Thrombectomy - Dr. A. L. Periyakaruppan
24 Obesity and Weight Management-Current concepts - Dr. Isaac Christian Moses
25 Convertible Visceral Fat as a Therapeutic Target to Curb Obesity - Dr. P.G. Sundararaman
26 Inotropes and Heart : When to Use and When Not to Use - Dr. J. Cecily Mary Majella
27 Integrated Management of Diabetes Through Novel Therapies - Dr. Dina Nagodra
28 Initiation & Intensification of Insulin Therapy in T2DM - Dr. Palaniappen
29 Cardio Diabetic Therapeutics – When to Use? When Not to Use –OHA - Dr. A. J. Asirvatham
30 Novel Oral Anti Coagulants in Chronic Kidney Disease - Dr. Georgi Abraham
31 Sulfonylureas and Cardiovascular Mortality? - Dr. Vimala Paul
32 Glucose Lowering Strategies and Cardiovascular Outcomes - Dr. Rakesh Sahay

Cardio Diabetes Medicine

402 Real World Effect of Type 2 Diabetes
Therapies On HbA1c and Weight

GCDC 2017

Cardio Diabetes Medicine 2017 403

Real World Effect of Type 2 Diabetes
Therapies On HbA1c and Weight

Dr. Kevin Shotliff, UK

Consultant Physician, Diabetes and Endocrinology
beta Cell Diabetes Centre

Chelsea and Westminster Hospital, London.

Abstract: Conclusions: These results suggest that it may be ap-
propriate to tailor treatment choices towards individu-
Background: Type 2 Diabetes Mellitus is an ever-in- al patients. GLP-1 receptor agonists and Dapagliflozin
creasing healthcare problem worldwide. Several new- may have a role if weight loss is particularly desired.
er agents have been developed in order to tackle this
burden and reduce the incidence of diabetes related Keywords: Type 2 diabetes, Therapies, Weight
complications. Revised National Institute for Health
and Care Excellence (NICE) guidelines for the man- Introduction
agement of Type 2 Diabetes have met with some
controversy, including the order and combination in Type 2 Diabetes Mellitus (T2DM) is an increasingly
which some therapeutic options have been recom- prevalent worldwide issue, affecting over 3.2 million
mended. people, and causing 22,000 premature deaths a year
in England and Wales. There are also a further 5 mil-
Objectives: To collect and analyse patient data re- lion people who have blood glucose levels giving a
lated to Type 2 Diabetes for those who have been high risk of developing type 2 diabetes (PHE August
commenced upon newer agents in order to compare 2015). This chronic metabolic condition, costing 10%
the performance of different therapies/ class against of the NHS budget or £8.8 billion per year, involves
each other. a combination of pancreatic insufficiency and insu-
lin resistance resulting in hyperglycemia and is typi-
Methods: Patient records for those with Type 2 Dia- cally associated with obesity. Management of blood
betes Mellitus who had attended the Beta cell clinic glucose levels and other cardiovascular risk factors
at Chelsea and helps to reduce the number developing microvascu-
lar and macrovascular complications, such as chronic
Westminster Hospital were examined for commence- kidney disease (CKD), cardiovascular disease, periph-
ment upon Sulphonylureas, GLP-1 receptor agonists, eral neuropathy and diabetic retinopathy, the leading
DPP-4 cause of preventable sight loss in people of working
age in the UK (1,2,3).
inhibitors and SGLT-2 inhibitors. Demographic and
biochemical data relevant to the assessment of Type The association between T2DM and obesity is well
2 Diabetes was collected at baseline and after 3 and documented and in England at present.~90% of adults
12 months. Data were analysed using Analysis of with T2DM have a BMI>25. The benefits of weight
Variance (ANOVA) and the Unpaired T Test. loss in T2DM are not only to improve glycaemic con-
trol, but also on other obesity related co-morbidities
Results: There was no significant difference for such as; hypercholesterolaemia, cardiovascular dis-
change in any of the outcome measures, exclud- ease and arthritis. NICE / National Institute of Clinical
ing change in weight, between any of the treatment Excellence guidance on the management of T2DM
options. GLP-1 receptor agonists and Dapagliflozin (NG28) now reinforces medical management deci-
caused the largest fall in weight, and Sulphonylureas sions based not only on HbA1c, but also body weight.
caused a slight rise in weight. Within the individual This is helped by several newer therapies, such as
therapeutic classes, there were no significant differ- Glucagon-like peptide-1 (GLP-1) receptor agonists, Di-
ences between individual agents for change in any
of the outcome measures.

Cardio Diabetes Medicine

404 Real World Effect of Type 2 Diabetes
Therapies On HbA1c and Weight

peptidyl peptidase-4 (DPP-4) inhibitors, and SGLT-2 Results
inhibitors that not only reduce blood glucose, but can
also have a beneficial impact on body weight, com- Baseline demographics for HbA1c and weight for
pared to older agents such as the sulphonylureas, each treatment group are shown in table one. For all
which are typically associated with weight gain, as patients, the mean blood pressure was 137/78 mmHg
is insulin therapy (4,5,6). and the average lipid profile of patients was; total
cholesterol 4.39mmol/L, triglyceride 2.09mmol/L,
Clinical trials suggest GLP-1 agonists reduce HbA1c LDL 2.34 mmol/L and HDL 1.13mmol/L. There was
by 9-16mmol/mol and weight by 2- 3kg(7), SGLT-2 no significant difference within each class for blood
inhibitors reduce HbA1c by 6-11mmol/mol and weight pressure and lipid profile at any of the time intervals.
2-3kg(8,9) , whilst DPP-4 inhibitors reduce HbA1c by
7-11mmol/mol and have a more weight neutral effect Analysis within each class
(5,10)
All therapy groups demonstrated statistically signif-
AIMS icant falls in HbA1c, at both 3 and 12 months, when
compared to baseline (table 2). There were no signif-
This study reviewed the use, in routine clinical prac- icant differences between the individual treatments
tice, of additional glucose lowering agents in a T2DM within each drug class, and there were also no signif-
population attending a hospital based secondary care icant changes in the HbA1c level achieved, between
clinic, rather than a clinical trial setting, to assess the 3 and 12 months, for any drug.
effect of these additional agents on HbA1c and body
weight. The null hypothesis is that, there were no dif- Of all therapies, only Gliclazide demonstrated a sta-
ferences between the changes in outcome measures tistically significant rise in weight after 12 months (+
between the different therapies used. 0.368 Kg.) However there was no significant differ-
ence between the sulphonylureas for their effects on
Methods weight, at all time intervals. The DPP4 inhibitors, GLP-
1 agonists and SGLT-2 inhibitors all demonstrated sig-
Notes for 1,000 consecutive patients attending the nificant weight reductions, at both 3 and 12 months,
Diabetes Clinic at Chelsea and Westminster Hospi- when compared to baseline (table 2). Furthermore,
tal, between January and July 2014, were reviewed. for both Dapagliflozin and Sitagliptin, the weight re-
Of the 628 patients identified as having T2DM, 512 duction after 12 months was significantly more, than
were commenced on additional therapies for gly- at 3 months.
caemic control, and so were included in the study.
Data was collected from the start date of each ther- The results demonstrated no significant difference
apy and again at 3 and 12 months. All information within the DPP4 inhibitors, GLP-1 agonists and SGLT-
was obtained from a review of; paper based medi- 2 inhibitors for all of the changes in outcome mea-
cal records, Electronic Patient Record, a clinic letter sures, at all time intervals.
database and an electronic biochemistry database.
Data collected included; age, sex, HbA1c (mmol/mol), Analysis between each class
glucose, weight (kg), height (m), BMI, blood pressure
(mmHg), lipid profile. ANOVA analysis demonstrated that there was no

The mean changes in patient indices were calculated significant difference between baseline HbA1c levels
for; baseline data, change after 3 months and change
after 12 months. These results were compared to in- for any of the therapies added, however there was a
dividual agents and between drug classes.
significant difference between th1.2e5d8if×fe1r0e1n1t).oAptfitoenr s3,
The results were analyzed using ANOVA (Analysis for baseline weight (p value of
of Variance). The means of the change in each re-
corded variable after 3 and 12 months were analyzed and 12 months, there was no significant difference
to determine if there were any significant differenc-
es in outcome between the medications. For those between the treatment options, for changes in HbA1c,
variables, for which a significant difference was iden-
tified, they underwent further analysis by Unpaired however ANOVA showed a significant difference for
Student T tests. A p value of <0.05 was used to high-
light significance. change in body weight after both 3 (p <0.01 ) and 12

months (p<0.01) for the treatment options Table 1 and

2. (Figure 1).

GCDC 2017

Cardio Diabetes Medicine 2017 405

Demographics Sulphonylureas (n= 154) DPP4- inhibitors (n=153) GLP-1 agonists (n=115) SGLT-2 inhibitors (n=90)
Dapagliflozin (n=90)
Age Gliclazide Glimepiride Sitagliptin Linagliptin Exenatide Liraglutide
Men (n=141) (n=13) (n=128) (n=25) (n=47) (n=68) 59.17
Women 58.9%
HbA1c mmol/mol 57.6 53.2 59 66 58.2 68 41.1%
Weight (Kg) 79.2
BMI 46.8% 53.8% 52.3% 44% 48.9% 64.7% 97.6
32.9
53.2% 46.2% 47.7% 66% 51.1% 35.3%

77.2 77.8 76.2 76.5 73.7 76.6

82.9 88.9 86.2 89.1 100.8 101.9

28.5 30.2 29.3 30.7 34.5 34

Table 1. Baseline information for patients prior to addition of new therapies.

Outcome Time (Mo) Sulphonylureas DPP4 inhibitors GLP-1 agonists SLGT-2 inhibitors
measure (n = 154) (n=153) (n=115)

Gliclazide Glimepiride Sitagliptin Linagliptin Exenatide Liraglutide Dapagliflozin
(n= 141) (n=13) (n=128) (n=25) (n=47) (n=68) (n=90)

HbA1c 0 77.27 77.78 76.18 76.52 73.72 76.59 71.18
(mmol/mol) 3 -9.48 * -9.85 * -6.59 * -6.48 * -7.32 * -10.28 * -8.97 *

12 -10.57 * -6.62 * -7.72 * -7.4 * -4.62 * -10.10 * -11.54 *

Weight (kg) 0 82.99 88.7 86.15 89.1 100.8 101.95 97.58

3 + 0.13 + 0.34 -0.47 * -0.83 * -2.57 * -1.71 * -1.96 *

12 + 0.37 * + 0.02 -1.12 * -0.95 ** -3.46 * -2.47 * -2.73 **

Table 2: Changes in HbA1c and weight at 3 and 12 months after initiation of additional therapies (* Significant difference
from baseline value , and ** Significant difference from baseline and between 3 and 12 months p<0.01)

Figure 1: Weight changes at 3 and 12 months com- tenders, with whom the Physician reviewing the pa-
pared to baseline after initiation of new glucose low- tient prescribed what they felt was the most logical
ering therapies therapy on an individual basis. Comparisons between
this study and pharmaceutical trial data, where there
Discussion may be a more careful selection of the cohort in-
volved, and different study lengths, should therefore
This study reviewed patients attending a secondary be done with caution.
care diabetes clinic, into which other Secondary Care
teams and Primary Care Physicians / General Practi- Agents felt to reduce weight more from clinical trial
tioners (GPs) typically refer patients to improve their data, such as the GLP-1 agonists and SGLT-2 inhib-
glycaemic control. Once glycaemic control has been itors, appear to have been given to patients with a
improved, the patients are then referred back to their higher mean BMI than those given sulphonylureas,
GP, or to a Consultant led Intermediate Care / Com- which is not unexpected, particularly in view of the
munity Diabetes Clinic for further monitoring. known side effects of each of these groups of drugs,
but the baseline BMI is higher than seen in many
The cohort of patients reviewed in our unit was not pharmaceutical trials (5,11,13,15). The small weight
part of any clinical trial but were routine clinic at- gain seen, in our cohort put onto these agents is
less than the standard teaching for the effect of sul-
phonylureas (15,16). It is also encouraging to see no
significant difference in the HbA1c reduction between
the different therapies used. Interestingly the only
variable that did vary between the different groups
was subsequent weight at both 3 and 12 months.

This was an observational study, and did not aim
to show which was the more effective at lowering
glucose, but as HbA1c reduction seen was similar,

Cardio Diabetes Medicine

406 Real World Effect of Type 2 Diabetes
Therapies On HbA1c and Weight

and not statistically different, between the different between any of the treatment options in this audit,
agents used, suggests that while glucose lowering after 3 and 12 months. This result is combined with
is the main effect we were aiming to achieve, the the fact that there were large ranges for how individ-
additional effects on weight may need further review ual patients responded to all outcome measures for
and consideration. It was not structured to determine all treatments, suggests that it may be more appro-
which therapy should be used first in individual cas- priate to tailor treatment choices towards individual
es. Interestingly though, the baseline BMI and HbA1c patients, to ensure they receive what works best for
in the sulphonylurea group was higher than many them, rather than using these different classes of
of the previous trials when these agents were used drug in a strict set order. There were no side effect
(16,17), with a weight gain, which was not as high as profiles and treatment regimens. The results suggest
typically reported for this group of agents, suggest- that GLP-1 receptor agonists and Dapagliflozin may
ing we should consider them, not just in the very have a role if weight loss is particularly desired.
low BMI group, where we as a unit have historically
thought of them as being more appropriate. Revised NICE guidelines which recommend a particu-

Dapagliflozin caused the greatest loss of weight af- lar order and suggests that BthMeIu<s3e5okfgG/mLP2-1isrecaet ptthoer
ter 3 and 12 months. Sulphonylureas, caused a slight agonists for those with a
rise in weight, although this was not significant, apart
from Gliclazide treatment after 12 months. DPP-4 in- discretion of clinicians do not appear to follow what
hibitors produced minor falls in weight that were not
significant, apart from Sitagliptin treatment after 12 has been noted in this audit. (18,19)
months. Baseline results suggested that some of this
difference may be due to significant differences in REFERENCE :
baseline weight between the treatment options, with
greater falls being more likely in those with a high- 1. Zhang P, Zhang X, Brown J, Vistisen D, Sicree R, Shaw J, et al. Global
er baseline. This higher baseline weight would also healthcare expenditure on diabetes for 2010 and 2030. Diabetes Research
have been behind the rationale for the selection of and Clinical Practice 2010;87:293-301.
different agents.
2. Holman N, Young B, Gadsby R. What is the current prevalence of di-
It is also worth noting that, whilst on the whole ‘n’ agnosed and yet to be diagnosed diabetes in the UK. Diabetic Med
numbers were good, for a few of the treatment op- 2014;31(5):510-511.
tions analysed ‘n’ numbers were much lower than
the others, particularly Glimepiride and Linagliptin. 3. The DECODE Study Group. Age- and Sex-Specific Prevalences of Diabetes
This would have had impacts on the significance and Impaired Glucose Regulation in 13 European Cohorts. Diabetes Care
of results that we have seen. Further to this, there 2003 January 01;26(1):61-69.
were some treatments for which no patients had
been commenced on during the period of this review 4. Lindblad U, Melander A. Sulphonylurea dose and response relationships:
(Canagliflozin, Vildagliptin). relation to clinical practice. Diabetes, Obesity and Metabolism 2000;2:25-
31.
Conclusions
5. Inkster B, Duthie L, Strachan M. Seeing through the plethora of medica-
In the most part, the results of this audit were compa- tions for diabetes. Clinical Focus Primary Care 2011;5(3):186-191.
rable to the previously published pharmaceutical data
company. Whilst there was some disparity in change 6. SHI H, MOUSTAID-MOUSSA N, WILKISON WO, ZEMEL MB. Role of
in some outcomes for some treatment, in particular, the sulfonylurea receptor in regulating human adipocyte metabolism. The
a greater fall in HbA1c, and a lesser weight increase FASEB Journal 1999 October 01;13(13):1833-1838.
for Gliclazide treatment in these results, (15,16) there
were some differences in study designs or the pa- 7. Lorenz M, Evers A, Wagner M. Recent progress and future options in the
tients themselves, which may account for at least development of GLP-1 receptor agonists for the treatment of diabesity.
some of this difference. There is a large disparity in Bioorganic & Medicinal Chemistry Letters 2013:4011-4018.
baseline data between the baseline patient HbA1c
and weight data in this audit and the pharmaceuti- 8. Livingstone R, Fisher M, Mckay G. Do we need another SGLT2 inhibitor?
cal data in the case of Gliclazide treatment. (15,16, ) Practical Diabetes 2015;32(2):47-48.

There was no significant difference for mean change 9. Dziuba J, Alperin P, Racketa J, Iloeje U, Goswami D, Hardy E, et al. Mod-
in any of the outcome measures, excluding weight, eling effects of SGLT-2 inhibitor dapagliflozin treatment versus standard
diabetes therapy on cardiovascular and microvascular outcomes . Diabetes,
Obesity and Metabolism 2014;16:628-635.

10. Dara L, Mize E, Salehi M. The Place of GLP-1–Based Therapy in Diabetes
Management: Differences Between DPP-4 Inhibitors and GLP-1 Receptor
Agonists. Curr. Diab Rep. 2013;13:307-318.

11. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose
control with sulphonylureas or insulin compared with conventional treat-
ment and risk of complications in patients with type 2 diabetes (UKPDS
33). The Lancet 1998;352(9131):837-853.

12. Del Prato S. Effect of linagliptin monotherapy on glycaemic control and
markers of beta-cell function in patients with inadequately controlled
type 2 diabetes: a randomized controlled trial. Diabetes Obes Metab.
2011;13(3):258-267.

GCDC 2017

Cardio Diabetes Medicine 2017 407

13. Nyeland M, et al. Evaluation of the effectiveness of Liraglutide and sita-
gliptin in type 2 diabetes: A retrospective study in UK primary care. Int.
J. Clinical Practice 2015;69(3):281-291.

14. Sabale U, Ekman M, Granstrom O, Bergenheim K. Cost Effectiveness of
dapagliflozin (forxiga) added to metformin compared with sulfonylurea
added to metformin in type 2 diabetes in the Nordic countries. Primary
Care Diabetes 2015;9:39-47.

15. Drouin P. Two year efficacy and safety of Diamicron MR in inadequately
controlled patients with type 2 diabetes. J Nutr Health Aging 2001;5.

16. McGavin J, Perry C, Goa K. Gliclazide Modified Release Adis Interna-
tional Limited, Auckland, New Zealand. ADIS New Formulation Profile
2002;62(9):1357- 1364.

17. Wang H, Ni Y, Yang S, Li H, Li X, Feng B. The Effects of Gliclazide,
Metformin, and Acarbose on Body Composition in Patients with New-
ly Diagnosed Type 2 Diabetes Mellitus. Current Therapeutic Research
2013;75:88-92.

18. NICE Internal Clinical Guidelines Team. Type 2 diabetes in adults Type
2 diabetes: management of type 2 diabetes in adults. Available at:
https://www.nice.org.uk/guidance/gid-cgwave0612/resources/type-2-diabe-
tes-draft- guideline2.

Cardio Diabetes Medicine

408 Cardio Diabetes Medicine 2017

Raising The Standard of Care In Cardiodiabetes:
Post Graduate Diploma in Cardiodiabetes

Professor Ram Dhillon (UK),

London North West Healthcare NHS Trust,
Plymouth University, UK, Medical Director, Rila Institute, London

Abstracts resulted in a dearth of doctors able to understand
and manage the disease.
The prevalence of diabetes is set to escalate interna-
tionally, with India having ~ 70-80million diagnosed In order to address this diabetes pandemic and its
diabetics alone. The medium to long term conse- consequences a decision was taken by Rila Institute
quences of diabetes are myriad but the awareness of Health Sciences, London, with its collaborative
of these effects is low, consequently, the patient partner, Plymouth University Peninsula School of
mortality and morbidity is unnecessarily high. Medicine and Dentistry, UK, to design a Postgradu-
ate Diploma in Cardiodiabetes.
Education of doctors in the emerging medical con-
dition of cardiodiabetes is therefore vital to raise the Design and structure of the Postgraduate
standards of care and improve patient quality of life. Diploma in Cardiodiabetes

The initiative of devising a Postgraduate Diploma in The design is based on a well-established model of
Cardiodiabetes, with subsequent eligibility to an MSc, work based training and education which Rila Insti-
has been designed to address the deficit in knowl- tute pioneered some 20 years ago and has success-
edge and skills and will be a spur to create a new fully been using to deliver postgraduate education
specialty of Cardiodiabetes. across a number of specialty areas3. The training
programmes are a collaboration between Rila Insti-
Key words: Cardiodiabetes, Education, Postgraduate tute and Plymouth University, with the final award
Diploma, Qualification made by the University and the successful individu-
als’ name appearing on the University’s roll call.
Introduction
The syllabus, covering some 28 key areas of cardio-
Education, with key knowledge and skills acqui- diabetes, created by cardiodiabetes experts, is deliv-
sition, is an absolute in raising standards of care. ered through a blended form of learning comprising
With the increasing prevalence of diabetes it major such elements as indicated below, and covered over
consequences are forming an increasing proportion approximately 12 months:
of clinical disorders. Type 2 diabetes was estimated
at a worldwide figure of 250 million in 2008 to 380 1. Face to face work shops
million by 20251, of which approximately 4 million die
of its consequence each year1. 2. Online core reading and formative assessments
across the syllabus
The major cause of death is Cardiovascular dis-
ease1, and the personal, social and economic costs 3. Regular mini examinations
are huge. It has also now become apparent that not
only does diabetes cause CVD but that there is a 4. Facilitated face to face interactive webinars with
strong link with Obstructive sleep apnoea2, and that specialists
in itself has consequent negative effects on blood
pressure, CVD, weight gain and a variety of mental 5. Reflective case studies
issues such as memory loss. The rapidity of this rise
in prevalence and its undoubted consequences has 6. A clinical/practical skills module

GCDC 2017

Raising The Standard of Care In Cardiodiabetes : 409
Post Graduate Diploma in Cardiodiabetes

7. A final summative examination Finally, any Postgraduate Diploma award enables
the individual to apply for the 12 month MSc course,
8. Eligibility to continue to a 12 month MSc with which is delivered in a similar format as the Diploma.
Plymouth University
Conclusion
Unique design of the Rila Institute
Postgraduate Diploma programmes The Postgraduate Diploma in Cardiodiabetes is an
innovative education programme to address the ed-
As previously mentioned, these are work based pro- ucation deficit in cardiodiabetes. It is delivered in a
grammes and the Postgraduate Diploma will follow work based format to enable the costs to be con-
standard format that Rila Institute has developed with tained and be minimally disruptive to participants. It
face to face time and a dedicated eLearning platform. is an easily scalable model that could be utilized by
public organisations and other healthcare bodies to
The key features are: support doctors to participate.

• The face to face contact time is fixed and partici- References
pants are expected to attend these elements. This
is 1-2 days upfront and then half or 1 day every 4-6 1. Diabetes Atlas, 3rd Edition, International Diabetes Federation, 2006
weeks of further face to face teaching and about
6 interactive webinars accessed through the inter- 2. Young T.; Palta M et al The occurrence of sleep disordered breathing
net and coordinated and delivered by a specialist among middle aged adults NEJM 1993, 328:1230-1235,
clinician.
3. Rila Institute of Health Sciences website:
• There is an endpoint formal summative examina-
tion

• Apart from the face to face components all ele-
ments can be done flexibly, usually requiring half
to one-day equivalent per week.

• The delivery mode means that participants can
continue to work while learning, do not need to
leave families for extended periods of time. There
is thus a huge cost saving to the individual

• The model of delivery and the relative low costs
of the delivery format means that more individuals
can access high quality education and the model
is scalable, by potentially enabling 100s of partici-
pants every year and therefore having a rapid and
significant impact on healthcare.

Award and graduation

The final award is made by Plymouth University Pen-
insula School of Medicine & Dentistry, UK. It is the
exact same award as if the participant had studied
in UK.

The award is 120 Level & Masters credits and has
international recognition as a clinical academic qual-
ification and is recognized formally by many national
medical councils e.g. Australia, Canada. The qualifi-
cation also enables individuals to gain employment
under many jurisdictions provided they can fullfil na-
tional regulatory requirements.

The successful individual is also eligible to attend the
formal graduation ceremony of their award in the UK
and information is provided on how to do this.

Cardio Diabetes Medicine

410 Cardio Diabetes Medicine 2017

DM Management in Special Situations –
Post Renal Transplant and Post CABG

Prof. (Dr.) Sandeep Bansal, Dr. Preeti Gupta

Vardhaman Mahavir Medical College and Safdarjung Hospital,

Introduction Consequences (immediate and long term)
• Dehydration and hemodynamic instability(os-
The diabetic patient faces additional hazards when
undergoing surgery as compared to the non-diabetic motic diuresis)
population. These are as follows: • Negative nitrogen balance
• Loss of lean body mass
1. Hyperglycemia and possible ketoacidosis caused • Impaired wound healing
by the body’s stress response to surgery • Reduced resistance to infection
• Loss of adipose tissue and energy reserve(lip-
2. Hypoglycemia due to peri-operative fasting wors-
ened by the prolonged action of certain long acting olysis)
insulins or oral hypoglycemic agents. • Deficiency of essential amino acids, vitaminsand

3. Peri-operative complications that are increased minerals.
by diabetes, e.g. incidence of wound infections and
myocardial infarctions Table 1: Endocrine and Metabolic Responseto Sur-
gery in Diabetic Patients.1

Metabolic Response to Surgery DM management Post CABG-

Surgery causes a prototypical stress response in a Glucose containing fluids are used to prime the by-
diabetic. There is a combination of anti-insulin ef- pass pumps. There are unusual degrees of trauma
fects of surgical stress and direct catabolic effects to tissues during bypass surgeries and inotropes
of stress hormones. with catecholamine like action are often used. This,
along with the hypothermia induced per-operatively
Endocrine increases insulin resistance. Thus, very high dosage
• Increased secretion of counter regulatoryhor- of insulin may be required perioperatively in patients
undergoing open-heart surgeries.2, 3 However, with
mones: newer surgical techniques, like ‘beating heart sur-
Catecholamines; glucagon; cortisol;growth gery’ for CABG the surgical stress associated with
hormone cardiac surgery is coming down.
• Decreased insulin secretion (Loss of anticata-
boliceffect) The IV insulin infusion can be set up by two
Decreased insulin action (insulinresistance) methods:-

Metabolic I.Glucose-potassium-insulin or GKI Regimen: The GKI
• Hyperglycemia drip or the glucose potassium insulin drip also known
• Decreased glucose disposal (utilization) as Alberti regimen. It involves starting an i.v. infusion
• Increased glucose production (secondary togly- of a pre-mixed cocktail of 10% glucose solution and
10 mmol of potassium chloride and 15 units of sol-
cogenolysis and neoglucogenesis) uble insulin, which is to be infused at the rate of
• Increased protein catabolism 100ml/hour.4 The GKI system assumes that the pa-
• Increased lipolysis and ketogenesis (variable)
• Increased metabolic rate and catabolism

GCDC 2017

DM Management in Special Situations 411
Post Renal Transplant and Post CABG

tient’s metabolism is in steady statewith reasonable arately and thus offers greater flexibility. Hence it is
pre-operative blood glucose levels; hence it should better used in severely uncontrolled, brittle patients
not be used in severely hyperglycemic, unstable or or in special circumstances like CABG surgery. This
brittle patients. After the start of the infusion the system needs more dosage adjustments than the
blood glucose levels are monitored hourly. Special GKI regimen Overall outcome with regards to glycae-
caution needs to be taken in patients with compro- mic control, hypoglycaemic events, post- operative
mised renal function or those on ACE inhibitors.The infection rates and duration of stay in hospital was
GKI regimen is considerably simpler and because similar to GKI regimen.
insulin is given in balanced proportion the infusion
rate is not so critical. After surgery patient often develops hypoglycaemia,
which might go undetected. As soon as the patient
II. Separate line approach: In this system, one infusion is able to eat, we can restart subcutaneous injections
line is used to deliver 10% dextrose solution at 100ml/ of insulin. The i.v. insulin should be discontinued after
hr preferably using a high precision pump while the about one hour of resumption of subcutaneous insu-
soluble insulin infusion can be given either through lin injection. The insulin requirement increases over
a separate vein or ‘piggy-backed’ (preferable) into the baseline requirements on the day of surgery and the
glucose line and the rate is titrated to maintain blood first two postoperative days and usually comes down
glucose in target range.5This facilitates the ability to to normal levels on the third post-operative day in
make changes in the insulin or glucose infusion sep- an otherwise uncomplicated surgery. The mean in-

Clinical scenario concerns Treatment considerations Potential problems
Immediate post High-dose immune suppression, Frequently require iv insulin
transplant pain ,and stress are common, Infusion protocol Requires diligent monitoring of
Often under observation in Hourly blood glucose moni- blood glucose
First week post intensive care unit or Require toring
transplant critical care Frequent adjustment of insulin
High-dose immuno suppression dose based on algorithm and
Increased nutritional intake Transition to sc insulin when or anticipated dose changes to
Steroid doses weaning and/or stable cover corticosteroids or other
starting oral intake Calculate sc insulin dose from changes
Rapid improvement in renal last 8–24h iv insulin require-
function (after kidney transplant) ment Insulin requirements may
change, Daily due to renal
function changes, Increased
Nutritional intake

Acute steroid bolus Increased insulin requirements Monitor blood glucose atleast If blood glucose rises signifi-
4times daily cantly when

Consider NPH insulin for steroid

(eg. for Acute rejec- Bolus or, if very high-dose ste- Transition back to previous On sc insulin, consider tempo-
tion) roid, temporary iv insulin insulin Regimen once steroid rary iv insulin
complete, Noting any changes
Fluctuations in renal function, in renal function Adjust insulin dose for chang-
particularly, after kidney trans- es in TPN/tube feed rate or
plant Consider iv insulin as drip dextrose concentration, Long
acting insulin held or decreased
TPN or Enteral Increased insulin requirements Once iv requirements are significantly if TPN or tube
feeding and/or in TPN bag established and stable, switch feeds stopped
to NPH insulin every8h plus
fast-acting correction insulin
every 4 to 6h

Table 1: DM management Post Renal transplant-

Cardio Diabetes Medicine

412 Cardio Diabetes Medicine 2017

Agent Safetyor Efficacy Studies in Transplant Patients Potential Considerations in Organ Transplant Patient
Metformin
Effective in stable KTX patients But contraindicated Should not be used during acute hospitalization, with
Sulfonylureas for many other TX groups,including during Acute ↓GFR, ↑LFTs,CHF,oractive, significant, infection;and
hospitalizations should be held for planned iv contrast procedure

Efficacy is not well documented in transplant Increased risk of more frequent and more prolonged
patients. hypoglycaemia With ↓ GFR

Repaglinide Did not alter cyclosporine pharmacokinetics in a Less risk of hypoglycaemia With ↓GFRthan
Thiazolidinedione (eg, small study of KTX recipients with PTDM sulfonylureas
pioglitazone) Effective and safe with no interaction with CNIs in a Known risk for weight gain, edema, heart failure,
small study of KTX recipients with PTDM and reduced bone Mass; contraindicated with known
Glucosidase inhibitors Effective and safe in small elevated liver function tests with the exception
GLP1agonists (exenatide, studies of KTX recipients for known fatty liver disease including after liver
liraglutide, lixisenatide) transplant; contraindicated with known heart failure;
DPP-4inhibitors(sitagliptin, No studies of safety or efficacy to date in organ unknown impact on risk for heart failure risk after
vildagliptin) transplant populations transplant Avoid with ↓GFR unlikely to be an effective
SGLT-2inhibitors (dapagliflozin, Liraglutide did not affect tacrolimus concentration in single agent
canagliflozin, empagliflozin) a very small study of KTX recipients
Decreases bowel motility, which may impact
Retrospective and small random controlled trials absorption of immune suppression agents and has
of KTX recipients show safety of several DPP-4 not yet been studied; should not use if GFR 40mL/min
inhibitors Reduce dose of all but linagliptin with ↓GFR
Known to increase risk of genitourinary infections
in those with previous history, which is a concern Avoid until safety studies are performed
in immune compromised transplant patients, known
to cause volume dehydration and hypotension,
which may also be a concern in these patients as
well as recent reports of diabetic ketoacidosis raise
concerns of safety for most transplant populations

sulin requirement increases about 66% on the day B. Outpatient glucose management- Long-term glu-
of surgery and increases by about 23% and 15% over cose management of frequentlyrequires insulin over
baseline requirements on the first two days following time, particularly in those with thegreatest obesity.
surgery.6 However, somepatients may be candidates for oral
hypoglycemic medicationsalone or in combination
Sulphonylureas, alpha glucosidase inhibitors and gl- with insulin therapy. Notall agents have been stud-
itazones can be restarted in those who were pre-op- ied after transplant, and the availablestudies of both
eratively well controlled on these, once the patients safety and efficacy are often verysmall. The potential
started eating. Metformin should be restarted after risks that need to be considered areoutlined in Table
72 hours only after re-evaluation of renal status and 3.8
documentation of normal renal function post- oper-
atively.7

DM management Post Renal transplant-

A. Treatment of the hospitalized patient- The treat-
ment of diabetes in hospitalized transplantrecipients
requires attention to a multitude of factors thatcan
impact glycemic control and influence the risk for-
adverse effects (Table 2).8

GCDC 2017

DM Management in Special Situations 413
Post Renal Transplant and Post CABG

References:

1. Chandalia HB, Lamba PS. Management of diabetes mellitus during non-
metabolic emergency situations. International J Diab Developing Countries
2002;22:1-11.

2. Crock PA, Ley CJ, Martin IK, Alford FP, Best JD. Hormonal and metabolic
changes during hypothermic coronary artery bypass surgery in diabetic and
non-diabetic subjects. Diabet Med 1988;5:47-52.

3. Devineni R, Mckinzie FN. Surgery for coronary artery disease in patients
with diabetes mellitus. Can J Surg 1985;28:367-370.

4. Gill GV, Sherif IH, Alberti KGMM. Management of diabetes during open-
heart surgery. Br J Surg 1981;68:171-2

5. Simmons D, Morton K, Laughton S, Scott DJ. A comparison of two intra-
venous insulin regimens among surgical patients with insulin-dependant
diabetes mellitus. Diabetes Educ 1994;20:422-7

6. Kaufman FR, Devgan S, Roe TF, Costin G. Perioperative management with
prolonged intravenous insulin infusion versus subcutaneous insulin in chil-
dren with Type 1 Diabetes Mellitus. J. Diab Complications 1996;10:6-11.

7. Bailey CJ, Turner RC. Drug therapy: Metformin. N Engl J Med
1996;334:574-579

8. Vijay Shivaswamy, Brian Boerner, Jennifer Larsen; Post-Transplant Diabetes
Mellitus: Causes, Treatment, and Impact on Outcomes, Endocrine Re-
views, Volume 37, Issue 1, 1 February 2016, Pages 37–61

Cardio Diabetes Medicine

414 Cardio Diabetes Medicine 2017

Cardiac Emergencies in Diabetes Mellitus

Dr. Arvinth Soundarrajan

Registrar, Institute of Emergency Medicine,
Meenakshi Mission Hospital & Research Centre, Madurai.

Dr. Narendra Nath Jena

Director & Head, Institute of Emergency Medicine,
Meenakshi Mission Hospital & Research Centre, Madurai.

Introduction: Mechanism of Sudden Death in DM:

Sudden cardiac death (SCD) is an event that can oc- In diabetic population, in addition to thee above fac-
cur in asymptomatic individuals, as well as in those tors several other mechanisms have been proposed
with advanced cardiovascular (CV) disease. SCD typ- to account for the excess of SCD observed. They are
ically manifests as a structural abnormality coupled silent myocardial ischemia, autonomic dysfunction,
with a disturbance in cardiac electrical activity that QT interval prolongation, hypoglycemia, a hyperco-
leads to fatal arrhythmias. Sudden cardiac death agulable state associated with DM, diabetic cardio-
(SCD) has been associated with diabetes, although myopathy and decreased ventilator response to hy-
it is unclear whether diabetes is a risk factor for SCD. poxia and hypercapnea.
Diabetes is a risk factor for common preventable co-
morbidities associated with SCD, including coronary Acute Myocardial Infarction in Diabetes:
artery disease (CAD), myocardial infarction, and heart
failure[13-14]. Heart disease, particularly coronary heart disease
(CHD), is a major cause of morbidity and mortality
Sudden Cardiac Arrest in Diabetes: among patients with diabetes mellitus. Compared
with nondiabetics, diabetics are more likely to have
The reduction of mortality from sudden cardiac ar- CHD, to have multivessel disease when it occurs, and
rest (SCA) in the setting of coronary heart disease to have episodes of silent ischemia. As a result of
(CHD) remains a major challenge, especially among these and other factors, diabetics with CHD have a
patients with type 2 diabetes . There is mounting ev- worse outcome and poorer long-term survival com-
idence that type 2 diabetes is associated with an in- pared to nondiabetics with CHD. Glycemic control is
creased risk of mortality from coronary heart disease a powerful predictor of survival and in-hospital com-
and SCA. The increased risk of CHD mortality and plications[1,3].
SCA among patients with diabetes likely results, at
least in part, from the increased presence and extent Effect of Hyperglycemia on AMI[2,3] :
of coronary atherosclerosis (macrovascular disease)
due to abnormalities of glucose/insulin homeostasis • Endothelial dysfunction
and/or other risk factors, such as dyslipidemia, high
blood pressure, and renal disease. • Platelet hyper reactivity

Diabetes also is associated with micro-vascular dis- • Increased cytokine activation
ease and autonomic neuropathy; and, these non-cor-
onary atherosclerotic pathophysiologic processes • Increased lipolysis and FFA levels
also have the potential to influence CHD mortality
and SCA among patients with diabetes. However, • Reduced glycolysis and glucose oxidation
few prior studies have assessed the risk of CHD mor-
tality and SCA associated with clinically-recognized • Increased oxidative stress
and subclinical micro-vascular disease or diabetic
autonomic neuropathy[11-13]. • Impaired microcirculatory function.

• Impaired ischemic preconditioning

• Impaired insulin secretion and insulin stimulated
glucose uptake.

GCDC 2017

Cardiac Emergencies In Diabetes Mellitus 415

The possible explanations for hyperglycemia Factors associated with HF in diabetic
worsening the condition of ACS are as patients[9]:
follows:
• Age
• Abolition of ischemic preconditioning and promo- • Ischemic heart disease
tion of myocardial apoptosis. • Nature of diabetes
• Duration of diabetes
• Higher circulatory catecholamine level. • Poor glycemic control
• Elevated serum creatinine
• Elevation of blood pressures and prolongation of • Insulin use
QT interval. • Peripheral artery disease
• Microalbuminuria.
• Microvascular dysfunction and resultant perfusion
defect.

• Endothelial dysfunction.

• No reflow phenomenon after reperfusion.

Treatment targets after ACS with DM: Substrate Toxicity and Heart Failure

• Revascularisation If the classical view of myocardial dysfunction in
diabetes emphasized “energy starvation” as a con-
• Anti-ischemic drugs sequence of reduced ability to generate ATP via
glycolysis and glucose oxidation, more recent the-
• Anti-platelet and Anti- thrombin drugs. ories have focused on the countervailing concepts
of substrate toxicity and substrate-mediated intra-
• Secondary prevention by cellular signaling. This change in perspective arose
from the recognition that whereas the overall energy
• Modulation of lifestyle including smoking. charge of the diabetic heart is relatively normal un-
der most conditions, the heart and blood vessels of
• Blood pressure, sugar, lipid control. patients with type 2 diabetes are chronically exposed
to significantly elevated concentrations of glucose,
• Renin angiotensin blockers FFA, and other substrates. As with most other mol-
ecules, intracellular concentrations of glucose and
• Beta Blockers FFA are normally maintained within a narrow phys-
iologic range. Emerging evidence suggests that ex-
• Platelet inhibitors. posure to chronic excesses of either substrate may
affect such diverse targets as coronary flow reserve,
Heart Failure in Diabetes: vascular and myocardial compliance, and myocardi-
al gene transcription. Equally important, the adverse
Type 2 diabetes mellitus substantially increases the effects of excess glucose (“glucotoxicity”) and FFA
lifetime risk of both developing and dying from heart (“lipotoxicity”) on the myocardium may conceivably
failure. While this appears to be explained in part by amplify those of other conditions (e.g., hypertension)
the well-known association of diabetes with hyper- commonly associated with type 2 diabetes[9,10].
tension, dyslipidemia, and coronary atherosclero-
sis, additional pathophysiologic mechanisms linking Diabetic Cardiomyopathy :
type 2 diabetes and heart failure have recently been
suggested. These include the potentially adverse ef- Independent of the severity of coronary artery dis-
fects of hyperglycemia on endothelial function and ease, diabetic patients have an increased risk of de-
redox state, effects of excess circulating glucose veloping heart failure. This clinical entity has been
and fatty acids on cardiomyocyte ultra-structure, in- considered to be a distinct disease process referred
tracellular signaling and gene expression, and the to as ‘diabetic cardiomyopathy’. Experimental studies
possibility that diabetes may impair recruitment of suggest that extensive metabolic perturbations may
the myocardial insulin-responsive glucose transport underlie both functional and structural alterations of
system in response to ischemia. Because many of the diabetic myocardium. Translational studies are,
these putative pathophysiologic mechanisms should however, limited and only partly explain why diabetic
be amenable to normalization of the diabetic met- patients are at increased risk of cardiomyopathy and
abolic milieu, strategies designed to more carefully
control circulating levels of glucose and fatty acids
might conceivably delay or prevent the development
of heart failure[6-8].

Cardio Diabetes Medicine

416 Cardio Diabetes Medicine 2017

heart failure. The probable mechanisms are intersti- pacity and symptoms of HF without an effect on
tial fibrosis, glycation of collagen leading to impaired mortality.
contractility , changes in calcium homeostasis and
autonomic dysfunction. Although a range of diagnos- • Angiotensin II is considered to be a major player
tic methods may help to characterize alterations in in the development of cardiac dysfunction.ARBs
cardiac function in general, none are specific for the (angiotensin II type 1 receptor blockers) have been
alterations in diabetes[7,8]. proposed to have additive effects on haemody-
namic measurements, neurohumoral activity and
The principles of managing HF are as LV remodelling when added to ACE inhibitors in
follows: patients with chronic HF.

• Rapid diagnosis to determine the cause ofsymptos • Statins (hydroxymethylglutaryl CoA reductase in-
or excerbations. hibitors): The ability of statins to lower serum cho-
lesterol and reduce CHD end points has confirmed
• BNP estimation. portions of the lipid hypothesis. However, the time
to benefit and increased benefit in overlapping
• Detect the cardiovascular related conditions : MI, populations, in particular diabetic patients, have
Arrythmia, HTN, Pulmonary Embolus, Infection, suggested that they induce pleiotropic effects.
Renal Failure
• TZDs are a new class of compounds for treating
• Medical or Dietary adherence patients with Type II diabetes mellitus, which act
by increasing insulin sensitivity in skeletal muscle
• Oxygen therapy : Pulse oximetry and adipose tissue through binding and activa-
tion of PPAR-δ, a nuclear receptor that has a reg-
• Monitoring : Cardiac, Including ECGG, Central pres- ulatory role in differentiation of cells. Additionally
sures if available, Vital signs they also act on PPAR-α and increase serum HDL
(high-density lipoprotein)-cholesterol, decrease
• Intake and output serum triacylglycerols (triglycerides) and increase
LDL-cholesterol levels marginally (pioglitazone to
• Daily weight a lesser extent).

The principles of inpatient management of Prevention of SCD in DM:
HF are as follows[7,9]:
• Controlling the risk factors by slowing the pro-
• Clinical signs of perfusion and congestion gression or development of CV diseases should
indirectly reduce SCD incidence.Controlling the co-
• Intravenous (IV) fluids or medications morbid conditions associated with diabetes such
as CAD, hypercholesterolemia and hypertension
• Loop diuretics if significant fluid overload lessen the risk of SCD in diabetes patients.

• Vasodilators : Nitroprusside, Nitroglycerin, Nesir- • Pharmacologic agents that improve CV longevity
itide are ACE inhibitors, beta bloackers, and antiplatelet
agents.
• Thromboembolic prophylaxis
• Class I antiarrhythmics are not recommended for
• Inotropes : Dopamine, Dobutamine, Milrinone SCD prevention.

• IV fluids limitation. • Non pharmacologic prevention strategies of help
are weight reduction, dietary education, smoking
Treatment of Heart Failure: sessation, stress management, and physical ac-
tivity [11 – 13].
• Glycaemic control: Poor glycaemic control has
been associated with an increased risk of cardio- Conclusion:
vascular mortality, with an increase of 11% for ev-
ery 1% rise in HbA1c levels, and a recent study has There are insufficient data to define the individual
shown a link between HbA1c and HF. Thus it has contributions that any of these changes exert on the
been assumed that improving glycaemic control risk of SCD in patients with diabetes. We are in need
should have a beneficial effect on cardiovascular of future studies on SCD and DM to establish the
morbidity and mortality . relationship between DM and SCD. Early recognition

• ACE inhibitors form the cornerstone for treatment
of HF. The captopril multi-centre study demon-
strated a significant improvement in exercise ca-

GCDC 2017

Cardiac Emergencies In Diabetes Mellitus 417

and improvements in CVD risk factors such as low-
ering smoking prevalence and total cholesterol and
blood pressure levels have been major drivers for
these improvements in CVD outcomes[14,]

Reference:

1. Raz, P. W. Wilson, K. Strojek, Hyperglycemia and Diabetes in Myocardial
InfarctionDiabetes Care2009Mar;3233816

2. Siegelaar SE, Kerr L, Jacober SJ. A Decrease in Glucose Variability Does
Not Reduce Cardiovascular Event Rates in Type 2 Diabetic Patients After
Acute Myocardial Infarction Diabetes Car e2001, 34:855-857,

3. T. Thom, N. Haase, W. Rosamond, etal.the. for, Heart. American, Statis-
tics. Association, Committee, Statistics. Stroke, Subcommittee, Hypergly-
cemia and Diabetes in Myocardial Infarctionstics Committee and Stroke
Statistics Subcommittee. Circulatione85e151.

4. S. M. Haffner, S. Lehto, T. Ronnemaa, K. Pyörälä, M. Laakso, Hyperglyce-
mia and Diabetes in Myocardial InfarctionNEngl J Med. 1998339229234

5. J. Stamler, O. Vaccaro, Wentworth. D. Neaton, other. Diabetes, factors.
risk, cardiovascular. 12-yr, for. mortality, screened. men, the. in, Risk. Mul-
tiple, Intervention. Factor, Trial, Hyperglycemia and Diabetes in Myocardial
InfarctionDiabetes Care199316434444

6. Kannel WB, McGee DL.Hyperglycemia and Diabetes in Myocardial Infarc-
tionDiabetes Care19792120126

7. Cowie MR, Mosterd A, Wood DA, et al. The epidemiology of HF. Eur
Heart J. 1997;18:208–25.

8. Nichols GA, Hiller TA, Erbey JR, Brown JB. Congestive heart failure in
type 2 diabetes: prevalence, incidence, and risk factors. Diabetes Care.
2001;24:1614–9.

9. Delea TE, Edelsberg JS, Hagiwara M, Oster G, Phillips LS. Use of thiazo-
lidinediones and risk of heart failure in people with type 2 diabetes: a
retrospective cohort study. Diabetes Care. 2003;26:2983–9.

10. Kannel WB, McGee DL. Diabetes and cardiovascular disease: the Fram-
ingham study. JAMA. 1979;241:2035–8.

11. Bertoni AG, Tsai A, Kasper EK, Brancati FL. Diabetes and idiopath-
ic cardiomyopathy: a nationwide case-control study. Diabetes Care.
2003;26:2791–5.

12. Spooner PM. Sudden cardiac death: influence of diabetes. Diabetes
ObesMetab. 2008;10(7):523–32.

13. El-Atat FA, McFarlane SI, Sowers JR, Bigger JT. Sudden cardiac death in
patients with diabetes. CurrDiab Rep. 2004;4(3):187–93.

14. Fox CS, Coady S, Sorlie PD, Levy D, Meigs JB, D’Agostino RB, Sr, et al. Trends
in cardiovascular complications of diabetes. JAMA.2004;292(20):24959.

Cardio Diabetes Medicine

418 Cardio Diabetes Medicine 2017

“Don’t Let Diabetes Pull Down Our Foot”

Prof. Dr. J. A. Jayalal

Professor Of Surger, Kanyakaumari Government Medical College

ABSTRACT diabetic foot ulcers is essential for successful out-
come.
In the present age of Global village, non-communi-
cable environmental diseases become a major public Keywords: diabetes, ulcer, prevention, infection, am-
health concern. Urbanization, life style changes, so- putation
cio cultural changes, pollution, increase in stress and
tensions among people in the society are the con- INTRODUCTION
tributory factors for the increase in the prevalence of
non-communicable diseases. Worldwide, above 75% All over the world for every 30 seconds one foot is
of all deaths happens due to non-communicable dis- amputated due to diabetes and 85% of this can be
eases (NCDs). This is particularly more widespread in prevented if early detection and adequate care is pro-
underdeveloped and developing countries, due to de- vided. 25% of all diabetics patient will develop foot
prived health system. Diabetes mellitus is one among ulcerations in their life period. One third of diabetic
the most common non communicable diseases. patient will develop significant peripheral neuropathy
and /or peripheral vascular diseases. One third of
Globally Diabetes affects 6% of total population. In diabetic patient seek hospital admissions due to di-
India, more than 62 million people which is nearly abetic foot ulcer .
7.1% of adult population of India have diabetes. The
combination of genetic susceptibility plus use of high The onset of diabetic foot ulcer is not spontaneous
calories diet and decreased activity life style pave and many warning signs precede. “Diabetic gan-
way for the higher incidence among the middle class grene is not heaven sent but is born” said Dr. Elliot
Indian population. Diabetes about 75 years ago (1). Predicting the factors leading
to diabetic foot ulcer and its complication can inform
Increases the risk of numerous serious health prob- health care professionals to selectively concentrate
lems including Foot disorders. 70 % of people lose to prevent amputations..
their leg because of diabetes. People with known Di-
abetes mellitus have 15 times greater prevalence of Limb loss results due to delay in wound healing, in-
losing their leg than non-diabetic persons. Peripheral sufficient treatment of foot infection and bacterial
neuropathy, resistance.

Foot deformities, minor foot trauma, infection and Numerous trial blessing innovative and explorative
peripheral vascular disease are the major contributo- researchers are being carried out on diabetic foot
ry factors for the development of diabetic foot Ulcer. ulcers and the methods of curing them from time
Recent technological advancements combined with immemorial. Foot ulcer management requires mul-
better understanding of the wound healing process tidisciplinary approach, by health care specialists.
have resulted in a myriad of advanced wound healing Debridement, offloading, and infection control plays
modalities in the treatment of diabetic foot ulcers. a major part in management of Diabetic foot ulcer.
However, it is imperative to remember the fundamen- Management of underlying systemic illness, such as
tal basics in the healing of diabetic foot ulcers such hypertension, hyperlipidemia, atherosclerotic heart
as adequate perfusion, debridement, infection con- disease, obesity, or renal disease, is essential. It is
trol, and pressure mitigation. Early recognition of the also necessary to treat the arterial insufficiency, in-
etiological factors along with prompt management of fection with suitable antibiotics, offloading the area
of the ulcer, and wound care. Though there have

GCDC 2017

Don’t Let Diabetes Pull Down Our Foot 419

been many treatment options for diabetic ulcer, op-
timal results are yet to be obtained.
Fig 1 Arteriolar Hyalinosis and Medial Calcinosis
There are various strategies in wound dressing to
facilitate wound healing. If the standard treatment Diabetic peripheral neuropathy:
fails to heal the Diabetic foot ulcer, supplementary
and advanced treatment modalities would be re- The pathophysiology of diabetic peripheral neurop-
quired. They are comparatively effective and have athy is multifactorial and is thought to result from
minimal side effects. They are collagen products • Vascular disease occluding the vasa nervorum
(COL), biological skin equivalents (BSE), biological • Endothelial dysfunction
dressings (BD), silver products, intermittent pneu- • Deficiency of myoinositol-altering myelin synthesis
matic compression therapy (IPC), negative pressure • Diminishing sodium-potassium adenine triphos-
wound therapy (NPWT), electromagnetic therapy
(EMT), keratinocytes, platelet-derived growth factor phatase (ATPase) activity
(PDGF), platelet-rich plasma (PRP), hyperbaric oxygen • Chronic hyperosmolarity, causing edema of nerve
(HBOT), topical oxygen, Honey dressing and ozone
oxygen etc. trunks
• Effects of increased sorbitol and fructose. 
PATHOPHYSIOLOGY The result of loss of sensation in the foot is repetitive
stress; unnoticed injuries and fractures; structural foot
Atherosclerosis and peripheral neuropathy occur deformity, such as hammertoes, bunions, metatarsal
with increased frequency in persons with diabetes deformities, or Charcot foot, further stress; and even-
mellitus (DM) and are the major etiology or the de- tual tissue breakdown. Unnoticed excessive heat or
velopment of foot ulcers. cold, pressure from a poorly fitting shoe, or damage
from a blunt or sharp object inadvertently left in the
Diabetes-related atherosclerosis: shoe may cause blistering and ulceration. These fac-
tors, combined with poor arterial inflow, confer a high
Overall, people with diabetes mellitus (DM) have a risk of limb loss on the patient with diabetes.
higher incidence of atherosclerosis, thickening of Diabetic Peripheral neuropathy will have three com-
capillary basement membranes, arteriolar hyalinosis, ponents namely
and endothelial proliferation. Calcification and thick- • Sensory neuropathy
ening of the arterial media (Mönckeberg sclerosis) • Motor neuropathy
are also noted with higher frequency in the diabet- • Autonomy neuropathy
ic population, although whether these factors have Constitute for the formation of ulcer. The algorithm
any impact on the circulatory status is unclear.Dia- of Diabetic neuropathy causing foot ulcer are shown
betic persons, like people who are not diabetic, may in fig 2(a), (b)
develop atherosclerotic disease of large-sized and
medium-sized arteries, such as aortoiliac and femo-
ropopliteal atherosclerosis. However, significant ath-
erosclerotic disease of the infrapopliteal segments is
particularly common in the diabetic population. Un-
derlying digital artery disease, when compounded
by an infected ulcer in close proximity, may result
in complete loss of digital collaterals and precipitate
gangrene.

The reason for the prevalence of this form of arte-
rial disease in diabetic persons is thought to result
from a number of metabolic abnormalities, including
high low-density lipoprotein (LDL) and very-low-den-
sity lipoprotein (VLDL) levels, elevated plasma von
Willebrand factor, inhibition of prostacyclin synthe-
sis, elevated plasma fibrinogen levels, and increased
platelet adhesiveness (2). Fig 1shows the arteriolar Hy-
alinosis and Medial Calcification.

Cardio Diabetes Medicine

420 Cardio Diabetes Medicine 2017

Table : 1: Neuropathy versus Ischemic ulcer

Wagner Classification of diabetic foot ulcers

Wagner classification is based on depth and infec-
tion and has 6 grades. However this is not inter
connected and hence ulcer with infection in the su-
perficial ulcer will not be included in the classification
as shown in Tab 2.(3)

Figure: 2(a),(b),(c) - Diabetic Peripheral neuropathy caus- The differentiating features of each ulcer are shown in ta-
ing Foot ulcer. ble 1.

Staging and Classification of Diabetic Foot Characteristic Neuropathic Ischemic Ulcers
Ulcer: Ulcers
Older (seventh to
• Staging and classification are important for Patients age Younger(fifth to eighth decades)
sixth decades) None
• Assume the etiology
Pedal deformities Hammer or claw Cool, often red
• Predict this prognosis toes, Charcot
deformity Dry black eschar,
• Choose appropriate treatment often located on
Skin Warm with good dorsal surface of
• Monitor program colour feet and toes

• Serve as a form of communication Ulcer features Wet with drain- Diminished to
age, often locat- absent
There are numerous classifications of Diabetic foot ed on pressure Often painful
ulcer. Based on the etiology the diabetic foot ulcers points of planter
are classified as surface

1. Neuropathic ulcer Pulses Intact

2. Neuro Ischemic ulcer Pain Often absent

GCDC 2017

Don’t Let Diabetes Pull Down Our Foot 421

3 CLI 1-3cm2 Fascia, Ab-   2
3
Mus- scess,

cle, Fascitis,

tendon Arthritis

4  >3cm2 Bone SIRS
or joint

Table 4.PEDIS classification

Table : 2-Wagner classification FACTORS CONTRIBUTING FOOT
ULCERATION

Multiple intrinsic and extrinsic factors contribute the
formation of diabetic foot ulcer as shown in Table 5.

University of Texas Diabetic Wound Intrinsic factors Extrinsic factors
Classification System • Bony prominences Walking barefoot
• Limited joint mobility Inappropriate footwear
University of Texas classified foot ulcers based on • Deformities Falls and accidents
depth as grade and presence or absence of infection • Callus formation Objects inside shoes
/or ischemia as stages. The classification is shown • Previous foot ulcer Thermal trauma
in Table 3 • Neuroarthopathy (charcot) Activity level

Stage Grade I II III Table: 5. Factors contributing diabetic foot ulcer
  Wound
A 0 Superficial Wound penetrating Various treatment modalities:
(no wound not penetrating to bone or
infection or Pre- or involving to tendon joint. 1. Wound debridement:
ischemia) Post- Ul- tendon, or capsule
cerative capsule, or Infection
B lesion bone. Ischemia Never be kind with diabetic foot. All devitalized tis-
C completely Infection sues must be removed till fresh bleeding come. De-
D epithelial- Infection Infection and isch- bridement can be done by
ized emia
Ischemia Ischemia • Surgical (in fig 3 a.) • Larva (fig 3.b.)
Infection
Infection Infection • Hydro surgery • Autolytic
Ischemia and isch- and isch- • Ultrasonic
emia emia
Infection Fig 3.a: Surgical debridement
and isch-
emia

Table 3. University of Texas classification Fig 3.b: Larva for wound debridement

PEDIS classification is based on the
expansion of each letter

• P-Perfusion • E-Extent • D-Depth

• I-Infection • S-Sensation

The system of PEDIS is shown in Table 4.

Grade Perfusion Extent Depth Infec- Sensa-
1 tion tion
2 No PAD Skin Skin None 0
Intact Intact No 1
PAD NO Surface Loss
CLI <1cm2 Super-
ficial Loss

Fig 3.a: Surgical debridement

Cardio Diabetes Medicine

422 Cardio Diabetes Medicine 2017

the wound. The details of plasma preparation and re-
sults of PRP use are shown in fig 5 (a) & (b)

Fig 3.b: Larva for wound debridement Fig: 5 (a) and (b) Platelet rich Plasma

Pressure off loading: 4: Epidermal growth factor:

Pressure mitigation is the most important treatment Recombinant Human epidermal growth factors
in neuropathy ulcer. Either total contact cast or dia- initiates and promote healing in neuropathic foot
betic air walker is used. Using Barometric study on ulcer when applied locally.
dynamic and static method the potential neuropathic
ulcer development can be prevented by giving differ- 5. Bone Marrow Aspirate:
ent pressure soles (4) Fig 4(a) and (b.)
Bone marrow stem cells and progenitor cells are po-
tential new therapeutic option to induce angiogene-
sis. Bone marrow aspirate concentrate is made from
fluid taken from bone marrow. The bone marrow
aspirate contains stem cells that can help the heal-
ing of some bone and joint conditions. Bone marrow
aspirate concentrate is obtained with a minimally in-
vasive procedure that avoids the risks of an open
bone graft procedure. The instruments and method
shown in fig (6).

Fig: 6 -Bone marrow aspiration

Fig: 4 (a) (b) Pressure Offload methods. 6. Hyperbaric oxygen therapy:

3. Platelet Rich Plasma: Increasing the partial pressure of oxygen is the
main therapeutic value of hyperbaric oxygen thera-
Autologous plasma concentrate delivers high con- py. When a patient breathes pure oxygen at 3 times
centration of growth factors in the wound. Growth atmospheric pressure, arterial oxygen pressures in
factors in the PRP initiate chemotaxis, promotes excess of 2000 mmHb are possible. This is around
proliferation and angiogenesis can be used as gel, 20 times higher than normal. This is bactericidal to
powder preparation or local injections in and around clostridium perfringens, stops toxin production in gas
gangrene, and more rapidly displaces carbon mon-
oxide from possible neurological damage (5). Fig 7.

GCDC 2017

Don’t Let Diabetes Pull Down Our Foot 423

 Anatomical
 Aorto-bifemoral
 Ileo-femoral
 Femoro-popliteal
 Extra-anatomical
 Axillo-bifemoral
 Femoro-femoral

Fig 7: Hyperbaric oxygen therapy unit 9. Tenotomy

Primary effects of HBOT: Using open method or needle the flexor contracture
is released by cutting the flexor tendon capsule. This
• Vascoconstriction procedure may be used in the treatment of flexible
• Angiogenesis digital contractures, and is especially useful in distal
• Leucocyte oxidative killing digital hyper keratotic lesions and/or distal digital
• Antibiotic properties ulcerations or in the neuropathic or diabetic patient
• Toxin inhibition with preulcerative or ulcerative distal lesions. This
minimally invasive technique has been expanded
7. Negative pressure wound therapy/VAC: to include flexor dominant hammer toe deformities,
hallux malleus deformities, and floating digital defor-
VAC therapy applies sub atmospheric pressure to the mities.
wound to create an environment to promote wound
healing by granulation tissue formation The key to choosing this procedure is that the digital
VAC has 3 components deformity must be flexible or semi-rigid at the inter
1. VAC therapy unit: provides intermittent and con- phalangeal joint level and no contracture or a reduc-
ible deformity at the metatarsophalangeal joint level
tinuous negative pressure with safety features
2. Sensa T.R.A.C. Technology: regulates pressure 10. TA Lengthening:
3. Granufoam / White foam
In severe contracture of the foot ,the tendoachilic
• Removes infectious materials tendon is partially cut and patient is put on complete
• Provides protected wound healing environ- cast for 6 weeks. Achilles tendon is one of the main
ment biomechanical stresses that led to the ulceration (5).
• Removes exudate TA lengthening surgery is perfomed through a longi-
• Reduces edema provides moist healing en- tudinal incision at least 7cm in length. The subcuta-
vironment neous tissue must be carefully dissected to reduce
• Promotes perfusion risk of injury to the sural nerve. The deep fascia and
• Facilitates cell migration and proliferation paratenon must be carefully separated and then an-
atomically re-approximated. This procedure helps in
healing of long standing forefoot ulcers in diabetic
foot patients and in preventing recurrence of ulcers
at forefoot.

Conclusion:

Prevention is better than cure and most often the Di-
abetic foot ulcer can be prevented when the affected
patient follow adequet foot care as follows

8. Direct Arterial surgical intervention: Educate patients on proper foot care-the
DO’s
Endovascular: Balloon angioplasty +/-stent
• Check feet every day for cuts, cracks, bruises,
Surgery: Bypass blisters, sores, infections, unusual markings

Cardio Diabetes Medicine

424 Cardio Diabetes Medicine 2017

• Use mirror to see the bottom of feet 4. Boulton AJ. Pressure and the diabetic foot: clinical science and offloading
techniques. Am J Surg. 2004 May. 187(5A):17S-24S. [Medline].
• Check the color of legs anf feet-seek help if there
is swelling, warmth or redness 5. Baroni G, Porro T, Faglia E, Pizzi G, Mastropasqua A, Oriani G, Pedesini
G, Favales F. Hyperbaric oxygen in diabetic gangrene treatment. Dia-
• Wash and dry feet every day, especially between betes Care 1987; 10:81–86
the toes
6. DOI:10.1016/S0039-6109(02)00191-3
• Apply a good skin lotion every day on your heels
and soles. Wipe off excess.

• Change your socks every day.Trim your nails
straight across.

• Clean cut or stratch with mild soap and water and
cover with dry dressing.

• Wear good supportive shoes or professionally fit-
ted shoes with low heels(under 5cm)

• Buy shoes in the late afternoon since your feet
swell by then.

• Avoid extreme cold and heat(including the sun)

• See a foot care specialist if you need advice or
treatment.

Patient shall be advised not to do

• Cutting down corns or callouses

• Treating in-growing toenails or blisters with a razor
or scissors.

• Using over the counter medications to treat corns
and warts

• Applying heat with hot water bottle or electric
blanket

• Taking very hot baths and Using lotion between
your toes.

• Walking barefoot inside or outside

• Wearing tight socks, garter or elastics or knee
highs

• Siting for long periods of time and Smoking

References:

1. LR Simeone and A Veves (1997) Screening techniques to identify the
diabetic patient at risk of ulceration. Journal of the American Podiatric
Medical Association: July 1997, Vol. 87, No. 7, pp. 313-317.https://doi.
org/10.7547/87507315-87-7-313

2. Rice JB, Desai U, Cummings AK, Birnbaum HG, Skornicki M, Parsons NB.
Burden of diabetic foot ulcers for Medicare and private insurers. Diabe-
tes Care. 2014. 37 (3):651-8. [Medline].

3. Oyibo SO, Jude EB, Tarawneh I, Nguyen HC, Harkless LB, Boulton AJ. A
comparison of two diabetic foot ulcer classification systems: the Wagner
and the University of Texas wound classification systems. Diabetes Care.
2001 Jan. 24(1):84-8. [Medline].

GCDC 2017

Cardio Diabetes Medicine 2017 425

Glycemic Control- How Tight It Should Be?

Dr. R. M. Anjana,

MD, Dip. Diab (UK), Ph.D, FICP, FACP, FRCP (Glasg,Edin, Lond)

&
Dr. Janani Karthik, M.B.B.S.,

Dr. Mohan’s Diabetes Specialities Centre, 6B,
Conran Smith Road, Gopalapuram, Chennai.

INTRODUCTION 2 diabetes who is controlled on lifestyle measures
alone or on a small dose of metformin. An HbA1c val-
With the prevalence of type 2 diabetes now reach- ue corresponding to the threshold of microvascular
ing pandemic proportions, there is a concomitant in- complication risk is a valid therapeutic target in such
crease in diabetic complications. Until 1993, the rela- individuals, since they will be able to achieve such
tionship between blood glucose control and diabetic targets without significant hypoglycemia.
complications was arguable. With the publication of
results of large randomised controlled trials such as CURRENT RECOMMENDATIONS
the Diabetes Control and Complications trial(DCCT)
and United Kingdom Prospective Diabetes Study FOR GLYCEMIC TARGETS
(UKPDS), there is no longer any doubt that tight gly-
cemic control reduces the risk of development and Although most clinicians have set different glycemic
progression of long term complications of diabetes. targets for their patients with type 1 and type 2 diabe-
tes for more than three to four decades , these facts
The EDIC( Epidemiology of Diabetes Intervention and have only recently been reflected in the American
Complications) trial, the 10-year posttrial monitoring Diabetes Association (ADA),European Association
of the DCCT, showed a 40% reduction in cardiovascu- for the Study of Diabetes (EASD),and International
lar events and an almost 60% reduction in myocardial Diabetes Federation (IDF) guidelines.
infarction, stroke and cardiovascular death in those
patients whose sugars were initially intensively con- Current recommendations for glycemic targets in type
trolled compared to those who were less intensively 2 diabetes in non-pregnant adults
controlled.
ADA/ AACE/ACE IDF CDA NICE
Individualization of glycemic targets is based upon EASD
the age of the patient, duration of diabetes, life ex- Fasting <110 <115 72– Not men-
pectancy, type of diabetes, type of therapy, presence glucose 70–130 mg/dL mg/ 126 tioned
of complications, propensity for hypoglycemia, hypo- mg/dL dL mg/dL
glycemia awareness, availability of family support, <140 Not men-
patient motivation, and patient education. 2-h PP <180 mg/dL <160 90– tioned
glucose mg/dL mg/ 180
FIXING TIGHT GLYCEMIC TARGETS ≤6.5 % dL mg/dL 6.5–7.0%
HbA1c <7 %
For fixing glycemic targets, theoretically, there are at <7 % <7 %
least two approaches: the HbA1c or blood glucose
can be rendered completely normal or alternatively TREATING EARLY GIVES THE BEST
lowered to the extent that it minimizes complica- BENEFITS
tions without producing distressing incidence of hy-
poglycemia. Reduction of HbA1c to the normal level Three trials have looked at whether glycemic control
is difficult to achieve in most patients with diabetes to near-normoglycemia (i.e. control tighter than that
without significant hypoglycemia. The only exception achieved in the DCCT or UKPDS) reduces cardio-
to this would be a person with newly diagnosed type vascular disease in type 2 diabetes. These are the

Cardio Diabetes Medicine

426 Glycemic Control- How Tight It Should Be?

ACCORD,the ADVANCE (Action in Diabetes and Vas- However, the selected HbA1c target may need to be
cular Disease: Preterax and Diamicron MR Controlled relaxed to a range of 6.5–7.5 % for those being man-
Evaluation), and the VADT (Veterans Affairs Diabetes aged with basal-bolus insulin therapy. As duration of
Trial) studies. First, these trials were all short (3.5 to 5 diabetes increases beyond 10 years, microvascular
years). Secondly, the patient populations in these 3 and macrovascular complications set in; hence, the
trials were older, had diabetes for longer (eg, an av- selected targets can then fall into the range of HbA1c
erage of 10 years in the ACCORD study), and were at ≤ 7.0–8.0 %, with the lower end being pursued only if
higher risk of cardiovascular events, compared with safely achievable.
the DCCT and UKPDS studies in which the patient
populations were younger or recently diagnosed. TARGETS IN TYPE 2 DIABETES

All 3 trials were able to achieve sustained reduc- Selection of targets for the management type 2
tions in HbA1c levels for the duration of the studies, diabetes requires more factors to be considered:
something that was difficult to achieve in previous age, duration of diabetes, presence of microvascu-
trials, particularly the UKPDS. The ADVANCE study lar and/or macrovascular complications, complexity
showed a significant reduction in microvascular com- of therapeutic regimen, and risk for hypoglycemia.
plications (14%, 95% confidence interval 3% to 23%) Notably, the risk for hypoglycemia is strongly linked
and a non-significant reduction in the macrovascu- with the pharmacological therapies used. The risk is
lar events in the intervention group. By choosing an low with OHAs other than sulfonylureas, moderate
HbA1c target of 6.5%, there was a 21% reduction in with addition of basal insulin, and high with further
new or worsening nephropathy. Neither the VADT nor addition of prandial insulin. A glycemic target in the
the ADVANCE studies showed increased mortality range of HbA1c 6.5–7.0 % can be selected for patients
or cardiovascular event rate; however, the ACCORD <65 years of age, disease duration<10 years without
study, which attempted the most aggressive established microvascular and/or macrovascular
lowering of HbA1c levels (targeting < 6% in 6 months), complications, and where treatment used does not
showed a slight increase in deaths—1.7% versus 1.1% include prandial insulin. With advancing age (65–75
in the intensive control group as compared to the years), longer duration of diabetes >10 years, and
conventional control group. This was, however, the addition of prandial insulin to achieve glycemic
less than the predicted rate (4%), and overall the control, it is advisable to select a HbA1c target in the
cardiovascular event rates in the intensive and range of 7.0–7.5 %.In patients >75 years of age with
standard groups (6.9% and 10.6%, respectively) were pre-existing macrovascular complications, it is logical
much lower than expected. Moreover, a prespecified to select a glycemic target between 7.5 and 8.5 %
subanalysis in the ACCORD study showed that preferentially based on the potential risk for hypogly-
patients treated intensively who showed the greatest cemia. In all these situations, it is prudent to pursue
reduction in primary macrovascular end points were lower targets only if safely achievable.
at earlier stages of disease, with lower baseline
HbA1c values and no known baseline vascular Suggested glycemic targets for individuals with type 1 and
diseases.Likewise in the VADT study, those with the
shortest duration of diabetes (< 15 years) benefited type 2 diabetes mellitus
the most from intensive control.
Type 2 Initial 2–5 years of disease <6.5 %
TARGETS IN TYPE 1 DIABETES diabetes <7.0 %
mellitus 5–10 years of disease <7.5 %
In type 1 diabetes, the key factors to take into consid-
eration when selecting glycemic goals are duration Type 1 >10 years of disease with or with- <7.0 %
of diabetes, presence of microvascular complications diabetes out cardiovascular, renal, retinal,
and/or macrovascular complications, and treatment mellitus neurological complications <7.5 %
modality. As insulin therapy is the cornerstone of <8.0 %
management among these patients, risk for hypo- With intensified insulin therapy or
glycemia will remain moderate to high. A target range insulin pump therapy
of HbA1c 6.5–7.0 % can be used for those with dis-
ease duration <10 years with or without established With standard insulin therapy
microvascular complications. The lower end of this
range (HbA1c ≤ 6.5 %), if safely achievable, can be tar- With cardiovascular, renal, retinal,
geted especially for those on insulin pump therapy. neurological complications

GLYCEMIC TARGETS IN PREGNANCY

Physiologically, profound metabolic changes occur
during pregnancy to favor optimal growth of the fe-
tus. Maternal insulin resistance develops normally as
an adaptation to ensure availability of appropriate fu-

GCDC 2017

Cardio Diabetes Medicine 2017 427

els with pre-existing type 2 diabetes. to the fetus, a benefits of tight glycemic control on macrovascular
process termed “facilitated anabolism”. disease seem to become more evident with time, the
so-called “legacy effect” or “metabolic memory”.
It is advisable to select more stringent targets for
pregnant women with pre-existing type 2 diabetes HYPERGLYCEMIA AND DIABETIC
and gestational diabetes (FBG < 90 mg/dL, 1-h PP RETINOPATHY
< 130 mg/dL, and 2-h PP < 110 mg/dL) while more
relaxed glucose targets (FBG < 90 mg/dL, 1-h PP < The CURES Eye Study demonstrated a significant in-
140 mg/dL,and 2-h PP < 120 mg/dL) may be more crease in the prevalence of DR with increasing HbA1c
feasible in pregnant women with pre-existing type 1 levels. The multiple logistic regression analysis car-
diabetes. ried out using DR as a dependent variable showed a
significant trend of increasing retinopathy at different
HbA1c is lower in the first and second trimesters quartiles of HbA1c (trend χ 2 = 51.6, p < 0.001).
of pregnancy compared to non-pregnant women.
At present, the ADA recommends HbA1c ≤ 6 % for Prevalence of retinopathy in quartiles of HbA1c levels
women with diabetes during pregnancy. Compara- in the CURES Eye study
tively, the Australian Diabetes Society recommends
glycemic targets based on type of diabetes during <10.3 31.7
pregnancy, i.e., HbA1c ≤ 7 % for pregnant women with
pre-existing type 1 diabetes and HbA1c ≤ 6 % for preg- Quartiles of HbA1c (%) 8.5-10.3 20.0
nant women with pre-existing type 2 DM. The risk for
fetal malformations was particularly high with HbA1c ≥ 6.9-8.4 13.3
9.3 % while some degree of risk (3 %) was also associ-
ated with a lower HbA1c in the range of 5.6–6.5 %.The >6.9 8.1
corresponding blood glucose values below which the 0
risk of fetal malformations decreased were FBG < 5 10 15 20 25 30 35
104.4 mg/dL and PP < 163.8 mg/dL
Prevalence of DR (%)
HYPERGLYCEMIA AND MACROVASCULAR
EVENTS The long-term benefit of glycemic control on retinop-
athy has been evaluated by two large studies: The
An association between glucose and cardiovascular Diabetes Control and Complications Trial (DCCT) in
disease exists at levels below those used to define type 1 diabetes, and the United Kingdom Prospec-
diabetes. A recent meta-analysis of 20 studies in- tive Diabetes Study (UKPDS) in type 2 diabetes. The
cluding nearly 96,000 individuals without diabetes DCCT and the UKPDS have demonstrated that inten-
showed that cardiovascular events increased by 1/3rd sive glycemic control (HbA1c ≤7%) reduced both the
as the fasting glucose levels increased from 4.2 to development and progression of DR, with the bene-
6.1 mol/litre and by nearly 2/3rds when the 2-hour ficial effects of intensive
glucose level was greater than 7.8mol/litre.
glycemic control persisting up to 10–20 years.The
In patients with type 1 diabetes enrolled in the DCCT, overall inference from various trials is that good gly-
cardiovascular event rates were similar in the two cemic control right from the time of diagnosis of dia-
groups at the end of the study period but six years betes is beneficial in preventing the onset of DR and
later it had increased in both, with a significantly low- in delaying its progression. The long-term benefits
er increase in those patients who had undertaken of glycemic control outweigh the small risk of “early
intensified therapy. A meta-analysis on all appropri- worsening” of DR. Targeting HbA1c level of<7% is rec-
ate trial data in type1 diabetes confirms the bene- ommended for slowing down the progression of DR.
fits of glycemic control on macrovascular disease.
In type 2 diabetes, the UKPDS data suggests that Plots of data from three epidemiological survey show-
hyperglycemia has an independent effect on mac- ing prevalence of diabetic retinopathy against mea-
rovascular disease. A 14% reduction for MI was ob- surements of glycemic control (Source Ref No: 8)
served for every 1% reduction in HbA1c which was
highly significant. In UKPDS cohorts there was also a
28% increased risk of peripheral vascular disease for
every 1% rise in HbA1c. However, no such association
was observed for stroke. Similar to the DCCT, the

Cardio Diabetes Medicine