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Published by , 2018-09-22 10:39:45



Cardio Diabetes Medicine 2018 198

ing-stopped-early-positive-efficacy ). nal protective mechanisms of this new class

of drugs.

The precise mechanism/s by which SGLT2 in- 3) Metabolic theory: although SGLT2 inhi-
hibitors exert their cardio-renal protective effects
are currently unknown. bition exerts multiple metabolic benefits (de-
Different theories/possibilities have been postu- creases HbA1c, fall in body weight, and an
lated and research is ongoing to better define the increase in HDL cholesterol), all of which
cardio-renal protective effects of SGLT2 inhibi- could reduce cardiovascular-renal risk, it is
tors. unlikely that these metabolic benefits could
In line with the rapid (6-12 months) observed drive the rapid (~6-12 months) observed car-
cardio-renal vascular protective effects of SGLT2 dio-renal risk reduction seen in clinical trials
inhibitors, three major theories have been postu- with SGLT2 inhibitors. Some theories have
lated: proposed that the SGLT2 inhibitors-mediat-
ed shift from glucose to fat oxidation, could,
1) Intrarenal theory: this theory postulates in the presence of elevated glucagon levels
(as seen in patients with diabetes treated with
that the SGLT2-mediated renoprotective ef- SGLT2 inhibitors), favors an increase in circu-
fect could be secondary to modulation of the lating ketones, which have been proposed to
tubule-glomerular feedback whereby an in- improve cardiac muscle efficiency. This latter
crease in Na to the macula densa (second- theory has been highly debated and not cur-
ary to reduced SGLT2-mediated proximal rently fully supported.
tubule sodium reabsorption) results in vaso-
constriction of the glomerular afferent arteri-

olae. SGLT2 inhibitors also promote uric acid excre-

Further the inhibition of enhanced tubuli tion and reduce the plasma uric acid concentra-
sodium-coupled glucose transport seen in tion known to be associated with increased car-
diabetes, could result in reduction of glu- dio-renal risk.

cose-mediated tubulointerstitial injury. In some clinical trial the use of the SGLT2 antag-

Another theory proposes that the use of onist canagliflozin has been found to associate
SGLT2 inhibitors in combination with inhib- with an increased risk of amputation (6.3 vs 3.4

itors of the renin-angiotensin-aldosterone participants per 1000 patient-years; hazard ratio,

system could result in upregulation of an- 1.97; 95% confidence interval, 1.41 to 2.75)(3).

giotensin 1-7/1-9 known to retain a vasodi- The observed amputations were primarily at the

latory, anti-inflammatory and anti-oxidative level of the toe or metatarsal. The mechanisms

stress protective effects. behind these preliminary observations are un-

2) Systemic theory: the systemic theory clear and not fully explained.
It is important to remember that the use of SGLT2
suggests that plasma volume contraction is often paralleled by an increase in haematocrit
(driven by SGLT2 mediated glycosuria and of ~1% that could, in patients with significant car-
possibly natriuresis) and blood pressure re- dio-renal-peripheral vascular complications and
duction observed with SGLT2 therapy could specifically compromised peripheral microcircu-
be at the basis of the cardiovascular and re- lation, result in impaired vascular supply. More

Cardio Diabetes Medicine

Cardio Diabetes Medicine 2018 199

studies are required to further explore this un-
known aspect of SGLT2 inhibitors therapy.

The understanding of the cardio-renal protective
role of SGLT2 will help towards the understand-
ing of the pathophysiology of vascular complica-
tion in diabetes and possibly offer new targets for
cardio-renal-vascular chronic complications in
diabetic and non-diabetic patients in the future.


1. Zinman B, Wanner C, Lachin JM, Fitchett D,
Bluhmki E, Hantel S, et al. Empagliflozin, Car-
diovascular Outcomes, and Mortality in Type 2
Diabetes. N Engl J Med. 2015;373(22):2117-28.

2. Wanner C, Inzucchi SE, Lachin JM, Fitchett D,
von Eynatten M, Mattheus M, et al. Empagliflozin
and Progression of Kidney Disease in Type 2 Di-
abetes. N Engl J Med. 2016.

3. Neal B, Perkovic V, Mahaffey KW, de Zeeuw
D, Fulcher G, Erondu N, et al. Canagliflozin and
Cardiovascular and Renal Events in Type 2 Dia-
betes. N Engl J Med. 2017;377(7):644-57.


- Diabetic kidney disease is the major cause of
end stage renal failure.

- Studies suggest a renoprotective role of SGLT2

- The cardiovascular protective role of SGLT2
antagonist is likely to be mediated by haemo-
dynamic effects affecting the cardiovascular
renal system.

Cardio Diabetes Medicine

Cardio Diabetes Medicine 2018 200



DR.Dina Nagodra

MBBS,MSC Public and Tropical Health UMST.,Sudan

Introduction and Literature review 90%. Diabetic neuropathy is a dysfunction of the
peripheral nervous system – distal symmetrical
Epidemiology: sensorimotor neuropathy which has predilection
for neurons with the longest axons. The loss of
Prevalence of diabetes mellitus (DM) is sensation predisposes the diabetic patients to
about 19% in Sudan and the mortality from dia- lesions, especially of the feet, which become in-
betic septic foot (DSF) is about 20% and the risk fected readily and heal poorly. Thus, gangrene
of major foot amputation is about 40%. Risk and amputation are part of natural histories of di-
factors of diabetic foot ulcers are peripheral neu- abetic neuropathies. The most striking feature of
ropathy (sensory, motor and autonomic), periph- neuropahy is fibre loss in the more remote nerve
eral vascular disease, foot structural deformities, trunks. Diabetic neuropathies are heteroge-
limited joint mobility, previous foot ulcer, poor neous and there is variable involvement of large
metabolic control and increased dynamic foot myelinated fibers and small, thinly myelinated fi-
pressure. bers. In experimental models of diabetes there
is a reduction in the availability of neurotrophic
There are two types of foot ulcer: neuro- growth factors, which may be a consequence of
pathic and neuro-ischemic. Upto 50% of type metabolic abnormalities, or may be independent
2 diabetic patients have significant neuropathy of glycemic control. These neurotrophic factors
and at risk of developing foot ulcer from which are required for the maintenance of the neurons,
36% heal without amputation, 18% needs mi- the ability to resist apoptosis and regenerative
nor amputation and 30% results in major am- capacity.
putation. The Eurodiale study showed that 23%
of ulcers are not healed. Diabetic foot complica- There is increasing evidence that there is
tions are expensive; average cost of healing of 64% reduction of neurotrophin nerve growth fac-
foot ulcer is 10,000 USD and healing with am- tor (NGF) level in serum of Diabetic patients and
putation might reach up to 63,000 USD in USA the dependent neuropeptides substance P (SP)
and 10,000 Euros per treatment episode of new and calcitonin gene-related peptide (CGRP)
DFU in Europe. Foot ulcer develops in stages: also contribute to the clinical symptoms resulting
callus formation followed by subcutaneous hae- from small fiber dysfunction. NGF is a promising
morrhage, then skin breakdown resulting in deep agent exhibiting beneficial actions on both dia-
foot infection with osteomyelitis. betic peripheral neuropathy and on ulcer healing.

Diabetic Neuropathy: Role of Nerve Growth Factor

Neuropathy is one of the most debilitating The physiological role of the NGF has
complications of both type 1 and type 2 diabe been characterized, since its discovery in the
tes, with estimates of prevalence between 50-

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Cardio Diabetes Medicine 2018 201

1950s, first in the sensory and autonomic ner- genes that are responsive to nerve growth fac-
vous system, then in central nervous, endocrine tor. The latter is corrected by administration of
and immune systems. NGF plays its trophic exogenous nerve growth factor. Thus, deficient
role both during development and in adulthood, neurotrophic support might contribute to the
ensuring the maintenance of phenotypic and pathogenesis of diabetic neuropathy, and any
functional characteristic of several populations successful treatment might include exogenous
of neurons as well as immune cells. From a neurotrophins or other strategies to correct their
translational standpoint, the action of NGF on deficiency of action.
cholinergic neurons of the basal forebrain and
on sensory neurons in dorsal root ganglia first Deficits of NGF transport, serum and tis-
gained researcher’s attention, in view of possi- sue content, deregulation of NGF signaling path-
ble clinical use in Alzheimer’s disease patients way have been demonstrated in experimental
and in peripheral neuropathies respectively. The diabetic animal models . NGF supply in animal
translational and clinical research on NGF have, models of diabetic neuropathies reverses neuro-
since then, enlarged the spectrum of diseases pathic signs by proecting the affected PNS neu-
that could benefit from NGF treatment in the use rons and normalizing their activity.
of the neurotrophin as a drug. In this review we
give a comprehensive account for almost all of  In a case-controlled study on transgenic
the clinical trials attempted until now by using diabetic mice, NGF treatment (1 mg/kg, 3 times
NGF for peripheral neuropathy. per week subcutaneously) was shown to restore
abnormal small sensory C-fibre function.
Disease associated peripheral neuropa-
thies could be associated with either deregula- In experimental models of diabetes, NGF
tion of NGF synthesis, transport and utilization content of nerves was reduced, and such de-
by PNS neurons. It is very important as it leads crease caused hypoalgesia3 (whereby a higher
to development of neuropathic symptoms asso- heat-pain stimulus is needed to induce pain).
ciated with Diabetes, HIV, Infections or chemo-
therapy. In a phase II clinical trial of rhNGF in 250
patients with diabetic polyneuropathy, improve-
Aim: ments in signs and symptoms were seen after
6 months following treatment with either 0.1 or
To evaluate the results of NGF in diabetic neu- 0.3 μg/kg rhNGF, subcutaneously, three times a
ropathy and ulcer healing. week.

Method: Topical mNGF 25ug/day for 4 weeks ap-
plied in diabetic patients with foot ulcers induced
Comprehensive analysis and evaluation a local progressive restoration of nerve function
of preclinical and clinical trials of NGF. and an almost complete relapse of ulcers with-
in 5-14 weeks. Another case report investigated
Results: the effect of topical mNGF 10ug TID for 1 week
as treatment in ischemic skin revascularization,
Experimentally, diabetic rats show re- resulted in promoting of VEGF and neo-vascu-
duced expression of target-derived nerve growth larisation.
factor as well as reduced expression of neuronal
Human rhNGF phase II trial demonstrat-
ed better results than phase III trial because of

Cardio Diabetes Medicine

Cardio Diabetes Medicine 2018 202

high dose i.e. 0.3ug/kg with significant benefits loss of cholinergic neurons. The major brunt of
than 0.1 ug/kg used in phase III trial as well as diabetic neuropathy is initially borne by the long
possibility of low quality rhNGF used in the latter. parasympathetic, cholinergic nerves suggesting
The side effects were very minimum: injection that NGF may have a place in the treatment of
site hyperalgesia, myalgias and arthralgia. parasympathetic neuropathy.


Nerve growth factor (NGF) is essential for the Conclusion:
development and maintenance of small-diame-
ter sensory and autonomic nerve fibres, which Small fiber sensory neuropathy is one of the
bear the tyrosine kinase A receptor and which most common complications of diabetes mellitus.
are dysfunctional in human diabetic sensorimo- Currently, there is only supportive management
tor diabetic polyneuropathy.NGF activity is spe- and no adequate therapy to prevent this debil-
cifically associated with activation of p75 and/ itating problem. NGF is a protein that promotes
or trk A, with resultant effects on small sensory the survival and integrity of a large percentage
and autonomic nerve fibers. Beside its action as of sensory neurons including the small fiber pain
a neurotrophic factor for nerve cells, NGF has transmitting neurons which are often prominently
been characterized as a regulatory factor for affected in diabetic neuropathy. Phase II clinical
many non-neuronal cell types eg. Keratinocytes trials have been promising and more trials are
in skin cells, immune cells resident in traumatic required to support this evidence.
or inflamed epidermal tissue. Decreased micro-
vascular blood flow and increased vascular re- References:
sistance in diabetes could result from alterations
in dermal neurovascular function, atrophy of 1. Mysona et al, Imbalance of the Nerve
nerves, and possibly even cell death, may be a Growth Factor and Its Precursor as a Po-
consequence of a reduction of overall NGF ac- tential Biomarker for Diabetic Retinop-
tivity in diabetic neuropathy. Therefore NGF can athy), BioMed Research International
be useful for both neuropathic and neuroisch- Volume 2015 (2015)
emic ulcers.
2. Pittenger et al, Nerve growth factor and di-
Reduction in pain sensation was prevented, abetic neuropathy, Exp Diabesity Res. 2003
as was the fall in CGRP in DRG and SP in sen-
sory ganglia in the treated diabetic animals. NGF 3. Dyck P. J. et al, Nerve growth factor and dia-
did not, however, prevent the deficit in tibial mo- betic neuropathy, The Lancet  VOLUME 348,
tor conduction in diabetic rats, suggesting that ISSUE 9034, P1044-104
NGF may be a useful adjunct for the treatment of
diabetic sensory and autonomic, but not motor 4. Luigi et al, Nerve growth factor: from the early
neuropathy. NGF has been considered for the discoveries to the potential clinical use, Jour-
treatment of Alzheimer’s disease because of the nal of Translational Medicine 2012 10:239

5. Saifeldin et al, Epidimeology of diabetic foot
ulcer in Jabir Abuliz Center, Sudan Journal of

Cardio Diabetes Medicine

Cardio Diabetes Medicine 2018 203


Dr.T.Neelambujan MD.,DNB.,FESC.,FCSI.,FIAE.,FSCAI.,

Consultant Cardiologist & Interventionalist,
Sundaram Arulrhaj Hospitals,


Heart Failure (HF) is associated with significant diagnosis of HF is 50% at 5 years and 10 % at
morbidity, mortality and health care cost. Over
the last two decades, HF burden in India has in- 10 years. This dismal scenario continues despite
creased dramatically by 140% with a projected
prevalence of about 10 million. With an estimat- availability of various therapeutic agents like
ed prevalence of 5.8 million in the USA and over
23 million people worldwide, HF is growing in ep- angiotensin convertingenzyme inhibitors(ACE-1),
idemic proportions. Indian HF patients are rela-
tively younger compared to the western counter- angiotensin receptor blocker(ARB), beta
parts and only two of three HF patient, survive
at 1 year with a 31% cumulative all cause mor- blockers (BB), mineralocorticoid receptor
tality rate. The estimated survival rate after the
antagonist(MRA) all of which have shown

reduction in morbidity and mortality.

A recent addition to the HF therapeutic

armamentarium is the combination of sacubitril/

valsartan. It is a first-in-class angiotension re-

ceptor neprilysin inhibitor (ARNI) which acts by

simultaneously inhibiting angiotensin II receptor

LCZ 696

Vasoactive SACUBTRIL VALSARTAN Angiotensinogen
Natriuretic (Prodrug – AHU377) Angiotensin I
Peptides – (-) Angiotensin II
ANP, BNP CNP, LBQ 657 AT1 Receptor

Substance P

(-) (-) Deleterious Effects
Beneficial Effects -Vasoconstriction
-Vasodilation -↑ Blood Pressure
-↓ Blood Pressure -↑ Sympathetic tone
-↓ Sympathetic tone -↑ Aldosterone
-↓ Aldosterone -↑ Myocardial fibrosis
-Natriuresis / diuresis -↑ LeftVentricular


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Cardio Diabetes Medicine 2018 204

type I as well as neprilysin enzyme which is remain symptomatic despite optimal treatment
responsible for degradation of natriuretric pep- with ACEI, BB and an MRA (class I B recom-
sides. The inhibition of type I angiotensin II recep- mendation). The ESC guideline specify having
tors results in blockade of angiotensin mediated an LVEF <35% prior to intiation of Sacubitril /Val-
deleterious cardiovascular effects like vasocon- sartan and also require the patients to be tried on
striction, rise in blood pressure, increased sym- an MRA before initiating an ARNI.
pathetic tone, increased myocardial fibrosis and
left ventricular hypertrophy. The neprilysin inhibi- This approval was based on the robust data
tion leads to reduced degradation of natriuretic obtained from a large HF trial PARADIGM-HF.
peptides leading to beneficial CV effects like va- (Prospective comparison of ARNI with ACEI to
sodilatation, reduced sympathetic tone, reduced Determine Impact on Global Mortality and mor-
myocardial fibrosis, natriuresis and diuresis. bidity in Heart Failure). The PARADIGM-HF was
a phase III double blind controlled trial that ran-
INTERNATIONAL CONSENSUS domized 8,442 patients with NYHA class II-IV
RECOMMENDATION FOR SACUBITRIL HF and LVEF<35% to receive twice daily dosing
/ VALSARTAN IN HF: of either 200 mg of LCZ 696 or 10 mg of enal-
april in addition to standard medical therapy. The
Sacubitril /Valsartan was approved by US FDA study was interrupted early(March 2014) due to
for the treatment of all NYHA II - IV HFrEF (Heart excellent results in the Sacubitril /Valsartan arm
Failure with reduced ejection fraction) in July after a median followup of 27 months. The results
2015. The same year, the European Medical clearly and unequivocally showed the superiority
Agency (EMA) approved the use of sacubitril / of Sacubitril /Valsartan over enalapril in reducing
Valsartan in adult patients for treatment of symp- the risk of CV death and hospitalization of heart
tomatic chronic HFrEF. This drug is approved for failure. Sacubitril /Valsartan was associated with
Indian patients too since 2016. a 20% decrease in the composite of death from
CV causes or hospitalization for HF compared to
In their 2016 focussed update on HF guidelines, enalapril. Additionally there was 21% reduction
the American college of cardiology, the American (HR=0.79) in the first worsening HF hospitaliza-
Heart Association and the Heart Failure Society tion and 16% reduction(HR=0.84) in all cause
of America recommended replacing ACEI or ARB mortality in the Sacubitril /Valsartan arm. There
with an ARNI in patients with chronic symptomat- was also significant improvement in symptoms
ic HFrEF, NYHA class II or III, currently tolerating and quality of life as measured on Kansas City
an ACEI or ARB to further reduce morbidity and Cardiomyopathy Questionaire(KCCQ). Drug dis-
mortality(class I recommendation). continuation due to adverse events was seen in
10.7%( Sacubitril /Valsartan) Vs 12.3% (enal-
The 2016 European society of Cardiology(ESC) april). The incidence of hypotension(14% Vs 9%)
HF guidelines recommend the use of Sacubitril / and angioedema were slightly more in Sacubitril /
Valsartan as an ACEI replacement to further re- Valsartan arm. The incidence of cough was more
duce the risk of death and HF hospitalization in in the enalapril arm(14.3%)when compared to
ambulatory patient with HFrEF (LVEF<35%) who Sacubitril /Valsartan arm (11.3%). The incidence

Cardio Diabetes Medicine

Cardio Diabetes Medicine 2018 205

of hyperkalemia and elevated serum creatinine and diabetes compared with those normal

was more with enalapril arm than in Sacubitril / HbA1C levels. A ‘U’ shaped relationship be-

Valsartan and this was not statistically significant tween HbA1C and adverse outcome in patient

, with known and treated diabetes mellitus has

HEART FAILURE AND DIABETES: been observed in many studies. There has been
a measure of concern that some hypoglycae-
Heart Failure(HF) and Type 2 diabetes Meli- mic agents like thiazolidinediones (glitazones),
tus(DM) are two of the great epidemics in the re- saxagliptin and sodium retention potential of in-
cent era. The links between these two condition sulin may increase the risk of heart failure relat-
is complex and has not been fully elucidated. The

presence of DM is considered as a risk marker ed events.

for the development of HF. Diabetes also wors-

ens the outcome in the management of HF. The IMPACT OF ARNI IN DIABETIC
hypoglycaemic agents used in the management SUBSETS OF HEART FAILURE:
of HF may also have influence in cardiovascular
outcome. Sacubitril /Valsartan reduced the risk of CV
death and HF hospitalization compared to enal-
A patient with HFrEF without a history of april irrespective of glycaemic status. There were
DM has approximately 1- in- 5 chance of actually reduced CV death, HF hospitalization , all cause
having the condition(but not yet diagnosed) and mortality and worsening of KCCQ clinical score
a >1-in-3chance of having prediabetes based on in all heart failure patients whether thay had
HbA1C testing. Randomized Evaluatin of Strate- normoglycaemia or prediabetic state or undiag-
gies for Left Ventricular Dysfunction(RESOLVD) nosed diabetes mellitus or established diabetes
pilot study showed a 11% prevalence of undiag- mellitus.
nosed DM and another 12% prevalence of pre-

diabetes based on fasting blood sugar values. A recently published post hoc analysis of the
Egstrup et al using oral glucose tolerance testing PARAGIGM-HF trial found that Sacubitril /Val-
identified 18% prevalence of undiagnosed DM sartan decreased HbA1C levels by 0.26% during
and another 22% prevalence of impaired glu- the first year of followup compared to a 0.16%
cose tolerance. The PARADIGM-HF study had reduction on the enalapril group(P=0.0023).
20% prevalence of undiagnosed DM and 38% Over 3 years HbA1C levels remained persistent-
prevalence of prediabetes. The data from these ly lower in the patients treated with Sacubitril /
studies show that HF is an insulin resistance Valsartan compared to enalapril with an overall
state which needs further research. reduction of 0.14% (95%CI: 0.06-0.23P=0.0055).
In addition, 29% fewer sacubitril/ valsatan treat-

AND DIABETES: ed patients were initiated insulin therapy to

Prediabetes and Diabetes confer substantial- achieve glycaemic control(7% Vs10% patients,
ly elevated risk of adverse clinical outcome and HR 0.71,95% CI :0.56-0.90;P=0.0052). Similarly,
worse clinical status in HF. Presence of DM is fewer patients were started on oral hypoglycae-
associated with increasing symptoms and poor mic agents(HR 0.77, 95% CI:0.58-1.02;P=0.073)
quality of life as demonstrated by a worse KCCQ in the sacubitril / valsartan group . These studies
score, more edema and higher natriuretic pep- are interesting as they hypothesize an additional

tide levels in patients with prediabetes
Cardio Diabetes Medicine

Cardio Diabetes Medicine 2018 206

metabolic benefit and emphasize the extracar- thelial function. This is assessed by an increase
diac pleiotropic effect of sacubitril/valsartan in in flow mediated vasodilatation measured by bra-
HFrEF patients in addition to its CV efficacy. chial artery reactivity test. The PARADOR (Com-
paring ARNI with ACEI on Endothelial Function)
ANTIHYPERGLYCAEMIC EFFECT OF trial is a planned randomized double-blind trial
NEPRILYSIN INHIBITION: designed to compare the effects of sacubitril /
valsartan with enalapril on endothelial function in
Patients who receive sacubitril / valsartan has patients with HFrEF.
shown a greater longterm reduction of HbA1C
levels and also enhanced glycaemic control 2.PERIPHERAL ARTERIAL DISEASE:
compared to enalapril.
Mitochondrial and microvascular dysfunction
It has been proposed that an increase in gluca- are thought to play a role in the development
gon-like peptide-1 (GLP-1) concentration might of peripheral vascular disease which in quite
be responsible for the beneficial effects on gly- frequently observed in diabetics. Natriuretic
caemic control. Peptides are known to increase microvascular
and mitochondrial density to improve oxygen
Jelena saferovic measured the active ami- consumption and perfusion to skeletal muscles.
dated form of GLP-1 by radioimmunoassay in Neprilysin Inhibitors have been proposed to im-
plasma collected from 27 patients with HFrEF prove limb ischaemia and sacubitril / valsartan is
on sacubitril / valsartan. There was a consistent currently being studied in a randomized placebo
increase(median 57%) in plasma GLP-1 concen- controlled trial to evaluate increase in treadmill
tration after 3 months of treatment with sacubitril walk time to pain onset as the primary outcome
/ valsartan irrespective of clinical characterisa- and novel markers of mitochondrial and micro-
tion or antidiabetic treatment. This suggest that vascular function as secondary outcomes.
the treatment with this drug combination might
help to improve glycaemic control in patients 3.ALBUMINURIA:
with diabetes and also prevent the occurrence
of diabetes in people with HFrEF who have pre- As diabetes and heart failure population are
diabetes. Since both sacubitril / valsartan and at a high risk of renal involvement neprilysin in-
DPP4- inhibitor potentiate the effects of GLP-1, hibitors have the potential to improve both renal
although via different mechanisms further stud- and cardiovascular outcomes. Sacubitril / valsar-
ies are warranted to assess the potential syner- tan has been shown to be equally effective at
gy between these two drug classes. preserving renal function or reducing albumin-
BENEFITS OF SACUBITRIL / The UK HARP- III trial (Randomized multicentre
VALSARTAN : pilot study of sacubitril / valsartan Vs Irbesartan
in patients with CKD) showed that sacubitril / val-
1.ENDOTHELIAL FUNCTION sartan has similar effects on kidney function and
albuminuria compared to irbesartan. The prima-
The favourable neuroharmonal effects of sacubi- ry outcome eGFR at 12 months was similar be-
tril / valsartan are hypothesized to improve endo-

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Cardio Diabetes Medicine 2018 207

tween sacubitril / valsartan and irbesartan group. duce myocardial fibrosis with improvement in

Reduction in albuminuria as assessed by urine myocardial relaxation which leads to beneficial

albumin:creatinine rated at 12 months was also effects in HFpEF.

comparable to irbesartan. However sacubitril / The PARAGON HF(Prospective
valsartan was associated with improved blood comparison of ARNI with ARB global outcomes
pressure at 12 months. The clinical implication in HF with preserved EF), a Phase III random-
of this trial is that sacubitril / valsartan may be a ized controlled trial which has enrolled 4829 pa-
viable option for reducing elevated CV risk in the tients with HFpEF with elevated NT Pro BNP to
population with CKD. UK-HARP III trial had 39% sacubitril / valsartan and valsartan alone control
patients with diabetes enrolled. arm will study the primary outcome points of CV

death and total HF hospitalization. The study is

4.HYPERTENSION , OBESITY & DIA- expected to be completed by March 2019. This

BETES: study is anticipated with great expectation as the
previous studies with RAAAS (Renin-angioten-
Sacubitril / valsartan has been hypothesized sin aldosteron system) did not meet their primary
to improve insulin sensitivity and have beneficial endpoints and currently no therapy has received
pleiotrophic effects on glucose and lipid metab- regulatory approval to reduce morbidity and mor-
olism. In a recent study in obese patients with
hypertension randomized to receive either sacu- tality in this group of patients.

bitril / valsartan or amlodipine, sacubitril / val- CONCLUSION:

sartan had significant increases in the insulin Sacubitril / valsartan represent a major thera-

sensitivity index and abdominal adipose tissue peutic advance in the management of HFrEF.

interstitial glycerol concentration. Further studies The results of the ongoing PARAGON-HF trial

are needed to elucidate the clinical meaning of will establish its role in HFpEF. Sacubitril / val-

these findings which might have a role to play in sartan has shown tremendous promise in the

metabolic syndrome. treatment of associated risk factors of HF like di-

abetes, hypertension, obesity etc. Investigative

HEART FAILURE WITH PRESERVED research has shed light on the role of this drug
EJECTION FRACTION( HFPEF): in endothelial dysfunction, vascular protection
and cardiac remodeling. Numerous currently un-
HF with preserved EF account for a large pro- dergoing trials will study if the substantial clini-
portion of patients with HF and is associated with cal benefits of ARNI in HFrEF will extend across
substantial morbidity and mortality. Diabetics are various forms of other CV disease. Insulin resis-
at higher risk of HFpEF also. Patients with HF- tance is the area of focus for future research with
pEF can have an impaired atrial natriuretic pep- ARNI from diabetes perspective.
tide, renal cyclic GMP, and natriuretic response

to acute volume expansion. Neprilysin inhibition

augments endogenous biologically active natri- REFERENCES
uretic peptides and other vasoactive compounds 1. Srikanth Yandrpalli ., sacubitril / val-
sartan in cardiovascular disease: evidence
with increased generation of CGMP which is re-
to date and place in therapy. Therapeutic
ported to be reduced in myocardial cells in HF-
advances in cardiovascular disease 2018,
pEF. Natriuretic peptide augementaiton induces
diuresis, vasodilatation, natriuresis anCdarcdaionDriea-betes Medicine

Cardio Diabetes Medicine 2018 208

2. Srikanth Yandrpalli; Profile of sacubitril
/ valsartan in the treatment of heart failure.
Patient selection and perspectives. Vascular
health and risk management 2017:13,369-

3. Soren L.Kristensen; Risk related to
Pre-Diabetes Mellitus and Diabetes Mellitus
in Heart Failure with Reduced Ejection Frac-
tion. Insights from PARADIGM-HF Trial. Circ
Heart Fail.2016;9-e002560.

4. Scott D.Solonon, Angiotensin Recep-
tor Neprilysin Inhibition in Heart Failure with
preserved Ejection Fraction. Rationale and
Design of the PARAGON –HF Trial. JACC:
Heart Failure Volume 5,No7,2017.

5. Randomized multicentre pilot study of sacu-
bitril / valsartan Versus Irtesartan in patients
with CKD; UK HARP-III- rationale, trial de-
sign and baseline date. Nephrol Dial Trans-
plant(2017) 32:2043-2051.

Cardio Diabetes Medicine

Cardio Diabetes Medicine 2018 209

Dr Amal Kumar Banerjee

Consultant & Interventional Cardiologist

Introduction ed when the patient is less congested (“dry”) with
adequate resting heart rate.

As we progress into 2018, health care delivery, Only evidence-based beta blockers should be
particularly for heart failure patients, becomes used in patients with HFrEF. In selected patients
even more complicated and challenging. Heart with HFrEF, a clinician may choose to start a
failure has recently undergone major changes: low dose of a beta blocker and an ACEI/ARB;
while heart failure with reduced ejection fraction in persistently symptomatic patients who tolerate
or HFrEF is declining due to effective revascu- an ACEI or ARB, switching to an ARNI would be
larization of patients with acute coronary syn- recommended.
dromes, the prevalence and incidence of heart In one recent study 4 by Dipak Kotecha et al.
failure with preserved ejection fraction or HFpEF, in patients with sinus rhythm, beta-blockers re-
mainly characterized by diastolic dysfunction, is duced all-cause and cardiovascular mortality
increasing due to ageing Indian societies. In be- compared with placebo, an effect that was con-
tween there is a gap, and this has recently been sistent across left ventricular ejection fraction
filled in the most recent ESC Guidelines on Acute strata, except for those in the small subgroup
and Chronic Heart Failure1 with the introduction with left ventricular ejection fraction >_50%. Left
of a novel category, i.e. HFmrEF or heart failure ventricular ejection fraction increased with be-
with mid-range ejection fraction. ta-blockers in all groups in sinus rhythm except

Initiating Therapy in those with a value of>_ 50%. In patients with
atrial fibrillation, beta-blockers increased left ven-
Established therapies for chronic HFrEF in- tricular ejection fraction when <50% at baseline,
clude angiotensin-converting enzyme inhibitors but did not improve prognosis. Thus, beta-block-
(ACEIs), angiotensin receptor blockers (ARBs), ers improve left ventricular ejection fraction and
beta blockers, loop diuretics, aldosterone an- prognosis for patients with heart failure in sinus
tagonists, and hydralazine/ isosorbide dinitrate rhythm with a reduced left ventricular ejection
(HYD/ISDN); with the exception of loop diuretics, fraction. The data are most robust in HFrEF, but
all have been shown in randomized controlled similar benefit was observed in HFmrHF. These
trials to improve symptoms, reduce burden of relevant findings suggesting that HFrEF and
hospitalization, and/or provide survival benefit2. HFmrEF are just the same disease with different
Recently, in addition to established guideline severities.
directed medical therapy(GDMT), an angioten- Aldosterone antagonists are added in patients
sin receptor-neprilysin inhibitor (ARNI) and the with chronic HFrEF already receiving beta block-
hyperpolarization channel blocker ivabradine ers and ACEI/ ARB/ARNI who do not have con-
have been added to the treatment guidelines for traindications to this therapy. It is not necessary
HFrEF 3. to achieve target or maximally tolerated doses

Initiation of ACEI or ARB is often better tolerated of other drugs before adding aldosterone an-
when the patient is still congested (“wet”; when tagonists. The dose of aldosterone antagonists
renin-angiotensin-aldosterone system activation used in clinical trials, which is typically below that
is less), whereas beta blockers are better tolerat- which might influence blood pressure, is suffi-

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cient for clinical efficacy. It is recommended to and who are in sinus rhythm with a heart rate
monitor renal function and potassium. greater than 70 bpm at rest.
The most recent clinical HF guidelines 3 recom- Biomarkers—When to Order Natriuretic Pep-
mend ARNI, ACEI, or ARB to reduce morbidity tides
and mortality in patients with chronic HFrEF and B-type natriuretic peptide (BNP) and N-terminal
that patients with NYHA class II to III symptoms pro–B- type natriuretic peptide (NT-proBNP) are
who can tolerate an ACEI or ARB should transi- the most studied biomarkers in HF. They play
tion to an ARNI to further reduce morbidity and a role in diagnosis and prognostication. Higher
mortality. Use of an aldosterone antagonist, al- concentrations of BNP or NTproBNP in an am-
though also recommended to improve outcomes, bulatory patient with HFrEF inform high risk,
is not considered mandatory prior to changing a particularly when the concentrations are rising.
patient to ARNI. Current clinical practice guidelines give a Class I
recommendation to measure NT-proBNP or BNP
Angiotensin Receptor-Neprilysin Inhibition to support a clinical diagnosis of HF, to assess
Neprilysin, also known as neutral endopepti- disease severity, or to establish prognosis 2.
dase, is a zinc-dependent metalloprotease that More recently, biomarkers have been examined
inactivates several vasoactive peptides, includ- for their role as a marker of clinical responsive-
ing the natriuretic peptides, adrenomedullin, bra- ness to GDMT.This is, in part, due to the fact
dykinin, and substance P, each of which has an that a wide range of GDMT may reduce BNP
important role in the pathogenesis and progres- and NT-proBNP concentrations, in parallel with
sion of HF 5. Because angiotensin II is also a the benefits of these therapies. Patients whose
substrate for neprilysin, neprilysin inhibitors raise natriuretic peptide concentrations do not fall with
angiotensin levels, which explains the rationale GDMT (“nonresponders”) have a worse prog-
for coadministration of ARB. Neprilysin inhibi- nosis and more deleterious LV remodeling 7.
tors are not combined with ACEI due to a higher Therefore, measurement of BNP or NT-proB-
risk of angioedema. When making the transition NP is useful to monitor risk, to assist in decision
from an ACEI to ARNI, a 36-hour washout period making regarding the ordering of imaging stud-
should be strictly observed to avoid angioede- ies to evaluate LV remodeling, to support clinical
ma, a delay that is not required when switching judgment with respect to prescription of GDMT,
from an ARB to ARNI. Starting dose is Sacubitril/ and to provide helpful objective data regarding
valsartan: 24/26 mg–49/51 mg twice daily and decision-making for referral to advanced HF
target dose is 97/103 mg twice daily. therapies. In the setting of worsening symptoms,
Ivabradine the reassessment of BNP or NT-proBNP may be
Ivabradine is an adjunctive means to reduce informative. However, serial assessment of BNP
heart rate in patients with chronic HFrEF who are or NTproBNP to guide aggressive titration of
in sinus rhythm. Ivabradine is a specific inhibitor GDMT is not indicated and not warranted 8. Se-
of the If current involved in sinoatrial nodal activi- vere renal dysfunction may interfere with the in-
ty and reduces the heart rate of patients in normal terpretation of natriuretic peptide concentrations.
sinus rhythm without lowering blood pressure. While rising natriuretic peptide concentrations
In the SHIFT (Systolic HF Treatment with the If are correlated with adverse outcomes, this re-
Inhibitor Ivabradine Trial) trial of 6,505 subjects lationship can be confounded with the use of
with stable, chronic, predominantly NYHA class sacubitril/valsartan. Due to neprilysin inhibition,
II and III HFrEF, ivabradine therapy, when added concentrations of BNP rise in patients treated
to GDMT, resulted in a significant reduction in HF with sacubitril/valsartan and tend not to return
hospitalizations 6. to baseline despite chronic therapy. In contrast,
Ivabradine is recommended 3 to reduce the NT-proBNP concentrations typically decrease,
risk of HF hospitalization in patients with HFrEF as NTproBNP is not a substrate for neprilysin 9.
(LVEF < 35%) already receiving GDMT (includ- Therefore, clinicians should interpret natriuret-
ing a beta blocker at maximally tolerated dose), ic peptides in the context of GDMT; BNP con-

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centrations will increase (while NT-proBNP will ventricular dilatation and failure.
most often fall) with ARNI therapy, and thus it Functional mitral regurgitation is associated with
may be more prudent to check only NT-proBNP HF symptoms, increased hospitalization rates
in patients on ARNI. Also, transient increases in and worse long-term prognosis of patients with
natriuretic peptide levels have been document- chronic HF. However, it remains debated wheth-
ed in the initial phases of beta-blocker initiation; er FMR is a central driving force of HF progres-
such changes should not preclude up-titration sion or rather a bystander, reflecting the severity
of beta-blocker therapy, which should be guid- of the disease. Nevertheless, driven by recent
ed by patient tolerance instead of asymptomatic advances in percutaneous MV repair (PMVR),
change in natriuretic peptide levels. significant efforts are currently undertaken to
reduce FMR in patients with HF in the hope to
Filling Pressure Assessment improve prognosis.13 Similar to HF patients
Recent attention has focused on the use of im- without FMR, it is recommended to prescribe
plantable sensors to guide filling pressure as- optimized guideline-directed HF therapy (OMT)
sessment in ambulatory patients with HF. In the targeting LV dysfunction including cardiac resyn-
CHAMPION (CardioMEMS Heart Sensor Allows chronization therapy.
Monitoring of Pressure to Improve Outcomes However, whether OMT is able to counterbal-
in NYHA Class III Heart Failure Patients) study, ance maladaptive processes and the adverse
patients with NYHA class III HF symptoms were effects of FMR on long-term survival remain un-
randomly assigned to receive a wireless implant- known.14 Likewise, the impact of MV repair on
able pulmonary artery pressure monitor versus outcome in HF patients with severe FMR by in-
usual care 10. Patients managed with data from terruption of the presumed maladaptive effects is
implantable pulmonary artery pressure moni- unknown and several randomized clinical trials
toring had more changes in GDMT and diuretic (MITRA-FR, RESHAPE-HF, COAPT) are under-
doses11. Those managed with implantable pul- way to test this hypothesis.
monary artery pressure monitoring had a 37% In order to successfully tackle outcome, a more
relative reduction in HF hospitalization (p<0.001). profound understanding of the association be-
Such improvement was seen in patients with tween FMR and long-term mortality in patients
both HFrEF and HF with preserved EF. This sug- with various stages of HF seems necessary in
gests that in well-selected patients with recurrent order to identify those that will benefit most from
congestion, this highly specialized monitoring MV repair.
strategy may guide therapeutic decision making.
The impact on mortality is unknown. Non-Invasive Ventilation in Acute Heart Fail-
Functional Mitral Regurgitation in Chronic In acute heart failure (AHF) syndromes signifi-
Heart Failure cant respiratory failure (RF) is essentially seen
Chronic heart failure (HF) is frequently accompa- in patients with acute cardiogenic pulmonary
nied by functional mitral regurgitation (FMR)12 oedema (ACPE) or cardiogenic shock (CS).
caused by left ventricular (LV) remodelling and Non-invasive ventilation (NIV), the application
subsequent papillary muscle displacement re- of positive intrathoracic pressure through an in-
sulting in mitral valve (MV) leaflet tethering, dil- terface, has shown to be useful in the treatment
atation, and flattening of the mitral annulus and of moderate to severe RF in several scenarios.
reduced closing forces. The pathophysiologic ef- There are two main modalities of NIV: continu-
fects of FMR are not well understood, presumably ous positive airway pressure (CPAP) and pres-
volume overload on a failing ventricle increases sure support ventilation (NIPSV) with positive
diastolic wall stress and consequently stimulates end expiratory pressure. Appropriate equipment
further maladaptation including up-regulation and experience is needed for NIPSV, whereas
of pro-hypertrophic and antiapoptotic signalling CPAP may be administered without a ventilator,
and neurohumoral activation leading to further not requiring special training. Both modalities

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Cardio Diabetes Medicine 2018 212

have shown to be effective in ACPE, by a reduc- tients receiving cardiotoxic therapies. In patients
tion of respiratory distress and the endotracheal receiving high-dose chemotherapy, early eleva-
intubation rate compared to conventional oxygen tions in cardiac troponin I (cTnI)–predicted car-
therapy, but the impact on mortality is less con- diac events at 3 years 16, and troponin-guided
clusive. Non-invasive ventilation is also indicat- initiation of enalapril in a similar cohort was as-
ed in patients with AHF associated to pulmonary sociated with reduced risk of LVEF decline17.
disease and may be considered, after haemo- Decreases in global longitudinal strain (GLS), an
dynamic stabilization, in some patients with CS. echocardiographic marker investigated in breast
There are no differences in the outcomes in the cancer patients receiving doxorubicin and trastu-
studies comparing both techniques, but CPAP zumab, have also been shown to predict subse-
is a simpler technique that may be preferred in quent LV dysfunction in combination with ultra-
low-equipped areas like the pre-hospital setting, sensitive cTnI 18. In a systematic review, a 10%
while NIPSV may be preferable in patients with to 15% reduction in GLS predicted subsequent
significant hypercapnia. The new modality ‘high- LV systolic dysfunction 19, supporting the Amer-
flow nasal cannula’ seems promising in cases of ican Society of Echocardiography (ASE) recom-
AHF with less severe RF. The correct selection mendations to include GLS and cTnI in risk strat-
of patients and interfaces, early application of the ification of patients before and during treatment
technique, the achievement of a good synchro- with anthracyclines or trastuzumab 20. However,
ny between patients and the ventilator avoiding routine use of serum and imaging biomarkers in
excessive leakage, close monitoring, proactive asymptomatic oncology population remains lim-
management, and in some cases mild sedation, ited, primarily due to lack of data supporting im-
may warrant the success of the technique. proved outcomes.
Relevant to cardiologists, evidence is growing
Left Ventricular Dysfunction in Cancer Treat- for prophylactic use of beta-blockers, angioten-
ment sinconverting enzyme inhibitors, and angioten-
Contemporary cancer therapies have dramati- sin receptor blockers. These agents have been
cally improved cancer-free and overall survival mostly investigated in patients receiving lower
but have been accompanied by increasing can- anthracycline doses and overall have demon-
cer treatment–related cardiovascular toxicity, in- strated feasibility, safety, and varying degree of
cluding left ventricular (LV) systolic dysfunction. LVEF decline attenuation, which has been the
Previously, systemic chemotherapy with anth- most common endpoint.
racyclines and radiation therapy were the only
cancer treatments with significant cardiotoxicity. Conclusion
However, modern targeted cancer therapies, in- The prevalence of HF is escalating rapidly. Com-
cluding HER2 inhibitors, tyrosine kinase inhibi- pounding this, HF is an illness that consumes
tors (TKIs), proteasome inhibitors, and immune significant health care resources, inflicts signifi-
checkpoint inhibitors, have all been associated cant morbidity and mortality, and greatly impacts
with adverse cardiovascular events. quality of life. Important breakthroughs have re-
Moreover, an increasing number of patients defined opportunities to change the natural his-
are receiving longterm, including lifelong, can- tory of the disease with a broad range of medical
cer therapies with potential adverse CV effects. therapies, devices, percutaneous interventions
Cancer treatment–related CV complications in- along with different implants and care strategies,
clude, but are not limited to, left ventricular (LV) including readmission reduction programs and
dysfunction, heart failure (HF), coronary artery ambulatory outpatient disease management for
disease, myocardial infarction, hypertension, those with more advanced disease.
arterial and venous thromboembolism, and ar-
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Abstract risk of illness, and raises health-care costs in

Obesity is one of the prime public health issues countries in all parts of the world. Measurement

that affects the quality of life, increases the of obesity is done with the body-mass index

risk of illness, and raises health-care costs in (BMI; weight in kg/height in m²), which has a

countries in all parts of the world. Measurement good correlation with body fat. The BMI has

of obesity is done with the body-mass index, the advantage of simplicity in epidemiological

which has a good correlation with body fat. studies, but it has deficiencies because it does

Obesity has a multifactorial nature resulting from not distinguish between fat and lean body mass.

genetic, epigenetic, physiological, behavioural, Thus, BMI should be considered as a screening

sociocultural, and environmental factors that measurement rather than a diagnostic method.

lead to an imbalance between energy intake Additional measurements tocomplement the

and expenditure during an extended time period. BMI and should include waist circumference (or

Guidelines provides us the basis for outlining waist-to-height ratio). Both variables are strong

the therapy for obesity, which can include predictors of health risk. The clinician should take

lifestyle changes, dietary modification, increased ethnicity into consideration when assessingthe

physical activity, the use of medications, and in waist circumference of a particular patient. In

some cases the recommendation for surgery. addition to measures of central adiposity, blood

Five medications have been approved in the USA pressure, glucose, and lipids should also be

for chronic weight management which includes measured.

Liraglutide, Lorcaserin, Phentermine/ Topiramate

Naltrexone SR/Bupropion SR and Orlistat. As far Obesity has a multifactorial nature resulting

as bariatric procedures are concerned a range fromgenetic,epigenetic,physiological, behavioural,

of procedures are now well established, which sociocultural,and environmental factors that

result in varying degrees of weight loss. Each lead to animbalance between energy intake

procedure has its own risks and benefits which and expenditureduring an extended time

need to be considered carefully with each patient. period. Obesity affects the function ofmany

Though we are equipped with the range of options organ systems. Mortality results fromseveral

available, patients and clinicians considering diseases that are associated with obesity,

referral for bariatric surgery should be made fully includingdiabetes, chronic

aware of the risks and benefits of medical and kidney disease, gastro intestinal disease,and

surgical procedures. Medical Management with cardiovascular disease and maintaining weight

Liraglutide and other medications have shown loss isoften difficult or unsuccessful.

significant results in obesity management and Management of the patients with

this may prevent the patients from undergoing obesity

bariatric surgery.

The rising prevalence of obesity worldwide calls

Introduction forpreventive strategies to defuse the future

Obesity has become an international public health health andeconomic costs of this problem.

issue that affects the quality of life, increases the When prevention of obesity does not work, as

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Cardio Diabetes Medicine 2018 216

occursfor many people, treatment is indicated. 1Five medications have been approved in the
To guide healthcareprofessionals in treating USA for chronic weight management, and three
obesity effectively, severalguidelines have been of these havealso been approved in the Europe-
developed. We use these guidelines as the basis an Union (table 1). Since 2012, four medications
for outlining therapy for obesity, which can include have reached the marketin the USA: liraglutide
lifestyle changes, dietary modification, increased 3·0 mg, lorcaserin, a combination of phenter-
physical activity, the use of medications, and in mine/topiramate extended release (ER), a com-
some cases the recommendation for surgery. bination ofnaltrexone sustained release (SR)/bu-
propion SR.All drugs must showevidence of no
Pharmacotherapy increase in cardiovascular risk, which is likely to
require a cardiovascular outcome trial either be-
The indications for adding pharmacotherapy fore or after marketing. Furthermore, all of these
to a weight loss effort are history of failure to drugswere studied with a suicidality rating scale.
achieve clinicallymeaningful weight loss (>5% of These medications have an indication for chronic
total bodyweight) and to sustain lost weight, for weight management, indicating long-term usage,
patients who meet regulatoryprescribing guide- along with diet and physical activity in individuals
lines (BMI ≥27 kg/m² with one or morecomorbid- with BMI of 30 kg/m² or greater or a BMI 27 kg/
ities or a BMI >30 kg/m² with or without associat- m² or greater withone or more comorbidities.
ed metabolic effects).

Table 1

Drug Mechanism of Action

1 Liraglutide; 3·0 mg Injection GLP-1 receptor agonist

2 Lorcaserin; 10 mg orally twice a day 5-HT2C serotonin agonist with little affinity
for other serotonergic

3 Phentermine/ topiramate ER; Sympathomimetic anticonvulsant

7·5 mg/46 mg or 15 mg/92 mg orally (GABA receptor modulation, carbonican-

indicated as rescue hydrase inhibition, glutamateantagonism)

4 Naltrexone SR/ bupropion SR; Opioid receptor antagonist;
32 mg/360 mg orally dopamine and noradrenaline
reuptake inhibitor

5 Orlistat; 120 mg orally three times a Pancreatic lipase inhibitor
day before meals

ER=extended release, SR=sustained release

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Liraglutide is a GLP-1 agonist with a 97% ho- myopia with glaucoma and the drug is contrain-
mology to GLP-1 which extends its circulating dicated in glaucoma.
half-life. It has been used for management of
diabetes at doses of up to 1·8 mg, given by in- The combination of naltrexone SR/bupropion
jection.Though approval is still awaited in India it SR was approved in the USA in 2012 and in the
is now approved in the US and European Union European Union in 2015.5 Bupropion is a mild
for chronic weight management at a dose of reuptake inhibitor of dopamine and norepineph-
3·0 mg.2 Nausea has been one of the principal rine. Naltrexone, an opioid antagonist has mini-
complaints in patients injecting this drug and a mum effect on weight loss on its own.Naltrexone
slow dose escalation over 5 weeks is prescribed. is thought to block the inhibitory effects of opioid
GLP-1 agonists are associated with thyroid C cell receptors activated by the β-endorphin released
tumours in animals, but this has not been shown in the hypothalamus that stimulates feeding,
with certainty in humans. Liraglutide should not thus allowing the inhibitory effects of α-melano-
be prescribed in patients with family or person- cyte stimulating hormone to reduce food intake.
al history of medullary thyroid cancer or multiple Naltrexone SR/bupropion SR can increase blood
endocrine neoplasia. pressure, and therefore the combination should
only be prescribed to patients with controlled
Lorcaserin is a specific serotonin 2c receptor ag- hypertension and the patient’s blood pressure
onist.3Lorcaserin is remarkable for its tolerability should be monitored in the early weeks of ther-
and low rate of adverse events. The drug should apy. All antidepressants in the USA are required
not be used with monoamine oxidase inhibitors to carry a black box warning of suicidality and the
because of the risk of serotonin syndrome. It has combination’s label includes this. However, there
not been studied with serotonin reuptake inhib- was no signal for suicidality in phase 3 studies.
itors, serotoninnorepinephrine reuptake inhib-
itors, or other serotonergic drugs and extreme Orlistat is a pancreatic lipase inhibitor that blocks
caution should be used in combining it with those absorption of 30% of ingested fat when eating
drugs. a 30% fat diet. Additionally, a study of 4 years
duration supports its long-term safety and effi-
The combination of phentermine and topira- cacy and shows that it reduces the development
mate as an ER formulation uses lower doses of of diabetes mellitus in people with prediabe-
both drugs (7·5 mg of phentermine and 46 mg tes.6However the drug’s gastrointestinal side-ef-
of topiramate at the recommended dose) than fects limit its popularity with patients.
are usually prescribed when either drug is used
as alone.4This medication is associated with Bariatric Surgery
greater mean weight loss than other available
medications. Phentermine is a sympathomimet- Bariatric surgery has rapidly become used as a
ic drug with cardiostimulatory properties. It has treatment option for severe obesity, particularly
only been studied in short-term trials and is a since the advent of lower risk laparoscopic pro-
controlled substance in the USA. It has misuse cedures, with nearly half amillion procedures
potential and small risk of primary pulmonary done worldwide in 2013. A range of procedures
hypertension, thus making its use for managing are now well established, which result in vary-
a chronic disease less than ideal. Topiramate is ing degrees of weight loss; each procedure has
associated with fetal toxic effects and a pregnan- itsown risks and benefits which need to be con-
cy test before initiation of therapy, and monthly sidered carefully with each patient.Long term
thereafter, is recommended. The most common studies of outcomes after bariatric surgery have
side-effects include paraesthesias, dizziness, generally shown favourable results. The Swed-
dysgeusia, insomnia, constipation, and dry ish Obese Subjects study followed up 2000 pa-
mouth. A rare side-effect of topiramate is acute tients for up to20 years after surgery including
banded gastroplasty, gastric banding, and Roux-

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Cardio Diabetes Medicine 2018 218

en-Y gastric bypass done by open techniques, From a clinical perspective, patients and clini-
which have since been replaced by laparosco- cians considering referral for bariatric surgery
py. A 24% reduction in mortality was reported, should be made fully aware of the risks and ben-
mainly because of the reduced risk of myocardial efits. Medical Management with Liraglutide and
infarction and cancer (in women), compared with other medications have shown significant results
an observational control group.7 in obesity management and this may prevent the
patients from undergoing bariatric surgery. Good
Much other comorbidity such as type 2 diabe- practice might include provision of a detailed ed-
tes and sleep apnoea were also improved, and ucation session, attendance at patient support
patients reported consistent improvements in groups, and detailed lifestyle advice and psycho-
quality of life. Particularly striking and rapid im- logical support both before and after surgery.
provements in glucose control have been seen
in patients with type 2 diabetes,especially after References
gastric bypass, suggesting that part of the meta-
bolic improvement is independent of weight loss. 1. Ryan D, Heaner M. Guidelines (2013) for
Observational data also suggest thatthe future managing overweight andobesity in adults.
risk of diabetes-related microvascular and mac- Preface to the full report. Obesity (Silver
rovascular complications are also reduced. This Spring)2014; 22 (suppl 2): S1–3.
has led to the concept of metabolic surgery, and
revision of guidelines and recommendations to 2. Wadden TA, Hollander P, Klein S, et al, and
lower thresholds for considering surgery in peo- the NN8022-1923Investigators. Weight main-
ple with type 2 diabetes,particularly of recent on- tenance and additional weight loss withlira-
set, to include patients with a BMI between 30 glutide after low-calorie-diet-induced weight
kg/m² and 35 kg/m² and a move away from BMI loss: the SCALEMaintenance randomized
as the main criterion used to assess eligibility for study. Int J Obes (Lond) 2013;37: 1443–51.
surgery.8 These encouraging data need to be
put into the context of potential risks and side-ef- 3. Smith SR, Weissman NJ, Anderson CM, et
fects of surgery, which for some patients can be al, and the Behavioral Modification and Lor-
distressing or disabling. caserin for Overweight and ObesityManage-
ment (BLOOM) Study Group. Multicenter,pla-
Although mortality is low for modern laparoscop- cebo-controlled trial of lorcaserin for weight
ic surgery, re-operation rates for surgical compli- management.N Engl J Med 2010; 363: 245–
cations are high, particularly for gastric banding. 56.
Some patients find it hard to adapt to the pro-
found changes in the amount and type of food 4. Aronne LJ, Wadden TA, Peterson C, Winslow
they can eat once they have had the procedure D, Odeh S,Gadde KM. Evaluation of phen-
and lifelong replacement therapy and monitor- termine and topiramate versusphentermine/
ing is required for nutritional vitamin and miner- topiramate extended-release in obese adults.
al deficiencies, particularly after malabsorptive Obesity (Silver Spring) 2013; 21: 2163–71.
surgery.Dumping syndrome gastro-oesophageal
reflux and hypoglycaemia can be very distress- 5. Hollander P, Gupta AK, Plodkowski R, et
ing and a challenge to treat. Weight regain can al, and the COR-DiabetesStudy Group. Eff
also be a substantial issue, and revisional sur- ects of naltrexone sustained-release/bupro-
gery carries greater risks and no guarantee of pionsustained-release combination therapy
success. There is an increasing focus on lifestyle on body weight andglycemic parameters in
programmes after bariatric surgery to reduce the overweight and obese patients with type 2di-
risk of this occurring. abetes. Diabetes Care 2013; 36: 4022–29.

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Cardio Diabetes Medicine 2018 219

6. Torgerson JS, Hauptman J, Boldrin MN,
Sjöström L. XENical in theprevention of dia-
betes in obese subjects (XENDOS) study:a
randomized study of orlistat as an adjunct
to lifestyle changes forthe prevention of
type 2 diabetes in obese patients. Diabetes
Care2004; 27: 155–61.

7. Sjöström L, Narbro K, Sjöström CD, et al,
and the Swedish ObeseSubjects Study. Eff
ects of bariatric surgery on mortality in Swed-
ishobese subjects. N Engl J Med 2007; 357:

8. National Institute for Health and Clinical
Excellence: Guidance.Obesity: identifi cat-
ion, assessment and management of over-
weightand obesity in children, young people
and adults: partial update ofCG43. National
Clinical Guideline Centre (UK). London: Na-
tionalInstitute for Health and Care Excellence
(UK), 2014.

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Cardio Diabetes Medicine 2018 220



Senior Cardiothoracic & Heart-Lung Transplant Surgeon

Apollo Hospitals, Chennai

ABSTRACT: chanical Circulatory Support (MCS) (1). Diabe-
tes Mellitus (DM) has a significant effect on HF
Despite technological advances in the field of and HT which impacts on clinical outcomes. The
Mechanical Circulatory Support (MCS), Heart Bidirectional Relationship which exists between
Transplantation (HT) remains the gold standard DM and HF are discussed and the pre-opera-
for treatment of End Stage Heart Failure (HF) in tive considerations in such patients which have
appropriate patients. Diabetes Mellitus (DM) is a an impact on listing for HT are also examined
very common metabolic disorder which forms a further. The article then looks closely into the
significant risk factor in development of athero- perioperative challenges we are confronted with
sclerosis affecting the heart, major blood ves- in this group of patients. Furthermore, the new
sels, kidneys, autonomic and peripheral nervous onset of DM after HT is also discussed.
system. DM affects the heart, most commonly,
by its effects on causing coronary artery disease DM and HF:
leading to myocardial infarction and in some cas-
es culminating in heart failure due to Ischaemic The possible association between DM and HF
Cardiomyopathy. DM also causes heart failure was first suggested by Leyden in 1881 (2). The
in the absence of coronary artery disease, hy- Framingham study(3) of DM and HF reported a
pertension – a condition called Diabetic cardio- 2.4-fold increase in men and five fold increase
myopathy characterised by myocardial fibrosis, in women of HF in patients with DM. When
diastolic dysfunction and eventually systolic dys- patients with coronary disease and rheumatic
function. DM has significant impact on HF and diseases were excluded, the risk of HF in DM
HT with significantly poorer outcomes in diabetic increased to 3.8-fold in men and 5.5-fold in
patients compared to non-diabetic patients. The women. Furthermore, there is a high incidence
association of DM with HF and HT are discussed. of DM in HF patients with as much as 42% of
This article looks at the pre-operative diabetic patients hospitalised HF patients having DM in
status, glycemic control and perioperative issues OPTIMIZE -HF Registry (4). This highlights the
which have a significant impact on the outcomes “bi-directional relationship” which exists be-
following HT. The article further focuses on de- tween DM and HF – each having an effect on
velopment of New Onset Diabetes Mellitus af- the other(5)
ter Transplantation (NODAT) and its impact on
post-transplant survival.

DIABETES AND HEART The term “Diabetic cardiomyopathy” (DCM) was


Cardio Diabetes Medicine 2018 221

Pathophysiology of Cardiomyopathy: tervention or surgery

DM is associated with HF and plays a role in the 4. Intractable life-threatening arrhythmia not
responsive to medication, ablation, sur-
pathogenesis of both Ischaemic Cardiomyopa- gery or implantable defibrillators.

thy and Diabetic Cardiomyopathy.

Ischaemic Cardiomyopathy: Such patients are evaluated by the transplant
team for consideration of listing for transplant.
DM is an important risk factor in the pathogen-
esis of coronary artery disease (CAD), along TRANSPLANT DECISION: This section
with hypertension, dyslipidaemia and smoking.
Ischaemic cardiomyopathy results from the ef- discusses the decision-making process involved
fects of myocardial scarring following myocardi- in considering HT to patients.
al infarction due to CAD. The resultant negative
remodelling of the left ventricle (LV) and dilata- WHETHER TRANSPLANT IS APPRO-
tion of the LV causes worsening of the systolic PRIATE?
function of the LV and this eventually leads to
severe LV systolic dysfunction causing HFrEF The following three questions need to be con-
(Heart Failure with reduced Ejection Fraction). sidered by the physician/transplant team and
only if the answer to each of these questions
Diabetic Cardiomyopathy: is “yes”, should a transplant be recommended.
Q.1. Has the disease reached end stage? (Dis-
DM can directly have a deleterious effect on the ease point of view)
myocardial cells. At the myocardial cellular lev- Q.2. Can the patient tolerate the operation? (Pa-
el, DM has effects on calcium transport, defects tient point of view)
in contractile protein and collagen formation. Q.3. Have all contraindications been ruled out?
These result in myocardial fibrosis and myocar- Disease point of view: It is crucial that all
dial hypertrophy. Persistent hyperglycemia is non-transplant treatment options are tried/ con-
known to damage myocardium via modified pro- sidered and found to be futile, before decision to
teins such as advanced glycation end products transplant.
(AGE) and free oxygen radicals (ROS reactive Patient point of view: The comprehensive as-
oxygen species)(2), Thus, the resultant myocar- sessment by the multidisciplinary team of spe-
dial dysfunction results in cardiac failure. cialists is important in evaluating each organ sys-
tem and more importantly in ensuring that there
PREOPERATIVE CONSIDERATIONS IN are no absolute contraindications for transplant.
These considerations are discussed under the
following heads – Indications for heart transplan- The correct timing of transplant operation is a
tation, Decision making process in heart trans- crucial factor which has a significant impact on
plantation, DM and its impact on listing for HT. outcomes.

INDICATIONS FOR HT: End Stage HF of Transplant Window:

any aetiology is an indication for HT as listed un- is the ideal time period to consider the operation
der. – wherein the lung has reached end stage – but
all the other organ systems are well preserved.
1. Cardiogenic shock on inotropes, mechan- Such patients do well.
ical circulatory support to maintain tissue
perfusion Too well for transplant :

2. Persistent NHYA Class IV despite maxi- Considering transplant in a patient early on in the
mal medical or surgical therapy disease process – i.e. before end stage disease

3. Intractable angina despite maximal med-
ical therapy not amenable to coronary in-

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Cardio Diabetes Medicine 2018 222

is hazardous. This is because the risks to the od in view of high immunosuppressive doses of
patient from the transplant operation would be steroids and stress due to major surgery. While
higher than the risk to the patient from the heart there were no significant differences in outcomes
disease. between non-diabetics and carefully selected di-
abetic patients, the following deserve mention.
Too sick for transplant: Serious infections: There is an increased risk
of serious infections in the immediate and late
On the other hand, considering transplant in a post-operative period in diabetic HT recipients.
patient who has advanced disease with multi or- Survival: While in uncomplicated diabetic pa-
gan failure is inappropriate. This is because the tients the survival after HT is similar to non-di-
outcomes in the subgroup are often fatal. Also, abetics, diabetic patients with renal impairment,
donor organs are a scarce resource and should obesity, peripheral vascular disease have much
be used appropriately. lower survival.
Renal function: In diabetic patients without signif-
DECISION –MAKING PROCESS: icant renal dysfunction – the post HT outcomes
were similar to non-diabetic patients. Calcineurin
Two main risk assessment processes help in de- Inhibitors (CNI) – Cyclosporine, Tacrolimus -are
cision to register a patient for transplant. immunosuppressive agents which can be diabe-
Risk-benefit analysis of transplant operation: If togenic and nephrotoxic. In diabetics with normal
the anticipated are much higher than the possi- or mildly impaired renal function, the effects of
ble risks, decision to consider transplant is made. CNIs on renal function were similar to non-dia-
Conversely, if the risks are prohibitive in the face batic patients. In patients with severe renal im-
of very little benefit, the patient is strongly dis- pairment, combined heart kidney transplant has
suaded from having a transplant. outcomes comparable to isolated HT.
Risks with transplant versus risks without trans-
plant: This is another important consideration NEW ONSET DIABETES MELLITUS
which helps in decision making. If the risks from AFTER TRANSPLANTATION (NODAT):
the disease, without transplant, is much higher
than the risks involved in transplant operation, NODAT refers to the development of DM after
decision to consider transplant is made. Solid organ transplantation and its incidence var-
ies from 15 to 25 % and in one series as occurring
DM AND ITS IMPACT ON ASSESS- in 25% following HT(8). It is also referred to as
MENT OF CANDIDACY FOR HT: Post Transplant Diabetes Mellitus (PTDM). The
immunosuppressive drugs – steroids and CNIs
DM has been considered a contraindication to are diabetogenic which can lead to NODAT. It is
HT. However, with better immunosuppressive a risk factor for cardiovascular events and has a
protocols there has been an improvement in the negative effect on long term survival and kidney
metabolic control in these patients after HT and function following HT(8) as compared to non-di-
well controlled DM with no evidence of end organ abetic recipients. However, the survival in pa-
damage is no longer a contra-indication to HT. tients with NODAT were no different from surviv-
The current guidelines (7)the International Soci- al of Diabetic HT recipients. Early diagnosis and
ety for Heart and Lung\r\nTransplantation (ISHLT stricter glycemic control of NODAT may improve
has recommended DM with end organ damage long term survival in this subset of patients.
( nephropathy, neuropathy) or persistent poor
glycemic control (Hba1c > 7.5% )despite optimal REFERENCES:
effort as a relative contraindication to HT.
1. Sunder T, Paul Ramesh T, Madhan Ku-
PERIOPERATIVE CHALLENGES IN HT mar K. Heart & Heart Lung Transplantation :
PATIENTS WITH DM: Indian Scenario. In: Dr Santanu Guha, Editor.
Cardiology Update 2015. 1st Edition. New Delhi:
Adequate glycemic control after HT becomes a Jaypee Brothers; 2016. p. 1460–4.
challenge in the immediate perioperative peri-

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Cardio Diabetes Medicine 2018 223

2. Trachanas K, Sideris Sk, Aggeli C, Pouli-
daKis E, Gatzoulis K, Tousoulis D, et al. Diabet-
ic Cardiomyopathy: From Pathophysiology to
Treatment. Hell J Cardiol HJC. 2014;55:411–21.

3. Kannel WB, Hjortland M, Castelli WP. Role
of diabetes in congestive heart failure: The Fram-
ingham study. Am J Cardiol. 1974;34(1):29–34.

4. Greenberg BH, Abraham WT, Albert
NM, Chiswell K, Clare R, Stough WG, et al. In-
fluence of diabetes on characteristics and out-
comes in patients hospitalized with heart failure:
a report from the Organized Program to Initiate
Lifesaving Treatment in Hospitalized Patients
with Heart Failure (OPTIMIZE-HF). Am Heart J.

5. Tousoulis D, Oikonomou E, Siasos G,
Stefanadis C. Diabetes mellitus and heart fail-
ure. Eur Cardiol Rev 2014;9(1):37–42.

6. Rubler S, Dlugash J, Yuceoglu YZ, Kum-
ral T, Branwood AW, Grishman A. New type of
cardiomyopathy associated with diabetic glomer-
ulosclerosis. Am J Cardiol. 1972;30(6):595–602.

7. Mehra MR, Canter CE, Hannan MM,
Semigran MJ, Uber PA, Baran DA, et al. The
2016 International Society for Heart Lung Trans-
plantation listing criteria for heart transplanta-
tion: A 10-year update. J Hear Lung Transplant

8. Kim HJ, Jung S-H, Kim J-J, Yun T-J, Kim
JB, Choo SJ, et al. New-Onset Diabetes Melli-
tus after Heart Transplantation - Incidence, Risk
Factors and Impact on clinical Outcome. Circ J.

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Cardio Diabetes Medicine 2018 224


Dr Jamshed J Dalal

Director-Cardiac Sciences, Kokilaben Hospital, Mumbai

Abstract need for effective interventions to reduce mortal-

Novel oral anticoagulants (NOACS), have been ity and morbidity in the aging population.

used in a variety of situations, including stroke

prevention in atrial fibrillation, prevention and Anticoagulation for secondary preven-
treatment of deep vein thrombosis and in treat- tion of thrombotic events
ment of pulmonary embolism. In this article we
will discuss the new indications for NOACs in Following acute coronary syndrome (ACS), pa-
the prevention of cardiovascular events in stable tients still remain at risk of recurrent cardiovas-
atherosclerotic vascular disease. Atherosclero- cular events despite medical therapy, including
sis is a disease that results in development of long-term antiplatelet therapy with aspirin and
plaques, and is the underlying process common an adenosine diphosphate–receptor inhibitor.
to cardiovascular disease. Adverse events, such Despite dual antiplatelet therapy (DAPT) with
as stroke and acute coronary syndrome, are aspirin and a P2Y12 antagonist, approximately
a result of atherothrombosis, the formation of 1 in 10 patients discharged from hospital after
platelet and fibrin-rich clots after atherosclerotic an ACS experience a further cardiac event or
plaque rupture. Inhibition of both is essential for cardiovascular death within the first year2. This
complete protection from cardiovascular events. risk of cardiovascular events may be related in
The results of studies combining anticoagulants part to excess thrombin generation that persists
and antiplatelet agents, the ATLAS TIMI 46, AT- beyond the time of acute presentation within the
LAS TIMI 51, and COMPASS trial using a factor ACS patients3.

Xa inhibitor rivaroxaban with aspirin combina- Rothberg et al. performed a meta-analysis of pa-
tion, provide strong support for the use of this tients treated with warfarin in addition to aspirin
drug along with aspirin in management of pa- after myocardial infarction and ACS. Their ob-
servations from the ten trials involving a total of
tients with vascular disease.

INTRODUCTION 5938 patients and spanning over 14 years con-
firmed improved cardiovascular outcomes within

Atherosclerosis is a systemic disease that re- these patients supporting the dual antithrombot-

sults in development of plaques throughout the ic approach of adding anticoagulation therapy to

arterial system, and is the underlying pathologi- antiplatelet therap4 However, widespread use of

cal process common to Coronary Artery Disease long-term warfarin in such patients has been lim-

(CAD), Peripheral Artery Disease (PAD) and ited by challenges associated with drug adminis-

Cerebrovascular disease. On the other hand, tration and bleeding risks.
adverse cardiovascular events, such as vascular

stroke and acute coronary syndrome, are typi- The combination of antiplatelet and anticoagu-
cally a result of atherothrombosis, the formation lant treatment is based on the understanding of
of platelet and fibrin-rich clots after atheroscle- the platelet–thrombin interaction. The mecha-
rotic plaque rupture.Atherothrombosis is associ- nism of coagulation involves both platelet accu-
ated with a poor prognosis, and can significantly mulation at the damaged endothelium and the
reduce life expectancy. There is an urgent global conversion of pro-thrombin to thrombin, which in

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Cardio Diabetes Medicine 2018 225

turn causes fibrinogen to degrade to fibrin and that stratum 2 patients were receiving two anti-
stabilize the clot. Both processes of platelet ag- platelet agents.
gregation and thrombin formation are necessary Overall, rivaroxaban reduced incidence of prima-
to occlude a vessel.5. Anticoagulant therapy re- ry efficacy endpoint (Time to death or the first
duces the likelihood of secondary events after episode of MI, stroke, or severe ischemia re-
ACS via the latter mechanism, different to that quiring revascularization) although a statistical-
of antiplatelet agents. There is a lot of ongoing ly significant decrease was not achieved. Twice
research in this area, but finding the sweet spot, daily dosing of rivaroxaban appeared to be safer
where the risk of bleeding was adequately bal- and more efficacious than once-daily dosing in
anced by the benefit of reducing cardiovascular ACS. Rivaroxaban doses of 2.5 and 5 mg twice
events in ACS patients is the challenge. Fac- daily appeared to yield the optimal relationship
tor Xa is a vital component in the generation of between efficacy and safety for the secondary
thrombin, and has a central role in triggering fi- endpoint of death, MI, and stroke and were thus
brin generation and platelet activation, leading to selected for further assessment in the Phase III
thrombus formation6. Hence inhibiting thrombin pivotal trial, ATLAS ACS-TIMI 51.
generation also has resultant effect on reducing
platelet activation. Factor Xa inhibitors could, ATLAS ACS TIMI 51
therefore, support prevention of cardiovascular
events through its inherent dual approach of tar- The pivotal Phase III trial that investigated two
doses of rivaroxaban, 2.5 mg bid and 5 mg bid,
geting the clot. in addition to standard antiplatelet therapy for
prevention of ischemic events in stabilized ACS
Rivaroxaban in ACS patients. (FIGURE 1)

Rivaroxaban has already been studied i
n stroke prevention in non-valvular
AF, VTE prevention after hip and knee
replacement surgery and also for the
treatment and secondary prevention of
VTE. The consistent results with
rivaroxaban in different indications
and studies spanning the thrombotic
disease areas made it a logical choice

for further evaluation in the ACS setting.


It was designed to explore the safety and effica-

cy of rivaroxaban at escalating total daily doses,

ranging from 5 mg to 20 mg. This study assessed

eight different dosing regimens in total, where ri-

varoxaban was administered at once-daily and

twice-daily intervals. The risk of clinically signif-

icant bleeding with rivaroxaban versus placebo Randomization was up to 7 days after hospital-
increased in a dose dependent manner. Clinically ization for index ACS event, STEMI in 50.3% of
significant bleeding (Thrombolysis in Myocardial patients, NSTEMI in 25.6%, and Unstable Angi-
Infarction [TIMI] major, TIMI minor, or requiring na in 24.0%. Taking this into account, as well
medical attention) occurred in 12.1% of patients as the requirement for diabetes or MI in young-
dosed once daily, and 11.3% of those dosed er patients, the study population of ATLAS ACS
twice daily (difference not statistically significant, 2-TIMI 51 can be considered ‘high risk’ for recur-
p=0.52). Absolute rates of bleeding were lower in
stratum 1 than in stratum 2 (p<0.0001) for both rent events.

once- and twice-daily dosing, as expected given

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Cardio Diabetes Medicine 2018 226

In line with what would be expected of an ACS

study in high-risk patients, approximately 60% of Patients with CAD and with PAD are at high

patients were treated with revascularization for risk of cardiovascular death arising from athero-

their index event, and 93% received DAPT. thrombosis. Antiplatelets are the current stan-

Rivaroxaban significantly reduced the prima- dard recommended for the primary and second-

ry efficacy endpoint (death from cardiovascu- ary prevention of atherothrombosis in patients

lar causes, MI, or stroke) in the combined dose with CAD and PAD. 2013 European Society of

groups, as compared with placebo with rates of Cardiology (ESC) guidelines on the manage-

8.9% and 10.7%. These results were consistent ment of stable CAD recommend low-dose ace-

in the intention to treat analysis (p=0.002). The tylsalicylic acid (ASA) for all patients with chronic

decrease in events for primary efficacy endpoint stable CAD and clopidogrel as an alternative in

with 2.5 mg of Rivaroxaban represented a 34 % case of ASA intolerance8. However, there is still

RRR, and a 1.4% absolute risk reduction. an unacceptably high residual risk of CV events

associated with the use of antiplatelet monother-

Rivaroxaban significantly increased the rate of apies (~4–6%)9. DAPT is only recommended in

the primary safety endpoint (TIMI major bleed- selected patients with chronic CAD at high risk

ing not related to CABG) compared with pla- of ischemic events; such treatment cannot be

cebo  (2.1% vs. 0.6%, p<0.001). There was no recommended universally because the risk of

excess risk of fatal intra cranial hemorrhage or bleeding outweighs the benefits.

fatal bleeding with rivaroxaban. There was no

significant difference in the rates of fatal bleed- Vitamin K antagonist plus single antiplatelet ther-

ing associated with rivaroxaban compared with apy have had limited success and are not rou-

placebo  (0.3% vs. 0.2%, p=0.66). The rates of tinely recommended for patients with stable dis-

fatal bleeding were significantly lower for the 2.5 ease. This exemplifies a need to establish new

mg BID dose of rivaroxaban compared with the 5 or add-on treatments in high risk groups. As we

mg BID dose (0.1% vs. 0.4%, P = 0.04). have noted above, Factor Xa is a vital compo-

nent in the generation of thrombin, which in turn

Anticoagulation in stable cardiovascu- has a central role in triggering fibrin generation
lar diseases and platelet activation, leading to thrombus for-
mation. With this rationale, the COMPASS study
Compared with patients with symptomatic ath- evaluated rivaroxaban for the prevention of ath-
erothrombotic events.
erosclerotic disease affecting a single vascular

bed, patients with polyvascular disease are at

increased risk of cardiovascular (CV) events and
death, and the prognosis worsens as the number COMPASS TRIAL: Cardiovascular

of affected arterial beds increases. A 1-year fol- OutcoMes for People using Anticoag-
low-up study of REACH registry demonstrated a ulation StrategieS

higher risk of all-cause mortality, CV disease-re-

lated death, non-fatal MI and stroke compared The COMPASS study10 investigated the efficacy
with disease in a single arterial bed in patients and safety of rivaroxaban, alone or in combina-
with polyvascular disease. Patients with prior MI tion with aspirin for the secondary prevention of
are at increased risk of future events. In patients atherothrombotic events in patients with chronic
with prior MI and no prior stroke/transient isch- CAD or PAD. (FIGURE 2)
emic attack, the incidence of CV death, MI  or

stroke was 4.7% at 1 year, and increased by The individual cardiovascular risk profiles varied
approximately 3.5%/year thereafter to 15.1% at depending on the presence of cardiovascular
risk factors or the occurrence of previous cardio-
4 years7. vascular events. Indeed, the inclusion criteria in

Return of Anticoagulation for chronic COMPASS covered a high-riskpopulation. Spe-

coronary artery disease cific high-risk groups within the COMPASS pop-

Cardio DiabetuelsatMioendiicnicnleuded: patients with a history of CAD

Cardio Diabetes Medicine 2018 227

(90.6%) and PAD (27.3%) (Approximately 15% lar death, stroke, MI, fatal bleeding and critical
of total population had concomitant CAD and organ bleeding. This endpoint was reduced by
PAD); patients with a history of prior MI (62.0% 20% with rivaroxaban vascular dose plus aspi-
rin compared with aspirin alone.
of total population);

patients with a history of prior MI (62.0% of total The comparisons of rivaroxaban (5 mg twice dai-
population); and patients who smoke (21.3% of ly) alone with aspirin alone did not show a sig-
total population). Patients who had an ongoing nificant difference in the primary outcome or the
indication for DAPT or non-acetylsalicylic acid net-clinical-benefit outcome.
antiplatelet therapy were excluded.

The vascular doses of rivaroxaban (2.5 mg Conclusion
BID with ASA and 5 mg BID without ASA used
in COMPASS were selected to provide an opti- The results of previous studies combining an-
mal balance between efficacy and bleeding risk, ticoagulants and antiplatelet agents, and the
based on previous studies of rivaroxaban in pa- conclusive efficacy and safety evidence from
tients after an ACS event. COMPASS trial using a factor Xa inhibitor with
aspirin combination, provide strong support for
the use of combined small dose of rivaroxaban

In patients with chronic CAD or PAD, dual along with aspirin in the long term management
pathway inhibition with rivaroxaban vascular of patients with coronary, cerebral and peripheral
dose 2.5 mg bid plus aspirin, versus aspirin artery disease. If we are to stem the epidemic
alone, significantly reduced the combined risk of of cardiovascular disease in our country, we will
stroke, CV death and MI by 24%, demonstrating need to be far more aggressive in the manage-
a very substantial 44% reduction in stroke, 23% ment of atherosclerosis and atherothrombosis.
significant reduction in total mortality, and 14% The reduction of LDL cholesterol to very low
reduction in MI. levels using statins and PCSK9 inhibitors, along

with the use of anticoagulation with a small dose

As expected, it resulted in increased major of rivaroxaban and aspirin may be the way for-

bleeding, higher by 70% (3.1% vs 1.9%). How- ward.
ever, there was no significant increase in intra-

cranial, critical organ or fatal bleeding. The net References
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Task Force on the Management of Stable
Coronary Artery Disease of the European
Society of Cardiology. Eur Heart J 2013;
9. CAPRIE Steering Committee. A randomised,
blinded, trial of clopidogrel versus aspi-

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Stroke prevention in Non-Valvular Atrial Fibrillation

Dr.Nihar Mehta

Fellowship in interventional cardiology,S.Korea
Fellowship in intervenntional cardiology,Mount Sinai,Newyork

Consultant cardiologist
Jaslok hospital&Reseach centre
bhatia hospital,K.J.Somaiya superspeciality hospital


INTRODUCTION valves, Rheumatic or Artificial) categorization is
proposed, depending on the type of OAC use in
Non-vitamin K antagonist oral anticoagulants patients with AF. In this scheme, EHRA Type 1
(NOACs) are an alternative for vitamin K an- refers to AF patients with VHD needing therapy
tagonists (VKAs) to prevent stroke in patients with a vitamin K antagonist (VKA), including in
with non-valvular atrial fibrillation (AF) and have particular moderate–severe mitral stenosis of
emerged as the preferred choice, particularly in rheumatic origin and mechanical prosthetic valve
patients newly started on anticoagulation.These replacement. In contrast, EHRA Type 2 valvular
drugs are also referred to as ‘direct oral antico- heart disease refers to VHD patients needing
agulants (DOACs)’ however, we prefer to con- thromboembolic prevention therapy for AF with
tinue to use the term NOACs. Ultimately, both a VKA or a NOAC, including essentially all other
terms are interchangeable when referring to the native valvular stenoses and insufficiencies as
direct factor Xa inhibitors: Apixaban, Edoxaban, well as mitral valve repair, bioprosthetic valve
and Rivaroxaban as well as the direct thrombin replacements and transaortic valve intervention
inhibitor Dabigatran. (TAVI).

Compared to the VKAs, NOACs have an
• Improved efficacy/ safety ratio, Before prescribing a NOAC to a patient with AF,
• A predictable anticoagulant effect it needs to be decided that anticoagulation is
• No need for routine coagulation indicated based on a risk/benefit analysis. The
monitoring choice of anticoagulant (VKA or NOAC; choice
• Fewer food and drug interactions of NOAC) should be made on the basis of indica-
• Fixed dosing schedule tions , creatinine clearance (CrCl), patient-relat-
• Faster onset of action ed clinical factors, and patient preference.

THE TERM ‘NON VALVULAR AF’ The decision to start anticoagulation in patients
with atrial fibrillation should be based on the
Strictly, the term ‘non-valvular AF’ refers to AF CHADS-VASc Score. As the score increases,
in the absence of a mechanical prosthetic heart the risk of thromboembolic events increases. If
valve or moderate to severe mitral stenosis (usu- the score is more than 2, the patient should re-
ally of rheumatic origin) which were exclusion ceive NOACs or VKA irrespective of the dura-
criteria for all Phase III NOAC vs. warfarin trials tion of Atrial fibrillation or the conversion to sinus
in AF. rhythm. (Table 1 and Figure 1)
Guidelines have expressed a preference for NO-
A novel classification has recently been suggest- ACs over VKA in stroke prevention
ed where a functional EHRA (Evaluated Heart

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Cardio Diabetes Medicine 2018 230

for AF patients, especially if newly initiated. This
recommendation (Class I, level of evidence A) is
based on the overall clinical benefit of NOACs.

Risk factor Points CHADS 1 YEAR RISK OF
Congestive heart fail- 1 SCORE BOLISM PER 100
1 0
Hypertension 1 0.78
1 1
Age 65–74 years 2 2.01
3 3.71
Diabetes mellitus 4 5.92
Prior Stroke, TIA or SE 2 6 9.27
Vascular disease 1 8 15.26
Age ≥75 years 2 9 19.74
Sex: Female gender 1 21.5

Table 1: CHADS-VASc Score and 1 Year Risk of Thromboembolism per 100
Patient years

Figure 1 : ESC Guidelines on management of Anticoagulation in AF

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CHOOSING THE TYPE AND DOSE OF NON-VI- Whenever possible, the tested standard dose
TAMIN K ANTAGONIST ORAL ANTICOAGU- of NOACs should be used. In addition, it is also
LANT (Table 2 & 3)
important to consider co-medications, some of

which may be contraindicated or result in un-
With four NOACs available in different dosages favourable drug–drug interactions. The patient
for different indications and with different dose age, weight, renal function, and other comorbid-
reduction criteria, identification of the correct ities also influence the choice. In some patients,
dose has become more complicated and is one proton pump inhibitors (PPIs) may be considered
of the key challenges in the daily use and individ- to reduce the risk for gastrointestinal (GI) bleed-
ualization of treatment.

Table 2

Table 3

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PATIENT EDUCATION: and/or SMS messages to alert the patient.

It is critically important to educate patients at SWITCHING BETWEEN
each visit about the modalities of intake [once ANTICOAGULANT REGIMENS
daily (OD) or twice a day (BID); intake with food  VKA TO NOACS
in case of 15 mg/20mg of rivaroxaban], the im-
portance of strict adherence to the prescribed The NOAC can immediately be initiated once the
dosing regimen, how to deal with any lapse in INR is <_2.0. If the
dosing, and to be careful not to leave their med- INR is 2.0–2.5, NOACs can be started immedi-
ication behind ately or (better) the
when travelling. next day
Patients on VKAs/NOACs should routinely been
advised to carry information about their antico-  NOACs to VKA
agulant therapy to alert any healthcare provider
about their treatment. NOAC and VKA should be administered con-
comitantly until the INR is in a range that is con-
FOLLOW UP: sidered appropriate —similar to the situation
when low molecular weight heparins (LMWHs)
The absence of a need for routine plasma level are administered during VKA initiation.
monitoring means that NOAC patients are like- When concomitant administration of a NOAC
ly to be less frequently seen for follow-up com- during the initiation of the VKA is not deemed ap-
pared with VKA patients. However, there are propriate, initiation of the VKA can be performed
arguments in favour of regular follow-up assess- after switching the NOAC to LMWH
ment for patients on NOACs, particularly in case
of relevant co-morbidities such as renal failure,  NOACS TO PARENTERAL ANTICO-
older age, multiple comorbidities, or frailty. AGULANTS
The follow-up of AF patients who are taking anti-
coagulant therapy needs to be carefully specified The parenteral anticoagulant [unfractionated
and communicated. Patients’ treatment should heparin (UFH) and LMWH] can be initiated when
be reviewed on a regular basis (preferably af- the next dose of the NOAC would be due.
ter 1 month initially and at least every 3 months
Bleeding risk should be systematically as-
sessed, e.g. by the HAS-BLED score, which has Intravenous UFH: NOACs can usually be started
also been validated in patients on NOACs 3 and 2 (to 4) h after intravenous UFH (half-life 2 h) is
has shown a better prediction than an approach discontinued.
based only on modifiable bleeding risk factors. Low molecular weight heparin: NOACs can be
initiated when the next dose of LMWH would be

Adherence to NOAC intake is crucial as its anti-  NOAC TO NOAC
coagulant effect wanes within 12–24 h after the
last intake. Although there is evidence for signifi- The alternative NOAC can be initiated when the
cantly lower discontinuation rates with NOACs next dose of the initial
than with VKAs, discontinuation is still a relevant NOAC is due.

Patient education on the need for oral anticoag- Many drugs used in AF patients are P-gp inhib-
ulation therapy and the importance of strict ad- itors (e.g. verapamil, dronedarone, amiodarone,
herence is important. Many technological aids and quinidine) will result in increased plasma
are being explored to enhance adherence: the levels. Strong CYP3A4 inhibition or induction
day-marked blister pack format; medication box- may affect plasma concentrations.
es (conventional or with electronic verification of Conversely, strong inducers of P-gp and/or CY-
intake); smartphone applications withCrearmdiinodDeirasbetPe3sAM4ed(sicuicnhe as rifampicin, carbamazepine, etc.)

Cardio Diabetes Medicine 2018 233

will markedly reduce NOAC plasma levels; such for renal insufficiency.
combinations should be avoided or used with
great caution and surveillance • Oral Anticoagulant Therapy in patients with a
Dose reduction of all NOACs is primarily rec- CrCl of 15–29 mL/min:
ommended along the published dose reduction
criteria. Whenever possible, the tested standard There are no RCT data on the use of NOACs for
doses of NOACs should be used. stroke prevention in AF patients with severe CKD
or on renal replacement therapy (RRT) since all
Apart from the pharmacokinetic interactions, landmark NOACs trials essentially excluded pa-
co-administration of NOACs with other antico- tients with a CrCl of <30mL/min
agulants, platelet inhibitors (e.g. aspirin, clopi-
dogrel, ticlopidine, prasugrel, ticagrelor, others),
and non-steroidal anti-inflammatory drugs in-
creases the risk of bleeding.6 Therefore, such
combinations should be carefully balanced
against the potential benefit in each clinical sit-
uation. Coadministration of NOACs with dual
antiplatelet drugs requires active measures to
reduce time on triple therapy

Rivaroxaban 15mg/20mg for stroke prevention ANTICOAGULANTS IN LIVER DISEASE
in AF needs to be taken with food while there is
no food interaction with the other NOACs. The Advanced liver disease is asseffect allows prop-
concomitant use of PPIs and H2-blockers leads erly timed short-term cessation of NOAC therapy
to a small reduction in bioavailability of dabiga- before surgery
tran, but without effect on clinical efficacy. There
is also no relevant antacid interaction for the oth- After a procedure with immediate and complete
er NOACs. haemostasis,
Data have shown that administration in crushed NOACs can generally be resumed 6–8 h after
form, e.g. via a nasogastric tube, does not alter the end of the intervention.
the bioavailability for apixaban, rivaroxaban and
edoxaban. In contrast, dabigatran capsules must CONCLUSION:
not be opened as it results in a substantial in-
crease in drug bioavailability. NOACs are a valuable addition to the small ar-
mamentarium of oral anti-coagulants available
ORAL ANTICOAGULATION IN CHRON- today. In the setting of Non-valvular atrial fibrilla-
IC KIDNEY DISEASE (Figure 1) tion, they provide a comfortable and predictable
method of preventing thromboembolic events,
Compared with warfarin, all four NOACs showed without increasing major bleeding events. Sev-
consistent efficacy and safety in patients with eral guidelines have embraced the NOACs as
mild to moderate CKD compared with non-CKD drugs of choice in the selected patients. In the
patients in the respective Subgroup analyses of Indian context, where drug monitoring and pa-
pivotal NOAC trials. Appropriate dosing is an es- tient follow up is inadequate, this drug deserves
sential issue to be addressed when using NO- a special place in the management of atrial fibril-
ACs in patients with CKD. While rivaroxaban, lation.
apixaban, and edoxaban doses were reduced
according to renal function in their respective
randomized clinical trials (RCTs), patients in
the RE-LY trial were randomized to dabigatran
150mg BID or 110mg BID without dose reduction

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1. Heidbuchel H, Verhamme P, Alings M, Antz M,
Hacke W, Oldgren J, Sinnaeve
P, Camm AJ, Kirchhof P; European Heart Rhythm
Association. European Heart
Rhythm Association Practical Guide on the use
of new oral anticoagulants in
patients with non-valvular atrial fibrillation. Eu-
ropace 2013;15:625–651.
2. Baumgartner H, Falk V, Bax JJ, De Bonis M,
Hamm C, Holm PJ, Iung B,
Lancellotti P, Lansac E, Munoz DR, Rosenhek R,
Sjogren J, Tornos Mas P,
Vahanian A, Walther T, Wendler O, Windecker
S, Zamorano JL; ESC Scientific
Document Group. 2017 ESC/EACTS Guidelines
for the management of valvular
heart disease. Eur Heart J 2017;38:2739–2791
3.Lip GYH, Skjoth F, Nielsen PB, Kjaeldgaard
JN, Larsen TB. The HAS-BLED,
ATRIA, and ORBIT bleeding scores in atrial fibril-
lation patients using
non-vitamin K antagonist oral anticoagulants.
Am J Med 2017; [Epub ahead of
4. Beyer-Westendorf J, Ehlken B, Evers T. Re-
al-world persistence and adherence
to oral anticoagulation for stroke risk reduction in
patients with atrial fibrillation.
Europace 2016;18:1150–1157.
5. Guo Y, Chen Y, Lane DA, Liu L, Wang Y, Lip
GYH. Mobile health
technology for atrial fibrillation management inte-
grating decision support,
education, and patient involvement: MAF App
Trial. Am J Med
6. Dans AL, Connolly SJ, Wallentin L, Yang S,
Nakamya J, Brueckmann M,
Ezekowitz M, Oldgren J, Eikelboom JW, Reilly
PA, Yusuf S. Concomitant use of
antiplatelet therapy with dabigatran or warfarin in
the Randomized Evaluation
of Long-Term Anticoagulation Therapy (RE-LY)
trial. Circulation

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Amal Kumar Banerjee

Consultant & Interventional Cardiologist

Introduction ically develop thrombi in the left atrial append-
age. In patients with mechanical prosthetic heart
Valvular heart disease (VHD) and atrial fibrillation valves, thrombi commonly form on the prosthe-
(AF) often coexist. They are independent caus- sis or in the left atrium as a result of non-phys-
es of mortality and morbidity, and both increase iologic blood flow patterns due to prosthesis.
the risk of stroke and systemic arterial embolic Patients with bioprosthetic heart valves are at
events (SSEE). Stroke prevention is central to a lower risk of thrombosis, but the risk is not
the management of patients with AF. For many zero. Risk of thrombosis in patients who receive
years, the use of oral anticoagulant therapy with a bioprosthetic valve increases in the setting of
warfarin, described as a vitamin K antagonist concurrent AF or mitral stenosis (MS). Porcine
(VKA), has been the standard therapy for the valves confer a higher risk of thrombosis than
prevention of thromboembolism in patients with pericardial valves. In both cases, thrombosis can
AF. Regular blood monitoring and dose adjust- be propagated by decreased cardiac output and
ment are necessary to maintain the internation- valve deterioration. While the exact mechanism
al normalized ratio within the target therapeutic is unclear, the presence of MS increases the risk
range. of thrombosis as well, likely related to decreased
The introduction of non-vitamin K oral anticoag-
ulants (NOACs) has expanded the therapeutic blood flow through the left atrium.
options for primary and secondary stroke pre-
vention in patients with nonvalvular AF (NVAF). Nonvalvular AF
Unlike warfarin, NOACs act through the direct
inhibition of coagulation factors thrombin (dab- However, NOAC clinical trials typically exclud-
igatran) or factor Xa (rivaroxaban, apixaban, and ed patients with certain types of valvular heart
edoxaban). The NOACs do not require routine disease (VHD), and uncertainty remains as to
monitoring or dose adjustment and they have whether the use of NOACs is safe or effective
short half-lives, no food interactions, and rela- in this population. Valvular heart disease is a
tively few drug interactions, which makes them broad category of disorders characterized by
more convenient alternatives to warfarin to re- damage to or a defect in one or more of the 4
duce the risk of stroke and systemic embolism. heart valves.1 Clinical trials of NOAC use in pa-
It is hypothesized that thrombus formation in pa- tients with AF included only a small proportion of
tients with nonvalvular AF may be different from patients with valve-related disorders (13%-26%),
and yet as many as 60% of patients with AF have
that of patients with VHD. Patients with AF typ- concomitant VHD.2 Patients with mechanical
heart valves were systematically excluded from
NOAC clinical trials, and there have been very

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few clinical trials evaluating NOAC use in these out, there was no evidence of differential effects
specific populations. of apixaban compared with warfarin on stroke,
In clinical practice, the term non-valvular AF has major bleeding, and all-cause mortality between
created considerable confusion among physi- patients with and without VHD.
cians who use it to ask which patients fall into In a post hoc analysis of the ROCKET-AF (Ri-
which category and may be treated by novel varoxaban Once Daily Oral Direct Factor Xa In-
anticoagulants. This has been confirmed in a hibition Compared With Vitamin K Antagonism
recent prospectively conducted web-based sur- for Prevention of Stroke and Embolism Trial in
vey of cardiologists and internists. Proper under- Atrial Fibrillation), 14.1% had significant VHD
standing of which type of valve disease belongs and 5.3% had prior valvular procedures. Among
to non-valvular AF is critical when considering patients with VHD, the rates of systemic throm-
the use of an NOAC in patients with AF. boembolism and all-cause mortality were similar,
In order to avoid confusion, the term non-valvu- but major bleeding risk was significantly high-
lar has been eliminated in the 2016 ESC guide- er with rivaroxaban versus warfarin. A recent
lines on the management of patients with AF, analysis of the RE-LY (Randomized Evaluation
and reference is made to the specific underlying of Long-Term Anticoagulation Therapy) trial
valvular heart disease (VHD).However, the term demonstrated that 21.8% of patients with AF had
is still found in the individual summary of prod-
uct characteristics, of each of the NOACs due to VHD (excluding prosthetic valves and significant
the original wording used in the exclusion criteria mitral stenosis) and that the presence of VHD
of the clinical trials on which their regulatory ap- did not affect the comparison between dabig-
proval was based. atran and warfarin.After propensity-matching
analysis, non–vitamin K antagonist oral antico-
Clinical Trials agulants were associated with reduced all cause
mortality risk compared with warfarin in patients
Valvular heart disease (VHD) coexists in >50% with and without valvular heart disease and with
of patients with AF and is associated with a high- atrial fibrillation. Ischemic stroke rates were sim-
er risk of thromboembolic events, independent of ilar between anticoagulants in patients with val-
the underlying cardiac rhythm. Among patients vular heart disease, whereas rivaroxaban was
with mitral valve stenosis or prosthetics valves, associated with lower stroke rates than warfarin
AF portends high thromboembolic risk and vita- in the patients without valvular heart disease.
min K antagonists are indicated for stroke and Non-gastrointestinal bleeding risk was lower with
systemic embolism prevention. Some patients non–vitamin K antagonist oral anticoagulants
with VHD have been included in the NOAC trials. than warfarin in patients with and without val-
In the ARISTOTLE (Apixaban for Reduction in vular heart disease. Therefore, clinicians have
Stroke and Other Thromboembolic Events in >1 anticoagulation option available for patients
Atrial Fibrillation) trial, 26% of patients had a his- without hemodynamically significant valvular dis-
tory of moderate or severe VHD (most of them ease requiring surgery.
with mitral regurgitation) or previous valve sur- A Systematic Review and Meta-Analysis has
gery. Although these patients had higher rates of shown among patients with AF and native VHD,
stroke and systemic embolism than those with-

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NOACs reduce stroke and systemic embolism patients with VHD needing therapy with a vita-

compared with warfarin. Evidence shows that min K antagonist (VKA), including in particular

apixaban, dabigatran, and edoxaban also re- mod erate–severe mitral stenosis of rheumatic

duce bleeding in this patient subgroup, whereas origin and mechanical prosthetic valve replace-

major bleeding (but not intracranial hemorrhage ment. In contrast, EHRA Type 2 valvular heart

or mortality rate) is significantly increased in VHD disease refers to VHD patients needing throm-

patients treated with rivaroxaban. NOACs are a boembolic prevention therapy for AF with a VKA

reasonable alternative to warfarin in AF patients or a NOAC, including essentially all other native

with VHD. valvular stenoses and insufficiencies as well as

Present Scenario mitral valve repair, bioprosthetic valve replace-
ments and transaortic valve intervention (TAVI).5
Based on these new developments, a novel clas- Patients with EHRA Type 2 valvular heart dis-
sification has recently been suggested where a ease were variously included in these trials and
functional EHRA (Evaluated Heartvalves, Rheu- NOACs demonstrated a comparable relative ef-
matic or Artificial) categorization is proposed, de- ficacy and safety vs. warfarin in patients with vs.
pending on the type of OAC use in patients with without valvular disease, except for a higher risk
AF.5 In this scheme, EHRA Type 1 refers to AF of bleeding with rivaroxaban vs. warfarin in pa-

tients with valvular heart disease in a post hoc

analysis of the ROCKET-AF trial. Non-vitamin K

antagonist oral anticoagulants may therefore be

Condition used in such patients (Table 1).
Eligibility for NOAC therapy

Mechanical prosthetic valve Contraindicated

Moderate to severe mitral stenosis Contraindicated

(usually of rheumatic origin)

Mild to moderate other native valvular

disease (e.g., mild-moderate aortic Included in NOAC trials

stenosis or regurgitation, degenerative

mitral regurgitation etc.)

Severe aortic stenosis Limited data (excluded in RE-LY) Most

will undergo intervention

Bioprosthetic valve (after > 3 months Not advised if for rheumatic mitral

post operatively) stenosis Acceptable if for degenera-

tive mitral regurgitation or in the aortic


Mitral valve repair (after > 3 months Some patients included in some

post operatively) NOAC trials

PTAV and TAVI No prospective data yet May require

combination with single or dual anti-

platelet therapy

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Table 1. Selected indications and contraindications for NOAC therapy in valvular AF pa-

PTAV : percutaneous transluminal aortic valvuloplasty;
TAVI : transcatheter aortic valve implantation.

Atrial fibrillation in patients with biological valves terms should be therefore either always defined
or after valve repair constitute a grey area, even
though these patients were included in some of or abandoned for a more specific terminology.
the landmark NOAC trials.5,8,9,14 Since most It would be more logical to propose the term me-
of these patients do not require long-term oral chanical and rheumatic mitral valvular AF (acro-
anticoagulation following their valve procedure, nym: MARM-AF) as an accurate description of
the use of a NOAC for the management of con- a disease entity worthy of being kept separated
comitant AF is considered to be a valid option. from other forms of AF, but with possible internal
One exception may be AF in the presence of a differences between the two conditions
biological mitral prosthesis implanted for rheu-
matic mitral stenosis. Although mitral valve flow Conclusion
is normalized post-mitral valve replacement in
these patients, their atria usually remain large In patients with AF and VHD (other than mod-
and severely diseased. As such, VKA may be the erate/ severe mitral stenosis or mechanical
preferred option over NOACs in these patients, heart valves) NOACs are attractive alternatives
but more data are needed. to VKAs because the coexistence of VHD does
There are no prospective data available yet on not affect the overall relative efficacy or safety
NOACs in patients after percutaneous aortic of NOACs in terms of prevention of SSEE and
major bleeding. Current definitions of valvular
valve interventions [percutaneous transluminal and nonvalvular AF are misleading, and the use
of NOACs should be permitted in most patients
aortic valvuloplasty or transcatheter aortic valve with VHD. The recently proposed term MARM-
implantation (TAVI)] in the presence of AF. Per- AF, could be useful to identify the true high risk
cutaneous transluminal aortic valvuloplasty or AF patients for whom VKAs are the anticoagu-
TAVI usually requires single or even transient lants of choice.
dual antiplatelet therapy (DAPT).The addition
of an anticoagulant increases the bleeding risk, References
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JD, O’Fallon WM, Wiebers DO. Predictors of Comparative effectiveness and safety of non-vi-
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14.De Caterina R, Renda G, Carnicelli AP, Nor-
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Hamm C, Holm PJ, Iung B, Lancellotti P, Lansac
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lar’ atrial fibrillation? A reappraisal. Eur Heart J
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Prof Luigi Gnudi, MD, PhD, FRCP, FASN

Head, Unit for Metabolic Medicine,
School of Cardiovascular Medicine & Science, King’s College London School of Medicine & Life

Department of Diabetes and Endocrinology, Guy’s and St Thomas Hospital NHS Foundation Trust,

London, UK

Abstract abolic and haemodynamic control has proven
to be efficacious in delaying the progression of
Diabetic nephropathy (DN) is currently the most chronic kidney disease in diabetes in younger
feared chronic microvascular complication of di- and relatively uncomplicated subjects. Aggres-
abetes. DN is characterized by a progressive sive metabolic control could expose patients (es-
decline in glomerular filtration rate, that ultimate- pecially with chronic kidney disease-CKD stage
ly leads to end stage renal disease (ESRD) and 4-5) to potentially catastrophic consequences of
is often paralleled by an increase in cardiovascu- hypoglycaemic episodes. In those with concom-
lar morbidity and mortality. itant renal vascular disease -that will be the vast
majority- and CKD stage 4-5, RAAS inhibitor
Optimized metabolic and blood pressure con- therapy might accelerate renal disease progres-
trols remain the cornerstone of treatment. Renin sion and expose the patient to episodes of acute
Angiotensin Aldosterone System (RAAS) inhibi- kidney injury (pre-renal), or hyperkalemia. A re-
tors have proven very successful in delaying the sponse-driven approach titrated to both efficacy
progression of kidney disease and in preventing and tolerability, and combined with close mon-
ESRD. Data have shown that diabetic kidney itoring and patient counselling, will be the key
disease can be delayed in its progression. component of effective intervention to minimize
Different experimental therapies targeting vascu- harm in the frailest patients.
lature/haemodynamic effects, inflammation and
oxidative stress are currently being tested. Tri- Novel recent treatment approaches have been
als are providing promising results and it is likely trying to target different aspects of the patho-
that some of these therapies will be available for physiology of CKD in diabetes, and their future
use is tested on top of current standard of care
clinical use within the next decade. for metabolic control and hypertension with
RAAS inhibition.
Diabetic kidney disease: current and
future treatments Of the many new potential molecules that could,
in the future, develop as potential future treat-
The current treatment strategies are not suffi- ment for diabetic nephropathy, we should high-
cient to completely prevent progression of dia-
betic kidney disease to ESRD. Intensive met-

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Cardio Diabetes Medicine 2018 242

light molecules targeting the vasculature (vascu- This approach could result in us missing poten-
lo-protective), molecules targeting inflammation tial drug-related beneficial effects in earlier stag-
and anti-oxidative stress molecules. es of CKD (e.g. microalbuminuria); these studies
are clearly longer, more expensive, and possibly
The most promising treatments, currently under not affordable today.
investigations in early discovery phase, have
been investigating inflammation inhibitors (e.g. Future better phenotypic patients’ characteriza-
CCR2/CCR5 antagonist, pentoxifylline), oxida- tion with novel biomarker, possibly derived from
tive stress inhibitors (e.g. allopurinol, Nox1-4 proteomics and metabolomics analysis, might
inhibitors, Nrf2 activators), novel endothelin and help our understanding of novel treatments stud-
aldosterone/renin receptor system inhibitors, vi- ied at different stages of kidney disease.
tamin D activators, inhibitors of advanced gly-
cation end products (AGE) and their receptor Recent novel advances in the mechanisms in-
(RAGE), Jak1-2 inhibitors, Transforming Growth volved in diabetic kidney disease have recent-
Factor-α (TGF-α) and Epidermal Growth Fac- ly opened some hopes in the fight for the treat-
tor Receptor (“EGFR”) blockers, Apoptosis Sig- ment of diabetic kidney disease. Indeed, within
nal-regulating Kinase 1 (ASK1) inhibitors, and the class of oral hypoglycaemic agents, recent
TGFβ1 and CTGF inhibitors. Tie-2 activators are studies have suggested a potential renoprotec-
currently being tested in diabetic eye disease tive effects for SGLT2 antagonists (1) and incre-
and might, in a near future, be explored also in tin-mimetic drugs such as glucagon-like peptide
diabetic kidney disease. (GLP)-1 analogues.

In the past few years, many failures have char- Of the multiple factors contributing to the devel-
acterized the search for new agents for the opment of T2DM (e.g. insulin resistance at the
treatment of CKD in diabetes. One of the main tissue level, beta cell failure, increased gluca-
problems is patients’ phenotype; despite we can gon secretion, and decrease incretin effect), the
usually obtain a pretty clear phenotypic charac- increased renal proximal tubular glucose reab-
terization in patients with T1DM, in the T2DM sorption, secondary to an upregulation of the
population we encounter a huge phenotypic het- SGLT2 transporters, has been implicated in the
erogeneity. Importantly recent data suggest that pathophysiology of diabetes. The glucose prox-
other renal pathologies often coexist or drive imal tubule reabsorption is mediated by an en-
CKD in patients with T2DM. ergy-dependent sodium-coupled glucose trans-
porter called SGLT2 which has recently been
Further we should be aware that any treatment proposed as a target for treatment of hypergly-
could have a different efficacy when utilized in caemia in diabetes.
different stages of chronic kidney disease; many
of the trials conducted today have been con- Recent clinical trials have demonstrated an
sidering patients solely in the advanced stages important cardiovascular (2) and renoprotec-
of kidney disease often with macro-proteinuria. tive effect (3) (

Cardio Diabetes Medicine

Cardio Diabetes Medicine 2018 243

news-releases/phase-3-credence-renal-out- 2.Zinman B, Wanner C, Lachin JM, Fitchett D,
comes-trial-of-invokana-canagliflozin-is-be- Bluhmki E, Hantel S, et al. Empagliflozin, Car-
ing-stopped-early-for-positive-efficacy-find- diovascular Outcomes, and Mortality in Type 2
ings-300681634.html?tc=eml_cleartime). Diabetes. N Engl J Med. 2015;373(22):2117-28.
Clinical trials on GLP-1 analogues have demon- 3.Wanner C, Inzucchi SE, Lachin JM, Fitchett D,
strated a cardiovascular protective role for this von Eynatten M, Mattheus M, et al. Empaglifloz-
new class of drugs with suggestion of parallel in and Progression of Kidney Disease in Type 2
renoprotective effects (4, 5). Like for SGLT2 in- Diabetes. N Engl J Med. 2016.
hibitors the cardiovascular-renal protective role 4.Marso SP, Daniels GH, Brown-Frandsen K,
of these drugs occurs within 6-12 months from Kristensen P, Mann JF, Nauck MA, et al. Lira-
their initiation and it appears to be beyond the glutide and Cardiovascular Outcomes in Type 2
improvement in glucose control. Diabetes. N Engl J Med. 2016;375(4):311-22.

Studies have suggested direct effects of GLP-1 5.Okerson T, Chilton RJ. The cardiovascular
receptor agonists on endothelial function, renal effects of GLP-1 receptor agonists. Cardiovasc
sodium excretion and improvement in systolic Ther. 2012;30(3):e146-55.
blood pressure but more work is needed to dis-
sect the mechanisms for cardio-renal protection Highlights
of these agents. Experimental research has sug-
gested GLP-1-mediated reduction in glomerular - Diabetic kidney disease is the major cause of
filtration rate (GFR) in models characterized by end stage renal failure.
glomerular hyperfiltration, and an increase in
GFR in models with normal glomerular filtration. - Diabetic nephropathy is an irreversible pro-
gressive disease though some evidence sug-
gests its reversibility.

- As diabetic renal diseases progress hypogly-
caemic and blood pressure treatment needs to
be personalized to preserve patient safety.

Discussion - Preliminary studies strongly suggest a reno-
protective role of SGLT2 antagonist and GLP-1
Several experimental therapies for DN that are analogues.
currently being tested and under development.
The understanding of the putative renoprotective - The cardiovascular protective role of SGLT2
role of SGLT2 and GLP-1, the two currently most antagonist and GLP-1 analogues is likely to be
promising molecules for the treatment of CKD mediated by haemodynamic effects affecting
in diabetes will help towards the understanding the cardiovascular renal system.
their reno-protective effect and possibly offer
new target for treatment in the future.


1.DeFronzo RA, Norton L, Abdul-Ghani M. Re-
nal, metabolic and cardiovascular consider-
ations of SGLT2 inhibition. Nat Rev Nephrol.

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Cardio Diabetes Medicine 2018 244


Dr.R.Ramprasad MD(Gen.Medicine) DNB(Nephrology)

Consultant Nephrologist

NU Hospitals,Bangalore

Diabetes prevalence has reached epidemic sta- egy in management of DKD.
tus in most of the developed and also in develop- There is concern that the measurement of HbA1c
ing parts of the world. The significant proportion may be affected in kidney disease due to iron de-
of the diabetics are still either untreated or inad- ficiency, hemolysis, short life span of red blood
equately treated that leads to increased preva- cells ,uremic toxins and acidosis. One study
lence of micro and macrovascular complications. says HbA1c underestimates glycemic control in
Diabetic nephropathy is one of the major such dialysis population . Whereas the other one con-
complications and also it significantly rises the cludes that it overestimates. Hence it is unclear,
incidence of cardiovascular events,that together how far A1c indicates glycemic control in chronic
results in high morbidity and mortality risks,as kidney disease. Alternative measurements like
well as loss of resources. Diabetic therapy in serum fructosamine also failed to have signifi-
kidney disease carries lot of challenges includ- cant correlation in CKD. Serum glucose monitor-
ing search of valid diagnostic tools, selection of ing remains still gold standard for glycemic con-
antidiabetic drugs in the setting of low glomeru- trol measurement in CKD. Continuous glucose
lar filtration(GFR) status, dietary restrictions and monitoring disc is found to be a very useful tool
correcting the hemodynamic and metobolic dys- in this regard, which is widely used in our center
regulations. and gives better results

Diabetic Nephropathy(DN) is currently the most Pharmacological treatment of hyperglycemia to
feared diabetic chronic complication and is char- be undertaken with caution in patients with DKD
acterized by a progressive decline in GFR, even- since many drugs requires dose adjustment and
tually resulting in end stage renal disease(ES- some of them to be avoided in low GFR(table1).
RD). The all cause mortality in patients with DN The frequency of hypoglycemic episodes with in-
is nearly 20-40 times higher than that in patients sulin is as much as five times more with kidney
without nephropathy.. Traditionally, Chronic kid- disease patients. Exogenous insulin is normal-
ney disease (CKD) believed to result from diabe- ly metabolized by kidney. Hence, CKD patients
tes has been termed “Diabetic Nephropathy.”Re- have delayed degradation of insulin. Never-
cently, the Diabetes and CKD work group of the theless, the effect of regular insulin is impaired
National Kidney Foundation Kidney disease out- which is not seen with lispro. Thus, a higher dose
comes Quality Initiative (KDOQI) suggested that of regular insulin may be required ,despite the
a diagnosis of CKD presumed to be caused by lower clearance in patients with DKD.
diabetes should be referred to as “Diabetic Kid-
ney Disease” and the term “Diabetic Nephrop- Among oral diabetic drugs thiazolidinediones,
athy” should be reserved for kidney disease at- meglitinides do not require dose adjustments.
tributed to diabetes with histopathological injury Most of the sulphonylureas need dose reduction
demonstrated by renal biopsy. in early CKD and to be avoided,as it advances
About 40% of people with diabetes will develop to stage 3-5.Glipizide doses not have active me-
chronic kidney disease. Diabetic control in dia- tabolites so that not requires dose adjustment.
betic kidney disease is pivotal to reduce the rate Similarly Gliclazide also does not need dose ad-
of decline in GFR. Trials of intensive glycemic justment. Glimipride may be used in lower doses
control ,such as DCCT/EDIC trial in type 1 DM , in advanced CKD. Eventhough ,Aplha glucosi-
ADVANCE trial in type 2 DM supports this strat- dase inhibitors are metobolised mainly in liver

Cardio Diabetes Medicine

Cardio Diabetes Medicine 2018 245

this group may cause hepatotoxicity in patients
with creatinine more than 2mg/dL.

Cardio Diabetes Medicine

Cardio Diabetes Medicine 2018 246

Sodium glucose cotransporter 2(SGLT2) inhibi- 3.Morgan L et al.,Glycated proteins as indices of
tors are found to have caused marked reduction glycaemic control in diabetic patients with chron-
in cardiovascular mortality and renal risk in clini- ic renal failure.Diabet Med13:514-519,1996.
cal trials like EMPA-REG OUTCOME TRIAL and 4.Joy MS,Cefalu WT,Hogan SL,Nachman
CANTATA-SU trial. Hence, this group of drugs to PH:Long-term glycemic control measurements
be tried in early stages of CKD and many trials in diabetic patients receiving hemodialysis.Am J
are in pipeline to ascertain their role in future. Kidney Dis 39:297-307,2002.
As per Kidney Disease improving global out- 5.Muhlhauser I,Toth G,Sawicki PT,BergerM M:-
comes (KDIGO) guidelines recommends to con- Severe hypoglycemia in type 1 diabetic patients
tinue metformin in established patients as low as with impaired kidney function.Diabetes Care
GFR of 30ml/min. Also, metformin may be start- 14:344-346,1991.
ed newly in patients with estimated GFR above 6.National kidny foundation:KDOQI clinical prac-
45ml/min. Metformin induced lactic acidosis is tice guidelines and clinical recommendations for
very rare as evidenced by many trials and meta- diabetes and chronic kidney disease.Am J Kid-
analysis consistently. ney Dis 49S1-S180,2007
Dipeptidyl-peptidase IV inhibitors require dose
reduction (sitagliptin 25% reduction if eGFR
30-50ml/min/1.73m2;50%reduction if less than
30ml/min).Linagliptin and teneligliptin do not re-
quire dose reduction in this group of drugs.
Renoprotective measures like blood pressure
control, correction of dyslipidemia in early CK-
D,avoiding nephrotoxic medications, nutritional
considerations are to be implemented stringent-
ly,to prevent the CKD progression. Current rec-
ommendation is to manage cardiovascular dis-
eases aggressively in all primary, secondary and
tertiary level interventions to improve the longev-
ity and quality of life among diabetic kidney dis-
ease patients.


Comprehensive and Optimal management of di-
abetes in DKD is necessary to reduce the rate
of decline in GFR and cardiovascular events. Im-
proving the quality of life in DKD population with
minimising the therapy related side effects is a
challenge .


1.Luigi Gnudi,The patient with diabetes
mellitus,Neil Turner,Oxford Texttbook of clinical
nephrology,oxford publisher,volume 2,fourth edi-
2.American Diabetes Association.standards
of medical care in diabetes-2014.Diabetes
Care.2014;37 Suppl 1:S14-S80.

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Cardio Diabetes Medicine 2018 247


Dr Virendra Kumar Goyal

Prof & Head-Internal Medicine

American International Institute Of Medical Sciences



A meta-analysis of clinical studies of patients with put patients at greater risk of exhibiting
cardiovascular disease showed that aspirin use ASA resistance; and
was associated with a 22% reduction in deaths

and relevant ischemic vascular events. Howev- (4) Discusses the clinical impact of ASA
er, clinical studies have shown that patients’ reg- resistance in patients requiring chronic
ularly taking aspirin had recurrence of cardiovas- therapy.

cular events.  This finding led to a questioning: Key words: Aspirin, drug resistance, laboratory
if, in some patients, aspirin was not effective in
blocking platelet aggregation, these patients be- tests, platelet aggregation.

ing called nonresponsive or resistant to aspirin.  INTRODUCTION

Clinical resistance to aspirin is defined by the Aspirin, also known as acetylsalicylic acid (ASA),
occurrence of cardiovascular events in patients is a medication used to treat pain, fever, or in-
under treatment with aspirin, while laboratory re- flammation.  Specific inflammatory conditions
sistance is defined as the persistence of plate- in which aspirin is used include  Kawasaki dis-
let aggregation, documented by laboratory test, ease,  pericarditis, and  rheumatic fever. Role of
in patients regularly taking aspirin.  Patients re- aspirin in treating & preventing primary & sec-
sistant to aspirin had, according to laboratory ondary cardiac catastrophe is well established.
tests, on average, 3.8 times more cardiovascular Aspirin is a  nonsteroidal anti-inflammatory
events when compared to nonresistant ones. drug (NSAID) and works similar to other NSAIDs

While dealing with aspirin resistance, noncom- but also suppresses the normal functioning

pliance & “pseudoresistance, reflecting delayed of platelets.

and reduced drug absorption” should always be
excluded. With the mechanisms of aspirin re- Significant side effects include  gastric upset,
sistance not fully understood and the phenome- stomach bleeding & ulcers, and worsening asth-
non commonly observed in individuals with poor ma. (Bleeding risk is greater among those who
compliance, the existence of aspirin resistance are older, drink alcohol, take other NSAIDs). 

has been challenged. In 1897, scientists at the Bayer company began

This article: studying acetylsalicylic acid as a less-irritating
replacement medication for common salicylate

(1) exposes the difficulties in defining ASA medicines & named it “Aspirin” and sold it around
resistance; the world.

(2) Discusses the mechanisms by which Aspirin is one of the most widely used medica-
ASA resistance may occur; tions globally. It is on the World Health Organiza-
tion’s (WHO’s) List of Essential Medicines, “the

(3) Presents the characteristics that may safest and most effective medicines needed in

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