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Cardiology TODAY

VOLUME XXIII No. 3May-June 2019

PAGES 77-120

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EDITORIALSkip the Breakfast – At your Peril ! 79OP YADAVA

REVIEW ARTICLEDiabetic Dyslipidemia: Is it a Distinct Entity ? 81JK SHARMA, GIRISH KHURANA, AMIT GUPTA, VIPUL GUPTA

REVIEW ARTICLEHow to Manage NSTEACS - Medically 87MANGESH TIWASKAR, M CHENNIAPPAN, G S WANDER

REVIEW ARTICLEMetabolic Syndrome In India: Is It Different ? 100AK PANCHOLIA

Cardiology Today VOL.XXIII NO. 3 MAY-JUNE 2019 77

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REVIEW ARTICLECoronary Interventions in Diabetics with Coronary Artery Disease 104LEKHA ADIK PATHAK, RONAK V. RUPARELIA

REVIEW ARTICLEUnderstanding the PATHWAY-3 Study: Adding Amiloride to Hydrochlorothiazide Prevents Glucose Intolerance and Improves Blood Pressure 111JPS SAWHNEY

ECG OF THE MONTHTransient Conversion of Atrial Fibrillation to Sinus Rhythm by Retrograde Conduction of Ventricular Ectopic Beat 117SR MITTAL

PICTORIAL CMEAnomalous Drainage of Hepatic Vein Directly Into The Right Atrium 118MONIKA MAHESHWARI

78 Cardiology Today VOL.XXIII NO. 3 MAY-JUNE 2019

Cardiology Today VOL.XXIII NO. 3 MAY-JUNE 2019 79

Skip the Breakfast – At your Peril !

EDITORIAL

Traditionally, across times and cultures, breakfast has had the pride of place as a full and wholesome main meal of the day. However, the hurry and worry of the modern life has relegated breakfast to one of an easily dispensable subsidiary meal. Infact it’s not an uncommon sight to see young corporate honchos munching at their empty-calorie and trans-fat laden breakfast, at the wheels of the motor vehicles and a large number, still worse, totally skip the breakfast. Instead they keep munching the whole day tit-bits of savouries and confectionaries, drained down the gullet with sugar laced colas and other artifi cial beverages. To the contrary, traditionally in a typical rural, agrarian family, there were essentially two meals – A breakfast, which infact may be called a brunch, and an early evening meal, on returning from the toils. This was driven partially by convenience, but largely by age old wisdom, albeit sans any conventional scientifi c or statistical scrutiny. However, now the sanctity of evidence-base is being provided to this lifestyle related personal behaviour by an analysis from the National Health and Nutrition Examination Survey III of USA.1 Looking at 6,550 adults, 40-75 years of age, only 59% consumed breakfast everyday. The authors adjusted for all confounding factors like age, sex, socio-economic disparity, ethnicity, body mass index, dietary and lifestyle factors and other cardiovascular risk factors like diabetes and hypertension and found that individuals never consuming breakfast had a higher hazard ratio of 1.87 (95% Confi dence Interval 1.14 – 3.04) for cardiovascular mortality and 1.19 (95% Confi dence Interval 0.99 – 1.42) for all-cause mortality, as compared to those who consumed breakfast on daily basis. This is a whopping 75% increase in all-cause mortality, and 158% increase in risk of cardiovascular mortality over a median follow-up of 18.8 years. However, in this study, causality could not be established and there may be other confounders, which may have contributed. However, there seems to be no denial to the fact that skipping breakfast is harmful. Though the exact reason for this is not known, changes in the circadian rhythm may be at the root cause. Even extending the over-night fasting state by not eating breakfast, depletes body’s reserves of energy stores and kick-in the ‘Fight or Flight’ response of the body. This secondarily increases the blood pressure and blood sugar levels, with the attendant harms and consequent.

DR. OP YADAVACEO and Chief Cardiac Surgeon

National Heart Institute,New Delhi

80 Cardiology Today VOL.XXIII NO.3 MAY-JUNE 2019

Infact this is not the only study, and there are a number of other epidemiological studies which support the notion that breakfast consumption is associated with a better physiological and metabolic profi le and skipping it may even increase the mortality through increased incidence of cancers, circulatory diseases and other causes.2

What to eat is important and has been widely debated for times immemorial, but when to eat is probably equally, if not more, important. Its time that we borrow from the wisdom of our ancestors and pay need to our mom’s constant admonition, on ignoring the value of a healthful and mouthful breakfast.

So Folks – Breakfast ? Give the devil its due.

REFERENCES1. Rong S, Snetselaar LG, Xu G et al. Association of skipping breakfast with cardiovascular and all cause mortality. J Am Coll

Cardiol. 2019;73(16):2025-2032.2. Yokoyama Y, Onishi K, Hosoda T et al. Skipping breakfast and risk of mortality from Cancer, Circulatory diseases and all

causes: Findings from the Japan Collaborative Cohort Study. Yonago Acta Med 2016;59(1):55-60.

Cardiology Today VOL. XXIII NO. 3 MAY-JUNE 2019 81

Diabetic Dyslipidemia: Is it a Distinct Entity ?

REVIEW ARTICLE

JK SHARMA, GIRISH KHURANA, AMIT GUPTA, VIPUL GUPTA

Keywords diabetic dyslipidemia triglycerides LDL-C HDL-C lifestyle modifi cations insulin defi ciency statins fenofi brate

Dr. JK Sharma is Medical Director, Dr. Girish Khurana, Dr. Amit Gupta & Dr. Vipul Gupta are Consultant Cardiologists, Central Delhi Diabetes Centre, Old Rajinder Nagar, New Delhi

Abstract

Diabetic dyslipidemia consists of elevated serum concentration of triglycerides, low concentration of HDL-cholesterol, and a high prevalence of LDL-cholesterol with predominance of small dense LDL particles. Although the pathophysiology is only partially understood, alterations of insulin sensitive pathways and relative insulin defi ciency have been found to play a major role. Lifestyle modifi cation, glucose control and lipid-lowering therapy may improve the lipid profi le, as outcome data have proven their effectiveness in patients with diabetes.

INTRODUCTIONGlobally, approximately 32.2%

of individual with diabetes have cardiovascular disease (CVD), with about 42.6% reported from India.1 Numerous studies have demonstrated that CVD is linked more strongly to diabetic dyslipidemia (hypertriglyceridemia, reduced high-density lipoprotein [HDL] cholesterol concentration and the predominance of small dense low-density lipoprotein [LDL] than to hyperglycemia).2 Thus, aggressive glycemic control in these patients does not necessarily result in less cardiac death, stroke, and congestive heart failure or reduced mortality.3 Furthermore, newer data indicate that targeting lipid abnormalities in patients with type 2 diabetes is of particular benefi t to reduce cardiovascular morbidity and mortality.4,5

In this review, the pathophysiology of diabetic dyslipidemia and its role in causing the CVD will be summarized. Management approaches will also be addressed.

LIPID ABNORMALITIES IN TYPE 2 DIABETES MELLITUS (T2DM)In patients with T2DM, dyslipidemia is very common with about 72–85% prevalence rate.6 This is characterized by hypertriglyceridemia (fasting and postprandial), low HDL- C, mildly high LDL-C with predominance of small dense LDL, while total cholesterol may be normal or elevated.7 Detailed analysis showed that diabetic dyslipidemia is not only characterized by abnormal fasting lipid levels and post prandial lipoprotein metabolism, but also by an altered composition of lipoproteins.8

82 Cardiology Today VOL. XXIII NO. 3 MAY-JUNE 2019

REVIEW ARTICLE

INCREASE IN TRIGLYCERIDEST2DM patients have an abundance of free fatty acids and glucose in the liver which prevents degradation of apoB, thus causing an overproduction of very low-density lipoprotein (VLDL) especially in insulin resistant states. This increased production of the VLDL, a main transporter of fasting triglyceride (TG), plays a major role in the elevations of serum TG levels.9 T2DM patients have three major sources of free fatty acids in the liver (Table 1).10

In addition to the increased production of TG-rich lipoproteins, a decrease in its clearance also contributes to hypertriglyceridemia in patients with T2DM.10 The factors associated with decreased clearance rate of TG-rich lipoproteins are shown in Table 2.

SMALL, DENSE LOW DENSITY LIPOPROTEIN (LDL)The number of small, dense LDL particles (known as subclass B particles)

seems to be a better predictor of risk in patients with T2DM as an association has been found between its presence and higher prevalence of CVD.11 Further, these particles are also thought to be more atherogenic because of their lower binding affi nity for the LDL receptor, better penetration of the arterial wall and longer plasma half-life.12 The mechanisms for formation of sdLDL are summarized as follows:

Cholesteryl ester transfer protein (CETP) facilitates the transfer of TGs to LDL.13

Resulting TG-rich LDL is a preferred substrate for hepatic lipase.13

Lipolysis by hepatic lipase results in the formation of sdLDL.13

HDLsPatients with T2DM characteristically exhibit reduced plasma HDL-C concentrations and dysfunctional HDL. The mechanisms for formation of this

TG-rich lipoproteins are summarized below:

CETP facilitates the transfer of TGs from TG-rich VLDL and chylomicrons to LDL and HDL.10

Resulting TG-rich HDL particles are less stable, have less plasma residence time and also a preferred substrate for hepatic lipase.10

Lipolysis by hepatic lipase results in the formation of small HDL particles, which are rapidly cleared.10

ROLE OF ADIPOCYTOKINES AND RETINOL-BINDING PROTEINSADIPONECTINIn T2DM patients, low adiponectin plasma levels are associated with augmented VLDL production and catabolism.14 In addition, plasma adiponectin levels are negatively correlated with HDL-ApoA-I catabolism. It is very important to mention that this correlation is independent of insulin resistance and plasma lipids, suggesting a direct eff ect of adiponectin on HDL metabolism.15

RETINOL-BINDING PROTEIN 4 (RBP4)In patients with T2DM, a strong, independent, negative association has been reported between plasma RBP4 and VLDL catabolism. This negative association suggests that RBP4 may be involved in the pathophysiology of hypertriglyceridemia in T2DM.16

ROLE OF DIABETIC DYSLIPIDEMIA IN ATHEROSCLEROSISPrevious studies have reported LDL-C as a signifi cant independent predictor of CVD in diabetic patients, even when the LDL level is below 130 mg/dl.17 Small dense LDL particles in the intima appear more susceptible to modifi cation under conditions of oxidative stress.18 Further, this may initiate a cascade of processes leading to infl ammation and plaque formation.18 About 12% increase in CVD risk in individuals with diabetes has been observed with every 10 mg/dL increase in LDL cholesterol by Strong Heart Study.17

Table 1: Three major sources of free fatty acids in the liver of diabetic patients

Sources of fatty acids Impact of T2DMSources of fatty acids Impact of T2DM

Flux of fatty acids from adiposeFlux of fatty acids from adipose Insulin resistance and T2DM, causes increased lipolysis of Insulin resistance and T2DM, causes increased lipolysis of

tissue to the livertissue to the liver TG leading to increased flow of free fatty acid to the liver TG leading to increased flow of free fatty acid to the liver

De novoDe novo fatty acid synthesis fatty acid synthesis In hyperglycemic state, glucose can induce carbohydrate In hyperglycemic state, glucose can induce carbohydrate

from glucosefrom glucose responsive element binding protein (ChREBP), which in responsive element binding protein (ChREBP), which in

turn stimulates the transcription of the enzymes required turn stimulates the transcription of the enzymes required

for fatty acid synthesis.for fatty acid synthesis.

Uptake of TG-richUptake of TG-rich In type 2 diabetes, enhanced secretion of chylomicrons in In type 2 diabetes, enhanced secretion of chylomicrons in

lipoproteins by the liver lipoproteins by the liver the intestine leads to the increased flow of fatty acids to the intestine leads to the increased flow of fatty acids to

the liver. the liver.

Table 2: Factors associated with decreased clearance rate of TG-rich lipoproteins

Metabolic abnormalities Impact of diabetesMetabolic abnormalities Impact of diabetes

Modest decrease inModest decrease in In T2DM patients, decreased insulin activity results In T2DM patients, decreased insulin activity results

lipoprotein lipase activitylipoprotein lipase activity in a decrease in lipoprotein lipase as its expression is in a decrease in lipoprotein lipase as its expression is

stimulated by insulin. Thereby it reduces the clearance of stimulated by insulin. Thereby it reduces the clearance of

TG-rich lipoproteins.TG-rich lipoproteins.

An increase in Apo C-III levelsAn increase in Apo C-III levels Glucose stimulates and insulin suppresses ApoC-III Glucose stimulates and insulin suppresses ApoC-III

expression.expression.

In patients with Type 2 diabetes, decreased insulin activity In patients with Type 2 diabetes, decreased insulin activity

results in a decrease in ApoC-III expression (an inhibitor results in a decrease in ApoC-III expression (an inhibitor

of lipoprotein lipase activity) and thereby reduces the of lipoprotein lipase activity) and thereby reduces the

clearance of TG-rich lipoproteins.clearance of TG-rich lipoproteins.

ApoC-III also inhibits the cellular uptake of lipoproteins. ApoC-III also inhibits the cellular uptake of lipoproteins.


insulin resistance. Although moderate weight loss results in improvements of insulin sensitivity, glycemic control and lipid profi le, this did not decrease the rate of cardiovascular events.22 In addition, American Diabetes Association (ADA) recommends low intake of trans fat, saturated fat, and cholesterol while high intake of plant stanols/sterols, n-3 fatty acids, and viscous fi ber; though dietary interventions also have not been successful in demonstrating the mortality benefi t.20

EFFECT OF ANTIDIABETIC AGENTS (ADAs) ON LIPID LEVELSNormalization of blood glucose levels is also the important treatment goal in all individuals with diabetes, as hyperglycemia may exacerbate lipid abnormalities, particularly hypertriglyceridemia.23 Among glucose lowering therapy, non insulinotropic antidiabetic agents should be preferred because these ADAs not only reduce glucose concentrations but also improve insulin resistance.18 Currently available ADAs have varying eff ects on plasma lipids (Table 4).10,18

LIPID-LOWERING DRUGSLipid-lowering drugs should be initiated if patients do not achieve lipid goals with lifestyle modifi cations and glucose control.18

STATIN THERAPYStatins should be used as the drug of fi rst choice in diabetic patients with an LDL- C concentration >100 mg/dL (>2.6 mmol/L). A meta- analysis has demonstrated 23% reduction in risk for myocardial infarction or cardiovascular death with each 40 mg/dL (1 mmol/L) reduction of LDL -C.18 Large number of clinical trials on statin has demonstrated similar relative risk reduction in both patients with or without diabetes.19 However, 47% of American patients >40 years of age with diabetes but without established CVD were not using statins in 2013–2014.24 One in seven patients with diabetes treated with statins still goes on to suff er a cardiovascular event over 5 years.25

The exact role of HDL in CVD is complex. HDL has long been regarded as the “good” lipoprotein because this is a central component of the reverse cholesterol transport system and has also shown an inverse association between HDL concentration and CVD.19 HDL from healthy subjects has also shown anti-oxidative, anti-infl ammatory and endothelium-dependent vasodilatory eff ects.19

It should be noted that elevated concentration of TG-rich lipoproteins is the main culprit for the predominance of small dense LDL and the abnormal HDL metabolism in diabetic patients.

LIPID GOALS IN PATIENTS WITH DIABETES Guideline recommendations for lipid goals in patients with diabetes are shown in Table 3.

MANAGEMENT OF DIABETIC DYSLIPIDEMIAThe integral components of diabetic dyslipidemia management are lifestyle modifi cation and pharmacotherapy.

LIFESTYLE MODIFICATION Normalization of weight is the important treatment goal as diabetic dyslipidemia is primarily the result of obesity and

Table 3: Guideline recommendations for lipid goalsSr. No. Society RecommendationSr. No. Society Recommendation

1. American Diabetes1. American Diabetes High-dose statin therapy in addition to lifestyle modification High-dose statin therapy in addition to lifestyle modification

AssociationAssociation2020 should be considered in should be considered in

• Patients of all ages with diabetes with established ASCVD • Patients of all ages with diabetes with established ASCVD

or 10-year ASCVD risk >20% or with multiple ASCVD risk or 10-year ASCVD risk >20% or with multiple ASCVD risk

factorsfactors

• Consider moderate-dose statin therapy for patients • Consider moderate-dose statin therapy for patients

with diabetes aged <40 years with additional atherosclerotic with diabetes aged <40 years with additional atherosclerotic

cardiovascular disease risk factorscardiovascular disease risk factors

• For patients with diabetes aged 40–75 years (Class A) and • For patients with diabetes aged 40–75 years (Class A) and

>75 (Class B) years without atherosclerotic cardiovascular >75 (Class B) years without atherosclerotic cardiovascular

diseasedisease

• Consider adding additional LDL-lowering therapy (such as • Consider adding additional LDL-lowering therapy (such as

ezetimibe or PCSK9 inhibitor) if LDL-cholesterol is ezetimibe or PCSK9 inhibitor) if LDL-cholesterol is 70 mg/dL 70 mg/dL

(1.8 mmol/L) on maximally tolerated dose of statins(1.8 mmol/L) on maximally tolerated dose of statins

2. ESC/EAS2. ESC/EAS Patients at very high risk (those with established atherosclerotic Patients at very high risk (those with established atherosclerotic

guidelinesguidelines2121 disease and/or end organ damage, such as nephropathy, and/disease and/or end organ damage, such as nephropathy, and/

or additional risk factors): an LDL-cholesterol < 70 mg/dL (1.8 or additional risk factors): an LDL-cholesterol < 70 mg/dL (1.8

mmol/L) is recommendedmmol/L) is recommended

Patients at high risk (diabetic patients without the above- Patients at high risk (diabetic patients without the above-

mentioned characteristics): the LDL-cholesterol goal is <100 mentioned characteristics): the LDL-cholesterol goal is <100

mg/dL (2.6 mmol/L).mg/dL (2.6 mmol/L).

In both groups, a > 50% reduction from baseline LDL-C In both groups, a > 50% reduction from baseline LDL-C

level is recommended level is recommended

Table 4: Effect of ADAs on lipid profileADAs Impact on lipid profileADAs Impact on lipid profile

Metformin Decreases TGs and modestly decreases LDL-CMetformin Decreases TGs and modestly decreases LDL-C

Sulfonylureas No effectSulfonylureas No effect

DPP4 inhibitors, GLP1 Improves fasting TGs and also postprandial DPP4 inhibitors, GLP1 Improves fasting TGs and also postprandial

analogues lipoprotein metabolism analogues lipoprotein metabolism

Acarbose Decreases postprandial TGsAcarbose Decreases postprandial TGs

Pioglitazone Decreases TGs and increases HDL-C Pioglitazone Decreases TGs and increases HDL-C

SGLT2 inhibitors Small increase in LDL-C and HDL-CSGLT2 inhibitors Small increase in LDL-C and HDL-C

Insulin Increases HDL-C and reduces circulating TG levelsInsulin Increases HDL-C and reduces circulating TG levels


REVIEW ARTICLE

bile acid absorption in the ileum. Colesevelam hydrochloride eff ectively reduced total cholesterol, LDL-C, apoB, and non-HDL-C levels. In 2008, the US Food and Drug Administration approved colesevelam for the treatment of T2DM as it has favorable eff ects on glucose homeostasis and lowers HbA1c.33

FIBRATES: REDUCE TGs AND MODESTLY INCREASES HDL-C LEVELSFibrates are useful drugs for patients with mixed dyslipidemia as they reduce serum TG and increase HDL-C levels through activation of peroxisome proliferator activated receptor α

With regards to statin use, another point of concern is the development of new-onset diabetes. A meta-analysis of statin trials shows that the risk of developing new onset diabetes is one in 255 patients treated with statins for 4 years. In the same period 5.4 vascular events would be avoided in these 255 patients.26

EZETIMIBEEzetimibe has its greatest clinical utility as an adjunct to statin therapy (Table 5).

BILE ACID SEQUESTRANTSBile acid sequestrants (BAS) lower cholesterol pool by interfering with

(PPAR-α).34 Fenofi brate has been shown to reduce TG concentration by 30–50%, increase HDL-C levels by 2–20%, and exert many pleiotropic eff ects on the distribution of LDL and HDL particles.35 A meta-analysis of 6 large trials clearly demonstrated that the fi brates signifi cantly reduce this risk of vascular events (16%-29%) in those with hypertriglyceridemia and low HDL levels.36 However, mixed fi ndings have been reported for patients with T2DM. In the Fenofi brate Intervention and Event Lowering in Diabetes (FIELD) study, fenofi brate showed signifi cant 11% reduction in CVD events (p=0.035) while Action to Control Cardiovascular Risk in

Table 5: Key clinical trials analyzing combination of ezetimibe and statin

Trial Patients Design ResultsTrial Patients Design Results

EASE, 2005EASE, 20052727 3030 patients with Patients were randomized LDL control 3030 patients with Patients were randomized LDL control LDL exceeding ATP 2:1 to receive Statin and LDL exceeding ATP 2:1 to receive Statin and III goal ezetimibe or Statin and III goal ezetimibe or Statin and placebo for 6 week placebo for 6 week (71% for combination (71% for combination vs. 21% for Statin, p<0.05) vs. 21% for Statin, p<0.05)

VYTAL, 2006VYTAL, 20062828 1229 adults with Patients were randomized LDL better controlled 1229 adults with Patients were randomized LDL better controlled type 2 diabetes to receive ezetimibe with combination type 2 diabetes to receive ezetimibe with combination vsvs.. and simvastatin or atorvastatin alone and simvastatin or atorvastatin alone atorvastatin for 6 week atorvastatin for 6 week

ENHANCE, 720 patients with Patients were randomized LDL levels were loweredENHANCE, 720 patients with Patients were randomized LDL levels were lowered200820082929 familial in this double-blind study by 16% in combination familial in this double-blind study by 16% in combination hypercholesterolemia to receive simvastatin group hypercholesterolemia to receive simvastatin group 80 mg with ezetimibe and 80 mg with ezetimibe and simvastatin 80 mg alone simvastatin 80 mg alone for 24 months for 24 months

SANDS, 499 individuals with Simvastatin and No difference in LDLSANDS, 499 individuals with Simvastatin and No difference in LDL200820083030 diabetes >40 years ezetimibe vs. lowering and CIMT diabetes >40 years ezetimibe vs. lowering and CIMT old without CVD simvastatin alone (LDL regression in statin old without CVD simvastatin alone (LDL regression in statin goal <70 mg/dL, SBP alone vs. combination goal <70 mg/dL, SBP alone vs. combination <115 mmHg) vs. statin group <115 mmHg) vs. statin group alone (conventional arm). alone (conventional arm). Duration: 3 years. Duration: 3 years.

ARBITER 208 patients with Extended release niacin Greater CIMT regressionARBITER 208 patients with Extended release niacin Greater CIMT regression6-HALTS, CVD with LDL and statin vs. ezetimibe and lower cardiovascular6-HALTS, CVD with LDL and statin vs. ezetimibe and lower cardiovascular200920093131 <100 mg/dL and and Statin. events (1% <100 mg/dL and and Statin. events (1% vs.vs. 5%, p 5%, p HDL <50–55 mg/dL =0.04) with niacin HDL <50–55 mg/dL =0.04) with niacin This study was terminated compared to ezetimibe This study was terminated compared to ezetimibe early after 14 months early after 14 months on the basis of efficacy on the basis of efficacy

IMPROVE 4933 diabetic Ezetimibe and simvastatin Absolute risk reductionIMPROVE 4933 diabetic Ezetimibe and simvastatin Absolute risk reductionIT Diabetic patients vs. 13,211 40 mg IT Diabetic patients vs. 13,211 40 mg vs.vs. simvastatin of 5.5% in diabetics simvastatin of 5.5% in diabeticsSub-Study, non-diabetics; both 40 mg alone. and 0.7% (non-Sub-Study, non-diabetics; both 40 mg alone. and 0.7% (non-201820183232 post-acute coronary Patients were followed significant) in non post-acute coronary Patients were followed significant) in non syndromes with LDL for 6 years -diabetics in primary syndromes with LDL for 6 years -diabetics in primary <125 mg/dL (statin outcome <125 mg/dL (statin outcome naive) or/and >79 mg/dL naive) or/and >79 mg/dL


CONCLUSIONUnderstanding the pathophysiology of diabetic dyslipidemia is signifi cant in the quest for new therapeutic strategies and in reducing the risk of CVD. Lifestyle and pharmacological interventions are the most important treatment strategies. However, many questions remain unanswered and additional studies are needed to gain further insight into the precise mechanisms of diabetic dyslipidemia.

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regulatory effects of adiponectin, insulin resistance, and fat compartments on VLDL apolipoprotein B-100 kinetics? Diabetes. 2005; 54:795–802.

16. Vergès B, Guiu B, Cercueil JP, et al. Retinol-binding protein 4 is an independent factor associated with triglycerides and a determinant of very low-density lipoprotein-apolipoprotein B100 catabolism in type 2 diabetes mellitus. Arterioscler Thromb Vasc Biol. 2012; 32:3050–3057.

17. Howard BV, Robbins DC, Sievers ML, Lee ET, Rhoades D, Devereux RB, Cowan LD, Gray RS, Welty TK, Go OT, Howard WJ. LDL cholesterol as a strong predictor of coronary heart disease in diabetic individuals with insulin resistance and low LDL: The Strong Heart Study. Arterioscler Thromb Vasc Biol. 2000 Mar; 20(3):830-5.

18. Sugden M, Holness M. Pathophysiology of diabetic dyslipidemia: implications for atherogenesis and treatment. Clinical Lipidology. 2011 Aug 1; 6(4):401-11.

19. Wu L, Parhofer KG. Diabetic dyslipidemia. Metabolism. 2014 Dec;63(12):1469-79.

20. American Diabetes Association. 10. Cardiovascular Disease and Risk Management: Standards of Medical Care in Diabetes—2019. Diabetes Care. 2019 Jan 1; 42(Supplement 1):S103-23.

21. Catapano AL, Graham I, De Backer G, Wiklund O, Chapman MJ, Drexel H, Hoes AW, Jennings CS, Landmesser U, Pedersen TR, Reiner Ž, Riccardi G, Taskinen MR, Tokgozoglu L, Monique Verschuren WM, Vlachopoulos C, Wood DA, Luis Zamorano J; Additional Contributor, Cooney MT. 2016 ESC/EAS Guidelines for the Management of Dyslipidaemias. Rev Esp Cardiol (Engl Ed). 2017 Feb; 70(2):115.

22. Wing RR, Lang W, Wadden TA, et al. Benefits of modest weight loss in improving cardiovascular risk factors in overweight and obese individuals with type 2 diabetes. Diabetes Care 2011; 34(7):1481–6.

23. Parhofer KG, Laubach E, Geiss HC, Otto C. [Effect of glucose control on lipid levels in patients with type 2 diabetes]. Dtsch Med Wochenschr. 2002 May 3; 127(18):958-62.

24. Salami JA, Warraich H, Valero-Elizondo J, Spatz ES, Desai NR, Rana JS, et al. National Trends in statin use and expenditures in the US adult population from 2002 to 2013: insights from the medical expenditure panel survey. JAMA Cardiol. 2017; 2(1):56–65.

25. Cholesterol Treatment Trialists Collaborators. Kearney PM, Blackwell L, et al. Efficacy of cholesterol-lowering therapy in 18,686 people with diabetes in 14 randomised trials of statins: a meta-analysis. Lancet. 2008; 371:117–125.

26. Sattar N, Preiss D, Murray HM, Welsh P, Buckley BM, de Craen AJ et al. Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials. Lancet. 2010 Feb 27; 375(9716):735-42.

27. Pearson TA, Denke MA, McBride PE, Battisti WP, Brady WE, Palmisano J. A community-based, randomized trial of ezetimibe added to statin therapy to attain NCEP ATP III goals for LDL cholesterol in hypercholesterolemic patients: the ezetimibe add-on to statin for effectiveness (EASE) trial. Mayo Clin Proc. 2005 May; 80(5):587-95.

28. Goldberg RB, Guyton JR, Mazzone T, Weinstock RS, Polis A, Edwards P, Tomassini JE, Tershakovec AM. Ezetimibe/simvastatin vs atorvastatin in patients with type 2 diabetes mellitus and hypercholesterolemia: the VYTAL study. Mayo Clin Proc. 2006 Dec; 81(12):1579-88.

29. Kastelein JJ, Akdim F, Stroes ES, Zwinderman AH, Bots ML, Stalenhoef AF, Visseren FL, Sijbrands EJ, Trip MD, Stein EA, Gaudet D, Duivenvoorden R, Veltri EP, Marais AD, de Groot E; ENHANCE Investigators. Simvastatin with or without ezetimibe in familial hypercholesterolemia. N Engl J Med. 2008 Apr 3; 358(14):1431-43.

30. Fleg JL, Mete M, Howard BV, Umans JG, Roman MJ, Ratner RE, Silverman A, Galloway JM, Henderson JA, Weir MR, Wilson C, Stylianou M, Howard WJ. Effect of statins alone versus statins plus ezetimibe on carotid atherosclerosis in type 2 diabetes: the SANDS (Stop Atherosclerosis in Native Diabetics Study) trial. J Am Coll Cardiol. 2008 Dec 16; 52(25):2198-205.

31. Taylor AJ, Villines TC, Stanek EJ, Devine PJ, Griffen L, Miller M, Weissman NJ, Turco M. Extended-release niacin

Diabetes (ACCORD) lipid trial reported non-signifi cant reduction with fenofi brate in the fi rst myocardial infarction, stroke and death from CVD causes.37,38 Caution must be taken when using statins concomitantly with fi brate because there is an increased risk of myopathic adverse reaction.39

PCSK9 INHIBITORSRecently, Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) inhibitors have received considerable attention as promising nonstatin therapeutic options for the management of lipid disorders in patients with or without diabetes mellitus. Currently, there are two FDA approved PCSK9 inhibitors, Alirocumab and Evolocumab. A patient level meta-analysis of three clinical trials has demonstrated the signifi cant effi cacy of evolocumab in improving lipid profi le in individuals with diabetes.40 Prespecifi ed analysis of patients with diabetes from the pivotal FOURIER trial reported similar effi cacy of evolocumab for both individuals with diabetes (HR 0.83, 95% CI 0.75–0.93) and normal subjects (HR 0.87 95% CI 0.79–0.96, P =0.60) in reducing the CV death, stroke, MI, hospitalization of angina, or coronary revascularization.41 PCSK9 inhibitors also showed no increase in new-onset diabetes or glycemic derangements.41

A pooled analysis of fi ve placebo-controlled phase 3 trials also showed the effi cacy of alirocumab in reducing the LDL profi le in patients with diabetes; mean LDL reduction was observed in 57% of patients whereas non-HDL cholesterol decreased by 47%.42

OMEGA-3 FATTY ACIDSTreatment with omega-3 fatty acids signifi cantly reduced TGs, but it has little eff ect on HDL- or LDL-C levels.43 Although omega-3 fatty acid have been reported for their benefi cial hypotensive and antithrombotic eff ects, no eff ect was found on CHD risk in a trial involving patients with metabolic syndrome or type 2 diabetes.44


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or ezetimibe and carotid intima-media thickness. N Engl J Med. 2009 Nov 26; 361(22):2113-22.

32. Giugliano RP, Cannon CP, Blazing MA, Nicolau JC, Corbalán R, Špinar J, Park JG, White JA, Bohula EA, Braunwald E; IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial) Investigators. Benefit of Adding Ezetimibe to Statin Therapy on Cardiovascular Outcomes and Safety in Patients With Versus Without Diabetes Mellitus: Results From IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial). Circulation. 2018 Apr 10;137(15):1571-1582.

33. Brunetti L, Kalabalik J. Management of type-2 diabetes mellitus in adults: focus on individualizing non-insulin therapies. P T. 2012 Dec; 37(12):687-96.

34. Wierzbicki AS. Fibrates: no ACCORD on their use in the treatment of dyslipidemia. Curr Opin Lipidol. 2010;21:352–358.

35. Moutzouri E, Kei A, Elisaf MS, Milionis HJ. Management of dyslipidemias with fibrates, alone and in combination with statins: role of delayed-release fenofibric acid. Vasc Health Risk Manag. 2010 Aug 9; 6:525-39.

36. Lee M, Saver JL, Towfighi A, Chow J, Ovbiagele B. Efficacy of fibrates for cardiovascular risk reduction in

persons with atherogenic dyslipidemia: a meta-analysis. Atherosclerosis. 2011 Aug; 217(2):492-8.

37. Scott R, Best J, Forder P, Taskinen MR, Simes J, Barter P, Keech A; FIELD Study Investigators. Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study: baseline characteristics and short-term effects of fenofibrate [ISRCTN64783481]. Cardiovasc Diabetol. 2005 Aug 22; 4:13.

38. Reyes-Soffer G, Ngai CI, Lovato L, Karmally W, Ramakrishnan R, Holleran S, Ginsberg HN. Effect of combination therapy with fenofibrate and simvastatin on postprandial lipemia in the ACCORD lipid trial. Diabetes Care. 2013 Feb; 36(2):422-8.

39. Jacobson TA. Myopathy with statin-fibrate combination therapy: clinical considerations. Nat Rev Endocrinol. 2009 Sep; 5(9):507-18.

40. Sattar N, Preiss D, Robinson JG, Djedjos CS, Elliott M, Somaratne R, Wasserman SM, Raal FJ. Lipid-lowering efficacy of the PCSK9 inhibitor evolocumab (AMG 145) in patients with type 2 diabetes: a meta-analysis of individual patient data. Lancet Diabetes Endocrinol. 2016 May; 4(5):403-10.

41. Sabatine MS, Leiter LA, Wiviott SD, Giugliano RP,

Deedwania P, De Ferrari GM, Murphy SA, Kuder JF, Gouni-Berthold I, Lewis BS, Handelsman Y, Pineda AL, Honarpour N, Keech AC, Sever PS, Pedersen TR. Cardiovascular safety and efficacy of the PCSK9 inhibitor evolocumab in patients with and without diabetes and the effect of evolocumab on glycaemia and risk of new-onset diabetes: a prespecified analysis of the FOURIER randomised controlled trial. Lancet Diabetes Endocrinol. 2017 Dec; 5(12):941-950.

42. Ginsberg HN, Farnier M, Robinson JG, Cannon CP, Sattar N, Baccara-Dinet MT, Letierce A, Bujas-Bobanovic M, Louie MJ, Colhoun HM. Efficacy and Safety of Alirocumab in Individuals with Diabetes Mellitus: Pooled Analyses from Five Placebo-Controlled Phase 3 Studies. Diabetes Ther. 2018 Jun; 9(3):1317-1334.

43. Swanson D, Block R, Mousa SA. Omega-3 fatty acids EPA and DHA: health benefits throughout life. Adv Nutr. 2012 Jan; 3(1):1-7.

44. ORIGIN Trial Investigators. N–3 Fatty acids and cardiovascular outcomes in patients with dysglycemia. New England Journal of Medicine. 2012 Jul 26; 367(4):309-18.


How to Manage NSTEACS - Medically

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MANGESH TIWASKAR, M CHENNIAPPAN, G S WANDERKeywords anticoagulants coronary artery disease myocardial infarction antiplatelet agents revascularisation

Dr. Mangesh Tiwaskar is Consultant Physician and Diabetologist & Hon. Professor National IMA Shilpa Medical Re-search Centre, Dahisar Mumbai; Prof. Emir. Dr. M. Chenniappan is Professor Emeritus Dr. MGR University Chennai; Prof. Dr. Gurpreet Singh Wander is Professor and Head Dept. of Cardiology, Dayanand Medical College & Hospital, Ludhiana

AbstractNon-ST segment elevation acute coronary syndromes (NSTE-ACS) include a clinical spectrum that ranges from unstable angina to NSTE myocardial infarction. Management goals aim to prevent recurrent ACS and improve long-term outcomes by choosing a treatment strategy according to an estimate of the risk of an adverse outcome. The present article evaluates the evidence for recommended treatment using information from recent trials and guidelines. Using this information, a multidisciplinary group developed a simplifi ed algorithm that uses risk stratifi cation to select an optimal early management strategy. Long-term outcomes are improved by a multi-faceted vascular protection strategy that is initiated at the time of hospitalization for NSTE-ACS.

INTRODUCTIONCardiovascular Disease (CVD), the single most common cause of deaths in adults, accounts for one in every 3 deaths, worldwide. As per the Global Burden of Diseases, Injuries and Risk Factors Study (GBD) 2017, CVDs accounted for 17.8 million deaths, an increase of 21% between 2007 and 2017. Coronary artery disease (CAD) and stroke together accounted for 85% of deaths due to CVDs (ischaemic heart disease 8.93 million; stroke 6.17 million).1 CAD and its manifestation as acute coronary syndrome (ACS), carries enormous social and economic burden in addition to

being a major determinant of morbidity and mortality across races, ethnic groups and cultures.2

ACS is typically caused by acute thrombosis induced by the rupturing or erosion of an atherosclerotic plaque, leading to an abrupt and dangerous reduction in blood fl ow.3 The three clinical manifestations of ACS include ST-segment elevation, myocardial infarction (STEMI), non-ST-segment elevation myocardial infarction (NSTEMI) and unstable angina (UA).4 The symptomatic harbinger of ACS is chest pain. The electrocardiogram (ECG) helps demarcate those with suspected


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ACS (Figure 1) into three main types (a) chest pain with persistent ST-elevation (of >20 min) – STEMI; (b) chest pain without ST-elevation but with cardiomyocyte necrosis (as ascertained with positive cardiac troponin test) - NSTEMI; and (c) chest pain without ST-elevation but no cell necrosis – UA (troponin -ve).5

The latter two are together termed as NSTE-ACS. ECG in NSTE-ACS may either be normal or include persistent/transient ST-segment depression, T-wave inversion, fl at T waves or pseudo-normalization of T waves. Anginal pain in NSTE-ACS patients may present as either prolonged (>20 min) pain at rest, de novo angina, crescendo angina or post-MI angina. Other symptoms which may occur include nausea, sweating, dyspnoea, abdominal pain and syncope. If symptoms are enhanced by physical exertion and relieved by rest, there are increased chances of myocardial ischaemia.5

ACS AND INDIAN SUBCONTINENTIndia bears the greatest burden of ACS in the world.4 In India, the estimates for disability-adjusted life-years (DALYs; age-standardised) lost due to CAD/1000 population are 3-fold higher than that observed in developed countries. Asian Indians are at 3–4 times greater risk of CAD than white Americans, at 6 times elevated risk than the Chinese and at 20 times higher risk than the Japanese.6 Additionally, Indians tend to have more severe manifestations of CVD and higher fatality rates.7 Of particular concern is the fact that the onset of the disease occurs almost a decade earlier than their

highest (15%).10 This detrimental impact of ACS, especially NSTE-ACS, shows that there is a pressing need for optimal management of these patients, both initially and through every stage of their ongoing care.

DEFINITION AND CLASSIFICATION OF MIOver the years, several diff erent defi nitions of MI have been used, leading to controversy and confusion. An initial ECG-based defi nition of MI was established by the World Health Organisation (WHO) in the 1950-70s. Subsequently, on the basis of sensitive cardiac biomarkers, a biochemical and clinical approach was used to redefi ne MI by the Joint European Society of Cardiology (ESC)/American College of Cardiology (ACC). The evolution of the defi nition continued with the Global MI Task Force introducing a novel MI classifi cation system in 2007, followed by its updation in the current fourth Universal Defi nition of MI (UDMI) consensus document in 2018 (Table 1). This document is endorsed by the ESC, the ACC, American Heart Association (AHA) and World Heart Federation (WHF) and adopted by the WHO.11

DIAGNOSISChest pain is the leading symptom that initiates the diagnostic and therapeutic cascade in patients with suspected ACS. For the diagnosis of NSTEMI, in addition to the rise/fall of cardiac biomarkers (especially troponin) one or more of the following characteristics must also exist in the patient – ischaemic symptoms, ECG changes, regional wall motion abnormality or new/apparently new loss of viable myocardium (detected via imaging), or lastly, intracoronary thrombus (uncovered by angiography/autopsy).

The initial evaluation of the suspected ACS patient involves clinical presentation (physical examinations, vital signs and symptoms, lab tests), 12-lead ECG and measurement of cardiac biomarkers such as high-sensitivity cardiac troponin (hs-cTn) to assess myocyte necrosis.5 ECG identifi es ~one-third of ACS patients who

western counterparts and during their most productive years. Nearly, 52% of CVD-related deaths occur in those <50 years and the mean age of Indians for the fi rst presentation of acute MI (AMI) is 53 years. One in every four patients with AMI are below the age of 40 years and 5–10% of MI occurs in Indians < 40 years of age.6

In the Kerala ACS registry of 25,748 consecutive ACS admissions from 2007 to 2009 in 125 hospitals, 31% patients had NSTEMI with mean age at presentation of 60 years.8 The treatment and outcomes of acute coronary syndromes in India (CREATE) registry involved 20,937 ACS patients across 89 centres from 10 regions and 50 cities in India. Nearly, 39% of the Indian ACS patients had NSTEMI while the rest had STEMI. Compared to similar studies from Western countries, Indian ACS patients were nearly 5 to 10 years younger, predominantly male, with hypertension, diabetes and smoking being the key risk factors. The time taken to reach the hospital was exceptionally long ranging from 6 hours for STEMI and 7.5 hours for NSTEMI patients. Moreover, the quality of care dwindled from the rich to the poor.4

Ellis CJ et al.9 conducted a 12-year follow-up of ACS patients from New Zealand which demonstrated an overall mortality rate of 52%, with NSTEMI patients contributing the most to this fi gure (61%). The Organisation to Assess Strategies for Ischaemic Syndromes (OASIS) registry also found that, amongst the low and middle income countries, the 2-year mortality rates of Indian patients with NSTE-ACS was the

Figure 1: Classification of Acute Coronary Syndrome

STE-ACS – ST-elevation Acute Coronary Syndrome, NSTE-ACS – Non-ST-elevation Acute Coronary Syndrome, STE-ACS – ST-elevation Acute Coronary Syndrome, NSTE-ACS – Non-ST-elevation Acute Coronary Syndrome,

STEMI – ST-elevation myocardial infarction, NSTEMI – Non-ST-elevation myocardial infarction, UA – Unstable AnginaSTEMI – ST-elevation myocardial infarction, NSTEMI – Non-ST-elevation myocardial infarction, UA – Unstable Angina[Adapted from Hamm CW et al.3, Roffi M et al.5]

Acute Coronary Syndrome (ACS)Acute Coronary Syndrome (ACS)

STE-ACSSTE-ACS NSTE-ACSNSTE-ACS

STEMISTEMI PRINZMETAL AnginaPRINZMETAL Angina NSTEMINSTEMI UAUA

Persistent pain & ST-elevationPersistent pain & ST-elevation Transient ST-elevation & painTransient ST-elevation & pain Troponin +veTroponin +ve Troponin -veTroponin -ve


require immediate intervention while cardiac troponin distinguishes ~two-third of ACS patients who require either a conservative (UA) or early-invasive approach (NSTEMI).13 Cardiac rhythm monitoring is essential till diagnosis is confi rmed and is to be continued in a NSTEMI patient.5

Ischaemic risk assessment can be done via standard scores such as the Global Registry of Acute Coronary Events (GRACE) score and bleeding risk can be determined by Can Rapid risk stratifi cation of Unstable angina patients Suppress ADverse outcomes with Early implementation of the ACC/AHA guidelines (CRUSADE) bleeding risk score. These scores help demarcate those at very high risk (needing immediate invasive management), those who will benefi t from early invasive management (4–48h) and those who may remain at risk even post-discharge.14 An integration of the ECG, biomarkers, clinical manifestation and risk scores will

together help in accurate diagnosis and subsequent optimal management of the patient (Figure 2).

Once the diagnosis of NSTEMI is confi rmed, the acute phase is managed

with the help of appropriate anti-ischaemic therapy and antithrombotic (antiplatelet and anticoagulant) therapy. Both aspirin and parenteral anticoagulation should be used in conjunction with each other.

Table 1: Classification of MITypType of MI Presentation Possible etiologiese of MI Presentation Possible etiologiesType 1 MI Spontaneous MI Causes: Atherosclerotic plaque rupture, ulceration, fissuring, erosion or dissection Type 1 MI Spontaneous MI Causes: Atherosclerotic plaque rupture, ulceration, fissuring, erosion or dissection

with resulting intraluminal thrombus in one or more of the coronary arteries, with resulting intraluminal thrombus in one or more of the coronary arteries, leading to decreased myocardial blood flow or distal platelet emboli with ensuing leading to decreased myocardial blood flow or distal platelet emboli with ensuing myocyte necrosismyocyte necrosis

Type 2 MI Myocardial injury with necrosis Causes: Other than coronary plaque instability; e.g. coronary artery spasm,Type 2 MI Myocardial injury with necrosis Causes: Other than coronary plaque instability; e.g. coronary artery spasm, where a condition other than CAD coronary endothelial dysfunction, tachyarrhythmias, bradyarrhythmias, anaemia, where a condition other than CAD coronary endothelial dysfunction, tachyarrhythmias, bradyarrhythmias, anaemia, contributes to an imbalance respiratory failure, hypotension and severe hypertension contributes to an imbalance respiratory failure, hypotension and severe hypertension between myocardial oxygen between myocardial oxygen supply and demand supply and demandType 3 MI Sudden unexpected cardiac death Symptoms suggestive of myocardial ischaemia accompanied by presumed newType 3 MI Sudden unexpected cardiac death Symptoms suggestive of myocardial ischaemia accompanied by presumed new before cardiac biomarkers obtained. ischaemic ECG changes or new LBBB—but without available biomarker values before cardiac biomarkers obtained. ischaemic ECG changes or new LBBB—but without available biomarker valuesType 4a MI MI associated with PCI In patients with normal baseline values: cTn values >5 times the 99th percentile Type 4a MI MI associated with PCI In patients with normal baseline values: cTn values >5 times the 99th percentile

URLURL In patients with elevated pre-procedure cTn in whom the cTn levels are stable In patients with elevated pre-procedure cTn in whom the cTn levels are stable

(<20% variation) or falling CTn values >20% to an absolute value more than 5 (<20% variation) or falling CTn values >20% to an absolute value more than 5 times the 99th percentile URLtimes the 99th percentile URL

Type 4b MI Stent/scaffold thrombosis associated Important to indicate the time of the occurrence with respect to timing of theType 4b MI Stent/scaffold thrombosis associated Important to indicate the time of the occurrence with respect to timing of the with PCI PCI procedure. acute, 0–24 h; subacute, >24 h to 30 days; late, >30 days to 1 year; with PCI PCI procedure. acute, 0–24 h; subacute, >24 h to 30 days; late, >30 days to 1 year;

and very late >1 year after stent/ scaffold implantationand very late >1 year after stent/ scaffold implantationType 4c MI Restenosis associated with PCI Defined as focal or diffuse restenosis, or a complex lesion associated with a rise Type 4c MI Restenosis associated with PCI Defined as focal or diffuse restenosis, or a complex lesion associated with a rise

and/or fall of cTn values above the 99th percentile URLand/or fall of cTn values above the 99th percentile URLType 5 MI MI associated with CABG cTn value >10 times the 99th percentile URL is applied as the cut-off point duringType 5 MI MI associated with CABG cTn value >10 times the 99th percentile URL is applied as the cut-off point during the first 48 h following CABG, occurring from a normal baseline cTn value (<99th the first 48 h following CABG, occurring from a normal baseline cTn value (<99th

percentile URL)percentile URL)

CAD – Coronary Artery Disease, CABG - Coronary Artery Bypass Grafting, cTn - Cardiac Troponin, ECG - Electrocardiogram, LBBB – Left Bundle Branch Block, PCI - Percutaneous Coronary CAD – Coronary Artery Disease, CABG - Coronary Artery Bypass Grafting, cTn - Cardiac Troponin, ECG - Electrocardiogram, LBBB – Left Bundle Branch Block, PCI - Percutaneous Coronary

Intervention, URL - Upper Reference Limit., h - hourIntervention, URL - Upper Reference Limit., h - hour

[Adapted from Thygesen K.[Adapted from Thygesen K.11,1211,12]]

Figure 2: Initial evaluation of a suspected ACS patient

Admitted to hospital with acute chest pain Admitted to hospital with acute chest pain

Persistent ST-elevation Persistent ST-elevation (>20 min)(>20 min)

ACS suspected ACS suspected Step 1: History, Physical exam, Clinical presentation Step 1: History, Physical exam, Clinical presentation Step 2: 12-lead ECGStep 2: 12-lead ECGStep 3: hs-cTn and other lab tests*Step 3: hs-cTn and other lab tests*Step 4: Ischaemic and bleeding risk assessment, cardiac Step 4: Ischaemic and bleeding risk assessment, cardiac rhythm monitoring rhythm monitoring

STEMISTEMI

Immediate reperfusion Immediate reperfusion with fibrinolytic therapy or with fibrinolytic therapy or

primary angioplastyprimary angioplasty

ECG normal or with abnormalities other than ST-elevationECG normal or with abnormalities other than ST-elevation

hs-cTn >ULNhs-cTn >ULNRetesRetest at 3ht at 3h

hs-cTn<ULNhs-cTn<ULNNo change at 3hNo change at 3h

Pronounced rise/Pronounced rise/fall in hs-cTn levelsfall in hs-cTn levels

NSTEMI**NSTEMI**

Invasive/Conservative management based on risk evaluation Invasive/Conservative management based on risk evaluation *serum creatinine, estimated glomerular filtration rate, haemoglobin, glucose, etc as required, **exclude other cardiac causes such as myocarditis, Tako-*serum creatinine, estimated glomerular filtration rate, haemoglobin, glucose, etc as required, **exclude other cardiac causes such as myocarditis, Tako-Tsubo cardiomyopathy, or tachyarrhythmias. ; ACS – Acute Coronary Syndrome, ECG – Electrocardiogram, hs-cTn – high-sensitivity cardiac troponin, ULN Tsubo cardiomyopathy, or tachyarrhythmias. ; ACS – Acute Coronary Syndrome, ECG – Electrocardiogram, hs-cTn – high-sensitivity cardiac troponin, ULN – Upper Limit of Normal, STEMI – ST-elevation myocardial infarction, NSTEMI – Non-ST-elevation myocardial infarction– Upper Limit of Normal, STEMI – ST-elevation myocardial infarction, NSTEMI – Non-ST-elevation myocardial infarction

[Adapted from Roffi M et al.,[Adapted from Roffi M et al.,55 Anantharaman V et al. Anantharaman V et al.1414]]

Painfree, low risk score, Painfree, low risk score, exclude differentialexclude differential

diagnosesdiagnoses

Discharge/Stress testingDischarge/Stress testing


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The choice of agents should be made on the basis of the management strategy to be adopted (conservative or invasive) as well as the method of revascularisation [Percutaneous Coronary Intervention (PCI) or Coronary Artery Bypass Grafting (CABG)]. The doses should take the age of the patient and their renal function also into account.

Assessment of risk is critical to making the decision with respect to invasive management of NSTE-ACS patients. The decision for coronary angiography and subsequent revascularisation should be done only after taking into account the long-term risks of morbidity and mortality vs. benefi ts such as symptomatic relief, improved quality of life and the associated duration of stay in the hospital related to the modality applied (PCI or CABG). Some of the criteria which help demarcate the risks are outlined in the table below.5

THE KEY ELEMENTS IN ACS MANAGEMENT Plaque rupture, the most frequent type of plaque complication, is responsible for nearly 70% of fatal AMI and/or sudden coronary deaths. The rupture of the vulnerable plaque may be clinically silent

but can contribute to plaque progression and luminal stenosis. Vulnerable plaques in addition to vulnerable blood (prone to thrombosis) and vulnerable myocardium (prone to fatal arrhythmia) are the major culprits for the development of ACS, MI and sudden cardiac death (Figure 3). Managing the total vulnerability burden may help reduce risk and improve outcomes.15

HOW TO ENSURE AN EFFECTIVE

MANAGEMENT OF NSTEMINSTEACS patients are a high-risk cohort in whom secondary CV prevention is highly eff ective. Platelets, coagulation, systemic infl ammation and cholesterol have a crucial role to play and provide a perspective on a personalized, targeted approach to reducing future events.16 Low-risk patients with NSTEACS are documented to benefi t substantially from Guideline – Directed Medical Therapy (GDMT), but this is often suboptimally

Figure 3: The Vulnerable ACS patient

Table 2: Risk evaluation for invasive therapy in NSTE-ACS

Very high-risk High-risk Intermediate risk Low-riskVery high-risk High-risk Intermediate risk Low-risk

Haemodynamic instability/ MI-compatible changes Diabetes mellitus Any characteristic notHaemodynamic instability/ MI-compatible changes Diabetes mellitus Any characteristic not

cardiogenic shock in in cardiac troponin Renal dysfunction (eGFR mentioned in the other columnscardiogenic shock in in cardiac troponin Renal dysfunction (eGFR mentioned in the other columns

<60 mL/min/1.73 m <60 mL/min/1.73 m22))

Chest pain unresponsive to Symptomatic or silent dynamic LVEF <40% /CHFChest pain unresponsive to Symptomatic or silent dynamic LVEF <40% /CHF

treatment ST- or T-wave changestreatment ST- or T-wave changes

Life-threatening cardiac GRACE score >140 Early post-infarction MILife-threatening cardiac GRACE score >140 Early post-infarction MI

arrhythmias/cardiac arrest arrhythmias/cardiac arrest

Acute heart failure Prior PCI/CABGAcute heart failure Prior PCI/CABG

Mechanical complications of MI GRACE >109 to <140Mechanical complications of MI GRACE >109 to <140

Repeated dynamic ST-T wave Repeated dynamic ST-T wave

changes, especially with changes, especially with

intermittent ST-elevationintermittent ST-elevation

Immediate invasive therapy Early invasive therapy Invasive therapy Either invasive (<72 hours) orImmediate invasive therapy Early invasive therapy Invasive therapy Either invasive (<72 hours) or

(<2 hours) (<24 hours) (<72 hours) non-invasive testing, (<2 hours) (<24 hours) (<72 hours) non-invasive testing,

as deemed appropriate as deemed appropriate

NSTE-ACS - Non-ST-elevation acute coronary syndrome, MI – Myocardial Infarction, GRACE - Global Registry of Acute Coronary Events, eGFR – estimated Glomerular Filtration Rate, NSTE-ACS - Non-ST-elevation acute coronary syndrome, MI – Myocardial Infarction, GRACE - Global Registry of Acute Coronary Events, eGFR – estimated Glomerular Filtration Rate,

LVEF – Left Ventricular Ejection Fraction, CHF – Congestive Heart Failure, PCI – Percutaneous Coronary Intervention, CABG – Coronary Artery Bypass Grafting LVEF – Left Ventricular Ejection Fraction, CHF – Congestive Heart Failure, PCI – Percutaneous Coronary Intervention, CABG – Coronary Artery Bypass Grafting

[Adapted from Roffi M et al.5]

[Adapted from Naghavi M et al.[Adapted from Naghavi M et al.1515]]


used. Clinicians should always aim to achieve the goals recommended by GDMT which represents recommended medical therapy as defi ned mainly by Class I measures, generally a combination of lifestyle modifi cation and drug- and device-based therapeutics. Evidence-based care through lifestyle modifi cation and eff ective pharmacological therapies can modify the underlying disease process.17 In addition to modifi cation of lifestyle factors, long-term management of the patient post-discharge may include anti-thrombotic, lipid-lowering, antihypertensive and antidiabetic

medications, depending on the existing comorbidities. Left ventricular (LV) dysfunction or heart failure may require the addition of beta-blockers or mineralocorticoid receptor antagonist to the treatment schedule.5 The diagnostic evaluation and early pharmacological management of NSTEMI are discussed below.

PHARMACOLOGICAL TREATMENT OF NSTEMIANTI-ISCHAEMIC THERAPYAnti-ischaemic or anti-anginal therapy aims to off er pain relief. Some of

the medications that help in this regard are detailed below. Guideline recommendations for the same are given in Table 3.1. Nitrates: Though both intravenous

(i.v.) and sublingual nitrates can be used, i.v. nitrates are more eff ective in relieving ischaemic pain and in reversing ST-depression. The i.v. form can also be used in those with recurrent angina, with signs of heart failure and those with uncontrolled hypertension.5 Doses should be titrated slowly upwards, with continuous blood pressure (BP)

Table 3: Guideline recommendations for anti-ischaemic therapy in NSTE-ACS

NitratesNitrates

I. V. MorphineI. V. Morphine

BBsBBs

CCBsCCBs

ACEIs/ARBsACEIs/ARBs

Sublingual/i.v. nitrates: anginal pain reliefSublingual/i.v. nitrates: anginal pain relief

i.v. nitrate: recurrent angina, uncontrolled i.v. nitrate: recurrent angina, uncontrolled

hypertension or signs of HFhypertension or signs of HF

Only if non-responsive to nitroglycerin, if Only if non-responsive to nitroglycerin, if

there are no contraindicationsthere are no contraindications

• Early initiation: ongoing ischaemic • Early initiation: ongoing ischaemic

symptoms (without contraindications).symptoms (without contraindications).

• Continue therapy: unless Killip class III or • Continue therapy: unless Killip class III or

higher presenthigher present

• Contraindication: suspected/confirmed • Contraindication: suspected/confirmed

vasospastic anginavasospastic angina

Patients with suspected/confirmed Patients with suspected/confirmed

vasospastic angina along with nitratesvasospastic angina along with nitrates

• Sublingual nitrates: every 5 min X 3 for continuing ischaemic pain, • Sublingual nitrates: every 5 min X 3 for continuing ischaemic pain,

followed by i.v. nitrates if neededfollowed by i.v. nitrates if needed

• i.v. nitrates: persistent ischaemia, HF, or hypertension• i.v. nitrates: persistent ischaemia, HF, or hypertension

• Contraindication: recent use of a phosphodiesterase inhibitor• Contraindication: recent use of a phosphodiesterase inhibitor

• For continued ischaemic chest pain, in spite of maximally tolerated • For continued ischaemic chest pain, in spite of maximally tolerated

anti-ischaemic medications.anti-ischaemic medications.

• Early initiation (<24 h) of oral BBs: if HF, low-output state, risk for • Early initiation (<24 h) of oral BBs: if HF, low-output state, risk for

cardiogenic shock, or other contraindications absentcardiogenic shock, or other contraindications absent

• Concomitant NSTE-ACS, stabilized HF, and reduced systolic function: • Concomitant NSTE-ACS, stabilized HF, and reduced systolic function:

sustained-release metoprolol succinate, carvedilol, or bisoprololsustained-release metoprolol succinate, carvedilol, or bisoprolol

• Reassess: those with initial contraindications to beta-blockers• Reassess: those with initial contraindications to beta-blockers

• Continue therapy: NSTE-ACS with normal LV function• Continue therapy: NSTE-ACS with normal LV function

• Avoid i.v. BB: when risk factors for shock present• Avoid i.v. BB: when risk factors for shock present

• When BB not effective, contraindicated or cause unacceptable side • When BB not effective, contraindicated or cause unacceptable side

effectseffects

• Nondihydropyridine CCBs: in recurrent ischaemia (if BBs • Nondihydropyridine CCBs: in recurrent ischaemia (if BBs

contraindicated), persistent ischaemia (after use of BB/nitrates), LV contraindicated), persistent ischaemia (after use of BB/nitrates), LV

function normal, risk for cardiogenic shock, PR interval >0.24s, or 2° or function normal, risk for cardiogenic shock, PR interval >0.24s, or 2° or

3° atrioventricular block without a cardiac pacemaker3° atrioventricular block without a cardiac pacemaker

• Long-acting CCBs and nitrates: coronary artery spasm• Long-acting CCBs and nitrates: coronary artery spasm

• Avoid: immediate-release nifedipine without a BB• Avoid: immediate-release nifedipine without a BB

• Initiate/continue: LVEF<40%, hypertension, diabetes mellitus, or stable • Initiate/continue: LVEF<40%, hypertension, diabetes mellitus, or stable

CKD, cardiac or other vascular disease, unless contraindicatedCKD, cardiac or other vascular disease, unless contraindicated

• ARBs: ACEI intolerant patients with HF or MI with LVEF <40%, cardiac • ARBs: ACEI intolerant patients with HF or MI with LVEF <40%, cardiac

or other vascular diseaseor other vascular disease

• Aldosterone blocker + ACEI + BB: post–MI patients without significant • Aldosterone blocker + ACEI + BB: post–MI patients without significant

renal dysfunction* or hyperkalemia** with LVEF renal dysfunction* or hyperkalemia** with LVEF 40%, diabetes 40%, diabetes

mellitus, or HF mellitus, or HF *(creatinine >2.5 mg/dL in men or >2.0 mg/dL in women), **(Kþ >5.0 mEq/L), ESC – European Society of Cardiology, ACC/AHA – American College of Cardiology/American Heart *(creatinine >2.5 mg/dL in men or >2.0 mg/dL in women), **(Kþ >5.0 mEq/L), ESC – European Society of Cardiology, ACC/AHA – American College of Cardiology/American Heart Association, i.v. – Intravenous, NSTE-ACS – Non-ST-elevation Acute Coronary Syndrome, LV- Left ventricular, HF – Heart Failure, LVEF – Left Ventricular Ejection Fraction, MI – Myocardial Association, i.v. – Intravenous, NSTE-ACS – Non-ST-elevation Acute Coronary Syndrome, LV- Left ventricular, HF – Heart Failure, LVEF – Left Ventricular Ejection Fraction, MI – Myocardial Infarction, BB – Beta-blocker, CCB – Calcium channel blocker, ACEI – Angiotensin converting enzyme inhibitor, ARB – Angiotensin receptor blocker, CKD- Chronic kidney diseaseInfarction, BB – Beta-blocker, CCB – Calcium channel blocker, ACEI – Angiotensin converting enzyme inhibitor, ARB – Angiotensin receptor blocker, CKD- Chronic kidney disease

ESC 2015ESC 2015 ACC/AHA 2014ACC/AHA 2014

[Adapted from Roffi M et al.,5 Amsterdam EA et al.[Adapted from Roffi M et al.,5 Amsterdam EA et al.1717]]


REVIEW ARTICLE

monitoring, till symptomatic relief is achieved/side eff ects do not occur. Nitrates should not be administered in those who have recently ingested a phosphodiesterase type 5 inhibitor (sildenafi l, vardenafi l, tadalafi l), in those with systolic blood pressure (SBP) <90 mmHg and in whom right ventricular infarction is suspected.18 If the patient is non-responsive to nitroglycerin, i.v. morphine can be given, provided there are no contraindications.5

2. Beta-blockers: Beta-blockers can be initiated early in patients with ongoing ischaemic symptoms and in the absence of contraindications. Evidence for this comes from a meta-analysis of 27 early studies which showed that beta-blocker therapy reduced relative risk (RR) of mortality by 13% in the 1st week post-MI.5 Another meta-analysis (n=73,396) showed that in-hospital mortality was reduced by 8% with i.v. beta-blocker therapy and also reduced the risk of ventricular tachyarrhythmias (-39%) and myocardial reinfarction (-27%) without enhancing the risk of cardiogenic shock or stroke.19 However, early administration of beta-blockers should be avoided in those at increased risk of cardiogenic shock and in those with symptoms indicating coronary vasospasm/cocaine use. Chronic beta-blocker therapy is recommended, except in patients who are in Killip class III or higher.5

3. Calcium channel blockers (CCBs): CCBs can be used for patients already on nitrates/beta-blockers or for those in whom beta-blockers are contraindicated or for those with coronary vasospasm.14 In fact CCBs and nitrates are preferred in those with confi rmed or suspected vasospastic angina, and beta-blockers should be avoided. CCBs and ranolazine can be used in those who cannot be revascularized eff ectively and in those who present with residual angina after beta-blocker therapy.20 Amongst the various CCBs, diltiazem and verapamil have a similar impact

on ischaemic symptoms as beta-blockers.21,22

4. Angiotensin converting enzyme inhibitors (ACEIs): If not contraindicated, ACEIs can be administered within 24 hours of NSTEMI in patients with pulmonary venous congestion/left ventricular ejection fraction (LVEF) ≤40% or in those without hypotension. If contraindicated, angiotensin receptor blockers (ARBs) such as valsartan, telmisartan or losartan can be given.14

CHOLESTEROL MANAGEMENT This forms an important part of the initial treatment of the NSTEACS patient wherein obtaining a fasting lipid profi le <24 hours after presentation is recommended. Both the ESC5 and ACC/AHA17 guidelines on NSTEACS management recommend initiation/continuation of high-intensity statin therapy in all patients with NSTEACS with no contraindications for its use. Therapy with statins is eff ective in reducing rates of CV events such as recurrent MI, need for myocardial revascularisation, stroke and even coronary heart disease mortality. NSTEACS patients, who are already at high CV risk will thus benefi t substantially from the impact of high-intensity statin therapy which lowers low-density lipoprotein cholesterol (LDL-C) levels by ≥50%. The high-intensity statins include atorvastatin (40/80 mg) and rosuvastatin (20/40 mg).23 A meta-analysis of 26 trials involving more than 1,70,000 patients also showed that compared to less intensive statin treatment, the more intensive ones resulted in a signifi cantly 15% higher reduction in major vascular events. Moreover, separately signifi cant reductions in coronary death/non-fatal MI, coronary revascularisation and ischaemic stroke by 13%, 19% and 16%, respectively, were also observed.24

The Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis in Myocardial Infarction 22 (PROVE IT–TIMI 22)25 enrolled ACS patients (n=4162) and compared the impact of pravastatin (40 mg/day; standard therapy) with atorvastatin (80

mg/day; intensive therapy) on the primary composite end point of all-cause death, MI, UA requiring rehospitalization, revascularization (>1 month after randomisation) and stroke. At the end of 2 years, the intensive regimen was found to be superior with a relative risk reduction of 16% in the primary endpoint, compared to the standard therapy. Similarly, the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) Study26 (n=3086 NSTE-ACS patients) showed that there was a 16% relative risk reduction with high-intensity therapy (atorvastatin 80 mg/day) in the composite endpoint of death, cardiac arrest with resuscitation, nonfatal acute MI, or recurrent myocardial ischaemia requiring emergency rehospitalization.

ANTIPLATELET THERAPYSince ACS is mainly thought to be initiated by the formation of a thrombus over an eroded plaque,20 antiplatelet agents form an important part of the therapeutic arsenal in the treatment of these patients.14 The 3 main classes of antiplatelet agents are aspirin, P2Y12 receptor antagonists and glycoprotein (GP) IIb/IIIa receptor antagonists. Guideline recommendations for their use are given in Table 4. 1. Aspirin: Aspirin, a cyclooxygenase

inhibitor, used at the initial oral dose of 150–300 mg (in Aspirin-naïve patients) or i.v. 500 mg is recommended for all NSTEMI patients without contraindications. This can be titrated to a long-term maintenance dose of 75–100 mg/day, irrespective of the treatment strategy.5 Several studies have shown that aspirin reduces the incidence of MI and death in patients with UA.27-30 A collaborative meta-analysis indicated that, for up to 2 years, treatment with aspirin signifi cantly reduced major vascular events by 46%.5

2. P2Y12 inhibitors5,14: Once the diagnosis is made, all NSTE-ACS patients being conservatively managed can be given a P2Y12 inhibitor (preferably ticagrelor), if there are no contraindications.


A combination of aspirin with a P2Y12 inhibitor is recommended for 1-year in NSTEMI patients, unless contraindications such as enhanced bleeding risk exist. Beyond a year,

continuation of this combination should be made only after carefully considering the ischaemic/bleeding risks. A shorter treatment period of 3–6 months may be considered in

those implanted with drug-eluting stents (DES) and believed to be at high bleeding risk. The commonly used P2Y12 inhibitors include:• Clopidogrel: Clopidogrel can be

Table 4: Guideline recommendations for antiplatelet therapy in NSTE-ACS

AspirinAspirin

P2YP2Y1212 inhibitors inhibitors

P2YP2Y1212 inhibitor inhibitor

discontinuationdiscontinuation

GP IIb/IIIa GP IIb/IIIa

inhibitorsinhibitors

All patients without contraindications, long-All patients without contraindications, long-

term regardless of treatment strategyterm regardless of treatment strategy

LD: 150–300 mg; MD: 75–100 mg/dayLD: 150–300 mg; MD: 75–100 mg/day

• P2Y12 inhibitors + Aspirin: one year, if there • P2Y12 inhibitors + Aspirin: one year, if there

are no contraindications; >1 year, check are no contraindications; >1 year, check

ischaemic/bleeding risksischaemic/bleeding risks

• Ticagrelor (LD: 180 mg, MD: 90 mg bid), if not • Ticagrelor (LD: 180 mg, MD: 90 mg bid), if not

contraindicated, all patients at moderate-to-contraindicated, all patients at moderate-to-

high risk of ischaemic events, irrespective of high risk of ischaemic events, irrespective of

initial treatment strategyinitial treatment strategy

• If pretreated, use Ticagrelor after • If pretreated, use Ticagrelor after

discontinuing Clopidogreldiscontinuing Clopidogrel

• Prasugrel (LD: 60 mg, MD: 10 mg daily dose) • Prasugrel (LD: 60 mg, MD: 10 mg daily dose)

before PCI, if no contraindications exist; before PCI, if no contraindications exist;

avoid in unknown coronary anatomyavoid in unknown coronary anatomy

• Clopidogrel (LD: 300–600 mg, MD: 75 mg): • Clopidogrel (LD: 300–600 mg, MD: 75 mg):

where Ticagrelor/Prasugrel not possiblewhere Ticagrelor/Prasugrel not possible

• DES implantation: For 3–6 months (those at • DES implantation: For 3–6 months (those at

high bleeding risk)high bleeding risk)

• DAPT: Add PPI for those > average risk of • DAPT: Add PPI for those > average risk of

gastrointestinal bleedsgastrointestinal bleeds

• Non-emergency major non-cardiac surgery: • Non-emergency major non-cardiac surgery:

Ticagrelor or Clopidogrel 5 days and Ticagrelor or Clopidogrel 5 days and

Prasugrel 7 days before surgery , unless high Prasugrel 7 days before surgery , unless high

risk of ischaemic events presentrisk of ischaemic events present

• Non-cardiac surgical procedure that cannot • Non-cardiac surgical procedure that cannot

be postponed/ bleeding complication: be postponed/ bleeding complication:

discontinue after 1 and 3 months from discontinue after 1 and 3 months from

PCI with BMS and new-generation DES, PCI with BMS and new-generation DES,

respectivelyrespectively

• During PCI only for bailout situations or • During PCI only for bailout situations or

thrombotic complications.thrombotic complications.

• Avoid: In unknown coronary anatomy• Avoid: In unknown coronary anatomy

Non–enteric-coated; all Non–enteric-coated; all

patients promptly after patients promptly after

presentation, LD: 162–325 mg; presentation, LD: 162–325 mg;

MD: 81–325 mg/day continued MD: 81–325 mg/day continued

indefinitelyindefinitely

• Clopidogrel (LD: 300 or • Clopidogrel (LD: 300 or

600 mg, MD: 75 mg/day) if 600 mg, MD: 75 mg/day) if

Aspirin contraindicatedAspirin contraindicated

• Clopidogrel/Ticagrelor (LD: • Clopidogrel/Ticagrelor (LD:

180 mg, MD: 90 mg BID) + 180 mg, MD: 90 mg BID) +

Aspirin: 1 year, both early Aspirin: 1 year, both early

invasive or initial ischaemia-invasive or initial ischaemia-

guided strategyguided strategy

• PCI with coronary stents: • PCI with coronary stents:

P2YP2Y1212 inhibitor for at inhibitor for at

least 1 year (Ticagrelor least 1 year (Ticagrelor

preferred over Clopidogrel), preferred over Clopidogrel),

irrespective of strategyirrespective of strategy

• Early invasive strategy: • Early invasive strategy:

Eptifibatide or Tirofiban Eptifibatide or Tirofiban

• Intermediate/high-risk: DAPT• Intermediate/high-risk: DAPT

As soon as possible to all patients (LD: As soon as possible to all patients (LD:

300 mg), continue indefinitely unless 300 mg), continue indefinitely unless

contraindicated by bleeding risk or contraindicated by bleeding risk or

Aspirin hypersensitivity.Aspirin hypersensitivity.

If contraindicated, use ClopidogrelIf contraindicated, use Clopidogrel

• Clopidogrel (LD: 300 mg) + Aspirin: • Clopidogrel (LD: 300 mg) + Aspirin:

patients with predicted 6-month patients with predicted 6-month

mortality of >1.5% and no mortality of >1.5% and no

contraindications contraindications

• Clopidogrel (LD: 300 mg): All • Clopidogrel (LD: 300 mg): All

patients (with no contraindications) patients (with no contraindications)

undergoing PCI <24 hours post-undergoing PCI <24 hours post-

hospital admissionhospital admission

• Continue Clopidogrel for up • Continue Clopidogrel for up

to a year in NSTEMI patients, to a year in NSTEMI patients,

irrespective of treatmentirrespective of treatment

• Low CV risk: Discontinue • Low CV risk: Discontinue

Clopidogrel 5 days before CABGClopidogrel 5 days before CABG

• Intermediate or high CV risk: • Intermediate or high CV risk:

Discuss discontinuation before Discuss discontinuation before

CABG with the cardiac surgeonCABG with the cardiac surgeon

• Intermediate or higher CV risk, • Intermediate or higher CV risk,

angiography <96h after admission: angiography <96h after admission:

i.v. Eptifibatide or Tirofibani.v. Eptifibatide or Tirofiban

• Intermediate or higher CV risk: • Intermediate or higher CV risk:

Abciximab as an adjunct to PCI, if Abciximab as an adjunct to PCI, if

not on GP IIb/IIIa (assess risk/benefit not on GP IIb/IIIa (assess risk/benefit

ratio carefully)ratio carefully)

NSTE-ACS - Non-ST-elevation Acute Coronary Syndrome, NSTEMI – Non-ST-elevation Myocardial Infarction, ESC – European Society of Cardiology, ACC – American College NSTE-ACS - Non-ST-elevation Acute Coronary Syndrome, NSTEMI – Non-ST-elevation Myocardial Infarction, ESC – European Society of Cardiology, ACC – American College of Cardiology, AHA – American Heart Association, NICE - National Institute for Health and Care Excellence, LD – Loading Dose, MD – Maintenance Dose, BID – Twice daily, of Cardiology, AHA – American Heart Association, NICE - National Institute for Health and Care Excellence, LD – Loading Dose, MD – Maintenance Dose, BID – Twice daily,

PCI – Percutaneous Coronary Intervention,, DAPT – Dual Antiplatelet therapy, DES – Drug Eluting Stent, PPI – Proton Pump Inhibitor, CV – Cardiovascular, PCI – Percutaneous Coronary Intervention,, DAPT – Dual Antiplatelet therapy, DES – Drug Eluting Stent, PPI – Proton Pump Inhibitor, CV – Cardiovascular, CABG – Coronary Artery Bypass Grafting, BMS – Bare Metal Stent, i.v. – IntravenousCABG – Coronary Artery Bypass Grafting, BMS – Bare Metal Stent, i.v. – Intravenous

ESC 2015ESC 2015 ACC/AHA 2014ACC/AHA 2014 NICE 2010NICE 2010

[Adapted from Roffi M et al.,5 Amsterdam EA et al.,[Adapted from Roffi M et al.,5 Amsterdam EA et al.,1717 NICE 2010 NICE 20104646]]


REVIEW ARTICLE

administered as a 300–600 mg loading dose followed by a 75 mg daily dose to those who need oral anticoagulation but cannot be given ticagrelor/prasugrel. Clopidogrel is a pro-drug (only 15% is available in its active form) and inhibits the P2Y12 subtype of ADP receptor, thereby reducing platelet aggregation. It also blocks activation of the GP IIb/IIIa pathway. When given in combination with aspirin (dual antiplatelet therapy or DAPT), it had a benefi cial impact on recurrent ischaemic events31 in NSTEMI patients, and reduced major CV events in those undergoing PCI.32 However, great inter-individual variation has been noticed in the response to Clopidogrel33 wherein patients who have a variant allele for the CYP2C19 isozyme had a 3.58 times greater risk for CV events than those without it.34

• Prasugrel: Prasugrel can be administered as a 60 mg loading dose and a 10 mg daily dose in patients scheduled for PCI. It has a faster onset of action and a more potent inhibitory eff ect as compared to clopidogrel. In the TRial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet InhibitioN with Prasugrel–Thrombolysis In Myocardial Infarction (TRITON-TIMI 38),35 treatment with clopidogrel vs prasugrel was compared in patients with UA/NSTEMI (n=10,074) and STEMI (n=3534) scheduled for PCI. The primary endpoint of death from CV causes, nonfatal MI, or nonfatal stroke occurred in fewer patients on prasugrel (9.9%) vs clopidogrel (12.1%; p<0.001). This impact was mostly due to the reduction in nonfatal MI (7.3% with prasugrel vs 9.5% with clopidogrel; p<0.001). Stent thrombosis was observed in >2-fold patients on clopidogrel compared to prasugrel (2.4% vs 1.1%, p<0.001). However, more

patients suff ered from severe bleeding complications with Prasugrel vs clopidogrel (% patients with non–CABG-related TIMI major bleeding 2.4% vs. 1.8%, respectively, p=0.03). Prasugrel is also to be avoided in patients with prior stroke/transient ischaemic attack (TIA) due to lack of benefi t seen in this group. In a sub-analysis of the study, when compared by stent type and vs. clopidogrel, prasugrel reduced thrombosis by 64% in patients with DES and by 48% in patients with bare-metal stents (BMS).36 Hence, prasugrel can be utilised in patients who present with stent thrombosis, in spite of adherence with clopidogrel therapy.

• In NSTE-ACS patients (n=7243; <75 yrs) who were medically managed (without revascularisation), The Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes (TRILOGY ACS) showed no diff erence in the primary endpoint of death from CV causes, MI, or stroke with prasugrel (10 mg/day) vs clopidogrel (75 mg/day) during a 30-month treatment period, though multiple recurrent ischaemic events were reduced by 15% with prasugrel.37

• Prasugrel should not be administered in patients whose coronary anatomy is unknown.

• Ticagrelor: Ticagrelor is given as a 180 mg loading dose with a maintenance dose of 90 mg bid for all patients at moderate-to-high ischaemic risk irrespective of initial treatment strategy, when there are no contraindications. Patients pretreated with clopidogrel can also be treated with ticagrelor, provided the former agent is discontinued. Ticagrelor binds P2Y12 reversibly and is an oral formulation that also inhibits reuptake of adenosine via the equilabrative nucleoside transporter 1 (ENT1). It has a

more rapid onset of action than clopidogrel along with faster recovery of platelet function.

• In The Study of Platelet Inhibition and Patient Outcomes (PLATO), ACS patients (n=18,624) were treated with either ticagrelor (180 mg loading dose, 90 mg bid maintenance dose) or clopidogrel (300–600 mg loading dose, 75 mg/day maintenance dose) for 12 months. The primary endpoint (composite of death from vascular causes, MI or stroke) occurred in fewer patients on ticagrelor (9.8%) vs clopidogrel (11.7%; P<0.001).38 In the NSTE-ACS subgroup (n=11,080), ticagrelor reduced the primary endpoint, MI, CV death and all-cause death by 17%, 14%, 23% and 24%, respectively vs. clopidogrel. Bleeding event rates seen in this subgroup were similar to the overall group, though Ticagrelor had increased risk of non-CABG-related PLATO-defi ned major bleeds compared to clopidogrel (4.8% vs 3.8%), but life-threatening or fatal bleeds were similar. The benefi ts of ticagrelor remained, regardless of whether or not revascularisation was performed within 10 days post-randomization.39 There was 33% reduction in defi nite stent thrombosis seen with ticagrelor in the NSTE-ACS subgroup which was similar to that seen in the overall trial.39,40

3. GP IIb/IIIa inhibitors5: Administration of GP IIb/IIIa inhibitors (e.g. Eptifi batide, Tirofi ban, and Abciximab) in patients already on P2Y12 inhibitors during PCI, may be needed only during bailout situations/thrombotic complications. They are to be avoided in patients whose coronary anatomy is unknown and their use should be withheld till after angiography.20

A meta-analysis of studies involving platelet GP IIb/IIIa inhibitors, used in chiefl y medically managed NSTE-ACS (n=29,570), showed that their use reduced death or non-fatal MI by 9% at


ACSACS

Figure 4: Use of DAPT in ACS patients

Medical treatment alone Medical treatment alone

If yes, If yes, Aspirin + Aspirin +

Clopidogrel Clopidogrel for for 1 month1 month

If no, If no, Aspirin + Ticagrelor/Aspirin + Ticagrelor/Clopidogrel* for 12 Clopidogrel* for 12

monthsmonthsAspirin + Ticagrelor/Aspirin + Ticagrelor/

Clopidogrel* for Clopidogrel* for >12 months>12 months

If yes, Aspirin If yes, Aspirin + Ticagrelor or + Ticagrelor or Clopidogrel for Clopidogrel for

6 months6 months

CABGCABG

If no, If no, Aspirin + Aspirin + Ticagrelor/Ticagrelor/

Prasugrel or Prasugrel or Clopidogrel ** for Clopidogrel ** for

12 months12 monthsAspirin + Aspirin + Ticagrelor Ticagrelor

or Prasugrel/ or Prasugrel/ Clopidogrel* for Clopidogrel* for

>12months>12months

If yes, If yes, Aspirin + Aspirin +

Ticagrelor or Ticagrelor or Clopidogrel Clopidogrel

for 6 months for 6 months

ACSACS

[Adapted from Valgimigli M et al.[Adapted from Valgimigli M et al.4747]]

High bleeding High bleeding risk?risk?


PCI with DES/BMS or DCBPCI with DES/BMS or DCB


If no, Aspirin + Ticagrelor/If no, Aspirin + Ticagrelor/Prasugrel or Clopidogrel Prasugrel or Clopidogrel

** for 12 months** for 12 months

Aspirin + Ticagrelor Aspirin + Ticagrelor or Prasugrel/Clopidogrel or Prasugrel/Clopidogrel

for >12 monthsfor >12 months

Aspirin + Aspirin + Ticagrelor/Ticagrelor/

Prasugrel or Prasugrel or Clopidogrel ** Clopidogrel ** for for 12 months12 months

BRSBRS

30 days. Patients who were undergoing PCI benefi ted more with this therapy (ischaemic events reduced by 18%) as compared to medically managed ones (5% reduction). Moreover, if the agent was infused during the procedure, the impact was greater (26% reduction) than if revascularisation was carried out after drug discontinuation (13% reduction). Though major bleeding complications increased with their use, there was an insignifi cant increase in intracranial haemorrhage.41

When it comes to conjoint use of GP IIb/IIIa and P2Y12 inhibitors, TRITON TIMI 38 found that the effi cacy of prasugrel was consistent with/without prior treatment with GP IIb/IIIa inhibitors,42 the effi cacy and safety of these drugs when added to P2Y12 inhibitors has not been adequately addressed.

GP IIb/IIIa inhibitors can also be used safely used with anticoagulants such as enoxaparin and fondaparinux with decrease in bleeding complications seen with the latter.43 In the ACUITY (Acute Catheterization and Urgent Intervention Triage strategY) trial, the use of either Bivalirudin or unfractionated heparin (UFH)/low-molecular weight heparin (LMWH) along with aspirin, clopidogrel and a GP IIb/IIIa inhibitor, in NSTEACS patients, resulted in equivalent safety and effi cacy outcomes.44 However, a sub-analysis showed similar reduction in ischaemic events but higher bleeding rates with bivalirudin + GP IIb/IIIa combination as compared to bivalirudin

alone.45

Dual antiplatelet therapy (DAPT): Use of DAPT in various situations form the bulk of the recommendations for NSTE-ACS patients. An overview of DAPT use as developed by the 2017 ESC focused update on DAPT in CAD is depicted in Figure 4.47

Clinical situations may arise wherein switching one P2Y12 inhibitor for another may be required. The results from the PLATO study showed that 50% of the trial population had been pretreated with clopidogrel and were subsequently switched to ticagrelor. The effi cacy of the latter regimen remained unaltered.47 A concise guide for the switching of P2Y12 inhibitors is detailed in Table 5. ANTICOAGULATION5

Anticoagulants act at various stages of the coagulation cascade, inhibiting thrombin generation. After assessing the ischaemic and bleeding risks, parenteral anticoagulation can be administered at the time of NSTEMI diagnosis. In a meta-analysis of 12 trials, the combination of aspirin along with short-term anticoagulant therapy in NSTE-ACS resulted in halving the risk of MI and death.48 Some of the key anticoagulants in use are detailed below and the guideline-based recommendations for the same are given in Table 6.1. UFH: The pharmacokinetics

of UFH show a greater inter-individual variability along with a narrow therapeutic window, with the possibility of heparin-induced thrombocytopenia (HIT) as the most

Table 5: Switching P2Y12 inhibitors in ACS patients (acute and chronic setting)Switch from Acute setting (LD) Chronic settingSwitch from Acute setting (LD) Chronic settingClopidogrel to Prasugrel 60 mg, regardless Prasugrel 10 mg qd MD, 24hrsClopidogrel to Prasugrel 60 mg, regardless Prasugrel 10 mg qd MD, 24hrsPrasugrel of prior therapy after last Clopidogrel dosePrasugrel of prior therapy after last Clopidogrel dose

Clopidogrel to Ticagrelor 180 mg, regardless Ticagrelor 90 mg bid MD,Clopidogrel to Ticagrelor 180 mg, regardless Ticagrelor 90 mg bid MD,Ticagrelor of prior therapy 24hrs after last Clopidogrel doseTicagrelor of prior therapy 24hrs after last Clopidogrel dose

Prasugrel to Clopidogrel 600 mg, Clopidogrel 75 mg qd MD,Prasugrel to Clopidogrel 600 mg, Clopidogrel 75 mg qd MD,Clopidogrel 24hrs after last Prasugrel dose 24hrs after last Prasugrel doseClopidogrel 24hrs after last Prasugrel dose 24hrs after last Prasugrel dose

Prasugrel to Ticagrelor 180 mg, Ticagrelor 90 mg bid MD,Prasugrel to Ticagrelor 180 mg, Ticagrelor 90 mg bid MD,Ticagrelor 24hrs after last Prasugrel dose 24hrs after last Prasugrel doseTicagrelor 24hrs after last Prasugrel dose 24hrs after last Prasugrel dose

Ticagrelor to Prasugrel 60 mg, 24hrs after Prasugrel 60 mg LD,Ticagrelor to Prasugrel 60 mg, 24hrs after Prasugrel 60 mg LD,Prasugrel last Ticagrelor dose 24hrs after last Ticagrelor dosePrasugrel last Ticagrelor dose 24hrs after last Ticagrelor dose

Ticagrelor to Clopidogrel 600 mg, Clopidogrel 600 mg LD,Ticagrelor to Clopidogrel 600 mg, Clopidogrel 600 mg LD,Clopidogrel 24hrs after last Ticagrelor dose 24hrs after last Ticagrelor doseClopidogrel 24hrs after last Ticagrelor dose 24hrs after last Ticagrelor dose

ACS - Acute coronary syndrome, LD – Loading dose, MD – Maintenance dose, qd – Once a day, bid – Twice dailyACS - Acute coronary syndrome, LD – Loading dose, MD – Maintenance dose, qd – Once a day, bid – Twice dailykk [Adapted from Valgimigli M et al. [Adapted from Valgimigli M et al.4747] ]


REVIEW ARTICLE

notable side-eff ect. The recommended weight-adjusted dose range includes an initial i.v. bolus of 60–70 IU/kg up to 5000 IU, followed by an infusion of 12–15 IU/kg/h up to 1000 IU/h. The use of UFH in PCI is unpredictable due to the need for close monitoring, interaction with other clotting factors and the rebound formation of thrombin after discontinuation.49 However, it remains the most widely used anticoagulant in practice with the weight-adjusted dose during PCI being 70–100 IU/kg, or 50–70 IU/kg in combination with a GP IIb/IIIa inhibitor, with cessation of the

drug after the procedure. Following the initial UFH treatment, additional activated clotting time (ACT)-guided i.v. boluses may also be given during PCI.

2. LMWH: The most well-known LMWH is enoxaparin which exhibits a more predictable pharmacokinetic profi le compared to UFH and causes HIT less frequently. In NSTE-ACS, enoxaparin at the subcutaneous (s.c.) dose of 1 mg/kg/bid is eff ective.50 It should be continued as the anticoagulant when patients pre-treated with it undergo PCI. In case of renal dysfunction

(eGFR <30 mL/min/1.73m2, the dose should be reduced to 1 mg/kg once daily and not administered in those with eGFR <15 mL/min/1.73m2. Anti-Xa monitoring is not required except in patients with eGFR 15–30 mL/min/1.73m2 or bodyweight >100 kg. In NSTE-ACS patients, during PCI, if pre-treatment with enoxaparin was carried out, no additional enoxaparin is recommended during the procedure if the last s.c. injection was given <8 hours prior to PCI. However, if given ≥8 hours before PCI, an additional 0.3 mg/kg i.v. bolus is needed.50 When compared to UFH in

Table 6: Guideline recommendations for anticoagulant therapy in NSTE-ACS

• Parenteral anticoagulation: start at time • Parenteral anticoagulation: start at time of diagnosis (assess ischaemic/bleeding of diagnosis (assess ischaemic/bleeding risks).risks).

• Fondaparinux (2.5 mg s.c. daily): most • Fondaparinux (2.5 mg s.c. daily): most favourable efficacy–safety profile favourable efficacy–safety profile regardless of the management strategy.regardless of the management strategy.

• NSTEMI patients with no prior stroke/• NSTEMI patients with no prior stroke/TIA, high ischaemic/low bleeding risk, on TIA, high ischaemic/low bleeding risk, on Aspirin + Clopidogrel: Rivaroxaban (2.5 Aspirin + Clopidogrel: Rivaroxaban (2.5 mg bid for 1 year) post-discontinuation of mg bid for 1 year) post-discontinuation of parenteral anticoagulation.parenteral anticoagulation.

Recommendations for PCI.Recommendations for PCI.

• Bivalirudin (LD: 0.75 mg/kg i.v., 1.75 • Bivalirudin (LD: 0.75 mg/kg i.v., 1.75 mg/kg/h up to 4 h after the procedure) mg/kg/h up to 4 h after the procedure) instead of UFH + GP IIb/IIIa inhibitors. instead of UFH + GP IIb/IIIa inhibitors.

• Patients undergoing PCI without • Patients undergoing PCI without anticoagulation: UFH 70–100 IU/kg i.v. anticoagulation: UFH 70–100 IU/kg i.v. (50–70 IU/kg if concomitant GP IIb/IIIa (50–70 IU/kg if concomitant GP IIb/IIIa inhibitors).inhibitors).

• Patients on Fondaparinux (2.5 mg s.c. • Patients on Fondaparinux (2.5 mg s.c. daily) undergoing PCI: add a single i.v. daily) undergoing PCI: add a single i.v. bolus of UFH (70–85 IU/kg, or 50–60 IU/bolus of UFH (70–85 IU/kg, or 50–60 IU/kg if concomitant GP IIb/IIIa inhibitors) kg if concomitant GP IIb/IIIa inhibitors) during the procedure.during the procedure.

• Enoxaparin (1 mg/kg s.c. bid) or UFH: if • Enoxaparin (1 mg/kg s.c. bid) or UFH: if Fondaparinux unavailable.Fondaparinux unavailable.

• s.c. Enoxaparin pretreatment: continue • s.c. Enoxaparin pretreatment: continue with same for PCI.with same for PCI.

• UFH: during PCI, additional ACT-guided • UFH: during PCI, additional ACT-guided i.v. boluses may be needed after initial i.v. boluses may be needed after initial treatment.treatment.

• Discontinue anticoagulation after PCI • Discontinue anticoagulation after PCI (unless otherwise indicated).(unless otherwise indicated).

• Avoid crossover between UFH and LMWH.• Avoid crossover between UFH and LMWH.

• Enoxaparin: 1 mg/kg s.c. bid during • Enoxaparin: 1 mg/kg s.c. bid during hospitalization or until PCI.hospitalization or until PCI.

• CrCl <30 mL/min: 1 mg/kg/d s.c. • CrCl <30 mL/min: 1 mg/kg/d s.c. 30 mg i.v. loading dose in selected 30 mg i.v. loading dose in selected

patients.patients.• Bivalirudin (LD: 0.10 mg/kg, MD: 0.25 • Bivalirudin (LD: 0.10 mg/kg, MD: 0.25

mg/kg/h) till diagnostic angiography/mg/kg/h) till diagnostic angiography/PCI is performed (early invasive strategy PCI is performed (early invasive strategy only).only).

• GP IIb/IIIa inhibitor: provisional use in • GP IIb/IIIa inhibitor: provisional use in those also on DAPT.those also on DAPT.

• Fondaparinux: s.c. 2.5 mg daily for • Fondaparinux: s.c. 2.5 mg daily for hospital stay/till PCI is performed; add hospital stay/till PCI is performed; add anticoagulant with anti-IIa activity if PCI anticoagulant with anti-IIa activity if PCI is performed while on Fondaparinux.is performed while on Fondaparinux.

• UFH: i.v. for 48 h or until PCI is • UFH: i.v. for 48 h or until PCI is performed [(LD: 60 IU/kg (max 4,000 performed [(LD: 60 IU/kg (max 4,000 IU) with initial infusion 12 IU/kg/h (max IU) with initial infusion 12 IU/kg/h (max 1,000 IU/ h)], adjust to therapeutic aPTT 1,000 IU/ h)], adjust to therapeutic aPTT range.range.

• Fondaparinux: not at high bleeding risk, unless • Fondaparinux: not at high bleeding risk, unless coronary angiography <24 h of admission.coronary angiography <24 h of admission.

• UFH: Early coronary angiography planned (<24 h) or • UFH: Early coronary angiography planned (<24 h) or renal impairment present.renal impairment present.

• Factors which enhance bleeding risk: advancing age, • Factors which enhance bleeding risk: advancing age, known bleeding complications, renal impairment known bleeding complications, renal impairment and low body weight.and low body weight.

• UFH (50–100 units/kg): adjunct to Fondaparinux • UFH (50–100 units/kg): adjunct to Fondaparinux patients undergoing PCI.patients undergoing PCI.

• Intermediate or higher CV risk and not already • Intermediate or higher CV risk and not already on GP IIb/IIIa inhibitor/Fondaparinux, undergoing on GP IIb/IIIa inhibitor/Fondaparinux, undergoing angiography <24 hours post-admission: Bivalirudin angiography <24 hours post-admission: Bivalirudin instead of UFH + GP IIb/IIIa inhibitor.instead of UFH + GP IIb/IIIa inhibitor.

• Undergoing PCI and not already on a GP IIb/IIIa • Undergoing PCI and not already on a GP IIb/IIIa inhibitor/Fondaparinux: Bivalirudin instead of UFH + inhibitor/Fondaparinux: Bivalirudin instead of UFH + GP IIb/IIIa inhibitor.GP IIb/IIIa inhibitor.

NSTE-ACS - Non-ST-elevation Acute Coronary Syndrome, s.c. – subcutaneous, TIA – Transient Ischaemic Attack, NSTEMI – Non-ST-elevation Myocardial Infarction, UFH – Unfractionated NSTE-ACS - Non-ST-elevation Acute Coronary Syndrome, s.c. – subcutaneous, TIA – Transient Ischaemic Attack, NSTEMI – Non-ST-elevation Myocardial Infarction, UFH – Unfractionated Heparin, IU – International Units, i.v. – Intravenous, ESC – European Society of Cardiology, ACC – American College of Cardiology, AHA – American Heart Association, NICE - National Heparin, IU – International Units, i.v. – Intravenous, ESC – European Society of Cardiology, ACC – American College of Cardiology, AHA – American Heart Association, NICE - National Institute for Health and Care Excellence, LD – Loading Dose, MD – Maintenance Dose, BID – Twice daily, PCI – Percutaneous Coronary Intervention,, DAPT – Dual Antiplatelet therapy, Institute for Health and Care Excellence, LD – Loading Dose, MD – Maintenance Dose, BID – Twice daily, PCI – Percutaneous Coronary Intervention,, DAPT – Dual Antiplatelet therapy, DES – Drug Eluting Stent, PPI – Proton Pump Inhibitor, CV – Cardiovascular, CABG – Coronary Artery Bypass Grafting, BMS – Bare Metal Stent, LMWH - Low Molecular Weight Heparin, DES – Drug Eluting Stent, PPI – Proton Pump Inhibitor, CV – Cardiovascular, CABG – Coronary Artery Bypass Grafting, BMS – Bare Metal Stent, LMWH - Low Molecular Weight Heparin,

CrCl – Creatinine Clearance, h – hour, ACT – Activated Clotting TimeCrCl – Creatinine Clearance, h – hour, ACT – Activated Clotting Time

ESC 2015ESC 2015 ACC/AHA 2014ACC/AHA 2014 NICE 2010NICE 2010

[Adapted from Roffi M et al.,[Adapted from Roffi M et al.,55 Amsterdam EA et al., Amsterdam EA et al.,1717 NICE 2010 NICE 20104646]]


ACS, enoxaparin showed a slightly signifi cant reduction (-10%) in the combined endpoint of death or MI at 30 days without any signifi cant impact on major bleeds after 7 days.51 In ACS patients undergoing PCI, enoxaparin showed signifi cantly better effi cacy than UFH, with relative risk reduction of 33%, 32%, 25% and 20% in death, composite of death or MI, complications of MI and major bleeds, respectively. The impact was even more profound in those undergoing primary PCI, with relative risk reduction in death being 48% and that in major bleeding being 28%.49

3. Fondaparinux: Fondaparinux is a pentasaccharide which specifi cally binds antithrombin in a reversible manner and with high affi nity, decreasing thrombin generation. It has 100% bioavailability, can be given once daily and does not need any monitoring with minimal fear of HIT.52 It has the most favourable effi cacy-to-safety profi le amongst all parenteral anticoagulants and can be used in all NSTE-ACS patients except for those undergoing coronary angiography. The dose in ACS is 2.5 mg s.c. once daily and its use is contraindicated when Glomerular Filtration Rate (GFR) <20 mL/min/1.73m2. In the OASIS-5 study, NSTE-ACS patients (n=20,078) were treated with fondaparinux 2.5 mg s.c. once daily or enoxaparin. Both had a similar impact on ischaemic events (death, MI or refractory ischaemia at 9 days). However, fondaparinux signifi cantly reduced in-hospital major bleeds by nearly 50%, 30-day mortality by 17% and 6-month mortality by 11%, compared to enoxaparin.53 In the OASIS-5 patients who underwent PCI too, there was a signifi cantly lower rate of major bleeding complications, irrespective of concomitant GP IIb/IIIa treatment. Catheter thrombus was seen more often with fondaparinux vs enoxaparin (0.9% vs 0.4%) but that was taken care by administering empirically determined bolus of

UFH. Hence, a standard UFH bolus is recommended at the time of PCI in patients pre-treated with fondaparinux. When fondaparinux is not available, enoxaparin (1 mg/kg s.c. twice daily) or UFH can be used as alternatives.

4. Bivalirudin: Bivalirudin binds directly to thrombin (both fi brin-bound and fl uid-phase) and indirectly inhibits formation of fi brin. Its anticoagulation impact is more predictable than UFH and has a half-life of 25 min after cessation of the infusion. In NSTE-ACS patients (n=13,819) from the ACUITY trial45, a bivalirudin dose of 0.1 mg/kg i.v. bolus followed by an infusion of 0.25 mg/kg/h was used for those undergoing early invasive treatment. In patients undergoing PCI, an additional i.v. bolus of 0.5 mg/kg bivalirudin was administered prior to the procedure and the infusion dose was increased to 1.75 mg/kg/h and stopped post-procedure. The 3 treatment groups included (a) UFH/LMWH + GP IIb/IIIa inhibitor, (b) Bivalirudin + GP IIb/IIIa inhibitor or (c) Bivalirudin with bailout use of GP IIb/IIIa inhibitor. There was no signifi cant diff erence between group (a) and (b) for the composite ischaemia endpoint at 30 days [death, MI or unplanned revascularisation) or major bleeds. Group (c) was non-inferior to group (a) for the composite ischaemia endpoint, but major bleeds were reduced, as discussed earlier. In the Intracoronary Stenting and Anti-thrombotic Regimen–Rapid Early Action for Coronary Treatment (ISAR-REACT) 3 study, bivalirudin was directly compared to UFH alone (140 IU/kg) in stable CAD patients as well as biomarker-negative NSTE-ACS patients undergoing PCI. The rates of death, MI and urgent revascularisation at 30 days were comparable in both arms but bleeding events were relatively reduced by 34% with bivalirudin.54 It is thus recommended as an alternative to UFH + GP IIb/IIIa during PCI at a dose of 0.75 mg/kg i.v. bolus,

followed by 1.75 mg/kg/h (up to 4 h post-procedure).

Anticoagulation after the acute phase with rivaroxaban (the factor Xa inhibitor at the dose of 2.5 mg/bid) vs placebo has been assessed in the study Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Aspirin with or without Thienopyridine Therapy in Subjects with Acute Coronary Syndrome–Thrombolysis in Myocardial Infarction (ATLAS ACS 2-TIMI 51) in ACS patients (n= 15,526) for a mean of 13 to 31 months. The comparative risk of the primary composite endpoint of death from CV causes, MI or stroke was reduced by 16% with rivaroxaban. The 2.5 mg bid dose also signifi cantly reduced the rates of death both from all causes (2.9% vs 4.5% with placebo, p=0.002) and CV causes (2.7% vs 4.1% with placebo, p=0.002). This survival benefi t was not seen with the 5 mg bid dose. Moreover, compared to placebo, rivaroxaban increased the rates of major bleeding not related to CABG (2.1% vs. 0.6%, p<0.001) and intracranial haemorrhage (0.6% vs. 0.2%, p=0.009), but did not have a signifi cant impact on fatal bleeding.55 Based on this study, European Medicines Agency (EMA) has approved rivaroxaban (2.5 mg twice daily) for anticoagulation in NSTEMI and STEMI patients after the acute phase. Rivaroxaban 2.5 mg twice daily, can be considered in combination with aspirin and clopidogrel in NSTEMI patients with high ischaemic and low bleeding risks, if

Table 7: 10 Commandments of NSTE-ACS1. 1. Any chest pain : Attend immediatelyAny chest pain : Attend immediately2. 2. ECG should be taken and seen ECG should be taken and seen

immediatelyimmediately3. 3. Compare with Old ECGsCompare with Old ECGs4. 4. Send cardiac biomarkersSend cardiac biomarkers5. 5. In case of ACS, initiate In case of ACS, initiate

pharmacotherapy immediatelypharmacotherapy immediately6. 6. No THROMBOLYSIS for NSTE-ACSNo THROMBOLYSIS for NSTE-ACS7. 7. Transfer the patient immediately to Transfer the patient immediately to

ICU/CCUICU/CCU8. 8. Alert Cardiologist, Intensivist and Alert Cardiologist, Intensivist and

InstituteInstitute9. 9. Alert Cath Lab in in case of very high-Alert Cath Lab in in case of very high-

risk ACSrisk ACS

10. 10. Follow the GDMT protocolsFollow the GDMT protocols


REVIEW ARTICLE

ticagrelor and prasugrel are not available. It can be continued for up to 1 year after cessation of parenteral anticoagulation. It is contraindicated in those with a prior history of ischaemic stroke/TIA and is to be used with caution in those >75 years of age or <60 kg bodyweight.

CONCLUSION The diagnosis of NSTEMI is one of exclusion and no decision in its management can be made without assessing the ischaemic and bleeding risks. Symptomatic relief followed by appropriate antiplatelet and anticoagulant therapy form the crux of the early management of NSTEMI. Associated risk assessment helps to decide the management strategy to be adopted. The dual weapons of antiplatelet and anticoagulant therapy help to keep both short-term and long-term complications at bay, if used appropriately. In-patient GDMT medical regimens should be continued after discharge. Selection of a medical regimen should be individualized to each patient on the basis of in-hospital fi ndings, risk factors for CAD, drug tolerability, and recent procedural interventions.17 Judicious use of the recommendations from several esteemed organisations assist in making the correct decisions in NSTEMI management.5,17,46

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30. Cairns JA, Gent M, Singer J, Finnie KJ, Froggatt GM, Holder DA, Jablonsky G, Kostuk WJ, Melendez LJ, Myers MG, et al. Aspirin, sulfinpyrazone, or both in unstable angina. Results of a Canadian multicenter trial. N Engl J Med. 1985 Nov 28;313(22):1369-75.

31. Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK; Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators. Effects of Clopidogrel in addition to Aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med. 2001 Aug 16;345(7):494-502.

32. Mehta SR, Yusuf S, Peters RJ, Bertrand ME, Lewis BS, Natarajan MK, Malmberg K, Rupprecht H, Zhao F, Chrolavicius S, Copland I, Fox KA; Clopidogrel in Unstable angina to prevent Recurrent Events trial (CURE) Investigators. Effects of pretreatment with Clopidogrel and Aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study. Lancet. 2001 Aug 18;358(9281):527-33.

33. Matetzky S, Shenkman B, Guetta V, Shechter M, Beinart R, Goldenberg I, Novikov I, Pres H, Savion N, Varon D, Hod H. Clopidogrel resistance is associated with increased risk of recurrent atherothrombotic events in patients with acute myocardial infarction. Circulation. 2004 Jun 29;109(25):3171-5.

34. Simon T, Verstuyft C, Mary-Krause M, Quteineh L, Drouet E, Méneveau N, Steg PG, Ferrières J, Danchin N, Becquemont L; French Registry of Acute ST-Elevation and Non-ST-Elevation Myocardial Infarction (FAST-MI) Investigators. Genetic determinants of response to Clopidogrel and cardiovascular events. N Engl J Med. 2009 Jan 22;360(4):363-75.

35. Wiviott SD, Braunwald E, McCabe CH, Montalescot G, Ruzyllo W, Gottlieb S, Neumann FJ, Ardissino D, De Servi S, Murphy SA, Riesmeyer J, Weerakkody G, Gibson CM, Antman EM; TRITON-TIMI 38 Investigators. Prasugrel versus Clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2007 Nov 15;357(20):2001-15.

36. Wiviott SD, Braunwald E, McCabe CH, Horvath I, Keltai M, Herrman JP, Van de Werf F, Downey WE, Scirica BM, Murphy SA, Antman EM; TRITON-TIMI 38 Investigators. Intensive oral antiplatelet therapy for reduction

of ischaemic events including stent thrombosis in patients with acute coronary syndromes treated with percutaneous coronary intervention and stenting in the TRITON-TIMI 38 trial: a subanalysis of a randomised trial. Lancet. 2008 Apr 19;371(9621):1353-63.

37. Roe MT, Armstrong PW, Fox KA, White HD, Prabhakaran D, Goodman SG, Cornel JH, Bhatt DL, Clemmensen P, Martinez F, Ardissino D, Nicolau JC, Boden WE, Gurbel PA, Ruzyllo W, Dalby AJ, McGuire DK, Leiva-Pons JL, Parkhomenko A, Gottlieb S, Topacio GO, Hamm C, Pavlides G, Goudev AR, Oto A, Tseng CD, Merkely B, Gasparovic V, Corbalan R, Cintez M, McLendon RC, Winters KJ, Brown EB, Lokhnygina Y, Aylward PE, Huber K, Hochman JS, Ohman EM; TRILOGY ACS Investigators. Prasugrel versus Clopidogrel for acute coronary syndromes without revascularization. N Engl J Med. 2012 Oct 4;367(14):1297-309.

38. Wallentin L, Becker RC, Budaj A, Cannon CP, Emanuelsson H, Held C, Horrow J, Husted S, James S, Katus H, Mahaffey KW, Scirica BM, Skene A, Steg PG, Storey RF, Harrington RA; PLATO Investigators, Freij A, Thorsén M. Ticagrelor versus Clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009 Sep 10;361(11):1045-57.

39. Lindholm D, Varenhorst C, Cannon CP, Harrington RA, Himmelmann A, Maya J, Husted S, Steg PG, Cornel JH, Storey RF, Stevens SR, Wallentin L, James SK. Ticagrelor vs. Clopidogrel in patients with non-ST-elevation acute coronary syndrome with or without revascularization: results from the PLATO trial. Eur Heart J. 2014 Aug 14;35(31):2083-93.

40. Steg PG, Harrington RA, Emanuelsson H, Katus HA, Mahaffey KW, Meier B, Storey RF, Wojdyla DM, Lewis BS, Maurer G, Wallentin L, James SK; PLATO Study Group. Stent thrombosis with Ticagrelor versus Clopidogrel in patients with acute coronary syndromes: an analysis from the prospective, randomized PLATO trial. Circulation. 2013 Sep 3;128(10):1055-65.

41. Roffi M, Chew DP, Mukherjee D, Bhatt DL, White JA, Moliterno DJ, Heeschen C, Hamm CW, Robbins MA, Kleiman NS, Théroux P, White HD, Topol EJ. Platelet glycoprotein IIb/IIIa inhibition in acute coronary syndromes. Gradient of benefit related to the revascularization strategy. Eur Heart J. 2002 Sep;23(18):1441-8.

42. O'Donoghue M, Antman EM, Braunwald E, Murphy SA, Steg PG, Finkelstein A, Penny WF, Fridrich V, McCabe CH, Sabatine MS, Wiviott SD. The efficacy and safety of Prasugrel with and without a glycoprotein IIb/IIIa inhibitor in patients with acute coronary syndromes undergoing percutaneous intervention: a TRITON-TIMI 38 (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel-Thrombolysis In Myocardial Infarction 38) analysis. J Am Coll Cardiol. 2009 Aug 18;54(8):678-85.

43. Jolly SS, Faxon DP, Fox KA, Afzal R, Boden WE, Widimsky P, Steg PG, Valentin V, Budaj A, Granger CB, Joyner CD, Chrolavicius S, Yusuf S, Mehta SR. Efficacy and safety of Fondaparinux versus Enoxaparin in patients with acute coronary syndromes treated with glycoprotein IIb/IIIa inhibitors or thienopyridines: results from the OASIS 5 (Fifth Organization to Assess Strategies in Ischemic Syndromes) trial. J Am Coll Cardiol. 2009 Jul 28;54(5):468-76.

44. White HD, Chew DP, Hoekstra JW, Miller CD, Pollack CV Jr, Feit F, Lincoff AM, Bertrand M, Pocock S, Ware J, Ohman EM, Mehran R, Stone GW. Safety and efficacy of switching from either unfractionated heparin or Enoxaparin to Bivalirudin in patients with non-ST-segment elevation acute coronary syndromes managed with an invasive strategy: results from the ACUITY (Acute Catheterization and Urgent Intervention Triage strategY) trial. J Am Coll Cardiol. 2008 May 6;51(18):1734-41.

45. Stone GW, McLaurin BT, Cox DA, Bertrand ME, Lincoff AM, Moses JW, White HD, Pocock SJ, Ware JH, Feit F, Colombo A, Aylward PE, Cequier AR, Darius H, Desmet W, Ebrahimi R, Hamon M, Rasmussen LH, Rupprecht HJ, Hoekstra J, Mehran R, Ohman EM; ACUITY Investigators. Bivalirudin for patients with acute coronary syndromes. N Engl J Med. 2006 Nov 23;355(21):2203-16.

46. Unstable angina and NSTEMI: early management. National Institute for Health and Care Excellence [Internet] 2010 [cited 2019 May 21] Available from https://www.nice.org.uk/guidance/cg94/resources/unstable-angina-and-nstemi-early-management-pdf-975749355205.

47. Valgimigli M, Bueno H, Byrne RA, Collet JP, Costa F, Jeppsson A, Jüni P, Kastrati A, Kolh P, Mauri L, Montalescot G, Neumann FJ, Petricevic M, Roffi M, Steg PG, Windecker S, Zamorano JL, Levine GN; ESC Scientific Document Group ; ESC Committee for Practice Guidelines (CPG) ; ESC National Cardiac Societies . 2017 ESC focused update on dual antiplatelet therapy in coronary artery disease developed in collaboration with EACTS: The Task Force for dual antiplatelet therapy in coronary artery disease of the European Society of Cardiology (ESC) and of the European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J. 2018 Jan 14;39(3):213-260.

48. Eikelboom JW, Anand SS, Malmberg K, Weitz JI, Ginsberg JS, Yusuf S. Unfractionated heparin and low-molecular-weight heparin in acute coronary syndrome without ST elevation: a meta-analysis. Lancet. 2000 Jun 3;355(9219):1936-42.

49. Silvain J, Beygui F, Barthélémy O, Pollack C Jr, Cohen M, Zeymer U, Huber K, Goldstein P, Cayla G, Collet JP, Vicaut E, Montalescot G. Efficacy and safety of Enoxaparin versus unfractionated heparin during percutaneous coronary intervention: systematic review and meta-analysis. BMJ. 2012 Feb 3;344:e553.

50. Collet JP, Montalescot G, Lison L, Choussat R, Ankri A, Drobinski G, Sotirov I, Thomas D. Percutaneous coronary intervention after subcutaneous Enoxaparin pretreatment in patients with unstable angina pectoris. Circulation. 2001 Feb 6;103(5):658-63.

51. Murphy SA, Gibson CM, Morrow DA, Van de Werf F, Menown IB, Goodman SG, Mahaffey KW, Cohen M, McCabe CH, Antman EM, Braunwald E. Efficacy and safety of the low-molecular weight heparin Enoxaparin compared with unfractionated heparin across the acute coronary syndrome spectrum: a meta-analysis. Eur Heart J. 2007 Sep;28(17):2077-86.

52. Reindl I, Schlitt A. Treatment Options in Acute Coronary Syndromes: Focus on Fondaparinux Sodium. Clinical Medicine Insights: Therapeutics 2010:2 869–876.

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Metabolic Syndrome In India: Is It Different ?

REVIEW ARTICLE

AK PANCHOLIA

Keywords metabolic syndrome CVD central obesity Y-Y hypothesis waist circumference hyperinsulinemia

Dr. A K Pancholia, Department of Clinical & Preventive Cardiology, Arihant Hospital & RC, Gumasta Nagar, Indore

AbstractMetabolic syndrome (MetS) is the cluster of several cardiovascular risk factors which is highly prevalent in the country like India because of various lifestyle factors. The prevalence of MetS in India varies according to region, extent of urbanization, lifestyle patterns, and socioeconomic/cultural factors. Recent data show that about one-third of the urban population in large cities in India has the MetS. Apart from that, there is increased prevalence of MetS among migrant Indians. Early occurrence, low body mass index (BMI), less waist circumference (WC), increase, skin fold thickness and high fat percentage in Indians makes MetS different from that of Caucasians.

INTRODUCTIONThe metabolic syndrome is the cluster of risk factors, which predisposes subjects to increased risk of diabetes and cardiovascular disease (CVD).1,2 These risk factors are Hypertension, Insulin resistance, Adiposity and Dyslipidemia. There are various defi nitions proposed for the metabolic syndrome.3 National

Cholesterol Education Program – Adult Treatment Panel III (NCEP-ATP III) and the American Heart Association (AHA)/National Heart Lung and Blood Institute (NHLBI) defi ned the metabolic syndrome as presence of any three out of the fi ve components namely central obesity, raised triglycerides, low HDL, raised plasma glucose and raised blood pressure. On

Figure 1: The New IDF definitionCentral Obesity (Defined as waist circumference *with ethnicity specific values) plus any two Central Obesity (Defined as waist circumference *with ethnicity specific values) plus any two

of the following four factors:of the following four factors: Raised triglycerides Raised triglycerides >150 mg/dL ( >150 mg/dL (≥≥1.7 mmol/L)1.7 mmol/L) Or specific treatment for this lipid abnormality Or specific treatment for this lipid abnormality

Reduced HDL cholesterol Reduced HDL cholesterol <40 mg/dl (<1.03 mmol/L) in males <40 mg/dl (<1.03 mmol/L) in males 50 mg/dL (<1.29 mmol/L) in females 50 mg/dL (<1.29 mmol/L) in females or specific treatment for these lipid abnormalities or specific treatment for these lipid abnormalities

Raised blood pressure Raised blood pressure Systolic BP 130 or diastolic BP Systolic BP 130 or diastolic BP ≥≥85 mmHg85 mmHg Or treatment of previously diagnosed hypertension Or treatment of previously diagnosed hypertension

Raised fasting plasma glucose Raised fasting plasma glucose (FPG) (FPG) ≥≥100 mg/dL (100 mg/dL (≥≥5.6 mmol/L)5.6 mmol/L) Or previously diagnosed type 2 diabetes Or previously diagnosed type 2 diabetes


Figure 2: Indian criteria of MetSRisk factor Defining levelRisk factor Defining level1. Abdominal obesity Waist circumference1. Abdominal obesity Waist circumference Men >90 cm Men >90 cm Women >80 cm Women >80 cm2. Triglycerides 2. Triglycerides ≥≥150 mg/dL150 mg/dL3. HDL cholesterol3. HDL cholesterol Men <40 mg/dL Men <40 mg/dL Women <50 mg/dL Women <50 mg/dL4. Blood pressure >130/ 4. Blood pressure >130/ ≥≥85 mmHg85 mmHg5. Fasting glucose 5. Fasting glucose ≥≥110 mg/dL110 mg/dL

Misra A, et al. J Assoc Physicians India. 2009;57:163–170.Misra A, et al. J Assoc Physicians India. 2009;57:163–170.

the other hand, the International Diabetes Federation (IDF) defi nition includes central obesity as an essential component of the metabolic syndrome in addition to any two of the four above-mentioned components (Figure 1).3

Indian criteria of MetS is almost similar to the IDF criteria (Figure 2). PREVALENCEIn a developing country like India, increasing urbanization and lifestyle changes have led to an increased incidence of diabetes.4 It's projected that, by the year 2030, India will have the most number of diabetic patients worldwide, double the amount from China (which would be second), in addition to the maximum increase in the absolute number of diabetic patients.5 Though a limited amount of data is available on the prevalence of metS in India, prevalence data from the diabetic population is lacking.

The prevalence of metS is increasing exponentially in India, both in the urban and rural areas. It has escalated in diff erent parts of India to fi gures now ranging from 11% to 41%.6 There are diff erences in the prevalence of MetS in India according to diff erent defi nition. In the CURES study, the prevalence of MetS by WHO criteria is 23.2%, by ATP III criteria 18.3% and by IDF criteria it is 24.8%7 Available data indicates that prevalence varies according to the region, extent of urbanization, lifestyle patterns and socio-economic/ cultural factors.

Surveys in large cities in diff erent parts of the country suggest that about one -third of the urban population have MetS.6,8,9 All classical risk factors comprising the MetS are prevalent in Asian Indians

residing in India; 31.4% abdominal obesity, 45.6% hypertriglyceridemia, 65.5% low HDL, 55.4% hypertension, and 26.7% raised fasting plasma glucose have been reported from South India. Data from North India show that 66% of men and 88% of women, classifi ed as “nonobese” on the basis of the international cut-off of body mass index (BMI), had ≥1 cardiovascular risk factors.10 Abdominal obesity is quite prevalent in Asian Indian, with females outnumbering males.6 Several studies have indicated that body fat, abdominal adiposity, and cardiovascular risk are higher in Asian Indian compared to Caucasians at similar BMI and lower average waist circumference (WC) levels.11,12,13 An analysis of the Chennai Urban Rural Epidemiology Study (CURES) study demonstrated that the optimal BMI cut-off point for identifying two cardiometabolic risk factors was 23 kg/m2 for Indians of both sexes and a WC of 87 cm for men and 82 cm for women.14 A more recent WHO consultation in 2004 opined that the proportion of Asian Indian people with a high-risk of type 2 diabetes mellitus (T2DM) and CVD is considerable at BMI values lower than the existing WHO cut-off point for overweight (25 kg/m2). A study has reported signifi cantly high odds ratio (OR) for hypertension and hypertriglyceridemia even at a lower WC range (70–80 cm) in Indians.10 Studies have shown that the prevalence of type 2 diabetes is particularly high in Asian Indians, with the prevalence of insulin resistance in healthy, young lean Asian Indian men being three to four times higher than lean men in other ethnic groups.15,16

SUBCUTANEOUS BODY FATA number of studies using skinfold thickness have shown that subcutaneous body fat is thicker in Asian Indians compared to Caucasians across all age groups.17-19 In an Indian study, candidate defi nitions using the criterion of subscapular skinfold thickness (>18 mm) have shown an increase in prevalence of MetS compared to the NCEP ATP III defi nition. However, a candidate defi nition comprising only anthropometric criteria showed poor predictability for MetS in Asian Indians, implying a signifi cant role of the laboratory in diagnosing the same.

INTRAMYOCELLULAR LIPIDStudies indicate that unlike Caucasians, intramyocellular lipid content (IMCL) is not related to insulin resistance in Asian Indians.20-21 It has been shown to be related to excess body fat and abdominal obesity in this population, but the overall signifi cance of IMCL in the pathogenesis of insulin resistance remains to be determined.20

OBSTRUCTIVE SLEEP APNOEA (OSA)Commonly co-occurs with obesity, hypertension, and hyperglycemia, suggesting it to be a part of the syndrome. Despite some evidence, relationship of OSA with insulin resistance independent of obesity remains to be defi nitely established and more investigations in Asian Indians are necessary in this regard.6

NONALCOHOLIC FATTY LIVER DISEASE (NAFLD)

NAFLD is quite prevalent in South Asians and is an important hepatic correlate of insulin resistance and the MetS , with non-alcoholic steatohepatitis often being the fi rst clinical indication of insulin resistance.6,22 Both obese and non-obese Indians with NAFLD have signifi cantly higher insulin resistance compared to those without NAFLD.6

PECULIARITIES OF METS IN INDIANSAsian Indians with MetS are phenotypically distinct from Caucasians. Investigators have shown that compared to Caucasians, Asian Indians have


REVIEW ARTICLE

lower BMI, WC, and muscle mass.23 Studies in South Asian adults as well as children have shown that hyperglycemia, hypertension, and hypertriglyceridemia occur at lower levels of BMI and WC.24,25 This is beautifully epitomized by the Y-Y hypothesis whereby the researchers Yajnik (Indian) and Yudkin (British) were found to have a similar BMI of 22.3 kg/m2, but the body fat percentages in the two diff er widely; 21.2% in Yagnik and 9.1% in Yudkin (Figure 3).26

Other diff erences between Asian Indians and Caucasians include lower disease awareness and health-seeking behavior, delayed diagnosis due to atypical presentation, language barriers, religious and sociocultural factors. All these factors result in poorer prevention, less aggressive therapy, poorer response to medical and surgical interventions, and higher morbidity and mortality. In view of

these data, prevention and management strategies should be more aggressive for Asian Indians for more positive health outcomes. Hence, lower cut-off s of obesity and abdominal obesity for Asian Indians are expected to help physicians in better and more eff ective prevention for MetS and its associated ills, especially diabetes and coronary artery diseases.27

DETERMINANTS OF METS IN INDIANS: The Asian Indians are physically less active compared to other ethnic groups. Increasing usage of computers and mechanization in workplaces and at household work is leading to a sedentary lifestyle. Leisure-time activities have also shifted from outdoor games to indoor entertainment like television and computer games. Importantly, girls and women have been found to

be more sedentary than men.28 Energy dense imbalanced foods (high calories, carbohydrates, saturated fats, and low fi bre) are being consumed increasingly in the Indian subcontinent.29 Asian Indians consume higher carbohydrates as compared with Europeans, and this may lead to hyperinsulinemia, postprandial hyperglycemia, high serum TG, and low HDL levels associated with insulin resistance.30 Overall, increasing carbohydrate and fat intake, along with decreased fi bre intake is likely to contribute to obesity, the MetS, and type 2 diabetes in Asian Indians.31

CONCLUSION In India, the prevalence of obesity,

metabolic syndrome and diabetes is high and rising, especially in the urban setting

Obesity is a major driver for the widely prevalent MetS and T2DM

Despite lower BMI, Indians have---• more abdominal fat• more insulin resistance and

hyperinsulinemia• higher levels of CRP• Lower levels of adiponectin• characteristic atherogenic

dyslipidemia• increased susceptibility to diabetes

and coronary artery disease

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INTRODUCTIONDiabetes mellitus (DM) is a chronic metabolic disorder defi ned by presence of hyperglycemia and/or insulin resistance. DM can be classifi ed as type 1 DM or type 2 DM based on baseline pathology. Currently, diabetes aff ects > 180 million people worldwide. Multiple risk factors are found to be associated with DM which can make diabetics prone to development of coronary artery disease (CAD).

These risk factors are dyslipidemia, hyperglycemia, hypertension, kidney failure and overweight. Owing to all these risk factors, diabetic patients are at increased risk for cardiovascular diseases (CVD). Patients with DM comprise as many as 25-30% of those who undergo revascularisation. The risk of CAD increases two to four fold in diabetics as compared to non-diabetics.1 Diabetics have accelerated atherothrombosis as

Coronary Interventions in Diabetics with Coronary Artery Disease

REVIEW ARTICLE

LEKHA ADIK PATHAK, RONAK V. RUPARELIA

Keywords atherosclerosis CAD type 1 diabetes type 2 diabetes atherothrombosis angiography

Dr. Lekha Adik Pathak is Director of Dept. of Cardiology, Nanavati Superspeciality Hospital, Mumbai; Dr. Ronak V. Ruparelia is Consultant Cardiologist, Bankers Superspeciality Hospital, Vadodara, Gujarat

AbstractCoronary artery disease (CAD) is a major determinant of the long-term prognosis among patients with diabetes mellitus (DM). DM is associated with a 2 to 4-fold increased mortality risk from heart disease. Furthermore, in patients with DM there is an increased mortality after MI, and worse overall prognosis with CAD. Near-normal glycemic control for a median of 3.5 to 5 years does not reduce cardiovascular events. Thus, the general goal of HbA1c <7% appears reasonable for the majority of patients. Iatrogenic hypoglycemia is the limiting factor in the glycemic management of diabetes, and is an independent cause of excess morbidity and mortality. Selection of the optimal myocardial revascularisation strategy for patients with DM and multivessel coronary artery disease is crucial and requires a multidisciplinary team approach (‘heart team’). Percutaneous coronary intervention (PCI) with drug-eluting or bare metal stents is appropriate for patients who remain symptomatic with optimal medical therapy (OMT). Randomized trials comparing multivessel PCI to coronary artery bypass grafting (CABG) have consistently demonstrated the superiority of CABG in reducing mortality, myocardial infarction and the need for repeat revascularisations.


well as early onset of atherosclerosis.2,3 The atherosclerosis related to DM is more diff use, extensive, complex and rapidly progressive as compared to non-diabetics. Coronary angiogram in a diabetic is more often complex multivessel CAD. A heart team approach is usually necessary to determine an optimal management strategy. Furthermore, these patients derive less benefi t from the standard therapies of CAD. As a result of these and other factors, diabetic patients with CAD have a lower long-term survival rate than nondiabetic patients with CAD.

The NCEP (National Cholesterol Education Program) report from United States as well as guidelines from Europe considered type 2 DM as CAD equivalent, and considered it as the highest risk category.4,5 This recommendation was based upon the observation that patients with “type 2 DM without a prior MI” were at the same risk for MI (20% and 19%, respectively) and coronary mortality (15% vs 16%) as compared to patients “without DM with prior MI”.6

Coronary interventions in diabetics with CAD is an important therapeutic intervention for the improvement of symptoms and prognosis. The indication for revascularisation, medical stabilization and revascularisation options remains similar in patients with and without diabetes. Prior to revascularisation, patients must receive guideline recommended medical therapy.7,8 Best revascularisation results achieved with percutaneous coronary intervention (PCI) are with new generation drug eluting stents (DES).7,8 CABG results in more complete revascularization than PCI, particularly in complex multivessel CAD, which is frequently observed in patients with diabetes. The short- and long-term results of revascularisation with PCI or CABG surgery are often worse in diabetic patients. However, as the technology, techniques and experience of operators in PCI are evolving, the understanding of revascularisation strategies and patterns of clinical practice are changing.

Despite improved outcome, the gradient of increased risk of mortality and morbidity as compared with non-diabetics persists throughout the spectrum

of CAD. Both types of revascularisation strategies have been evaluated extensively. Preoperative mortality, repeat revascularisation and long-term mortality are the issue of concern.

PATHOPHYSIOLOGYLong-standing hyperglycemia induces infl ammation in the vessel wall, promoting atherosclerosis and abnormal vascular fi ndings (e.g. earlier onset, higher degree, and more disseminated and aggressive) are much more common in diabetics compared with individuals without diabetes.9 Impaired fi brinolytic system balance and abnormalities of platelet structure and function results in a persistent prothrombotic milieu.10 Various adverse eff ects induced by hyperglycemia are as follows:A. Metabolic factors: Endothelial

dysfunction, vascular eff ects of advanced glycation end products, adverse eff ects of circulating free fatty acids and increased systemic infl ammation.

B. Vascular anatomic characters: More frequent diff use disease, higher prevalence of extensive CAD, left main disease and multivessel disease. The narrow calibre vessels are associated with impaired collateral development.

C. Adverse prothrombotic milieu and high atherosclerotic burden: Diabetics have a higher atherosclerotic burden and plaques, which are high-risk and vulnerable to rupture.11 Proteofi brinolytic system and platelet biology are also unfavourably altered in diabetes.

REVASCULARISATION STRATEGIES IN DIABETICS (CABG OR PCI??):As indicated by number of studies in past, CABG should be the preferred strategy for multivessel revascularisation in diabetics. It tends to improve survival, reduce risk of myocardial infarction and the need for repeat revascularisation as compared to PCI.7,8

CARDIa (Coronary Artery Revascularisation in Diabetes) trial12 was the fi rst randomized trial in diabetics with CAD. It did not show any signifi cant

superiority for CABG compared with PCI. However, the study was underpowered (510 patients only).

A subgroup (452 patients) analysis of SYNTAX13 trial also demonstrated survival benefi t to the patients undergoing CABG. Diabetics had higher mortality after paclitaxel-eluting stents (PES) use in highly complex lesions, that is, SYNTAX score >33.

FREEDOM trial14 was the fi rst study (1900 patients) which clearly demonstrated that CABG should be the preferred strategy of revascularisation in patients with diabetes and multivessel disease. Patients who underwent CABG had reduced risk of composite endpoint of death from any cause, nonfatal myocardial infarction or nonfatal stroke during 5 years follow-up. FREEDOM was a landmark trial which concluded that CABG was better, regardless of SYNTAX score, number of diseased vessels, ejection fraction, race or sex of the patient.

A recently published meta-analysis15 from 8 trials, comprising 3612 patients with diabetes and multivessel stable CAD, compared revascularisation by PCI or CABG in terms of all cause mortality. At 5 year follow-up, patients who underwent CABG had lower all-cause mortality than those who underwent PCI and there was no diff erence in outcome observed whether PCI stenting was done with bare metal stent (BMS) or DES.

Taking all randomized studies together, there is to date no study that suggests a survival advantage of PCI over CABG in patients with diabetes and multivessel CAD.

OUTCOME AFTER PCI IN DIABETICS:Balloon angioplasty and BMS: Early studies had shown more procedural complications and in-hospital complications in diabetics. The rate of angiographic success was same as non-diabetics.16 However, patients with diabetes poorly tolerate the ischemic complications of PCI.17 Renal dysfunction after PCI also occurs more frequently in diabetics.18

Drug eluting Stents (DES): DES altered both rate and type of restenosis


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compared with BMS. However, the result was still inferior to that of non-diabetics. The TAXUS IV and SIRIUS trials provided enough evidence favouring DESs and showed reduction of target lesion revascularisation and restenosis rates to the tune of 65%.19,20 Presto (Prevention of REStenosis with Tranilast and its Outcomes) trial showed that diabetics had higher 9-month rate of death, target vessel revascularisation and the composite of death/MI & target vessel revascularisation (TVR).21

BMS vs. DES: DES reduce the rate of angiographic restenosis and need of repeat revascularisation in diabetics. In DIABETES Trial,22 target-lesion revascularisation at 9 months was signifi cantly lower in the sirolimus-eluting stent (SES) group as compared with that in the BMS group. Whether these reduced rates of restenosis translate into mortality benefi t in the complex multivessel PCI in diabetics is unknown.

Sirolimus vs Paclitaxel Eluting Stents: Three major trials were SES wtih PES. ISAR-DIABETES trial23 included patients with angina or a positive stress test and a native vessel culprit lesion (exclusion: ST-segment elevation MI, left main stem [LMS] disease and restenosis). The extent of in-segment late luminal loss was 0.24 mm greater in the paclitaxel-stent group than in the sirolimus-stent group (p=0.002). In the SIRTAX trial24 the major adverse cardiac events (MACE) was less in SES when compared with that in PES patients and this diff erence was more pronounced in diabetics.

Zotarolimus Eluting Stent (ZES): The resolute ZES is a new-generation DES consisting of a thin-strut cobalt alloy BMS coated with a durable biostable polymer and the cell-cycle inhibitor zotarolimus. No DES prior to the resolute has been specifi cally indicated by the US FDA for use in this high-risk population based on 1-year target vessel failure (TVF) outcomes. A meta-analysis of published literature (which included six trials with Cypher SES and Taxus PES) and pooled data for the endeavour ZES showed that at 1 year, the rate of TVF was signifi cantly lower in diabetics treated with ZES. The recent data presented at

the American College of Cardiology25 also report similar results.

WHICH DIABETIC PATIENTS SHOULD UNDERGO PCI?In current scenario, diabetic patients, who remain symptomatic despite Optimal Medical Treatment (OMT) or who have substantial ischemia and severe CAD, PCI may be appropriate. In particular, diabetic patients with focal disease, and a low SYNTAX score of ≤22.26 Favourable long-term outcomes were reported for this subgroup treated with PCI.

Acute Coronary Syndrome: Diabetic patients with acute coronary syndrome (ACS) and focal disease may benefi t from early revascularisation with PCI.26 Diabetic patients with multivessel CAD and ACS refractory to MT should probably have urgent or emergency PCI for the culprit lesion and a Heart Team consultation to discuss whether medical therapy (MT), PCI, or CABG would be most suitable for the remaining signifi cant obstructive CAD.27

Although, surgical revascularisation is the recommended strategy in diabetics with multivessel disease, recent trials have resulted in a changing paradigm for revascularisation strategies.

PRIMARY PCI IN DIABETICSPatients with diabetes more often present with late and with congestive heart failure, after a ST elevation MI. CABG is usually done in cases with mechanical complications or failed PCI. PCI is more eff ective than fi brinolytic therapy. Studies comparing fi brinolytic therapy with primary angioplasty with or without use of GP IIb/IIIa report better short- and long-term outcomes with primary PCI in diabetics. In a recent study of 6315 patients (14% diabetics), 30-day mortality (9.4% vs 5.9%, p=0.001) was higher in patients with diabetes.28 Mortality was lower after primary PCI compared with fi brinolysis in both patients with diabetes (unadjusted OR, 0.49, 95% CI 0.31 to 0.79, p=0.004) and without diabetes (unadjusted OR 0.69, 95% CI 0.54 to 0.86, p=0.001). Recurrent infarction and stroke were also reduced after primary PCI in both patient groups.

After multivariable analysis, primary PCI was associated with decreased 30-day mortality in patients with and without diabetes, with a point estimate of greater benefi t in patients with diabetes. In non-ST MI, patients with acute coronary syndrome, there is no interaction between the eff ect of myocardial revascularisation and diabetic status.29 However, an early invasive strategy was associated with improved outcomes; in TACTICS-TIMI 18, the benefi t in patients with diabetes was greater than in non-diabetics.

FACTORS THAT MAY COMPROMISE PCI SUCCESS30:The hallmarks of DM are hyperglycemia, insulin resistance or an absolute lack of endogenous insulin. These metabolic derangements may lead to premature atherosclerosis, cardiomyocyte dysfunction, and renal failure through several mechanisms.

Diabetic Arteriopathy: In an early stage of atherogenesis, the presence of cholesterol crystals may induce the formation of small hydroxyapatite mineral clefts, which are also called microcalcifi cations, in the intima or media.31 In DM, medial calcifi cation develops independently of hypercholesterolemia and may cause sheet-like calcifi c deposits that reduce vascular compliance.32 The formation of vulnerable atherosclerotic lesions may be related to hyperglycemia or insulin resistance.33 Kuroda, et al., observed that mean amplitude of glycemic excursion was the only independent predictor for the development of thin-cap fi broatheromas, which have been associated with spontaneous plaque rupture and ischemic clinical events.34

Myocardial Dysfunction: An emerging evidence has identifi ed a potential molecular link between insulin resistance and cardiomyopathy. The FoxO group of transcription factors that regulate cell size, viability, and metabolism are targets of insulin and growth factor signalling. FoxO activation is an important factor in the pathogenesis of diabetic cardiomyopathy in the absence of CAD, a similar mechanism may contribute to ventricular dysfunction


in the presence of obstructive CAD as well.35

Chronic Kidney Disease: Hyperglycemia contributes to diabetic nephropathy, a microvascular complication of DM, initially by causing glomerulomegaly and later by inducing mesangial expansion, glomerular basement membrane thickening, and glomerular sclerosis.36 Like DM, chronic kidney disease is associated with the macrovascular complication of medial calcifi cation.

Altered antiplatelet pharmacokinetics: Patients with DM have an impaired response to clopidogrel, but it has been unclear whether this is caused by altered metabolism or an upregulation of the platelet-membrane P2Y12 receptor. Using a comprehensive pharmacokinetic and pharmacodynamic approach, Angiolillo, et al.,37 observed that the active metabolites of clopidogrel were signifi cantly lower in diabetic patients than in nondiabetic patients after a load of 600 mg. The fi ndings suggested that the impaired responsiveness of diabetic patients to clopidogrel is caused by the pharmacokinetic profi le of the drug and less so by an alteration in the functional status of the P2Y12 signalling pathway.

SPECIFIC CHALLENGES IN DIABETIC PATIENTS WHO NEED REVASCULARISATION:Although RCTs are helpful for making broad treatment recommendations, they cannot identify fi ne mechanistic details. A discussion of trial results, viewed against a background of known pathogenetic mechanisms, may explain some of the limitations of PCI and identify approaches to improve outcomes in diabetic patients who need revascularisation.

Diabetic Arteriopathy and PCI Outcomes: Two factors that compromise long-term success after PCI are high rates of restenosis and the development of vulnerable plaques outside stented segments. Almost all trials enrolling diabetic patients, including FREEDOM have reported higher rates of repeat revascularisation after PCI than after CABG. Most studies of diabetic patients

have reported higher rates of MI after PCI than after CABG. These fi ndings suggest that bypass conduits in diabetic patients provide better protection against the future development of clinically important lesions in longer segments of the coronary tree than does spot treatment with stents, despite the theoretical drawback of anastomosing bypass conduits to poor targets in small diabetic vessels.38

A hallmark of diabetic arteriopathy is medial calcifi cation. Although it is diffi cult to quantify angiographically39 coronary calcifi cation may be associated with suboptimal outcomes after PCI. The use of adjunctive ablative therapies for diabetic patients with calcifi ed lesions has undergone limited investigation. An earlier overview of randomized trials suggested that the routine use of ablative therapies does not improve long-term outcomes compared with standard approaches during PCI. Additional studies are needed to compare ablative therapies with standard approaches for diabetic patients with calcifi ed lesions.

A major advance in interventional cardiology has been the development of drug-eluting stents. Bangalore et al reported that survival after implantation of platinum–chromium everolimus-eluting stents might be no diff erent from that after CABG in diabetic patients with multivessel disease. It is important to recognize, however, in the absence of a survival advantage with each successive improvement in stent design in the general population of patients undergoing PCI,40 that survival after spot treatment with everolimus-eluting stents would be unlikely to match the survival rate after CABG in diabetic patients in a prospectively designed randomized trial.

Heart Failure: The presence of systolic dysfunction and multivessel CAD generally favours a recommendation of CABG over PCI to improve survival,27 but the disadvantage of PCI in this setting has not been fully understood. A recent study suggested that a left ventricular ejection fraction of <40% is a risk factor for stent thrombosis.

Chronic Kidney Disease: Patients with chronic kidney disease have been

under-represented in clinical trials. In BARI 2D and FREEDOM, patients were excluded if serum creatinine exceeded 2 mg/dL. Like DM, chronic kidney disease is associated both with medial calcifi cation and suboptimal outcomes after PCI. In patients with advanced renal failure with or without DM, a recent study found that CABG was associated with a 2- to 3-fold higher risk of causing acute kidney injury in the short term than was PCI,42 but other studies have found that CABG was associated with a greater survival benefi t in the long term. Although current data might be more robust for CABG than for PCI in observational studies of patients with chronic kidney disease and multivessel CAD, no dedicated RCTs have been completed in this patient population.

Altered Pharmacokinetics: Given the impaired metabolism of clopidogrel in diabetic patients, many investigators have performed subgroup analyses of RCTs to evaluate alternative P2Y12 inhibitors. In TRITON TIMI 38 trial,43 lower rates of cardiovascular death, nonfatal MI, or nonfatal stroke were seen with prasugrel than with clopidogrel in patients with DM (12.2% versus 17.0%), without DM (9.2% vs 10.6%), and without increased major bleeding (2.6% vs 2.5%).

In PLATO trial,44 lower rates of all-cause mortality (HR, 0.82; 95% CI, 0.66–1.01) and stent thrombosis were seen with ticagrelor than with clopidogrel, without increased major bleeding. In this study, the absence of P2Y12 blocker therapy was the strongest predictor of ST, and the presence of DM itself was a major risk factor for ST (adjusted odds ratio, 1.82; 95% CI, 1.02–3.24).

Although the 2011 PCI guideline did not specify a preference of one P2Y12 agent over another, the more potent agents might be considered in diabetic patients undergoing PCI. Clinicians should recognize, however, that the potent P2Y12 receptor antagonists are not a panacea without complications, contraindications, or cost. Patients with DM will continue to have a higher risk of ischemic events than patients without DM, apart from the P2Y12 antagonist used.44


REVIEW ARTICLE

Glycemic Control: Using data from the FREEDOM trial, Dangas et al observed that the composite rate of death, MI, or stroke was higher in insulin-treated patients than in diabetic patients not treated with insulin. Moreover, the comparative advantage of CABG over PCI in lowering the primary endpoint was seen both in insulin-treated patients (24.3% vs 32.2%) and in diabetic patients not requiring insulin (15.6% vs 23.2%). A time-to-event analysis suggested that cardiovascular risk was related to the duration of DM, with event rates being higher in patients with DM of duration ≥9 years than in those with DM of duration <9 years. These results suggest that CABG is favoured over PCI for insulin-dependent or long-term diabetics. On the other hand, an analysis of the survival curves suggests that PCI is favoured over CABG for patients with a limited prognosis of <3 years because the event curves in the FREEDOM trial did not begin to separate and favour CABG over PCI until 2 to 4 years after revascularisation.45

In ADVANCE trial, there was no signifi cant eff ect of the type of glucose control on major macrovascular events, death from cardiovascular causes, or death from any cause.46

GUIDELINES-BASED APPROACHRevascularisation guidelines for the management of stable CAD emphasize two treatment goals, namely, reduction of death or MI and symptom relief.47,48,49,50 In routine practice, CAD patients, particularly those with type 2 diabetes mellitus (T2DM) and severe angina, are more likely to have an expedited assessment of ischemic burden which, in turn, often leads to cardiac catheterization followed by PCI or CABG often without a full assessment of the eff ects of OMT.51 Conversely, patients with less severe or minimal angina understandably may be more accepting of an initial strategy of OMT, choosing to defer “upfront” revascularisation, particularly CABG, unless symptom status dictates the need subsequently.

Contemporary PCI guidelines52 emphasize the long-term survival benefi t of CABG over PCI in diabetics

with multivessel disease. However, individual clinician judgment on the revascularisation strategy remains an important decisive factor. Although PCIs with DES have narrowed the gap with surgery, the eff ectiveness of PCI in CABG-eligible diabetic patients with stable multivessel disease is still not clear. Primary PCI is preferred over fi brinolysis if it can be performed within recommended time frame (class I, level of evidence-a). The use of DES is recommended to reduce restenosis and repeat TVR (class I, level of evidence-a). CABG should be considered when the extent of the CAD justifi es a surgical approach (especially multivessel disease), and the patient’s risk profi le is acceptable (class II, level of evidence-A).

CONCLUSIONPeople with diabetes have an increased risk for CAD compared with people without diabetes. Coronary angiography often reveals complex multivessel CAD in patients with diabetes, addressing an important challenge for the best revascularization options, in which strong evidence supports the use of CABG over PCI.

Interventional cardiologists currently

have a diff erent perspective about treating diabetic patients with PCI than they had in 1997 when the BARI sub-study was published. Current evidence suggests that the development of vulnerable lesions, impaired left ventricle function, altered thienopyridine metabolism, renal failure, and the use of exogenous insulin impair the response to PCI. To optimize outcomes after PCI or CABG in diabetic patients, physicians recognize that a revascularisation procedure is one component of a comprehensive strategy involving cardiac rehabilitation, blood pressure control, smoking cessation, statins for lipid lowering, and angiotensin-converting enzyme inhibitors to prevent renal failure; but many challenges remain. Using PCI to treat patients with DM will become better understood and develop into a logical science if additional research can elucidate the molecular links between the metabolic derangements and the clinical manifestations of DM and if dedicated clinical trials continue to inform the best practices.

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41. Chan W, Ivanov J, Ko D, Fremes S, Rao V, Jolly S, Cantor WJ, Lavi S, Overgaard CB, Ruel M, Tu JV, Dž aví k V. Clinical outcomes of treatment by percutaneous coronary intervention versus coronary artery bypass graft surgery in patients with chronic kidney disease undergoing index revascularization in Ontario. Circ Cardiovasc Interv. 2015;8:e001973.

42. Chang TI, Leong TK, Boothroyd DB, Hlatky MA, Go AS. Acute kidney injury after CABG versus PCI: an observational study using 2 cohorts. J Am Coll Cardiol. 2014;64:985–994.

43. Wiviott SD, Braunwald E, Angiolillo DJ, Meisel S, Dalby AJ, Verheugt FW, Goodman SG, Corbalan R, Purdy DA,


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Murphy SA, McCabe CH, Antman EM; TRITON-TIMI 38 Investigators. Greater clinical benefit of more intensive oral antiplatelet therapy with prasugrel in patients with diabetes mellitus in the trial to assess improvement in therapeutic outcomes by optimizing platelet inhibition with prasugrel-Thrombolysis in Myocardial Infarction 38. Circulation. 2008;118:1626–1636.

44. James S, Angiolillo DJ, Cornel JH, Erlinge D, Husted S, Kontny F, Maya J, Nicolau JC, Spinar J, Storey RF, Stevens SR, Wallentin L; PLATO Study Group. Ticagrelor vs. clopidogrel in patients with acute coronary syndromes and diabetes: a substudy from the PLATelet inhibition and patient Outcomes (PLATO) trial. Eur Heart J. 2010;31:3006–3016.

45. Farkouh ME, Domanski M, Sleeper LA, Siami FS, Dangas G, Mack M, Yang M, Cohen DJ, Rosenberg Y, Solomon SD, Desai AS, Gersh BJ, Magnuson EA, Lansky A, Boineau R, Weinberger J, Ramanathan K, Sousa JE, Rankin J, Bhargava B, Buse J, Hueb W, Smith CR, Muratov V, Bansilal S, King S III, Bertrand M, Fuster V; FREEDOM Trial Investigators. Strategies for multivessel revascularization in patients with diabetes. N Engl J Med. 2012;367:2375–2384.

46. Patel A, MacMahon S, Chalmers J, Neal B, Billot L, Woodward M, Marre M, Cooper M, Glasziou P, Grobbee D, Hamet P, Harrap S, Heller S, Liu L, Mancia G, Mogensen

CE, Pan C, Poulter N, Rodgers A, Williams B, Bompoint S, de Galan BE, Joshi R, Travert F; The ADVANCE Collaborative Group. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358:2560–2572.

47. S.D. Fihn, J.C. Blankenship, K.P. Alexander, J.A. Bittle, J.G. Byrne, et al., 2014 ACC/AHA/AATS/PCNA/SCAI/STS focused update of the guideline for the diagnosis and management of patients with stable ischemic heart disease: a report of the American college of cardiology/American heart association task force on practice guidelines, and the American association for thoracic surgery, preventive cardiovascular nurses association, society for cardiovascular angiography and interventions, and society of thoracic surgeons, Circulation 130 (19) (2014) 1749e1767.

48. G.B. Mancini, G. Gosselin, B. Chow, W. Kostuk, J. Stone, et al., Canadian Car- diovascular Society guidelines for the diagnosis and management of stable ischemic heart disease, Can. J. Cardiol. 30 (8) (2014) 837e849.

49. Task Force Members, G. Montalescot, U. Sechtem, S. Achenbach, F. Andreotti, et al., 2013 ESC guidelines on the management of stable coronary artery disease: the Task Force on the management of stable coronary artery disease of the European Society of Cardiology, Eur. Heart J. 34 (38) (2013) 2949e3003.

50. M.R. Patel, J.H. Calhoon, G.J. Dehmer, J.A. Grantham, J.M. Maddox, et al., ACC/ AATS/AHA/ASE/ASNC/SCAI/SCCT/STS 2017 appropriate use criteria for coronary revascularization in patients with stable ischemic heart disease: a report of the American college of cardiology appropriate use criteria task force, American association for thoracic surgery, American heart association, American society of echocardiography, American society of nuclear Cardiology, society for cardiovascular angiography and interventions, society of cardiovascular Computed tomography, and society of thoracic surgeons, J. Am. Coll. Cardiol. 69 (17) (2017) 2212e2241.

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Understanding the PATHWAY-3 Study: Adding Amiloride to Hydrochlorothiazide Prevents Glucose Intolerance and Improves Blood Pressure

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JPS SAWHNEY

Keywords hypertension hydrochlorothiazide amiloride glucose intolerance hypokalemia

AbstractOne of the main risk factors for cardiovascular disease is hypertension, and it has shown an increasing prevalence over the past few years owing to lifestyle changes, dietary factors, etc. Although thiazide diuretics have been recommended by several guidelines as the fi rst-line treatment for hypertension, there remains concern over the metabolic changes induced by treatment with this class of antihypertensives. In particular, thiazide diuretics such as hydrochlorothiazide have been noted to increase blood glucose levels, likely in correlation with a decrease in serum potassium. One strategy to combat this adverse effect is the addition of potassium-sparing diuretics such as amiloride which maintain serum potassium levels, and thus prevent the development of glucose intolerance. The PATHWAY-3 study compared the effect of hydrochlorothiazide monotherapy, amiloride monotherapy and hydrochlorothiazide plus amiloride on blood pressure, blood glucose and other metabolic parameters. The study conclusively showed that the combination effectively lowered blood pressure while maintaining potassium and glucose levels, compared with hydrochlorothiazide alone. This review covers the adverse metabolic changes effected by hydrochlorothiazide, and the utility of adding amiloride to this thiazide diuretic for the effective management of hypertension.

Dr. JPS Sawhney is the Senior Consultant Cardiologist, Chief Clinical and Preventive Cardiology, Chairman Department of Cardiology and member Board of Management at Sir Ganga Ram Hospital, New Delhi, India.

INTRODUCTIONEssential hypertension (HTN) is the most common type of HTN, aff ecting 95% of hypertensive patients. It tends to be familial and is likely to be the

consequence of an interaction between environmental and genetic factors.1 HTN is the most common modifi able risk factor for cardiovascular disease (CVD) and death. However, resistant


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HTN develops in 10% to 15% of the general hypertensive population, wherein blood pressure (BP) is uncontrolled on ≥3 antihypertensive drugs of diff erent classes, including a non-potassium-sparing diuretic, at optimal doses, or requiring ≥4 drugs to achieve control. Furthermore, ≈0.5% of hypertensive patients have refractory HTN, which is defi ned as uncontrolled BP on ≥5 drugs.2

In India, HTN is the most important risk factor for chronic disease burden. HTN is present in 25–30% of urban adults and 10–20% of rural adults. The Fourth National Family Health Survey (NFHS-4) was a survey of 699,866 households. The prevalence of HTN among the younger age group (men 15–49 years, women 15–54 years) was 13.6% in men, 8.8% in women and 11.3% overall. Urban India has a signifi cantly higher prevalence of HTN compared with rural India (men 15.1% vs. 12.6%, women 9.6% vs. 8.5%, p<0.01). Pooled data from District Level Household Survey-4 (DLHS-4) and Annual Health Survey (AHS) found that the unadjusted prevalence of HTN was 25.3% (men 27.4%, women 23.6%). Once again, the prevalence was higher in urban adults than rural adults. HTN is prevalent across all socioeconomic groups in the country.3

DIURETICS FOR THE MANAGEMENT OF HYPERTENSIONDiuretics are an invaluable and heterogeneous class of agents commonly used in the treatment of HTN.4 However, their eff ectiveness does not always relate to their diuretic eff ect.5 Diuretics function initially by blocking sodium reabsorption in various sites within the renal tubules.4 Guidelines from the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC) recommend

thiazide diuretics for most patients with HTN.6 In fact, most guidelines recommend thiazide diuretics as a fi rst-line treatment option.7 Thiazide diuretics decrease peripheral vascular resistance by an unknown mechanism and thereby lower BP.5 The site of action is the cortical portion of the ascending loop of Henle´ and the distal convoluted tubule where they inhibit sodium and chloride re-absorption by inhibiting the electroneutral Na+–Cl- symport. Initially, thiazides decrease extracellular fl uid (ECF) and cardiac output, but the ECF gradually returns to near normal over the course of several weeks-to-months.5 The cardiovascular benefi ts of thiazide diuretics are evident through reduction in cardiovascular events in hypertensive patients, even when given at low doses.4

HYPOKALEMIA AND GLUCOSE INTOLERANCE: WHERE THIAZIDE DIURETICS FAILRandomized trials have demonstrated that thiazide diuretics increase fasting plasma glucose in hypertensive patients compared with non-thiazide agents, placebo or no treatment.8 Studies have also found absolute diff erences of 1% and 3% in new-onset diabetes between angiotensin-converting enzyme (ACE) inhibitors, calcium-channel blockers (CCBs), and diuretics.9 There are reports of increases in HbA1c and worsening of 2-hour oral glucose tolerance.10 The development of glycemic changes could be linked to hypokalemia which occurs on treatment with thiazide diuretics.9 Studies have reported that K+ replacement corrects glucose intolerance.6,9 Analysis of the Systolic Hypertension in Elderly Program clinical trial found that each 0.5 mEq decrease in potassium was associated with a 45% higher

adjusted risk of diabetes, primarily occurring within the fi rst year of treatment.10 Additionally, for every 1-mEq/L decrease in K+, there is an approximately 10 mg/dL increase in glucose.11 One retrospective meta-analysis showed that thiazide diuretics led to a reduction in serum potassium by 0.23 mmol/L, and an increase in glucose by 3.26 mg/dL. In contrast, studies where supplementation was not given found a greater reduction in serum potassium (0.37 mmol/L) and increase in serum glucose (6.01 mg/dL). This diff erence was statistically signifi cant (p<0.03).12

Thiazide diuretics act mainly at the distal convoluted tubule, where the NaCl co-transporter is blocked, resulting in impaired Na+ and Cl-

reabsorption, increased delivery of Na+ to collecting ducts, enhanced exchange of Na+ and K+, and K+ wasting.4 Hyperglycemia and carbohydrate intolerance have been related to diuretic-induced hypokalemia which inhibits insulin secretion by the β-cells, and reductions in ECF volume and cardiac output. This is compounded by increase in catecholamines from sympathetic nerve activity which decrease peripheral glucose utilization.13

POTASSIUM-SPARING DIURETICS: AMILORIDEA major attraction of K+-sparing diuretics is the possibility that they will off set the diabetogenic potential of thiazides.14 Potassium-sparing diuretics act at the cortical collecting duct. The mechanism of action of amiloride (a pteridine analog) is to inhibit reabsorption by the epithelial Na+ channel (ENaC) of the collecting duct.4 It decreases the number of open ENaCs.5 Because only 3% of the fi ltered Na+ is reabsorbed at the collecting duct, these drugs do not


result in appreciable diuresis and lead to minimal antihypertensive effi cacy as monotherapies.

Instead, they are often used with other agents to correct K+ defi ciency. Inhibition of sodium reabsorption thus also leads to reduced excretion of K+.4,5

THE PATHWAY-3 STUDY: COMBINING HYDROCHLOROTHIAZIDE WITH AMILORIDEDiuretics are no longer used at doses achieving maximum reduction in BP. This is because of the evidence that higher doses are associated with

increased risk of diabetes mellitus (DM). The risk may be due to K+-depletion, and could be avoided by using potassium-sparing diuretics. Thus, it is hypothesized that the use of low-dose thiazide combined with a K+-sparing diuretic may achieve similar BP reduction, but with an improved


REVIEW ARTICLE

glucose tolerance compared to a high-dose thiazide. PATHWAY-3 (Prevention and Treatment of Hypertension With Algorithm based Therapy) was conducted to evaluate this hypothesis.14

This was a parallel-group, randomized, double-blind, multicenter phase-IV trial comparing three treatment strategies in patients with HTN, and at least one other component of the metabolic syndrome. The most common other component of the metabolic syndrome was central obesity, which was present in 99% of patients. A total of 663 adult patients (aged 18-80 years) were screened, of whom 486 were randomized. After a one-month run-in period of placebo treatment, patients received either hydrochlorothiazide 25-50 mg (n=146), amiloride 10-20 mg (n=145) or hydrochlorothiazide 12.5-25 mg plus amiloride 5-10 mg (n=150). All patients underwent force-titration to twice the initial dose at 12 weeks. The primary outcome was the diff erence in 2-hour glucose on the oral glucose tolerance test (OGTT) at baseline and 24 weeks. The principal secondary outcome was the diff erence in systolic BP (SBP) between baseline and 24 weeks.14,15

The combination therapy group showed the minimum change in plasma glucose concentration at the 2-hour timepoint during OGTT. The diff erence between the combination group and hydrochlorothiazide group was statistically signifi cant (Figure 1A). At 24 weeks, plasma potassium was unchanged in the combination group, while a dose-dependent increase in concentration was noted in the amiloride group (by 0.63 mmol/L; p<0.0001) and a signifi cant decrease was recorded in the hydrochlorothiazide group (by –0.27 mmol/L; p<0.0001 at 24 weeks) (Figure 1B). A total of 9 patients receiving the combination (8%), and 13 patients (12.6%) in the hydrochlorothiazide group developed DM during the study. The odds ratios (ORs) for developing diabetes compared with the hydrochlorothiazide group were 0.65 (95% confi dence interval [CI] 0.25–1.69) for the combination group and 1.07 (0.43–2.64) for the amiloride group.15

The reduction in BP in the combination group was signifi cantly greater than that in the hydrochlorothiazide group (Figure

2; p=0.0068). In fact, patients in the combination group were more likely to achieve BP control compared with patients in the hydrochlorothiazide group (OR 1.77, 95% CI 1.05 to 2.96, p=0.031). The more effi cacious lowering of BP among patients receiving amiloride plus hydrochlorothiazide compared with either drug alone is likely to be the factor that defi nes the success of the combination in avoiding induction of glucose intolerance.15

Other metabolic parameters were also studied, and it was noted that renin, urea and creatinine were higher in the combination group compared to the hydrochlorothiazide group, while sodium levels were lower (Table 1). The BP reduction in the combination group was associated with a near-doubling of the reactive rise in renin concentrations compared with those in the other two groups. Increasing renin concentrations are a sensitive measure of natriuresis. The authors concluded that the combination of amiloride and hydrochlorothiazide could confer the proven long-term benefi ts of hydrochlorothiazide without the possible downside of glucose intolerance.15


CONCLUSIONThe ideal management of the HTN should not be solely targeted to lowering BP. Rather, management

should also observe the holistic metabolic picture of these patients with the aim of minimizing the risk of cardiac events and progression

to metabolic syndrome. Thus, it is necessary to monitor blood glucose as well as potassium levels, and to tailor the treatment regimen to eff ectively

Table 1. Changes in metabolic parameters during the PATHWAY-3 study15

Time point Amiloride Amiloride +

hydrochlorothiazide Hydrochlorothiazide

Adjusted treatment diff erence; p-value (combination vs.

hydrochlorothiazide)

Renin (mU/L, log base 10)

Baseline 1.20 (1.09–1.31) 1.14 (1.03–1.24) 1.20 (1.11–1.30)

12 weeks 1.67 (1.53–1.80) 1.75 (1.61–1.89) 1.62 (1.50–1.74) 0.21 (0.08 to 0.34); p=0.0018)

24 weeks 1.83 (1.70–1.95) 1.95 (1.82–2.09) 1.74 (1.62–1.86) 0.25 (0.12 to 0.39); p=0.0002

Sodium (mmol/L)

Baseline 139.7 (139.3–140.2) 139.9 (139.5–140.4) 139.7 (139.2–140.2)

12 weeks 138.2 (137.8–138.6) 138.1 (137.7–138.5) 138.9 (138.5–139.3) -1.1 (-1.7 to -0.4);

p=0.0010

24 weeks 138.1 (137.7–138.5) 138.0 (137.5–138.4) 138.6 (138.1–139.0) -0.9 (-1.6 to -0.2);

p=0.0075

Urea (mmol/L)

Baseline 5.36 (5.12–5.60) 5.15 (4.92–5.38) 5.40 (5.15–5.65)

12 weeks 5.90 (5.68–6.12) 6.08 (5.85 –6.32) 6.03 (5.82–6.25) 0.34 (0.05 to 0.64); p=0.024

24 weeks 5.82 (5.59–6.06) 6.21 (5.98–6.44) 6.13 (5.87–6.39) 0.45 (0.14 to 0.76); p=0.0042

Creatinine (μmol/L)

Baseline 77.4 (74.4–80.4) 76.6 (73.3–79.9) 76.7 (73.8–79.6)

12 weeks 79.8 (77.5–82.2) 80.1 (77.6–82.7) 79.3 (76.9–81.6) 2.3 (-0.4 to 4.9); p=0.089

24 weeks 79.7 (77.2–82.3) 80.3 (77.7–83.0) 78.1 (75.6–80.6) 3.8 (1.1 to 6.5); p=0.0057


REVIEW ARTICLE

maintain the metabolic profi le of the patient. Towards this, the addition of the potassium-sparing diuretic namely, amiloride to the thiazide diuretic namely, hydrochlorothiazide would be an eff ective strategy to achieve target BP while also preventing the unintended and undesirable rise in blood glucose. This is especially important as hypertensive patients are already a high-risk group and the development of another cardiovascular risk factor, i.e., glucose intolerance or DM, must be avoided. The PATHWAY-3 study provides evidence in support of this combination through reduction of BP as well as prevention of hypokalemia

and glucose intolerance. Thus, the combination of hydrochlorothiazide and amiloride is useful in hypertensive patients who require a thiazide diuretic.

REFERENCES1. Nandhini S. Essential hypertension – A review. J Pharm Sci

Res. 2014;6(9):305–307.2. Oparil S, Schmieder RE. New approaches in the treatment

of hypertension. Circ Res. 2015;116(6):1074–1095.3. Gupta R, Gaur K, Ram VS. Emerging trends in hypertension

epidemiology in India. J Human Hypertens. 2018; doi: 10.1038/s41371-018-0117-3. [Epub ahead of print]

4. Roush GC, Kaur R, Ernst ME. Diuretics: A review and update. J Cardiovasc Pharmacol Ther. 2014;19(1):5–13.

5. Wile D. Diuretics: A review. Ann Clin Biochem. 2012; 49(Pt 5): 419–431.

6. Carter BL, Ernst ME, Cohen JD. Hydrochlorothiazide versus chlorthalidone. Evidence supporting their interchangeability. Hypertens. 2004;43(1):4–9.

7. Roush GC, Slca DA. Diuretics for hypertension: A review and update. Am J Hypertens. 2016;29(10):1130–1137.

8. Zhang X, Zhao Q. Association of thiazide-type diuretics with glycemic changes in hypertensive patients: A

systematic review and meta-analysis of randomized controlled clinical trials. J Clin Hypertens. (Greenwich). 2016;18(4):342–351.

9. Carter BL, Basile J. Development of diabetes with thiazide diuretics: The potassium issue. J Clin Hypertens. 2005;7(11):638–640.

10. Chatterjee R, Yeh HC, Edelman, et al. Potassium and risk of type 2 diabetes. Exp Rev Endocrin Metab. 2011;6(5):665–672.

11. Palmer BF. Metabolic complications associated with use of diuretics. Semin Nephrol. 2011;31(6):542–552.

12. Zillich AJ, Garg J, Basu S, et al. Thiazide diuretics, potassium, and the development of diabetes: A quantitative review. Hypertension. 2006;48(2):219–224.

13. Wilcox CS. Metabolic and adverse effects of diuretics. Semin Nephrol. 1999;19(6):557–568.

14. Brown MJ, Williams B, MacDonald TM, et al. Comparison of single and combination diuretics on glucose tolerance (PATHWAY-3): Protocol for a randomized double-blind trial in patients with essential hypertension. BMJ Open. 2015;5:e008086.

15. Brown MJ, Williams B, Morant SV, et al. Effect of amiloride, or amiloride plus hydrochlorothiazide, versus hydrochlorothiazide on glucose tolerance and blood pressure (PATHWAY-3): A parallel-group, double-blind randomized phase 4 trial. Lancet Diabetes Endocrinol. 2016;4(2):136–147.


Transient Conversion of Atrial Fibrillation to Sinus Rhythm by Retrograde Conduction of Ventricular Ectopic Beat

ECG OF THE MONTH

SR MITTALKeywords atrial fi brillation ectopic beat electrocardiogram retrograde depolarization

Dr. SR Mittal is Head, Department of Cardiology at Mittal Hospital and Research Centre, Ajmer, Rajasthan

before PVC-3. T wave of PVC-3 is followed by another negative defl ection (x). It is followed by transient conversion of atrial fi brillation to sinus rhythm (SR). Other ventricular ectopics (PVC-1, PVC-2 and PVC-4) were preceded by relatively short pause and did not show second negative defl ection aft er T wave.

We feel that the long pause preceding PVC-3 allowed full recovery of atrio-ventricular node allowing retrograde conduction of PVC-3. Th is resulted in retrograde depolarization of atria manifesting as second negative defl ection (x) aft er T wave of PVC-3 (Figure 2). Retrograde depolarization of atria allowed the sino-atrial node to capture the rhythm. Th is case shows that retrograde conduction of a properly timed ventricular ectopic can revert atrial fi brillation.

INTRODUCTIONWe have observed a transient reversal of atrial fi brillation to sinus rhythm by retrograde conduction of a ventricular ectopic beat.

Patient presented with the complaint of palpitation. Th ere was no history of any discomfort on eff ort. Electrocardiogram confi rmed atrial fi brillation. Functional parameters like 2-dimensional echocardiography, thyroid functions, lipid profi le and blood sugar were normal. During Holter monitoring patient remained in atrial fi brillation. Th ere were an occasional premature ventricular contractions (PVCs)(Figure 1).

Operator selected strip recorded at 10:23:03 (strip 2) shows two ventricular ectopic beats (PVC-2 and PVC-3). PVC-2 is followed by a pause of 1.08 second

Figure 1: Holter recordings showing atrial fibrillation(AF) and occasional ventricular ectopics (PVCs). In strip2, PVC-2 is followed by a pause of 1.08 second. T wave of next ventricular ectopic (PVC 3) is followed by another negative deflection (x). This is followed by transient sinus rhythm (SR).

Figure 2: Diagram explaining the observed findings in strip 2. PVC-2 is blocked in AV node as it was not fully repolarised due to short preceding cycle (marked A). Long pause after PVC-2 (marked B) allowed total recovery of AV node. This allowed retrograde conduction of PVC-3 and transient capture of rhythm by SA node. SAN- Sinoatrial node, AVN- Atrio-ventricular node.


PICTORIAL CME

MONIKA MAHESHWARI

Dr. Monika Maheshwari is Professor, Jawahar Lal Nehru Medical College, Ajmer, Rajasthan

Anomalous Drainage Of Hepatic Vein Directly Into The Right Atrium

Anomalous hepatic venous drainage directly into the right atrium (RA) is rare in adults and known to occur in infants with atrial isomerism, abdominal heterotaxy, and absence of the inferior vena cava (IVC). We report herein one such case, recently found in a male aged 27 years. A normal IVC entered the RA at its normal location, and an abnormal tongue like structure—an “extra Eustachian valve”—was attached near the entry of the anomalous directly draining hepatic vein in the RA wall. We speculate that an aberrant development of the embryonic sinus venosus resulted in this rare anomaly.

Figure 1: Trans thoracic 2D Echocardiogram (subcostal view) showing anomalous directly draining hepatic vein (HV) in the right atrium (RA) with extra Eustachian valve (EV-2)


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-ent throughout, and large enough to remain legible when the

self-explanatory as possible, since many will be used directly in slide presentations. Titles and detailed explanations belong in the legends—not on the illustrations themselves.Photomicrographs should have internal scale markers. Sym-bols, arrows, or letters used in photomicrographs should con-trast with the background.

-companied by written permission to use the photograph.Figures should be numbered consecutively according to the

been published previously, acknowledge the original source and submit written permission from the copyright holder to

authorship or publisher except for documents in the public domain.

-quires color negatives, positive transparencies, or color prints. Accompanying drawings marked to indicate the region

publish illustrations in color only if the author pays the ad-ditional cost.

Legends for Illustrations (Figures): Type or print out legends for illustrations using double spacing, starting on a separate page, with Arabic numerals corresponding to the illustrations. When symbols, arrows, numbers, or letters are used to iden-tify parts of the illustrations, identify and explain each one clearly in the legend. Explain the internal scale and identify the method of staining in photomicrographs.UNITS OF MEASUREMENTMeasurements of length, height, weight, and volume should be reported in metric units (meter, kilogram, or liter) or their decimal multiples.Temperatures should be in degrees Celsius/ Fahrenheit. Blood pressures should be in millimeters of mercury, unless

Journals vary in the units they use for reporting hematologic, clinical chemistry, and other measurements. Authors must

and should report laboratory information in both local and International System of Units (SI). Editors may request that authors add alternative or non-SI units, since SI units are not universally used. Drug concentrations may be reported in ei-ther SI or mass units, but the alternative should be provided in parentheses where appropriate.ABBREVIATIONS AND SYMBOLSUse only standard abbreviations; use of nonstandard ab-breviations can be confusing to readers. Avoid abbreviations in the title of the manuscript. The spelled-out abbreviation followed by the abbreviation in parenthesis should be used

measurement.

Address submissions to:The Publisher

CARDIOLOGY TODAYCIMS Medica India Pvt Ltd,

709, 7th Floor, Devika Tower, Nehru Place, New Delhi-110 019.

Tel: 011-4285 4300, Fax: 011-4285 4310E-mail: [email protected]

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