CAD prevention and challenges

Cardiovascular disease is the leading cause of death among adults worldwide Coronary Disease7.2 million Cancer6.3 million Cerebrovascular Disease4.6 million Acute Lower Respiratory Tract Infections3.9 million Tuberculosis3.0 million COPD (Chronic Obstructive Pulmonary Disease)2.9 million Diarrhoea (Including Dysentery)2.5 million Malaria2.1 million AIDS1.5 million Hepatitis B1.2 million

In 2005, cardiovascular diseases caused 17.5 million deaths worldwide, which is 3.3 times more than AIDS, tuberculosis and malaria combined. The problem is even worse in low-income and middle-income countries; four-fifths of all cardiovascular-related events occur in these parts of the world. Nature Clinical Practice Cardiovascular Medicine sanZ and fusTer february 2009 vol 6 no 2 Lancet 360;

An Alarm Prevalence of CHD: 10% in urban area. Prevalence of CHD: 4% in rural area. JACC 2007;50: fold increase in urban over the last 40 years. Doubled in rural over the past 30 years

CVD 29% Leader in the Causes of Death WHO Lancet 2005;366: OTHERS

INTERHEART: 9 Modifiable factors account for 90% of first-MI risk worldwide Yusuf S et al. Lancet. 2004;364: N = 15,152 patients and 14,820 controls in 52 countries PAR = population attributable risk, adjusted for all risk factors SmokingFruits/ veg ExerciseAlcoholPsycho- social LipidsAll 9 risk factors PAR (%) Diabetes Abdominal obesity Hyper- tension Lifestyle factors 50 Conclusion: Most of the CV Risk factors are modifiable, either by lifestyle modifications or by drugs

CAD & risk factors: their association LDL-C Abnormal TC/HDL ratio Smoking Hypertension DM n= 5748 Indian patients with CAD J Assoc Physicians India Feb;52:103-8

Evidence Based Poly-Portfolio for Secondary Prevention: A Strategy to Reduce Subsequent Event

Aggressive Secondary Prevention: Why? To reduce morbidity & mortality in patients with CAD, aggressive secondary prevention measures have been strongly recommended by multiple guidelines. J Am Coll Cardiol 2004;43:

O O O O 23 studies; subjects with MI (n=14211) followed up till 1980 for mortality; Absence of modern effective treatment

WHO guidelines (2007) for secondary prevention of CAD Statin: it is recommended for all patients with established CHD. Treatment should be continued in the long-term, probably lifelong. Antiplatelet drugs: all patients should be treated with regular aspirin in the absence of contraindications. Treatment should be initiated and continued lifelong. ACE-I: recommended for all patients following MI, which should be initiated as early as possible and continued long-term, probably lifelong. Beta-blockers: recommended in all patients with a history of MI and those with CHD who have developed major left ventricular dysfunction leading to heart failure. Treatment should be continued long-term, probably lifelong.

NICE guidelines All patients should be offered combined treatment with the following: –Statin –ACE-I –Aspirin –Beta-blocker Heart 2007;93:

AHA/ACC guidelines for secondary prevention of CAD Lipid lowering drug: –LDL-C should be < 100mg/dL. –Further reduction of LDL-C to <70mg/dL is reasonalbe. –If baseline LDL-C is ≥100mg/dL, initiate LDL-C lowering drug therapy. Antiplatelet drugs: Start aspirin mg/d and continue indefinitely in all patients unless contraindicated. ACE-I: –Start and continue in all patients with LVEF ≤40% and in those with hypertension, diabetes, or chronic kidney disease, unless contraindicated. –Consider for all patients. Beta-blockers: Start and continue in all patients who have had MI, acute coronary syndrome, or left ventricular dysfunction with or without HF, unless contraindicated. Circulation 2006;113:

Pharmacological therapies: –Statins –β-blockers –ACE-I –Antiplatelet Proven to be effective in secondary prevention of CAD. When coprescribed- additive effects Am J Manag Care 2007;13: Drugs for Poly-Portfolio

Antiplatelet Evidence: Secondary Prevention Antithrombotic Trialist Collaboration. BMJ 2002;324:71–86. Category % Odds Reduction Acute myocardial infarction Acute stroke Prior myocardial infarction Prior stroke/transient ischemic attack Other high risk Coronary artery disease (e.g. unstable angina, heart failure) Peripheral arterial disease (e.g. intermittent claudication) High risk of embolism (e.g. atrial fibrillation) Other (e.g. diabetes mellitus) All trials Control better Antiplatelet better Effect of antiplatelet therapy* on vascular events** *Aspirin was the predominant antiplatelet agent studied **Vascular events include MI, stroke, or death

? What is the right dose of Aspirin? Suggested Loading dose: mg Daily dose: mg Suggested Loading dose: mg Daily dose: mg

Suggested Loading dose: mg Daily dose: mg Suggested Loading dose: mg Daily dose: mg

Drugs for Poly-Portfolio –Antiplatelet –Statins –β-blockers –ACE-I

CAD-Mortality JAMA 1995;274:

New Recommendations for Very High-Risk Patients? NCEP Report 2004 Current ATP III LDL-C goal: <100 mg/dL (2.6 mmol/L) –For very high risk: “optional goal” <70 mg/dL (<1.8 mmol/L) “very high risk” patients defined as those with: –established CVD in addition to multiple major risk factors, uncontrolled risk factors, or multiple risk factors of the metabolic syndrome, and patients with ACS Circulation 2004;110:

Total Cholesterol & CAD JAMA 2000;284:

LaRosa JC et al. NEJM. 2005;352: LDL-C=Low density lipoprotein cholesterol; TNT=Treating to New Targets; HPS=Heart Protection Study; CARE=Cholesterol and Recurrent Events Trial; LIPID=Long-term Intervention with Pravastatin in Ischaemic Disease; 4S=Scandinavian Simvastatin Survival Study LDL-C (mg/dL) TNT (atorvastatin 80 mg/d) TNT (atorvastatin 10 mg/d) HPS CARE LIPID CARE HPS Event (%) 4S Statin Placebo Relationship between LDL Levels and Event Rates in Secondary Prevention Trials of Patients with Stable CHD HMG-CoA Reductase Inhibitor: Secondary Prevention

Drugs for Poly-Portfolio –Antiplatelet –Statins –β-blockers –ACE-I 3 large randomized placebo controlled trials: Bata-blockers in Post-MI Total mortality: by 26% to 36% during long-term followup. Lancet 1981;2:823–7; N Eng J Med 1981;2304:801–7; JAMA 1982;247:1707–14

Phase of Treatment Acute treatment Secondary prevention Overall Total # Patients 28,970 24,298 53, RR of death  -blocker better RR (95% CI) Placebo better 0.87 ( ) 0.77 ( ) 0.81 ( )  -blocker Evidence Antman E, Braunwald E. Acute Myocardial Infarction. In: Braunwald E, Zipes DP, Libby P, eds. Heart Disease: A textbook of Cardiovascular Medicine, 6th ed., Philadelphia, PA: W.B. Sanders, 2001, Summary of Secondary Prevention Trials of  -blocker Therapy CI=Confidence interval, RR=Relative risk

β-blocker recommendation ACC/AHA: Start and continue β-blocker indefinitely in all post MI, ACS, LV dysfunction with or without HF symptoms, unless contraindicated (Class I and evidence A). Circulation 2006;113: and J Am Coll Cardiol 2006;47:

Metoprolol succinate: MERIT-HF Subjects: Patients with CHF (NYHA Cl. II- IV) with EF<40% and history of being admitted for an acute MI (n=1926). Randomized to metoprolol succinate or placebo. Am Heart J 2003;146:721–8

Metoprolol CR/XL in postmyocardial infarction patients with chronic heart failure: Experiences from MERIT-HF Am Heart J 2003;146:721–8

Metoprolol CR/XL in postmyocardial infarction patients with chronic heart failure: Experiences from MERIT-HF Am Heart J 2003;146:721–8 In post-MI patients with symptomatic CHF, - blockade continues to exert a profound reduction in mortality and morbidity in the presence of contemporary management that includes early and late revascularization, angiotensin- converting enzyme inhibitors, aspirin, and statins.

Drugs for Poly-Portfolio –Antiplatelet –Statins –β-blockers –ACE-I

Years Probability of Event ACE-I Placebo OR: 0.74 (0.66–0.83) 0.1 Flather MD, et al. Lancet. 2000;355:1575–1581 SAVE Radionuclide EF  40% AIRE Clinical and/or radiographic signs of HF TRACE Echocardiogram EF  35% ACE Inhibitor Evidence: Post MI with LVD or HF ACE-I=Angiotensin converting enzyme inhibitors, LVSD=Left ventricular systolic dysfunction, MI=Myocardial infarction, OR=Odds ratio 26%

Ramipril and CV events Days of Follow-Up CV death, MI, or stroke (%) 22% RRR, P< Placebo Ramipril HOPE Investigators. NEJM 2000;342: Heart Outcomes Prevention and Evaluation (HOPE) Study ACE-I=Angiotensin converting enzyme inhibitors, DM=Diabetes mellitus, CV=Cardiovascular, HF=Heart failure, LVSD=Left ventricular systolic dysfunction, MI=Myocardial infarction 9,297 patients with DM or vascular disease plus one additional CV risk factor, but without HF or known LVSD randomized to ramipril (10 mg) or placebo for 5 years

HOPE: Heart Outcomes Prevention Evaluation study - RESULTS continued - P Primary outcome and deaths from any cause The Hope Study Investigators.N Engl J Med 2000;342:145–53. Relative risk (95% CI) MI, stroke, or death from cardiovascular causes Death from cardiovascular causes MI Stroke Death from noncardiovascular causes Death from any cause Ramipril n=4645 (%) Placebo n=4652 (%) (0.70–0.86) 0.74 (0.64–0.87) 0.80 (0.70–0.90) 0.68 (0.56–0.84) 1.03 (0.85–1.26) 0.84 (0.75–0.95) <

Relative risks of clinical events for primary and secondary prevention with selected drugs Lancet Aug 19;368(9536): Gaziano A T et al, Lancet 2006

Estimated reduction in the risk of Major CHD events and stroke over a period of 5-years in pts. with statins, antihypertensive, aspirin, and omega-3 Estimated reduction in relative risk of event over 5 year Type of patients Any CHDPost-MIPost- Stroke Major CHD events with combined drug therapy 84%91%77% Major CHD events with addition of lifestyle therapy 92%96% CHD death with combined drug therapy 93% CHD death with addition of lifestyle therapy 97% Stroke with combined drug therapy 83% Major CHD events: nonfatal MI and CHD death Am J Cardiol 2005;95: O Secondary Prevention Poly- Portfolio strategy: compelling suggestion of almost complete elimination of the risk of CHD death in post-MI patients with a combination of drug and lifestyle therapy over 5 years.

Impact of “Poly-Portfolio”, Evidence Based Medical Therapy on Mortality in Patients with ACS Subjects: 1358 patients admitted to or discharge with a diagnosis of unstable angina or acute MI. Use of drugs at discharge: –Antiplatelet: ≈ 95% –β-blockers: ≈ 82% –ACE-I: 60% –Lipid lowering drugs: 84% Circulation 2004;109:

Impact of “Poly-Portfolio”, Evidence Based Medical Therapy on Mortality in Patients with ACS Results: at 6 months No. of drugs* at discharge Odd ratio for deathP value 4 drugs vs. no drug0.10 (95% Cl, drugs vs. no drug0.17 (95% Cl, ) drugs vs. no drug0.18 (95% Cl, ) drug vs. no drug0.36 (95% Cl, )0.20 * Recommended four drugs were: antiplatelet, ACE-I, lipid lowering agents, beta-blocker Circulation 2004;109: % RRR 83% RRR Use of combination evidence- based medical therapies was independently and strongly associated with lower mortality in patients with ACS.

Are we compliant to evidence based therapy?

Am J Manag Care 2007;13: Use of evidence based therapies for CAD has improved but remains suboptimal. Although improved discharge prescription of these agents is needed, considerable attention must also be focused on long-term adherence to therapy.

Statins are underused: International data 46th Annual Meeting of the European Association for the Study of Diabetes (EASD 2010) Roughly a third of patients with type 2 diabetes who are eligible for statin therapy based on standard guidelines are not receiving a statin prescription Only 64% of eligible patients actually received a statin prescription. Statins were even less likely to be used in patients aged younger than 50 years.

Indian Prescription Data* 25% of the Diabetics patients are prescribed Lipid regulators (all specialties put together) 34% of the Diabetics patients are prescribed Lipid regulators if rxns from Diabetologists are considered * Nov-Feb’2010 CMARC Datacubes

Vascular Health and Risk Management 2009:5 1007–1014 Percent use of evidence-based therapies at different levels of care.

Patient’s compliance: A Challenge

Adherence to medication Of all written prescription, 14% are never filled and an additional 13% are filled but never taken. Ann Pharmacother 1993;27:S1-24.

With statin, discontinuation rates at 1 year ranged from 15% to 60%. Adherence to medication JAMA 1998;279:

AHA Scientific Sessions 2010 Analysis type 2 DM pts. 2 years follow up. Results: –28% pts. persisted with statin –41% pts. persisted with antihyperglycemic agents. –Younger patients (<65 years) were more likely to stop therapy prematurely than older patients (65+ years).

With antihypertensives, fill rates are approximately 50% and full adherence is only 20%. Adherence to medication Am J Hypertens 1997;10:

Concomitant adherence to statin and antihypertensive drugs in a managed case study was only 36% at 12months. Adherence to medication Arch Intern Med. 2005;165:

Eagle KA et al. Am J Med. 2004;117: Medication adherence declines within 6 months post-MI Global Registry of Acute Coronary Events Aspirin  -blockers Statins ACE inhibitors Decline in use (%)

Only 1 in 3 patients adherent to preventive therapy after 6 months Time from initiation of therapy (months) Patients adherent to both medications (%) N = 8406 managed-care enrollees receiving antihypertensive and lipid-lowering medications Chapman RH et al. Arch Intern Med. 2005;165: Concomitant antihypertensive and lipid-lowering therapy  pill burden and may  adherence

Aspirin withdrawal and mortality Aspirin non-adherence/withdrawal was associated with three-fold higher risk of major adverse cardiac events (OR = 3.14 [1.75–5.61], P= ). In patients with intracoronary stents, discontinuation of antiplatelet treatment was associated with an even higher risk of adverse events (OR= [29.90– ]). European Heart Journal (2006) 27, 2667–2674 OR, odd ratio.

Event rate curves (death, nonfatal MI) during 30-day follow- up period (after ACS) for patients with continued statin therapy, withdrawn statin therapy and without statin therapy. * Circulation 2002;105: Event rates in % (Mortality, MI) 30-day follow up period Statin withdrawal and mortality

Risk of Death according to the compliance score Br Med J 2006;333:522. Relative risks for death in patients with compliance scores of 0–33% and 34– 66% were 2.9 and 1.8, respectively, compared with those who had a score of 67% or more

CAD prevention: Polypharmacy is need Disadvantage of polypharmacy  Increase pill burden  Decrease compliance  Decrease efficacy  Increase cost  Lack of availability of all the drugs  Says to patient:- you are severely sick.

Direct association between dosing frequency and medication adherence Clin Ther 2001;23:1296–1310.

A Meta-analysis* Meta-analysis of 9 studies on fixed dose combination; 2TB + 4HT + 1HIV + 2DM. Subjects: A total of 11,925 patients on fixed-dose combination were compared against 8317 patients on free-drug component regimen. All patients were followed for 13.1±8.6 months. The American Journal of Medicine (2007) 120,

Results Fixed-dose combination resulted in a 26% decrease in the risk of non-compliance compared with free-drug component regimen. P< FDCFree Drug Component Regimen Conclusion Fixed-dose combination decreases the risk of non-compliance and should be considered in patients with chronic conditions for improving medication compliance which can translate into better clinical outcomes.

Effect of fixed-dose combinations on treatment adherence in patients with hypertension. Am J Med 2007;120: 713–719

An Indian Study: FDC of BP lowering agents + statin + aspirin (Polypill) is effective and well tolerated 1.The Polypill is similar to the added effects of each of its BP lowering components. There is greater BP lowering with incremental components. ASA does not interfere with the BP lowering effects. 2.The Polypill reduces LDL. 3.The Polypill lowers thromboxane B2 to a similar extent as aspirin alone. 4.The Polypill is well tolerated. 5.The Polypill could potentially reduce CVD risk by about half. TIPS, Lancet Published Online March 30, 2009 No interaction between BP lowering agents like BB, ACE-I with statin and aspirin

Undergoing polypill trials London, UK - A new trial examining adherence to a polypill— consisting of aspirin, a statin, and two antihypertensive agents—as compared with compliance with separate medications has begun in the UK, Ireland, and the Netherlands, with participants from India also expected to join the study at a later date. Sydney, Australia - The study, Use of a Multidrug Pill in Reducing Cardiovascular Events (UMPIRE), is part of collaborative effort called Single Pill to Avert Cardiovascular Events (SPACE) being run by the George Institute in Sydney, Australia. Guidelines Adherence with the Polypill (GAP) study, which is currently under way in Australia. Improving Adherence Using Combination Therapy (IMPACT) trial ongoing in New Zealand.

Summary International guidelines: evidence based combination therapy is the need for aggressive prevention of CAD in high risk pts. for CAD and in pts with established CAD. Current trends in the prescription of these evidence based therapy shows improvement, but still suboptimal. One should also pay considerable attention towards adherence to therapy. Take measures to improve adherence to therapy for optimal benefits of prevention therapy.

Diagnosis: high risk for CV events/patients with established CHD. Rx –Multiple antidiabetic agents –ACE-I –Cardioselective BB –Statin –Aspirin +/- Cost burden Pill burden Memory burden

Need of the hour…… Keep ourselves updated with evidences. Comply to the evidence based guidelines. Take the measures to improve treatment compliance: –Educate the patients –↓ Cost burden –↓ Pill burden

A healthy lifestyle strategy