CAD prevention and challenges. Cardiovascular disease is the leading cause of death among adults worldwide Coronary Disease7.2 million Cancer6.3 million.

CAD prevention and challenges

Cardiovascular disease is the leading cause of death among adults worldwide

Coronary Disease 7.2 million

Cancer 6.3 million

Cerebrovascular Disease 4.6 million

Acute Lower Respiratory Tract Infections 3.9 million

Tuberculosis 3.0 million

COPD (Chronic Obstructive Pulmonary Disease) 2.9 million

Diarrhoea (Including Dysentery) 2.5 million

Malaria 2.1 million

AIDS 1.5 million

Hepatitis B 1.2 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 2Lancet 360;1347-1360

An Alarm

• Prevalence of CHD: 10% in urban area.

• Prevalence of CHD: 4% in rural area.

JACC 2007;50:1370-2

4-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;366:1744-9

OTHERS

INTERHEART: 9 Modifiable factors

account for 90% of first-MI risk worldwide

Yusuf S et al. Lancet. 2004;364:937-52.

N = 15,152 patients and 14,820 controls in 52 countriesPAR = population attributable risk, adjusted for all risk factors

36

127

10

20

33

0

20

40

60

80

100

Smoking Fruits/veg

Exercise Alcohol Psycho-social

Lipids All 9 risk factors

PAR(%)

1418

90

Diabetes Abdominalobesity

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

39

59

31

1813.3

0

10

20

30

40

50

60

Fraction of Patients (with CAD) with various risk factors

LDL-C Abnormal TC/HDL ratio Smoking Hypertension DM

n= 5748 Indian patients with CAD

J Assoc Physicians India. 2004 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;43:1517-23.

O

OO

O23 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.

http://www.who.int/cardiovascular_diseases

NICE guidelines

• All patients should be offered combined treatment with the following:– Statin– ACE-I– Aspirin– Beta-blocker

Heart 2007;93:862-864

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 75-162 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;113:2363-72

• 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;13:142-147.

Drugs for Poly-Portfolio

Antiplatelet Evidence: Secondary PreventionAntiplatelet 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

1.00.50.0 1.5 2.0 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?

SuggestedLoading dose: 160-325 mgDaily dose: 75-81 mg

SuggestedLoading dose: 160-325 mgDaily dose: 75-81 mg

SuggestedLoading dose: 160-325 mgDaily dose: 75-81 mg

SuggestedLoading dose: 160-325 mgDaily dose: 75-81 mg

Drugs for Poly-Portfolio

– Antiplatelet– Statins– β-blockers– ACE-I

CAD-Mortality

JAMA 1995;274:131-136.

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;110:227-39.

Total Cholesterol & CAD

JAMA 2000;284:311-318.

LaRosa JC et al. NEJM. 2005;352:1425-1435

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.

30

25

20

15

10

5

00 70 90 110 130 150 170 190 210

LDL-C (mg/dL)

TNT (atorvastatin 80 mg/d)

TNT (atorvastatin 10 mg/d)HPS

CARE

LIPIDLIPID

CAREHPS

Eve

nt (

%) 4S

4SStatinPlacebo

Relationship between LDL Levels and Event Rates in Secondary Prevention Trials of Patients with Stable CHD

HMG-CoA Reductase Inhibitor: HMG-CoA Reductase Inhibitor: Secondary PreventionSecondary 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; JAMA1982;247:1707–14

Phase of Treatment

Acute treatment

Secondaryprevention

Overall

Total #Patients

28,970

24,298

53,268

0.5 1.0 2.0RR of death

-blockerbetter

RR (95% CI)

Placebobetter

0.87 (0.77-0.98)

0.77 (0.70-0.84)

0.81 (0.75-0.87)

-blocker Evidence-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, 1168.

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;113:2363-2372 and J Am Coll Cardiol 2006;47:2130-2139

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

Pro

babili

ty o

f Event

0

0.05

0.15

0.2

0.25

0.3

0 1 2 3

0.35

0.4

4

ACE-I

Placebo

OR: 0.74 (0.66–0.83)OR: 0.74 (0.66–0.83)0.1

Flather MD, et al. Lancet. 2000;355:1575–1581

SAVERadionuclideEF 40%

AIREClinical and/or radiographic signs of HF

TRACEEchocardiogramEF 35%

ACE Inhibitor Evidence: Post MI ACE Inhibitor Evidence: Post MI with LVD or HFwith LVD or HF

ACE-I=Angiotensin converting enzyme inhibitors, LVSD=Left ventricular systolic dysfunction, MI=Myocardial infarction, OR=Odds ratio

26%

Ramipril and CV eventsRamipril and CV events

Days of Follow-Up

CV

dea

th, M

I, or

st

roke

(%

)

22% RRR, P<0.0010.00

0.05

0.10

0.15

0.20

0 500 1000 1500

Placebo

Ramipril

HOPE Investigators. NEJM 2000;342:145-153

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 fromcardiovascular causes

Death from cardiovascular causes

MI

Stroke

Death from noncardiovascular causes

Death from any cause

Ramipriln=4645

(%)

14.0

6.1

9.9

3.4

4.3

10.4

Placebon=4652

(%)

17.8

8.1

12.3

4.9

4.1

12.2

0.78 (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)

<0.001

<0.001

<0.001

<0.001

0.74

0.005

Relative risks of clinical events for primary and secondary prevention with selected drugs

Lancet. 2006 Aug 19;368(9536):679-86 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 CHD Post-MI Post-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;95:373-378

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;109:745-749.

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 death P value

4 drugs vs. no drug 0.10 (95% Cl, 0.03-0.42 0.0001

3 drugs vs. no drug 0.17 (95% Cl, 0.04-0.75) 0.00018

2 drugs vs. no drug 0.18 (95% Cl, 0.04-0.77) 0.019

1 drug vs. no drug 0.36 (95% Cl, 0.08-1.75) 0.20

* Recommended four drugs were: antiplatelet, ACE-I, lipid lowering agents, beta-blocker

Circulation 2004;109:745-749.

90% 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;13:142-147.

•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 data46th 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;279:1458-62.

AHA Scientific Sessions 2010

• Analysis 52414 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;10:697-704

Eagle KA et al. Am J Med. 2004;117:73-81.

Medication adherence declines within 6 months post-MI

Global Registry of Acute Coronary Events

Aspirin-blockersStatinsACE

inhibitors0

5

10

15

20

Decline in use

(%)

20

12

8

13

Only 1 in 3 patients adherent to preventive therapy after 6 months

44.7

35.9

0

10

20

30

40

50

3Time from initiation of therapy (months)

Patientsadherent

to bothmedications

(%)

N = 8406 managed-care enrollees receiving antihypertensive and lipid-lowering medications

Chapman RH et al. Arch Intern Med. 2005;165:1147-52.

6

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= 0.0001).

• In patients with intracoronary stents, discontinuation of antiplatelet treatment was associated with an even higher risk of adverse events (OR= 89.78 [29.90–269.60]).

European Heart Journal (2006) 27, 2667–2674OR, 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;105:1446-1452.

Eve

nt r

ates

in %

(M

orta

lity,

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

withcompliance scores of 0–33% and 34–66% were 2.9 and 1.8, respectively,

comparedwith 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, 713-719.

ResultsFixed-dose combination resulted in a 26% decrease in

the risk of non-compliance compared with free-drug component regimen.

33

34

35

36

37

38

Non-compliance rate (%)

P<0.0001

FDC Free 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

tolerated1. 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 burdenPill 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