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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