Transcript ACE-I - Atorvaacademics.com

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 2
Lancet 360;1347-1360
An Alarm
• Prevalence of CHD: 10% in urban area.
• Prevalence of CHD: 4% in rural area.
4-fold increase in
urban over the last 40
years.
Doubled in rural over
the past 30 years
JACC 2007;50:1370-2
Leader in the Causes of Death
WHO
CVD 29%
OTHERS
Lancet 2005;366:1744-9
INTERHEART:
9 Modifiable factors
account for 90% of first-MI risk worldwide
100
N = 15,152 patients and 14,820 controls in 52 countries
PAR = population attributable risk, adjusted for all risk factors
Yusuf S et al. Lancet. 2004;364:937-52.
80
PAR
(%)
90
60
40
50
36
20
33
14
20
18
12
10
7
0
Smoking
Fruits/
veg
Exercise
Alcohol
Hypertension
Diabetes Abdominal Psychoobesity
social
Lipids
All 9 risk
factors
Lifestyle factors
Conclusion: Most of the CV Risk factors are modifiable,
either by lifestyle modifications or by drugs
CAD & risk factors: their association
n= 5748 Indian patients with CAD
Fraction of Patients (with CAD) with various risk
factors
59
60
50
40
39
31
30
20
18
13.3
10
0
LDL-C
Abnormal TC/HDL ratio
Smoking
Hypertension
J Assoc Physicians India. 2004 Feb;52:103-8
DM
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
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.
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
Drugs for Poly-Portfolio
• 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.
Antiplatelet Evidence: Secondary Prevention
Effect of antiplatelet therapy* on vascular events**
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
0.0
0.5
1.0
1.5
2.0
Antiplatelet better Control better
*Aspirin was the predominant antiplatelet agent studied
**Vascular events include MI, stroke, or death Antithrombotic Trialist Collaboration. BMJ 2002;324:71–86.
?
What is the right
dose of Aspirin?
Suggested
Loading dose: 160325 mg
Daily dose: 75-81
mg
Suggested
Loading dose: 160325 mg
Daily 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.
HMG-CoA Reductase Inhibitor:
Secondary Prevention
Relationship between LDL Levels and Event Rates in
Secondary Prevention Trials of Patients with Stable CHD
30
4S
Statin
Placebo
Event (%)
25
4S
20
LIPID
15
LIPID
CARE
10
HPS
5
0
CARE
HPS
TNT (atorvastatin 10 mg/d)
TNT (atorvastatin 80 mg/d)
0
70
90
110
130
150
LDL-C (mg/dL)
170
190
210
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.
LaRosa JC et al. NEJM. 2005;352:1425-1435
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
b-blocker Evidence
Summary of Secondary Prevention Trials of b-blocker Therapy
Phase of
Treatment
Total #
Patients
RR (95% CI)
Acute
treatment
28,970
0.87 (0.77-0.98)
Secondary
prevention
24,298
0.77 (0.70-0.84)
Overall
53,268
0.81 (0.75-0.87)
0.5
CI=Confidence interval, RR=Relative risk
1.0
RR of death
b-blocker
Placebo
better
better
2.0
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.
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. IIIV) 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
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.
Am Heart J 2003;146:721–8
Drugs for Poly-Portfolio
– Antiplatelet
– Statins
– β-blockers
– ACE-I
ACE Inhibitor Evidence: Post MI
with LVD or HF
AIRE
SAVE
Probability of Event
Radionuclide
EF  40%
0.4
TRACE
Clinical and/or
radiographic
signs of HF
Echocardiogram
EF  35%
Placebo
0.35
26%
ACE-I
0.3
0.25
0.2
0.15
0.1
OR: 0.74 (0.66–0.83)
0.05
0
0
1
2
3
4
Years
ACE-I=Angiotensin converting enzyme inhibitors, LVSD=Left ventricular systolic dysfunction,
MI=Myocardial infarction, OR=Odds ratio
Flather MD, et al. Lancet. 2000;355:1575–1581
Ramipril and CV events
Heart Outcomes Prevention and Evaluation (HOPE) Study
CV death, MI, or
stroke (%)
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
0.20
Ramipril
0.15
Placebo
0.10
0.05
22% RRR, P<0.001
0.00
0
500
1000
1500
Days of Follow-Up
ACE-I=Angiotensin converting enzyme inhibitors, DM=Diabetes mellitus, CV=Cardiovascular,
HF=Heart failure, LVSD=Left ventricular systolic dysfunction, MI=Myocardial infarction
HOPE Investigators. NEJM 2000;342:145-153
HOPE: Heart Outcomes Prevention Evaluation study
- RESULTS continued -
Primary outcome and deaths from any cause
Placebo
n=4652
(%)
Ramipril
n=4645
(%)
Relative risk
(95% CI)
P
17.8
14.0
0.78 (0.70– 0.86)
<0.001
8.1
6.1
0.74 (0.64– 0.87)
<0.001
12.3
9.9
0.80 (0.70– 0.90)
<0.001
Stroke
4.9
3.4
0.68 (0.56– 0.84)
<0.001
Death from noncardiovascular causes
4.1
4.3
1.03 (0.85– 1.26)
0.74
12.2
10.4
0.84 (0.75– 0.95)
0.005
MI, stroke, or death from
cardiovascular causes
Death from cardiovascular causes
MI
Death from any cause
The Hope Study Investigators. N Engl J Med 2000;342:145– 53.
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
Type of patients
relative risk of event over
5 year
Secondary
PolyAny CHD Prevention
Post-MI
Portfolio strategy: compelling
Major CHD events with suggestion
84%
91%
of almost
combined drug therapy
complete elimination of the
Major CHD events with
92%
96%
risk
of
CHD
death
in
post-MI
addition of lifestyle
patients with a combination of
therapy
drug and lifestyle therapy
CHD death with
93%
combined drug therapy
over 5 years .
CHD death with addition
of lifestyle therapy
O
Stroke with combined
83%
drug therapy
Major CHD events: nonfatal MI and CHD death
Am J Cardiol 2005;95:373-378
97%
PostStroke
77%
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
90%
RRR
4 drugs vs. no drug Use
0.10of
(95%
Cl, 0.03-0.42 evidence0.0001
combination
83%
RRR
medical
therapies was0.00018
3 drugs vs. no drug based
0.17 (95%
Cl, 0.04-0.75)
independently and strongly
2 drugs vs. no drug 0.18 (95% Cl, 0.04-0.77)
associated with lower mortality0.019
in
patients with ACS.
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.
Are we compliant to evidence
based therapy?
•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.
Am J Manag Care 2007;13:142-147.
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
Percent use of evidence-based therapies at different levels of care.
Vascular Health and Risk Management 2009:5 1007–1014
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.
Adherence to medication
• With statin, discontinuation rates at 1
year ranged from 15% to 60%.
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).
Adherence to medication
• With antihypertensives, fill rates are
approximately 50% and full adherence is
only 20%.
Am J Hypertens 1997;10:697-704
Medication adherence declines within
6 months post-MI
0
ACE
inhibitors
Statins
b-blockers
Aspirin
5
Decline
in use
(%)
10
8
15
13
12
20
20
Global Registry of Acute Coronary Events
Eagle KA et al. Am J Med. 2004;117:73-81.
Only 1 in 3 patients adherent to
preventive therapy after 6 months
N = 8406 managed-care enrollees receiving antihypertensive and
lipid-lowering medications
50
40
44.7
35.9
Patients
adherent
30
to both
medications
(%)
20
Concomitant
antihypertensive and
lipid-lowering therapy
 pill burden and may
 adherence
10
0
3
6
Time from initiation of therapy (months)
Chapman RH et al. Arch Intern Med. 2005;165:1147-52.
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]).
OR, odd ratio.
European Heart Journal (2006) 27, 2667–2674
Event rates in % (Mortality, MI)
Statin withdrawal and mortality
30-day follow up period
Event rate curves (death, nonfatal MI) during 30-day followup period (after ACS) for patients with continued statin
therapy, withdrawn statin therapy and without statin therapy.
* Circulation 2002;105:1446-1452.
Risk of Death according to the compliance score
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
Br Med J 2006;333:522.
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.
Results
Fixed-dose combination resulted in a 26% decrease in
the risk of non-compliance compared with free-drug
component regimen.
Non-compliance rate (%)
Conclusion
38
37
36
35
34
P<0.0001
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.
33
FDC
Free Drug Component Regimen
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.
No interaction between
2. The Polypill reduces LDL.
BP lowering agents like
3. The Polypill lowers
to a similar extent as
BB,thromboxane
ACE-I with B2
statin
aspirin alone.
and aspirin
4. The Polypill is well tolerated.
5. The Polypill could potentially reduce CVD risk by about half.
TIPS, Lancet Published Online March 30, 2009
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