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Trials of ace inhibitors
1. Trials of ACE inhibitors and ARB’s
in Myocardial infarction and Heart
failure
Dharam Prakash Saran
2.
3. 7.2. Renin-Angiotensin-Aldosterone System Inhibitors
Class I
1. An angiotensin-converting enzyme inhibitor should be administered within the first 24 hours to all patients
with STEMI with anterior location, HF, or ejection fraction less than or equal to 0.40, unless
contraindicated.174–177 (Level of Evidence: A)
2. An angiotensin receptor blocker should be given to patients with STEMI who have indications for but are
intolerant of angiotensin-converting enzyme inhibitors. 178,179 (Level of Evidence: B)
3. An aldosterone antagonist should be given to patients with STEMI and no contraindications who are
already receiving an angiotensin-converting enzyme inhibitor and beta blocker and who have an ejection
fraction less than or equal to 0.40 and either symptomatic HF or diabetes mellitus.180 (Level of Evidence:B)
Class Iia
1. Angiotensin-converting enzyme inhibitors are reasonable for all patients with STEMI and no
contraindications to their use.181–183 (Level of Evidence: A)
4.
5. ACE Inhibitor ARB
HYPERTENSION ALLHAT
PROGRESS
LIFE
VALUE
CAD HOPE
EUROPA
PEACE
ONTARGET
VALUE
ACS SAVE
AIRE
TRACE
GISSI 3
ISIS 4
VALIANT
OPTIMAAL
HEART FAILURE CONSESUS
SOLVD
ATLAS
CHARM
I-PRESERVE
ValHeFT
6. ACE Inhibitor
MI Mortality Trials
Selective
(higher risk, long term)
SAVE (EF 40%)
AIRE (clinical HF)
TRACE (wall motion score,
EF 35%)
Broad
(short term)
CONSENSUS II
GISSI-3
ISIS-4
7. SAVE TRIAL 1992
Survival and Ventricular Enlargement Trial
Design:
Randomized placebo controlled trial.
Patients:
Total - 2231 randomly selected, 3 to 16 days after MI.
All with EF < 40% (by MUGA Scan) and no symptoms of heart failure - Class 1 to 2.
1115 recieved Captopril
1116 recieved placebo.
Inclusion Criteria:
1987 to 1990
b/n 21 and 80 years of age, both sex
8. • Exclusion Criteria:
Failure to randomize with in 16 days of MI
Serum Cr > 2.5
Contraindication or allergy to ACEI
Another reason to use the ACEI like HTN or CHF symptoms.
Unwillingness to participate.
Unstable course after MI
Recurrent ischemia with in 72 hour after MI.
Average Follow-up: 42 months..
9. • REPEAT MUGA SCAN TO ASSES LV EJECTION FRACTION AT AN AVERAGE OF 36
MONTHS OF TIME.
Dosage:
Starting 6.25 to 12.5 tds and gradually increased to 25 tds at the time of discharge with a target dose of 50
tds.
10. End Points:
Primary - All cause mortality - reduced by 5 percent (20 versus 25% in
placebo)
Secondary - Risk Reductions:
Death from Cardiovascular Causes - 21% risk reduction.
CHF requiring hospitalization - 22% risk reduction
Recurrent MI - 25% reduction in risk
Death from CV causes or MI - 22% risk reduction
Death from Cv causes, CHF or MI - 24% risk reduction.
11. • Conclusions:
In patient who had a recent MI addition of ACEI (Captopril) reduces all cause
mortality and morbidity even on top of standard beta blockers, aspirin and
nitrates.
Importance:
First trial to show mortality and morbidity reduction by ACEI in post-MI patient
with LVEF of < 40% without HF symptoms.
12. AIRE: Acute Infarction Ramipril Efficacy study
Purpose
To determine whether the ACE inhibitor ramipril reduces mortality in patients with evidence of
heart failure after MI
Design
Multicenter, multinational, randomized, double-blind, placebo-controlled
Patients
2006 patients, aged >18 years, with evidence of heart failure
3–10 days after MI;
patients with severe heart failure (usually NYHA class IV) or ongoing ischemia excluded
Follow up and primary endpoint
Average 15 months follow up. Primary endpoint all-cause mortality
Treatment
Placebo or ramipril initiated at 2.5 mg twice daily; increased to
5 mg twice daily after 2 days if tolerated
13. AIRE: Acute Infarction Ramipril Efficacy study
- RESULTS -
• Significant reduction in all-cause mortality in ramipril group compared with placebo (17
vs. 23%, relative risk reduction 23%, P=0.002)
• Reduction in mortality apparent as early as 30 days and consistent across a wide range of
subgroups
• Fewer patients in ramipril group developed severe/resistant
heart failure
• No significant reduction in reinfarction or stroke
15. AIRE: Acute Infarction Ramipril Efficacy study
- SUMMARY -
In patients with non-severe heart failure after MI, ramipril started 3–10
days after MI and continued for a mean 15-month period:
• Significantly reduced all-cause mortality
• Conferred benefit independent of age, sex, hypertension, angina or
concomitant therapy
• No significant reduction in reinfarction or stroke
16. TRACE (1995)
Trandolapril Cardiac Evaluation Study
A clinical trial of the trandolapril in patients with left ventricular dysfunction after myocardial
infarction.
BACKGROUND:
• Treatment with ACE inhibitors reduces mortality among survivors of acute myocardial infarction, but
whether to use ACE inhibitors in all patients or only in selected patients is uncertain.
17. METHODS:
• Screened 6676 consecutive patients with 7001 myocardial infarctions confirmed by enzyme studies.
• A total of 2606 patients had echocardiographic evidence of left ventricular systolic dysfunction (ejection
fraction, < or = 35%).
• On days 3 to 7 after infarction, 1749 patients were randomly assigned to receive oral trandolapril (876
patients) or placebo (873 patients).
• Trandolapril 1 mg daily initial dose, up to 4 mg daily vs placebo.
• The duration of follow-up was 24 to 50 months.
18. CONCLUSIONS:
• Long-term treatment with trandolapril in patients with reduced left ventricular
function soon after myocardial infarction significantly reduced the risk of overall
mortality, mortality from cardiovascular causes, sudden death, and the
development of severe heart failure but not that of recurrent myocardial
infarction.
19. TRACE
Echocardiographic
EF 35%
AIRE
Clinical and/or
radiographic
signs of HF
SAVE
Radionuclide
EF 40%
SAVE AIRE TRACE
DURATION 1987-1990 1989-1992 1991-1993
DRUG CAPTOPRIL RAMIPRIL TRANDOLAPRIL
Target dose 50 mg tds 5 mg bd 4 mg od
NO. OF PATIENTS 2231 Patients 2006 patients 1749 patients
SELECTION DAY 3 to 16 days after MI 3 to 10 days after MI 3 to 7 days after infarction
SELECTION CRITERIA EF < 40% (by
Radionucleotide MUGA
Scan) and no symptoms of
heart failure
Patients with evidence of
heart failure (Clinical or
Radiographic)
Echocardiographic evidence
of left ventricular systolic
dysfunction (ejection
fraction, < or = 35%).
AGE GROUP b/n 21 and 80 years >18 years of age
Average Follow-up 42 months 15 months 24 to 50 months
20. Effects of ACE Inhibition in Early Myocardial Infarction: Results of
GISSI-3
The third Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico
(GISSI-3) study was a controlled, randomized, multicenter, open study undertaken to
investigate the effects of early intervention (within 24 h of symptom onset) with an
angiotensin-converting enzyme (ACE) inhibitor in the management of acute myocardial
infarction (MI).
21. A total of 19,394 patients were treated with oral lisinopril 10 mg/day, glyceryl
trinitrate (GTN) (intravenous followed by transdermal 10 mgday) or their
combination for 6 weeks.
24. Aims
VALIANT was designed as a mortality trial in high-risk MI patients who
derived particular benefits from an ACE inhibitor (SAVE, AIRE, TRACE).
To determine whether:
• the ARB valsartan was superior to captopril in improving survival
and
• the addition of the ARB valsartan to captopril was superior to the proven
dose of captopril in improving survival
If valsartan was not superior to captopril, a non-inferiority
analysis was prespecified to determine whether valsartan
could be considered “as effective as” captopril
25. Acute MI (0.5–10 days)—SAVE, AIRE or TRACE eligible
(either clinical/radiologic signs of HF or LV systolic dysfunction)
Captopril 50 mg tid
(n = 4909)
ExExclusion:
— Serum creatinine > 2.5 mg/dL
— BP < 100 mm Hg
— Prior intolerance of an ARB or ACE-I
— Nonconsent
Valsartan 160 mg bid
(n = 4909)
Captopril 50 mg tid +
Valsartan 80 mg bid
(n = 4885)
median duration: 24.7 months
Primary Endpoint: All-Cause Mortality
Secondary Endpoints: CV Death, MI, or HF
Other Endpoints: Safety and Tolerability
26. Cap 6.25 mg
Val 20 mg
Step II Step III Step IV
Cap 12.5 mg
Val 20 mg
Cap 25 mg
Val 40 mg
Cap 50 mg (tid)
Val 80 mg (bid)
COMBINATION
Cap 6.25 mg
Cap 12.5 mg
Cap 25 mg
Cap 50 mg (tid)
CAPTOPRIL (tid)
Val 20 mg
Val 40 mg
Val 80 mg
Val 160 mg (bid)
VALSARTAN (bid)
Step I
GOAL by 3 months
Study Drug
Dose Titration
Am Heart J. 2000;140:727–734.
27. Captopril
0.3
0.25
0.2
0.15
0.1
0.05
0
Valsartan
Valsartan + Captopril
0 6 12 18 24 30 36
Probability of Event
Mortality by Treatment
Valsartan 4909 4464 4272 4007 2648 1437 357
Pfeffer, McMurray, Velazquez, et al. N Engl J Med 2003;349
Months
Valsartan vs. Captopril: HR = 1.00; P = 0.982
Valsartan + Captopril vs. Captopril: HR = 0.98; P = 0.726
Captopril 4909 4428 4241 4018 2635 1432 364
Valsartan + Cap 4885 4414 4265 3994 2648 1435 382
28. Mortality in SAVE,
TRACE, AIRE, and VALIANT
Hazard Ratio for Mortality
0.5 1 2
Favors
Active Drug
Favors
Placebo
Pfeffer, McMurray, Velazquez, et al. N Engl J Med 2003;349
SAVE
TRACE
AIRE
Combined
VALIANT
Valsartan
preserves
99.6% of
mortality
benefit of
captopril.
29. CV Death, MI, or HF
by Treatment
Captopril
Pfeffer, McMurray, Velazquez, et al. N Engl J Med 2003;349
0.4
0.3
0.2
0.1
Months
Valsartan vs. Captopril: HR = 0.96; P = 0.198
Valsartan + Captopril vs. Captopril: HR = 0.97; P = 0.369
0
0 6 12 18 24 30 36
Probability of Event
Valsartan
Valsartan + Captopril
30. Conclusion
In patients with MI complicated by heart failure, left
ventricular dysfunction or both:
Valsartan is as effective as a proven dose of
captopril in reducing the risk of:
—Death
—CV death or nonfatal MI or heart failure admission
Combining valsartan with a proven dose of
captopril produced no further reduction in
mortality—and more adverse drug events.
Implications:
In these patients, valsartan is a clinically effective
alternative to an ACE inhibitor.
31. ACE Inhibitor ARB
HYPERTENSION ALLHAT
PROGRESS
LIFE
VALUE
CAD HOPE
EUROPA
PEACE
ONTARGET
VALUE
ACS SAVE
AIRE
TRACE
GISSI 3
ISIS 4
VALIANT
HEART FAILURE CONSESUS
SOLVD
ATLAS
CHARM
I-PRESERVE
ValHeFT
32. Class I
1. ACE inhibitors are recommended in patients with HFrEF and current or prior symptoms, unless
contraindicated, to reduce morbidity and mortality (343, 412-414). (Level of Evidence: A)
33. 7.3.2.3. ARBs: Recommendations
Class I
1. ARBs are recommended in patients with HFrEF with current or prior symptoms who areACE
inhibitor intolerant, unless contraindicated, to reduce morbidity and mortality (108, 345, 415,
450). (Level of Evidence:A)
Class IIa
1. ARBs are reasonable to reduce morbidity and mortality as alternatives to ACE inhibitors as
firstline
therapy for patients with HFrEF, especially for patients already taking ARBs for other
indications, unless contraindicated (451-456). (Level of Evidence: A)
Class llb
1. Addition of an ARB may be considered in persistently symptomatic patients with HFrEF who are
already being treated with an ACE inhibitor and a beta blocker in whom an aldosterone
antagonist is not indicated or tolerated (420, 457). (Level of Evidence: A)
Class III: Harm
1. Routine combined use of an ACE inhibitor, ARB, and aldosterone antagonist is potentially
harmful for patients with HFrEF. (Level of Evidence: C)
34. Landmark trials with ACE inhibitors in HF
Trial n EF% Drug Death Hospitalisation Follow up NNT
(death)
CONSENSUS
1987
253 <35%
(IV)
enalapril 36 vs 50 reduced 1 year 6
SOLVD-P
1992
4228 <35
(I)
enalapril trend to
reduction
reduced 4 years 104
SOLVD – T
1991
2500 < 40
(II-III)
enalapril 12.3 vs 15.5 reduced 3 years 31
ATLAS
1997
3164 <35
(II-IV)
lisinopril no difference reduced 4 years -
36. The CONSENSUS trial
• NEJM 1987
• Show prognostic improvement by an ACE inhibitor.
• STUDIED TREATMENT: Enalapril (2.5 to 40 mg per day)
• CONTROL TREATMENT: Placebo
37. Method and design
• RANDOMIZED EFFECTIVES: 127/126 (Enp. vs Cnt.)
• DESIGN: Parallel Groups
• TYPE: Double Blind
• DURATION: 188 days
• AREA: Finland, Sweeden, Norway
• PRIMARY ENDPOINT: Mortality
38. • Severe congestive heart failure (new york heart association [NYHA]
functional class IV)
PATIENTS
ISCHEMIC ORIGIN: 73%
FEMALE: 30%
AGE: 70
DILATED CARDIOMYOPATHY: 16%
HYPERTENSION: 21%
39. RESULTS
• Mortality was reduced by 31 percent at one year
• A significant improvement in NYHA classification was observed in the enalapril
group, together with a reduction in heart size and a reduced requirement for other
medication for heart failure.
• the addition of enalapril to conventional therapy in patients with severe
congestive heart failure can reduce mortality and improve symptoms.
40. • Surviving CONSENSUS patients were followed for an additional 10 years after termination of the trial, at
which time five patients remained alive, all from the enalapril group.
41. SOLVD
Effect of Enalapril on Survival in Patients with Reduced Left Ventricular Ejection Fractions
and Congestive Heart Failure
42. SOLVD
• Enalapril vs placebo in 6,794 patients
• Ejection fraction < 35%
• End points include:
– Delaying the progression of heart failure
– Improving signs and symptoms
– Reducing mortality
• Treatment arm - 2,568 symptomatic class II-III patients most on digitalis and diuretics
• Prevention arm - 4,226 asymptomatic class I-II patients, most on no concomitant therapy
N Engl J Med 1991:325:293-302
43. SOLVD Treatment Trial
All Cause Mortality
50
40
30
20
10
0
0 6 12 18 24 30 36 42 48
Months
Mortality%
Placebo
Enalapril
N Engl J Med 1991;325:293-302
16% Risk Reduction
p = 0.0036
44. Benefits of Enalapril
• Patients: Symptomatic HF patients with LVD (EF < 35%)
• 11% reduction of overall mortality at end of study (P=0.0036)
The SOLVD Investigators, N Engl J Med. 1991;325:293
45. SOLVD Treatment Trial
Mortality or Hospitalization for CHF
70
60
50
40
30
20
10
0
0 6 12 18 24 30 36 42 48
Months
Events %
Placebo
Enalapril
N Engl J Med 1991;325:293-302
26% Risk Reduction
p<0.0001
46. SOLVD Treatment Trial
• Implications:
– Treating 1,000 patients for 3 years
• Prevents about 50 deaths
• Prevents about 350 hospitalizations
47. SOLVD Treatment Trial Conclusions
• Hospitalizations:
– Risk reduced by 20% (p<0.001)
– Significant reduction in CHF hospitalization by 1/3 (p<0.0001)
– Sustained benefit over 4 years
N Engl J Med 1991;325:293-302
48. SOLVD Prevention Trial
All Cause Mortality
25
20
15
10
5
0
0 6 12 18 24 30 36 42 48
Months
Mortality from All Causes (%)
Placebo
Enalapril
Risk Reduction 8%
P=0.30
N Engl J Med 1992;327:685-91
49. SOLVD Prevention Trial
Death or Development of CHF
50
45
40
35
30
25
20
15
10
5
0
0 6 12 18 24 30 36 42 48
Months of Follow-up
% Events
Placebo
Enalapril
Risk Reduction 29%
p<0.001
N Engl J Med 1992;327:685-91
50. SOLVD Prevention Trial
First Hospitalization for CHF
18
16
14
12
10
8
6
4
2
0
0 6 12 18 24 30 36 42 48
Months of Follow-up
% Events
Placebo
Enalapril
Risk Reduction 36%
p<0.001
N Engl J Med 1992;327:685-91
51. SOLVD Prevention Trial
Morbidity and Combined Outcomes
Endpoint Placebo
%
Enalapril
%
RR P value
Development of CHF 30.2 20.7 37% <0.001
Development of CHF and
anti-CHF Rx
22.5 13.9 43% <0.001
First Hospitalization for CHF 12.9 8.7 36% <0.001
Multiple Hospitalization for
CHF
4.8 2.7 44% <0.001
Death or Development of CHF 38.6 29.8 29% <0.001
Death or Hospitalization for
CHF
24.5 20.6 20% <0.001
52. ATLAS Study
Comparative Effects of Low and High Doses of the Angiotensin-Converting
Enzyme Inhibitor, Lisinopril, on Morbidity and Mortality in Chronic Heart
Failure
53. Background
Angiotensin-converting enzyme (ACE) inhibitors are generally prescribed by
physicians in doses lower than the large doses that have been shown to reduce
morbidity and mortality in patients with heart failure.
It is unclear, however, if low doses and high doses of ACE inhibitors have similar
benefits.
54. Methods
3164 patients with New York Heart Association class II to IV heart failure
an ejection fraction <30%
double-blind treatment with either low doses (2.5 to 5.0 mg daily, n51596) or high
doses (32.5 to 35 mg daily, n51568) of the ACE inhibitor, lisinopril, for 39 to 58
months,
while background therapy for heart failure was continued.
55. Results
When compared with the low-dose group, patients in the high-dose group had a
•Nonsignificant 8% lower risk of death (P=0.128) but
•A significant 12% lower risk of death or hospitalization for any reason (P=0.002)
and
•24% fewer hospitalizations for heart failure (P=0.002).
•Dizziness and renal insufficiency was observed more frequently in the high-dose
group, but
•The 2 groups were similar in the number of patients requiring discontinuation of
the study medication.
56. Conclusions
Patients with heart failure should not generally be maintained on very low doses of
an ACE inhibitor (unless these are the only doses that can be tolerated)
The difference in efficacy between intermediate and high doses of an ACE inhibitor
(if any) is likely to be very small.
58. 3 Individual component randomized trials with the ARB candesartan (4
CHARM Added
or 8 mg/day, titrated to target dose of 32 mg) or placebo
Patients with LVEF
<40% and treated with an
ACE-inhibitor
CHARM Trial
7,601 patients with heart failure
CHARM Alternative
Patients with LVEF
<40% and ACE-inhibitor
intolerant
CHARM Preserved
Patients with LVEF
>40% with or without
Endpoints (follow-up minimum 2 years):
ACE-inhibitor
Primary – Component trials: cardiovascular mortality or CHF
hospitalization
Primary – Overall trial results: All-cause mortality
European Society of Cardiology 2003
59. CHARM Overall Program
All-cause mortality
HR 0.91
95% CI 0.83-1.00
p=0.055
23.3%
24.9%
30%
20%
10%
0%
Candesartan Placebo
CV Mortality or
CHF Hospitalization
HR 0.84
p<0.0001
30.2%
34.5%
40%
30%
20%
10%
0%
Candesartan Placebo
European Society of Cardiology 2003
60. CHARM Added Trial
CV Mortality or
CHF hospitalization
HR 0.85
p=0.011
37.9%
42.3%
50%
40%
30%
20%
10%
0%
Candesartan Placebo
CV Mortality
HR 0.84
p=0.02
23.7%
27.3%
30%
20%
10%
0%
Candesartan Placebo
European Society of Cardiology 2003
61. CHARM Alternative Trial
CV Mortality or
CHF hospitalization
HR 0.77
p=0.0004
33.0%
40.0%
50%
40%
30%
20%
10%
0%
Candesartan Placebo
CV Mortality
HR 0.85
p=0.072
21.6%
24.8%
30%
20%
10%
0%
Candesartan Placebo
European Society of Cardiology 2003
62. CHARM Preserved Trial
CV Mortality or
CHF hospitalization
HR 0.89
p=0.118
22.0%
24.3%
30%
20%
10%
0%
Candesartan Placebo
CV Mortality
HR 0.99
p=0.918
11.2% 11.3%
15%
10%
5%
0%
Candesartan Placebo
European Society of Cardiology 2003
63. ACE Inhibitors and ARB in HFpEF
Class IIa
The use of beta-blocking agents, ACE inhibitors, and ARBs in patients with hypertension is
reasonable to control blood pressure in patients with HFpEF. (Level of Evidence: C)
Class IIb
1. The use of ARBs might be considered to decrease hospitalizations for patients with HFpEF (589).
(Level of Evidence: B)
66. Effects of an Angiotensin-Converting
Enzyme Inhibitor, Ramipril, on Death from
Cardiovascular Causes, Myocardial
Infarction, and Stroke in High-Risk Patients
The Heart Outcomes Prevention Evaluation (HOPE) Study
Investigators
N Engl J Med, January 20, 2000
67. HOPE - Background
• ACEIs improve the outcome in patients with LV dysfunction, whether
or not they have symptomatic heart failure.
• This study assessed the role of an ACEI, ramipril, in patients who
were at high risk for cardiovascular events but who did not have LV
dysfunction or heart failure.
N Engl J Med, January 20, 2000
68. HOPE (Heart Outcome Prevention Evaluation)
• 9297 Patients
• Age >55
• DM + 1 other CV factor
• Normal EF (>40%)
• Ramipril (10mg) vs. Placebo
69. HOPE (Primary endpoints)
• Death (CV) - 6.1 vs 8.1 P<0.001 RR=0.75
• MI - 9.9 vs 12.2 P<0.001 RR=0.80
• Stroke - 3.4 vs 4.9 P<0.001 RR=0.69
70. HOPE - Design
• A total of 9,297 high-risk patients,
• > 55 years old,
• who had evidence of vascular disease
• or diabetes plus one other cardiovascular risk factor and who were not known
to have a low EF or heart failure were randomly assigned to receive ramipril (10
mg per day) or matching placebo for a mean of 5 years.
• The primary outcome was a composite of MI, stroke or death from cardiovascular
causes.
• Secondary endpoints were death from any cause, the need for revascularization,
hospitalization for unstable angina or heart failure, and complications related to
diabetes.
N Engl J Med, January 20, 2000
71. HOPE - Kaplan-Meier Estimates of the Composite
Endpoint of CV Death, MI or Stroke in the Ramipril and
Placebo Groups
0.2
0.15
0.1
0.05
0
0 500 1000 15000
Days of Follow-up
% of Patients
Ramipril
Placebo
N Engl J Med, January 20, 2000
P<0.001
72. HOPE - Primary Endpoint Results
14.1
6.1
9.9
3.4
0% Risk Reduction
p=0.78
4.3
10.4
17.7
8.1
12.2
4.9
4.1
12.2
25
20
15
10
5
0
% with an event
Ramipril
Placebo
MI/Stroke/
CV Death
CV Death MI Stroke Total
Mortality
22% Risk Reduction
p<0.001
25% Risk Reduction
p<0.001
20% Risk Reduction
p=<0.001
31% Risk Reduction
p=<0.001
16% Risk
Reduction
p=0.006
N Engl J Med, January 20, 2000
Non CV Death
73. HOPE - Secondary and Other Endpoint Results
16
6.2
3.3
9.2
3.7
18.6
7.4
3.8
11.7
5.3
25
20
15
10
5
0
% with an event
Ramipril
Placebo
Revascularization DM
Complications
New diagnosis of
Diabetes Mellitus
16% Risk Reduction
p<0.001
16% Risk Reduction
p=0.03
23% Risk Reduction
p<0.001
HF
Hospitalization
Heart Failure
N Engl J Med, January 20, 2000
13% Risk Reduction
p=0.19
32% Risk Reduction
p=0.002
74. HOPE - Results in Patients with Diabetes
Endpoint Ramipril Placebo RR P n=1808 n=1770
Primary Endpoint 15.3% 19.6% 0.76 0.0007
CV Death 6.0% 9.6% 0.62
G. Dagenais, ESC 1999
75. HOPE - Results in Patients with Diabetes
34% Risk Reduction
p=0.0007
15.3
38% Risk Reduction
6
19.6
9.6
25
20
15
10
5
0
% with an event
Ramipril
Placebo
MI/Stroke/CV Death CV Death
G. Dagenais, ESC 1999
76. HOPE - Summary of Results
• Patients randomized to ramipril had risk reductions of:
MI, stroke, CV death -22%
CV death -25%
MI -20%
Stroke -31%
Revascularization procedures* -16%
New onset of diabetes -32%
*Revascularization procedures included PTCA, CABG or peripheral angioplasty
N Engl J Med, January 20, 2000
77. HOPE - Summary of Results (continued)
• The beneficial effect of treatment with ramipril on the composite outcome was
consistently observed among the following predefined subgroups:
patients with and without diabetes
men and women
those with and without evidence of cardiovascular disease
those < 65 years of age and those > 65 year of age
those with and without hypertension at baseline*
those with and without microalbuminuria
*A reduction of 2 mm Hg in diastolic blood pressure (as seen in this trial) might at best
account for about 40% of the reduction in the rate of stroke and about 25% of the reduction of MI.
N Engl J Med, January 20, 2000
78. HOPE - Conclusions
• “Ramipril significantly reduces the rates of death, myocardial
infarction, and stroke in a broad range of high-risk patients who are
not known to have a low ejection fraction or heart failure”
N Engl J Med, January 20, 2000
79.
80. Primary endpoint
CV mortality + non fatal MI + cardiac arrest
Secondary endpoints
Total mortality + non fatal MI + unstable angina +
cardiac arrest
Heart failure
Revascularisation (PCI/CABG)
Stroke
82. Selection criteria
Male or female > 18 years of age
Documented coronary disease
Not scheduled for revascularisation
No clinical signs of heart failure
83. Documented coronary disease
Previous MI > 3 months
PCI / CABG > 6 months
Angiographic evidence ( 70% stenosis)
In males with chest pain: positive exercise or
stress test
84. Primary endpoint
% CV death, MI or cardiac arrest
RRR: 20%
14
12
10
8
6
4
2
Placebo annual event rate: 2.4%
Placebo
Perindopril
p = 0.0003
Years
0
0 1 2 3 4 5
85. Primary and first secondary endpoint
Perindopril RRR (%)
0.5 1.0 2.0
20
14
22
46
14
better
Placebo
better
CV mortality, MI, CA
CV mortality
Non fatal MI
Cardiac arrest
Total mortality, MI, UAP,CA
86. Fatal and non fatal MI
Placebo
Perindopril
10
8
6
4
2
0
RRR: 24%
0 1 2 3 4 5 Years
(%)
p < 0.001
89. Summary of results
In EUROPA, the largest and longest trial of stable,
low risk CAD patients, perindopril 8 mg/d
significantly reduced:
CV mortality + non fatal MI + cardiac arrest: 20%
CV mortality and non fatal MI: 19%
Fatal + non fatal MI: 24%
Heart failure: 39%
90. Summary of results
Benefits occurred on top of recommended therapy (92% platelet inhibitors, 58% lipid
lowering drugs, 62% -blockers) and are consistent across predefined sub-groups
Perindopril should be considered for chronic therapy in all patients with coronary
disease
91. The Prevention of Events with Angiotensin Converting Enzyme
Inhibition (PEACE) Trial
A double-blind, placebo-controlled, randomized trial
Sponsored by the National Heart, Lung, and Blood Institute
92. Inclusion Criteria
• Age 50 years
• Coronary artery disease
MI, or
CABG or PCI, or
Coronary angiogram with obstruction of 50% luminal diameter in at least one native
vessel
• LVEF > 40%
• Tolerated 2 week run-in of 2 mg/day trandolapril
93. 1º Outcome
CV Death, MI, CABG, or PCI
0.35
0.30
0.25
0.20
0.15
0.10
0.05
0.00
HR=0.96 (95% CI, 0.88-1.06) P=0.43
0 1 2 3 4 5 6
Years from Randomization
Incidence of Primary Outcome
Placebo
Trandolapril
Number of Patients
Placebo 4132 3992 3722 3491 3034 1941 906
Active 4158 4019 3758 3515 3093 1981 985
94. Conclusions
PEACE was conducted in a population with CAD and preserved LV function who received
intensive contemporary management.
— This usually included coronary revascularization, lipid lowering and blood pressure control
In this population, which represents the majority of patients with CAD, the addition of an ACE
inhibitor did not reduce further clinical atherosclerotic events.
95. Conclusions
In patients with stable CHD and preserved LV function who are receiving contemporary
management, there is no evidence of further benefit from the addition of an ACE inhibitor for
CV death, MI or coronary revascularization.
96. ACE Inhibitor Evidence: Secondary Prevention
Comparison between the HOPE and PEACE trials
20
15
10
5
0
HOPE, placebo
HOPE, active drug (ramipril)
PEACE, placebo
0 1 2 3 4 5
MI, Cardiac death,
or Stroke (%)
Patients enrolled in the PEACE trial were at lower risk*
*Reflects better blood pressure control, revascularization, and use of other risk-reducing medications (i.e., antiplatelet
therapy, -blocker, lipid-lowering medication)
CHD=Coronary heart disease, MI=Myocardial infarction
The PEACE Trial Investigators. NEJM 2004;351:2058-68
Years
98. • Telmisartan, Ramipril, or Both in Patients at High Risk for Vascular Events
• Effects of ARB, ACE-Inhibitors, combination therapy in death from cardiovascular causes, MI, stroke, or
hospitalization for heart failure.
ONTARGET
99. ONTARGET
• 29,019 patients were recruited from 733 centers in 40 countries.
Single-Blind run in-period
2.5mg ramipril daily x 3days
40mg telmisartan and 2.5mg ramipril daily x 7 days
5mg ramipril and 40mg telmisartan x 11-18 days
100. • Blood pressure ONTARGET
Telmisartin and combination group maintained slightly lower blood pressure levels
• Serum Creatinine
Number of patients with increased levels was similar in three groups
• Potassium
Similar number of patients with levels more then 5.5 mmmol per liter in monotherapy groups. (283/287)
Significantly higher levels in combination group
480 patients
p=<0.001
101. ONTARGET
• Primary Outcomes
1412 (16.5%) in Ramipril group,
1423 (16.7%) patients in Telmisartan group
1386 (16.3) patients in combination group
102. ONTARGET
Telmisartan was noninferior to Ramipril, nor was it superior
Upper boundary of CI for RR of primary outcome was lower then predetermined
(noninferiority)
Lower boundary of CI (not superior)
No significant difference in total number of deaths between mono therpay
groups.
Higher number of deaths in combination group, but not statistically significant.
106. 42,418 patients with hypertension
SBP >140mmHg and/or DBP >90 mmHg OR
Took medication for hypertension and had at least one additional risk factor for CHD
Age >55 years
NHLBI funded trial
Diuretic
Chlorthalidone
12-25 mg/day (n=15,255)
Endpoints:
Primary – Fatal coronary heart disease and nonfatal MI
Secondary – All-cause mortality, stroke, and major cardiovascular
disease events (CHF, coronary revascularization, angina, and
peripheral artery disease)
Mean follow-up 4.9 years
JAMA 2002;288:2981-2997
Calcium Channel Blocker
Amlodipine
2.5-10 mg/day
(n=9,048)
ACE Inhibitor Lisinopril
10-40 mg/day
(n=9,054)
Alpha Blocker
Doxazosin*
2-8 mg/day
(n=9,061)
* Discontinued prior to study completion
107. ALLHAT: Primary Endpoint*
11.5% 11.3%
15%
10%
5%
0%
Chlorthalidone vs Amlodipine
Primary Endpoint
RR = 0.98
p = 0.65
Chlorthalidone
Chlorthalidone vs Lisinopril
Primary Endpoint
JAMA 2002;288:2981-2997
Amlodipine
11.5% 11.4%
15%
10%
5%
0%
* Primary Endpoint = Fatal CHD or nonfatal MI
RR = 0.99
p = 0.81
Chlorthalidone Lisinopril
108. ALLHAT: Secondary Endpoints
17.3% 16.8%
20%
15%
10%
5%
0%
All Cause Mortality
RR = 0.96
p = 0.20
Chlorthalidone
JAMA 2002;288:2981-2997
Amlodipine
7.7%
10.2%
15%
10%
5%
0%
Heart Failure
RR = 1.38
p < 0.001
Chlorthalidone Amlodipine
Chlorthalidone vs Amlodipine
109. ALLHAT: Secondary Endpoints
Stroke
RR = 1.15
p = 0.02
5.6%
6.3%
10%
8%
6%
4%
2%
0%
17.3% 17.2%
20%
15%
10%
5%
0%
All Cause Mortality
RR = 1.00
p = 0.90
Chlorthalidone
JAMA 2002;288:2981-2997
Lisinopril
Chlorthalidone vs Lisinopril
7.7%
8.7%
15%
10%
5%
0%
Heart Failure
RR = 1.19
p < 0.001
Chlorthalidone Lisinopril Chlorthalidone Lisinopril
110. Second Australian National Blood Pressure Study (ANBP-2)
• Enalapril/ACEI vs. HCTZ, n = 6,083
• Randomized, open-label (blinded endpoint review)
NEJM 2003;348:583-92 110
111. Second Australian National Blood Pressure Study (ANBP-2)
• All CV events or death from any cause
HR = 0.89 (0.79-1.00), p=0.05
• First events
CVD: HR = 0.88 (0.77-1.01), p = 0.07
CHD: HR = 0.86 (0.70-1.06), p = 0.16
Stroke: HR = 1.02 (0.78-1.33), p = 0.91
HF: HR = 0.85 (0.62-1.18), p = 0.33
NEJM 2003;348:583-92 111
112. The LIFE Trial
Losartan Intervention For Endpoint reduction in hypertension study (LIFE)
113. LIFE: Study Design
Patients with hypertension (blood pressure 160-200/ 95-115 mm Hg)
and left ventricular hypertrophy
Atenolol
Beta-blocker
Dose titrated to BP <140/90 mm Hg
(n=4,588)
Losartan
Angiotensin II antagonist
Dose titrated to BP <140/90 mm Hg
(n=4,605)
Followed for >4 years - Mean follow-up 4.8 years
Cardiovascular death, MI, stroke
114. LIFE: Primary Composite Endpoint
Composite of CV Death / MI / Stroke
11.0%
12.8%
15%
10%
5%
0%
P=0.021
Adjusted
Hazard
Ratio = 0.87
Rate 23.8/1,000
patient yrs
Rate 27.9/1,000
patient yrs
n=508 n=588
Losartan Atenolol
