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VALsartan In Acute myocardial iNfarcTion
Marc A. Pfeffer, MD, PhD (Chair), John J.V. McMurray, MD (Co-Chair),
Eric J. Velazquez, MD, Jean-Lucien Rouleau, MD, Lars Køber, MD, Aldo P. Maggioni, MD, Scott
D. Solomon, MD, Karl Swedberg, MD, PhD, Frans Van de Werf, MD, PhD,
Harvey D. White, DSc, Jeffrey D. Leimberger, PhD, Marc Henis, MD, Susan Edwards, MS,
Steven Zelenkofske, DO, Mary Ann Sellers, MSN, and Robert M. Califf, MD,
for the VALIANT Investigators
Other Steering Committee Members:
P. Armstrong, P. Aylward, S. Barvik, Y. Belenkov, A. Dalby, R. Diaz, H. Drexler, G. Ertl, G. Francis,
J. Hampton, A. Harsanyi, J. Kvasnicka, V. Mareev, J. Marin-Neto, J. Murin, M. Myers,
R. Nordlander, G. Opolski, J. Soler-Soler, J. Spac, T. Stefenelli, D. Sugrue,
W. Van Gilst, S. Varshavsky, D. Weaver, F. Zannad.
Dr. Pfeffer is named as a coinventor on a patent awarded to the Brigham and Women’s Hospital regarding the use of
inhibitors of the renin-angiotensin system in selected survivors of myocardial infarction; there is a licensing agreement
between Novartis Pharmaceuticals and the Brigham and Women’s Hospital, which is not linked to sales.
Supported by a grant from Novartis Pharmaceuticals
Copyright © 2003 Duke Clinical Research Institute. All rights reserved.
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:
u the ARB valsartan was superior to captopril in improving
survival
and with equal statistical power
u the addition of the ARB valsartan to captopril was superior
to the proven dose of captopril in improving survival
u If valsartan was not superior to captopril, a non-inferiority
analysis was prespecified to determine whether valsartan
could be considered “as effective as” captopril
Copyright © 2003 Duke Clinical Research Institute. All rights reserved.
Acute MI (0.5–10 days)—SAVE, AIRE or TRACE eligible
(either clinical/radiologic signs of HF or LV systolic dysfunction)
Major Exclusion Criteria:
— BP < 100 mm Hg
— Serum creatinine > 2.5 mg/dL
— Prior intolerance of an ARB or ACE-I
— Nonconsent
double-blind active-controlled
Captopril 50 mg tid
(n = 4909)
Valsartan 160 mg bid
(n = 4909)
Captopril 50 mg tid +
Valsartan 80 mg bid
(n = 4885)
median duration: 24.7 months
event-driven
Primary Endpoint:
All-Cause Mortality
Secondary Endpoints: CV Death, MI, or HF
Other Endpoints:
Safety and Tolerability
Copyright © 2003 Duke Clinical Research Institute. All rights reserved.
Enrollment and Follow-up
14,808 Patients Randomized
Informed consent
not ensured: 105 patients
14,703 Patients
Captopril
Valsartan
Combination
4909
4909
4885
Vital status
unknown:
38 (0.8%)
4871 (99.2%)
Vital status
unknown:
53 (1.1%)
4856 (98.9%)
Vital status
unknown:
48 (1.0%)
4837 (99.0%)
Median follow-up: 24.7 months
Vital status ascertained in 14,564 patients (99.05%)
Vital status not ascertained in 139 patients (0.95%)
(lost to follow-up at 1 year: 0.4%; 2 years: 0.7%)
Copyright © 2003 Duke Clinical Research Institute. All rights reserved.
Baseline
Characteristics
Mean age (years)
64.8
Thrombolytic therapy (%)
35.2
Women (%)
31.1
Primary PCI (%)
14.8
Other PCI after MI,
before randomization (%)
19.8
Qualifying MI site (%)
Anterior
Inferior
59.4
34.4
Qualifying MI type (%)
Q wave
Non Q wave
66.6
31.9
Mean BP (mm Hg)
Killip class (%)
Mean LVEF* (%)
Creatinine
Days to
randomization
123/72
I
II
III
IV
28.0
48.3
17.3
6.4
35.3
1.1 mg/dL
98 µmol/L
4.9
*data on LVEF were available for 11,338 patients
Copyright © 2003 Duke Clinical Research Institute. All rights reserved.
Baseline
Characteristics
Medical History (%):
Baseline Medications (%):
Diabetes mellitus
23.1
ACE inhibitor*
Hypertension
55.2
ARB*
Smoking
31.7
Beta-blocker
70.4
Aspirin
91.3
Other antiplatelet
24.8
Potassium-sparing
diuretic
9.0
Prior:
Myocardial infarction
27.9
Heart failure
14.8
Stroke
6.1
CABG
7.0
PCI
7.3
39.6
1.2
Other diuretic
50.3
Statin
34.1
*stopped before randomization
Copyright © 2003 Duke Clinical Research Institute. All rights reserved.
Study Drug
Dose Titration
Step I
Step II
Step III
Step IV
Cap 50 mg (tid)
Cap 25 mg
CAPTOPRIL (tid) Cap 6.25 mg
Cap 12.5 mg
Val 160 mg (bid)
Val 80 mg
Val 40 mg
VALSARTAN (bid) Val 20 mg
COMBINATION
Cap 12.5 mg
Cap 6.25 mg Val 20 mg
Val 20 mg
Cap 25 mg
Val 40 mg
Cap 50 mg (tid)
Val 80 mg (bid)
GOAL by 3 months
Am Heart
J. 2000;140:727–734
Copyright © 2003 Duke Clinical Research
Institute.
All rights reserved.
Mortality by Treatment
0.3
Captopril
Valsartan
Probability of Event
0.25
Valsartan + Captopril
0.2
0.15
0.1
0.05
Valsartan vs. Captopril: HR = 1.00; P = 0.982
Valsartan + Captopril vs. Captopril: HR = 0.98; P = 0.726
0
Months
0
Captopril 4909
Valsartan 4909
Valsartan + Cap 4885
6
12
18
24
30
36
4428
4464
4414
4241
4272
4265
4018
4007
3994
2635
2648
2648
1432
1437
1435
364
357
382
N Engl
J Med
2003;349:1893-1905
Copyright © 2003 Duke Clinical
Research
Institute.
All rights reserved.
All-Cause Mortality:
Noninferiority Analyses
Hazard Ratio
(97.5% CI)
P-value
noninferiority
margin
(noninferiority)
Intention-to-Treat
Patient Population
(n = 14,703)
0.004
Per Protocol
Patient Population
(n = 14,285)
0.002
Noninferiority not
Demonstrated
Noninferiority
Val Superior to Cap
0.8
Cap Superior to Val
1
1.13
1.2
Copyright © 2003 Duke Clinical Research Institute. All rights reserved.
Mortality in SAVE,
TRACE, AIRE, and VALIANT
Hazard Ratio for Mortality
SAVE
TRACE
Valsartan
preserves
99.6% of
mortality
benefit of
captopril
AIRE
Combined
VALIANT
(imputed placebo)
0.5
Favors
Active Drug
1
Favors
Placebo
2
Pfeffer,
McMurray,
Velazquez,
et al.
NInstitute.
Engl
J Med
2003;349
N Engl
J Med
2003;349:1893-1905
Copyright
© 2003 Duke
Clinical
Research
All rights
reserved.
CV Death, MI, or HF
by Treatment
0.4
Captopril
Valsartan
Probability of Event
Valsartan + Captopril
0.3
0.2
0.1
Valsartan vs. Captopril: HR = 0.96; P = 0.198
Valsartan + Captopril vs. Captopril: HR = 0.97; P = 0.369
0
Months
0
6
12
18
24
30
36
Pfeffer,
McMurray,
Velazquez,
et al.
NInstitute.
Engl
J Med
2003;349
N Engl
J Med
2003;349:1893-1905
Copyright
© 2003 Duke
Clinical
Research
All rights
reserved.
Cardiovascular
Mortality and Morbidity
Hazard Ratio
(97.5% CI)
P-value
noninferiority
margin
(noninferiority)
CV Death
0.001
(1657 events)
CV Death or MI
0.00001
(2234 events)
0.0001
CV Death or HF
(2661 events)
CV Death,
MI, or HF
0.000001
(3096 events)
Noninferiority not
Demonstrated
Noninferiority
Val Superior to Cap
0.8
Cap Superior to Val
1
1.13
1.2
Copyright © 2003 Duke Clinical Research Institute. All rights reserved.
Adverse Experience
Leading to Dose Reduction
Captopril
20
% of Patients
15
Valsartan
†
Valsartan + Captopril
* P < 0.05 Valsartan vs. Captopril
†P
*
< 0.05 Valsartan + Captopril vs. Captopril
10
*
5
†
*
0
n=
*
Hypotension
Renal
Causes
Hyperkalemia
Cough
Skin
Rash
2205
619
162
555
146
*
Taste
AngioDisturbance edema
82
56
Copyright © 2003 Duke Clinical Research Institute. All rights reserved.
Adverse Experience Leading to
Study Drug Discontinuation
Captopril
3.5
Valsartan
Valsartan + Captopril
* P < 0.05 Valsartan vs. Captopril
% of Patients
3
†P
< 0.05 Valsartan + Captopril vs. Captopril
2.5
†
2
1.5
*
†
1
*
*
0.5
*
0
n=
Hypotension
201
Renal
Causes
154
Hyperkalemia
23
Cough
253
Skin
Rash
90
Taste
AngioDisturbance edema
46
34
Copyright © 2003 Duke Clinical Research Institute. All rights reserved.
Conclusion
In patients with MI complicated by heart failure, left
ventricular dysfunction or both:
u 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
u 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.
Copyright © 2003 Duke Clinical Research Institute. All rights reserved.