Supported by a grant from Novartis Pharmaceuticals

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

Marc A. Pfeffer, M.D., Ph.D. (Chair), John J.V. McMurray, M.D. (Co-Chair), Eric J. Velazquez, M.D., Jean-Lucien Rouleau, M.D., Lars Køber, M.D., Aldo P.

Maggioni, M.D., Scott D. Solomon, M.D., Karl Swedberg, M.D., Ph.D., Frans Van de Werf, M.D., Ph.D.,

Harvey D. White, D.Sc., Jeffrey D. Leimberger, Ph.D., Marc Henis, M.D., Susan Edwards, M.S.,

Steven Zelenkofske, D.O., Mary Ann Sellers, M.S.N., and Robert M. Califf, M.D., for the VALIANT Investigators

VALsartan In Acute myocardial iNfarcTion

Other Steering Committee Members: P. Aylward, P. Armstrong, 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.

ACE InhibitorMI Mortality Trials

Selective(higher risk, long term)

SAVE (EF 40%)AIRE (clinical HF)SMILE (anterior MI, no lytic)TRACE(wall motion score,

EF 35%)

Broad (short term)

CONSENSUS IIGISSI-3ISIS-4

Chinese-Cap

All-Cause Mortality

Years

Prob

abili

ty o

f Eve

nt

0

0.05

0.1

0.15

0.2

0.25

0.3

0 1 2 3

0.35

0.4

4

ACE-IPlacebo

ACE-I 2995 2250 1617 892 223Placebo 2971 2184 1521 853 138

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

OR: 0.74 (0.66–0.83)ACE-I: 702/2995 (23.4%)

Placebo: 866/2971 (29.1%)

TRACEEchocardiographicEF 35%

AIREClinical and/or radiographic signs of HF

SAVERadionuclideEF 40%

Readmission for HF

n =460

n =355

(0.63 – 0.85)

0.73*

Reinfarction

n =324

n =391

(0.69 – 0.95)

0.80*

*odds ratio (95% CI)

Death and Major CV Events

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

Placebo (n = 2971)ACE-I (n = 2995)

Death/MI or Readmission for HF

Even

ts (

%)

0

10

20

30

40

n =1049

n =1244

(0.67 – 0.83)

0.75*

TRACEEchocardiographicEF 35%

AIREClinical and/or radiographic signs of HF

SAVERadionuclideEF 40%

Renin-AngiotensinAldosterone System

Angiotensinogen

Non-ACE Pathways(e.g., chymase)

Vasoconstriction Cell growth Na/H2O retention Sympathetic activation

renin Angiotensin I

Angiotensin IIACE

Cough,Angioedema

Benefits? Bradykinin Inactive

Fragments

Vasodilation Antiproliferation

(kinins)

Aldosterone AT2

AT1

Aims

VALIANT was designed as a mortality trial in high-risk MI

patients (SAVE, AIRE, TRACE) who derived particular benefits

from an ACE inhibitor.To determine whether: the ARB valsartan was superior to captopril in

improving survivaland with equal statistical power

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

ACE-I Comparator MI Trial

MI Trials with Mortality Benefit

Early Use Long-TermGISSI 3 lisinopril SAVE captoprilISIS 4 captopril AIRE ramiprilChinese-Cap captopril TRACE

trandolapril

Captopril—most extensively studied with survival benefits in both early initiation and long-term trialsTwo prior direct ARB-ACE-I comparisons to captopril (50 mg tid) showed a trend for fewer deaths and major CV events with captopril therapy.

Primary Endpoint: All-Cause MortalitySecondary Endpoints: CV Death, MI, or HFOther Endpoints: Safety and Tolerability

Captopril 50 mg tid(n = 4909)

Valsartan 160 mg bid

(n = 4909)

Captopril 50 mg tid + Valsartan 80 mg

bid(n = 4885)

Acute MI (0.5–10 days)—SAVE, AIRE or TRACE eligible(either clinical/radiologic signs of HF or LV systolic dysfunction)

Major Exclusion Criteria:— Serum creatinine 2.5 mg/dL— BP 100 mm Hg— Prior intolerance of an ARB or ACE-I— Nonconsent

double-blind active-controlled

median duration: 24.7 monthsevent-driven

Enrollment

Europe:5163

Australia/New Zealand:

443

Brazil andArgentina

:848

South Africa:

58

Russia:3135Canada:

1092USA:3964

24 Countries. 931 Sites. 14,703 Patients.

Captopril4909

4871 (99.2%)

Vital status unknown:38 (0.8%)

Enrollment and Follow-up

Median follow-up: 24.7 months

Valsartan4909

4856 (98.9%)


14,808 Patients Randomized

4837 (99.0%)


Combination4885

Informed consent not ensured: 105 patients

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%)

14,703 Patients

13

BaselineCharacteristics

Mean age (years) 64.8Women (%) 31.1Mean BP (mm Hg)123/72Killip class (%) I 28.0

II 48.3III 17.3IV 6.4

Mean LVEF* (%) 35.3Creatinine 1.1 mg/dL

98 μmol/LTime to randomization (d) 4.9

Pfeffer, McMurray, Velazquez, et al. N Engl J Med 2003;349:1893–1906

Thrombolytic therapy (%) 35.2

Primary PCI (%) 14.8

Other PCI after MI,prior to randomization (%)19.8

Qualifying MI site (%)Anterior 59.4Inferior 34.4

Qualifying MI type (%)Q wave 66.6Non Q wave 31.9

*data on LVEF were available for 11,338 patients

Baseline Medications (%):ACE inhibitor* 39.6ARB* 1.2Beta-blocker 70.4Aspirin 91.3Other antiplatelet 24.8Potassium-sparing diuretic 9.0Other diuretic 50.3Statin 34.1



*stopped prior to randomization

Medical History (%):Diabetes mellitus 23.1Hypertension 55.2Smoking 31.7

Prior:Myocardial infarction 27.9Heart failure 14.8Stroke 6.1CABG 7.0PCI 7.3


Valsartan +Valsartan Captopril Captopril

Characteristic (n = 4909) (n = 4885) (n = 4909)

Age (yr) 65.0 ± 11.8 64.6 ± 11.9 64.9 ± 11.8

RaceCaucasian 4604 (93.8%) 4553 (93.2%) 4591 (93.5%)Black 125 (2.5%) 137 (2.8%) 145 (3.0%)Asian 44 (0.9%) 53 (1.1%) 44 (0.9%)Other 136 (2.8%) 142 (2.9%) 129 (2.6%)

Females 1544 (31.5%) 1490 (30.5%) 1536 (31.3%)

Blood pressure (mm Hg)Systolic 122.7 ± 16.8 122.5 ± 17.1 122.8 ± 17.0Diastolic 72.3 ± 11.3 72.3 ± 11.4 72.4 ± 11.2

Heart rate (beats/min) 76.2 ± 13.0 76.2 ± 12.7 76.2 ± 12.8



Valsartan +Valsartan Captopril Captopril

Characteristic (n = 4909) (n = 4885) (n = 4909)BMI (kg/m2) (median) 27.34 27.24 27.14

(25th, 75th percentile) (24.69, 30.47) (24.62, 30.35) (24.54, 30.22)LVEF* (%) 35.3 ± 10.4 35.3 ± 10.3 35.3 ± 10.4Killip class

I 1294 (26.5%) 1381 (28.4%) 1424 (29.1%)II 2401 (49.2%) 2329 (47.9%) 2346 (48.0%)III 874 (17.9%) 842 (17.3%) 813 (16.6%)IV 313 (6.4%) 312 (6.4%) 306 (6.3%)

Days from MIto randomization 4.8 4.9 4.9Serum creatinine (mg/dL) 1.1 ± 0.3 1.1 ± 0.3 1.1 ± 0.4


*measured in 11,338 (77.1%) of the patients


Valsartan Combination CaptoprilCharacteristic n = 4909 n = 4885 n = 4909

Qualifying MI site (%)Anterior 58.7 60.3 59.3Inferior 34.1 34.4 34.7

Qualifying MI type (%)Q wave 65.8 66.4 67.5Non Q wave 32.5 32.2 31.1

Thrombolytic therapy (%) 35.5 35.0 35.0

Primary PCI (%) 14.9 14.9 14.6

Other PCI after MI,prior to randomization (%) 20.6 19.4 19.5


BaselineMedications

Valsartan Combination CaptoprilMedication n = 4909 n = 4885 n = 4909ACE inhibitor* 39.4 40.8 38.5Angiotensin-receptorblocker* 1.1 1.1 1.4Beta blockers 70.6 70.4 70.1Aspirin 91.3 91.1 91.4Other antiplatelets 25.1 24.7 24.6Potassium-sparing diuretic 9.1 9.0 9.1Other diuretics 51.3 50.3 49.4HMG CoA reductase inhibitors 33.8 34.1 34.4


*stopped prior to randomization

Medical HistoryValsartan +Valsartan Captopril Captopril

History of… (n = 4909) (n = 4885) (n = 4909)

MI 1395 (28.4%) 1376 (28.2%) 1333 (27.2%)

Hypertension 2732 (55.7%) 2700 (55.3%) 2690 (54.8%)

Diabetes mellitus 1134 (23.1%) 1146 (23.5%) 1120 (22.8%)

Heart failure 759 (15.5%) 701 (14.4%) 714 (14.5%)

Stroke 292 (5.9%) 305 (6.2%) 298 (6.1%)

Smoking 1556 (31.7%) 1546 (31.7%) 1562 (31.9%)

Prior CABG 355 (7.2%) 327 (6.7%) 344 (7.0%)

Prior PCI 376 (7.7%) 337 (6.9%) 354 (7.2%)


Cap 6.25 mgVal 20 mg

Cap 12.5 mgVal 20 mg

Cap 25 mgVal 40 mg

Cap 50 mg (tid)Val 80 mg (bid)

COMBINATION

Cap 6.25 mgCap 12.5 mg

Cap 25 mgCap 50 mg (tid)

CAPTOPRIL (tid)

Val 20 mgVal 40 mg

Val 80 mgVal 160 mg (bid)

VALSARTAN (bid)

Step I

GOAL by 3 months

Step IVStep IIIStep II

Study DrugDose Titration

Am Heart J. 2000;140:727–734.

Captopril

0

0.05

0.1

0.15

0.2

0.25

0.3

0 6 12 18 24 30 36

Prob

abili

ty o

f Eve

ntMortality by Treatment

Pfeffer, McMurray, Velazquez, et al. N Engl J Med 2003;349

Valsartan 4909 4464 4272 4007 2648 1437 357

Months

Valsartan vs. Captopril: HR = 1.00; P = 0.982Valsartan + 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

ValsartanValsartan + Captopril

All-Cause Mortality:Non-Inferiority Analyses

0.8 1 1.2

Hazard Ratio(97.5% CI)

1.13

P-value(noninferiority)

0.002Per ProtocolPatient

Population(n = 14,285)

0.004Intention-to-Treat

Patient Population

(n = 14,703)

NoninferiorityVal Superior to

Cap Cap Superior to Val

Noninferiority not Demonstrated

noninferiority margin

Favors Valsartan Favors Captopril

Mortality in SAVE,TRACE, AIRE, and VALIANT

Hazard Ratio for Mortality

FavorsActive Drug

FavorsPlacebo


0.5 1 2

Combined

TRACE

SAVE

AIRE

VALIANT(imputed placebo)

Valsartan preserves 99.6% of mortality benefit of captopril.25% risk for total Mortality

Captopril

CV Death, MI, or HFby Treatment


Months

Valsartan vs. Captopril: HR = 0.96; P = 0.198Valsartan + Captopril vs. Captopril: HR = 0.97; P =

0.3690

0.1

0.2

0.3

0.4

0 6 12 18 24 30 36

Prob

abili

ty o

f Eve

nt

Valsartan

Valsartan + Captopril

NoninferiorityVal Superior to

Cap Cap Superior to Val

Noninferiority not Demonstrated

CardiovascularMortality and Morbidity

0.8 1 1.2

Hazard Ratio(97.5% CI)

1.13

P-value(noninferiority)

noninferiority margin

CV Death(1657 events)

0.001

CV Death or HF(2661 events)

0.0001

CV Death or MI(2234 events)

0.00001

CV Death, MI, or HF

(3096 events)

0.000001

Favors Valsartan Favors Captopril

Hazard Ratios (95% CI)for CV Death, MI, or HF


Favors Combination

Favors Captopr

il

Median 65Age 65Sex Male

FemalePrior MINo

YesDM No

YesSBP median

medianSerum medianCr medianKillip IClass II

IIIIV

Beta- NoBlocker Yes

0.5 1 2Favors Valsarta

n

Favors Captopr

il

# of Pts. P-Value(interaction)

0.5 1 2

# of Pts. P-Value(interaction)

461852006738308070882730756422545632418249704837271847471687

619

0.96

0.55

0.93

0.12

0.71

0.67

0.84

467551196768302670852709752822665642414949084878280546751655

618

1.00

0.47

0.26

0.85

0.68

0.92

0.11

29076911 0.48 2910

6882 0.56

Hazard Ratios (95% CI)for CV Death, MI, or HF


Valsartan vs. Captopril:No Beta-Blocker (n = 2907)

Beta-Blocker (n = 6911)Combination vs. Captopril:No Beta-Blocker (n = 2910)

Beta-Blocker (n = 6882)

0.5 1 2

Favors CaptoprilFavors Valsartan

Favors CaptoprilFavors Combination

0.56

0.48

P-Value (interaction)

Off Drug

0%

15%

30%

1 6 12 20 36

Study Drug Use

Month

Target Dose

0%

30%

60%

Valsartan247 mg

Captopril117 mgmean dose at 1 year =

Valsartan + Captopril116 mg 107 mg

Captopril

0

0.1

0.2

0.3

0.4

0 6 12 18 24 30 36

Months

Prob

abili

ty o

f Eve

nt

Study DrugDiscontinuation

Overall

Due to Adverse Events

*P < 0.05 vs Captopril

Valsartan + Captopril*

*

Valsartan

*

**

*

*

Valsartan

†

†

Valsartan + CaptoprilCaptopril

Hypo- Renal Hyper- Cough Skin Taste Angio-tension Causes kalemia Rash Disturbanceedema

Adverse Experience Leading to Study Drug Discontinuation

* P < 0.05 Valsartan vs. Captopril†P < 0.05 Valsartan + Captopril vs. Captopril

0

0.5

1

1.5

2

2.5

3

3.5

% o

f Pat

ient

s

n = 201 154 23 253 90 46 34

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

effectivealternative to an ACE inhibitor.

Thank You

The following persons participated in the VALIANT trial.

Executive Committee: M. Pfeffer (Chair), J. McMurray (Co-Chair), R. Califf, A. Maggioni,

J-L. Rouleau, F. Van de Werf, E. Velazquez.

Steering Committee: P. Aylward, P. Armstrong, S. Barvik, Y. Belenkov, A. Dalby, R. Diaz, H. Drexler, G. Ertl, G. Francis, J. Hampton, A. Harsanyi, L. Køber, J.

Kvasnicka, V. Mareev, J. Marin-Neto, J. Murin, M. Myers, R. Nordlander, G. Opolski,

J. Soler-Soler, J. Spac, T. Stefenelli, D. Sugrue, K. Swedberg, W. Van Gilst,

S. Varshavsky, D. Weaver, H. White, F. Zannad.

Clinical Endpoint Committee, Brigham and Women's Hospital:S. Solomon (Chair), D. Aguilar, A. Alvarez, M. Al-Taweel, N.

Anavekar, P. Finn, F. Lopez-Jimenez, R. Mercier, M. Pfeffer, E. Lewis, S. Massoom, C. Manes,

A. Mirza, U. Sampson, H. Skali, N. Skali, K. Szummer, M. Tokmakova, L. Zornoff.

Clinical Endpoint Committee, Duke Clinical Research Institute:T. Bozeman, R. Doletski, R. Lail, K. Mahaffey, M. Smith, L. Taylor, B.

Thomas.

Data and Safety Monitoring Board (DSMB):A. Leizorovicz (Chair), F. Boutitie (Independent statistician), R.

Cody, H. Dargie, C. Hennekens, S. Pocock.

Countries:Argentina (635 patients), Australia (307 patients), Austria: (27 patients), Belgium (68 patients), Brazil (213 patients), Canada (1092 patients), Czech Republic (207 patients), Denmark (681

patients), France (163 patients), Germany (323 patients), Hungary (400 patients), Ireland (38 patients), Italy (753 patients),

Netherlands (255 patients), New Zealand (136 patients), Norway (263 patients), Poland (348 patients), Russia (3,135 patients), Slovakia (184 patients), South Africa (58 patients), Spain (123

patients), Sweden (490 patients), United Kingdom (840 patients), United States (3964 patients)

Monitoring and Site Management Organizations:Canadian VIGOUR Centre: Lead Monitor, C. Boyd, M. Adam; Montreal Heart Institute: Lead Monitor, L. Whittom, J. Marquis; ECLA-Estudios

Cardiologicos Latinoamerica: Project Leader, A. Pascual, Lead Monitor, A. Medina; Flinders Coordinating Centre: Lead Monitor, C.

Astley, M. Schofield; Green Lane Coordinating Centre: Lead Monitor, M. Kelkar, O. Bucan; Scandinavian Clinical Research Institute:

Research Manager, S. Lindbratt; Henry Ford Coordinating Center: Lead Coordinator, C. Sherlitz; Mayo Alliance for Clinical Trials: Lead

Coordinator, K. Cornwell; Medicon Scandinavia A/S: Medical Director, J. Carlsen; Brigham and Women's Hospital: Research

Coordinator, R. Mercier; PAREXEL International: Project Director, T. Spencker, Lead Monitor, K. Pohlner; Quintiles: Project Director, A. Black, IVR Project Director, T. Steven; University of Toronto: Lead

Coordinator, C. Leblanc.

Trial Operations: Duke Clinical Research Institute Project Leader: M.A. Sellers, Lead

Coordinator: L. Rittenhouse, Lead Monitor: L. Sunas, Lead Statistician: J. Leimberger, Lead Data Manager: A. Walden; Leuven

Coordinating Centre Safety Manager, M. Moreira, Project Manager, K. Houbracken, K. Vandenberghe; Russian Clinical Helplines – Moscow: F. Ageev, A. Skvortsov, O. Narusov, G. Mareeva, J.

Gurskaya; St. Petersburg: A. Shargorodskaya.

Sponsor:Novartis Pharmaceuticals Corporation – Medical Directors: S.

Zelenkofske, M. Henis; Project Leader: S. Edwards; Statistician: J. Gong;

Programmers: X. Han, J. Shinomoto; Clinical Team: P. Barbiero, T. Jezek, J. Kaczor,

N.B. Keating, R. Koempf, R. McGarry, G. Rossy, C. Salemi, A. Trapani.

24 Countries. 931 Sites.14,703 Patients.

Supported by a grant from Novartis Pharmaceuticals

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