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Supported by a grant from Novartis Pharmaceuticals

VAL sartan I n A cute myocardial i N farc T ion.

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Supported by a grant from Novartis Pharmaceuticals

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  1. VALsartan In AcutemyocardialiNfarcTion 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 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. 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

  2. ACE InhibitorMI Mortality Trials Broad (short term) CONSENSUS II GISSI-3 ISIS-4 Chinese-Cap Selective(higher risk, long term) SAVE (EF £ 40%) AIRE (clinical HF) SMILE (anterior MI, no lytic) TRACE (wall motion score, EF £ 35%)

  3. 0.4 ACE-I 0.35 Placebo 0.3 0.25 0.2 0.15 0.1 0.05 0 4 0 1 2 3 SAVERadionuclideEF £ 40% AIREClinical and/or radiographic signs of HF TRACEEchocardiographicEF £ 35% All-Cause Mortality Probability of Event Placebo: 866/2971 (29.1%) ACE-I: 702/2995 (23.4%) OR: 0.74 (0.66–0.83) Years ACE-I 2995 2250 1617 892 223 Placebo 2971 2184 1521 853 138 Flather MD, et al. Lancet. 2000;355:1575–1581

  4. 0.75* ACE-I (n = 2995) Placebo (n = 2971) (0.67 – 0.83) 40 30 0.73* Events (%) 0.80* (0.63 – 0.85) 20 (0.69 – 0.95) 10 n =324 n =391 n =355 n =460 0 Reinfarction Readmission for HF SAVERadionuclideEF £ 40% AIREClinical and/or radiographic signs of HF TRACEEchocardiographicEF £ 35% Death and Major CV Events n =1049 n =1244 Death/MI or Readmission for HF Flather MD, et al. Lancet. 2000;355:1575–1581 *odds ratio (95% CI)

  5. Renin-AngiotensinAldosterone System Non-ACE Pathways(e.g., chymase) • Vasoconstriction • Cell growth • Na/H2O retention • Sympathetic activation Angiotensinogen AT1 Angiotensin I renin Angiotensin II ACE AT2 Aldosterone • Vasodilation • Antiproliferation(kinins) Cough,Angioedema Benefits? InactiveFragments Bradykinin

  6. 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 survival and 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

  7. ACE-I Comparator MI Trial MI Trials with Mortality Benefit Early Use Long-Term GISSI 3 lisinopril SAVE captopril ISIS 4 captopril AIRE ramipril Chinese-Cap captopril TRACE trandolapril Captopril—most extensively studied with survival benefits in both early initiation and long-term trials Two prior direct ARB-ACE-I comparisons to captopril (50 mg tid) showed a trend for fewer deaths and major CV events with captopril therapy.

  8. 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 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 monthsevent-driven Primary Endpoint: All-Cause Mortality Secondary Endpoints: CV Death, MI, or HF Other Endpoints: Safety and Tolerability

  9. Russia:3135 Canada:1092 USA:3964 Europe:5163 South Africa:58 Brazil andArgentina:848 Australia/New Zealand:443 Enrollment 24 Countries. 931 Sites. 14,703 Patients.

  10. Enrollment and Follow-up 14,808 Patients Randomized Informed consent not ensured: 105 patients 14,703 Patients Captopril 4909 Valsartan 4909 Combination 4885 Vital status unknown: 38 (0.8%) Vital status unknown: 53 (1.1%) Vital status unknown: 48 (1.0%) 4871 (99.2%) 4856 (98.9%) 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%) 13

  11. BaselineCharacteristics Mean age (years) 64.8 Women (%) 31.1 Mean BP (mm Hg) 123/72 Killip class(%) I 28.0 II 48.3 III 17.3 IV 6.4 Mean LVEF* (%) 35.3 Creatinine 1.1 mg/dL 98 μmol/L Time to randomization (d) 4.9 Thrombolytic therapy (%) 35.2 Primary PCI (%) 14.8 Other PCI after MI,prior to randomization (%) 19.8 Qualifying MI site (%) Anterior 59.4 Inferior 34.4 Qualifying MI type (%) Q wave 66.6 Non Q wave 31.9 *data on LVEF were available for 11,338 patients Pfeffer, McMurray, Velazquez, et al. N Engl J Med 2003;349:1893–1906

  12. Pfeffer, McMurray, Velazquez, et al. N Engl J Med 2003;349:1893–1906 BaselineCharacteristics Medical History (%): Diabetes mellitus 23.1 Hypertension 55.2 Smoking 31.7 Prior: Myocardial infarction 27.9 Heart failure 14.8 Stroke 6.1 CABG 7.0 PCI 7.3 Baseline Medications (%): ACE inhibitor* 39.6 ARB* 1.2 Beta-blocker 70.4 Aspirin 91.3 Other antiplatelet 24.8 Potassium-sparing diuretic 9.0 Other diuretic 50.3 Statin 34.1 *stopped prior to randomization

  13. BaselineCharacteristics Valsartan + Valsartan Captopril CaptoprilCharacteristic(n = 4909) (n = 4885) (n = 4909) Age (yr) 65.0 ± 11.8 64.6 ± 11.9 64.9 ± 11.8 Race Caucasian 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 ± 17.0 Diastolic 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 Pfeffer, McMurray, Velazquez, et al. N Engl J Med 2003;349:1893–1906

  14. BaselineCharacteristics Valsartan + Valsartan Captopril CaptoprilCharacteristic(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 ± 10.4 Killip 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 4.9 Serum creatinine (mg/dL) 1.1 ± 0.3 1.1 ± 0.3 1.1 ± 0.4 *measured in 11,338 (77.1%) of the patients Pfeffer, McMurray, Velazquez, et al. N Engl J Med 2003;349:1893–1906

  15. BaselineCharacteristics Valsartan Combination CaptoprilCharacteristicn = 4909 n = 4885 n = 4909 Qualifying MI site (%) Anterior 58.7 60.3 59.3 Inferior 34.1 34.4 34.7 Qualifying MI type (%) Q wave 65.8 66.4 67.5 Non 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 Pfeffer, McMurray, Velazquez, et al. N Engl J Med 2003;349:1893–1906

  16. Pfeffer, McMurray, Velazquez, et al. N Engl J Med 2003;349:1893–1906 BaselineMedications Valsartan Combination CaptoprilMedicationn = 4909 n = 4885 n = 4909 ACE inhibitor* 39.4 40.8 38.5 Angiotensin-receptorblocker* 1.1 1.1 1.4 Beta blockers 70.6 70.4 70.1 Aspirin 91.3 91.1 91.4 Other antiplatelets 25.1 24.7 24.6 Potassium-sparing diuretic 9.1 9.0 9.1 Other diuretics 51.3 50.3 49.4 HMG CoA reductase inhibitors 33.8 34.1 34.4 *stopped prior to randomization

  17. Medical History Valsartan + Valsartan Captopril CaptoprilHistory 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%) Pfeffer, McMurray, Velazquez, et al. N Engl J Med 2003;349:1893–1906

  18. Step I Step II Step III Step IV Cap 50 mg (tid) Cap 25 mg Cap 12.5 mg CAPTOPRIL (tid) Cap 6.25 mg Val 160 mg (bid) Val 80 mg Val 40 mg Val 20 mg VALSARTAN (bid) Cap 50 mg (tid) Val 80 mg (bid) Cap 25 mg Val 40 mg Cap 12.5 mg Val 20 mg Cap 6.25 mg Val 20 mg COMBINATION GOAL by 3 months Study DrugDose Titration Am Heart J. 2000;140:727–734.

  19. Valsartan Valsartan + Captopril Captopril Mortality by Treatment 0.3 0.25 0.2 0.15 Probability of Event 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 6 12 18 24 30 36 Captopril 4909 4428 4241 4018 2635 1432 364 Valsartan 4909 4464 4272 4007 2648 1437 357 Valsartan + Cap 4885 4414 4265 3994 2648 1435 382 Pfeffer, McMurray, Velazquez, et al. N Engl J Med 2003;349

  20. Intention-to-TreatPatient Population(n = 14,703) 0.004 Per ProtocolPatient Population(n = 14,285) 0.002 Noninferiority not Demonstrated Noninferiority Val Superior to Cap Cap Superior to Val All-Cause Mortality:Non-Inferiority Analyses Hazard Ratio(97.5% CI) P-value(noninferiority) noninferiority margin 0.8 1 1.2 1.13 Favors Valsartan Favors Captopril

  21. SAVE TRACE AIRE Combined VALIANT (imputed placebo) 0.5 1 2 Pfeffer, McMurray, Velazquez, et al. N Engl J Med 2003;349 Mortality in SAVE,TRACE, AIRE, and VALIANT Hazard Ratio for Mortality Valsartan preserves 99.6% of mortality benefit of captopril. 25% risk for total Mortality FavorsActive Drug FavorsPlacebo

  22. Valsartan Valsartan + Captopril Captopril CV Death, MI, or HFby Treatment 0.4 0.3 Probability of Event 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. N Engl J Med 2003;349

  23. CV Death(1657 events) 0.001 CV Death or MI(2234 events) 0.00001 0.0001 CV Death or HF(2661 events) CV Death, MI, or HF(3096 events) 0.000001 Noninferiority not Demonstrated Noninferiority Val Superior to Cap Cap Superior to Val CardiovascularMortality and Morbidity Hazard Ratio(97.5% CI) P-value(noninferiority) noninferiority margin 0.8 1 1.2 1.13 Favors Valsartan Favors Captopril

  24. Favors Combination Favors Captopril Pfeffer, McMurray, Velazquez, et al. N Engl J Med 2003;349:1893–1906 Hazard Ratios (95% CI)for CV Death, MI, or HF # of Pts. P-Value(interaction) # of Pts. P-Value(interaction) Median < 65Age³ 65 Sex Male Female Prior MI No Yes DM No Yes SBP£ median> median Serum £ medianCr> median Killip IClass II III IV 46185200 67383080 70882730 75642254 56324182 49704837 271847471687619 46755119 67683026 70852709 75282266 56424149 49084878 280546751655618 0.96 0.55 0.93 0.12 0.71 0.67 0.84 1.00 0.47 0.26 0.85 0.68 0.92 0.11 29106882 29076911 Beta- NoBlocker Yes 0.48 0.56 0.5 1 2 0.5 1 2 Favors Valsartan Favors Captopril

  25. Pfeffer, McMurray, Velazquez, et al. N Engl J Med 2003;349:1893–1906 Hazard Ratios (95% CI)for CV Death, MI, or HF Favors Valsartan Favors Captopril P-Value (interaction) Valsartan vs. Captopril: No Beta-Blocker (n = 2907) Beta-Blocker (n = 6911) 0.48 Combination vs. Captopril: No Beta-Blocker (n = 2910) Beta-Blocker (n = 6882) 0.56 0.5 1 2 Favors Combination Favors Captopril

  26. Valsartan247 mg Valsartan + Captopril116 mg 107 mg Captopril117 mg Study Drug Use mean dose at 1 year = Target Dose 60% 30% 0% Off Drug 30% 15% 0% Month 1 6 12 20 36

  27. Valsartan Valsartan + Captopril * Captopril * * Study DrugDiscontinuation 0.4 0.3 Overall 0.2 Probability of Event Due to Adverse Events 0.1 0 0 6 12 18 24 30 36 Months *P < 0.05 vs Captopril

  28. Valsartan Valsartan + Captopril Captopril † * † * * * Adverse Experience Leading to Study Drug Discontinuation 3.5 * P < 0.05 Valsartan vs. Captopril †P < 0.05 Valsartan + Captopril vs. Captopril 3 2.5 2 % of Patients 1.5 1 0.5 0 Hypo- Renal Hyper- Cough Skin Taste Angio- tension Causes kalemia Rash Disturbance edema n = 201 154 23 253 90 46 34

  29. 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.

  30. 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. Thank You

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