Supported by a grant from Novartis Pharmaceuticals VALsartan In Acute myocardial iNfarcTion 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. The Valsartan in Acute Myocardial Infarction Trial –VALIANT. 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

ACE Inhibitor MI 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%) Angiotensin-converting enzyme inhibitors or ACE inhibitors are of proven clinical value in a broad spectrum of patients with cardiovascular disease. With over one hundred thousand patients with acute myocardial infarction enrolled in placebo-controlled randomized trials, a clear survival benefit was demonstrated with the use of ACE inhibitors. The relative and absolute benefits of ACE inhibitors were most pronounced when administered long-term to patients selected for higher risk based on LV dysfunction and/or clinical signs of acute heart failure. GISSI 3 Captopril SAVE Captopril ISIS 4 Captopril AIRE Ramipril Chinese-Cap Captopril SMILE Xofenipril TRACE Trandolopril Swedberg, et al., CONSENSUS II, NEJM:327:678-684,1992. GISSI 3 investigators, LANCET, 343: 1115-22, 1994. ISIS-4 (Fourth International Study of Infarct Survival) Collaborative Group,Lancet; 345:669-85,1995 Chinese Cardiac Study Collaborative Group,Lancet; 345:686-7,1995 Kober L, Torp-Pedersen C, Carlsen JE, et al for the Trandolapril Cardiac Evaluation (TRACE) Study Group N Engl J Med; 333:1670-6,1995. Pfeffer MA, Braunwald E, Moye LA, et al on behalf of the SAVE Investigators. N Engl J Med; 327:669-77,1992. The Acute Infarction Ramipril Efficacy (AIRE) Study Investigators.Lancet; 342:821-8, 1993. Ambrosioni, SMILE investigators, NEJM: 332; 80-85, 1995.

SAVE Radionuclide EF £ 40% AIRE Clinical and/or radiographic signs of HF TRACE Echocardiographic EF £ 35% All-Cause Mortality 0.05 0.1 0.15 0.2 0.25 0.3 1 2 3 0.35 0.4 4 Placebo ACE-I Probability of Event Placebo: 866/2971 (29.1%) SAVE, AIRE and TRACE represent the 3 placebo-controlled trials that tested an ACE inhibitor in higher risk MI patients and maintained the therapy beyond 6 months. The survival advantage occurred early and increased to approximately 60 lives saved per thousand treated with long-term therapy. In this meta-analysis, ACE inhibitor use reduced the odds ratio for death by approximately 26%. With over 1500 deaths, the confidence intervals were narrow and the results considered sufficiently robust so that no further placebo-controlled trials are warranted Flather MD, et al. Lancet:2000;355:1575-1581 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

Death and Major CV Events SAVE Radionuclide EF £ 40% AIRE Clinical and/or radiographic signs of HF TRACE Echocardiographic EF £ 35% Death and Major CV Events (0.67 – 0.83) 0.75* Events (%) 10 20 30 40 Placebo (n = 2971) ACE-I (n = 2995) Readmission for HF n = 460 n = 355 (0.63 – 0.85) 0.73* Reinfarction n = 324 n = 391 (0.69 – 0.95) 0.80* In addition to the survival benefit shown in the three post-infarction trials with ACEIs, rates of readmission for heart failure were lower than with placebo, as were rates of reinfarction or the composite of these events. The benefits were observed early after the start of therapy and persisted long term. The benefits of treatment on all outcomes were independent of age, sex, and baseline use of diuretics, aspirin, and beta-blockers. The use of ACE inhibitors in these patients was also associated with important reductions in the risk of major nonfatal CV events, such as hospital admission for the management of heart failure and experiencing a recurrent myocardial infarction. Indeed, in the meta-analysis with over 2200 events, there was a 25% reduction in the risk of death, non-fatal MI or heart failure in those randomized to an ACE inhibitor as compared to placebo plus conventional medical therapies. Flather MD, et al. Lancet:2000;355:1575-1581 1. Flather MD, Yusuf S, Kober L, et al. Long-term ACE-inhibitor therapy in patients with heart failure or left-ventricular dysfunction: a systematic overview of data from individual patients. Lancet. 2000;355:1575–1581. n = 1049 n = 1244 Death/MI or Readmission for HF Flather MD, et al. Lancet. 2000;355:1575–1581 *odds ratio (95% CI)

Renin-Angiotensin Aldosterone System Non-ACE Pathways (e.g., chymase) Vasoconstriction Cell growth Na/H2O retention Sympathetic activation Angiotensinogen AT1 renin Angiotensin I Angiotensin II ACE Angiotensin-receptor blockers, or ARBs, provide an opportunity to inhibit the renin-angiotensin system directly at the angiotensin II type 1 receptor level, which has been postulated to provide more complete inhibition of the deleterious effects of angiotensin. Alternatively, because ACE inhibitors (kininase II inhibitors) also reduce bradykinin breakdown, the combination of an ACE inhibitor plus an ARB may result in incremental clinical benefits. These assumptions must be rigorously tested as direct comparisons of these three modes of inhibiting the renin-angiotensin system to provide the quantitative data needed to guide clinical practice. Aldosterone AT2 Cough, Angioedema Benefits? Vasodilation Antiproliferation (kinins) Inactive Fragments  Bradykinin

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 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, with equal statistical power, to determine whether, 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 in improving survival. Am Heart J;2000;140:727-734 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-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 Captopril was chosen as a comparator because it was the most studied ACE inhibitor with the most extensive proof of clinical benefit. No head to head trial has previously shown a benefit or “as good as” captopril. 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.

double-blind active-controlled 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) Patients with acute MI (12 hours to 10 days), complicated by either clinical and/or radiologic signs of heart failure and/or LV dysfunction (radionuclide EF less than 40 % or echocardiographic EF less than or equal to 35%) were eligible. Major exclusions were persistent cardiogenic shock, systolic blood pressure less than 100 mmHg, serum creatinine above 2.5 mg/dl, prior intolerance to an ACE inhibitor or ARB, unwillingness to provide consent. This was an active therapy trial with no placebo and all comparisons are made against the captopril group. Consenting patients were randomized in a 1:1:1 manner to either captopril using the SAVE regimen - target of 50 mg, t.i.d; valsartan – target to 160 mg b.i.d.; or the combination captopril (SAVE regimen) plus valsartan target to 80 mg b.i.d.  The primary end point was all-cause mortality and the trial was designed to be event driven. Other important end points were CV death, hospitalization for heart failure and recurrent MI. Safety and tolerability were assessed and compared. The median duration of follow-up in VALIANT was 24.7 months. Pfeffer, et al., NEJM 2003;349:1893-1906 median duration: 24.7 months event-driven Primary Endpoint: All-Cause Mortality Secondary Endpoints: CV Death, MI, or HF Other Endpoints: Safety and Tolerability

24 Countries. 931 Sites. 14,703 Patients. Enrollment 24 Countries. 931 Sites. 14,703 Patients. Europe: 5163 Australia/ New Zealand: 443 Brazil and Argentina:848 South Africa: 58 Russia: 3135 Canada: 1092 USA: 3964 VALIANT was truly an international study conducted in 24 countries with 931 participating sites that randomized the 14,703 patients.

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%) 14,703 patients randomized and consented. Vital status was ascertained in just over 99% and was even in all 3 groups. Median follow-up 24.7 months. Vital status known similar in all 3 groups. 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

Baseline Characteristics 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 Baseline characteristics of the three groups were well balanced. The mean age was approximately 65 years and just over 30% were female. 28% were Killip Class 1 qualifying by ejection fraction criteria, and over three quarters developed some degree of pulmonary congestion. The ejection fraction was 35%. Randomization occurred just under five days, with 50% receiving some form of reperfusion therapy - 35% thrombolytic; 15% primary angioplasty. Two thirds of the infarcts were considered Q-wave. Pfeffer, et al., NEJM 2003;349:1893-1906 *data on LVEF were available for 11,338 patients Pfeffer, McMurray, Velazquez, et al. N Engl J Med 2003;349:1893–1906

Baseline Characteristics 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 Study drug therapy in VALIANT as given in addition to all the standard therapies patients receive with an acute MI. 23% had a history of diabetes; over half hypertension; and 32% were smokers at the time of the infarct. 28% had a previous infarct; and 15% had a history of heart failure prior to the infarct. ACE inhibitors and ARBs could be used prior randomization and were discontinued 12 hours prior to randomization. Aspirin was used in over 90% with other anti-platelets also administered to about 25%; and over 70% of the patients were on a beta-blocker at randomization. Pfeffer, et al., NEJM 2003;349:1893-1906 *stopped prior to randomization Pfeffer, McMurray, Velazquez, et al. N Engl J Med 2003;349:1893–1906

Baseline Characteristics 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 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 Baseline demographics and vital signs were comparable between the 3 groups. Pfeffer, et al., NEJM 2003;349:1893-1906 Pfeffer, McMurray, Velazquez, et al. N Engl J Med 2003;349:1893–1906

Baseline Characteristics 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 ± 10.4 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 MI to randomization 4.8 4.9 4.9 Serum creatinine (mg/dL) 1.1 ± 0.3 1.1 ± 0.3 1.1 ± 0.4 Slightly more patients had no HF at baseline with Killip I in the combination and the captopril groups as compared to the valsartan group. Time to randomization, creatinine, and LVEF were all similar. Pfeffer, et al., NEJM 2003;349:1893-1906 *measured in 11,338 (77.1%) of the patients Pfeffer, McMurray, Velazquez, et al. N Engl J Med 2003;349:1893–1906

Baseline Characteristics Valsartan Combination Captopril Characteristic n = 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 Types, location and treatment for acute MI were similar in all 3 groups. Pfeffer, et al., NEJM 2003;349:1893-1906 Pfeffer, McMurray, Velazquez, et al. N Engl J Med 2003;349:1893–1906

Baseline Medications Valsartan Combination Captopril Medication n = 4909 n = 4885 n = 4909 ACE inhibitor* 39.4 40.8 38.5 Angiotensin-receptor blocker* 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 All treatments were consistent among the 3 groups. Pfeffer, et al., NEJM 2003;349:1893-1906 *stopped prior to randomization Pfeffer, McMurray, Velazquez, et al. N Engl J Med 2003;349:1893–1906

Medical History Valsartan + 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%) Disease characteristics were similar in all 3 groups. Pfeffer, et al., NEJM 2003;349:1893-1906 Pfeffer, McMurray, Velazquez, et al. N Engl J Med 2003;349:1893–1906

Study Drug Dose Titration Cap 6.25 mg Val 20 mg Cap 12.5 mg Cap 25 mg Val 40 mg Cap 50 mg (tid) Val 80 mg (bid) COMBINATION CAPTOPRIL (tid) Val 80 mg Val 160 mg (bid) VALSARTAN (bid) Step I GOAL by 3 months Step IV Step III Step II The dose titration regimen for captopril mirrored that used in SAVE, starting with 6.25 mg titrating in four steps to 50 mg t.i.d. The valsartan arm titrated from 20 mg to 160 twice a day (the dose used in the Val-HeFT study). The combination arm in VALIANT is unique in that the ARB valsartan was added from 20 to 80 mg twice daily to a proven effective regimen of an ACE inhibitor Am Heart J;2000;140:727-734 Am Heart J. 2000;140:727–734.

Mortality by Treatment 0.3 Captopril Valsartan 0.25 Valsartan + Captopril 0.2 Probability of Event 0.15 0.1 In this active-controlled, randomized trial, the mortality of the captopril group served as the comparator. Those randomized to the valsartan arm experienced a very similar incidence of death of any cause, with a hazard ratio of 1.00. Patients randomized to the combination of valsartan plus captopril also had a very similar incidence of death, with a hazard ratio of 0.98. Neither group being significantly different from the captopril event rate. Pfeffer, et al., NEJM 2003;349:1893-1906 0.05 Valsartan vs. Captopril: HR = 1.00; P = 0.982 Valsartan + Captopril vs. Captopril: HR = 0.98; P = 0.726 Months 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

All-Cause Mortality: Non-Inferiority Analyses Hazard Ratio (97.5% CI) P-value (noninferiority) noninferiority margin 0.004 Intention-to-Treat Patient Population (n = 14,703) 0.002 Per Protocol Patient Population (n = 14,285)  To demonstrate non-inferiority, the hazard ratio for death in the valsartan group compared to captopril had to meet the prespecified margin of 1.13. This threshold was chosen since it preserves at least 55% of the survival benefit of the ACE inhibitor. The point estimate for valsartan compared to captopril, as stated, was 1.00 and, importantly, the lower limit of the 97.5% confidence interval was well within the non-inferiority range-- P = 0.004. (one-sided UCL 1.094) A per protocol population of 14,285 patients that had all received study medication and met stricter cardiac-marker-based-inclusion criteria for myocardial infarction was also conducted to provide another validation of the non- inferiority test. The criteria for non-inferiority were, again, well satisfied in this more restricted population – P=0.002 (one-sided UCL 1.085).In VALIANT, the per-protocol population analysis was important for the non-inferiority analysis, since it was more stringent. Pfeffer, et al., NEJM 2003;349:1893-1906 Noninferiority Val Superior to Cap Cap Superior to Val Noninferiority not Demonstrated 0.8 1 1.13 1.2 Favors Valsartan Favors Captopril

Mortality in SAVE, TRACE, AIRE, and VALIANT Hazard Ratio for Mortality Combined TRACE SAVE AIRE Valsartan preserves 99.6% of mortality benefit of captopril. With the proven survival value of ACE inhibitors in these high-risk MI patients, our evaluation of valsartan was against active therapy rather than placebo. An estimate of the effectiveness of valsartan, as compared to that of an imputed placebo, was derived by the methods of Fisher, Hasselblad and Kong. We estimated that valsartan had an effect that was 99.6% of that of captopril (the 95% confidence interval: 60 to 139%.) Pfeffer, et al., NEJM 2003;349:1893-1906 התוצאות הראו יעילות זהה בין הקבוצה שטופלה בדיובן, לקבוצת הקפטופריל ולקבוצה המשולבת. כלומר: דיובן שימר את יתרונות קפטופריל המוכחים בהצלת חיים POST-MI. מכאן גם מסקנת החוקרים כי שעור הפחתת התמותה ע"י דיובן הינו 25%, כפי שהוכיחו מעכבי האייס זה מכבר. מעכבי אייס הינם "גולד סטנדרד" בטיפול לאחר MI. VALIANT הוכיח שדיובן מהווה חלופה מצוינת למי שלא סובל את הטיפול בהם. האינדיקציה אושרה באוגוסט 2005 ע"י ה-FDA וכעבור חודשיים, בנובמבר - גם ע"י משרד הבריאות 25% risk for total Mortality VALIANT (imputed placebo) 0.5 1 2 Favors Active Drug Favors Placebo Pfeffer, McMurray, Velazquez, et al. N Engl J Med 2003;349

CV Death, MI, or HF by Treatment 0.4 Captopril Valsartan Valsartan + Captopril 0.3 Probability of Event 0.2 Since ACE inhibitors have been shown to reduce the risk of heart failure admissions and nonfatal MIs, as well as death, we compared the hazard ratios for this composite event of the valsartan groups to the proven captopril regimen. The event rate for the valsartan monotherapy group was similar to captopril with a hazard ratio of 0.96. The combination of valsartan plus captopril was also no different than captopril alone with a hazard ratio of 0.97. Pfeffer, et al., NEJM 2003;349:1893-1906 0.1 Valsartan vs. Captopril: HR = 0.96; P = 0.198 Valsartan + Captopril vs. Captopril: HR = 0.97; P = 0.369 Months 6 12 18 24 30 36 Pfeffer, McMurray, Velazquez, et al. N Engl J Med 2003;349

Cardiovascular Mortality and Morbidity Hazard Ratio (97.5% CI) P-value (noninferiority) noninferiority margin CV Death (1657 events) 0.001 CV Death or MI (2234 events) 0.00001 CV Death or HF (2661 events) 0.0001 The effects of valsartan relative to captopril were compared for a hierarchy of cardiovascular events. For each of the CV fatal and nonfatal composites, the point estimates favored valsartan and, importantly, the lower limit of the 97.5% confidence intervals were well within the non- inferiority range. Specifically, with over 3000 composite events, the hazard ratio and confidence intervals for valsartan relative to captopril demonstrates that all of these cardiovascular benefits of captopril were preserved in the valsartan group. (UCL fpr valsartan vs captopril- one-sided 1.075 for CV mortality, 1.024 for composite of CVM + MI + HF) Pfeffer, et al., NEJM 2003;349:1893-1906 CV Death, MI, or HF (3096 events) 0.000001 Noninferiority Val Superior to Cap Cap Superior to Val Noninferiority not Demonstrated 0.8 1 1.13 1.2 Favors Valsartan Favors Captopril

Hazard Ratios (95% CI) for CV Death, MI, or HF # of Pts. P-Value (interaction) # of Pts. P-Value (interaction) Median < 65 Age ³ 65 Sex Male Female Prior MI No Yes DM No Yes SBP £ median > median Serum £ median Cr > median Killip I Class II III IV 4618 5200 6738 3080 7088 2730 7564 2254 5632 4182 4970 4837 2718 4747 1687 619 4675 5119 6768 3026 7085 2709 7528 2266 5642 4149 4908 4878 2805 4675 1655 618 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 The relative effectiveness of valsartan compared to captopril, or the combination valsartan plus captopril compared to captopril, was not influenced by key demographic factors, past medical history, the severity of the infarct, or use of concurrent medications. The analysis of subgroups was consistent with the primary outcome with no difference in all-cause mortality or the secondary endpoints in all subgroups. Pfeffer, et al., NEJM 2003;349:1893-1906 Beta- No Blocker Yes 2907 6911 2910 6882 0.48 0.56 0.5 1 2 0.5 1 2 Favors Valsartan Favors Captopril 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 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) Beta-blocker use was a subgroup of particular interest because of a prior potential safety issue when valsartan was used with both an ACE inhibitor and beta-blocker in heart failure patients in Val-HeFT. With over 70% baseline beta-blocker use, VALIANT had over 10,000 patients on a beta-blocker randomized to either captopril, valsartan or both (so called triple therapy). We found no concerning interactions for the composite CV outcome or death when valsartan was given concomitantly with a beta-blocker, either alone or with an ACE inhibitor. Data on file DCRI 0.56 0.5 1 2 Favors Combination Favors Captopril Pfeffer, McMurray, Velazquez, et al. N Engl J Med 2003;349:1893–1906

Study Drug Use Target Dose Off Drug Month Captopril 117 mg Valsartan + Captopril 116 mg 107 mg Valsartan 247 mg mean dose at 1 year = Target Dose 60% 30% 0% The dose titration of the blinded study medication was similar for the two monotherapies, both achieving target dose in about 55%. In contrast, the proportion of patients on the combination that achieved the target dose was consistently lower than both monotherapies therapies. Approximately 45% achieved target dose in the combination. Conversely, those randomized to the combination therapies were consistently more likely to discontinue study medication.( valsartan 20.5%, captopril 21.4%, combination 23.5%) Of those taking study medication at one-year, the mean daily dose of valsartan was 247 mg; in the combination: valsartan 116 mg plus captopril 107 mg; and the captopril monotherapy group was 117 mg. Pfeffer, et al., NEJM 2003;349:1893-1906 Off Drug 30% 15% 0% Month 1 6 12 20 36

Study Drug Discontinuation 0.4 Captopril Valsartan * Valsartan + Captopril * 0.3 Overall 0.2 Probability of Event Discontinuation of study medications increased as a function of time in all groups. Relative to captopril patients, the valsartan group was less likely to discontinue due to an adverse event attributed to study medication. In contrast, those on the combination therapies were more likely to discontinue their study medication and more likely to experience study drug-related reasons for this discontinuation. Due to Adverse Events 0.1 6 12 18 24 30 36 Months *P < 0.05 vs Captopril

Adverse Experience Leading to Study Drug Discontinuation † Valsartan + Captopril Captopril Valsartan 3.5 * P < 0.05 Valsartan vs. Captopril 3 †P < 0.05 Valsartan + Captopril vs. Captopril 2.5 2 % of Patients * 1.5 The patterns of adverse experiences leading to discontinuation of study medication differed in that valsartan, which had slightly greater blood pressure lowering, was more likely to be associated with hypotension or renal concerns, whereas captopril discontinuation was more frequently attributed to rash, cough, or taste disturbance. Combining therapies resulted in additive adverse experiences. Pfeffer, et al., NEJM 2003;349:1893-1906 1 0.5 Hypo- Renal Hyper- Cough Skin Taste Angio- tension Causes kalemia Rash Disturbance edema 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 effective alternative to an ACE inhibitor. 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 hospital admission for heart failure. Combining valsartan with a proven dose of captopril produced no further reductions in mortality and resulted in more adverse drug events. Implications are that by preserving all the cardiovascular benefits of an ACE inhibitor in this population, valsartan is a clinically effective alternative for high risk patients post-MI.

24 Countries. 931 Sites. 14,703 Patients. 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