1. The Ongoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial ONTARGET

2. ACE-inhibitors (e.g. ramipril in the HOPE trial) reduces CV death, MI, stroke and HF hosp in those with CVD or DM in the absence of ventricular dysfunction or heart failure. ACE-inhibitors are not tolerated by 15% to 25% of patients. Will an ARB (telmisartan) be as effective and better tolerated? Is the combination superior? The Ongoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial Adapted from ACC 2008.

3. Questions: 1.Is telmisartan “non-inferior” to ramipril? 2.Is the combination superior to ramipril? Outcome: 1.Primary: CV death, MI, stroke, CHF hosp 2.Key secondary: CV death, MI, stroke (HOPE trial outcome) Design: Single blind run-in (n=29, 019) Randomized, double blind, double dummy study conducted in 733 centers in 41 countries (n=25,620) 56 months of follow-up with 99.8% outcome ascertainment ONTARGET Study Design Adapted from ACC 2008.

4. ONTARGET Study is Based on the Following Statistical Considerations In HOPE the hazard ratio for ramipril vs placebo: 0.77 40 th percentile: 0.794 Excess risk of placebo/ramipril: l.26 Half of above: l.l3 For non-inferiority (Telmisartan vs ramipril) the one-sided 97.5% CI should be below 1.13 Assuming an annual event rate of 3.97%, 7800 patients per group Followed for 4.5 yrs provides: -89% power for NI (T v R) -93% power superiority Total randomized: 25,620 in 18 months Adapted from ACC 2008.

5. ONTARGET Study Medications Titration Run-in (Single Blind) Day 1-3Ram 2.5 mg + Tel Placebo Day 4-10Ram 2.5 mg + Tel 40 mg Day 11-18Ram 5.0 mg + Tel 40 mg Randomization (Double Blind) 2 weeksRam Placebo + Tel 80 mg Ram 5. mg + Tel Placebo Ram 5 mg + Tel 80 mg ThenFull doses (Tel 80 mg daily, Ram 10 mg daily) for the arms Adapted from ACC 2008.

6. ONTARGET Study: Reasons for Not Randomizing Patients % Run-in Completed (n=29,018)100 Not Randomized11.71 Creatinine elevated0.22 Potassium elevated0.77 Persistent symptomatic hypotension1.70 Death0.092.78 Total Medical Reasons Compliance <75%3.87 Other reasons3.01 Patient Decision2.06 Total Patient Reasons5.93 Adapted from ACC 2008.

7. RamiprilTelmisartanCombination N857685428502 Age66.4 66.5 % females27.226.326.5 % CAD74.474.574.7 % Stroke/TIA21.020.620.9 % Diabetes36.738.037.9 BP141.8/82.1141.7/82.1141.9/82.1 Statins61.062.061.8 Antiplatelet80.581.1 B-blocker56.556.957.4 Key Baseline Characteristics in ONTARGET Study Adapted from ACC 2008.

8. Change in BP (mmHg) in ONTARGET Study RamiprilTelmisartanCombination Systolic-6.0-6.9-8.4 Diastolic-4.6-5.2-6.0 Adapted from ACC 2008.

9. Time to Permanent Discontinuation of Study Medication Adapted from ACC 2008.

10. Reasons for Permanently Stopping Study Medications in ONTARGET Study RamiprilTelmisartanTelmisartan vs. Ramipril N=8576N=8542RRP Hypotension1492291.540.0001 Syncope15191.270.4850 Cough360930.26<0.0001 Diarrhea12191.590.20 Angioedema25100.400.0115 Renal60681.140.46 Impairment Any Discontinuation209919620.940.02 Adapted from ACC 2008.

11. Time to Primary Outcome Telmisartan Adapted from ACC 2008.

12. Primary Outcome & HOPE Primary Outcome RamiprilTelmisartanTelmisartan vs. Ramipril N (%) RR (95% CI)P (non.inf) N85768542 Primary Outcome CV Death, MI, Stroke,141214231.01 (0.94-1.09)0.0038 CHF Hosp (Adjusted for SBP) (16.46%)(16.66%) 1.02 (0.95-1.10)0.0055 HOPE Primary Outcome CV Death, MI, Stroke1210 (14.11%) 1190 (13.93%) 0.99 (0.91-1.07)0.0009 (Adjusted for SBP)0.99 (0.91-1.07)0.0012 Adapted from ACC 2008.

13. ONTARGET Non-inferiority Comparison Adapted from ACC 2008.

14. Time to Primary Outcome Adapted from ACC 2008.

15. Reasons for Permanently Stopping Study Medications in ONTARGET Study RamRam +TelRam+Tel vs. Ram N=8576N=8502RRP Hypotension1494062.75<0.0001 Syncope15291.950.032 Cough3603921.100.1885 Diarrhea12393.280.0001 Angioedema25180.730.30 Renal Impairment 60941.580.0050 Any Discontinuation 209924951.20<0.0001 Adapted from ACC 2008. Ram=ramipril; Tel=telmisartan

16. ONTARGET Study Conclusions: Telmisartan vs. Ramipril 1. Telmisartan is clearly « non-inferior » to ramipril Primary composite outcome (P=0.0038) HOPE primary outcome (P=0.001) Most (>90%) of the benefits or ramipril are preserved 2. Consistent results on a range of: Secondary outcomes Subgroups 3. Sensitivity analysis using a per protocol approach confirms this 4. Telmisartan exhibits slightly superior tolerability Less cough and angioneurotic edema More mild hypotensive symptoms, but no difference in severe hypotensive symptoms, such as syncope Adapted from ACC 2008.

17. ONTARGET Study Conclusions: Telmisartan plus Ramipril vs. Ramipril 1.Combination therapy does not reduce the primary outcome to a greater extent compared to ramipril alone. 2. Higher rates of adverse events: hypotension related, including syncope renal dysfunction Adapted from ACC 2008.

18. Implication Regarding ONTARGET Findings Telmisartan is as effective as ramipril, with a slightly better tolerability. Combination therapy is not superior to ramipril and has increased side effects. Adapted from ACC 2008.