1. TRANSCEND: Telmisartan Randomized AssesmeNt Study in aCE iNtolerant Subjects with Cardiovascular Disease ONTARGET / TRANSCEND Investigators Koon K. Teo, MB, PhD, FRCPC

2. TRANSCEND Question: 1. Is telmisartan superior to placebo in patients at high risk of CV events who are intolerant of ACE-I? 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=6,666) Randomized, double blind, placebo controlled study conducted in 630 centers in 40 countries (n=5,926) 56 months follow-up with 99.7% outcome ascertainment

3. Trial Profile 2954 assigned telmisartan (80mg) 2972 assigned placebo 2944 completed study 10 lost to follow-up 8 lost to follow-up 5926 patients randomized 2964 completed study 6666 entered Run-in

4. History at Randomization (%) ONTARGETTRANSCENDHOPE Randomized (n)25,6205,9269,541 Females26.743.026.7 Age (yrs)66.466.965.9 CAD74.6 78.2 PAD13.511.313.9 Stroke/TIA20.822.06.4 Hypertension68.776.446.6 Diabetes37.535.738.3 Cancer6.34.9-

5. Change in Sitting Systolic BP (mm Hg) From Pre-Run-in Over Time Tel (n=2954)Pl (n=2972)Tel - Pl Baseline140.7141.3-0.6 6 weeks-7.2-6.2 1 year-6.4-1.8-4.7 2 years-4.4-0.3-4.2 Study End-4.3-1.1-3.2 Average-6.6-2.6-4.0

6. Concomitant Medications by Visit (%) BaselineYear 2Final Tel PlTelPlTelPl Antiplatelet 79.8 79.078.077.376.877.0 Beta-blockers 59.3 57.256.358.156.659.0 Diuretics 33.2 32.832.637.233.740.0* CCB 39.9 40.436.943.438.045.9* Statins 55.7 54.759.459.663.863.1 *P<0.0001, compared to Telmisartan

7. Time to Permanent Discontinuation of Study Medication Years of Follow-up Cumulative Hazard Rates 0.0 0.1 0.2 0.3 0.4 012345 Telmisartan Placebo # at RiskYr 1Yr 2Yr 3Yr 4Yr 5 T295427842663254722711086 Pl297228142629250922421063

8. Reasons for Permanently Stopping Study Medications Tel N=2954 (%) Pla N=2972 (%) Tel vs. Pla RR P Hypotension29 (0.98)16 (0.54)1.820.0493 Syncope1(0.03)0-- Cough15 (0.51)18 (0.61)0.840.6127 Diarrhea7 (0.24)2 (0.07)3.520.094 Angioedema2 (0.07)3 (0.10)0.670.660 Renal Abnormality24 (0.81)13 (0.44)1.860.067 Any Permanent Discontinuation 639 (21.6)705 (23.7)0.910.055

9. RESULTS

10. Primary Outcome & HOPE: Primary Outcome TelPlaTel vs Pla N (%) HR (95% CI)P value N29542972 Primary Outcome CV Death, MI, Stroke, CHF Hosp 465 (15.74%)504 (16.96%)0.92 (0.81-1.05)0.2158 (Adjusted for SBP)0.92 (0.81-1.05)0.2257 HOPE Primary Outcome CV Death, MI, Stroke384 (13.00%)440 (14.80%)0.87 (0.76-1.00)0.0475 (Adjusted for SBP)0.87 (0.76-1.00)0.0495

11. Time to Primary Outcome HR: 0.92 (0.81-1.05) P-value = 0.2158 Years of Follow-up Cumulative Incidence Rates 0.0 0.05 0.10 0.15 0.20 012345 No. at Risk T Pl 295428072699257722781091 297228392713257522531069 Telmisartan Placebo

12. Time to Secondary Outcome HR: 0.87 (0.76 – 1.00) P-value = 0.0475 Years of Follow-up Cumulative Incidence Rates 0.0 0.05 0.10 0.15 0.20 012345 Telmisartan Placebo No. at Risk T Pl 295428392745263423441127 297228662745262623061103

13. Primary and Key - Secondary Outcomes TelmPlacHR (CI)P Primary465 (15.7%)504 (17.0%)0.92 (0.81-1.05)0.2158 CV death, MI, Stroke 384 (13.0%)440 (14.8%)0.87 (0.76-1.00)0.0475 CV death227 (7.7%)223 (7.5%)1.03 (0.85-1.24) MI116 (3.9%)147 (5.0%)0.79 (0.62-1.01) Stroke112 (3.8%)136 (4.6%)0.83 (0.64-1.06) CHF hosp134 (4.5%)129 (4.3%)1.05 (0.82-1.34)

14. ADVANCE: Analyses of Macro + Microvascular Outcome TelmPlaceboHR (CI)P Overall523 (17.7%)587 (19.8%)0.89 (0.79-1.00)0.0493 Diab +248 (23.4%)275 (26.0%)0.91 (0.77-1.08) *0.7404 Diab -275(14.5%)312 (16.3%)0.87 (0.74-1.03) *P for interaction

15. ADVANCE: Macro + Microvascular including Microalb Telm n(%) Placebo n(%) HR (CI)P Overall742 (25.1)861 (29.0)0.85 (0.77-0.94)0.0013 Diab +346 (32.7)405 (38.2)0.86 (0.74-0.99) *0.9415 Diab -396 (20.9)456 (23.9)0.85 (0.74-0.97) *P for interaction

16. Subgroup Analysis of Primary Outcome 0.40.71.01.31.6 HR(95% CI) Telmisartan betterPlacebo better Primary Composite Hx of CVD No Hx of CVD SBP <= 133 133 < SBP <= 149 SBP > 149 Diabetes No Diabetes HOPE Score <= 3.624 3.624<= HOPE Score <= 4.034 HOPE Score > 4.034 Age < 65 65 <= Age < 75 Age >= 75 Male Female Statin No Statin No. Patients 5926 5418 505 1955 1996 1969 2118 3805 1978 1934 2014 2375 2576 975 3379 2547 3272 2654 Incidence (%) Placebo Group 17.0 17.2 14.1 16.2 15.8 18.8 19.9 15.3 9.3 16.1 25.4 13.5 16.9 25.7 18.9 14.4 16.2 17.9 p for interaction 0.6102 0.7956 0.3109 0.4615 0.8945 0.0842 0.2867

17. Subgroup Analysis of Secondary Outcome 0.40.71.01.31.6 HR (95% CI) Telmisartan betterPlacebo better Primary Composite Hx of CVD No Hx of CVD SBP <= 133 133 < SBP <= 149 SBP > 149 Diabetes No Diabetes HOPE Score <= 3.624 3.624<= HOPE Score <= 4.034 HOPE Score > 4.034 Age < 65 65 <= Age < 75 Age >= 75 Male Female Statin No Statin No. Patients 5926 5418 505 1955 1996 1969 2118 3805 1978 1934 2014 2375 2576 975 3379 2547 3272 2654 % Incidence Placebo Group 14.8 15.0 12.9 13.8 13.7 16.9 17.8 13.2 7.9 13.3 23.0 11.4 14.8 23.2 16.6 12.4 14.1 15.7 p for interaction 0.4001 0.7725 0.6092 0.4597 0.7996 0.1586 0.2790

18. META-ANALYSIS

19. Telmisartan Meta-analysis (CV Death, MI, Stroke, CHF Hosp) 0.70.80.91.01.11.2 OR (95% CI) Telmisartan betterPlacebo better PROFESS TRANSCEND OVERALL OVERALL <= 6M OVERALL > 6M No. events/No. randomized Telmisartan 1367/10146 (13.5%) 466/2954 (15.7%) 1833/13100 (14.0%) 546/13100 (4.2%) 1287/12484 (10.3%) Placebo 1463/10186 (14.4%) 505/2972 (17.0%) 1968/13158 (14.9%) 492/13158 (3.7%) 1476/12575 (11.7%) p-value 0.067 0.205 0.026 0.075 <0.001

20. Telmisartan Meta-analysis (CV Death, MI, Stroke) 0.70.80.91.01.11.2 OR (95% CI) Telmisartan betterPlacebo better PROFESS TRANSCEND OVERALL OVERALL <= 6M OVERALL > 6M No. events/No. randomized Telmisartan 1289/10146 (12.7%) 385/2954 (13.0%) 1674/13100 (12.8%) 502/13100 (3.8%) 1172/12526 (9.3%) Placebo 1377/10186 (13.5%) 441/2972 (14.8%) 1818/13158 (13.8%) 450/13158 (3.4%) 1368/12616 (10.8%) P-value 0.086 0.045 0.013 0.074 <0.001

21. Conclusions: Telmisartan vs. Placebo 1.Telmisartan reduces the primary outcome by 8% (P=0.22), but reduces significantly the main secondary outcome of CV death, MI or stroke by 13% (P=0.048). 2.There is no impact on heart failure events with telmisartan. 3.Telmisartan is well tolerated and there is no excess of adverse events

22. TRANSCEND and PROFESS Meta-Analysis 1.Clear reduction in the relative risk of the composite of CV death, MI or stroke by 9% (p=0.013), with little effect in the first 6 months after randomization, but a 15% RRR after 6 months (significant heterogeneity over the two time periods). 2.Neutral effect of telmisartan on heart failure events, which is surprising (OR of 1.00, 95% CI of 0.85 to 1.17), but this is consistent with the results of HF in ONTARGET (more events with telmisartan compared to ramipril). 3.Lower rates of MI and stroke.