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TRANSCEND: T elmisartan R andomized A ssesme N t S tudy in a CE i N tolerant S ubjects with C ardiovascular D isease. TRANSCEND. Question: Is telmisartan superior to placebo in patients at high risk of CV events who are intolerant of ACE-I? Outcome:
E N D
TRANSCEND:Telmisartan RandomizedAssesmeNt Study in aCE iNtolerant Subjects with Cardiovascular Disease
TRANSCEND Question: • Is telmisartan superior to placebo in patients at high risk of CV events who are intolerant of ACE-I? Outcome: • Primary: CV death, MI, stroke, CHF hosp • 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
Trial Profile TRANSCEND 6666 entered Run-in 5926 patients randomized 2954 assigned telmisartan (80mg) 2972 assigned placebo 10 lost to follow-up 8 lost to follow-up 2944 completed study 2964 completed study
Change in Sitting Systolic BP (mm Hg)From Pre-Run-in Over Time
Concomitant Medications by Visit (%) *P<0.0001, compared to Telmisartan
TRANSCEND Time to Permanent Discontinuation of Study Medication 0.4 # at Risk Yr 1 Yr 2 Yr 3 Yr 4 Yr 5 T 2954 2784 2663 2547 2271 1086 Pl 2972 2814 2629 2509 2242 1063 0.3 Telmisartan Cumulative Hazard Rates Placebo 0.2 0.1 0.0 0 1 2 3 4 5 Years of Follow-up
Time to Primary Outcome TRANSCEND 0.20 Telmisartan 0.15 Placebo Cumulative Incidence Rates 0.10 0.05 HR: 0.92 (0.81-1.05) p-value = 0.2158 0.0 0 1 2 3 4 5 Years of Follow-up No. at Risk T 2954 2807 2699 2577 2278 1091 Pl 2972 2839 2713 2575 2253 1069
Time to Secondary Outcome TRANSCEND 0.20 Telmisartan Placebo 0.15 Cumulative Incidence Rates 0.10 HR: 0.87 (0.76 – 1.00) p-value = 0.0475 0.05 0.0 0 1 2 3 4 5 Years of Follow-up No. at Risk T 2954 2839 2745 2634 2344 1127 Pl 2972 2866 2745 2626 2306 1103
ADVANCE: Analyses of Macro + Microvascular Outcome *p for interaction
ADVANCE: Macro + Microvascular including Microalb *p for interaction
TRANSCEND Subgroup Analysis of Primary Outcome Incidence (%) p for Placebo Group interaction No. Patients Primary Composite 5926 17.0 Hx of CVD 5418 17.2 0.6102 505 14.1 No Hx of CVD SBP <= 133 1955 16.2 133 < SBP <= 149 1996 15.8 0.7956 SBP > 149 1969 18.8 Diabetes 2118 19.9 0.3109 No Diabetes 3805 15.3 HOPE Score <= 3.624 1978 9.3 3.624<= HOPE Score <= 4.034 1934 16.1 0.4615 HOPE Score > 4.034 2014 25.4 Age < 65 2375 13.5 65 <= Age < 75 2576 16.9 0.8945 Age >= 75 975 25.7 Male 3379 18.9 0.0842 Female 2547 14.4 Statin 3272 16.2 0.2867 No Statin 2654 17.9 Telmisartan better Placebo better 0.4 0.7 1.0 1.3 1.6 HR(95% CI)
TRANSCEND Subgroup Analysis of Secondary Outcome % Incidence p for Placebo Group interaction No. Patients Primary Composite 5926 14.8 Hx of CVD 5418 15.0 0.4001 No Hx of CVD 505 12.9 SBP <= 133 1955 13.8 133 < SBP <= 149 1996 13.7 0.7725 SBP > 149 1969 16.9 Diabetes 2118 17.8 0.6092 No Diabetes 3805 13.2 HOPE Score <= 3.624 1978 7.9 3.624<= HOPE Score <= 4.034 1934 13.3 0.4597 HOPE Score > 4.034 2014 23.0 Age < 65 2375 11.4 65 <= Age < 75 2576 14.8 0.7996 Age >= 75 975 23.2 Male 3379 16.6 0.1586 Female 2547 12.4 Statin 3272 14.1 0.2790 No Statin 2654 15.7 Telmisartan better Placebo better 0.4 0.7 1.0 1.3 1.6 HR (95% CI)
Telmisartan Meta-analysis (CV Death, MI, Stroke, CHF Hosp) TRANSCEND No. events/No. randomized p-value Telmisartan Placebo 0.067 PROFESS 1367/10146 (13.5%) 1463/10186 (14.4%) 0.205 TRANSCEND 466/2954 (15.7%) 505/2972 (17.0%) 0.026 OVERALL 1833/13100 (14.0%) 1968/13158 (14.9%) 0.075 OVERALL <= 6M 546/13100 (4.2%) 492/13158 (3.7%) <0.001 OVERALL > 6M 1287/12484 (10.3%) 1476/12575 (11.7%) Telmisartan better Placebo better 0.7 0.8 0.9 1.0 1.1 1.2 OR (95% CI)
Telmisartan Meta-analysis (CV Death, MI, Stroke) TRANSCEND No. events/No. randomized p-value Telmisartan Placebo 0.086 PROFESS 1289/10146 (12.7%) 1377/10186 (13.5%) 0.045 TRANSCEND 385/2954 (13.0%) 441/2972 (14.8%) 0.013 OVERALL 1674/13100 (12.8%) 1818/13158 (13.8%) 0.074 OVERALL <= 6M 502/13100 (3.8%) 450/13158 (3.4%) <0.001 OVERALL > 6M 1172/12526 (9.3%) 1368/12616 (10.8%) Telmisartan better Placebo better 0.7 0.8 0.9 1.0 1.1 1.2 OR (95% CI)
Conclusions: Telmisartan vs. Placebo • 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). • There is no impact on heart failure events with telmisartan. • Telmisartan is well tolerated and there is no excess of adverse events
TRANSCEND and PROFESS Meta-Analysis • 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). • 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). • Lower rates of MI and stroke.