TRANSCEND: Telmisartan Randomized AssesmeNt Study in aCE iNtolerant Subjects with Cardiovascular Disease

1
TRANSCEND Telmisartan RandomizedAssesmeNt Study
in aCE iNtolerant Subjects with Cardiovascular
Disease

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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 (n6,666)
• Randomized, double blind, placebo controlled
  study conducted in 630 centers in 40 countries
  (n5,926)
• 56 months follow-up with 99.7 outcome
  ascertainment

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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
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History at Randomization ()
ONTARGET TRANSCEND HOPE
Randomized (n) 25,620 5,926 9,541
Females 26.7 43.0 26.7
Age (yrs) 66.4 66.9 65.9
CAD 74.6 74.6 78.2
PAD 13.5 11.3 13.9
Stroke/TIA 20.8 22.0 6.4
Hypertension 68.7 76.4 46.6
Diabetes 37.5 35.7 38.3
Cancer 6.3 4.9 -
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Change in Sitting Systolic BP (mm Hg)From
Pre-Run-in Over Time
Tel (n2954) Pl (n2972) Tel - Pl
Baseline 140.7 141.3 -0.6
6 weeks -7.2 -1.0 -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
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Concomitant Medications by Visit ()
Baseline Year 2 Year 2 Final Final
Tel Pl Tel Pl Tel Pl
Antiplatelet 79.8 79.0 78.0 77.3 76.8 77.0
Beta-blockers 59.3 57.2 56.3 58.1 56.6 59.0
Diuretics 33.2 32.8 32.6 37.2 33.7 40.0
CCB 39.9 40.4 36.9 43.4 38.0 45.9
Statins 55.7 54.7 59.4 59.6 63.8 63.1
Plt0.0001, compared to Telmisartan
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Time to Permanent Discontinuation of Study
Medication
TRANSCEND
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
8
Reasons for Permanently Stopping Study
Medications
Tel N2954 () Pla N2972 () Tel vs. Pla RR P Tel vs. Pla RR P
Hypotension 29 (0.98) 16 (0.54) 1.82 0.0493
Syncope 1(0.03) 0 - -
Cough 15 (0.51) 18 (0.61) 0.84 0.6127
Diarrhea 7 (0.24) 2 (0.07) 3.52 0.094
Angioedema 2 (0.07) 3 (0.10) 0.67 0.660
Renal Abnormality 24 (0.81) 13 (0.44) 1.86 0.067
Any Permanent Discontinuation 639 (21.6) 705 (23.7) 0.91 0.055
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RESULTS
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Primary Outcome HOPE Primary Outcome
Tel Pla Tel vs Pla Tel vs Pla
N () N () HR (95 CI) P value
N 2954 2972
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, Stroke 384 (13.00) 440 (14.80) 0.87 (0.76-1.00) 0.0475
(Adjusted for SBP) 0.87 (0.76-1.00) 0.0495
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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
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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
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Primary and Key Secondary Outcomes
Telm Plac HR (CI) HR (CI) P P
Primary 465 (15.7) 465 (15.7) 504 (17.0) 504 (17.0) 0.92 (0.81-1.05) 0.92 (0.81-1.05) 0.2158
CV death, MI, Stroke 384 (13.0) 384 (13.0) 440 (14.8) 440 (14.8) 0.87 (0.76-1.00) 0.87 (0.76-1.00) 0.0475
CV death 227 (7.7) 227 (7.7) 223 (7.5) 223 (7.5) 1.03 (0.85-1.24) 1.03 (0.85-1.24)
MI 116 (3.9) 116 (3.9) 147 (5.0) 147 (5.0) 0.79 (0.62-1.01) 0.79 (0.62-1.01)
Stroke 112 (3.8) 112 (3.8) 136 (4.6) 136 (4.6) 0.83 (0.64-1.06) 0.83 (0.64-1.06)
CHF hosp 134 (4.5) 134 (4.5) 129 (4.3) 129 (4.3) 1.05 (0.82-1.34) 1.05 (0.82-1.34)
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ADVANCE Analyses of Macro Microvascular Outcome
Telm Placebo HR (CI) P
Overall 523 (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) 0.7404
p for interaction
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ADVANCE Macro Microvascular including Microalb
Telm n() Placebo n() HR (CI) P
Overall 742 (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) 0.9415
p for interaction
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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 lt 133
1955
16.2
133 lt SBP lt 149
1996
15.8
0.7956
SBP gt 149
1969
18.8
Diabetes
2118
19.9
0.3109
No Diabetes
3805
15.3
HOPE Score lt 3.624
1978
9.3
3.624lt HOPE Score lt 4.034
1934
16.1
0.4615
HOPE Score gt 4.034
2014
25.4
Age lt 65
2375
13.5
65 lt Age lt 75
2576
16.9
0.8945
Age gt 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)
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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 lt 133
1955
13.8
133 lt SBP lt 149
1996
13.7
0.7725
SBP gt 149
1969
16.9
Diabetes
2118
17.8
0.6092
No Diabetes
3805
13.2
HOPE Score lt 3.624
1978
7.9
3.624lt HOPE Score lt 4.034
1934
13.3
0.4597
HOPE Score gt 4.034
2014
23.0
Age lt 65
2375
11.4
65 lt Age lt 75
2576
14.8
0.7996
Age gt 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)
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META-ANALYSIS
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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 lt 6M
546/13100 (4.2)
492/13158 (3.7)
lt0.001
OVERALL gt 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)
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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 lt 6M
502/13100 (3.8)
450/13158 (3.4)
lt0.001
OVERALL gt 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)
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Conclusions Telmisartan vs. Placebo

1. Telmisartan reduces the primary outcome by 8
   (p0.22), but reduces significantly the main
   secondary outcome of CV death, MI or stroke by
   13 (p0.048).
2. There is no impact on heart failure events with
   telmisartan.
3. Telmisartan is well tolerated and there is no
   excess of adverse events

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TRANSCEND and PROFESS Meta-Analysis

1. Clear reduction in the relative risk of the
   composite of CV death, MI or stroke by 9
   (p0.013), 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.