TRANSCEND: Telmisartan Randomized

AssesmeNt Study in aCE iNtolerant Subjects with Cardiovascular Disease

ONTARGET / TRANSCEND Investigators

Koon K. Teo, MB, PhD, FRCPC

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 hosp2. 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

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

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 -

Change in Sitting Systolic BP (mm Hg)From Pre-Run-in Over Time

Tel (n=2954) Pl (n=2972) 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

Concomitant Medications by Visit (%)

Baseline Year 2 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

*P<0.0001, compared to Telmisartan

Time to Permanent Discontinuation of Study Medication

Years of Follow-up

Cum

ulat

ive

Haz

ard

Rat

es

0.0

0.1

0.2

0.3

0.4

0 1 2 3 4 5

Telmisartan

Placebo

# 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

Reasons for Permanently Stopping Study Medications

Tel

N=2954 (%)

Pla

N=2972 (%)

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

Primary Outcome & HOPE: Primary Outcome

Tel 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

Time to Primary Outcome

HR: 0.92 (0.81-1.05)

P-value = 0.2158

Years of Follow-up

Cu

mu

lati

ve In

cid

ence

Rat

es

0.0

0.0

50

.10

0.1

50

.20

0 1 2 3 4 5

No. at RiskT

Pl

2954 2807 2699 2577 2278 1091

2972 2839 2713 2575 2253 1069

Telmisartan

Placebo

Time to Secondary Outcome

HR: 0.87 (0.76 – 1.00)

P-value = 0.0475

Years of Follow-up

Cu

mu

lati

ve In

cid

ence

Rat

es

0.0

0.0

50

.10

0.1

50

.20

0 1 2 3 4 5

Telmisartan

Placebo

No. at RiskTPl

2954 2839 2745 2634 2344 11272972 2866 2745 2626 2306 1103

Primary and Key - Secondary Outcomes

Telm Plac HR (CI) P

Primary 465 (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 death 227 (7.7%) 223 (7.5%) 1.03 (0.85-1.24)

MI 116 (3.9%) 147 (5.0%) 0.79 (0.62-1.01)

Stroke 112 (3.8%) 136 (4.6%) 0.83 (0.64-1.06)

CHF hosp 134 (4.5%) 129 (4.3%) 1.05 (0.82-1.34)

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)

*P for interaction

ADVANCE:Macro + Microvascular including Microalb

Telmn(%)

Placebon(%)

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)

*P for interaction

Subgroup Analysis of Primary Outcome

0.4 0.7 1.0 1.3 1.6HR(95% CI)

Telmisartan better Placebo better

Primary Composite

Hx of CVD No Hx of CVD

SBP <= 133133 < SBP <= 149 SBP > 149

DiabetesNo Diabetes

HOPE Score <= 3.6243.624<= HOPE Score <= 4.034HOPE Score > 4.034

Age < 6565 <= Age < 75Age >= 75

MaleFemale

StatinNo Statin

No. Patients

5926

5418505

195519961969

21183805

197819342014

23752576975

33792547

32722654

Incidence (%) Placebo Group

17.0

17.214.1

16.215.818.8

19.915.3

9.316.125.4

13.516.925.7

18.914.4

16.217.9

p for interaction

0.6102

0.7956

0.3109

0.4615

0.8945

0.0842

0.2867

Telmisartan Meta-analysis (CV Death, MI, Stroke, CHF Hosp)

0.7 0.8 0.9 1.0 1.1 1.2

OR (95% CI)

Telmisartan better Placebo 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

Telmisartan Meta-analysis (CV Death, MI, Stroke)

0.7 0.8 0.9 1.0 1.1 1.2

OR (95% CI)

Telmisartan better Placebo 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

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

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.