Elsevier

The Lancet

Volume 372, Issue 9644, 27 September–3 October 2008, Pages 1174-1183
The Lancet

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Effects of the angiotensin-receptor blocker telmisartan on cardiovascular events in high-risk patients intolerant to angiotensin-converting enzyme inhibitors: a randomised controlled trial

https://doi.org/10.1016/S0140-6736(08)61242-8Get rights and content

Summary

Background

Angiotensin-converting enzyme (ACE) inhibitors reduce major cardiovascular events, but are not tolerated by about 20% of patients. We therefore assessed whether the angiotensin-receptor blocker telmisartan would be effective in patients intolerant to ACE inhibitors with cardiovascular disease or diabetes with end-organ damage.

Methods

After a 3-week run-in period, 5926 patients, many of whom were receiving concomitant proven therapies, were randomised to receive telmisartan 80 mg/day (n=2954) or placebo (n=2972) by use of a central automated randomisation system. Randomisation was stratified by hospital. The primary outcome was the composite of cardiovascular death, myocardial infarction, stroke, or hospitalisation for heart failure. Analyses were done by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00153101.

Findings

The median duration of follow-up was 56 (IQR 51–64) months. All randomised patients were included in the efficacy analyses. Mean blood pressure was lower in the telmisartan group than in the placebo group throughout the study (weighted mean difference between groups 4·0/2·2 [SD 19·6/12·0] mm Hg). 465 (15·7%) patients experienced the primary outcome in the telmisartan group compared with 504 (17·0%) in the placebo group (hazard ratio 0·92, 95% CI 0·81–1·05, p=0·216). One of the secondary outcomes—a composite of cardiovascular death, myocardial infarction, or stroke—occurred in 384 (13·0%) patients on telmisartan compared with 440 (14·8%) on placebo (0·87, 0·76–1·00, p=0·048 unadjusted; p=0·068 after adjustment for multiplicity of comparisons and overlap with primary outcome). 894 (30·3%) patients receiving telmisartan were hospitalised for a cardiovascular reason, compared with 980 (33·0%) on placebo (relative risk 0·92, 95% CI 0·85–0·99; p=0·025). Fewer patients permanently discontinued study medication in the telmisartan group than in the placebo group (639 [21·6%] vs 705 [23·8%]; p=0·055); the most common reason for permanent discontinuation was hypotensive symptoms (29 [0·98%] in the telmisartan group vs 16 [0·54%] in the placebo group).

Interpretation

Telmisartan was well tolerated in patients unable to tolerate ACE inhibitors. Although the drug had no significant effect on the primary outcome of this study, which included hospitalisations for heart failure, it modestly reduced the risk of the composite outcome of cardiovascular death, myocardial infarction, or stroke.

Funding

Boehringer Ingelheim.

Introduction

Angiotensin-converting enzyme (ACE) inhibitors reduce mortality, myocardial infarction, stroke, and heart failure in patients with cardiovascular disease or high-risk diabetes.1, 2, 3 However, up to about 20% of patients—particularly women or Asians—are unable to tolerate an ACE inhibitor, mainly due to cough, but also due to hypotensive symptoms, renal dysfunction, or angioneurotic oedema.4, 5 Angiotensin-receptor blockers are similar in efficacy and are better tolerated than ACE inhibitors in high-risk patients after myocardial infarction,6 or in those with cardiovascular disease or high-risk diabetes.7 Angiotensin-receptor blockers reduce mortality and rehospitalisation for heart failure, compared with placebo, in patients intolerant to ACE inhibitors with low ejection fraction and heart failure,8, 9 and also reduce stroke and cardiovascular morbidity compared with β blockers, in those with moderate hypertension and left ventricular hypertrophy.10 However, direct evidence of benefit of an angiotensin-receptor blocker in reducing major cardiovascular events in broader high-risk populations is lacking.

In the Telmisartan Randomised AssessmeNt Study in ACE iNtolerant subjects with cardiovascular Disease (TRANSCEND), we investigated whether an angiotensin-receptor blocker—telmisartan—given long term, reduces cardiovascular death, myocardial infarction, stroke, or hospitalisation for heart failure in patients with cardiovascular disease or high-risk diabetes and without heart failure, who are intolerant to ACE inhibitors, compared with placebo, in addition to other usual therapies.11

Section snippets

Patients

The design of the ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) programme has been described in detail elsewhere.11 Briefly, patients intolerant to ACE inhibitors were enrolled if they had established coronary artery, peripheral vascular or cerebrovascular disease, or diabetes with end-organ damage. Intolerance to ACE inhibitors was defined as previous discontinuation by a physician because of intolerance, with a specific documented cause. Patients

Results

The trial profile is shown in figure 1. Patients were enrolled between November, 2001, and May, 2004. At the end of the run-in period, 874 (29·6%) patients randomised to receive telmisartan and 899 (30·2%) to placebo were receiving, or had previously received, an angiotensin-receptor blocker. Of the randomised population, the most common reason for intolerance to ACE inhibitors was cough (5225 participants, 88·2%), followed by symptomatic hypotension (244, 4·1%), angio-oedema or anaphylaxis

Discussion

Although fewer patients experienced the primary outcome of cardiovascular death, myocardial infarction, stroke, or hospitalisation for heart failure with telmisartan than with placebo, this result was not statistically significant. However, there was a reduction in the HOPE secondary outcome of cardiovascular death, myocardial infarction, and stroke with telmisartan, compared with placebo. These results are reinforced by similar trends in the recent PRoFESS study comparing telmisartan with

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