ARB may be less effective than ACE-inhibitors for reducing adverse cardiovascular events?

The results of a large controlled trial suggest that telmisartan, and by implication other angiotensin-2 receptor blockers (ARB), may be less effective in reducing cardiovascular events in high-risk patients.

There is robust evidence based on studies with several members of the group that ACE-inhibitors reduce a range of adverse outcomes in patients with cardiovascular disease or high-risk diabetes. A significant proportion of patients cannot tolerate ACE-inhibitors, however, and in this group ARB are often used: while there is evidence of benefit for this group in some patient populations, evidence on major clinical outcomes for a broad population is limited.  The TRANSCEND study was intended to clarify the place of these drugs in a broad population. Participants had cardiovascular disease or diabetes with end-organ damage., and were intolerant of ACE-inhibitors. There was a single-blind run-in period consisting of placebo for one week followed by telmisartan for two weeks, after which patients were randomised to telmisartan or placebo, in addition to other proven therapies as required. Primary outcome was a composite of cardiovascular death, myocardial infarction, stroke, or hospitalisation for heart failure, and median duration of follow-up 56 months (4.7 years).

A total of 6,666 patients entered the run-in phase, of whom 5,926 were randomised (main reason for exclusion poor compliance) – 2,954 received telmisartan and 2,972 placebo. At the end of the study, there was no significant difference between the groups for the primary outcome, which occurred in 465 patients in the telmisartan group compared with 504 in the placebo group (15.7% vs. 17.0%; hazard ratio 0.92, 95% CI 0.81 to 1.05, p=0.216). There was a borderline significant difference in one of the secondary outcomes – the composite of cardiovascular death, myocardial infarction, or stroke (13.4% vs. 14.8%; HR 0.87; 95% CI, 0.76 to 1.00), but the significance of this was reduced after adjustment for multiplicity of comparisons and overlap with primary outcome (p=0.048 unadjusted; p=0.068 after adjustment). Telmisartan was generally well tolerated.

The authors conclude that telmisartan did not improve the primary outcome in this patient population.

An accompanying editorial discusses the study and its implications. The authors comment that the role of ARB in prevention of cardiovascular disease has been unclear: while there has been speculation that they might be equivalent to or even better than ACE-inhibitors based on pharmacology, and there is evidence of similar effectiveness in heart failure, clinical evidence in other situations has been limited. The results of this study are unexpected, as other trials have suggested similar efficacy to ramipril. Overall, data on ARB in prevention of adverse cardiovascular events are incomplete, except in heart failure. At present, they suggest, although the data are too limited to reach definitive conclusions, the clinical effects of ARB seem to be less robust than those of ACE-inhibitors, which therefore remain the preferred renin-active agents to prevent vascular events in patients with or at high risk for cardiovascular disease.

[comment: given the failure of the primary outcome to reach statistical significance, apparent differences in any secondary outcomes cannot be considered to be at all robust - especially when their statistical significance is borderline.]

Lancet, published early online 31 August 2008; DOI:10.1016/S0140-6736(08)61242-8 (link to abstract); Lancet, published early online 31 August 2008; DOI:10.1016/S0140-6736(08)61243-X (Editorial; link to full text, available to subscribers only)