NPC Archive Item: ARBs as effective as ACE inhibitors in CV risk reduction? — Jury still out.

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

Results from a large randomised controlled trial (TRANSCEND) question whether the angiotensin receptor antagonist (ARB) telmisartan is as good as ACE inhibitors in reducing the risk of important clinical outcomes in people at high risk of cardiovascular (CV) events intolerant to ACE inhibitors. In fact, telmisartan was not significantly more effective than placebo in this study.

The TRANSCEND study reinforces the importance of only prescribing angiotensin receptor blockers (ARBs) as an alternative to ACE inhibitors where there is clear intolerance to ACE inhibitors (most often due to cough). The evidence base for ACE inhibitors in primary and secondary prevention of CV disease is well established, whereas that of ARBs is less so.

What is the background to this?
Although equivalent or even superior clinical effectiveness of ARBs can be postulated on pharmacological grounds, there is little direct evidence from comparative clinical studies measuring patient-oriented outcomes to support these claims (see Editorial). ARBs are generally recognised as suitable alternatives to ACE inhibitors where ACE inhibitors cannot be tolerated (e.g. because of cough). The TRANSCEND study evaluated the effectiveness of telmisartan compared with placebo in patients with cardiovascular disease or diabetes with end-organ damage and who were intolerant to ACE inhibitors.

What does this study claim?
Although telmisartan was well tolerated, the reduction in the primary outcome (CV death, myocardial infarction, stroke and hospitalisation for heart failure) was not significantly different from placebo. Over a median period of 56 months, 15.7% of patients receiving telmisartan experienced the primary outcome compared with 17.0% who received placebo (hazard ratio [HR] 0.92, 95% confidence interval [CI] 0.81 to 1.05, P=0.216). Telmisartan and placebo were given in addition to patients other medications for heart disease.

How does this relate to other studies?
Equivalence of telmisartan to the ACE inhibitor, ramipril, in reducing cardiovascular events and heart failure in similar patients to those of the TRANSCEND study was demonstrated previously in the ONTARGET study. Over a median of 56 weeks, the occurrence of the primary outcome, which was the same as that of TRANSCEND, occurred in 16.7% of patients in the telmisartan group compared 16.5% in the ramipril group 16.5%, (relative risk, 1.01; 95%CI 0.94 to 1.09). As suggested in an accompanying editorial to TRANSCEND, the reason for not showing a similar level of benefit for an ARB in TRANSCEND, compared for example with ramipril in the HOPE study, may have been due to the greater use of other preventative drugs (statins, antiplatelets, beta-blockers) in TRANSCEND. It is also possible that the failure to show a benefit for telmisartan, as for trandolapril in the PEACE study, is an example of the “law of diminishing returns”, i.e. the absolute benefit becomes increasingly less with each added preventative drug, and the ability to demonstrate statistical benefit becomes increasingly difficult.

So what?
This study questions the equivalence in clinical effectiveness of telmisartan (and possibly other ARBs) and ACE inhibitors when prescribed for patients at high risk of cardiovascular events. However, definitive conclusions can not be made about their relative effectiveness, especially in view of the ONTARGET study, which demonstrated non-inferiority of telmisartan to ramipril in a similar patient group. What we can say is that the clinical evidence for the benefits of ARBs in preventing cardiovascular events and heart failure is less robust than that of ACE inhibitors. Therefore, where a renin-angiotensin system agent is required for primary or secondary prevention of cardiovascular disease, an ACE inhibitor, rather than an ARB should be the first choice. Concern over the risk of ACE-inhibitor induced cough is insufficient reason to prescribe ARBs ahead of ACE inhibitors – around 32 people need to be prescribed an ARB rather than an ACE to prevent one person having to stop taking it because of cough  (see previous blog of the ONTARGET study).

Study details
Patients – this was a randomised, double-blind, placebo-controlled study of patients (mean age 67) with existing cardiovascular disease or diabetes with end organ damage, and who had previously been discontinued from an ACE inhibitor because of intolerance. Patients with heart failure were excluded. Many of the patients were already receiving concomitant therapies (e.g. 56% statins, 80% antiplatelets, 33% diuretics, 40% calcium channel blockers, 59% beta-blockers).
Intervention and comparator – patients received either telmisartan 80 mg/day (n=2954) or placebo (n=2972).
Outcome – The primary outcome was the composite of cardiovascular death, myocardial infarction, stroke, or hospitalisation for heart failure.
Results – Thee median duration of follow-up was 56 months. Mean blood pressure (BP) was lower in the telmisartan group than in the placebo group throughout the study (by about 4/2mmHg, on average). 15.7% of patients experienced the primary outcome in the telmisartan group compared with 17.0% in the placebo group (HR 0·92, 95%CI 0.81 to1.05, P=0.216). One of the secondary outcomes — a composite of cardiovascular death, myocardial infarction, or stroke — occurred in 13.0% of patients on telmisartan compared with 14.8% on placebo (HR 0.87, 95%CI 0.76 to 1.00, P=0.068 after adjustment for multiplicity of comparisons and overlap with primary outcome). There was no significant difference in the number of patients who discontinued study medication in the telmisartan group compared with the placebo group (21.6% vs. 23.8%, respectively, P=0.055).

This study was funded by Boehringer Ingelheim.

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