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1. The angiotensin receptor blocker (ARB) telmisartan is non-inferior to the ACE-inhibitor rampiril in improving cardiovascular outcomes in high-risk populations
2. Telmisartan is significantly less often associated with angioedema and cough compared to ramipril
3. Telmisartan in addition to ramipril in high risk populations does not offer additional benefit, and is associated with increased risk of complications
Original Date of Publication: April 10, 2008
Study Rundown: This study provided evidence that telmisartan is a non-inferior alternative to ramipril in reducing cardiac outcomes in high risk patients, and is associated with significantly lower risk of cough and angioedema. Combination therapy with both drugs, however, does not provide additional benefit as compared to ramipril alone and is associated with increased adverse effects including renal failure.
For improving cardiac outcomes, an angiotensin receptor blocker (ARB) can be considered as an alternative for high-risk patients who are not able to tolerate ACE-I. Combination therapy with an ARB and ACE-I should be avoided.
Primer:Â ARBs reduce the activation of the renin-angiotensin-aldosterone system by blocking the angiotensin-II (ANG-II) receptor. With their introduction, there was uncertainty whether ARBs were a viable alternative to ACE-inhibitors (ACE-I). There is theoretical enhanced effectiveness of these drugs as they act directly on the ANG-II receptor as opposed to the upstream pathway inhibition of ACE-Is. Furthermore, it was thought that ARBs would be less associated with adverse effects. ARBs, unlike ACE-inhibitors, do not reduce bradykinin degradation, which is associated with cough and angioedema.
One of the indications for ACE-Is is in high-risk patients without systolic heart failure. Evidence for this indication was provided by the 2008 HOPE (Heart Outcomes Prevention Evaluation) trial, which showed that addition of the ACE-I ramipril reduced adverse cardiac outcomes in high-risk populations with normal ejection fractions. The subsequent ONTARGET study was published in NEJM in 2008. This landmark randomized control trial sought to determine whether the ARB telmisartan was a non-inferior alternative to ramipril in improving cardiac outcomes in a similar patient population. The study also investigated whether that combination therapy with both telmisartan and ramipril offered additional benefit to ramipril alone.
Relevant Reading:
- Pfeffer MA, McMurray JJ, Velazquez EJ, et al. Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. NEJM 2003;349:1893-1906.
- Granger CB, McMurray JJ, Yusuf S, et al. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function intolerant to angiotensin-converting-enzyme inhibitors: The CHARM-Alternative trial. Lancet 2003;362:772-776.
In-Depth [randomized controlled study]:Â This trial enrolled 25,620 patients from 40 countries. Patients were eligible for the enrolment if they were considered high-risk for adverse cardiac outcomes. Patients underwent double-blind randomization to one of three groups receiving 1) 80 mg telmisartan daily, 2) 5 mg ramipril, or 3) a combination of both drugs.
Results showed that telmisartan was non-inferior to ramipril, but also non-superior. Furthermore, patients receiving telmisartan were significantly less likely to develop cough and angioedema than those receiving ramipril. The combination of the drugs, however, was non-superior to ramipril alone. Patients receiving both drugs were more likely to develop hypothensive symptoms, syncope, diarrhea and renal impairment than those receiving ramipril alone. There were also a higher number of deaths in the combination-therapy group than ramipril group, but this did not reach statistical significance.
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