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Managing high-risk patients with ARBs
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Initial results from the ONTARGET study confirm that telmisartan, an angiotensin receptor blocker, is a viable option for patients with vascular disease or high-risk diabetes.
This is the first time that an ARB has been shown to be as efficacious as the established angiotensin-converting enzyme inhibitor for reduction of CVD risk in a broad population of patients with underlying vascular disease or diabetes with evidence of end-organ damage. Telmisartan had a favorable safety profile in comparison with ramipril, the “gold standard” ACE, in this patient population.
Researchers enrolled 25,620 high-risk patients aged 55 years or older with controlled BP and either coronary artery, peripheral artery or cerebrovascular disease or diabetes with end-organ damage. They randomly assigned patients to receive treatment with telmisartan (80 mg daily), ramipril (10 mg daily), or a combination of telmisartan (80 mg daily) plus ramipril (10 mg daily). Patients with a known hypersensitivity or intolerance to ACEs or ARBs, symptomatic HF, uncontrolled hypertension (BP >160 mmHg/100 mm Hg), or other medical conditions such as renal artery disease were excluded from this trial. The primary end point was the composite of CV death, MI, stroke or hospitalization for HF.
Targeting the renin-angiotensin system
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It has been postulated that the combination of an ARB with an ACE may have additive effects on CV risk reduction. However, it remains unknown if this translates into a significant clinical benefit in a broad spectrum of high-risk patients. Current clinical evidence on combination therapy of renin-angiotensin system inhibitors is conflicting. The results from the CHARM study suggested that additional clinical benefits resulted from adding an ARB (candesartan) to an ACE in the treatment of patients with HF. However, results of the VALIANT study, in which patients with previous MI were treated with a combination of an ACE (captopril) and an ARB (valsartan) showed no significant clinical benefit to the combination treatment compared with captopril alone, but showed a higher incidence of drug-related adverse events.
The results of ONTARGET concur with the findings of the VALIANT study, because they revealed no additional benefit, CV or otherwise, to the use of combination therapy compared with the use of an ACE alone. Specifically, ONTARGET showed that the combination of telmisartan (80 mg daily) and ramipril (10 mg daily) was not superior to ramipril alone in reduction of the composite outcome of CV death, MI, stroke or hospitalization for chronic HF. Although the two drugs taken together reduced systolic BP by an additional 2.4 mm Hg on average compared with ramipril alone, combination RAS blockade did not result in any additional clinical benefit.
The study also examined whether telmisartan (80 mg daily) alone is at least as effective as (i.e., noninferior to) ramipril (10 mg daily) alone. ONTARGET demonstrated that telmisartan is noninferior to ramipril for the specified primary outcome of death from CV causes, MI, stroke or HF. The primary outcome occurred in 16.7% of patients in the telmisartan group, as compared with 16.5% in the ramipril group (RR, 1.01; 95% CI, 0.94-1.09). Thus, telmisartan is an alternative to ramipril in patients with vascular disease or high-risk diabetes without HF.
Although telmisartan was as effective as ramipril, it appears to be better tolerated. Patients in the telmisartan group had lower rates of cough (1.1% vs. 4.2%; P<.001) and angioedema (0.1% vs. 0.3%; P=.01) than those in the ramipril group, even though the study excluded patients with known ACE intolerance. However, the telmisartan group had a higher rate of hypotension (2.6% vs. 1.7%; P<.001), which is consistent with the slightly lower BP levels associated with telmisartan. Combination therapy was associated with increased adverse events when compared with ramipril alone. Combination therapy was associated with a significantly increased risk of hypotensive symptoms (4.8% vs. 1.7%; P<.001), syncope (0.3% vs. 0.2%; P=.03) and renal dysfunction (13.5% vs. 10.2%; P<.001) when compared with ramipril alone.
These findings establish for the first time noninferiority between an ACE and an ARB in a clinically relevant patient population. Clinicians can now be comfortable that telmisartan is a safe and effective option when given to high-risk patients. Although patients given combination therapy did have a greater reduction in systolic BP, this treatment regimen was found to be no more effective than ramipril alone and was associated with a greater number of adverse events. Thus, the simple message is that there is an established, better-tolerated alternative for high-risk patients.
George Bakris, MD, is Professor of Medicine and Director, Hypertensive Diseases Unit at the University of Chicago, Pritzker School of Medicine and is a Member of the Cardiology Today Editorial Board.
For more information:
- Cohn JN, Tognoni G, Valsartan Heart Failure Investigators. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N Engl J Med. 2001;345:1667-1675.
- McMurray JJ, Ostergran J, Swedberg K, et al. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function taking angiotensin-converting-enzyme inhibitors: the CHARM-Added trial. Lancet. 2003;362:767-771.
- Pfeffer MA, McMurray JJ, Velazquez EJ, et al. Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. N Engl J Med. 2003;349:1893-1906.