ONTARGET: ACE or ARB? Or both?
In high-risk patients without heart failure who could not tolerate ACE inhibitors, the angiotensin-receptor blocker (ARB) telmisartan is equally effective in reducing cardiovascular risk as the ACE inhibitor ramipril and less likely to cause angioedema. However, while dual blockade with both an ARB and ACE inhibitor produced a larger biologic effect in terms of greater blood pressure lowering and an increase in the number of patients showing a potassium level >5.5 mmol/l, the combination was associated with more adverse events.
Telmisartan provides sustained antihypertensive activity effect over the 24-hour period between doses and the comparator, ramipril, was chosen based on the Heart Outcomes Protection Evaluation (HOPE – Ramipril) trial that showed fewer cardiovascular events compared to placebo when used in a similar patient population toONTARGET
The ONTARGET investigators randomized these high-risk patients to 10 mg ramipril (n = 8,576), 80 mg telmisartan (n = 8,542), or both drugs (n = 8,502) daily. The primary composite outcome was death from cardiovascular causes, myocardial infarction, stroke, or hospitalization for heart failure. Telmisartan was clearly noninferior to ramipril http://www.eshonline.org/education/congresses/2008/esh/a with the primary outcome occurring in 1,412 patients in the ramipril group (16.5%) versus 1,423 patients in the telmisartan group (16.7%; relative risk, 1.01; 95% confidence interval [CI], 0.94 to 1.09). At the targeted dose of 80 mg once daily, telmisartan preserved 94% (95% CI, 83 to 105) of the benefit of ramipril 10 mg daily in the HOPE trial. There were high rates of adherence to both drug regimens, providing additional confidence in establishing the noninferiority of telmisartan.
The telmisartan group had lower rates of cough (1.1% vs. 4.2% for ramipril; p < 0.001) and less angioedema (0.1% vs. 0.3%; p = 0.01), a rare but serious and unpredictable complication. However, this benefit of full-dose combination therapy was partially offset by a higher rate of hypotensive symptoms (2.6% vs. 1.7%; p < 0.001) associated with telmisartan use, although the rate of syncope was the same (0.2% for both groups).
ACE plus ARB
Combination therapy produced a greater reduction in BP but did not reduce the primary outcome to a greater extent versus ramipril alone. However, full-dose dual therapy did lead to higher rates of adverse events compared to monotherapy, including more hypotension-related events (e.g., syncope) and an increased incidence of renal dysfunction.
Why did a 2 mm Hg greater reduction in BP not provide more benefit? Prof. Peter Sleight, Oxford (UK), was co-chair of the ONTARGET and TRANSCEND trials (along with Prof. Salim Yusuf, McMaster University, Canada). In his Monday presentation, Dr. Sleight noted that a separate analysis of the ONTARGET BP data will be presented as a late-breaking clinical trial on Thursday. However, he offered several points for consideration. In this elderly population (mean age: 66 years) with known vascular disease, the combination caused more renal failure, more hypotension, and possibly more occult renal vascular problems, too.
Previous small trials suggested a benefit of combining ACE and ARB therapy (especially for proteinuria), but these trials were likely too small, he said, to identify risk or harder outcomes. Also, in elderly patients who get volume depleted, it may be hazardous to block the renin-angiotensin-aldosterone system “too fiercely.” Given the findings, he said, use of full-dose dual blockade should be an exception and followed by specialists monitoring potassium and creatinine.
As for the use of telmisartan, Dr. Sleight said, it is a superior albeit more costly drug. He expects that insurers and governments will mandate starting with a generic ACE inhibitor and reserve ARBs only for ACE-intolerant patients. However, this policy has hidden costs, he said. For example, in ONTARGET, compliance was consistently better for those on telmisartan across more than 4 years of follow-up, while discontinuation of study drug was greater in the ramipril arm. Moreover, time to permanent discontinuation was consistently better in the telmisartan group across the years of follow-up.
Coming soon: publications on renal data from ONTARGET, more data on mono versus dual renin-angiotensin system blockade, and the aforementioned BP analyses.