No Benefit to Dual RAS Blockade in Meta-Analysis

January 30, 2013

NEW YORK — A large meta-analysis of randomized trials comparing dual blockade of the renin-angiotensin system (RAS) with ACE inhibitors and angiotensin-receptor blockers (ARBs) failed to show any benefit in terms of reducing mortality compared with monotherapy [1].

In fact, dual blockade of the RAS was associated with an increased risk of hyperkalemia, hypotension, and renal failure, as well as a significantly increased risk of drug withdrawal due to adverse effects. The 33 trials in the meta-analysis explored RAS blockade in patients with hypertension, diabetes, renal disease, or heart failure. Researchers are hoping their results are the final nail in the coffin when it comes to dual blockade of the RAS.

"It's still not uncommon to use both of these drug classes," senior researcher Dr Franz Messerli (St Luke's Roosevelt Hospital/Columbia University College of Physicians and Surgeons, New York) told heartwire . "It's a bit less common now than before, but it still happens. These are nephrologists that look at proteinuria, and there is no question that proteinuria diminishes when you add an ARB to an ACE inhibitor, although it would probably diminish just as much if you doubled the dose of the ACE inhibitor. For some reason or another, dual blockade of the RAS still has some magic attraction."

The attraction, however, is quickly diminishing. In 2009, the Canadian Hypertension Education Program (CHEP) urged physicians and patients to stop using ACE inhibitors and ARBs together. A guideline alert issued simultaneously by the Canadian Heart and Stroke Foundation advised patients to see their family physicians as soon as possible to get their treatment changed. Weeks later, Messerli published a viewpoint in the Journal of the American College of Cardiology [2] urging physicians to avoid using dual RAS blockade with ARBs and ACE inhibitors in clinical practice.

In addition, the Renal Outcomes with Telmisartan, Ramipril, or Both, in People at High Vascular Risk (ONTARGET) study showed the ARB telmisartan to be noninferior to the ACE inhibitor ramipril, but the combination of the two together was associated with more adverse events and no increased benefit. An analysis looking only at renal outcomes in ONTARGET showed that the ARB/ACE-inhibitor combination was associated with an increased risk of dialysis, doubling of serum creatinine, and death, compared with using either agent alone.

Meta-Analysis of More Than 68 000 Patients

The new meta-analysis, with first author Dr Harikrishna Makani (St Luke's Hospital, New York), is published January 28, 2013 in BMJ. The analysis included 33 randomized controlled trials with 68 405 patients treated for a mean duration of one year.

Dual blockade of the RAS was not associated with a reduction in the risk of mortality or cardiovascular mortality compared with monotherapy but was associated with a significant 18% reduction in admissions for heart failure. The reduction was driven largely by studies that included patients with heart failure (hazard ratio [HR] 0.77; 95% CI 0.68–0.88), although there was a trend toward a reduction in the cohort without heart failure (HR 0.91; 0.82–1.01). Regarding adverse events, dual therapy was associated with a significant 55% increased risk of hyperkalemia, a significant 66% increased risk of hypotension, and a significant 41% increased risk of renal failure.

The enthusiasm for dual blockade of the RAS is based on beneficial changes in blood pressure and proteinuria, with the use of ARBs and ACE inhibitors initially believed to provide greater cardioprotective and nephroprotective effects. In 2003, the COOPERATE study showed that dual therapy with trandolapril and losartan reduced the time to doubling of serum creatinine/end-stage renal disease by 60%. While it became one of the most cited studies in the Lancet, the study was later pulled for inconsistencies.

"Once this paper had been published, it was one of the most quoted papers in the Lancet for a little while," said Messerli. "And then a retraction happens four or five years later, but the same doctors don't always see the retraction, and therefore they continue to prescribe both drugs as they have done."

For Messerli, the eighth version of the Managing Blood Pressure in Adults: Report from the Joint National Committee (JNC 8) can't come soon enough, as he believes only the clinical guidelines will change clinical practice and get physicians to stop prescribing ARBs and ACE inhibitors to hypertensive patients or diabetic patients with evidence of proteinuria.

As reported previously by heartwire , there is still some debate about heart-failure patients based on the results of the CHARM study. The study showed that dual blockade of the RAS improved left ventricular ejection fraction and reduced hospital admissions, but there was no reduction in all-cause mortality, coupled with a high rate of drug discontinuation due to renal effects and hypotension. Even in these patients, Messerli said he would not use ARBs and ACE inhibitors together, noting that he never prescribes both in clinical practice.