Dual renin angiotensin system blockade: too many cons

By Caroline Price, Senior medwireNews Reporter

Any benefit of dual blockade of the renin angiotensin system (RAS) is limited to its effects on surrogate endpoints, and outweighed by an excessive risk for adverse events such as hypotension, hyperkalemia, and renal failure, argue hypertension experts.

Franz Messerli (Columbia University, New York, USA) and colleagues draw their conclusions from a systematic review and meta-analysis of 33 randomized trials, involving nearly 70,000 patients in all, comparing dual RAS blockade with monotherapy.

As reported in the BMJ, they found that dual RAS blocker therapy did not result in any reductions in all-cause or cardiovascular mortality, although it reduced admissions to hospital for heart failure.

In light of the significantly increased risks for adverse events, "considerations of risk-benefit argue against the routine use of dual therapy," the team writes.

Dual RAS blockade has appeared in several sets of guidelines despite a lack of solid evidence, write the researchers, becoming "fashionable" not only for treatment of patients with hypertension who also have diabetes, proteinuria, both, or treatment-resistant heart failure, but also now among patients with uncomplicated essential hypertension.

Indeed, in the USA more than 200,000 patients are currently treated with dual RAS blockade, most with a combination of an angiotensin receptor blocker (ARB) and an ACE inhibitor (70%), they note. Two ACE inhibitors, two ARBs, or an ACE inhibitor and an ARB combined with a direct renin inhibitor are combinations that are also sometimes used.

However, the authors' meta-analysis found no reduction in all-cause or cardiovascular mortality with dual RAS blockade compared with monotherapy, either overall or among patients with heart failure.

There was a small, but significant, 7% increase in all-cause mortality among patients without heart failure who received dual RAS blockade, but no difference was seen for cardiovascular mortality in this group.

Dual therapy was, however, associated with a significant 18% reduction in admissions to hospital for heart failure, largely driven by a 13% reduction among patients with existing heart failure, although there was also a trend towards a benefit among those without prior heart failure, in whom a nonsignificant 9% reduction in heart failure hospitalizations was seen.

Nevertheless, an overall 55% increased risk for hyperkalemia, 66% increased risk for hypotension, and 41% increased risk for renal failure was seen with dual therapy compared with monotherapy. The same pattern for hyperkalemia and hypotension was seen in patients with and without heart failure, but the risk for renal failure was not elevated in those without heart failure.

Still, withdrawal owing to drug-related adverse events was 27% more likely among the dual therapy patients, both overall and irrespective of heart failure status.

"Given these facts it may appropriately be asked why dual therapy was and still is extensively used to treat many patients with hypertension and heart failure," comment Messerli and co-investigators.

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