EMA: Don't Combine ARBs, ACE Inhibitors, and Direct Renin Inhibitors

Shelley Wood


April 11, 2014

LONDON, UK — No two drug classes that act separately on the renin-angiotensin system (RAS) should be used in combination, the European Medicines Agency (EMA) warned today[1]. According to the European drug regulator, angiotensin-receptor blockers (ARBs), ACE inhibitors, and direct renin inhibitors should not routinely be used in combination. In particular, patients with diabetic nephropathy should not be given an ARB with an ACE inhibitor, the agency concluded.

The recommendation from the EMA's Pharmacovigilance Risk Assessment Committee (PRAC) comes after a 10-month review, first reported by heartwire last May. A final decision rests with the Committee for Medicinal Products for Human Use (CHMP), which typically adopts the PRAC recommendation.

"Where such combination (dual blockade) is considered absolutely necessary, it must be carried out under specialist supervision with close monitoring of kidney function, fluid and salt balance, and blood pressure," an EMA press release states. This includes the licensed use of the ARBs candesartan or valsartan as add-on therapy to ACE inhibitors in patients with heart failure in whom the combination is deemed necessary, the statement adds. "The combination of aliskiren (Tekturna, Novartis) with an ARB or ACE inhibitor is strictly contraindicated in those with kidney impairment or diabetes."

Concerns over the combined use of these drug classes stems from a large meta-analysis by Makani et al, with senior author Dr Franz Messerli (St Luke-Roosevelt Hospital, New York), published last year in BMJ. The analysis was a follow-up to a viewpoint Messerli published in 2009, calling for physicians to stop using dual RAS blockade in clinical practice, based on a signal of harm seen in the ONTARGET study.

Key risks of combining several RAS-acting agents include hyperkalemia, low blood pressure, and worsening of kidney function compared with using one of these medicines alone, without a corresponding improvement in the anticipated clinical benefits of enhanced BP lowering, the EMA statement notes.

The 2014 Evidence Based Guidelines for the Management of High Blood Pressure in Adults (published by the majority of panel members from the Eighth Joint National Committee, but not officially the "JNC8 guidelines") specifically state that ACE inhibitors and ARBs should not be used in combination.

The US Food and Drug Administration (FDA), however, has not reviewed the concerns or issued any warnings on the combined use of these drug classes. By contrast, the Canadian Heart and Stroke Foundation issued a guideline alert back in 2009 advising patients to see their family physicians as soon as possible to get their treatment changed if they were taking both an ARB and an ACE inhibitor.

Back in 2012, both the FDA and EMA formally warned against the use of the direct renin inhibitor aliskiren in combination with an ACE inhibitor or ARB.


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