Physicians' Academy for Cardiovascular Education

EMA recommends against combined use RAS-inhibitors

News - Apr. 16, 2014

The European Medicines Agency (EMA) recommended that drug classes that act separately on the renin-angiotensin system (RAS) should not be used in combination [1].
In particular, patients with diabetic nephropathy should not be given an ARB with an ACE-inhibitor. Where 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.
The combination of the direct renin inhibitor aliskiren with an ARB or ACE-inhibitor is strictly contraindicated in patients with kidney impairment or diabetes.
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. Benefits were thought to outweigh risk only in a selected group of patients with heart failure in whom other treatments were unsuitable.
Concerns over the combined use of these drug classes stem from a large meta-analysis by Makani et al [2], which showed that using multiple RAS-acting agents failed to reduce mortality and was associated with an excessive risk of adverse events, arguing against the use of dual therapy.
The recommendation from the EMA's Pharmacovigilance Risk Assessment Committee (PRAC) comes after a 10-month review. The PRAC recommendation will now be forwarded to the Committee for Medicinal Products for Human Use (CHMP), which typically adopts the PRAC recommendation.

UPDATE 23.05.14:

THe CHMP has endorsed the PRAC recommendation. The CHMP opinion will now be forwarded to the European Commission, which will issue a final decision valid throughout the EU in due course.


1.European Medicines Agency. PRAC recommends against combined use of medicines affecting the renin-angiotensin (RAS) system [press release]. April 11, 2014. Available here.
2. Makani H, Bangalore S, Desouza KA, Shah A, Messerli FH. Efficacy and safety of dual blockade of the renin-angiotensin system: meta-analysis of randomized trials. BMJ. 2013 Jan 28;346:f360. doi: 10.1136/bmj.f360.

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