May 21st, 2013
European Medicines Agency Starts Review of Combined Use of Drugs that Block the Renin-Angiotensin System
Larry Husten, PHD
The European Medicines Agency (EMA) said last week that it was initiating a review of the combined use of agents that block the renin-angiotensin system (RAS). The three classes of RAS-blocking drugs (ACE inhibitors, ARBs, and direct renin inhibitors) are used to treat hypertension and congestive heart failure.
The EMA said that the review was being performed to address concerns that combined RAS-blocking drugs could increase the risk for hyperkalemia, hypotension, and kidney failure when compared with a single agent. A recent meta-analysis of 33 clinical studies published in the British Medical Journal (BMJ) concluded that “although dual blockade of the renin-angiotensin system may have seemingly beneficial effects on certain surrogate endpoints, it failed to reduce mortality and was associated with an excessive risk of adverse events… The risk to benefit ratio argues against the use of dual therapy.”
Franz Messerli, senior author of the BMJ meta-analysis, applauded the EMA action and said that “as usual the FDA is dragging its feet.”
The FDA said that it had completed a review of the subject and had “recently updated the labels of nearly all agents affecting the RAS to describe the risks associated with dual inhibition including hypotension, renal dysfunction, and hyperkalemia.” However, Messerli was critical of the updated label, which states:
Dual blockade of the RAS with angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy. Closely monitor blood pressure, renal function, and electrolytes in patients on Diovan and other agents that affect the RAS.”
Messerli responded that this “means you still may use dual RAS provided you ‘closely monitor’ the above. To my way of thinking this is not acceptable. Since we have no outcome data showing benefit for dual RAS blockade, this is not simply a question of closely monitoring.”
Messerli said he supported the 2009 Canadian hypertension guidelines, which specifically warned against the dual use of ACE inhibitors and ARBs. U.S. and European guidelines have not taken a similar strong stand.
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Clyde Yancy, speaking on behalf of the American Heart Association, sent the following comment:
We have been aware of the complexity of risk associated with combined use of ACE-I & ARBs.The available evidence for HTN would suggest that there is no additional benefit but an additional risk to renal function. For heart failure we remain aware of the CHARM-added component of the CHARM trials but view the evidence to be modest and the risk real. In the 2009 focused update the HF guidelines held the combination out as a IIB. The 2013 HF guidelines remain embargoed but there have been no new data that would fundamentally change our opinions.
When the combination is a renin inhibitor plus an ACE-I, the issues differ as there are more data regarding risk in the setting of HTN. Renin inhibitors are not indicated for heart failure and thus are not addressed in our guidelines but the recent trials studying aliskerin in HF have been underwhelming.