Letters Dual blockade of the renin-angiotensin system

Sodium depletion in patients in clinical trials may account for the increased cardiovascular risk of dual blockade of the renin-angiotensin system

BMJ 2013; 346 doi: http://dx.doi.org/10.1136/bmj.f1685 (Published 19 March 2013) Cite this as: BMJ 2013;346:f1685
  1. John H Laragh, professor of medicine, department of cardiothoracic surgery1,
  2. Jean E Sealey, research professor emerita of physiology and biophysics in medicine, department of medicine1
  1. 1Weill Cornell Medical College, New York, NY 10065-4896, USA
  1. jsealey{at}med.cornell.edu

Makani and colleagues’ meta-analysis of clinical trials of cardiovascular patients found that giving one renin-angiotensin system blocker reduces cardiovascular mortality but adding a second fails to reduce mortality and increases the frequency of hypotension, hyperkalaemia, and renal failure.1 We suspect that most adverse events occurred in sodium depleted patients who reactively increase plasma renin levels to vasoconstrict arterioles to protect from undue hypotension,2 stimulate aldosterone secretion to protect from attendant hyperkalaemia,3 and vasoconstrict efferent renal arterioles more than afferent ones to protect from renal failure.4

This explanation is supported by recent reports that cardiovascular patients enrolled in clinical trials of renin-angiotensin system blockers or observational studies who have high treatment plasma renin levels die sooner of cardiovascular disease.5 Analysis of those reports found evidence of excessive sodium depletion among subgroups with the highest plasma renin.5

We suggest that in clinical trials of such blockers, the first drug reduces cardiovascular risk in most patients but increases risk in sodium depleted subsets, resulting in net cardiovascular benefit for the group as a whole. Then, the second blocker adds little benefit to patients whose renin-angiotensin system has already been blocked but increases cardiovascular risk in the sodium depleted ones, resulting in a net increase in cardiovascular risk for the group as a whole.

In conclusion, hypotension, hyperkalaemia, and deteriorating glomerular filtration rate are expected consequences of renin-angiotensin system blockade in sodium depleted patients. However, sodium depletion can be avoided by identifying patients with high plasma renin activity (>4.5 ng/mL/h) and withdrawing natriuretic drugs or low salt diets sufficiently to reduce plasma renin but not increase blood pressure unduly. With this approach, more patients might benefit from one or even two renin-angiotensin system blocking drugs.


Cite this as: BMJ 2013;346:f1685