Can aliskiren reduce the incidence of cough caused by ramipril?

reported results from a double-blind, multi-centre trial in which 837 patients with diabetes mellitus and hypertension were randomised to once-daily aliskiren (150 mg titrated to 300 mg after four weeks; n=282), ramipril (5 mg titrated to 10 mg; n=278) or the combination of aliskiren and ramipril for eight weeks. We are not commenting on the effects on blood pressures. We noticed that aliskiren significantly reduced plasma renin activity as monotherapy (by 66%) or in combination with ramipril (by 48%), despite large increases in plasma renin concentration in all treatment groups. Of particular interest was the reported rate of cough; 4.7% in patients receiving ramipril, but only 1.8% of patients receiving the aliskiren/ramipril combination and 2.1% of patients receiving aliskiren only. Although the difference between ramipril and combined ramipril/ aliskiren groups did not achieve significance (p=0.08), the authors noticed the possibility that aliskiren might reduce the incidence of angiotensinconverting enzyme (ACE) inhibitor-induced cough, a property of potential therapeutic value. No explanation for a possible mechanism by which aliskiren might reduce the incidence of ACE inhibitor-induced cough was presented. We would like to offer a theoretical explanation. Induction of cough by ACE inhibitors is believed to be linked to increased tissue accumulation of mainly bradykinin and possibly of other autacoids. ACE both generates angiotensin II from angiotensin I and degrades bradykinin. No ACE inhibitor can cause complete ACE inhibition, but there will always be some ‘escape’ from the inhibitory action. Aliskiren treatment is known to reduce plasma renin activity and plasma concentrations of angiotensin I, a major substrate of ACE. This would leave more active sites of ACE free to cleave bradykinin, which in turn would lead to less accumulation of bradykinin and to – less cough. Future studies will show whether aliskiren or other renin inhibitors may indeed reduce the incidence of cough in patients treated with ACE inhibitors. If true, this would offer possible advantages of combined drug treatment.