Dual renin-angiotensin system blockade and outcome benefits in hypertension: a narrative review

Inhibition of the renin-angiotensin system (RASi) lowers blood pressure, reduces cardiovascular outcomes and blunts the progressive course of heart failure and of chronic kidney disease. This narrative article summarizes why the hypothesis came up that more complete RASi with two different agents should be more beneficial compared with one agent and how this hypothesis was deflated in randomized clinical trials (RCTs).

The hypothesis was based on experimental findings and surrogate endpoints in patients, namely lowering of blood pressure and reduction of proteinuria. Three large RCTs in patients with atherosclerotic vascular disease or in diabetic kidney disease randomized almost 40, 000 patients. RASi with one agent was compared with RASi with two agents. All three RCTs ruled out benefits of dual RASi on major cardiovascular outcomes and reported substantial adverse effects of dual RASi. The latter included hyperkalemia, acute kidney injury, symptomatic hypotension and syncope. There was also no substantial advantage of dual over monotherapy on decline in kidney function. In one RCT, there was a hint of nonsustained, early benefit on kidney outcomes with dual therapy.

Outside heart failure, RASi with two agents is not indicated to treat hypertension because of substantial safety concerns and lack of benefit on major cardiovascular and kidney outcomes.