Renin-Angiotensin System Blockers May Create More Risk Than Reward for Sodium-Depleted Cardiovascular Patients With High Plasma Renin Levels

Abstract

Four recent reports revealed differences in survival rates among treated cardiovascular patients taking renin-angiotensin system-blocking drugs. Patients with higher on-treatment plasma renin activity (PRA) levels died sooner of cardiovascular mortality than those with lower levels. We investigated whether excessive sodium depletion might have induced the higher PRA levels and contributed to the greater morbidity and mortality. Using published data, ranges of PRA, blood pressures, drug usage, and biochemical parameters were compared among various groups of cardiovascular patients. We showed (i) that PRA levels are usually medium to low in treated cardiovascular patients, but are sometimes abnormally high, (ii) that excessive sodium depletion can induce such high PRA levels, (iii) that the higher PRA patients exhibited evidence of sodium depletion: lower blood pressures, more frequent natriuretic drug usage, lower N-terminal pro b-type natriuretic peptide (NT-proBNP), and higher blood urea nitrogen and uric acid levels, with similar usage of renin-angiotensin blocking drugs. We hypothesize that patients with high on-treatment PRA levels die sooner of cardiovascular events because they are excessively sodium-volume depleted. Moreover, renin-angiotensin system-blocking drugs may be harmful in such patients because they can functionally interfere with the effects of reactive rises in PRA that are triggered to prevent potentially dangerous falls in blood pressure, increases in plasma potassium, and falls in glomerular filtration rate. Careful liberalization of salt intake and subtraction of natriuretic drugs, sufficient to reduce reactive hyperreninemia without inducing unacceptable increases in blood pressure, might benefit such patients and decrease risk of adverse effects from drugs that block the renin-angiotensin system.