angiotensin-converting enzyme inhibitors + angiotensin ii receptor blocker + angiotensin receptor-neprilysin inhibitor

This entry refers to the combination of three classes of antihypertensive and heart failure medications: - Angiotensin-converting enzyme (ACE) inhibitors, which block the conversion of angiotensin I to angiotensin II, reducing vasoconstriction and aldosterone secretion. - Angiotensin II receptor blockers (ARBs), which selectively block the binding of angiotensin II to its AT1 receptor, thereby reducing vasoconstriction, aldosterone release, and other effects mediated by this pathway. - Angiotensin receptor-neprilysin inhibitors (ARNIs), a class that combines an ARB with a neprilysin inhibitor. Neprilysin inhibition increases levels of natriuretic peptides leading to natriuresis, diuresis, vasodilation, and reduced blood pressure. The rationale for combining these mechanisms is theoretically robust—addressing multiple neurohormonal pathways involved in hypertension and heart failure. However, clinical evidence shows that combining all three classes is not recommended due to increased risk of adverse effects such as severe hypotension or life-threatening angioedema. Specifically: - ACE inhibitor plus ARB plus ARNI therapy has not been approved or recommended because dual inhibition (ACEi + ARNI) significantly increases the risk for serious side effects like angioedema[1][3][10]. - The only approved ARNI is sacubitril/valsartan (Entresto), which should not be used concurrently with either an ACE inhibitor or another ARB[1][2][3].