Pharmacological Management of Heart Failure

Angiotensin-converting enzyme inhibitors block the enzyme that converts angiotensin I to angiotensin II. With less angiotensin II being formed, blood vessels relax, afterload falls, and aldosterone secretion decreases, which reduces sodium retention. Angiotensin-converting enzyme inhibitors also blunt the harmful fibrotic and hypertrophic effects of angiotensin II on the heart muscle described in Module 1, contributing to reverse remodeling over time.

The same enzyme that converts angiotensin I to angiotensin II also breaks down bradykinin, a peptide that causes vasodilation. Blocking this enzyme therefore raises bradykinin levels in addition to lowering angiotensin II. Elevated bradykinin contributes a small additional vasodilator benefit, but it is also responsible for the two adverse effects that distinguish angiotensin-converting enzyme inhibitors from the other RAAS blockers discussed later in this module: a dry cough and, rarely, angioedema.

Angiotensin-converting enzyme inhibitors are started at a low dose and increased gradually as tolerated, while blood pressure, kidney function, and potassium are monitored. A mild rise in creatinine after starting therapy is expected and reflects the drug working as intended on kidney blood flow; it is not by itself a reason to stop the medication.

Sacubitril/valsartan combines two drugs in one tablet. Sacubitril inhibits neprilysin, the enzyme that normally breaks down the protective natriuretic peptides introduced in Module 1, so blocking it raises natriuretic peptide levels and amplifies their beneficial effects of vasodilation, sodium excretion, and reduced cardiac fibrosis. Valsartan is an angiotensin receptor blocker, providing the same angiotensin II blockade described in Section 3.

Neprilysin also happens to break down angiotensin II, so inhibiting neprilysin alone would raise angiotensin II levels and work against the goal of treatment. Combining a neprilysin inhibitor with an angiotensin receptor blocker solves this problem: angiotensin II signaling is blocked at the receptor regardless of how much is produced. This combination, amplifying the protective natriuretic peptide system while blocking the harmful renin-angiotensin-aldosterone system at the same time, produces a more complete neurohormonal effect than an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker alone.

In patients with heart failure with reduced ejection fraction who can tolerate it, sacubitril/valsartan is now preferred over an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker alone, since it has demonstrated a greater reduction in mortality and hospitalization in clinical trials. Patients already taking an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker are commonly switched to sacubitril/valsartan for this reason.

Because sacubitril/valsartan contains an angiotensin receptor blocker, it shares the same major contraindications as angiotensin-converting enzyme inhibitors and angiotensin receptor blockers: pregnancy and bilateral renal artery stenosis. A history of angioedema with an angiotensin-converting enzyme inhibitor is also a contraindication, since sacubitril, like an angiotensin-converting enzyme inhibitor, raises bradykinin levels by blocking one of the enzymes that degrades it.

Hypotension is the most common reason for dose adjustment. Hyperkalemia and a modest rise in creatinine can occur, just as with the other renin-angiotensin-aldosterone system blockers in this module. An important safety rule: sacubitril/valsartan must never be combined with an angiotensin-converting enzyme inhibitor or another angiotensin receptor blocker, since this would cause excessive bradykinin elevation and a high risk of angioedema.