Pharmacological Management of Heart Failure

As introduced in Module 1, heart failure with reduced ejection fraction is primarily driven by neurohormonal activation following myocardial injury, the pathway targeted by the four pillars of guideline-directed medical therapy. Heart failure with preserved ejection fraction has a different primary driver: a systemic, low-grade inflammatory state generated by chronic conditions such as obesity, hypertension, and diabetes, which causes the heart muscle to become stiff and slow to relax rather than weak to contract.

Because the underlying problem is different, drug classes that block the renin-angiotensin-aldosterone system or the sympathetic nervous system, the cornerstones of heart failure with reduced ejection fraction therapy, do not address the primary driver of heart failure with preserved ejection fraction. This explains why angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and beta-blockers have repeatedly failed to show a clear survival benefit in heart failure with preserved ejection fraction, even though they are each pillars of therapy in heart failure with reduced ejection fraction.

Sodium-glucose cotransporter 2 inhibitors, introduced in Module 5, remain the one drug class with consistent, reproducible benefit across the heart failure with preserved ejection fraction population, and they are now the central pharmacological intervention for this syndrome. Loop diuretics continue to play an important symptomatic role for fluid overload, used carefully, since a stiff ventricle depends on adequate filling pressure and can be harmed by overly aggressive fluid removal.

Heart failure and chronic kidney disease frequently coexist and worsen each other in both directions. Reduced cardiac output lowers blood flow to the kidneys, activating the same renin-angiotensin-aldosterone system and sympathetic nervous system pathways described in Module 1 and further injuring the kidneys. Conversely, chronic kidney disease itself contributes to heart failure through fluid retention and its own activation of these same neurohormonal pathways. This bidirectional relationship is sometimes called the cardiorenal syndrome.

Most heart failure drug classes require caution, not avoidance, in patients with chronic kidney disease. As established in Module 2, a modest rise in creatinine after starting a renin-angiotensin-aldosterone system blocker is expected and is not by itself a reason to stop therapy. The general principle across nearly all heart failure pharmacology is that the cardioprotective benefit of guideline-directed medical therapy generally extends well into chronic kidney disease, and these drugs should not be reflexively withheld simply because a patient has reduced kidney function.