Four classes of medication have strong evidence for reducing death in heart failure with reduced ejection fraction (HFrEF), the form of heart failure where the heart pumps too weakly. When all four are used together, an actuarial analysis of major trials estimated that a 55-year-old patient could gain roughly 6.3 additional years of life compared to older conventional therapy. A fifth combination, hydralazine plus a nitrate, has a proven mortality benefit in a specific population. Beyond these, no other heart failure drugs have convincingly reduced death in clinical trials.
The Four Pillars of Treatment
Current guidelines organize the drugs that improve survival into four “pillars,” each targeting a different pathway that drives heart failure progression. The goal is to get patients on all four as quickly as tolerated, because the survival benefit compounds when they’re used together. These four classes are: drugs that block the renin-angiotensin system (with a preference for a newer combination agent), beta-blockers, aldosterone blockers, and a newer class originally developed for diabetes called SGLT2 inhibitors.
Each class works partly by slowing or reversing a process called cardiac remodeling, where the weakened heart gradually stretches and becomes less efficient over time. Animal and human studies confirm that blocking the hormonal stress systems (the renin-angiotensin-aldosterone system and the sympathetic “fight or flight” system) can prevent this stretching and, in some patients, actually reverse it. That reversal is linked to better long-term outcomes.
Renin-Angiotensin System Blockers
The preferred drug in this pillar is sacubitril/valsartan, a combination pill that blocks angiotensin (a hormone that constricts blood vessels and promotes scarring in the heart) while simultaneously boosting the body’s own protective hormones that reduce fluid retention and lower blood pressure. In the landmark PARADIGM-HF trial of over 8,000 patients, sacubitril/valsartan reduced cardiovascular death by 20% compared to enalapril, an older ACE inhibitor that itself already had proven survival benefits.
If sacubitril/valsartan isn’t tolerated or isn’t accessible, an ACE inhibitor or an angiotensin receptor blocker (ARB) still provides meaningful mortality reduction. These older drugs were the first to prove that blocking the renin-angiotensin system saves lives in heart failure, and they remain reasonable alternatives. Higher doses are associated with lower risks of death and hospitalization, so clinicians aim for target doses rather than stopping at the initial low dose.
Beta-Blockers
Three specific beta-blockers have proven mortality benefits in heart failure: carvedilol, bisoprolol, and metoprolol succinate (the extended-release form). Other beta-blockers have not shown the same benefit and are not interchangeable. These drugs work by shielding the heart from the damaging effects of chronically elevated adrenaline and related stress hormones, which in heart failure are persistently activated. Over months, this protection allows the heart muscle to recover some of its pumping strength.
Beta-blockers are typically started at a very low dose and increased gradually over weeks, because they can temporarily make symptoms feel worse before the long-term benefit kicks in. The target dose for carvedilol, for example, is 25 to 50 mg twice daily, far above the usual starting dose. As with the renin-angiotensin blockers, reaching higher doses is associated with greater survival benefit.
Aldosterone Blockers
Spironolactone and eplerenone are the two aldosterone blockers proven to reduce death in heart failure. Aldosterone is a hormone that causes the body to retain salt and water, but in heart failure it also promotes scarring and stiffening of the heart muscle. Blocking it addresses both the fluid overload and the structural damage.
The evidence here is striking. The RALES trial, testing spironolactone in patients with severe heart failure, was stopped early because the benefit was so clear: a 30% reduction in death from any cause over a median follow-up of just two years. The EMPHASIS-HF trial later showed eplerenone reduced all-cause mortality by 22% in patients with milder symptoms. Eplerenone causes fewer hormonal side effects (like breast tenderness in men) than spironolactone, so the choice between them often depends on tolerability. Both require monitoring of potassium levels and kidney function.
SGLT2 Inhibitors
The newest pillar, SGLT2 inhibitors (dapagliflozin and empagliflozin), were originally developed to lower blood sugar in diabetes. Researchers discovered they also substantially reduce heart failure hospitalizations and cardiovascular death, even in patients without diabetes. Their exact mechanism in heart failure isn’t fully understood, but they appear to reduce fluid overload, improve the heart’s energy metabolism, and protect the kidneys.
Head-to-head comparisons between dapagliflozin and empagliflozin in heart failure patients have not shown a meaningful difference in cardiovascular death between the two, so either one is a reasonable choice. These drugs were added to guidelines more recently, meaning many patients diagnosed before 2020 may not yet be taking one.
Hydralazine Plus Nitrate for Black Patients
A combination of hydralazine and isosorbide dinitrate has a specific and powerful mortality benefit in Black patients with heart failure. The A-HeFT trial, published in the New England Journal of Medicine, enrolled only self-identified Black patients and found a 43% reduction in death from any cause with this combination added to standard therapy. The trial was stopped early because of the clear survival advantage.
This combination works by relaxing blood vessels through a different pathway than ACE inhibitors or ARBs, and it may also counteract oxidative stress that appears to be more pronounced in this population. Guidelines recommend it as an add-on to the four pillars for Black patients with HFrEF, and as an alternative to ACE inhibitors or ARBs in patients of any race who cannot tolerate those drugs.
Drugs That Help Symptoms but Not Survival
Several other heart failure medications improve symptoms or reduce hospitalizations without a proven effect on death. Diuretics like furosemide are essential for managing fluid buildup and breathlessness, but they have never been shown to extend life. Digoxin reduces hospitalizations but does not lower mortality. Vericiguat, a newer drug that works by enhancing a signaling molecule that relaxes blood vessels, reduced the combined risk of death or hospitalization in the VICTORIA trial but did not significantly reduce death from any cause on its own.
These drugs still matter. Feeling less breathless, staying out of the hospital, and being able to walk comfortably are meaningful outcomes. But when the specific question is which drugs help patients live longer, the evidence points clearly to the four pillars plus hydralazine/nitrate in appropriate patients.
Heart Failure With Preserved Ejection Fraction
Everything above applies to HFrEF, where the heart’s pumping strength is reduced. In heart failure with preserved ejection fraction (HFpEF), where the heart pumps normally but is too stiff to fill properly, the picture is less clear. SGLT2 inhibitors are the only class with strong evidence for reducing hospitalizations in HFpEF, and they now carry guideline recommendations for this group. However, no drug class has a robust, proven mortality benefit specifically in HFpEF. ACE inhibitors, ARBs, and beta-blockers have not shown the same survival advantages in these patients that they show in HFrEF.
Why Reaching Target Doses Matters
Having a prescription for the right drug classes is only part of the equation. Clinical data consistently show that higher doses of beta-blockers, ACE inhibitors, and ARBs are associated with lower risks of death and hospitalization compared to lower doses. Yet studies of real-world practice find that many patients remain on starting doses indefinitely, either because side effects limit increases or because the dose was never titrated upward.
If you’re taking heart failure medications and aren’t sure whether you’re at target doses, it’s worth asking. For reference, the target for sacubitril/valsartan is 97/103 mg twice daily, carvedilol is 25 to 50 mg twice daily, and lisinopril is 20 to 35 mg daily. Getting closer to these targets, even if you can’t reach the full dose, is associated with better outcomes than staying at minimal doses.