What Drugs Increase Ejection Fraction?

Several drug classes can raise left ventricular ejection fraction, but the ones that matter most are four pillars of long-term heart failure therapy: ACE inhibitors or ARBs (or the newer combination sacubitril/valsartan), beta-blockers, mineralocorticoid receptor antagonists, and SGLT2 inhibitors. These medications work by different mechanisms, and together they can recover a meaningful number of percentage points over months to years. The picture gets more interesting when you look beyond these mainstays to acute-care drugs, newer agents, and the thorny question of what happens when the heart bounces back.

Sacubitril/Valsartan and the ARNI Class

Sacubitril/valsartan, sold as Entresto, is an angiotensin receptor-neprilysin inhibitor (ARNI) that has become one of the most effective drugs for improving ejection fraction in people with heart failure and reduced EF. It works on two fronts: one component blocks the hormone angiotensin II, which constricts blood vessels and promotes harmful structural changes in the heart, while the other prevents the breakdown of beneficial peptides that reduce fluid overload and ease the heart’s workload.

In one study of patients starting sacubitril/valsartan with an average baseline EF around 25%, EF rose by about 5 percentage points over a median of three months, with the heart also shrinking in size as measured by reductions in both the chamber diameter and the mass of the left ventricle.¹ With longer treatment, the gains can be larger. A study looking at heart failure duration found that patients who had been diagnosed less than a year earlier gained roughly 12 percentage points at one year, while those with longer-standing disease gained between 7 and 9 points.² The takeaway is that newer heart failure responds more dramatically, but even people who have lived with the condition for over five years still see meaningful improvement.

ACE Inhibitors and ARBs

Before sacubitril/valsartan came along, ACE inhibitors like enalapril and lisinopril were the standard first-line drugs for heart failure with reduced EF. They lower blood pressure by blocking the production of angiotensin II, and they reduce the stress hormones that drive the heart to enlarge over time. ARBs like losartan and valsartan do something similar but target the receptor angiotensin II binds to rather than its production.

Both classes raise EF, though the magnitude tends to be somewhat smaller than what sacubitril/valsartan achieves. A large study of patients with dilated cardiomyopathy found that those on ARBs had a slightly greater EF recovery than those on ACE inhibitors, with the ARB group gaining about 16 percentage points over three years compared with 14 points for the ACE inhibitor group.³ That difference was consistent across subgroups regardless of kidney function, blood pressure, or whether patients were also on beta-blockers. In practice, guidelines now prefer sacubitril/valsartan where tolerated, but ACE inhibitors and ARBs remain widely used as alternatives, especially when cost or side effects are a factor.

Beta-Blockers

Beta-blockers were once considered dangerous in heart failure because they reduce the force of heart contractions. That thinking reversed when large trials showed that certain beta-blockers, particularly carvedilol, metoprolol succinate, and bisoprolol, dramatically reduced death and hospitalization. They also raise ejection fraction, and researchers have a good handle on how.

A study that carefully dissected the mechanisms behind carvedilol’s effect found that EF rose by about 7 percentage points over six months, climbing from an average of 25% to 32%. In patients who gained at least 5 points, roughly 60% of the improvement came from slowing the heart rate, about 30% from increased contractile strength of the heart muscle itself, and the remainder from reduced resistance in the blood vessels.⁴ This is a useful illustration of why EF improvement is not always the same thing as the heart muscle getting stronger. Slowing the heart rate gives the ventricle more time to fill with blood each beat, which alone can push the fraction of blood pumped out higher even without any change in how hard the muscle squeezes.

Mineralocorticoid Receptor Antagonists

Spironolactone and eplerenone block the hormone aldosterone, which in excess drives fluid retention and scar tissue formation in the heart. The anti-scarring effect is especially relevant: aldosterone promotes collagen deposits in heart muscle, and blocking it can slow or partially reverse that process, improving the heart’s ability to relax and contract.⁵

In a head-to-head trial comparing eplerenone and spironolactone in patients with new-onset heart failure and reduced EF, eplerenone produced a significantly greater increase in EF and a larger decrease in left ventricular size.⁶ Both drugs improved function, but eplerenone also tends to cause fewer hormonal side effects (spironolactone can cause breast tenderness and menstrual irregularities because it binds to other hormone receptors). Despite those differences, both are firmly established parts of guideline therapy.

SGLT2 Inhibitors

Originally developed for type 2 diabetes, SGLT2 inhibitors like dapagliflozin and empagliflozin surprised the cardiology world when diabetes trials revealed unexpectedly large reductions in heart failure hospitalizations. They have since been tested specifically in heart failure populations and are now a standard part of the drug regimen for reduced EF, regardless of whether the patient has diabetes.

Their effect on ejection fraction itself tends to be more modest than the other pillars. In one trial comparing dapagliflozin to placebo in patients with both type 2 diabetes and reduced EF, the drug group gained about 2.5 percentage points more than placebo over a year.⁷ A separate study found that roughly half of patients starting dapagliflozin met at least one criterion for reverse remodeling at six months, including improvements in chamber volumes or ejection fraction.⁸

What makes SGLT2 inhibitors stand out is less about raw EF points and more about how they reduce deaths and hospitalizations through mechanisms that are still not fully nailed down. Metabolic studies suggest they shift the heart’s fuel source toward fats and ketone bodies while reducing markers of oxidative stress and cardiovascular strain.⁹ SGLT2 inhibitors are also the first drug class to show clear benefit in heart failure with preserved ejection fraction, a condition that had resisted virtually every other pharmacologic intervention.¹⁰

Drugs That Boost EF Acutely but Carry Long-Term Risk

In the emergency and ICU setting, doctors sometimes need to prop up a failing heart quickly. Intravenous drugs like dobutamine and milrinone accomplish this by directly revving up the heart muscle’s contractile machinery. Both improve EF and cardiac output in the short term.¹¹ The problem is that the way they work, by flooding heart cells with signaling molecules that force stronger contractions, tends to wear the heart out faster and raise the risk of dangerous heart rhythms. Studies have repeatedly shown that these short-term improvements in pumping do not translate into longer survival; in fact, prolonged or repeated use has been linked to worse outcomes.¹²

Levosimendan takes a different approach. Rather than increasing the concentration of calcium inside heart cells (which is what makes dobutamine and milrinone risky over time), it makes the contractile proteins more sensitive to the calcium already present. In severe heart failure patients, levosimendan infusion increased cardiac output by up to 39% and stroke volume by 28%.¹³ It is used in acute decompensated heart failure in many countries, though it is not approved in the United States. Its long-term survival benefit remains uncertain, but its safety profile appears more favorable than traditional inotropes because it avoids the cellular calcium overload that predisposes the heart to arrhythmias.¹⁴

Digoxin’s Complicated Legacy

Digoxin, derived from the foxglove plant, is one of the oldest heart failure treatments. It increases the force of cardiac contractions by raising calcium levels inside heart cells, and it has a documented ability to raise EF. In one trial, increasing the maintenance dose of digoxin while keeping blood levels in the safe range raised EF from about 24% to 27%, and withdrawing digoxin dropped EF by nearly 6 points.¹⁵

But improving EF is not the same as keeping patients alive longer. The landmark DIG trial showed that digoxin reduced hospitalizations for heart failure without reducing overall mortality.¹⁶ A more recent trial testing low-dose digoxin found no significant reduction in the combined endpoint of worsening heart failure and cardiovascular death, with cardiovascular mortality essentially the same between digoxin and placebo groups.¹⁷ Digoxin has a narrow therapeutic window, meaning the difference between an effective dose and a toxic one is small, which further limits its appeal. Today it is mostly reserved for patients whose symptoms persist despite optimal therapy with the four main drug classes.

Newer Agents on the Horizon

Omecamtiv mecarbil is a first-in-class cardiac myosin activator. Instead of manipulating calcium signaling, it works directly on the motor proteins responsible for contraction, extending the time the heart spends actively pumping during each beat. In a phase 2 trial, intravenous omecamtiv mecarbil increased EF by about 7 percentage points and stroke volume by 15 milliliters at the maximum tolerated dose, with clear dose-related effects.¹⁸ One concern flagged in preclinical work is that the drug may increase the heart’s oxygen demand, which could reduce its efficiency under certain conditions.¹⁹ Despite that, the oral form showed a modest reduction in heart failure events in a large outcome trial, and it remains under active investigation.

Vericiguat takes yet another angle. It stimulates an enzyme called soluble guanylate cyclase, which is part of the nitric oxide signaling pathway. When heart failure sets in, this pathway becomes impaired, contributing to blood vessel stiffness and inflammation. By restoring its activity, vericiguat lowers the burden on the heart. It is approved for heart failure with reduced EF in patients who have recently worsened despite standard therapy.²⁰ Its role is more about reducing hospitalizations and worsening events than dramatically raising EF numbers, making it a useful add-on rather than a standalone remodeling agent.

Even further out is gene therapy aimed at restoring levels of a calcium-handling protein called SERCA2a, which is depleted in failing hearts. Early-phase trials using a viral vector to deliver the gene directly into the coronary arteries showed the concept could improve both contraction and relaxation of the heart.²¹ The larger follow-up trial did not meet its primary endpoint, but the approach has not been abandoned; newer delivery methods and gene targets are in development.

When EF Recovers, Can You Stop the Drugs?

A natural question for anyone whose EF normalizes on therapy is whether the medications are still necessary. The TRED-HF trial addressed this directly by randomizing patients with recovered dilated cardiomyopathy to either continue treatment or gradually withdraw it. Within six months, 44% of the withdrawal group relapsed, compared with none in the group that stayed on their medications.²² When the continuing-treatment group was later allowed to attempt withdrawal as well, about a third of them also relapsed.

A larger observational study reinforced that message, finding that withdrawing ACE inhibitors, ARBs, sacubitril/valsartan, or mineralocorticoid receptor antagonists in patients with improved EF was independently associated with a higher risk of cardiovascular death or hospitalization for heart failure. Interestingly, beta-blocker withdrawal did not show the same independent association in that dataset.²³ The general consensus in current practice is that most patients should remain on their medications indefinitely even after recovery, because the normal EF often reflects ongoing drug effect rather than a truly healed heart.

Who Responds Best and Who Does Not

Not everyone sees the same EF gains on the same drugs. A study tracking patients on sacubitril/valsartan identified several factors associated with remaining in the reduced-EF category after a year of treatment. Older age, male sex, and larger baseline heart chamber size predicted a stubbornly low EF, while atrial fibrillation and high systolic blood pressure were also associated with poorer remodeling response.²⁴

The cause of heart failure also matters enormously. People whose reduced EF stems from a reversible insult, such as a viral infection, alcohol or substance abuse, or cancer chemotherapy, often recover substantially when the offending trigger is removed and standard heart failure drugs are started. Case reports and systematic reviews of steroid-induced cardiomyopathy, for instance, show that most patients see their heart function improve after stopping anabolic steroids and beginning guideline-directed therapy, though some develop permanent damage requiring lifelong treatment.²⁵ In chemotherapy-related heart damage, early intervention with ACE inhibitors or ARBs and beta-blockers is key; delay reduces the likelihood of full recovery.²⁶ In contrast, patients whose heart failure is caused by extensive scarring from a large heart attack or long-standing untreated disease tend to have more limited EF gains regardless of how aggressively they are treated.

Heart Failure with Preserved EF Is a Different Problem

Everything discussed so far applies primarily to heart failure with reduced ejection fraction, where the EF is meaningfully below normal. But about half of all heart failure patients have a preserved EF, meaning the number looks normal even though the heart is stiff, fills poorly, and cannot keep up with the body’s demands. Raising EF further in these patients is not the goal, and most drugs that help in reduced EF have failed to show benefit in the preserved-EF population.

The notable exception is the SGLT2 inhibitor class. Trials of both empagliflozin and dapagliflozin in patients with preserved EF showed reductions in heart failure hospitalizations and cardiovascular death, breaking a long streak of disappointments.¹⁰ These drugs do not raise EF in preserved-EF patients; instead, they appear to work through other mechanisms like reducing fluid overload, lowering inflammation, and shifting cardiac metabolism. For anyone with preserved EF looking at this question, the answer is less about raising a number and more about treating the underlying stiffness and metabolic dysfunction that the normal-looking EF conceals.

Pediatric Heart Failure and the Evidence Gap

Children with heart failure are generally treated with the same drug classes used in adults: ACE inhibitors, beta-blockers, and spironolactone form the backbone of chronic therapy, and intravenous milrinone is commonly used to bridge critically ill children toward heart transplantation. But the pediatric-specific evidence behind these choices is thin, often conflicting, and heavily borrowed from adult trials.²⁷ The causes of heart failure in children, which include congenital heart defects, inherited cardiomyopathies, and myocarditis, differ substantially from the coronary artery disease and hypertension that dominate adult cases. Whether the EF improvements seen in adult trials translate proportionally to pediatric hearts remains an open question, and conducting large randomized trials in children is both ethically and practically challenging because of the small patient population.

Devices and Drugs Together

Drugs are not the only way to raise EF. Cardiac resynchronization therapy, a specialized pacemaker that coordinates the contraction of the left and right ventricles, can produce dramatic improvements in patients whose heart failure is partly caused by an electrical conduction delay. The remodeling benefit from CRT is additive with drug therapy, and guidelines recommend optimizing and up-titrating neurohormonal medications after CRT implantation to maximize the combined effect.²⁸ In clinical practice, some of the most impressive EF recoveries happen when CRT and aggressive drug therapy are combined, with patients going from severely reduced function to near-normal over the course of a year. The criteria used to define a meaningful recovery vary, but common benchmarks include an absolute EF gain of 10 to 15 percentage points or a significant reduction in the volume of the left ventricle.²⁹