Four classes of heart failure medications have strong evidence for increasing ejection fraction, and when used together, they can add years of life. These drugs work best in people with heart failure with reduced ejection fraction (HFrEF), defined as an ejection fraction of 40% or below. Improvements often begin within weeks, and roughly one-third of patients see their ejection fraction rise above 40% with proper treatment.
The Four Core Drug Classes
Cardiology guidelines give their highest recommendation to four types of medication for improving ejection fraction and reducing the risk of hospitalization and death. These are sometimes called the “four pillars” of heart failure therapy, and large clinical trials involving over 50,000 patients across 17 studies support their use. When a 55-year-old patient takes all four classes together, actuarial estimates suggest they gain roughly 6.3 additional years of survival and 8.3 years free from cardiovascular death or heart failure hospitalization compared with older, conventional treatment.
The four classes are:
- Neprilysin inhibitors combined with angiotensin blockers (ARNI): The combination of sacubitril and valsartan (sold as Entresto) is the preferred first-line option in this category. It works by blocking a hormone system that causes fluid retention and blood vessel constriction while simultaneously boosting the body’s natural heart-protective signaling. It has largely replaced older ACE inhibitors as the go-to choice.
- Beta-blockers: Specifically carvedilol and extended-release metoprolol. These slow the heart rate and reduce the demand on the heart muscle, allowing it to recover over time.
- Mineralocorticoid receptor antagonists (MRAs): Spironolactone and eplerenone. These block a hormone called aldosterone that drives scarring and stiffness in the heart muscle.
- SGLT2 inhibitors: Originally developed for diabetes, empagliflozin and dapagliflozin have proven benefits in heart failure regardless of whether you have diabetes.
How Beta-Blockers Reverse Heart Damage
Beta-blockers are among the most studied drugs for improving ejection fraction. In a landmark trial of extended-release metoprolol, patients saw their ejection fraction rise from 29% to 37% over the course of treatment. That 8-point jump is clinically meaningful, often translating into noticeably better exercise tolerance and fewer symptoms like shortness of breath.
The mechanism is straightforward: a failing heart is flooded with stress hormones (adrenaline and noradrenaline) that keep it beating faster and harder than it should. Over months and years, this wears the muscle out further. Beta-blockers dial down that stress response, giving the heart time to shrink back toward a more normal size and shape. Carvedilol, which blocks a slightly broader range of receptors, reduced mortality by 65% after 12 months in one early trial and 21% after 19 months in another.
What SGLT2 Inhibitors Do for the Heart
SGLT2 inhibitors are the newest addition to the four pillars, and the ejection fraction data is striking. In a year-long comparative study, patients taking these drugs saw an average ejection fraction increase of about 7 percentage points overall. The improvement varied by specific drug: those on empagliflozin gained roughly 9 percentage points, while those on dapagliflozin gained about 5 points.
These drugs also shrank the heart chambers. Both end-diastolic and end-systolic volumes (how much blood the heart holds when relaxed and when squeezed) decreased significantly, along with reductions in heart mass and left atrial size. One leading theory is that SGLT2 inhibitors push the heart’s fuel source from glucose toward ketone bodies, which are a more efficient energy source for struggling heart muscle. Patients on these drugs also showed drops in NT-proBNP, a blood marker that reflects how much stress the heart wall is under.
How MRAs Reduce Scarring
Aldosterone, a hormone that regulates salt and water balance, is overactive in heart failure. It drives inflammation and fibrosis (scarring) in the heart muscle, making it stiffer and less able to pump. Mineralocorticoid receptors are actually overexpressed in failing hearts, amplifying the damage. MRAs block these receptors directly.
In a 12-month study comparing the two available MRAs, eplerenone improved ejection fraction and reduced heart chamber dimensions to a greater degree than spironolactone. Eplerenone also caused fewer side effects, which matters because side effects are a common reason patients stop taking heart failure medications. Both drugs reduce the risk of hospitalization and cardiovascular death, but eplerenone appears to have an edge in terms of tolerability and the degree of cardiac improvement.
How Quickly Ejection Fraction Improves
Many patients wonder how long they need to wait before seeing results. The timeline varies, but improvement can begin surprisingly early. In one study tracking patients with both ischemic and nonischemic cardiomyopathy, 39% achieved meaningful improvement (ejection fraction rising to 35-40% or higher) within just 21 to 60 days. Larger analyses have found that about one-third of heart failure patients experience at least a 10-point increase in ejection fraction after 6 months of treatment.
The single strongest predictor of recovery is your starting ejection fraction. Paradoxically, patients who start with very low numbers sometimes show the most dramatic rebounds, particularly if the cause of heart failure is reversible (such as a viral infection or alcohol use). Your doctor will typically recheck your ejection fraction via echocardiogram after about 3 months of optimized therapy, though some centers reassess as early as 40 days.
Does Reaching Full Doses Matter?
Heart failure medications are usually started at low doses and gradually increased (titrated) to target levels. You might expect that reaching the highest recommended dose would predict the biggest ejection fraction gains, but the relationship is more nuanced than that. In a study of protocolized up-titration over 9 months, the percentage of target dose achieved for ACE inhibitors, ARNIs, and MRAs did not significantly predict how much ejection fraction improved. The baseline ejection fraction was by far the strongest predictor.
That said, higher doses of beta-blockers, ACE inhibitors, and ARBs are consistently linked to lower risks of death and hospitalization across large trials. So even if the ejection fraction bump is similar, reaching target doses still matters for long-term survival. Interestingly, a common reason patients in studies didn’t reach full MRA doses was that their symptoms had already resolved and their ejection fraction had already improved.
Additional Medications With Supportive Evidence
Beyond the four pillars, vericiguat is a newer option for patients whose heart failure worsens despite standard therapy. It works by stimulating an enzyme involved in blood vessel relaxation and cardiac signaling. In the VICTORIA trial published in the New England Journal of Medicine, vericiguat reduced the combined risk of cardiovascular death or heart failure hospitalization compared to placebo, with 27.4% of the vericiguat group hospitalized versus 29.6% on placebo. It is typically reserved for patients who remain high-risk after maximizing the four core drug classes.
Hydralazine combined with isosorbide dinitrate is another option, particularly for Black patients or those who cannot tolerate ACE inhibitors or ARNIs. Ivabradine, which purely lowers heart rate without the blood pressure effects of beta-blockers, is used when the resting heart rate remains above 70 beats per minute despite maximized beta-blocker therapy.
What “Improved” Ejection Fraction Means
Current guidelines recognize a specific category called heart failure with improved ejection fraction (HFimpEF). This applies to anyone whose ejection fraction was previously 40% or below and has since risen above 40%. It is a real and achievable goal for many patients on optimized therapy.
One critical point: even if your ejection fraction normalizes, stopping these medications is generally not recommended. The improvement depends on continued treatment. Studies consistently show that patients who discontinue their heart failure drugs, even after significant recovery, face a high risk of their ejection fraction dropping again. The drugs don’t cure the underlying condition so much as they create the conditions for the heart to function better on an ongoing basis.