Medications for Heart Failure: The 4 Pillars and Beyond

Heart failure treatment today relies on a layered strategy of medications, each targeting a different piece of the disease. For heart failure with reduced pumping ability, four drug classes now form the standard backbone: beta-blockers, drugs that block the renin-angiotensin-aldosterone system (including a newer combination called sacubitril-valsartan), mineralocorticoid receptor antagonists, and SGLT2 inhibitors. For heart failure where the pumping strength is preserved but the heart is stiff, treatment options were frustratingly limited until recently, though SGLT2 inhibitors have opened a genuine door. Beyond these core therapies, a growing roster of second-line agents, acute-care drugs, and emerging treatments fills specific gaps depending on each patient’s situation.

The Four Pillars for Reduced Ejection Fraction

When the heart’s left ventricle cannot squeeze forcefully enough, the condition is called heart failure with reduced ejection fraction, or HFrEF. Guidelines now recognize four drug classes as foundational therapy, and the current push is to get patients on all four as quickly as safely possible rather than adding them one at a time over months.

Beta-blockers were among the first drugs shown to reverse the downward spiral of a weakening heart. In heart failure, the body ramps up adrenaline-like signals to compensate for poor pumping. That compensation backfires over time, driving the heart to enlarge, remodel, and weaken further. Beta-blockers interrupt that cycle by shielding the heart from chronic adrenaline overdrive, which has been shown to improve the function of the failing ventricle, prevent or reverse its progressive dilation, and slow harmful remodeling.¹ The three beta-blockers with strong trial evidence in heart failure are carvedilol, metoprolol succinate, and bisoprolol. In patients with end-stage kidney disease and HFrEF, carvedilol specifically has been linked to meaningful improvements in ejection fraction and a roughly halved mortality rate over two years compared with placebo.²

The second pillar involves blocking the renin-angiotensin-aldosterone system, a hormonal cascade that retains fluid and promotes harmful remodeling. Older ACE inhibitors and ARBs were long the standard here, but sacubitril-valsartan, the first angiotensin receptor-neprilysin inhibitor (ARNI), has largely displaced them in HFrEF. This combination drug blocks the angiotensin receptor while simultaneously preventing the breakdown of beneficial natriuretic peptides. Compared with the ACE inhibitor enalapril, it significantly reduces both death and hospitalization for heart failure.³ Beyond headline outcomes, sacubitril-valsartan appears to improve ejection fraction and cardiac remodeling, and may offer metabolic benefits such as better blood-sugar control and kidney function.⁴

Mineralocorticoid receptor antagonists (MRAs) such as spironolactone and eplerenone make up the third pillar. Aldosterone, the hormone they block, promotes fibrosis, or scarring, in heart muscle. Spironolactone has been shown to reduce this fibrosis, decrease markers of collagen turnover, and improve the function of blood vessel linings.⁵ The chief practical worry with MRAs is elevated potassium, which requires monitoring through blood tests. A newer nonsteroidal MRA, finerenone, has shown anti-fibrotic effects in animal studies and may carry a lower risk of certain side effects, though its role in heart failure treatment is still being defined.⁶

SGLT2 inhibitors, originally developed to lower blood sugar in diabetes, are the newest pillar. Their heart failure benefits appear largely independent of blood-sugar control. The DAPA-HF trial demonstrated that dapagliflozin worked equally well in heart failure patients whether or not they had diabetes, and the speed of benefit, appearing within days of starting therapy, is too fast to be explained by glucose lowering alone.⁷ Researchers believe these drugs work through several mechanisms at once, including promoting sodium excretion, reducing fluid overload, and possibly influencing how heart cells handle sodium and hydrogen at the cellular level.⁸

Why Starting All Four Matters

For years, doctors typically introduced one drug at a time, titrating to target doses before adding the next class. A growing body of evidence now favors getting patients onto all four pillars quickly, even at low doses, rather than perfecting each one sequentially. One single-center study found that a rapid simultaneous introduction strategy cut the risk of heart failure rehospitalization by about three-quarters within six months compared with the conventional stepwise approach.⁹ The reasoning is straightforward: each drug class targets a different harmful pathway, and waiting months to add the fourth one leaves those pathways unchecked during a period when patients are especially vulnerable to worsening.

Medications for Heart Failure With Preserved Ejection Fraction

Heart failure with preserved ejection fraction, or HFpEF, accounts for roughly half of all heart failure cases. Here the heart squeezes adequately but fills poorly because the muscle is stiff. For decades, nearly every drug trial in HFpEF came up empty. That changed with the SGLT2 inhibitors. In the EMPEROR-Preserved trial, empagliflozin reduced the combined risk of cardiovascular death or heart failure hospitalization by about a fifth, driven mainly by fewer hospitalizations.¹⁰ Dapagliflozin showed similar benefits in a separate trial, with patients walking further and reporting meaningfully better symptom scores.¹¹

A meta-analysis pooling all available randomized controlled trials confirmed that SGLT2 inhibitors cut the composite of cardiovascular death or heart failure hospitalization by about 17% and reduced heart failure hospitalization alone by 25% in HFpEF patients. The benefit in overall survival pointed in a favorable direction but did not reach statistical significance.¹² So while SGLT2 inhibitors are now the clearest evidence-based therapy for HFpEF, they are not a complete solution. Patients with HFpEF tend to receive fewer heart failure medications overall compared with HFrEF patients, reflecting the historically thinner evidence base.¹³

Spironolactone also has a role in HFpEF, though the evidence is more nuanced. It did not hit its primary endpoint in the large TOPCAT trial, but imaging studies suggest it slows the rate of fibrosis in heart muscle, reducing the expansion of scar tissue over time.¹⁴ Many clinicians still prescribe it for HFpEF, particularly in patients with fluid retention or elevated aldosterone levels, even though the mortality benefit remains debated.

Diuretics and Fluid Management

Loop diuretics like furosemide, bumetanide, and torsemide are the workhorse drugs for managing congestion, the fluid buildup in the lungs and extremities that makes heart failure patients short of breath and swollen. Unlike the four pillars, diuretics do not appear to improve long-term survival. Their value is in making patients feel and function better day to day, and in managing acute episodes where fluid overload becomes dangerous.

In acute heart failure, intravenous loop diuretics are typically the first treatment given. Dosing is more art than science: clinicians often start at roughly the patient’s home oral dose given intravenously and adjust based on urine output and symptom response. One persistent challenge is diuretic resistance, where high doses of a single loop diuretic stop producing adequate urine output. When that happens, adding a second diuretic that works on a different part of the kidney’s tubule system, a strategy sometimes called sequential nephron blockade, can overcome the resistance.¹⁵ Thiazide-type diuretics like metolazone are the most common add-on in this situation.

Second-Line Agents for Specific Situations

Not every patient responds adequately to the four pillars and diuretics. Several additional medications address particular scenarios in HFrEF.

Ivabradine works by slowing the heart rate through a mechanism different from beta-blockers. It blocks a specific current in the heart’s natural pacemaker cells, reducing heart rate without lowering blood pressure. European and American guidelines recommend ivabradine for HFrEF patients who remain in normal sinus rhythm with a heart rate above 70 beats per minute despite being on the maximum tolerated beta-blocker dose.¹⁶ It is not used in patients with atrial fibrillation, where the heart’s rhythm is irregular.

Vericiguat is a soluble guanylate cyclase stimulator, a fancy way of saying it enhances the body’s nitric oxide signaling pathway, which relaxes blood vessels and reduces stress on the heart. In the VICTORIA trial, vericiguat reduced the combined endpoint of cardiovascular death or heart failure hospitalization by about 10% in patients with worsening HFrEF who were already on standard therapy.¹⁷ The effect was modest but meaningful for a population that had few remaining options.

Hydralazine combined with isosorbide dinitrate (often abbreviated H-ISDN) has a unique place in heart failure treatment. This combination directly relaxes blood vessels and was one of the first drug therapies ever shown to improve survival in HFrEF. Its current role is twofold. First, it serves as an alternative for patients who cannot tolerate ACE inhibitors, ARBs, or sacubitril-valsartan, often because of severe kidney problems or dangerous drops in blood pressure. Second, the combination has specific evidence of benefit in Black patients with advanced HFrEF: the A-HeFT trial, conducted exclusively in self-identified Black patients, was stopped early because H-ISDN added to standard therapy cut the death rate from about 10% to about 6% and reduced heart failure hospitalizations by a third.¹⁸ A separate observational study of African-American patients with HFrEF found that H-ISDN use was associated with lower adjusted mortality at 18 months.¹⁹ However, a registry-based study that looked at a broader population, including both Black and non-Black patients, found no significant differences in mortality or readmission with H-ISDN use after adjusting for other factors, suggesting the benefit may be most pronounced in certain patient groups.²⁰

Drugs for Acute Crises and Advanced Disease

When heart failure deteriorates into cardiogenic shock, where the heart can no longer pump enough blood to sustain the organs, oral medications alone are not sufficient. Intravenous inotropes that directly strengthen the heart’s contractions become necessary. The two most commonly used are dobutamine and milrinone.

Dobutamine stimulates adrenaline-like receptors on heart muscle cells to increase the force of contraction. Milrinone takes a different route, blocking an enzyme called phosphodiesterase to increase calcium availability inside heart cells and simultaneously relax blood vessels. One observational study found milrinone associated with about half the risk of 30-day death compared with dobutamine in patients with acute decompensated heart failure and cardiogenic shock, along with better hemodynamic measurements.²¹ But a randomized trial directly comparing the two in cardiogenic shock found no significant difference in a composite of death, cardiac arrest, mechanical support, or dialysis.²² A meta-analysis combining the available data described the advantage of milrinone as marginal overall.²³ In practice, the choice between them often comes down to the patient’s blood pressure and heart rhythm: milrinone may be preferred when blood pressure is adequate, while dobutamine is sometimes favored when blood pressure needs support.

Digoxin, a descendant of the foxglove plant extract that has been used for centuries, still has a limited niche. It strengthens heart contraction modestly by inhibiting the sodium-potassium pump and also slows conduction through the heart, making it useful for controlling heart rate in atrial fibrillation.²⁴ Digoxin has not been shown to reduce mortality in heart failure, but it can reduce hospitalizations. Its narrow therapeutic window, where the effective dose sits uncomfortably close to the toxic dose, means blood levels must be monitored carefully.

Semaglutide and Obesity-Related HFpEF

One of the most talked-about developments in heart failure treatment has come from an unexpected direction: GLP-1 receptor agonists, the same drug class behind popular weight-loss medications. In the STEP-HFpEF trial, semaglutide produced striking improvements in patients with HFpEF and obesity. Symptom scores improved by nearly 8 points more than placebo on the Kansas City Cardiomyopathy Questionnaire, patients lost about 10 percentage points more body weight, and six-minute walk distance improved by about 20 meters.²⁵ These improvements spanned all major symptom domains and were accompanied by reductions in inflammation markers and a key heart failure biomarker.²⁶

A pooled analysis of the STEP-HFpEF trials, including patients with and without diabetes, confirmed that semaglutide produced significantly better symptom scores and weight loss at one year than placebo.²⁷ What makes this especially relevant is the recognition that obesity-related HFpEF is a distinct and growing phenotype. Excess fat tissue contributes to the stiff, inflamed heart and the fluid retention that define the condition. Whether semaglutide reduces actual cardiovascular death or heart failure hospitalization is being tested in larger, longer trials, but the symptom and functional improvements are already among the largest seen in any HFpEF therapy.

Managing Potassium to Keep Patients on Therapy

A quieter but genuinely impactful development involves potassium binders, medications that absorb potassium in the gut and lower blood levels. This matters because two of the four pillars, sacubitril-valsartan and MRAs, both raise potassium as a side effect. When potassium climbs too high, doctors often reduce or stop these drugs, leaving the patient on suboptimal therapy. Newer potassium binders like patiromer and sodium zirconium cyclosilicate have been shown in a meta-analysis to significantly improve the odds of reaching target MRA doses and reduce the frequency of dangerously high potassium episodes.²⁸ They are not heart failure drugs themselves; rather, they are enablers that help patients stay on the drugs that improve survival.

Cost as a Real Barrier

Having four proven drug classes is only useful if patients can afford them. Two of the four pillars, specifically SGLT2 inhibitors and sacubitril-valsartan, carry high price tags that can create genuine financial barriers.²⁹ Individualized cost estimates are rarely available during the clinical visit where prescriptions are written, which means patients often discover the out-of-pocket burden only at the pharmacy counter.³⁰ That sticker shock leads to abandoned prescriptions, dose skipping, and delayed treatment, all of which erode the survival benefits these drugs offer.

Patient assistance programs from manufacturers, pharmacy benefit navigators, and team-based care models can help bridge the gap.³¹ Generic empagliflozin has recently become available, which may ease costs for the SGLT2 inhibitor pillar over time. But cost remains one of the most common reasons patients with heart failure end up on fewer medications than the evidence supports, and having an honest conversation with a pharmacist or care team about affordability options is worth the effort.

Heart Failure Medications During Pregnancy

Pregnancy poses a distinct challenge because several cornerstone heart failure drugs are harmful to a developing fetus. ACE inhibitors, ARBs, sacubitril-valsartan, MRAs, and SGLT2 inhibitors are all contraindicated or strongly cautioned against during pregnancy. Women who develop peripartum cardiomyopathy, a form of HFrEF that emerges late in pregnancy or shortly after delivery, are treated along the same general lines as other HFrEF patients, but with careful substitutions: hydralazine and nitrates can replace the drugs that affect the renin-angiotensin system, and beta-blockers considered safer in pregnancy are used.³² After delivery and once breastfeeding considerations are resolved, therapy can transition to the standard four-pillar regimen.³³ Dosing also needs adjustment during pregnancy because blood volume, kidney filtration, and liver metabolism all change substantially, altering how drugs are absorbed and cleared.