# HFrEF vs HFpEF: Differences, Drugs & Mortality

> What is the difference between HFrEF and HFpEF?

EF cut-offs old and new, S3 versus S4, the drugs that lower heart failure mortality, and what SGLT2 inhibitors, finerenone and GLP-1 drugs do in HFpEF in 2026.

HFrEF, an ejection fraction of 40% or less, is a pumping failure: a dilated, weak ventricle, classically with an S3, treated by four mortality-lowering drug classes. HFpEF, an ejection fraction of 50% or more, is a filling failure: a stiff, often thick ventricle with an S4, where SGLT2 inhibitors and finerenone cut heart failure events without proven survival benefit.

## What is the difference between HFrEF and HFpEF?

Ejection fraction sets the label, but USMLE questions test the mechanism. In heart failure with reduced ejection fraction (HFrEF, systolic heart failure), contraction fails: stroke volume falls, end-systolic and end-diastolic volumes rise, and the ventricle remodels eccentrically, adding sarcomeres in series until the chamber dilates. Coronary disease is the most common cause; myocarditis, peripartum cardiomyopathy, anthracyclines, alcohol and inherited cardiomyopathies follow.

Heart failure with preserved ejection fraction (HFpEF, diastolic heart failure) fails at filling. A stiff, slowly relaxing ventricle needs high pressure to fill even to a normal volume, and that pressure backs up into the lungs while the fraction ejected looks normal. Hypertension adds concentric hypertrophy, with sarcomeres laid down in parallel. Patients are typically older, often women, with hypertension, obesity, type 2 diabetes, sleep apnea or atrial fibrillation, and HFpEF makes up at least half of heart failure diagnoses.

Congestion looks the same in both, so symptoms never separate them; the echocardiogram does. The [Cardiology](/topics/cardiology) hub links the rest of the system, and these [memory hooks](/blog/2026-05-26-mnemonic-to-remember-hfref-vs-hfpef) help recall.

## HFrEF vs HFpEF comparison table

Ten features separate the two syndromes on an exam stem.

| Feature | HFrEF | HFpEF |
| --- | --- | --- |
| LVEF (2022 AHA/ACC/HFSA) | 40% or less | 50% or more |
| Core defect | Weak contraction (systolic dysfunction) | Impaired relaxation and a stiff wall (diastolic dysfunction) |
| Remodeling | Eccentric: dilated chamber, sarcomeres in series | Concentric or normal size: thick wall, sarcomeres in parallel |
| Volumes and pressures | End-diastolic and end-systolic volumes high | End-diastolic volume normal or small; filling pressure high |
| Typical patient | Prior MI, dilated cardiomyopathy, myocarditis, anthracycline exposure | Older woman with hypertension, obesity, diabetes, atrial fibrillation |
| Gallop | S3 in early diastole | S4 in late diastole; absent in atrial fibrillation |
| Apical impulse | Displaced laterally | Not displaced |
| Echocardiogram | Dilated, poorly contracting left ventricle | Normal EF, often LV hypertrophy and a large left atrium |
| BNP or NT-proBNP | Raised | Raised but often lower; can be normal with obesity |
| Drugs proven to lower mortality | ARNI or ACE inhibitor/ARB, three beta-blockers, MRA, SGLT2 inhibitor | None proven; SGLT2 inhibitors and finerenone reduce heart failure events |

## Heart failure categories by ejection fraction

The 2022 AHA/ACC/HFSA guideline sorts heart failure into four ejection fraction groups, and US drug choice still follows them.

| Category | LVEF | Treatment anchor |
| --- | --- | --- |
| HFrEF | 40% or less | All four mortality-lowering classes; ICD or CRT when criteria are met |
| HFmrEF (mildly reduced) | 41% to 49% | SGLT2 inhibitor favored; other HFrEF drugs may be considered |
| HFpEF | 50% or more, with evidence of raised filling pressures | SGLT2 inhibitor, finerenone, diuretics for congestion, comorbidity control |
| HFimpEF (improved) | Previously 40% or less, now above 40% | Continue the full regimen; withdrawal invites relapse |

The Second Universal Definition of Heart Failure (AHA, ACC, European Society of Cardiology and World Heart Federation, June 2026) moves away from fixed LVEF cut-offs, grouping patients as HF with reduced EF, HFpEF or HF with improved EF. It puts the lower limit of normal LVEF near 53% in women and 52% in men, so an LVEF below 50% is unlikely to be normal, and defines HF with improved EF as a rise of at least 10 points to above 40%. It is not a treatment guideline: US therapy still follows the 2022 guideline, whose successor the AHA lists for the third quarter of 2027, and question banks still use 40% and 50%. The 2026 ESC guideline drops HFmrEF, calling LVEF below 50% HFrEF.

## Systolic vs diastolic dysfunction: S3, S4 and the pressure-volume loop

An S3 is a low-pitched early diastolic sound at the apex, made as blood rushes into a volume-overloaded ventricle. It can be normal in children and athletes, but in an older adult with dyspnea it signals high filling pressure in a dilated ventricle, the HFrEF picture. An S4 falls in late diastole, just before S1, when the atrium contracts against a stiff, hypertrophied ventricle; it marks left ventricular hypertrophy and HFpEF, and because it needs a coordinated atrial contraction it disappears in atrial fibrillation.

On a pressure-volume loop, HFrEF lowers contractility, shifting the loop right with a smaller stroke volume. HFpEF steepens the diastolic pressure-volume curve, so a small gain in volume sharply raises pressure: modest swings in volume, blood pressure or heart rate congest these patients, and overdiuresis drops output. Atrial fibrillation hurts twice, removing the atrial kick and shortening filling time.

## Diagnosis: echocardiogram, natriuretic peptides and mimics

Echocardiography separates HFrEF from HFpEF, measuring ejection fraction, chamber size, wall thickness and valves in one study. An ECG adds clues such as Q waves from an old infarct or LVH voltage from hypertension; the [ECG reading sequence](/blog/how-to-read-ecg-usmle) lists the criteria.

Natriuretic peptides are best at ruling heart failure out. In acute dyspnea, BNP below 100 pg/mL or NT-proBNP below 300 pg/mL makes heart failure unlikely; in outpatients, NT-proBNP below 125 pg/mL does the same. Levels run higher with age, kidney dysfunction and atrial fibrillation, while obesity lowers them through reduced production and faster clearance, so a normal value does not exclude HFpEF in an obese patient. Sacubitril raises BNP, a neprilysin substrate; NT-proBNP is not a substrate and falls with effective therapy, so follow NT-proBNP on an ARNI ([more BNP tips](/blog/2026-05-26-3-quick-tips-for-bnp-and-nt-probnp)).

HFpEF also requires its mimics to be excluded: aortic stenosis, which should be sought in every suspected case, hypertrophic and [restrictive cardiomyopathies such as amyloidosis](/blog/2026-05-27-everything-you-need-to-know-about-restrictive-cardiomyopathy-for-step-1), constrictive pericarditis and other valve lesions; the [murmur guide](/blog/valvular-heart-disease-murmur-usmle) covers the bedside clues.

## Which drugs reduce mortality in heart failure?

Four drug classes lower mortality in HFrEF, remembered as ABMS: ARNI (or an ACE inhibitor or ARB), Beta-blocker, MRA and SGLT2 inhibitor. The other rows either help a defined subgroup (hydralazine-nitrate, ICD, CRT) or ease symptoms and hospitalizations without a proven survival benefit.

| Drug or device | Survival effect in HFrEF | How it helps | Watch for |
| --- | --- | --- | --- |
| ARNI (sacubitril/valsartan) | Lowers mortality; 20% fewer cardiovascular deaths or HF hospitalizations than enalapril | AT1 blockade plus neprilysin inhibition | Angioedema; 36 hours apart from an ACE inhibitor; fetal toxicity |
| ACE inhibitor, or ARB if intolerant | Lowers mortality | Less angiotensin II effect: lower afterload, less remodeling | Cough (ACE inhibitor), angioedema, hyperkalemia, pregnancy |
| Carvedilol, metoprolol succinate or bisoprolol | Lowers mortality | Blocks sympathetic toxicity; EF improves over months | Start low in a stable patient; not in decompensation needing inotropes |
| MRA (spironolactone, eplerenone) | Lowers mortality; all-cause deaths down 30% with spironolactone in RALES | Blocks aldosterone-driven fibrosis and sodium retention | Hyperkalemia; start only if potassium is below 5.0 and eGFR above 30; gynecomastia (spironolactone) |
| SGLT2 inhibitor (dapagliflozin, empagliflozin) | Lowers mortality and HF hospitalization, diabetic or not | Natriuresis and glycosuria | Genital infections, volume depletion, ketoacidosis; hold at least 3 days before surgery |
| Hydralazine plus isosorbide dinitrate | Lowers mortality in self-identified Black patients with NYHA III-IV symptoms | Arteriolar plus venous dilation | Reflex tachycardia; drug-induced lupus |
| Ivabradine | No proven survival benefit; fewer HF hospitalizations | Blocks the funny (If) current in the SA node | LVEF 35% or less, sinus rhythm, resting rate 70 or more on a maximal beta-blocker; phosphenes |
| Vericiguat | No significant fall in cardiovascular death; fewer combined deaths or hospitalizations | Soluble guanylate cyclase stimulator | EF below 45% after worsening HF; not in pregnancy or with riociguat |
| Digoxin | No mortality effect; fewer hospitalizations | Na-K ATPase inhibition: inotropy, AV-node slowing | Toxicity with hypokalemia, renal failure, amiodarone, verapamil |
| Loop diuretic (furosemide) | No proven survival benefit | Relieves congestion | Hypokalemia, volume depletion |
| ICD | Lowers all-cause mortality | Terminates ventricular tachyarrhythmias | LVEF 35% or less with NYHA II-III, or 30% or less with NYHA I after MI |
| CRT | Lowers mortality and HF hospitalizations | Resynchronizes left ventricular contraction | LVEF 35% or less, sinus rhythm, LBBB, QRS 150 ms or more |

Neurohormonal activation, not low output alone, drives HFrEF forward: renin-angiotensin-aldosterone and sympathetic signaling cause sodium retention, myocyte hypertrophy and fibrosis, and each pillar interrupts that loop. An ARNI is preferred to an ACE inhibitor, and the 36-hour gap exists because blocking ACE and neprilysin together lets bradykinin accumulate, raising angioedema risk. A primary-prevention ICD is recommended once drug therapy is optimized, at least 40 days after any myocardial infarction, when expected survival exceeds one year.

## Drugs that worsen heart failure

Several common prescriptions precipitate decompensation and are classic wrong answers.

- **Verapamil and diltiazem:** negative inotropes; avoid them in HFrEF, even for rate control.
- **Pioglitazone and other thiazolidinediones:** PPAR-gamma stimulation in the collecting tubule increases sodium reabsorption; starting one in NYHA class III or IV heart failure is contraindicated in the US.
- **NSAIDs:** a recognized trigger of decompensation through sodium retention.
- **Flecainide:** negatively inotropic and proarrhythmic; contraindicated in structural heart disease after the CAST trial showed excess arrhythmic deaths after MI.
- **Carvedilol or ivabradine in acute decompensation:** carvedilol is contraindicated when decompensation needs inotropes, ivabradine in any acute decompensation.

## HFpEF treatment in 2026: the honest mortality answer

No drug has been shown to lower all-cause mortality in HFpEF. Current therapy reduces heart failure hospitalizations and urgent visits and improves symptoms; even for SGLT2 inhibitors, the chair of the 2026 ACC Expert Consensus Decision Pathway on HFpEF describes mixed signals on mortality.

- **SGLT2 inhibitors** come first. Dapagliflozin and empagliflozin are FDA-labeled for adults with heart failure at any ejection fraction, and the July 2026 ACC pathway recommends them for patients with HFpEF without a contraindication.
- **Finerenone**, a nonsteroidal MRA, gained an FDA indication in July 2025 to reduce cardiovascular death, heart failure hospitalization and urgent heart failure visits in adults with heart failure and LVEF 40% or more. In FINEARTS-HF (6,001 patients), it cut cardiovascular death plus total worsening heart failure events by 16% (rate ratio 0.84), driven by fewer heart failure events; cardiovascular death alone was 8.1% versus 8.7%, not significantly different. Potassium above 5.5 mmol/L occurred in 14.3% versus 6.9%, so it is not started above 5.0 mEq/L, and strong CYP3A4 inhibitors and adrenal insufficiency are contraindications. The 2026 pathway prefers it to spironolactone, although its chair says which MRA is better may never be settled.
- **GLP-1 and dual GIP/GLP-1 agonists** help HFpEF with obesity: in STEP-HFpEF, semaglutide improved symptoms, physical limitation and walking distance in patients with a BMI of 30 or more, and in SUMMIT, tirzepatide lowered the combined risk of cardiovascular death or worsening heart failure, through fewer heart failure events. The 2026 pathway includes incretin-based therapy, but as of October 2026 neither the Wegovy nor the Zepbound label carries a heart failure indication.
- **Diuretics and comorbidities:** loop diuretics for congestion, blood pressure below 130/80 mm Hg, atrial fibrillation and sleep apnea care, exercise and caloric restriction. An ARNI or ARB suits selected patients; the sacubitril/valsartan label says its benefit is clearest when LVEF is below normal.

HFmrEF borrows from both sides: an SGLT2 inhibitor first, finerenone (labeled for LVEF 40% or more), and the other HFrEF drugs considered case by case. Patients with HFimpEF keep the full regimen; in one withdrawal trial, 40% relapsed within six months of stopping therapy.

## ACC/AHA stages A to D vs NYHA classes I to IV

Stages describe progression along the heart failure continuum, and a patient whose symptoms resolve stays in stage C, whereas NYHA class describes today's symptoms and changes with treatment.

| ACC/AHA stage | Definition | NYHA class | Example |
| --- | --- | --- | --- |
| A: at risk | Risk factors such as hypertension, diabetes, obesity or cardiotoxins, without symptoms, structural change or abnormal biomarkers | -- | Hypertensive diabetic with a normal echo |
| B: pre-heart failure | No symptoms ever, but structural or functional abnormality, or raised natriuretic peptides or troponin | I | Asymptomatic LVEF of 35% after an MI |
| C: symptomatic heart failure | Current or prior symptoms caused by structural or functional heart disease | I to IV | Prior pulmonary edema, now symptom-free on therapy |
| D: advanced heart failure | Symptoms at rest or minimal exertion, recurrent hospitalizations despite therapy | IV | Evaluated for transplant, mechanical support or palliative care |

NYHA class I means no limitation of ordinary activity, class II means ordinary activity brings symptoms, class III means less than ordinary activity does, and class IV means symptoms at rest. Hydralazine-nitrate and device criteria depend on the NYHA class, so read it from the stem.

## Acute decompensated heart failure basics

Decompensation usually has a trigger planted in the stem: infection, missed medications, extra salt or a new NSAID. Congested but well-perfused patients need loop diuretics, and established therapy, including a beta-blocker, usually continues unless the patient is hypotensive or hypoperfused, since continuing guideline-directed therapy lowers post-discharge death and readmission.

Cool extremities, hypotension and falling urine output signal hypoperfusion. Cardiogenic shock pairs that hypoperfusion with a cardiac index of 2.2 L/min/m² or less and a pulmonary capillary wedge pressure above 15 mm Hg; dobutamine or milrinone supports contractility, norepinephrine treats severe hypotension, and no beta-blocker is started. The [cardiogenic shock review](/blog/2026-05-27-everything-you-need-to-know-about-cardiogenic-shock-for-step-1) covers the hemodynamics.

> **10-second exam strategy:** Find the EF first: 40% or less is HFrEF, 50% or more is HFpEF. No EF given? An S3 with a laterally displaced apex means a dilated, weak ventricle; an S4 with LVH means a stiff one. For a "reduces mortality" question, pick a missing HFrEF pillar, hydralazine-nitrate in the right patient, or a device in an eligible patient; ivabradine, digoxin and diuretics never qualify.

## How USMLE tests HFrEF vs HFpEF

Stems pair a phenotype with one drug decision and hide the discriminator in the exam or labs.

- **Obese 74-year-old woman, hypertension, S4, LVEF 60%, new orthopnea:** HFpEF; diurese, add an SGLT2 inhibitor, control blood pressure.
- **Lip swelling a day after lisinopril is switched to sacubitril/valsartan:** angioedema; the 36-hour washout was skipped.
- **HFrEF with new edema and weight gain after pioglitazone:** thiazolidinedione fluid retention; stop it.
- **Yellow vision and ventricular bigeminy on digoxin after a new loop diuretic:** toxicity unmasked by hypokalemia.

## Worked vignette: the missing mortality drug

A 66-year-old man had an anterior MI two years ago and now has NYHA class II dyspnea. Blood pressure is 114/70 mm Hg and pulse 62/min and regular. The apical impulse is displaced laterally, and an S3 is heard. Echocardiography shows a dilated left ventricle with an LVEF of 30%. He takes sacubitril/valsartan, metoprolol succinate, dapagliflozin and furosemide at stable doses. Potassium is 4.3 mEq/L and eGFR is 62 mL/min/1.73 m². Which addition is most likely to reduce his risk of death?

- A. Digoxin
- B. Diltiazem
- C. Ivabradine
- D. Spironolactone
- E. Hydralazine plus isosorbide dinitrate

**Answer: D.** He has HFrEF on three of the four pillars; the mineralocorticoid receptor antagonist is missing, and a potassium of 4.3 with an eGFR above 30 makes spironolactone safe to start with close potassium checks. Digoxin (A) lowers hospitalizations, not deaths. Diltiazem (B) is a negative inotrope that worsens HFrEF. Ivabradine (C) needs a resting rate of 70 or more and reduces hospitalization, not death; his rate is 62. Hydralazine plus isosorbide dinitrate (E) is for self-identified Black patients with NYHA class III or IV symptoms despite standard therapy; he has class II symptoms on a tolerated ARNI. If his LVEF stays at 35% or less on optimized therapy, he also needs evaluation for a primary-prevention ICD.

## Common wrong-answer traps

- **Calling ivabradine, vericiguat or digoxin a mortality drug.** None has a proven survival benefit.
- **Choosing metoprolol tartrate.** Only metoprolol succinate, carvedilol and bisoprolol are evidence-based.
- **Tracking BNP on sacubitril/valsartan.** Neprilysin inhibition raises BNP; follow NT-proBNP.
- **Diltiazem or verapamil for rate control in HFrEF.** Use a beta-blocker.
- **Assuming semaglutide or tirzepatide has an FDA heart failure label.** Neither does as of October 2026.

## Sources

- AHA: [Second Universal Definition of Heart Failure (2026)](https://professional.heart.org/en/science-news/expert-consensus-document-second-universal-definition-of-heart-failure-2026/top-things-to-know), [guideline publication schedule](https://professional.heart.org/en/guidelines-and-statements/guideline-publication-schedule)
- ACC: [guideline list](https://www.acc.org/Guidelines), [2026 HFpEF decision pathway summary](https://www.acc.org/latest-in-cardiology/journal-scans/2026/07/22/17/25/updated-acc-ecdp-addresses-management-of-hfpef), trial summaries for [FINEARTS-HF](https://www.acc.org/latest-in-cardiology/clinical-trials/2024/08/29/20/16/finearts-hf), [STEP-HFpEF](https://www.acc.org/latest-in-cardiology/clinical-trials/2023/08/23/19/18/step-hfpef) and [SUMMIT](https://www.acc.org/latest-in-cardiology/clinical-trials/2024/11/15/15/13/summit)
- StatPearls (NCBI Bookshelf): [Heart failure](https://www.ncbi.nlm.nih.gov/books/NBK430873/), [HFpEF](https://www.ncbi.nlm.nih.gov/books/NBK599960/), [heart sounds](https://www.ncbi.nlm.nih.gov/books/NBK541010/), [LVH](https://www.ncbi.nlm.nih.gov/books/NBK557534/), [dilated cardiomyopathy](https://www.ncbi.nlm.nih.gov/books/NBK441911/), [cardiogenic shock](https://www.ncbi.nlm.nih.gov/books/NBK482255/), [carvedilol](https://www.ncbi.nlm.nih.gov/books/NBK534868/), [spironolactone](https://www.ncbi.nlm.nih.gov/books/NBK554421/), [hydralazine](https://www.ncbi.nlm.nih.gov/books/NBK470296/), [digoxin](https://www.ncbi.nlm.nih.gov/books/NBK556025/), [pioglitazone](https://www.ncbi.nlm.nih.gov/books/NBK544287/), [flecainide](https://www.ncbi.nlm.nih.gov/books/NBK542291/)

Heart failure pharmacology becomes pattern recognition after enough vignettes: [Master heart failure pharmacology with StepGenie](https://dashboard.stepgenie.app/sign-up).

## Frequently asked questions

### Which drugs reduce mortality in heart failure with reduced ejection fraction?

Four classes lower mortality in HFrEF: sacubitril/valsartan (or an ACE inhibitor or ARB), one of three beta-blockers (carvedilol, metoprolol succinate or bisoprolol), a mineralocorticoid receptor antagonist such as spironolactone or eplerenone, and an SGLT2 inhibitor such as dapagliflozin or empagliflozin. Hydralazine with isosorbide dinitrate adds a survival benefit in self-identified Black patients with NYHA class III or IV symptoms. Digoxin, ivabradine, vericiguat and loop diuretics ease symptoms or hospitalizations without a proven survival benefit.

### Does any drug have a mortality benefit in HFpEF?

Not yet. No drug has been shown to lower all-cause mortality in heart failure with preserved ejection fraction. SGLT2 inhibitors and the nonsteroidal MRA finerenone reduce heart failure hospitalizations and urgent visits, and in FINEARTS-HF cardiovascular death was 8.1% with finerenone versus 8.7% with placebo, a nonsignificant difference. In obese patients, semaglutide improved symptoms and tirzepatide lowered combined cardiovascular death or worsening heart failure through fewer heart failure events, but neither has an FDA heart failure indication as of October 2026.

### What ejection fraction defines HFrEF, HFmrEF and HFpEF?

The 2022 AHA/ACC/HFSA guideline defines HFrEF as an LVEF of 40% or less, HFmrEF as 41% to 49%, and HFpEF as 50% or more with evidence of raised filling pressures. Heart failure with improved EF means a previous LVEF of 40% or less that has risen above 40%. The 2026 Second Universal Definition moves away from fixed cut-offs and the 2026 ESC guideline drops HFmrEF, but US guidelines and exam questions still use these numbers.

### Is finerenone FDA-approved for heart failure?

Yes. In July 2025 the FDA approved finerenone (Kerendia) to reduce the risk of cardiovascular death, heart failure hospitalization and urgent heart failure visits in adults with heart failure and an LVEF of 40% or more, based on the FINEARTS-HF trial. It is not started when potassium is above 5.0 mEq/L, and it is contraindicated with strong CYP3A4 inhibitors and in adrenal insufficiency. Its earlier indication in chronic kidney disease with type 2 diabetes continues.

### How do S3 and S4 gallops differ in heart failure?

An S3 is an early diastolic sound made as blood fills a volume-overloaded, usually dilated ventricle, so in an adult with dyspnea it suggests HFrEF, although it can be normal in children and athletes. An S4 is a late diastolic sound made when the atrium contracts against a stiff, hypertrophied ventricle, so it suggests HFpEF or left ventricular hypertrophy. Because an S4 depends on atrial contraction, it is absent in atrial fibrillation.

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Canonical page: [HFrEF vs HFpEF: Differences, Drugs & Mortality](https://www.stepgenie.app/blog/hfref-vs-hfpef-usmle)
Topic hub: [Cardiology](https://www.stepgenie.app/topics/cardiology)