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Ivabradine, vericiguat, and hydralazine-isosorbide dinitrate in heart failure

The drugs added to the four foundational classes in heart failure with reduced ejection fraction: their mechanisms, trial evidence, eligibility, dosing, safety, sequencing, and the agents that failed.

Where add-on therapy fits after the four foundational drug classes

Guideline-directed medical therapy (GDMT) for HFrEF rests on four classes, each of which reduces death and hospitalization on its own: an angiotensin receptor-neprilysin inhibitor (ARNI; or an angiotensin-converting enzyme [ACE] inhibitor or angiotensin receptor blocker [ARB]), an evidence-based beta blocker, a mineralocorticoid receptor antagonist (MRA), and a sodium-glucose cotransporter 2 (SGLT2) inhibitor. Their evidence, doses, and rapid-sequence initiation are covered on the heart failure with reduced ejection fraction page. Add-on drugs sit on top of that foundation. None is a substitute for a foundational class, and each was tested in a defined population that sets its indication.

The 2022 American Heart Association/American College of Cardiology/Heart Failure Society of America (AHA/ACC/HFSA) guideline groups these agents as additional medical therapies for selected patients. The 2024 ACC Expert Consensus Decision Pathway (ECDP) places them after the foundational classes have been started and titrated, and it names self-identified African American patients, older adults, and patients with frailty as groups in whom additional therapies and modified titration are specifically addressed. Selection follows the patient's residual phenotype: a fast sinus rate, a recent decompensation, self-identified Black race with persistent advanced symptoms, or intolerance of renin-angiotensin inhibition.

Add-on drugs for HFrEF: residual phenotype, pivotal trial, guideline class, and US regulatory status. Classes and levels of evidence from the 2022 AHA/ACC/HFSA guideline; trial results from the primary publications and the US prescribing information. HF, heart failure; HR, hazard ratio; LVEF, left ventricular ejection fraction.

Three features separate these drugs from the foundational classes. First, the effect sizes are smaller and come mainly from fewer heart failure hospitalizations. Ivabradine did not reduce cardiovascular death in SHIFT, vericiguat did not reduce it significantly in VICTORIA, and omecamtiv mecarbil left it unchanged in GALACTIC-HF. Hydralazine-isosorbide dinitrate in A-HeFT is the exception, with a large mortality reduction in a population defined by self-identified race. Second, each indication is narrow and tied to trial entry criteria: rhythm and heart rate for ivabradine, a recent worsening event and natriuretic peptide level for vericiguat, and race and NYHA class for the fixed-dose nitrate combination. Third, each competes for the same blood pressure, pill burden, and out-of-pocket cost as the foundational drugs. Add-on therapy therefore follows, and never replaces, titration of the four classes.

Residual risk and the mechanisms that add-on drugs target

Patients who remain symptomatic or are readmitted on full foundational therapy have residual risk that the neurohormonal blockers do not address. The add-on drugs target four separate pathways: sinus node rate, the nitric oxide-soluble guanylate cyclase-cyclic guanosine monophosphate (NO-sGC-cGMP) pathway, arterial and venous loading with nitric oxide donation, and sarcomere function. Digoxin, in the last row, acts by inhibiting sodium-potassium adenosine triphosphatase.

Mechanisms of add-on drugs in HFrEF. Blood pressure and heart rate effects are taken from the prescribing information and trial reports (SHIFT, VICTORIA, A-HeFT, COSMIC-HF).

Ivabradine adds heart rate reduction without lowering blood pressure, so it fits a patient whose beta blocker dose is limited by hypotension. Vericiguat and the nitrate combination both act on the cGMP pathway. Each is therefore contraindicated with riociguat, and phosphodiesterase-5 inhibitors are contraindicated with nitrates and not recommended with vericiguat. Omecamtiv mecarbil raises systolic function without changing blood pressure and with only a slight fall in heart rate, and its effect is largest where systolic function is worst.

Heart rate as a therapeutic target in HFrEF

Resting heart rate predicts cardiovascular outcome in the general population and in HFrEF. A fast sinus rate shortens diastole, which reduces the time available for coronary perfusion and ventricular filling, raises myocardial oxygen consumption, and in the failing ventricle can worsen the force-frequency relationship. Part of the benefit of beta blockers in HFrEF tracks the heart rate reduction they achieve.

SHIFT tested whether heart rate is itself a target, independent of the other effects of beta blockade. In the placebo group, patients with a baseline rate of 87/min or more had more than twice the risk of cardiovascular death or heart failure hospitalization of patients with rates of 70 to 71/min (HR 2.34). Risk rose by 3% for every additional beat per minute and by 16% for every 5/min. In the ivabradine group, patients whose rate fell below 60/min at 28 days had the lowest subsequent event rates. When the analysis was adjusted for the change in heart rate at 28 days, the treatment effect of ivabradine disappeared (HR 0.95, 95% confidence interval [CI] 0.85 to 1.06). That result indicates that the benefit came through heart rate reduction.

The same principle governs the interaction with beta blockers. In a SHIFT analysis by background beta blocker dose, ivabradine reduced events significantly in patients taking less than 50% of the target beta blocker dose, and the apparent smaller effect at higher doses lost significance after adjustment for baseline heart rate. The magnitude of rate reduction achieved by beta blocker plus ivabradine, not the beta blocker dose itself, determined the effect. The US Food and Drug Administration (FDA) label, by contrast, notes that the benefit appeared to decrease as beta blocker dose increased, with little if any benefit demonstrated at guideline-defined target doses. Both readings lead to the same practice: the beta blocker is titrated first because it reduces mortality, and ivabradine is added only when the sinus rate remains at 70/min or more.

Heart rate reduction does not help every population. In stable coronary disease without heart failure (SIGNIFY) and in heart failure with preserved ejection fraction (EDIFY), lowering the sinus rate with ivabradine did not improve outcomes. The heart rate target is specific to the dilated, poorly contracting ventricle.

Ivabradine: funny current inhibition and pharmacokinetics

Ivabradine blocks the hyperpolarization-activated cyclic nucleotide-gated (HCN) channel that carries the funny current (I_f), the inward sodium-potassium current that drives spontaneous diastolic depolarization in sinoatrial node cells. HCN4 is the dominant isoform in the sinus node. Blocking it flattens the slope of phase 4 and slows the sinus rate. The drug enters the channel from the intracellular side when the channel is open, so the degree of block depends on how often the channel opens. The reduction in rate is larger when the baseline rate is higher. At recommended doses the resting rate falls by about 10/min, and the effect on heart rate plateaus above doses of 20 mg twice daily.

Ivabradine has no negative inotropic effect and does not prolong rate-corrected ventricular repolarization. The uncorrected QT interval lengthens as the rate slows. In electrophysiology studies of patients with conduction disease, intravenous ivabradine prolonged the PR interval by about 29 ms and the atrioventricular nodal (AH) interval by about 27 ms, so its effect is not entirely confined to the sinus node. Its rate-lowering action depends on sinus node automaticity, so it does not slow the ventricular rate in atrial fibrillation.

The drug also inhibits I_h, a closely related current in retinal photoreceptors that curtails the retinal response to bright light. Partial I_h block underlies the luminous visual phenomena (phosphenes) some patients describe.

Pharmacokinetics of ivabradine from the US prescribing information.

SHIFT and the trial evidence for ivabradine in HFrEF

SHIFT (Systolic Heart Failure Treatment with the I_f Inhibitor Ivabradine Trial) randomized 6,558 patients. Entry required symptomatic heart failure, LVEF 35% or less, sinus rhythm with a resting rate of 70/min or more, and a heart failure hospitalization within the previous 12 months. Patients had been stable for at least 4 weeks on a regimen that included a beta blocker at the maximally tolerated dose, unless a beta blocker was not tolerated. Ivabradine was started at 5 mg twice daily and adjusted between 2.5 and 7.5 mg twice daily to keep the resting rate between 50 and 60/min. At 1 month, 63% of patients took 7.5 mg twice daily.

Coronary disease was the cause of heart failure in 68%. About half were in NYHA class II, half in class III, and 2% in class IV, and mean LVEF was 29%. Background therapy reflected its era: 89% took a beta blocker, but only 26% at the guideline target dose; 91% took an ACE inhibitor or ARB, and 60% an MRA. Hypotension was the most common reason the beta blocker target was not reached. Fewer than 5% had an implantable cardioverter-defibrillator or a cardiac resynchronization device, and no patient took an ARNI or an SGLT2 inhibitor.

Over a median of 22.9 months, the primary composite of cardiovascular death or hospitalization for worsening heart failure occurred in 24% of the ivabradine group and 29% of the placebo group (HR 0.82, 95% CI 0.75 to 0.90; P<0.0001). Heart failure hospitalization fell from 21% to 16% (HR 0.74), and death from heart failure fell from 5% to 3% (HR 0.74). Cardiovascular death was not significantly reduced (HR 0.91, 95% CI 0.80 to 1.03). For that reason the FDA indication is limited to reducing the risk of hospitalization for worsening heart failure, while the 2022 guideline recommendation states the goal as reducing heart failure hospitalization and cardiovascular death.

Secondary analyses support a disease-modifying effect. Ivabradine reduced total (first and recurrent) heart failure hospitalizations by 25% (902 versus 1,211 events). In the echocardiographic substudy of 411 patients, left ventricular end-systolic volume index fell by 7.0 mL/m² with ivabradine and by 0.9 mL/m² with placebo at 8 months (estimated treatment difference 5.8 mL/m²; 95% CI 2.7 to 8.8). LVEF rose by 2.4 percentage points with ivabradine and fell by 0.1 point with placebo. Patients with the largest reductions in end-systolic volume had the lowest event rates.

Randomized trials of ivabradine. HF, heart failure; HFpEF, heart failure with preserved ejection fraction; LV, left ventricular; LVESVI, left ventricular end-systolic volume index; MI, myocardial infarction.

How SHIFT applies to contemporary practice is uncertain. Its patients took no ARNI or SGLT2 inhibitor, and few were at target beta blocker doses. A patient on full quadruple therapy with a resting rate still at 70/min or more is a smaller and probably lower-risk group than the SHIFT population. The 2022 guideline addresses this by requiring beta blocker titration before ivabradine is considered, so that ivabradine treats the rate that remains after the drug with proven mortality benefit has been maximized.

Ivabradine eligibility, initiation, and dose titration

The 2022 AHA/ACC/HFSA guideline states that ivabradine can be beneficial to reduce heart failure hospitalization and cardiovascular death (Class 2a, Level B-R). The recommendation applies to patients with symptomatic (NYHA class II to III) stable chronic HFrEF (LVEF 35% or less) who are receiving GDMT, including a beta blocker at the maximum tolerated dose. They must also be in sinus rhythm with a resting rate of 70/min or more. The FDA label is broader in one respect: it includes adults who have a contraindication to beta blocker use.

Eligibility is established in a stable outpatient. The resting rate is measured on the electrocardiogram or after several minutes of rest, because a rate counted during a clinic visit can overestimate it. Sinus rhythm is confirmed on the electrocardiogram, since frequent atrial ectopy, atrial flutter, or atrial fibrillation produces a rate that ivabradine cannot lower. Pacing dependence is excluded: patients with a demand pacemaker set at 60/min or more cannot reach the target rate and were excluded from SHIFT.

Adult ivabradine titration from the US prescribing information. The 5-mg tablet is scored and can be split to give 2.5 mg; an oral solution is available for adults who cannot swallow tablets.

The 2022 guideline lists 5 mg twice daily as the starting dose and 7.5 mg twice daily as the target, with a mean dose of 12.8 mg per day achieved in SHIFT. Older age does not change ivabradine pharmacokinetics, but older patients more often have sinus node disease and conduction disease, so the lower starting dose is often chosen in them.

Each review records the resting rate, blood pressure, rhythm on the electrocardiogram, visual symptoms, and the presence of other drugs that slow the heart. When the rate falls below 50/min, other negative chronotropes (digoxin, amiodarone, diltiazem, verapamil) are reviewed before the beta blocker dose is reduced, because the beta blocker carries the mortality benefit.

Ivabradine adverse effects, contraindications, and drug interactions

Bradycardia and conduction disturbance. In SHIFT, bradycardia occurred in 10% of the ivabradine group and 2.2% of the placebo group; the annual rate was 6.0% versus 1.3% per patient-year, and symptomatic bradycardia occurred in 5% versus 1%. Sinus arrest and heart block have also been reported. Risk is highest with sinus node dysfunction, first- or second-degree atrioventricular block, bundle branch block, ventricular dyssynchrony, and other negative chronotropes. Ivabradine is avoided in second-degree atrioventricular block unless a functioning demand pacemaker is present. Bradycardia can unmask QT prolongation, and torsades de pointes has been reported after marketing in patients with other risk factors.

Atrial fibrillation. Ivabradine increases the incidence of atrial fibrillation: 5.0% versus 3.9% per patient-year in SHIFT (8.3% versus 6.6% of patients). Rhythm is reviewed at each visit, and the drug is stopped if atrial fibrillation develops, because it then has no rate-lowering effect.

Phosphenes. Transient enhanced brightness in part of the visual field, halos, stroboscopic or kaleidoscopic effects, or multiple images occurred in 2.8% versus 0.5% of SHIFT patients. They are usually triggered by sudden changes in light intensity, begin within the first 2 months, are mild to moderate, and led to discontinuation in less than 1%. Most resolve during or after treatment. Patients are told that phosphenes can affect driving or machine operation in conditions of sudden light change.

Fetal toxicity. In rats, exposure 1 to 3 times the human exposure at the maximum recommended dose caused cardiac malformations, including ventricular septal defects and complex anomalies of the great arteries. The US label lists fetal toxicity as a warning, not a contraindication. Women of reproductive potential use effective contraception, and breastfeeding is not recommended.

Ivabradine contraindications, interactions, and adverse effects from the US prescribing information. Diltiazem and verapamil are in any case avoided in HFrEF because of negative inotropy.

Monitoring is clinical. No laboratory tests are needed for ivabradine itself. Each visit records the resting rate, rhythm, blood pressure, and visual symptoms, and an electrocardiogram is obtained when an irregular pulse, a rate below 50/min, or new symptoms appear.

Ivabradine outside chronic HFrEF: angina, sinus tachycardia syndromes, HFpEF, and cardiac CT

Chronic coronary disease. Ivabradine reduces angina by lowering myocardial oxygen demand, but it does not improve cardiovascular outcomes in patients with coronary disease, with or without left ventricular dysfunction. In SIGNIFY it increased the primary end point in the subgroup with activity-limiting angina. It is not approved in the United States for angina. Its place among antianginal drugs is covered on the chronic coronary disease page.

Inappropriate sinus tachycardia and postural tachycardia syndrome. The 2015 Heart Rhythm Society (HRS) expert consensus statement states that ivabradine can be useful in inappropriate sinus tachycardia (Class IIa, Level B-R), once reversible causes of sinus tachycardia have been sought and treated. Its recommendations for postural orthostatic tachycardia syndrome (POTS) do not include ivabradine. In a 22-patient randomized crossover trial in hyperadrenergic POTS, ivabradine lowered heart rate and improved physical and social functioning scores without hypotension. Both uses are off-label in the United States, and the contraception and drug-interaction precautions apply, and most patients with these syndromes are young women.

HFpEF. Rate reduction did not improve filling pressure surrogates, exercise capacity, or NT-proBNP in EDIFY, and ivabradine has no indication in heart failure with preserved ejection fraction. A slower rate can worsen symptoms in chronotropically incompetent patients with HFpEF.

Coronary computed tomography (CT) angiography. Ivabradine is used off-label to lower heart rate before the scan when beta blockers are contraindicated or insufficient; preparation is covered on the coronary CT angiography page.

Vericiguat: soluble guanylate cyclase stimulation

Nitric oxide produced by the endothelium binds the reduced heme group of soluble guanylate cyclase (sGC) in vascular smooth muscle and cardiomyocytes. The enzyme converts guanosine triphosphate to cGMP, which activates protein kinase G and relaxes vascular smooth muscle. In the myocardium, cGMP signaling opposes hypertrophy and fibrosis and improves relaxation. Heart failure impairs this pathway at several points: endothelial dysfunction reduces nitric oxide production, oxidative stress inactivates nitric oxide, and oxidation of the sGC heme reduces enzyme responsiveness.

Vericiguat is an sGC stimulator. It binds sGC at a site separate from the nitric oxide binding site, stimulates the enzyme directly, and sensitizes it to endogenous nitric oxide, so it raises cGMP both independently of and synergistically with nitric oxide. It was developed from riociguat, the first sGC stimulator, which is approved for pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension (see pulmonary hypertension). Structural changes reduced oxidative metabolism and lengthened the half-life, allowing once-daily dosing. Unlike a nitrate, vericiguat does not depend on bioconversion of a nitric oxide donor.

Pharmacokinetics of vericiguat from the US prescribing information. eGFR, estimated glomerular filtration rate.

VICTORIA, VICTOR, and the trial evidence for vericiguat

SOCRATES-REDUCED was the phase 2 dose-finding trial. It randomized 456 patients with LVEF below 45% within 4 weeks of a worsening event to placebo or vericiguat at 1.25 to 10 mg daily for 12 weeks. The pooled comparison of the three highest doses with placebo did not show a significant reduction in NT-proBNP, but an exploratory analysis found a dose-response relationship, with the largest NT-proBNP reduction at 10 mg. That finding set the 10-mg target for phase 3.

VICTORIA randomized 5,050 patients with NYHA class II to IV heart failure and LVEF below 45% after a worsening event, defined as a heart failure hospitalization within 6 months or outpatient intravenous diuretic therapy within 3 months. Natriuretic peptides had to be elevated within 30 days: NT-proBNP 1,000 pg/mL or more (B-type natriuretic peptide [BNP] 300 pg/mL or more) in sinus rhythm, and NT-proBNP 1,600 pg/mL or more (BNP 500 pg/mL or more) in atrial fibrillation. Patients taking long-acting nitrates or phosphodiesterase-5 inhibitors, with systolic pressure below 100 mm Hg, or with eGFR below 15 mL/min/1.73 m² were excluded. Median NT-proBNP was 2,800 pg/mL and mean LVEF 29%. Sixty-seven percent were enrolled within 3 months of a hospitalization. At baseline, 93% took a beta blocker, 73% an ACE inhibitor or ARB, 70% an MRA, 15% an ARNI, and 3% an SGLT2 inhibitor.

Over a median of 10.8 months, cardiovascular death or first heart failure hospitalization occurred in 35.5% of the vericiguat group and 38.5% of the placebo group (HR 0.90, 95% CI 0.82 to 0.98; P=0.02). The annualized absolute risk reduction was 4.2 events per 100 patient-years, a number needed to treat of about 24 patients for 1 year. Heart failure hospitalization (27.4% versus 29.6%; HR 0.90, 95% CI 0.81 to 1.00) and cardiovascular death (16.4% versus 17.5%; HR 0.93, 95% CI 0.81 to 1.06) moved in the same direction, but neither was significant on its own. All-cause death was 20.3% versus 21.2% (HR 0.95). After about 1 year, 90% of patients in each group took the 10-mg target dose.

The benefit varied with natriuretic peptide level. Patients in the highest NT-proBNP quartile (above 5,314 pg/mL) had no benefit for cardiovascular death or heart failure hospitalization. Patients with lower values had a consistent benefit. A very high NT-proBNP after a worsening event marks advanced disease, in which evaluation for advanced heart failure therapies takes precedence over another add-on drug.

VICTOR tested vericiguat in 6,105 ambulatory patients with LVEF 40% or less and no heart failure hospitalization within 6 months or outpatient intravenous diuretic within 3 months. Background therapy was contemporary, and 47.5% had never been hospitalized for heart failure. Over a median of 18.5 months, the primary end point of cardiovascular death or heart failure hospitalization occurred in 18.0% of the vericiguat group and 19.1% of the placebo group (HR 0.93, 95% CI 0.83 to 1.04; P=0.22). Because the primary end point was not met, the secondary results are nominal: cardiovascular death was 9.6% versus 11.3% (HR 0.83, 95% CI 0.71 to 0.97), and heart failure hospitalization 11.4% versus 11.9% (HR 0.95). Symptomatic hypotension occurred in 11.3% versus 9.2%.

A prespecified individual-participant pooled analysis of VICTORIA and VICTOR (11,155 patients) found a reduction in cardiovascular death or heart failure hospitalization (25.9% versus 27.9%; HR 0.91, 95% CI 0.85 to 0.98), with similar effects on cardiovascular death (HR 0.89) and heart failure hospitalization (HR 0.92). Pooled analyses of this kind generate hypotheses. The US indication remains limited to patients after a worsening event, and no guideline has extended the recommendation to stable patients.

Randomized trials of vericiguat. HF, heart failure; HFpEF, heart failure with preserved ejection fraction; KCCQ, Kansas City Cardiomyopathy Questionnaire.

Vericiguat eligibility, dosing, and monitoring

The 2022 AHA/ACC/HFSA guideline states that an oral sGC stimulator (vericiguat) may be considered to reduce heart failure hospitalization and cardiovascular death (Class 2b, Level B-R). The recommendation applies to selected high-risk patients with HFrEF and recent worsening of heart failure who are already on GDMT. The guideline notes that the 10% relative risk reduction was smaller than expected in a high-risk population, that symptomatic hypotension and syncope were numerically more frequent, and that the highest NT-proBNP quartile did not benefit. The FDA indication covers adults with symptomatic chronic heart failure and ejection fraction below 45% following a hospitalization for heart failure or need for outpatient intravenous diuretics.

The typical candidate has completed titration of the four foundational classes and has nevertheless been readmitted or needed an intravenous diuretic. The NT-proBNP level after stabilization is in the range in which VICTORIA showed benefit, and systolic pressure is 100 mm Hg or higher. The patient takes neither a long-acting nitrate nor a phosphodiesterase-5 inhibitor. Vericiguat is started once the patient is stable, often at or soon after discharge, when other changes to therapy have settled.

Dosing. The current US label recommends a starting dose of 5 mg once daily with food, or 2.5 mg once daily for patients at risk of symptomatic hypotension. The dose is doubled approximately every 2 weeks to the target of 10 mg once daily as tolerated. The 5-mg starting dose was supported by VELOCITY, a 2-week, single-arm, open-label study of 106 patients. In that study, 93.4% completed treatment at 5 mg without moderate or severe symptomatic hypotension or an interruption longer than 1 day. Its comparison with the 2.5-mg start used in VICTORIA was descriptive. The 2022 guideline dosing table, written before that label change, lists 2.5 mg as the starting dose. Tablets may be crushed and mixed with water for patients who cannot swallow them.

Monitoring. A pregnancy test is obtained before the first dose in women of reproductive potential, and effective contraception continues during treatment and for 1 month after the last dose. Blood pressure, including orthostatic pressure in older patients, is checked before each dose increase. Hemoglobin is measured at baseline and periodically, because vericiguat causes anemia. No dose adjustment is needed for kidney function down to an eGFR of 15 mL/min/1.73 m².

Vericiguat safety: hypotension, anemia, pregnancy, and interactions

Hypotension. Hypotension was reported in 16% of vericiguat-treated patients and 15% of placebo-treated patients in VICTORIA; symptomatic hypotension was 9.1% versus 7.9% and syncope 4.0% versus 3.5%, neither difference significant. Mean systolic pressure was 1 to 2 mm Hg lower than with placebo. In VICTOR, symptomatic hypotension was 11.3% versus 9.2% (adjusted HR 1.24). The placebo-corrected decrease in systolic pressure was about 1 mm Hg, similar in patients older than 75 years, in those with systolic pressure 110 mm Hg or less, and in those taking an ARNI or an SGLT2 inhibitor. The treatment effect on outcomes did not vary with baseline systolic pressure.

Anemia. Anemia was reported in 10% versus 7% in VICTORIA. The mechanism is not established, and hemoglobin is followed during treatment.

Embryo-fetal toxicity. In rabbits, exposure 4 or more times the human dose caused ventricular septal defects with truncus arteriosus communis, abortions, and resorptions. Vericiguat carries a boxed warning and is contraindicated in pregnancy. Breastfeeding is not recommended.

Vericiguat interactions from the US prescribing information. Pregnancy is the second contraindication.

Hydralazine-isosorbide dinitrate: mechanism and the vasodilator trials

Hydralazine is a direct arteriolar dilator. It lowers systemic vascular resistance and raises stroke volume, with reflex tachycardia and renin release when given alone. Isosorbide dinitrate is a nitric oxide donor that dilates veins at low doses and arteries at higher doses, lowering filling pressures. The two act on different vascular beds. Continuous nitrate exposure causes tolerance, in part through vascular superoxide production. In experimental models, hydralazine inhibits a membrane-bound NADH oxidase and prevents nitrate tolerance, an antioxidant action that supports the rationale for the combination. In a single-dose hemodynamic study in heart failure, the combination lowered pulmonary capillary wedge pressure more than hydralazine alone, while the increase in cardiac output was not larger. The mechanism of the clinical benefit, as the label states, has not been established, and the two components have never been tested separately in outcome trials.

V-HeFT I (Vasodilator-Heart Failure Trial, 1986) randomized 642 men taking digoxin and a diuretic to placebo, prazosin 20 mg daily, or hydralazine 300 mg daily with isosorbide dinitrate 160 mg daily (75 mg/40 mg four times daily). Two-year mortality, a protocol-specified end point, was 25.6% with the combination and 34.3% with placebo, a 34% risk reduction (P<0.028). Three-year mortality was 36.2% versus 46.9%. Mortality over the entire follow-up was of borderline significance. LVEF rose with the combination and not with prazosin, which had no effect on survival. V-HeFT I was the first evidence that a drug could prolong life in heart failure.

V-HeFT II (1991) compared the same combination with enalapril 20 mg daily in 804 men. Two-year mortality was 18% with enalapril and 25% with the combination (P=0.016), a difference attributed mainly to fewer sudden deaths with enalapril. Peak oxygen consumption increased only with the combination, and LVEF rose more with it during the first 13 weeks. ACE inhibition became the standard, and the combination moved to second line.

A-HeFT (African-American Heart Failure Trial, 2004) followed retrospective analyses of the V-HeFT trials that suggested a larger benefit in Black patients. It randomized 1,050 self-identified Black patients in NYHA class III or IV with LVEF 35% or less, or LVEF below 45% with a dilated left ventricle. They received a fixed-dose combination (isosorbide dinitrate 20 mg with hydralazine 37.5 mg, titrated to two tablets three times daily) or placebo, added to background therapy that included an ACE inhibitor or ARB in 93%, a beta blocker in 87%, and an MRA in 39%. The trial was stopped early for a mortality difference: 6.2% versus 10.2% (HR 0.57; 43% relative reduction). First heart failure hospitalization fell from 22.4% to 16.4% (33% relative reduction), and quality of life on the Minnesota Living with Heart Failure questionnaire improved. Blood pressure was on average 3/3 mm Hg lower with the combination.

Outcome trials of hydralazine with isosorbide dinitrate. HF, heart failure; LVEF, left ventricular ejection fraction.

A-HeFT has limits that the 2022 guideline acknowledges. Early termination for benefit makes the result vulnerable to a small number of events, and the benefit was seen at doses higher than those usually reached in practice. No patient took an ARNI or an SGLT2 inhibitor, and the guideline states that data are insufficient to guide use with an ARNI.

Hydralazine-isosorbide dinitrate in self-identified Black patients and in intolerance of renin-angiotensin inhibitors

Self-identified Black patients. For patients self-identified as African American with NYHA class III to IV HFrEF who are receiving optimal medical therapy, the combination of hydralazine and isosorbide dinitrate is recommended to improve symptoms and reduce morbidity and mortality (Class 1, Level A). The guideline also judges it to provide high economic value in this population. The FDA approved the fixed-dose tablet as an adjunct to standard therapy in self-identified Black patients to improve survival, prolong time to hospitalization for heart failure, and improve patient-reported functional status. The label notes little experience in NYHA class IV.

The race-based indication rests on self-identification, which was the A-HeFT entry criterion. Race is a social category and an imperfect proxy for any biological mechanism. The 2022 guideline describes ongoing research on biological hypotheses, particularly the absence of European ancestry, that may explain responsiveness to the combination. Until that research identifies a better marker, the indication follows the trial.

Patients who cannot take an ARNI, ACE inhibitor, or ARB. The guideline addresses patients with current or previous symptomatic HFrEF who cannot be given an ARNI, ACE inhibitor, or ARB because of drug intolerance or renal insufficiency. In them, a combination of hydralazine and isosorbide dinitrate might be considered to reduce morbidity and mortality (Class 2b, Level C-LD). The evidence is indirect, drawn from V-HeFT I before ACE inhibitors were available. Common situations are angioedema with an ACE inhibitor, hyperkalemia that persists despite potassium binders, and advanced chronic kidney disease. Before renin-angiotensin inhibition is abandoned, the severity and reversibility of kidney dysfunction or hyperkalemia are assessed, and a potassium binder is considered. The guideline recommends referral to a heart failure specialist in this situation, because the benefit is uncertain.

Use beyond these two groups. Whether the combination benefits non-Black patients taking modern therapy is unknown. In the Get With The Guidelines-Heart Failure registry linked to Medicare claims, only 22.7% of eligible Black patients and 18.2% of patients not taking an ACE inhibitor or ARB were newly prescribed hydralazine-isosorbide dinitrate at discharge. Treated and untreated patients had similar 3-year mortality and readmission, in both Black patients (HR for death 0.92) and others (HR 0.93), and postdischarge adherence was low. An observational registry cannot establish efficacy, but it documents underuse in the population with the strongest evidence.

Hydralazine with nitrate is also the vasodilator regimen used for HFrEF in pregnancy, when ACE inhibitors, ARBs, ARNIs, MRAs, and SGLT2 inhibitors are contraindicated; pregnancy management is covered on the HFrEF page.

Hydralazine-isosorbide dinitrate dosing, adverse effects, and adherence

Dosing from the 2022 AHA/ACC/HFSA guideline and the fixed-dose prescribing information. The fixed-dose tablet is scored; the dose can be reduced to half a tablet three times daily during intolerable side effects and increased again as they subside.

Titration can be rapid, over 3 to 5 days, but side effects often slow it. Volume or salt depletion is corrected before the first dose because symptomatic hypotension, particularly orthostatic, can occur even at small doses.

Adverse effects. In A-HeFT, headache occurred in 50% of the treated group and 21% of the placebo group, dizziness in 32% versus 14%, asthenia in 14% versus 11%, nausea in 10% versus 6%, and hypotension in 8% versus 4%. Twenty-one percent stopped the drug for adverse reactions, compared with 12% on placebo; headache was the most common reason (7%). Nitrate headache often lessens over the first weeks of treatment.

Drug-induced lupus. Hydralazine causes a drug-induced systemic lupus erythematosus syndrome, with arthralgia, rash, serositis, and antihistone antibodies. Risk is higher in slow acetylators and with higher cumulative doses. Symptoms usually regress after the drug is stopped.

Other hydralazine effects. Reflex tachycardia and hypotension can provoke angina, particularly in hypertrophic cardiomyopathy. Peripheral neuritis with paresthesia, attributed to an antipyridoxine effect, is treated with pyridoxine. Hydralazine increases exposure to some beta blockers: a single 50-mg dose roughly doubled propranolol exposure and increased metoprolol peak concentration by 50%.

Contraindications. The contraindications are allergy to organic nitrates; concomitant phosphodiesterase-5 inhibitors (avanafil, sildenafil, tadalafil, vardenafil), which can cause severe hypotension, syncope, or myocardial ischemia; and riociguat.

Adherence. Three-times-daily dosing on top of a four-class regimen, frequent headache, and cost limit long-term use. The 2022 guideline notes marked underuse and very low refill rates even when the drug is prescribed.

Omecamtiv mecarbil and cardiac myosin activation

Traditional inotropes (dobutamine, milrinone) raise contractility by increasing intracellular cyclic adenosine monophosphate and calcium. That raises myocardial oxygen demand and promotes arrhythmia, and long-term oral inotropes increased mortality. Omecamtiv mecarbil works downstream of calcium. It binds the catalytic domain of cardiac myosin and, by an allosteric mechanism, increases the rate at which myosin enters the strongly actin-bound, force-generating state. More myosin heads are engaged at each beat. The result is a longer systolic ejection time and a larger stroke volume without a faster rate of pressure rise and without a change in the calcium transient.

Phase 2 trials. ATOMIC-AHF tested a 48-hour intravenous infusion in 606 patients with acute heart failure and LVEF 40% or less. It did not meet its primary end point of dyspnea relief, although the highest-dose cohort had more dyspnea relief in a prespecified analysis; systolic ejection time rose with concentration, and troponin was slightly higher. COSMIC-HF tested oral dosing in 448 patients with chronic HFrEF over 20 weeks. With pharmacokinetic-guided titration, systolic ejection time increased by 25 ms, stroke volume by 3.6 mL, left ventricular end-systolic diameter fell by 1.8 mm, heart rate fell by 3/min, and NT-proBNP fell by 970 pg/mL compared with placebo. Pharmacokinetic guidance kept plasma levels in the range associated with benefit.

GALACTIC-HF randomized 8,256 inpatients and outpatients with symptomatic chronic heart failure and LVEF 35% or less to omecamtiv mecarbil (25, 37.5, or 50 mg twice daily, guided by plasma concentration) or placebo. Over a median of 21.8 months, the primary composite of a first heart failure event (hospitalization or urgent visit) or cardiovascular death occurred in 37.0% versus 39.1% (HR 0.92, 95% CI 0.86 to 0.99; P=0.03). Cardiovascular death was 19.6% versus 19.4% (HR 1.01). Symptom scores did not change. NT-proBNP fell 10% relative to placebo at 24 weeks, and median troponin I rose by 4 ng/L. Ischemic events and ventricular arrhythmias were not more frequent, and blood pressure, potassium, and kidney function did not change.

Ejection fraction was the strongest modifier of the treatment effect. In the lowest quartile (LVEF 22% or less), the primary end point fell by 17% (HR 0.83, 95% CI 0.73 to 0.95), an absolute reduction of 7.4 events per 100 patient-years. In the highest quartile (LVEF 33% or more), there was no effect (HR 0.99). This gradient fits the mechanism: a drug that improves systolic function helps most where systolic function is worst.

METEORIC-HF randomized 276 patients with LVEF 35% or less and reduced peak oxygen uptake. Over 20 weeks, omecamtiv mecarbil did not improve peak oxygen uptake (difference −0.45 mL/kg/min, 95% CI −1.02 to 0.13).

Trials of omecamtiv mecarbil. HF, heart failure; LVAD, left ventricular assist device; LVESD, left ventricular end-systolic diameter.

Regulatory status. In December 2022, the FDA Cardiovascular and Renal Drugs Advisory Committee voted 8 to 3 that the benefits of omecamtiv mecarbil did not outweigh its risks in HFrEF. In February 2023 the FDA issued a complete response letter that asked for an additional trial. COMET-HF, a confirmatory trial in patients with severely reduced ejection fraction and a recent heart failure event, began enrolling in December 2024 (ClinicalTrials.gov NCT06736574). Omecamtiv mecarbil is not approved in the United States or the European Union, where the marketing authorization application was withdrawn in May 2024 after the European Medicines Agency's provisional opinion that the benefits did not outweigh the risks. It has no recommendation in the 2022 US guideline or the 2023 European focused update, and is available only in trials.

Digoxin, omega-3 fatty acids, potassium binders, and intravenous iron as adjuncts

Several other therapies are added to GDMT in selected patients.

Digoxin. In patients with symptomatic HFrEF despite GDMT, or who cannot tolerate GDMT, digoxin might be considered to decrease heart failure hospitalization (Class 2b, Level B-R). The DIG trial showed no effect on mortality and fewer hospitalizations, and higher serum concentrations are associated with higher mortality. Dosing, target concentration (0.5 to below 0.9 ng/mL), interactions, and toxicity are covered on the HFrEF page, and rate control in atrial fibrillation on the atrial fibrillation page.

Omega-3 polyunsaturated fatty acids. In NYHA class II to IV heart failure, omega-3 fatty acid supplementation may be reasonable as adjunctive therapy to reduce mortality and cardiovascular hospitalization (Class 2b, Level B-R). In GISSI-HF, 1 g daily of eicosapentaenoic and docosahexaenoic acid ethyl esters reduced all-cause death from 29% to 27% (adjusted HR 0.91) over a median of 3.9 years, with 56 patients treated for that period to prevent one death. Omega-3 fatty acids carry a dose-related risk of atrial fibrillation.

Potassium binders. In patients with heart failure who develop potassium of 5.5 mEq/L or more while taking a renin-angiotensin-aldosterone system inhibitor, the effectiveness of patiromer or sodium zirconium cyclosilicate in improving outcomes by allowing continued therapy is uncertain (Class 2b, Level B-R). The binders lower potassium and allow MRA titration, but no outcome benefit has been shown.

Intravenous iron. Iron deficiency (ferritin below 100 ng/mL, or 100 to 299 ng/mL with transferrin saturation below 20%) is treated with intravenous iron to improve functional status and quality of life (Class 2a). Evidence on hospitalization and death is less consistent; the trials and agents are reviewed in iron deficiency and anemia in HFrEF.

Add-on drug eligibility and dosing checker

The checker applies the 2022 AHA/ACC/HFSA recommendations, the US prescribing information, and the entry criteria of SHIFT, VICTORIA, and A-HeFT to one patient. For ivabradine, vericiguat, and hydralazine-isosorbide dinitrate, it returns whether the patient meets the recommendation, which criterion excludes the drug, and the starting dose and titration. It assumes that the four foundational classes have already been started and titrated. Symptoms of hypotension, perfusion, adherence, and patient preference lie outside its inputs.

Thresholds. Ivabradine: LVEF 35% or less, sinus rhythm at 70/min or more, NYHA II to III, beta blocker at the target or maximally tolerated dose (Class 2a). Vericiguat: LVEF below 45% with a worsening event; VICTORIA entry NT-proBNP of 1,000 pg/mL in sinus rhythm and 1,600 pg/mL in atrial fibrillation; exclusion below 100 mm Hg systolic; no benefit above 5,314 pg/mL (Class 2b). Hydralazine-isosorbide dinitrate: self-identified Black patients in NYHA III to IV (Class 1) or inability to take renin-angiotensin inhibitors (Class 2b). PDE-5, phosphodiesterase-5; sGC, soluble guanylate cyclase.

Sequencing add-on drugs, the blood pressure budget, and polypharmacy

Order of therapy. The four foundational classes come first, started together or in rapid sequence and titrated toward target doses. Add-on drugs are chosen afterward according to the phenotype that remains. More than one add-on drug can apply: a self-identified Black patient in NYHA class III with a resting rate of 80/min who was recently readmitted meets the criteria for all three. In that situation the order follows the strength of evidence and the physiology. Hydralazine-isosorbide dinitrate carries the only mortality benefit and the strongest recommendation (Class 1). Ivabradine adds rate reduction without lowering blood pressure. Vericiguat adds the smallest relative effect and some hypotension.

The blood pressure budget. Most patients with advanced HFrEF have limited systolic pressure, and every vasodilator draws on it. The drugs' effects on blood pressure determine which add-on fits each situation:

Matching add-on drugs to the patient's blood pressure and rhythm.

Removing nonprognostic drugs first. Before an add-on drug is declined for low pressure, drugs without outcome benefit in HFrEF are reviewed: alpha blockers prescribed for prostatic symptoms (including tamsulosin), long-acting nitrates for angina that has resolved, centrally acting antihypertensives, and excess diuretic in a euvolemic patient.

Polypharmacy. A patient taking four foundational classes, a loop diuretic, a statin, an antithrombotic, and treatment for diabetes or atrial fibrillation already takes many tablets. Hydralazine-isosorbide dinitrate adds three to six tablets a day. Pill burden, cost, and adverse effects each reduce adherence to the drugs with the largest benefit. Pharmacist-led medication review, combination tablets, and synchronized refills are used to limit that burden. In older adults, orthostatic pressure, cognition, falls, and kidney function guide how far the regimen is extended.

Stopping, holding, and reassessing add-on drugs

Add-on drugs, like the foundational classes, are continued indefinitely while they are tolerated and the indication persists.

Indications to hold or stop add-on drugs, from the prescribing information and the trial protocols.

Improved ejection fraction. When LVEF recovers above 40% (heart failure with improved ejection fraction), foundational GDMT is continued, because withdrawal led to relapse in TRED-HF; the evidence is reviewed on the HFrEF page. No trial has tested withdrawal of an add-on drug after recovery. Ivabradine and vericiguat were studied in reduced ejection fraction, and their continuation after recovery is an individual decision weighed against pill burden and cost.

Advanced heart failure. Persistent NYHA class III to IV symptoms, recurrent hospitalization, intolerance of GDMT because of hypotension or kidney dysfunction, and NT-proBNP in the highest VICTORIA quartile are markers of advanced disease. They lead to referral for evaluation for mechanical circulatory support or transplantation, not to the addition of more drugs. Inotropes in advanced and acute heart failure are discussed on the cardiogenic shock page.

Special populations: pregnancy, older adults, kidney disease, and liver disease

Add-on drugs in special populations, from the US prescribing information. HFrEF in pregnancy and peripartum cardiomyopathy are covered on the HFrEF page.

Women. Women made up about one-quarter of VICTORIA and VICTOR participants and 40% of A-HeFT participants. Subgroup results were consistent with the overall trials, but the smaller numbers widen the uncertainty.

Patients with cardiac devices. Ivabradine is ineffective when the rate is driven by a pacemaker set at 60/min or more. SHIFT included few patients with an implantable cardioverter-defibrillator (3.2%) or a resynchronization device (1.1%).

Agents tested in HFrEF that showed no benefit or caused harm

Many drugs improved hemodynamics or surrogate markers in HFrEF and then failed or caused harm in outcome trials. Positive inotropes improve hemodynamics in the short term and increase mortality in the long term, as oral milrinone did in PROMISE and vesnarinone did in VEST. Vasodilators have mixed results: prazosin did not improve survival in V-HeFT I, whereas hydralazine with isosorbide dinitrate reduced mortality in V-HeFT I and A-HeFT.

Agents without benefit in HFrEF. Classes from the 2022 AHA/ACC/HFSA guideline. Drugs that cause or worsen heart failure (nonsteroidal anti-inflammatory drugs, thiazolidinediones, saxagliptin and alogliptin, class IC antiarrhythmics, dronedarone) are listed on the HFrEF page.

Coenzyme Q10 is widely used. In Q-SYMBIO, the largest randomized trial of the supplement, NYHA class did not change at 16 weeks, but major adverse cardiovascular events at 2 years were lower (HR 0.50). Slow recruitment and the small size of the trial limit confidence in that result, and the 2022 guideline does not recommend supplements beyond correction of deficiency.

Cost, access, and cost-effectiveness of add-on drugs

Cost shapes the use of add-on drugs in the United States. The 2022 guideline incorporated value statements for the first time and judged hydralazine-isosorbide dinitrate in self-identified African American patients to provide high economic value. In A-HeFT, the combination increased survival and reduced health care costs during the trial, and lifetime models found a cost per life-year below $60,000.

For ivabradine, a US Markov model based on SHIFT and claims data found the drug cost-saving in a commercially insured population over 10 years and an incremental cost-effectiveness ratio of $24,920 per quality-adjusted life-year in a Medicare Advantage population. That analysis predated generic ivabradine, which is marketed in the United States. For vericiguat, the economic analysis of VICTORIA estimated $66,509 per quality-adjusted life-year when the observed difference in benefit by NT-proBNP level was modeled and $124,512 when it was not, which meets criteria for intermediate value. Vericiguat is available only as a branded product.

Generic fixed-dose isosorbide dinitrate-hydralazine tablets have been approved, and the separate generic components are inexpensive, although they require more tablets and more frequent dosing. The 2024 ACC ECDP recommends lowering patients' costs through generic drugs where possible, patient assistance programs, pharmacy price matching, and prompt completion of prior authorizations. The multidisciplinary team shares that work. Out-of-pocket cost is assessed before an add-on drug is prescribed, because a drug that is not filled has no effect and may displace a foundational drug the patient can no longer afford.

How European guidance differs

The 2021 European Society of Cardiology (ESC) heart failure guideline, unchanged on these drugs by its 2023 focused update, gives ivabradine Class IIa (Level B). The recommendation applies to LVEF 35% or less in sinus rhythm at 70/min or more despite an evidence-based or maximally tolerated beta blocker dose, ACE inhibitor or ARNI, and MRA. Unlike the US guideline, it also gives Class IIa (Level C) to ivabradine in patients who cannot tolerate or have contraindications to a beta blocker. Hydralazine-isosorbide dinitrate is Class IIa (Level B) in self-identified Black patients with LVEF 35% or less, or below 45% with a dilated ventricle, in NYHA class III to IV. That is one class lower than the US Class 1. It is Class IIb (Level B) when ACE inhibitors, ARBs, and ARNIs cannot be tolerated. Vericiguat is Class IIb (Level B) in NYHA class II to IV after worsening heart failure, matching the US recommendation. The fixed-dose combination is not authorized in most European countries.

Sources of error in prescribing add-on heart failure drugs

• Ivabradine started before the beta blocker is titrated: the beta blocker reduces mortality, and ivabradine is added for the rate that remains at the maximally tolerated dose.
• Ivabradine prescribed in atrial fibrillation or atrial flutter: it acts only on sinus node automaticity and does not slow the ventricular rate.
• Heart rate taken from a single clinic reading after walking in: eligibility and titration use the resting rate, preferably on the electrocardiogram.
• Clarithromycin, an azole antifungal, diltiazem, or verapamil given to a patient taking ivabradine: strong CYP3A4 inhibitors are contraindicated and moderate inhibitors are avoided.
• Ivabradine titrated above 7.5 mg twice daily: higher doses were used in SIGNIFY, increased bradycardia, and gave no outcome benefit.
• Vericiguat prescribed to a stable patient without a recent worsening event: VICTOR did not show benefit in that population, and the indication requires a hospitalization or outpatient intravenous diuretic.
• Vericiguat started during acute decompensation or at systolic pressure below 100 mm Hg: VICTORIA enrolled stabilized patients and excluded lower pressures.
• Vericiguat given with riociguat, or a phosphodiesterase-5 inhibitor given with hydralazine-isosorbide dinitrate: both combinations are contraindicated because of hypotension.
• Vericiguat or ivabradine prescribed to a woman of reproductive potential without a contraception plan: both cause fetal harm in animal studies, and vericiguat requires a negative pregnancy test.
• Hydralazine-isosorbide dinitrate left at one tablet three times daily: A-HeFT titrated to two tablets three times daily, and the benefit was seen at doses higher than those usually reached in practice.
• Hydralazine-isosorbide dinitrate used in place of an ARNI, ACE inhibitor, or ARB in a patient who can take one: the combination is added to, not substituted for, renin-angiotensin inhibition except when that class cannot be used.
• Nitrate headache treated by stopping the drug: headache usually diminishes over weeks, and a temporary dose reduction preserves the regimen.
• Omecamtiv mecarbil described as an available option: it is not approved in the United States and is available only in trials.
• Additional drugs added for a patient with hypotension, rising creatinine, and recurrent admissions: these are markers of advanced heart failure that call for referral for advanced therapies.

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