Category:Heart failure medications

A heart failure medicine is one used in the management of heart failure, the clinical syndrome that results when the heart cannot pump enough blood to meet the metabolic demands of the body or can only do so at the cost of elevated filling pressures. The category covers, by clinical use, the medicines that have been shown to reduce mortality and hospitalisation in heart failure with reduced ejection fraction (HFrEF), the medicines that improve symptoms and reduce hospitalisation in heart failure with preserved ejection fraction (HFpEF), the diuretics and venodilators used to manage congestion across the spectrum, and the inotropes and mechanical-support adjuncts of acute decompensation.

The first effective heart-failure medicine was a botanical preparation that has remained in use, with refinements, for more than two centuries. In 1785 the English physician William Withering of Birmingham published An Account of the Foxglove, and Some of its Medical Uses, the result of a decade of careful observation in patients with dropsy (the clinical syndrome of fluid retention now recognised as congestive heart failure).^[1] Withering had been shown the foxglove (Digitalis purpurea) tea by a Shropshire countrywoman who had had clinical success with it, identified the leaf as the active part, established a dose-response, and characterised the cardiac glycoside toxicity (visual disturbance, nausea, bradycardia, arrhythmia) that has remained essentially as he described it. Digoxin, isolated from Digitalis lanata by Sydney Smith in 1930, retains some place in heart-failure management for symptomatic rate control in atrial fibrillation but, after the Digitalis Investigation Group trial of 1997 showed no mortality benefit of routine digoxin in HFrEF, has retreated from first-line maintenance use.^[2]

The transformative event of modern heart-failure pharmacology was the demonstration that the angiotensin-converting enzyme inhibitor enalapril reduced mortality in severe heart failure. The 1987 CONSENSUS trial of enalapril versus placebo in patients with NYHA class IV symptoms was stopped early after the active arm showed a 40 percent reduction in six-month mortality.^[3] The SOLVD trials in 1991 extended the benefit to milder disease. The angiotensin receptor blockers showed similar benefit a decade later in the ELITE-II and Val-HeFT trials. The beta-blocker story was more counterintuitive: it had been clinical doctrine for forty years that the negative inotropic effect of a beta-blocker would worsen the failing heart, and the demonstration that low-dose carvedilol (US Carvedilol Trials), bisoprolol (CIBIS-II), and metoprolol succinate extended-release (MERIT-HF) all reduced HFrEF mortality by approximately 35 percent in the late 1990s overturned that doctrine. The mineralocorticoid receptor antagonist spironolactone followed in the RALES trial (1999) and the more selective eplerenone in EPHESUS (2003) and EMPHASIS-HF (2011).

The first decade of the twenty-first century established a four-medicine standard for HFrEF: ACE inhibitor or ARB, beta-blocker, mineralocorticoid antagonist, and loop diuretic for congestion. The 2014 PARADIGM-HF trial of sacubitril/valsartan versus enalapril added a fifth class. Sacubitril/valsartan, the first angiotensin receptor / neprilysin inhibitor (ARNI), combined an ARB with a neprilysin inhibitor that increases circulating natriuretic peptides by blocking their degradation; the trial was stopped early for a 20 percent mortality reduction over enalapril alone.^[4] Sacubitril/valsartan has now replaced ACE inhibitor or ARB monotherapy as the standard initial blocker of the renin-angiotensin axis in HFrEF.

The most recent and most surprising addition is the sodium-glucose cotransporter-2 inhibitor class. Originally developed as antihyperglycemic medicines for type-2 diabetes, the SGLT2 inhibitors were tested in heart failure on a mechanistic rationale that combined modest natriuresis, glucose-energetics modulation, and an unexplained but reproducible cardiovascular signal in the EMPA-REG OUTCOME diabetes trial. The DAPA-HF (2019), EMPEROR-Reduced (2020), and EMPEROR-Preserved (2021) trials demonstrated that dapagliflozin and empagliflozin reduced heart-failure hospitalisation and cardiovascular mortality across the full ejection-fraction spectrum, in patients with and without diabetes.^[5] The contemporary guidelines therefore prescribe a quadruple therapy for HFrEF: an ARNI (or ACE inhibitor or ARB), a beta-blocker, a mineralocorticoid antagonist, and an SGLT2 inhibitor, with loop diuretics for congestion.

Heart failure with preserved ejection fraction (HFpEF), which accounts for approximately half of contemporary heart-failure presentations, had been a therapeutic disappointment for two decades: no medicine had shown clear mortality or hospitalisation benefit in the I-PRESERVE (irbesartan), TOPCAT (spironolactone), and other early HFpEF trials. The 2021 EMPEROR-Preserved and 2022 DELIVER trials of empagliflozin and dapagliflozin in HFpEF showed modest but clinically meaningful benefit, the first medicine class to do so in this phenotype. Sacubitril/valsartan in PARAGON-HF in 2019 showed a near-miss benefit that may be real in the lower-EF range of preserved-EF heart failure. The treatment of HFpEF therefore now consists of an SGLT2 inhibitor for all eligible patients, with consideration of ARNI in lower-range preserved EF, diuretics for congestion, and aggressive management of comorbid hypertension, atrial fibrillation, sleep apnea, and obesity (where the recent STEP-HFpEF trial of semaglutide showed substantial functional benefit).

The acute decompensation pharmacopoeia is a separate sub-category. Intravenous loop diuretics (furosemide, bumetanide, torsemide) for congestion; intravenous vasodilators (nitroglycerin, nitroprusside, nesiritide) for pulmonary congestion and afterload; and intravenous inotropes (dobutamine, milrinone, levosimendan in Europe) for low cardiac output dominate the inpatient management of cardiogenic shock and severe decompensation. Mechanical circulatory support (intra-aortic balloon pump, percutaneous left ventricular assist devices Impella and TandemHeart, venoarterial extracorporeal membrane oxygenation, durable LVADs as destination therapy or bridge to transplantation) extends the field beyond pharmacology.

By the contemporary HFrEF "four pillars":

• Renin-angiotensin-aldosterone system blockers:
  • Angiotensin receptor / neprilysin inhibitor (ARNI): sacubitril/valsartan (Entresto)
  • ACE inhibitors: enalapril, lisinopril, ramipril, benazepril, captopril, quinapril, perindopril
  • Angiotensin receptor blockers (for ACE inhibitor intolerance): losartan, valsartan, candesartan
  • Aldosterone antagonists: spironolactone, eplerenone
• Beta-blockers (the three demonstrated to reduce HFrEF mortality):
  • Carvedilol, bisoprolol, metoprolol succinate extended-release
• SGLT2 inhibitors (the fourth pillar, also indexed under SGLT2 inhibitors):
  • dapagliflozin, empagliflozin (the two with the HFrEF and HFpEF outcome data)
• Loop diuretics (symptom management, not mortality benefit):
  • furosemide, bumetanide, torsemide
• Vasodilator combinations (for ACE-intolerant or specific populations):
  • Hydralazine + isosorbide dinitrate (BiDil, approved in 2005 for self-identified Black patients with HFrEF, the first racially defined medicine approval)
• Sinus-node rate control (in selected patients): ivabradine (SHIFT trial 2010)
• Soluble guanylate cyclase stimulator: vericiguat (VICTORIA trial 2020, for HFrEF after a worsening event)
• Inotropes (acute or bridging): dobutamine, milrinone, levosimendan, digoxin
• Cardiac myosin activator (in trial / select use): omecamtiv mecarbil (GALACTIC-HF, 2020, did not meet primary endpoint)

The boundary of this category is "medicine used in the chronic or acute management of heart failure." The antihypertensive medicines that are also heart-failure medicines (the ACE inhibitors, ARBs, beta-blockers, MRAs, loop diuretics, SGLT2 inhibitors) are cross-listed; their primary classification is by mechanism but their HF indication is collected here. The antiarrhythmics used to manage atrial fibrillation in heart-failure patients are listed under antiarrhythmics rather than here. Cardiac amyloidosis (tafamidis, patisiran, vutrisiran, transthyretin gene-silencing agents) and amyloid-cardiomyopathy treatments are listed under their specific indication. Procedural treatments (cardiac resynchronisation therapy, implantable cardioverter-defibrillator, transcatheter mitral valve repair MitraClip, left ventricular assist devices, cardiac transplantation) are device-based and are referenced on the medicine pages but are not collected here.

This category page is an encyclopedia article about its subject. The actual index of medicines belonging to the category is generated automatically by the wiki engine, from category-membership declarations on the individual medicine pages, and appears at the foot of the page below the references.