Antihypertensive Drugs

Heart failure with reduced ejection fraction (left ventricular ejection fraction at or below 40 percent) is managed with four pillars of guideline-directed medical therapy, each with proven mortality benefit and each contributing antihypertensive effect as an added property.

Pillar 1 — Angiotensin pathway inhibition: Sacubitril-valsartan is preferred — the PARADIGM-HF trial demonstrated superiority over enalapril with 20 percent reduction in cardiovascular mortality and heart failure hospitalization. An angiotensin converting enzyme inhibitor or angiotensin receptor blocker is used when sacubitril-valsartan is not tolerated or affordable. Critical rule: sacubitril-valsartan must never be combined with an angiotensin converting enzyme inhibitor; a 36-hour washout from any angiotensin converting enzyme inhibitor is required before initiation to prevent angioedema.

Pillar 2 — Beta-blocker: Three agents have proven mortality benefit in heart failure with reduced ejection fraction. Carvedilol (COPERNICUS: 35 percent mortality reduction in severe heart failure with reduced ejection fraction), metoprolol succinate (MERIT-HF: 34 percent mortality reduction), and bisoprolol (CIBIS-II: 34 percent mortality reduction). Must be started at lowest dose when stable and uptitrated slowly — never initiated during acute decompensation.

Pillar 3 — Mineralocorticoid receptor antagonist: Spironolactone (RALES trial: 30 percent mortality reduction) or eplerenone (EMPHASIS-HF: 37 percent reduction in cardiovascular mortality and heart failure hospitalization in mild heart failure with reduced ejection fraction). Indicated when ejection fraction is at or below 35 percent already on pillar 1 and pillar 2 therapy. Contraindicated when potassium is above 5.0 mEq/L, creatinine above 2.5 mg/dL in men or above 2.0 mg/dL in women, or estimated glomerular filtration rate below 30 mL/min.

Pillar 4 — SGLT2 inhibitor: Dapagliflozin (DAPA-HF: 26 percent reduction in composite of cardiovascular death, heart failure hospitalization, or urgent heart failure visit regardless of diabetes status) and empagliflozin (EMPEROR-Reduced) are Class I guideline-directed medical therapy. Provide a modest additional antihypertensive effect of 3 to 5 millimeters of mercury systolic.

Non-dihydropyridine calcium channel blockers (verapamil, diltiazem) are absolutely contraindicated in heart failure with reduced ejection fraction — their negative inotropy worsens systolic function and outcomes. Dihydropyridine calcium channel blockers — specifically amlodipine — are safe in heart failure with reduced ejection fraction: the PRAISE trials demonstrated amlodipine does not worsen heart failure outcomes, and it is the only calcium channel blocker that can safely be added to guideline-directed medical therapy when additional blood pressure control is needed.

Heart failure with preserved ejection fraction (ejection fraction at or above 50 percent with heart failure symptoms) is predominantly driven by hypertension — pressure overload causing concentric left ventricular hypertrophy, myocardial fibrosis, and diastolic dysfunction. Effective blood pressure control to below 130/80 millimeters of mercury is the most powerful intervention. Unlike heart failure with reduced ejection fraction, heart failure with preserved ejection fraction lacks robust evidence for specific mortality-reducing drug classes. Renin-angiotensin-aldosterone system inhibitors are recommended for blood pressure control and left ventricular hypertrophy regression. Finerenone (FINEARTS-HF trial, 2024) showed significant benefit and is emerging as a preferred mineralocorticoid receptor antagonist. SGLT2 inhibitors (EMPEROR-Preserved, DELIVER) significantly reduced cardiovascular death and heart failure hospitalization and are now Class I or IIa guideline-directed medical therapy for heart failure with preserved ejection fraction regardless of diabetes status. Loop and thiazide diuretics provide essential symptomatic volume management.

Hypertension is the most common modifiable risk factor for atrial fibrillation, driving left ventricular hypertrophy, left atrial enlargement, interstitial fibrosis, and renin-angiotensin-aldosterone system activation — the structural and electrical substrate for atrial fibrillation. Approximately 60 to 80 percent of patients with atrial fibrillation have hypertension as a comorbidity.

For rate control, beta-blockers (metoprolol, bisoprolol, carvedilol) are first-line in most patients — they provide both rate control and antihypertensive benefit, and carvedilol serves dual roles as rate control agent and guideline-directed medical therapy when heart failure with reduced ejection fraction coexists. Non-dihydropyridine calcium channel blockers (diltiazem, verapamil) provide effective rate control through atrioventricular nodal slowing and antihypertensive benefit — but are absolutely contraindicated when heart failure with reduced ejection fraction is present. Must not be combined with beta-blockers due to additive atrioventricular block and bradycardia risk. Diltiazem is generally preferred over verapamil for fewer drug interactions and less constipation.

For upstream atrial fibrillation prevention, renin-angiotensin-aldosterone system inhibitors reduce risk of new-onset and recurrent atrial fibrillation by preventing atrial fibrosis through angiotensin II-mediated transforming growth factor beta inhibition and reducing left atrial size. The LIFE trial demonstrated losartan significantly reduced new-onset atrial fibrillation compared with atenolol in hypertensive left ventricular hypertrophy patients. For antithrombotic therapy, the CHA₂DS₂-VASc score guides anticoagulation; hypertension adds one point. Target systolic below 130 millimeters of mercury in patients with atrial fibrillation on anticoagulation to reduce intracranial hemorrhage risk.

In acute aortic dissection, simultaneously reduce blood pressure and heart rate to reduce the rate of aortic wall pressure rise (dP/dt). Beta-blockade first (intravenous esmolol or labetalol; target heart rate below 60 beats per minute) — vasodilators are added only after heart rate is controlled because vasodilation without rate control causes reflex tachycardia that increases dP/dt and propagates the dissection. Targets: systolic blood pressure 100 to 120 millimeters of mercury as rapidly as safely possible. For chronic post-dissection management, target systolic below 120 to 130 millimeters of mercury using beta-blockers as preferred agents, with angiotensin converting enzyme inhibitors or angiotensin receptor blockers for additional aortic wall protection. In Marfan syndrome, losartan has evidence for slowing aortic root dilation through inhibition of angiotensin II-mediated transforming growth factor beta signaling and is used alongside beta-blockers.

In peripheral arterial disease, renin-angiotensin-aldosterone system inhibitors are the preferred antihypertensive agents — the HOPE trial enrolled significant peripheral arterial disease populations, demonstrating cardiovascular event reduction. Cardioselective beta-blockers are acceptable in peripheral arterial disease when a compelling cardiac indication exists — meta-analyses have not confirmed clinically significant worsening of claudication with cardioselective agents. The ankle-brachial index should be routinely measured; use the higher arm blood pressure for antihypertensive monitoring when significant peripheral arterial disease is present.