ACE inhibitors competitively inhibit angiotensin-converting enzyme (ACE, also known as kininase II), blocking the conversion of angiotensin I (Ang I) to angiotensin II (Ang II).² The consequences of reduced Ang II signaling in HF are hemodynamic, neurohormonal, and structural: (1) arterial vasodilation reduces systemic vascular resistance (SVR), lowering afterload and improving forward stroke volume; (2) reduced aldosterone secretion decreases renal sodium retention and potassium wasting, reducing preload; (3) direct inhibition of Ang II-mediated cardiomyocyte hypertrophy, fibroblast activation, and myocardial apoptosis attenuates adverse remodeling; (4) improved endothelial function through reduced superoxide generation; and (5) reduced sympathetic nervous system activation, since Ang II normally amplifies catecholamine release from the adrenal medulla and sympathetic nerve terminals.² ACE is also kininase II, meaning its inhibition simultaneously reduces bradykinin degradation. Elevated bradykinin contributes to vasodilation (through endothelial nitric oxide and prostacyclin release) and is responsible for the class-effect dry cough (and the rare but serious adverse effect of angioedema) seen with ACE inhibitors.²

Multiple ACE inhibitors have been studied in HF, but only a subset have demonstrated mortality benefit in randomized trials. The most important agents are: Enalapril: The best-studied ACE inhibitor in HF. Starting dose 2.5 mg twice daily; target dose 10–20 mg twice daily. Evidence from CONSENSUS (severe HF, NYHA class IV) and SOLVD-Treatment (mild-to-moderate HFrEF).¹·³ Prodrug activated by hepatic hydrolysis. Lisinopril: Active drug (not a prodrug); commonly used due to once-daily dosing and wide availability. Starting dose 2.5–5 mg daily; target dose 20–40 mg daily. Evidence in post-MI LV dysfunction (ATLAS trial confirming high-dose superiority).⁴ Captopril: Short-acting, three-times-daily dosing limits adherence; used in SAVE trial (post-MI LV dysfunction). Starting dose 6.25 mg three times daily; target 50 mg three times daily. Clinically reserved for situations requiring short-acting RAAS blockade (e.g., initial titration in severe hypotension).² Ramipril: Once-daily dosing, widely used. Starting dose 1.25–2.5 mg daily; target 5 mg twice daily or 10 mg daily. The principle that higher ACE inhibitor doses are superior to lower doses within the therapeutic range was confirmed in the ATLAS trial (high-dose lisinopril 32.5–35 mg/day vs. low-dose 2.5–5 mg/day), which showed significant reductions in hospitalization and a trend toward mortality reduction with higher doses.⁴ Clinicians should titrate to the highest tolerated dose, not merely the lowest effective dose.

CONSENSUS (1987): 253 patients with NYHA class IV HF randomized to enalapril vs. placebo. Enalapril reduced all-cause mortality at 6 months by 40% (p=0.002) and by 31% at study end.¹ The trial was stopped early due to the magnitude of benefit. This was the first randomized controlled trial to demonstrate mortality benefit for any drug in HF. SOLVD-Treatment (1991): 2,569 patients with symptomatic HFrEF (left ventricular ejection fraction (LVEF) ≤35%) randomized to enalapril vs. placebo. Enalapril reduced all-cause mortality by 16% (p=0.0036) and reduced HF hospitalization by 26%.³ The SOLVD-Prevention arm additionally showed that enalapril reduced the progression from asymptomatic LV dysfunction to symptomatic HF. V-HeFT II (1991): Compared enalapril to the hydralazine/isosorbide dinitrate combination in HFrEF, demonstrating that enalapril produced a more sustained mortality reduction at 2 years (18% reduction with enalapril vs. 25% all-cause mortality with H/ISDN), though H/ISDN produced greater improvements in exercise capacity.⁵

Initiation: Start at the lowest available dose, particularly in patients with hypotension (systolic blood pressure (SBP) 90–100 mmHg), hyponatremia (Na⁺ <130 mEq/L), or impaired renal function (creatinine >2.5 mg/dL; eGFR <30 mL/min/1.73m²). These features predict a high likelihood of first-dose hypotension and worsening renal function. Patients should ideally be euvolemic before initiation; aggressive diuresis can activate the RAAS and predispose to first-dose hypotension. Check baseline electrolytes, renal function, and blood pressure before starting.² Titration: Double the dose every 2 weeks as tolerated, targeting the evidence-based dose. Check electrolytes and creatinine 1–2 weeks after each dose increase and at 3 months after reaching the target dose. Acceptable creatinine rise: A rise in creatinine of up to 30–35% above baseline (or absolute creatinine ≤3.0 mg/dL) upon ACE inhibitor initiation reflects reduced intraglomerular pressure and is expected, not an indication to stop therapy. This "creatinine bump" actually indicates effective RAAS blockade and correlates with renoprotection in the long term.² Creatinine that rises >50% above baseline, or is accompanied by hyperkalemia or symptomatic hypotension, warrants dose reduction or temporary hold and investigation for bilateral renal artery stenosis.

Absolute contraindications: Prior ACE inhibitor-associated angioedema, bilateral renal artery stenosis (or stenosis of a solitary functioning kidney), pregnancy (all trimesters: teratogenic; specifically causes oligohydramnios, renal tubular dysgenesis, and neonatal renal failure in the second and third trimesters), and known hypersensitivity. Hyperkalemia: The most clinically important metabolic complication, arising from aldosterone suppression and reduced urinary potassium excretion. Risk is amplified in CKD, diabetes, and with concurrent MRA or potassium supplementation. Potassium >5.5 mEq/L at baseline is a relative contraindication; the drug should be stopped if potassium exceeds 6.0 mEq/L on therapy. Cough: A class-effect, non-dose-dependent dry cough occurring in 5–20% of patients (more common in women and patients of East Asian ancestry due to altered bradykinin metabolism). This is the primary indication to switch from an ACE inhibitor to an ARB. Cough is not a contraindication to ARNI (sacubitril/valsartan), but a prior history of ACE inhibitor-associated angioedema is. Angioedema: Rare (<1%) but potentially life-threatening. Involves bradykinin-mediated vasodilation of deep dermis and submucosa (not mast-cell/IgE mediated). Most commonly affects the face, lips, tongue, and larynx. Requires immediate drug discontinuation; may not fully resolve for days due to bradykinin kinetics. Patients with a history of ACE inhibitor angioedema must not receive another ACEi, and should wait at least 36 hours before initiating sacubitril/valsartan (ARNI), as both raise bradykinin levels.

Sacubitril/valsartan (brand name Entresto) is a single oral tablet combining sacubitril (a neprilysin inhibitor prodrug, activated to LBQ657 (active metabolite of sacubitril)) with valsartan (an ARB) in a 1:1 molar ratio.² The drug simultaneously: (1) inhibits neprilysin, the primary enzyme responsible for degrading natriuretic peptides (atrial natriuretic peptide (ANP), BNP, C-type natriuretic peptide (CNP)), bradykinin, and adrenomedullin: thereby amplifying the beneficial effects of endogenous natriuretic peptides: natriuresis, vasodilation, anti-fibrosis, anti-hypertrophy, and inhibition of RAAS/sympathetic nervous system (SNS) activity; and (2) blocks the AT1 receptor (through valsartan), preventing Ang II-mediated vasoconstriction, fibrosis, and aldosterone release. Neprilysin inhibition alone would dangerously raise Ang II levels (since neprilysin also degrades Ang II); the concurrent AT1 receptor blockade by valsartan counters this effect.² The net result is simultaneous amplification of counter-regulatory (natriuretic peptide) mechanisms and suppression of maladaptive (Ang II/aldosterone) neurohormonal activation: a more complete neurohormonal rebalancing than ACEi or ARB alone. An important biomarker implication: because sacubitril inhibits BNP degradation, plasma BNP levels rise during ARNI therapy. NT-proBNP is not a neprilysin substrate and remains a reliable biomarker of HF severity in patients on sacubitril/valsartan; BNP levels should not be used to assess congestion or treatment response in these patients.²

The PARADIGM-HF trial (2014) was the pivotal randomized controlled trial comparing sacubitril/valsartan to enalapril in 8,442 patients with HFrEF (LVEF ≤40%, symptomatic despite background therapy, NYHA class II–IV).² Key findings: sacubitril/valsartan reduced the primary composite endpoint of cardiovascular death or HF hospitalization by 20% (HR 0.80; 95% CI 0.73–0.87; p<0.001). All-cause mortality was reduced by 16%. Cardiovascular mortality was reduced by 20%. HF hospitalization was reduced by 21%. Sudden cardiac death was reduced by 20%.² The trial was stopped early by the data safety monitoring board because the magnitude of benefit exceeded the prespecified stopping boundary. Quality-of-life scores were also significantly improved. The number needed to treat (NNT) to prevent one cardiovascular death or HF hospitalization over 27 months was approximately 21. Of clinical importance, PARADIGM-HF used a run-in period during which all patients received both enalapril and sacubitril/valsartan sequentially to ensure tolerability before randomization: meaning the enrolled population was selected for tolerability of both drugs, and the absolute benefits may be even greater in unselected patients.

PIONEER-HF trial (2019): 881 patients hospitalized for acute decompensated HFrEF randomized to sacubitril/valsartan vs. enalapril in-hospital, prior to discharge. Sacubitril/valsartan produced a greater reduction in NT-proBNP at 8 weeks (NT-proBNP decreased 46.7% vs. 25.3%; ratio of change 0.71, 95% CI 0.63–0.81) with no significant difference in adverse events (worsening renal function, hyperkalemia, symptomatic hypotension, angioedema).⁸ This trial established that in-hospital initiation of ARNI is safe and effective, accelerating decongestion. PARADIGM-HF subgroup analyses demonstrated consistent benefit across LVEF subgroups (down to LVEF ≤40%), diabetes status, race, age, etiology of HF, and background beta-blocker use. The relative risk reduction was proportionally larger in women. Current guidelines (2022 AHA/ACC/HFSA) give sacubitril/valsartan a Class I recommendation as the preferred RAAS-blocking agent for HFrEF patients (LVEF ≤40%) who can tolerate it.² In patients already on an ACEi or ARB, switching to sacubitril/valsartan is recommended to reduce mortality further.

Starting doses are weight- and blood-pressure-stratified. Standard starting dose: sacubitril/valsartan 49/51 mg (commonly labeled as 50 mg) twice daily, or 24/26 mg (labeled 25 mg) twice daily in patients with SBP <100 mmHg, eGFR <30, hepatic impairment (Child-Pugh B), or who were not previously on RAAS blockade. Target dose: 97/103 mg (labeled 100 mg) twice daily. Titration is recommended every 2–4 weeks as tolerated, doubling the dose at each step. Prior to switching from an ACEi to sacubitril/valsartan, a 36-hour washout of the ACEi is mandatory to reduce the risk of angioedema from combined bradykinin elevation.² If switching from an ARB, no washout is required.

Contraindications: History of ACE inhibitor-associated or ARNI-associated angioedema, concomitant ACEi use (or within 36 hours), bilateral renal artery stenosis, pregnancy. Sacubitril/valsartan contains valsartan and must not be combined with another ARB or ACEi. Hypotension: The most common adverse effect requiring dose adjustment; occurs in approximately 18% of patients in PARADIGM-HF (vs. 12% with enalapril). In many cases, this is a BP of 90–100 mmHg without symptoms and can be managed by reducing background diuretic dose, ensuring euvolemia, and adjusting dosing timing. Symptomatic hypotension requires dose reduction or temporary hold. Hyperkalemia: As with ACEi/ARBs, aldosterone suppression reduces urinary potassium excretion. Risk management is identical: monitor closely in patients with CKD, diabetes, or concurrent MRA use. Renal impairment: A modest creatinine rise (up to 30%) is acceptable and expected, as with ACEi/ARBs. Sacubitril/valsartan can be used with eGFR as low as 25–30 mL/min/1.73m²; dose reduction is recommended but not mandatory at lower eGFR values. Both sacubitril and valsartan are extensively protein-bound and not significantly dialyzed. Cough: Less common than with ACEi (approximately 5% vs. 15–20%), since valsartan does not raise bradykinin. Where cough occurs on ACEi and prompts a switch to an ARB, the patient can instead be switched directly to sacubitril/valsartan. Angioedema: Risk is elevated compared to ARBs alone because sacubitril inhibits bradykinin degradation (via neprilysin). The combination of neprilysin inhibition + AT1 receptor blockade in the ARNI does not raise bradykinin as high as ACEi + neprilysin inhibition would, but the risk is not zero. Angioedema history from ACEi or ARNI is an absolute contraindication.