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ACE inhibitors, angiotensin receptor blockers, and sacubitril/valsartan

Drugs that act on the renin-angiotensin system and neprilysin, from physiology and pharmacology through the heart failure, coronary, hypertension, and kidney trials, dosing and switching, monitoring of creatinine and potassium, angioedema and other adverse effects, and special populations.

The renin-angiotensin-aldosterone and natriuretic peptide systems as drug targets

Renin is an aspartyl protease stored in and secreted by the juxtaglomerular cells of the afferent arteriole. Its release is the rate-limiting step of the cascade and responds to three signals: a fall in renal perfusion pressure sensed by the afferent arteriolar baroreceptor, reduced sodium chloride delivery to the macula densa, and β₁-adrenergic stimulation. Angiotensin II feeds back to suppress renin release, so every drug that blocks angiotensin II formation or action raises plasma renin activity, a property used in the interpretation of the aldosterone-to-renin ratio. Renin cleaves angiotensinogen, a glycoprotein made in the liver, to the decapeptide angiotensin I, which has little intrinsic activity.

Angiotensin-converting enzyme, a zinc-dependent dipeptidyl carboxypeptidase on the luminal surface of vascular endothelium and most abundant in the pulmonary circulation, removes two C-terminal amino acids to form the octapeptide angiotensin II. The same enzyme, also called kininase II, inactivates bradykinin and substance P. ACE inhibition therefore has two effects: less angiotensin II and more bradykinin. Bradykinin acts on endothelial B₂ receptors to release nitric oxide and prostacyclin, which contribute to vasodilation and possibly to the anti-remodeling effect of ACE inhibitors. It is also responsible for the cough and the angioedema that distinguish ACE inhibitors from ARBs.

Angiotensin II acts through two G protein-coupled receptors. The AT₁ receptor mediates almost all of its recognized cardiovascular actions: arteriolar vasoconstriction, constriction of the glomerular efferent arteriole, aldosterone release from the zona glomerulosa, proximal tubular sodium reabsorption, vasopressin release and thirst, facilitation of sympathetic transmission, and cardiomyocyte hypertrophy, fibroblast proliferation, and collagen deposition. The AT₂ receptor is expressed in fetal tissue and, in adults, in injured myocardium and vasculature; its actions oppose those of AT₁, with vasodilation and antiproliferative effects. Angiotensin-converting enzyme 2 converts angiotensin II to angiotensin-(1–7), which acts on the Mas receptor and also opposes AT₁ signaling.

Aldosterone is released in response to angiotensin II and to a rise in serum potassium. It binds the mineralocorticoid receptor in the principal cells of the collecting duct, increasing the activity of the epithelial sodium channel and the basolateral sodium-potassium ATPase. Sodium is reabsorbed, and the lumen-negative potential drives potassium secretion. Aldosterone also promotes myocardial and vascular fibrosis, endothelial dysfunction, and magnesium loss. When angiotensin II formation falls, aldosterone secretion falls and potassium excretion falls with it, which is the mechanism of hyperkalemia with ACE inhibitors, ARBs, sacubitril/valsartan, and aliskiren.

The natriuretic peptide system is the counter-regulatory partner of the renin-angiotensin system. Atrial natriuretic peptide (ANP) is released from atrial myocytes in response to stretch, and B-type natriuretic peptide (BNP) is released mainly from ventricular myocytes in response to wall stress. Both act on natriuretic peptide receptor A, which generates cyclic guanosine monophosphate (cGMP) and produces natriuresis, vasodilation, suppression of renin and aldosterone release, and inhibition of hypertrophy and fibrosis. C-type natriuretic peptide is an endothelial and paracrine peptide. Natriuretic peptides are cleared by the clearance receptor (natriuretic peptide receptor C) and degraded by neprilysin, a membrane-bound zinc metalloendopeptidase also called neutral endopeptidase. In heart failure, natriuretic peptide concentrations are high, but their effect is blunted by receptor desensitization, enhanced degradation, and the opposing activation of the renin-angiotensin and sympathetic systems.

Neprilysin has many substrates. Besides ANP, BNP, and C-type natriuretic peptide, it degrades bradykinin, substance P, adrenomedullin, glucagon-like peptide 1, endothelin-1, and angiotensin I and II. Inhibiting neprilysin alone therefore raises vasodilator and vasoconstrictor peptides together: the rise in angiotensin II and endothelin offsets the natriuretic peptide effect, and neprilysin inhibitors given alone did not lower blood pressure reliably. Combination with AT₁ receptor blockade removes the angiotensin II component and leaves the natriuretic, vasodilator, and antifibrotic actions. That is the pharmacologic basis of sacubitril/valsartan.

ACE escape, aldosterone breakthrough, and the rationale for blocking more than one step

Chronic ACE inhibition does not suppress angiotensin II completely. Chymase, a serine protease in cardiac and vascular mast cells and in the adventitia, converts angiotensin I to angiotensin II independently of ACE, and cathepsin G and other enzymes contribute. As renin and angiotensin I accumulate behind the block, plasma angiotensin II returns toward baseline in a proportion of patients during long-term therapy, a phenomenon described as ACE escape. ARBs act at the receptor and block angiotensin II from any source, which was the original argument that they would be superior. The outcome trials did not confirm superiority, and the bradykinin component of ACE inhibition is the likely reason the two classes are clinically equivalent.

Aldosterone breakthrough is the return of plasma aldosterone toward or above pretreatment values in a substantial minority of patients after months of ACE inhibitor or ARB therapy. Potassium, adrenocorticotropic hormone, and non-angiotensin pathways sustain aldosterone secretion. Breakthrough has been associated with greater left ventricular mass, albuminuria, and reduced exercise capacity. It provides the physiologic rationale for adding a mineralocorticoid receptor antagonist (MRA) to a renin-angiotensin inhibitor in HFrEF, resistant hypertension, and diabetic kidney disease. The rationale does not extend to combining two drugs that both act upstream of the receptor (ACE inhibitor with ARB, or either with aliskiren). Their effects on angiotensin II signaling largely overlap, while their effects on potassium and glomerular pressure add.

Hemodynamic and renal effects of renin-angiotensin inhibition

Renin-angiotensin inhibitors lower systemic vascular resistance without reflex tachycardia, because angiotensin II blockade also reduces sympathetic outflow and resets the baroreflex. Venous capacitance increases modestly, and left ventricular filling pressure falls. Cardiac output rises in patients with heart failure as afterload falls. In a patient with high circulating renin (for example, from vigorous diuresis, hyponatremia, or renovascular disease), the first dose can cause a large fall in pressure, because blood pressure in that state depends on angiotensin II.

Glomerular filtration in a kidney with reduced perfusion is maintained partly by angiotensin II-mediated constriction of the efferent arteriole, which preserves glomerular capillary pressure. Blocking it dilates the efferent arteriole and lowers intraglomerular pressure. The early fall in glomerular filtration rate (GFR) is therefore expected and hemodynamic; over years, the lower glomerular pressure reduces hyperfiltration injury and proteinuria and slows the decline of kidney function. The size of the early fall depends on the reliance of filtration on efferent tone. It is small in a euvolemic patient with normal renal perfusion. It is large with volume depletion, heart failure with low cardiac output, concurrent nonsteroidal anti-inflammatory drugs (NSAIDs), which constrict the afferent arteriole, or bilateral renal artery stenosis. In bilateral stenosis, or stenosis of the artery to a solitary kidney, glomerular filtration can collapse after the first doses, causing acute kidney injury that resolves when the drug is stopped.

Potassium rises because aldosterone secretion falls and because a lower GFR reduces distal sodium delivery and potassium secretion. The increase averages a few tenths of a milliequivalent per liter in patients with normal kidney function. It is larger in diabetes with hyporeninemic hypoaldosteronism, chronic kidney disease (CKD), and advanced age, and in patients taking an MRA, potassium supplements, salt substitutes, trimethoprim, heparin, calcineurin inhibitors, or NSAIDs.

Proteinuria falls by about 30% to 40% with ACE inhibitors and ARBs, beyond what the fall in blood pressure would predict, through the reduction in glomerular pressure and through effects on podocyte injury and glomerular permeability. In the heart, renin-angiotensin inhibition reduces left ventricular hypertrophy, interstitial fibrosis, and progressive dilatation after myocardial infarction. In SAVE, captopril limited left ventricular enlargement after infarction, and in the HFrEF trials renin-angiotensin inhibitors produced modest increases in ejection fraction and reductions in end-systolic volume that parallel their survival benefit.

ACE inhibitors: chemistry, prodrugs, and pharmacokinetics

ACE inhibitors are grouped by the chemical moiety that binds the zinc ion at the enzyme's active site. Captopril, the first oral agent, contains a sulfhydryl group, which has been linked to rash, taste disturbance, and proteinuria at high doses. Most later agents are dicarboxylates (enalapril, lisinopril, ramipril, quinapril, perindopril, benazepril, trandolapril, moexipril). Fosinopril is a phosphinate. Captopril and lisinopril are active as given. All the others are ester prodrugs hydrolyzed in the liver to the active diacid (enalaprilat, ramiprilat, and so on). The ester improves oral absorption of the otherwise poorly absorbed diacid, and the need for hepatic conversion delays the onset of action. Enalaprilat is the only intravenous formulation available in the United States.

Elimination is predominantly renal for most agents, so doses are reduced in kidney disease. Fosinopril and, to a lesser degree, trandolapril and ramipril have a meaningful hepatic or biliary component, and fosinopril needs little adjustment for kidney function. Lipophilicity and binding affinity for tissue ACE differ among agents. Claims of superiority for tissue-penetrant agents such as ramipril and perindopril have not been tested head to head in outcome trials, and the outcome benefit is regarded as a class effect at trial doses. Long elimination half-lives of the active forms reflect tight binding to ACE and allow once-daily dosing for most agents, but captopril requires two or three doses daily, and enalapril is given twice daily in heart failure.

Pharmacology and hypertension dose ranges from the US prescribing information and the dosing table of the 2025 American Heart Association/American College of Cardiology (AHA/ACC) hypertension guideline. Heart failure starting and target doses are in the dosing table below.

Angiotensin receptor blockers: pharmacology and the agents

ARBs are competitive antagonists of the AT₁ receptor with selectivity for AT₁ over AT₂ of several thousand-fold. Several (candesartan, irbesartan, olmesartan, telmisartan, valsartan, and the losartan metabolite) dissociate slowly and behave as insurmountable antagonists, which prolongs their action. Plasma angiotensin II rises during ARB therapy as feedback inhibition of renin is removed, and the excess angiotensin II is free to stimulate unblocked AT₂ receptors. ARBs do not affect bradykinin degradation.

Losartan is active but is converted by cytochrome P450 2C9 and 3A4 to EXP3174, a metabolite 10 to 40 times more potent with a longer half-life that accounts for most of its effect. Candesartan cilexetil, olmesartan medoxomil, and azilsartan medoxomil are prodrugs hydrolyzed during absorption. Telmisartan has the longest half-life of the class, about 24 hours, is eliminated almost entirely in bile, and is a partial agonist of peroxisome proliferator-activated receptor γ, a property without demonstrated clinical consequence. Valsartan has low and variable oral bioavailability, which accounts for the dose equivalence in sacubitril/valsartan. Most ARBs are eliminated mainly by the liver and bile, so dose adjustment for kidney function is rarely needed, though the hemodynamic renal effects are the same as with ACE inhibitors.

Losartan has a uricosuric effect not shared by other ARBs: it inhibits the urate transporter URAT1 in the proximal tubule and lowers serum urate modestly. The 2020 American College of Rheumatology guideline conditionally recommends losartan as the preferred antihypertensive in patients with gout when feasible and a switch from hydrochlorothiazide to another antihypertensive. The effect is small and does not replace urate-lowering therapy. The olmesartan label warns of sprue-like enteropathy with severe chronic diarrhea and weight loss, which can begin months to years after starting the drug and resolves after withdrawal.

Between 2018 and 2019, several generic valsartan, losartan, and irbesartan products were recalled in the United States after nitrosamine impurities, including N-nitrosodimethylamine, were found in the active ingredient from some manufacturers. The impurities arose from a change in the synthesis of the tetrazole ring. The recalls were a supply problem, not a property of the drug class, and the products available after remediation meet the limits of the US Food and Drug Administration (FDA) for nitrosamines.

From the US prescribing information and the hypertension guideline dosing tables. Half-lives are approximate.

Sacubitril/valsartan: neprilysin inhibition and pharmacology

The first attempt to combine neprilysin and renin-angiotensin inhibition used omapatrilat, a single molecule that inhibits both ACE and neprilysin. In OCTAVE, among 25,302 patients with hypertension, angioedema occurred in 2.17% with omapatrilat and 0.68% with enalapril, and the excess was larger in Black patients; some cases involved the airway. Inhibiting two of the three main bradykinin-degrading enzymes (ACE, neprilysin, and aminopeptidase P) produced unacceptable angioedema, and omapatrilat was not approved. Sacubitril/valsartan was designed to avoid ACE inhibition: bradykinin is still degraded by ACE, and the angiotensin II that rises with neprilysin inhibition is blocked at the AT₁ receptor.

Sacubitril/valsartan is a crystalline complex of the two anions with sodium in a 1:1 molar ratio. Sacubitril is an ethyl ester prodrug converted by esterases to the active neprilysin inhibitor LBQ657 (sacubitrilat). Peak concentrations of sacubitril, LBQ657, and valsartan occur at about 0.5, 2, and 1.5 hours, and the elimination half-lives are about 1.4, 11.5, and 9.9 hours, which supports twice-daily dosing. LBQ657 is excreted mainly in the urine and accumulates in severe kidney impairment; valsartan is excreted mainly in the feces. The valsartan in the complex is more bioavailable than valsartan in other tablets: 26, 51, and 103 mg of valsartan in sacubitril/valsartan are equivalent to 40, 80, and 160 mg of conventional valsartan. The highest dose therefore delivers valsartan equivalent to 160 mg twice daily, the target dose of Val-HeFT. The tablets are labeled by the milligrams of each component (24/26, 49/51, and 97/103 mg); the trials referred to them by the total, as 50, 100, and 200 mg.

The drug is taken with or without food. It is highly protein bound and is not removed by hemodialysis. LBQ657 inhibits the hepatic uptake transporters organic anion-transporting polypeptide (OATP) 1B1 and OATP1B3 in vitro, which modestly increases atorvastatin exposure; the clinical relevance is small. The US label includes adult heart failure and, for children 1 year and older, symptomatic heart failure with systemic left ventricular systolic dysfunction, with weight-based dosing and an oral pellet formulation. Sacubitril/valsartan is not approved for hypertension in the United States, although it lowers blood pressure more than valsartan alone and is approved for hypertension in some other countries.

Aliskiren and direct renin inhibition

Aliskiren binds the active site of renin and blocks the first step of the cascade, so plasma renin activity falls, while the concentration of renin protein rises because the feedback loop is interrupted. It is approved for hypertension at 150 mg once daily, increased to 300 mg if needed; higher doses add diarrhea without additional effect, and 85% to 90% of the effect is reached within 2 weeks. Oral bioavailability is about 2.5%, the accumulation half-life about 24 hours, and a high-fat meal reduces exposure by about 70%, so it is taken the same way relative to meals each day. Cyclosporine and itraconazole raise aliskiren concentrations through P-glycoprotein and cytochrome P450 3A4 inhibition and are avoided with it. Angioedema has been reported.

Aliskiren lowers blood pressure about as much as an ACE inhibitor or ARB, but no outcome trial has shown benefit, and two showed harm in combination. ALTITUDE randomized 8,561 patients with type 2 diabetes and CKD, cardiovascular disease, or both who were already taking an ACE inhibitor or ARB to aliskiren 300 mg or placebo. It was stopped early for futility, with more hyperkalemia and hypotension and a nonsignificant excess of stroke in the aliskiren group. The label now contraindicates aliskiren with an ACE inhibitor or ARB in patients with diabetes and recommends avoiding the combination when the estimated glomerular filtration rate (eGFR) is below 60 mL/min/1.73 m². In heart failure, ATMOSPHERE randomized 7,016 patients with HFrEF to enalapril, aliskiren, or both. The combination did not reduce cardiovascular death or heart failure hospitalization compared with enalapril and caused more hypotension, hyperkalemia, and renal dysfunction. Aliskiren alone did not meet the criterion for noninferiority to enalapril. ASTRONAUT, in patients hospitalized for HFrEF, showed no benefit of adding aliskiren after discharge. Aliskiren has no role in heart failure, and in hypertension it is a fourth-line alternative used alone.

ACE inhibitor trials in HFrEF and asymptomatic left ventricular dysfunction

ACE inhibitors were the first neurohormonal drugs shown to prolong life in heart failure. CONSENSUS randomized 253 patients with New York Heart Association (NYHA) class IV heart failure to enalapril (titrated to 20 mg twice daily) or placebo on top of diuretics and digoxin. Mortality at 6 months was 26% with enalapril and 44% with placebo, a 40% relative reduction, and the benefit was confined to deaths from progressive heart failure. SOLVD-Treatment extended the finding to 2,569 patients with left ventricular ejection fraction (LVEF) of 35% or less and mainly NYHA class II to III symptoms. Over an average of 41 months, mortality was 35.2% with enalapril and 39.7% with placebo, a 16% relative reduction, and heart failure hospitalization fell substantially. V-HeFT II showed lower mortality with enalapril than with hydralazine-isosorbide dinitrate, which established the ACE inhibitor as the standard comparator.

Asymptomatic left ventricular dysfunction (stage B). SOLVD-Prevention randomized 4,228 patients with LVEF of 35% or less and no overt heart failure. Enalapril did not significantly reduce mortality (14.8% versus 15.8%), but it reduced the combined end point of death or development of heart failure and death or heart failure hospitalization by about 20% to 30%. Extended follow-up of the SOLVD cohorts showed a survival advantage that emerged over a decade. SAVE, AIRE, and TRACE established the same principle after myocardial infarction (described below). On this evidence, the 2022 AHA/ACC/Heart Failure Society of America (HFSA) guideline recommends an ACE inhibitor in patients with LVEF of 40% or less to prevent symptomatic heart failure and reduce mortality (Class 1). It also recommends an ARB in patients with a recent myocardial infarction and LVEF of 40% or less who do not tolerate an ACE inhibitor (Class 1). Whether an ARNI is superior to an ACE inhibitor in stage B has not been established by an outcome trial outside the post-infarction setting.

Dose of lisinopril. ATLAS randomized 3,164 patients with NYHA class II to IV HFrEF to low-dose lisinopril (2.5 to 5 mg daily) or high-dose lisinopril (32.5 to 35 mg daily). High dose reduced all-cause mortality by 8%, a difference that was not statistically significant. It also reduced the combined end point of death or hospitalization for any reason by 12% and heart failure hospitalization by 24%, with only modestly more dizziness and renal dysfunction. The trial is the basis for titrating to the doses used in the outcome trials, or to the highest tolerated dose, instead of stopping at the starting dose. The same principle was later shown for ARBs in HEAAL.

ACE inhibitor trials in heart failure and left ventricular dysfunction. HF, heart failure; MI, myocardial infarction.

ARB trials in heart failure: ELITE II, Val-HeFT, CHARM, and HEAAL

ARB instead of an ACE inhibitor. ELITE II randomized 3,152 older patients with HFrEF to losartan 50 mg daily or captopril 50 mg three times daily. Mortality was 17.7% with losartan and 15.9% with captopril (hazard ratio 1.13; not significant), so losartan at that dose was not superior and not proven equivalent, though it was better tolerated. CHARM-Alternative randomized 2,028 patients with LVEF of 40% or less who did not tolerate an ACE inhibitor, mostly because of cough, to candesartan titrated to 32 mg daily or placebo. Cardiovascular death or heart failure hospitalization occurred in 33% with candesartan and 40% with placebo (hazard ratio 0.77). Prior angioedema with an ACE inhibitor did not preclude enrollment, and angioedema recurred in 3 of the 39 patients with such a history who received candesartan. These two trials define the role of the ARB: a substitute for an ACE inhibitor in patients who cannot take one, not an equal first choice.

ARB added to an ACE inhibitor. Val-HeFT randomized 5,010 patients with NYHA class II to IV HFrEF, 93% taking an ACE inhibitor, to valsartan 160 mg twice daily or placebo. Mortality did not differ (19.7% versus 19.4%), but the combined morbidity and mortality end point fell from 32.1% to 28.8% (relative risk 0.87), driven by fewer heart failure hospitalizations. In a post hoc subgroup taking both an ACE inhibitor and a beta-blocker, valsartan was associated with higher mortality, which led to caution about triple neurohormonal therapy at the time. CHARM-Added, which did not confirm this signal, randomized 2,548 patients already taking an ACE inhibitor to candesartan or placebo. Candesartan reduced cardiovascular death or heart failure hospitalization from 42.3% to 37.9% (hazard ratio 0.85), with more hypotension, hyperkalemia, and creatinine elevation. Once MRAs became standard, the ACE inhibitor-ARB combination was abandoned in HFrEF: it adds hyperkalemia risk, and the 2022 guideline gives no indication for it.

Dose of losartan. HEAAL randomized 3,846 patients with HFrEF who did not tolerate ACE inhibitors to losartan 150 mg or 50 mg daily. Death or heart failure hospitalization occurred in 43% with the high dose and 46% with the low dose (hazard ratio 0.90; P = 0.027). Renal impairment, hypotension, and hyperkalemia were more frequent with the high dose but rarely led to discontinuation. This is why the guideline target for losartan in HFrEF is 50 to 150 mg daily and why 50 mg is not regarded as a target dose.

PARADIGM-HF and replacement of ACE inhibitors by sacubitril/valsartan

PARADIGM-HF randomized 8,442 patients with NYHA class II to IV heart failure and LVEF of 40% or less (amended to 35% or less early in the trial) to sacubitril/valsartan 97/103 mg twice daily or enalapril 10 mg twice daily. Entry required elevated natriuretic peptides, defined as BNP of at least 150 pg/mL or N-terminal pro-B-type natriuretic peptide (NT-proBNP) of at least 600 pg/mL, or lower values after a recent heart failure hospitalization. Screening also required an eGFR of at least 30 mL/min/1.73 m², potassium of 5.2 mEq/L or less, and systolic pressure of at least 100 mm Hg. All had taken an ACE inhibitor or ARB for at least 4 weeks, and most took a beta-blocker; 56% took an MRA. Before randomization, patients completed sequential single-blind run-in periods with enalapril and then sacubitril/valsartan, and about 20% withdrew during run-in, most often for renal dysfunction, hyperkalemia, or hypotension.

The trial was stopped early for benefit after a median follow-up of 27 months. The primary end point of cardiovascular death or first heart failure hospitalization occurred in 21.8% with sacubitril/valsartan and 26.5% with enalapril (hazard ratio 0.80; 95% confidence interval [CI] 0.73 to 0.87). Each component was reduced: cardiovascular death 13.3% versus 16.5% (hazard ratio 0.80) and heart failure hospitalization 12.8% versus 15.6% (hazard ratio 0.79). All-cause mortality was 17.0% versus 19.8% (hazard ratio 0.84). Both sudden death and death from pump failure fell, and symptoms and physical limitation improved more with sacubitril/valsartan. About 21 patients needed treatment for 27 months to prevent one primary event, against a comparator that itself reduces mortality.

Symptomatic hypotension was more frequent with sacubitril/valsartan (14.0% versus 9.2%), but it rarely caused discontinuation. Serum creatinine of 2.5 mg/dL or more (3.3% versus 4.5%), potassium above 6.0 mEq/L (4.3% versus 5.6%), and cough (11.3% versus 14.3%) were less frequent than with enalapril. Angioedema occurred in 0.5% with sacubitril/valsartan and 0.2% with enalapril in the double-blind period, with no airway compromise; in Black patients the rates were 2.4% and 0.5%, respectively. Among patients taking an MRA, severe hyperkalemia (potassium above 6.0 mEq/L) occurred at 2.2 per 100 patient-years with sacubitril/valsartan and 3.1 with enalapril. The decline in eGFR over time was slower with sacubitril/valsartan (−1.61 versus −2.04 mL/min/1.73 m² per year), although the urine albumin-to-creatinine ratio rose slightly more.

Two limitations qualify these results. The run-in design selected patients who tolerated both drugs, so hypotension and renal events in practice are more frequent than the randomized rates. The enalapril comparator dose, 10 mg twice daily, was the target dose of SOLVD and reflects the doses achieved in trials. Neither limitation altered guideline recommendations. In patients with chronic symptomatic HFrEF and NYHA class II to III symptoms, an ARNI is recommended to reduce morbidity and mortality (Class 1). In those who tolerate an ACE inhibitor or ARB, replacement by an ARNI is also recommended (Class 1). The full sequencing of foundational therapy with beta-blockers, MRAs, and sodium-glucose cotransporter 2 (SGLT2) inhibitors is covered in heart failure with reduced ejection fraction.

Starting sacubitril/valsartan in hospitalized and ACE inhibitor-naive patients

PARADIGM-HF required prior ACE inhibitor or ARB therapy and enrolled ambulatory patients. Two trials addressed initiation without that history and during hospitalization. PIONEER-HF randomized 881 patients hospitalized for acute decompensated HFrEF (LVEF of 40% or less) with elevated natriuretic peptides. Randomization followed hemodynamic stabilization: systolic pressure of at least 100 mm Hg for the preceding 6 hours, no increase in intravenous diuretic and no intravenous vasodilator for 6 hours, and no intravenous inotrope for 24 hours. About half (52%) were not taking an ACE inhibitor or ARB at admission, and about one-third (34%) were presenting with new-onset heart failure. The starting dose was 24/26 mg twice daily for systolic pressure of 100 to 119 mm Hg and 49/51 mg twice daily for 120 mm Hg or higher, with titration toward 97/103 mg twice daily. The comparator was enalapril 2.5 to 10 mg twice daily.

NT-proBNP fell by 46.7% with sacubitril/valsartan and 25.3% with enalapril between baseline and weeks 4 and 8 (ratio of change 0.71; 95% CI 0.63 to 0.81). Worsening renal function, hyperkalemia, symptomatic hypotension, and angioedema did not differ significantly. In exploratory analyses, rehospitalization for heart failure at 8 weeks was 8.0% versus 13.8% (hazard ratio 0.56), and the composite of death, heart failure rehospitalization, left ventricular assist device implantation, or transplant listing was 9.3% versus 16.8% (hazard ratio 0.54). TRANSITION randomized 1,002 patients hospitalized with HFrEF, including patients new to renin-angiotensin inhibition, to start sacubitril/valsartan before discharge or within 14 days after discharge. The proportion reaching the 97/103 mg target at 10 weeks was comparable with the two strategies (45.4% versus 50.7%; risk ratio 0.90; 95% CI 0.79 to 1.02).

These trials support de novo initiation of sacubitril/valsartan, without prior ACE inhibitor exposure, in stabilized hospitalized patients and in ambulatory patients. The 2024 ACC expert consensus decision pathway (ECDP) favors an ARNI as the first renin-angiotensin inhibitor in patients with HFrEF, including those who have not taken an ACE inhibitor. The 2022 guideline classifies in-hospital initiation of guideline-directed therapy after stabilization as a Class 1 recommendation.

Heart failure with mildly reduced and preserved ejection fraction

Renin-angiotensin inhibitors have weaker evidence when LVEF is above 40%. CHARM-Preserved randomized 3,023 patients with LVEF above 40% to candesartan or placebo; cardiovascular death or heart failure hospitalization occurred in 22% and 24% (hazard ratio 0.89; not significant), with fewer heart failure hospitalizations. I-PRESERVE, in 4,128 patients with LVEF of 45% or more, showed no benefit of irbesartan (hazard ratio 0.95). PEP-CHF, in 850 older patients with diastolic dysfunction, was underpowered and inconclusive for perindopril.

PARAGON-HF randomized 4,822 patients with LVEF of 45% or more to sacubitril/valsartan or valsartan. The primary end point of total heart failure hospitalizations and cardiovascular death was not significantly reduced (rate ratio 0.87; 95% CI 0.75 to 1.01; P = 0.06). Among prespecified subgroups, the possible benefit was greater in patients with LVEF at or below the median of 57% and in women. PARALLAX, in 2,572 patients with LVEF above 40%, showed a greater fall in NT-proBNP at 12 weeks with sacubitril/valsartan than with individualized comparator therapy but no improvement in the 6-minute walk distance. PARAGLIDE-HF randomized 466 patients with LVEF above 40% within 30 days of a worsening heart failure event. NT-proBNP fell more with sacubitril/valsartan than with valsartan (ratio of change 0.85; 95% CI 0.73 to 0.999), the effect was larger with LVEF of 60% or less, and symptomatic hypotension was more frequent.

A pooled analysis of PARADIGM-HF and PARAGON-HF showed that the treatment effect of sacubitril/valsartan diminished as LVEF rose and was apparent up to roughly the normal range. In February 2021, the FDA extended the label to adults with chronic heart failure, stating that benefits are most clearly evident in patients with LVEF below normal. The 2022 AHA/ACC/HFSA guideline rates an ARNI, ACE inhibitor, or ARB as possibly useful in heart failure with mildly reduced ejection fraction (HFmrEF; Class 2b, B-NR), and an ARNI or ARB as possibly useful in selected patients with heart failure with preserved ejection fraction (HFpEF) to reduce hospitalization, particularly at the lower end of the ejection fraction range (Class 2b, B-R). These drugs also treat the hypertension present in most patients with HFpEF. Phenotype-based treatment of HFpEF, including SGLT2 inhibitors, MRAs, and incretin therapy, is covered on the heart failure with preserved ejection fraction page.

Myocardial infarction: early and late ACE inhibition, VALIANT, and PARADISE-MI

Two strategies were tested after myocardial infarction. Broad early treatment within 24 to 36 hours of infarction, regardless of ventricular function, was studied in ISIS-4 (captopril, 58,050 patients) and GISSI-3 (lisinopril, 19,394 patients). Both showed small but significant reductions in 5- to 6-week mortality. The ACE Inhibitor Myocardial Infarction Collaborative Group meta-analysis of nearly 100,000 patients estimated about 5 lives saved per 1,000 treated in the first month, with most of the benefit in anterior infarction and patients with heart failure or tachycardia. CONSENSUS II, in which intravenous enalaprilat was given within 24 hours, showed no benefit and more early hypotension, which is why intravenous ACE inhibitors are not used after infarction. Selective treatment of patients with left ventricular dysfunction or heart failure after the first days, tested in SAVE, AIRE, and TRACE, produced relative mortality reductions of about 20% to 27%.

ARBs were compared with ACE inhibitors after infarction complicated by heart failure or left ventricular dysfunction. In OPTIMAAL, losartan 50 mg daily was not shown to be as effective as captopril, and mortality trended higher (18.2% versus 16.4%). VALIANT randomized 14,703 patients to valsartan 160 mg twice daily, captopril 50 mg three times daily, or both. Mortality was 19.9%, 19.5%, and 19.3%; valsartan was noninferior to captopril, and the combination added adverse effects without benefit. Valsartan is therefore an alternative to an ACE inhibitor after infarction.

PARADISE-MI randomized 5,661 patients 0.5 to 7 days after acute myocardial infarction complicated by LVEF of 40% or less, pulmonary congestion, or both, with at least one additional risk factor. The comparison was sacubitril/valsartan 97/103 mg twice daily versus ramipril 5 mg twice daily. Over a median of 22 months, cardiovascular death or incident heart failure occurred in 11.9% and 13.2% (hazard ratio 0.90; 95% CI 0.78 to 1.04). Hypotension was more frequent with sacubitril/valsartan. The trial does not support replacing an ACE inhibitor with an ARNI early after infarction in patients without established chronic heart failure; patients who develop HFrEF after infarction are treated as in chronic HFrEF.

The 2025 ACC/AHA acute coronary syndromes guideline recommends an ACE inhibitor after acute coronary syndrome in patients with LVEF of 40% or less, hypertension, diabetes, or anterior ST-elevation myocardial infarction (STEMI) (Class 1), with an ARB in patients intolerant of ACE inhibitors. It considers an ACE inhibitor reasonable in other patients (Class 2a). The drug is started orally in hospital once blood pressure and kidney function allow, beginning at a low dose. Acute management is covered on the ST-elevation myocardial infarction page.

Vascular protection in chronic coronary disease: HOPE, EUROPA, PEACE, and ONTARGET

HOPE randomized 9,297 patients aged 55 years or older with vascular disease or diabetes plus another risk factor, without known low ejection fraction or heart failure, to ramipril 10 mg daily or placebo. Over about 5 years, myocardial infarction, stroke, or cardiovascular death occurred in 14.0% with ramipril and 17.8% with placebo (relative risk 0.78), with reductions in each component, in new heart failure, and in new diabetes. EUROPA randomized 12,218 patients with stable coronary disease, most with preserved ventricular function, to perindopril 8 mg daily or placebo: cardiovascular death, myocardial infarction, or cardiac arrest occurred in 8.0% and 9.9% (a 20% relative reduction). PEACE, in 8,290 lower-risk patients with stable coronary disease and preserved function, most of whom had been revascularized and took lipid-lowering therapy, found no benefit of trandolapril (21.9% versus 22.5%). The difference among these trials is consistent with benefit proportional to baseline risk and to blood pressure lowering.

ONTARGET randomized 25,620 patients with vascular disease or high-risk diabetes to ramipril 10 mg, telmisartan 80 mg, or both. The primary end point of cardiovascular death, myocardial infarction, stroke, or heart failure hospitalization occurred in 16.5%, 16.7%, and 16.3%, respectively. Telmisartan was noninferior to ramipril, and the combination produced no benefit while increasing hypotensive symptoms, syncope, and renal dysfunction. TRANSCEND, in 5,926 ACE inhibitor-intolerant patients, did not show a significant reduction in the primary end point with telmisartan (hazard ratio 0.92), though a secondary end point matching the HOPE composite was modestly reduced.

The 2023 AHA/ACC chronic coronary disease guideline recommends an ACE inhibitor, or an ARB in patients intolerant of ACE inhibitors, in chronic coronary disease with hypertension, diabetes, LVEF of 40% or less, or CKD (Class 1). In patients without these conditions, the benefit is less certain and the decision rests on overall risk. These drugs are part of secondary prevention but do not relieve angina.

Hypertension: efficacy, choice, and dosing

ACE inhibitors and ARBs form one of the three first-line classes for hypertension, alongside thiazide-type diuretics and dihydropyridine calcium channel blockers, because each class lowers pressure and reduces cardiovascular events. Their dose-response curve for blood pressure is flat above the middle of the dose range, so adding a second class lowers pressure more than doubling the dose. They are preferred in hypertension with albuminuria, diabetic or nondiabetic CKD with albuminuria, HFrEF, and after myocardial infarction. LIFE randomized 9,193 patients with hypertension and electrocardiographic left ventricular hypertrophy to losartan or atenolol: at similar blood pressure, losartan reduced cardiovascular death, myocardial infarction, or stroke by 13%, driven by a 25% reduction in stroke.

Monotherapy with an ACE inhibitor or ARB lowered pressure less, on average, in Black adults than in White adults in older trials, a difference attributed to lower plasma renin activity and greater salt sensitivity; the distributions overlap widely. In ALLHAT, lisinopril was less effective than chlorthalidone in preventing stroke and heart failure in Black participants, partly because blood pressure was higher in the lisinopril group. The 2017 ACC/AHA guideline therefore favored a thiazide-type diuretic or calcium channel blocker as initial therapy in Black adults without HFrEF or CKD. The 2025 AHA/ACC guideline does not use race to choose drugs and relies on combination therapy, which makes the renin response less relevant: with a diuretic or calcium channel blocker, renin-angiotensin inhibitors are effective in all groups. In stage 2 hypertension the guideline recommends starting two first-line drugs of different classes, ideally as a single pill (Class 1). The usual combination pairs an ACE inhibitor or ARB with a calcium channel blocker or a thiazide-type diuretic. ACE inhibitors and ARBs reduce the ankle edema caused by dihydropyridines and offset diuretic-induced hypokalemia.

Thresholds, targets, measurement, and the full treatment algorithm are on the hypertension page. For resistant hypertension, the guideline adds an MRA to an ACE inhibitor or ARB, a calcium channel blocker, and a thiazide-type diuretic; an ACE inhibitor and ARB together are not a step in that sequence.

Chronic kidney disease and diabetic kidney disease

Renin-angiotensin inhibitors slow the progression of proteinuric kidney disease. In type 1 diabetic nephropathy, captopril reduced the risk of doubling of serum creatinine by 48% (Collaborative Study Group, 1993). In type 2 diabetic nephropathy, RENAAL (losartan, 1,513 patients) reduced the composite of doubling of creatinine, end-stage kidney disease, or death by 16%, and end-stage kidney disease by 28%. IDNT (irbesartan, 1,715 patients) reduced the same composite by 20% compared with placebo and by 23% compared with amlodipine, at similar blood pressure. IRMA-2 showed that irbesartan 300 mg daily reduced progression from moderately increased albuminuria to overt nephropathy. In nondiabetic proteinuric CKD, ramipril slowed decline in REIN, and in AASK ramipril slowed progression more than amlodipine in Black patients with hypertensive nephrosclerosis and proteinuria. The benefit is greatest when albuminuria is severely increased.

The 2024 Kidney Disease: Improving Global Outcomes (KDIGO) CKD guideline recommends an ACE inhibitor or ARB for patients with CKD and severely increased albuminuria (A3) without diabetes (grade 1B) and for patients with diabetes and moderately or severely increased albuminuria (A2 or A3) (grade 1B). It suggests one for moderately increased albuminuria without diabetes (grade 2C). It recommends against combining an ACE inhibitor, ARB, and direct renin inhibitor (grade 1B). Its practice points specify titration to the highest approved dose tolerated and measurement of blood pressure, creatinine, and potassium within 2 to 4 weeks of starting or changing the dose. Therapy continues unless creatinine rises by more than 30% within 4 weeks, and hyperkalemia is managed with potassium-lowering measures before the drug is reduced or stopped. The 2025 AHA/ACC hypertension guideline recommends an ACE inhibitor or ARB for adults with hypertension, eGFR below 60 mL/min/1.73 m², and albuminuria of 30 mg/g or more (Class 1).

Advanced CKD. STOP-ACEi randomized 411 patients with eGFR below 30 mL/min/1.73 m² taking an ACE inhibitor, ARB, or both to discontinuation or continuation. At 3 years, eGFR was 12.6 and 13.3 mL/min/1.73 m², a nonsignificant difference, and kidney failure, cardiovascular events, and death did not differ. Stopping the drug in advanced CKD did not preserve kidney function, so a renin-angiotensin inhibitor that is otherwise indicated, for example for heart failure, is continued in advanced CKD when potassium allows.

Sacubitril/valsartan in CKD. UK HARP-III randomized 414 patients with eGFR of 20 to 60 mL/min/1.73 m² to sacubitril/valsartan or irbesartan. Measured GFR at 12 months did not differ, while blood pressure, troponin, and NT-proBNP were lower with sacubitril/valsartan. In PARADIGM-HF, the slower eGFR decline with sacubitril/valsartan and the consistent cardiovascular benefit in patients with eGFR below 60 support its use in HFrEF with CKD. The label specifies a starting dose of 24/26 mg twice daily when eGFR is below 30 mL/min/1.73 m². Patients receiving dialysis were excluded from the outcome trials; observational data describe use in dialysis with hypotension as the main limitation, and the decision rests on blood pressure and potassium. The drug is not removed by dialysis.

SGLT2 inhibitors and the nonsteroidal MRA finerenone are added to renin-angiotensin inhibition in diabetic and nondiabetic CKD; their kidney trials were conducted in patients already taking a maximally tolerated ACE inhibitor or ARB.

Guideline recommendations for renin-angiotensin inhibitors

Classes and levels as published. The 2024 ACC expert consensus decision pathway does not assign classes; it favors an ARNI as the initial renin-angiotensin inhibitor in HFrEF. ACS, acute coronary syndrome; CCD, chronic coronary disease; CKD, chronic kidney disease; HF, heart failure.

Starting and target doses in heart failure

Starting and target doses from the 2022 AHA/ACC/HFSA guideline (drugs commonly used for HFrEF) and the 2024 ACC ECDP; sacubitril/valsartan starting doses also from the US prescribing information. Target doses are those of the outcome trials; when they cannot be reached, the highest tolerated dose is the goal, because benefit is dose related (ATLAS, HEAAL). Titration intervals are those used in practice; faster titration with laboratory monitoring is reasonable in stable patients.

Titration is guided by symptoms, blood pressure (including standing pressure in older adults), potassium, and creatinine, measured 1 to 2 weeks after starting or increasing a renin-angiotensin inhibitor. Target doses reflect the doses that produced the outcome benefit in the trials. In a patient whose systolic pressure is 95 mm Hg on sacubitril/valsartan 49/51 mg twice daily, maintaining the beta-blocker, MRA, and SGLT2 inhibitor doses takes priority over increasing the ARNI to target. The 2024 ECDP describes how the four foundational classes are started together and titrated within about 3 months, summarized on the heart failure with reduced ejection fraction page.

Sacubitril/valsartan starting dose, washout, and laboratory action tool

The tool applies the starting-dose rules of the US prescribing information, the 36-hour washout, and the potassium and creatinine thresholds of the 2022 AHA/ACC/HFSA guideline and the 2024 ACC ECDP to one patient. When the last ACE inhibitor dose is entered, it returns the earliest time of the first sacubitril/valsartan dose. Volume status, symptoms, and drug interactions are outside its inputs.

Low prior dose is defined as a total daily dose of enalapril 10 mg or less or valsartan 160 mg or less, the thresholds of the ACC decision pathways. For the other agents, the tool uses approximate equivalents of about half the lower heart failure target dose. For ACE inhibitors, these are lisinopril 10, ramipril 5, captopril 75, quinapril 20, perindopril 4, fosinopril 20, and trandolapril 2 mg per day. For ARBs, they are candesartan 16, irbesartan 150, telmisartan 40, and olmesartan 20 mg per day, with losartan at 50 mg per day, the low dose of HEAAL. Age 75 years or older, as in the decision pathways, and systolic pressure of 90 to 99 mm Hg, below the PARADIGM-HF and PIONEER-HF entry threshold of 100 mm Hg, are treated as reasons for the lower starting dose. In PIONEER-HF, hospitalized patients with systolic pressure of 100 to 119 mm Hg also started at 24/26 mg. The creatinine action uses the 30% threshold of KDIGO 2024.

Switching from an ACE inhibitor or ARB to sacubitril/valsartan, and back

From an ACE inhibitor. The ACE inhibitor is stopped, and the first dose of sacubitril/valsartan is given no sooner than 36 hours after the last ACE inhibitor dose. The interval allows ACE activity to recover so that ACE and neprilysin, two of the main enzymes that degrade bradykinin, are not inhibited at the same time. A patient taking lisinopril every morning takes the last dose on day 1, no dose on day 2, and the first sacubitril/valsartan dose on the evening of day 2 at the earliest, or on the morning of day 3. During the washout, blood pressure and congestion are rarely affected in a stable outpatient. In hospitalized patients the switch is planned so that the washout does not delay discharge: the ACE inhibitor is held at admission when an ARNI is intended, or the switch is made after discharge with early follow-up.

From an ARB. No washout is needed, because ARBs do not inhibit ACE. The ARB is stopped and sacubitril/valsartan is taken at the time of the next scheduled ARB dose. An ARB is never continued with sacubitril/valsartan, which already contains valsartan.

Starting dose. The label recommends 49/51 mg twice daily. Half that dose, 24/26 mg twice daily, is recommended for patients not taking an ACE inhibitor or ARB, those taking low doses, those with eGFR below 30 mL/min/1.73 m², and those with moderate hepatic impairment (Child-Pugh B). Use in severe hepatic impairment (Child-Pugh C) is not recommended. The ACC decision pathways define a low dose as 10 mg or less of enalapril or 160 mg or less of valsartan per day, or an equivalent. They also start at 24/26 mg in patients aged 75 years or older and in those with low or borderline blood pressure. The dose is doubled every 2 to 4 weeks to 97/103 mg twice daily as tolerated. In stable patients with adequate blood pressure, titration every 2 weeks is common practice.

From sacubitril/valsartan back to an ACE inhibitor. The label also forbids an ACE inhibitor within 36 hours of the last sacubitril/valsartan dose. The reverse switch is made after angioedema (in which case no further renin-angiotensin inhibitor is given), because of cost, or because the patient cannot obtain the drug. A switch to an ARB at an equivalent dose (for example valsartan 160 mg twice daily after 97/103 mg twice daily) needs no washout. Any interruption is accompanied by a plan for continued renin-angiotensin inhibition.

Monitoring after the switch. Blood pressure, potassium, and creatinine are measured 1 to 2 weeks after the first dose and after each dose increase. NT-proBNP, not BNP, is used to follow natriuretic peptides. Patients are told to stop the drug and seek care for swelling of the lips, tongue, face, or throat.

The expected creatinine rise and when to stop

A rise in serum creatinine of up to about 30% from baseline after starting or increasing an ACE inhibitor, ARB, or ARNI is expected. It reflects the fall in intraglomerular pressure, occurs within the first 1 to 2 weeks, stabilizes, and is associated with long-term preservation of kidney function. In the HFrEF trials, patients with an early decline in eGFR derived the same benefit as other patients, and in SOLVD and PARADIGM-HF the excess of renal events with active therapy was small. Stopping a renin-angiotensin inhibitor for a stable creatinine rise within this range is a common cause of undertreatment. The 2021 European Society of Cardiology (ESC) heart failure guideline accepts a rise in creatinine of up to 50% above baseline, or to 3.0 mg/dL, or a fall in eGFR to 25 mL/min/1.73 m², before reducing the dose.

A larger rise, a progressive rise after the first weeks, or oliguria leads to evaluation. Volume depletion from diuretics, vomiting, diarrhea, or poor intake is the most common cause; others are hypotension, NSAIDs including cyclooxygenase-2 inhibitors, nephrotoxic drugs and contrast, urinary obstruction, intercurrent illness, and bilateral renal artery stenosis. In heart failure, worsening renal function with congestion reflects venous congestion and low output more often than the drug. The diuretic dose is reduced if the patient is euvolemic or volume depleted. The renin-angiotensin inhibitor dose is halved, and creatinine is repeated within 1 to 2 weeks. The drug is withheld only if the decline persists or creatinine rises by more than about 50%. Once creatinine returns toward baseline, the drug is reintroduced at a lower dose.

A creatinine rise of more than 30% after the first doses of an ACE inhibitor or ARB, especially in an older patient with diffuse atherosclerosis, recurrent flash pulmonary edema, or asymmetric kidney size, raises the possibility of bilateral renal artery stenosis. The evaluation of renovascular disease is covered on the hypertension page.

Hyperkalemia: thresholds, potassium binders, and continuing therapy

Hyperkalemia is the most frequent laboratory reason for stopping or underdosing renin-angiotensin inhibitors and MRAs. Risk is highest with CKD, diabetes, older age, heart failure, high doses, combination with an MRA, potassium supplements or salt substitutes containing potassium chloride, and drugs that impair potassium excretion: NSAIDs, trimethoprim, pentamidine, heparin, calcineurin inhibitors, and potassium-sparing diuretics. Sacubitril/valsartan causes less hyperkalemia than enalapril, and SGLT2 inhibitors reduce the risk of hyperkalemia with renin-angiotensin inhibitors and MRAs.

Potassium action thresholds after the 2022 AHA/ACC/HFSA guideline, the 2024 ACC ECDP, and KDIGO 2024. Thresholds for MRAs follow the prescribing information of each agent.

Potassium binders. Patiromer is a nonabsorbed polymer that exchanges calcium for potassium in the colon; it is started at 8.4 g once daily, and other oral drugs are separated from it by 3 hours because it binds them. Sodium zirconium cyclosilicate exchanges sodium and hydrogen for potassium throughout the gut and acts within hours. It is given at 10 g three times daily for up to 48 hours to correct hyperkalemia and then 5 to 10 g daily for maintenance. It adds about 400 mg of sodium per 5 g, which can increase edema. DIAMOND randomized 878 patients with HFrEF and current or past hyperkalemia who had reached at least 50% of the recommended renin-angiotensin inhibitor dose and 50 mg of spironolactone or eplerenone on patiromer during run-in. Potassium was 0.10 mEq/L lower with continued patiromer than with placebo, potassium above 5.5 mEq/L was less frequent (hazard ratio 0.63), and MRA dose reductions were fewer. The trial was not designed for clinical outcomes, which is why the 2022 guideline rates binders Class 2b. Sodium polystyrene sulfonate is not used for chronic management because of gastrointestinal injury and poor tolerability.

Diet. Dietary potassium restriction is individualized. Potassium-rich diets are associated with lower blood pressure and cardiovascular risk in people with normal kidney function, and indiscriminate restriction removes fruit and vegetables. Restriction is directed at patients with hyperkalemia and CKD, with emphasis on salt substitutes based on potassium chloride, which provides about 13 mEq of potassium per gram, and on processed foods with potassium additives.

Combination with MRAs: hyperkalemia risk and monitoring

An MRA acts at the last step of the cascade and adds to renin-angiotensin inhibition in HFrEF, resistant hypertension, primary aldosteronism, and diabetic kidney disease (finerenone). The combination is the standard of care in HFrEF, and the MRA trials (RALES, EMPHASIS-HF) were conducted on a background of ACE inhibitor or ARB therapy. The combination increases the risk of hyperkalemia, and its safety depends on monitoring. After RALES was published in 1999, spironolactone prescribing rose sharply in Ontario. Hospital admissions for hyperkalemia among older patients taking ACE inhibitors after a recent heart failure hospitalization rose from 2.4 to 11.0 per 1,000 patients, with an increase in deaths. The strict entry criteria and monitoring of RALES had not been carried into practice.

The rules that make the combination safe are those of the MRA trials: an MRA is started only with potassium below 5.0 mEq/L and eGFR above 30 mL/min/1.73 m²; potassium and creatinine are measured at about 1 week and 4 weeks, then periodically; potassium supplements are stopped; NSAIDs are avoided; and the patient holds both drugs during dehydrating illness. Triple therapy with an ACE inhibitor, an ARB, and an MRA is harmful and has no indication. Sacubitril/valsartan with an MRA is preferred to an ACE inhibitor with an MRA when potassium is the limiting factor.

Hypotension during renin-angiotensin inhibition and dose reduction

Blood pressure falls most with the first doses in patients with high renin activity: those with recent intensive diuresis, hyponatremia, systolic pressure below 100 mm Hg, or advanced heart failure. First-dose hypotension with ACE inhibitors is reduced by correcting volume depletion, reducing or holding the diuretic for a day in a euvolemic patient, and starting at a low dose, sometimes given at bedtime. Sacubitril/valsartan lowers pressure more than an ACE inhibitor at target doses, and symptomatic hypotension was the most common reason for its dose reduction in PARADIGM-HF.

Asymptomatic systolic pressure of 85 to 100 mm Hg is common in HFrEF and is not by itself a reason to reduce therapy if perfusion is adequate. When symptoms occur, nonprognostic drugs that lower pressure (nitrates, alpha-blockers, calcium channel blockers, and other antihypertensives) are stopped first, the diuretic is reduced in a euvolemic patient, and doses of the prognostic drugs are staggered through the day. Only then is the ARNI or ACE inhibitor dose reduced, usually by one step, and it is not stopped unless there is hypoperfusion or shock. Phosphodiesterase-5 inhibitors add about 5/4 mm Hg of further lowering to sacubitril/valsartan, and tamsulosin and other alpha-blockers add orthostatic hypotension. In older adults, standing pressure is measured at each visit, because falls are the practical consequence of orthostasis.

ACE inhibitor cough

A dry, nonproductive cough with a tickling or scratching sensation in the throat occurs in about 5% to 35% of patients taking ACE inhibitors, depending on the population and how it is ascertained. It is more frequent in women, in nonsmokers, and in East Asian patients. The mechanism is accumulation of bradykinin, substance P, and prostaglandins in the airway, which sensitize the cough reflex. Cough is a class effect, is not dose related, and usually begins within the first weeks but can appear after months. It is not associated with bronchospasm, although ACE inhibitors can aggravate airway reactivity in some patients with asthma.

The American College of Chest Physicians guideline on ACE inhibitor cough recommends stopping the drug in patients with troublesome cough, because no dose reduction or change to another ACE inhibitor reliably abolishes it. Cough resolves within 1 to 4 weeks of stopping in most patients and occasionally persists for up to 3 months. Rechallenge reproduces the cough in most cases, and a patient whose cough persists after withdrawal has another cause. Cough is common in heart failure for other reasons, including pulmonary congestion, and congestion is excluded before the ACE inhibitor is blamed.

ARBs cause cough at rates similar to placebo and are the standard alternative. In HFrEF, sacubitril/valsartan is the preferred alternative: cough was less frequent with sacubitril/valsartan than with enalapril in PARADIGM-HF (11.3% versus 14.3%). Neprilysin also degrades bradykinin, so cough with an ARNI is somewhat more frequent than with an ARB alone.

Angioedema with ACE inhibitors, ARBs, and sacubitril/valsartan

ACE inhibitor angioedema is nonpitting, nonpruritic swelling of the deep dermis and submucosa, most often of the lips, tongue, face, and upper airway. It is bradykinin mediated, not histamine mediated: urticaria and pruritus are absent, and antihistamines, glucocorticoids, and epinephrine are often ineffective, although epinephrine is given when anaphylaxis cannot be excluded. Swelling develops over hours and usually resolves within 24 to 72 hours. Laryngeal involvement can obstruct the airway and has been fatal. Visceral angioedema of the small bowel presents as recurrent abdominal pain, vomiting, and diarrhea with bowel wall thickening on computed tomography, and is easily missed.

The incidence with ACE inhibitors is about 0.1% to 0.7%. It is several times higher in Black patients. It is also higher in women, smokers, older adults, patients with a history of drug rash or seasonal allergies, and patients taking dipeptidyl peptidase-4 (DPP-4) inhibitors, mammalian target of rapamycin (mTOR) inhibitors such as sirolimus and everolimus, or neprilysin inhibitors, all of which reduce bradykinin or substance P degradation. Alteplase can cause orolingual angioedema, more often in patients taking ACE inhibitors. Most episodes occur in the first months, but a substantial share occur after years of uneventful therapy, so the drug is not exonerated by long use. Recurrent unexplained swelling in a patient taking an ACE inhibitor is attributed to the drug until proved otherwise.

Distinguishing bradykinin-mediated from mast cell-mediated angioedema.

Treatment. The drug is stopped permanently, and the airway is assessed and secured early, by fiberoptic intubation or surgical airway when swelling involves the tongue, floor of the mouth, or larynx. Patients with lip or facial swelling alone are observed until the swelling regresses. Agents that act on the bradykinin pathway have been studied without proof of benefit. After a small positive phase 2 trial of icatibant, a bradykinin B₂ receptor antagonist, a phase 3 trial in 121 patients with at least moderately severe ACE inhibitor angioedema found no difference from placebo in the time to meeting discharge criteria. Ecallantide was also ineffective in a randomized trial, and C1 esterase inhibitor concentrate and fresh frozen plasma have been reported to help only in case series. None is approved for this indication, and none replaces airway management.

Subsequent therapy. After ACE inhibitor angioedema, no ACE inhibitor is given again. Sacubitril/valsartan is contraindicated in any patient with a history of angioedema related to an ACE inhibitor or ARB and is not used in hereditary angioedema. The 2022 guideline classes ARNI use in any patient with a history of angioedema as Class 3: Harm. An ARB can be used with caution. In a meta-analysis, the risk of recurrent angioedema on an ARB after ACE inhibitor angioedema was 2% to 17% for any recurrence and 0% to 9.2% for confirmed angioedema. In CHARM-Alternative, 3 of 39 such patients had a recurrence on candesartan. When the original episode involved the airway, many clinicians avoid all renin-angiotensin inhibitors and rely on other classes. In HFrEF without a renin-angiotensin inhibitor, the beta-blocker, MRA, SGLT2 inhibitor, and, in appropriate patients, hydralazine-isosorbide dinitrate remain available.

Angioedema with sacubitril/valsartan. In PARADIGM-HF, adjudicated angioedema occurred in 0.5% with sacubitril/valsartan and 0.2% with enalapril, without airway compromise, and in Black patients in 2.4% and 0.5%. These rates were obtained after a run-in that excluded patients who did not tolerate enalapril or sacubitril/valsartan, and patients with prior angioedema were also excluded. The 36-hour washout from ACE inhibitors exists to prevent combined ACE and neprilysin inhibition, the mechanism behind the angioedema seen with omapatrilat.

Other adverse effects: captopril, glucose, blood counts, and the liver

Captopril. The sulfhydryl group of captopril has been associated with maculopapular rash, taste disturbance (dysgeusia), and membranous glomerulopathy with proteinuria, mainly at doses above 150 mg per day used early in its history. Neutropenia and agranulocytosis are rare and occur mainly in patients with kidney impairment and collagen vascular disease, especially systemic lupus erythematosus and scleroderma, or with other drugs that suppress the marrow; the label recommends white cell counts in these patients. Captopril remains the ACE inhibitor of choice in scleroderma renal crisis, in which daily titration to control blood pressure preserves kidney function, and is used in captopril-enhanced renography.

Hypoglycemia and glucose metabolism. ACE inhibitors increase insulin sensitivity modestly, and a case-control study associated them with hospitalization for hypoglycemia in patients treated with insulin or sulfonylureas, an effect not established for ARBs. In HOPE, ramipril was associated with fewer new diagnoses of diabetes, and sacubitril/valsartan lowered glycated hemoglobin slightly and reduced new insulin use compared with enalapril in diabetic patients in PARADIGM-HF. These effects are small and do not alter drug choice, but patients with diabetes on insulin or secretagogues are counseled about low glucose after initiation.

Hematologic and hepatic effects. Renin-angiotensin inhibitors lower hemoglobin by a small amount through reduced erythropoietin secretion and are used to treat post-transplant erythrocytosis. Cholestatic jaundice progressing to fulminant hepatic necrosis is a rare class warning on ACE inhibitor labels; the drug is stopped if jaundice or a marked rise in liver enzymes occurs. Pancreatitis and, with ACE inhibitors, photosensitivity are rare.

Overdose. The principal effect is hypotension, managed with volume expansion and vasopressors; angiotensin II has been used in case reports of refractory vasodilatory shock from ACE inhibitor overdose. Captopril and enalaprilat are partly removed by hemodialysis; ARBs and sacubitril/valsartan are highly protein bound and are not.

Adverse effects by class, from the outcome trials and US prescribing information.

Dual renin-angiotensin blockade and why it is avoided

Combining two drugs that act upstream of the AT₁ receptor was expected to suppress angiotensin II signaling more completely and to reduce proteinuria further. Proteinuria did fall further, but outcome trials showed harm. In ONTARGET, ramipril plus telmisartan did not reduce cardiovascular events compared with ramipril alone and increased hypotensive symptoms, syncope, and renal dysfunction, including the need for dialysis. VA NEPHRON-D randomized 1,448 patients with type 2 diabetes and albuminuric CKD taking losartan to lisinopril or placebo. It was stopped early because hyperkalemia (6.3 versus 2.6 events per 100 person-years) and acute kidney injury (12.2 versus 6.7 per 100 person-years) were more frequent with the combination, without a significant effect on kidney outcomes. ALTITUDE and ATMOSPHERE showed the same pattern with aliskiren.

The 2025 AHA/ACC hypertension guideline classes the combination of an ACE inhibitor, ARB, or direct renin inhibitor with another of these as Class 3: Harm, and KDIGO 2024 recommends against it. In heart failure, the combination of an ACE inhibitor and an ARB has been superseded by an MRA, which acts at a different step and has mortality benefit. Sacubitril/valsartan is never given with an ACE inhibitor (angioedema) or another ARB (duplicate valsartan), and the label contraindicates it with aliskiren in diabetes and advises avoiding that combination when eGFR is below 60 mL/min/1.73 m².

Contraindications, renal artery stenosis, and cautions

Contraindications and cautions from the US prescribing information and the 2022 AHA/ACC/HFSA and 2025 AHA/ACC guidelines.

Unilateral renal artery stenosis is not a contraindication; the contralateral kidney maintains filtration, and ACE inhibitors and ARBs are used for blood pressure control in patients with unilateral stenosis, with creatinine monitoring. In bilateral stenosis, the drugs can be used with close monitoring when there is a strong indication and revascularization is not planned, but a rise in creatinine of more than 30% leads to withdrawal. In severe aortic stenosis, vasodilators were once avoided; cautious ACE inhibitor therapy is tolerated in patients with hypertension or heart failure, and blood pressure is lowered slowly (see the aortic stenosis page). In hypertrophic cardiomyopathy with outflow obstruction, vasodilators increase the gradient and are avoided.

Pregnancy, lactation, and patients who may become pregnant

All drugs acting on the renin-angiotensin system carry a boxed warning for fetal toxicity. Exposure in the second and third trimesters causes fetal renal hypoperfusion and failure, oligohydramnios, pulmonary hypoplasia, limb contractures, skull ossification defects, intrauterine growth restriction, and neonatal hypotension, anuria, and death. The fetal kidney depends on angiotensin II to maintain glomerular filtration, and the effects are the same for ACE inhibitors, ARBs, sacubitril/valsartan, and aliskiren.

First-trimester exposure is less clearly harmful. A Tennessee Medicaid cohort reported an increase in major malformations after first-trimester ACE inhibitor exposure (risk ratio 2.71). Larger cohorts that compared exposed women with women who had hypertension treated with other drugs found that the excess risk was associated with hypertension itself. Inadvertent first-trimester exposure therefore leads to prompt discontinuation and counseling but not to termination on that basis alone. The 2025 AHA/ACC guideline classes ACE inhibitors, ARBs, and direct renin inhibitors as Class 3: Harm in patients who are pregnant or planning pregnancy; labetalol and extended-release nifedipine are preferred.

Patients of reproductive potential who take a renin-angiotensin inhibitor are told about the risk, use effective contraception or plan conception with a change of drug, and stop the drug as soon as pregnancy is recognized. In heart failure, the switch before conception is planned with the cardiologist, because hydralazine-isosorbide dinitrate and beta-blockers are the main alternatives during pregnancy. Peripartum cardiomyopathy is covered on the heart failure with reduced ejection fraction page.

During lactation, enalapril and captopril have the most data, transfer into milk in very small amounts, and are regarded as compatible with breastfeeding, so they are the preferred renin-angiotensin inhibitors for postpartum heart failure or hypertension. Data for ARBs are sparse, and the sacubitril/valsartan label states that breastfeeding is not recommended during treatment.

Drug interactions of ACE inhibitors, ARBs, and sacubitril/valsartan

Drug interactions of ACE inhibitors, ARBs, and sacubitril/valsartan from the US prescribing information.

Surgery, procedures, and sick-day rules

Renin-angiotensin inhibitors taken on the morning of surgery increase the likelihood of hypotension after induction of anesthesia, because the vasoconstrictor response to anesthetic vasodilation is blunted. Stop-or-Not randomized 2,222 patients taking a renin-angiotensin inhibitor for at least 3 months before major noncardiac surgery to continuation until surgery or discontinuation 48 hours before. Major postoperative complications within 28 days occurred in 22% in both groups, while intraoperative hypotension was more frequent with continuation (54% versus 41%). Earlier cohort data had associated a 24-hour hold with fewer complications, and meta-analyses show less intraoperative hypotension and possibly less acute kidney injury with withholding, without an effect on mortality or cardiovascular events.

The 2024 AHA/ACC perioperative guideline states that omitting a renin-angiotensin inhibitor 24 hours before surgery may be beneficial to limit intraoperative hypotension in selected patients who take it for hypertension, have controlled blood pressure, and are undergoing elevated-risk surgery (Class 2b). Perioperative continuation is reasonable in patients taking one for HFrEF (Class 2a). The 2025 AHA/ACC hypertension guideline states that discontinuing an ACE inhibitor or ARB before major surgery may be considered to prevent intraoperative hypotension (Class 2b). In practice, patients taking these drugs for hypertension often omit the dose on the morning of major surgery or during the 24 hours before it. Patients with HFrEF, in whom withdrawal risks decompensation, usually continue them with attention to volume status and anesthetic technique. KDIGO 2024 allows planned discontinuation 48 to 72 hours before elective surgery in CKD with a clear restart plan. Failure to restart renin-angiotensin inhibitors after surgery or hospitalization is common and is associated with worse outcomes in heart failure. The drug is restarted once the patient is euvolemic, normotensive, and eating, and kidney function is stable, usually within 48 hours.

Sick-day guidance during a dehydrating illness, such as vomiting, diarrhea, fever with poor intake, or heat exposure, includes temporary withholding of ACE inhibitors, ARBs, ARNIs, diuretics, MRAs, SGLT2 inhibitors, metformin, and NSAIDs, with resumption 24 to 48 hours after normal eating and drinking. KDIGO 2024 notes that randomized evidence that sick-day rules prevent kidney injury is lacking and that the most common error is failure to restart. In patients with heart failure, sick-day rules are applied with judgment, because holding all drugs in a patient with congestion is harmful.

Older adults, frailty, hepatic impairment, and differences by race and sex

Older adults and frailty. Benefit in the outcome trials was consistent across age groups, and older patients have higher absolute risk and therefore higher absolute benefit. Adverse effects are more frequent: orthostatic hypotension, falls, hyperkalemia, and kidney injury during dehydration. In PARADIGM-HF, orthostasis and falls were more frequent with sacubitril/valsartan than with enalapril (2.1% versus 1.1% and 1.9% versus 1.3%, respectively). Doses start low, standing pressure is measured, titration is slower, and other drugs that lower pressure are reviewed. Frailty and limited life expectancy shift the goal of therapy toward symptoms and the avoidance of harm.

Hepatic impairment. ACE inhibitor prodrugs require hepatic activation, so active drug concentrations are lower and less predictable in cirrhosis; lisinopril and captopril are active as given. In cirrhosis with ascites, renin-angiotensin inhibitors lower blood pressure and can precipitate hepatorenal physiology and are generally avoided. Losartan starts at 25 mg in hepatic impairment. Sacubitril/valsartan starts at 24/26 mg twice daily in moderate (Child-Pugh B) impairment and is not recommended in Child-Pugh C.

Black patients. In HFrEF, the effect of renin-angiotensin inhibitors on outcomes was seen in Black patients, though post hoc analyses of SOLVD raised questions about the size of the effect. The A-HeFT trial showed added benefit of hydralazine-isosorbide dinitrate in self-identified Black patients taking standard therapy. Angioedema is several times more frequent in Black patients with ACE inhibitors and sacubitril/valsartan, a risk explained to patients but not a reason to withhold therapy.

Women. Cough and angioedema are more frequent in women. In PARAGON-HF, the possible benefit of sacubitril/valsartan was greater in women than men, which may reflect the higher normal range of ejection fraction in women.

Advanced heart failure, ventricular assist devices, and specific cardiomyopathies

PARADIGM-HF enrolled few patients with NYHA class IV symptoms, and none with systolic pressure below 100 mm Hg at screening. As heart failure advances, intolerance of renin-angiotensin inhibitors because of hypotension, worsening kidney function, or hyperkalemia is a marker of poor prognosis and one of the triggers for referral to an advanced heart failure center. When systolic pressure falls below about 90 mm Hg with symptoms or signs of hypoperfusion, the ARNI or ACE inhibitor is reduced or stopped before the beta-blocker is withdrawn.

After implantation of a continuous-flow left ventricular assist device, hypertension is common and is associated with stroke, pump thrombosis, and aortic regurgitation. Renin-angiotensin inhibitors, including sacubitril/valsartan, are used to keep mean arterial pressure in the target range recommended for the device, with evidence limited to observational studies. Renin-angiotensin inhibitors may also contribute to fewer gastrointestinal bleeding events in patients with ventricular assist devices through effects on angiogenesis, an observation from cohort studies.

In cardiac amyloidosis, renin-angiotensin inhibitors and ARNIs are poorly tolerated because cardiac output depends on heart rate and filling and because autonomic neuropathy causes orthostatic hypotension; they are used at low doses, if at all, for blood pressure. In hypertrophic cardiomyopathy without obstruction they are used for hypertension and for the hypokinetic phase; with obstruction they are avoided. Valsartan was tested in early nonobstructive sarcomeric hypertrophic cardiomyopathy in VANISH, with modest improvement in a composite measure of cardiac structure and function.

Natriuretic peptide interpretation and amyloid-β effects during sacubitril/valsartan therapy

BNP is a substrate of neprilysin, so sacubitril raises circulating BNP, while NT-proBNP is not a substrate. During the first weeks of therapy, BNP falls less than expected or rises even as wall stress falls, whereas NT-proBNP falls in proportion to the hemodynamic improvement. In PARADIGM-HF, NT-proBNP was lower with sacubitril/valsartan than with enalapril, while BNP was modestly higher. NT-proBNP is therefore the marker used to diagnose decompensation, to follow response, and to assess prognosis in patients taking an ARNI. Once treatment is established for several months, BNP values are again interpretable in trend, but a single BNP value compared with a pretreatment value can mislead. Urinary cGMP rises with neprilysin inhibition and reflects natriuretic peptide action. Diagnostic thresholds and confounders of natriuretic peptide testing are covered on the heart failure with reduced ejection fraction page.

Neprilysin is one of several enzymes that degrade amyloid-β in the brain, which raised a theoretical concern that long-term neprilysin inhibition might promote Alzheimer disease. In healthy volunteers, 2 weeks of high-dose sacubitril/valsartan increased cerebrospinal fluid amyloid-β 1-38, a soluble form, without changing the aggregable forms 1-40 and 1-42, and LBQ657 crosses the blood-brain barrier to a very limited extent. In PARADIGM-HF, dementia-related adverse events did not differ from enalapril, and a prespecified analysis of PARAGON-HF found no difference between sacubitril/valsartan and valsartan in the change in Mini-Mental State Examination score at 96 weeks. No clinical evidence of harm has emerged, and the concern does not alter prescribing.

Cost, generic availability, and access

Most ACE inhibitors and ARBs are inexpensive generics. Sacubitril/valsartan was available only as a branded product in the United States until generic versions, approved by the FDA, reached the market. Out-of-pocket cost still limits use for some patients, especially under Medicare Part D. The 2022 guideline assigns high economic value to ARNI therapy in place of an ACE inhibitor in symptomatic HFrEF, and it identifies out-of-pocket cost as a barrier to guideline-directed therapy. When sacubitril/valsartan is not affordable, an ACE inhibitor or ARB titrated to the target dose provides substantial benefit, and the patient is not left without renin-angiotensin inhibition while access is arranged. Pharmacist-led titration clinics, 90-day prescriptions, and single-pill combinations in hypertension improve adherence.

How European guidance on renin-angiotensin inhibitors differs

The 2021 ESC heart failure guideline, unchanged on this point by the 2023 focused update, places an ACE inhibitor or sacubitril/valsartan among the four first-line drug classes for HFrEF. It recommends an ACE inhibitor as the first choice (Class I), replacement of the ACE inhibitor by sacubitril/valsartan in patients who remain symptomatic (Class I), an ARB only for patients who cannot tolerate an ACE inhibitor or ARNI, and de novo sacubitril/valsartan in hospitalized patients (Class IIb). US guidance places the ARNI first. The ESC guideline accepts a larger creatinine rise before dose reduction (up to 50% or to 3.0 mg/dL) than US guidance does. The 2024 ESC hypertension guideline, like the US guideline, makes an ACE inhibitor or ARB one of the first-line classes and classes dual renin-angiotensin blockade as harmful.

Sources of error in prescribing renin-angiotensin inhibitors

• Starting sacubitril/valsartan less than 36 hours after the last ACE inhibitor dose, or prescribing both during a transition of care, which risks angioedema.
• Continuing an ARB with sacubitril/valsartan, which duplicates valsartan.
• Prescribing sacubitril/valsartan to a patient with any history of angioedema with an ACE inhibitor or ARB.
• Stopping a renin-angiotensin inhibitor for a creatinine rise of less than 30% that has stabilized, which forfeits long-term cardiac and kidney benefit.
• Attributing a large creatinine rise to the drug without excluding volume depletion, NSAIDs, obstruction, and bilateral renal artery stenosis.
• Stopping the renin-angiotensin inhibitor for mild hyperkalemia while potassium supplements, salt substitutes, or trimethoprim continue.
• Leaving a patient at the starting dose indefinitely, or regarding 50 mg of losartan as a heart failure target dose.
• Combining an ACE inhibitor with an ARB, or either with aliskiren, to reduce proteinuria.
• Reducing the ARNI dose for asymptomatic systolic pressure in the 90s while nonprognostic vasodilators continue.
• Interpreting a rising BNP during the first weeks of sacubitril/valsartan as worsening heart failure, instead of following NT-proBNP.
• Treating ACE inhibitor angioedema as allergic and discharging the patient on the same drug, or failing to recognize angioedema that begins after years of therapy.
• Continuing a renin-angiotensin inhibitor in a patient who has become pregnant, or failing to counsel a patient of reproductive potential.
• Failing to restart the drug after surgery, contrast exposure, or a dehydrating illness.
• Switching an ACE inhibitor to another ACE inhibitor for cough, which does not resolve it.

Expected relative benefit of renin-angiotensin inhibitors by indication

The size of benefit depends on baseline risk. In symptomatic HFrEF, an ACE inhibitor reduces mortality by about 16% to 40% relative to placebo depending on severity, and sacubitril/valsartan reduces cardiovascular death or heart failure hospitalization by a further 20% relative to enalapril. Modeling from PARADIGM-HF estimated a gain in life expectancy of about 1 to 2 years for a typical patient treated with sacubitril/valsartan instead of enalapril from middle age. After myocardial infarction with left ventricular dysfunction, ACE inhibitors reduce mortality by about one-fifth. In high-risk vascular disease without heart failure, ramipril and perindopril reduce major cardiovascular events by about one-fifth, while in well-treated low-risk patients (PEACE) the benefit is not detectable. In proteinuric diabetic and nondiabetic CKD, ACE inhibitors and ARBs reduce progression to kidney failure by about one-fifth to one-half, depending on the degree of albuminuria. In HFpEF, the benefit of renin-angiotensin inhibitors on clinical outcomes is modest at best and concentrated at the lower end of the ejection fraction range.

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