Sacubitril ValsartanEdit

Sacubitril/valsartan is a prescription cardiovascular drug that combines a neprilysin inhibitor with an angiotensin II receptor blocker. Sold under the brand name Entresto in many markets, the medication belongs to a class known as angiotensin receptor-neprilysin inhibitors (ARNIs). It is most prominently used in the management of chronic heart failure with reduced ejection fraction (HFrEF) and has been shown to lower the risk of cardiovascular death and hospitalization for heart failure in carefully selected patients who are already receiving standard heart failure therapy.

The arrival of sacubitril/valsartan marked a shift in how clinicians approach the renin–angiotensin system and natriuretic peptide signaling in heart failure. By combining blockade of angiotensin II receptors with enhanced natriuretic peptide activity, the drug aims to reduce cardiac stress, promote vasodilation, and limit maladaptive remodeling. In clinical practice, it is typically considered for adults with symptomatic chronic heart failure (NYHA class 2–4) who are already on guideline-directed medical therapy, including an ACE inhibitor or ARB, with the option to substitute sacubitril/valsartan for an ACE inhibitor or ARB in appropriate patients. See heart failure for background on the condition and its conventional treatments.

Medical use

Indications: Sacubitril/valsartan is approved for reducing the risk of cardiovascular death and hospitalization for heart failure in adults with chronic HFrEF. It is commonly used in patients who have tolerated an ACE inhibitor or ARB and who continue to have symptoms despite standard therapy. See sacubitril/valsartan and Entresto for product identity and labeling details.
Population notes: The drug is not indicated for heart failure with preserved ejection fraction (HFpEF) and has not demonstrated clear benefit in all patients with heart failure across all ejection fraction strata. In clinical use, patient selection emphasizes symptom burden, prior therapies, and tolerance to renin–angiotensin system blockade. See heart failure with reduced ejection fraction for the narrower definition used in trials and guidelines.

Mechanism of action

Sacubitril/valsartan works through dual actions:

Neprilysin inhibition: Sacubitril inhibits neprilysin, an enzyme that degrades natriuretic peptides. The resulting increase in natriuretic peptides promotes vasodilation, natriuresis, and anti-hypertrophic effects, which can ease cardiac workload. See neprilysin for background on this enzyme.
Angiotensin II receptor blockade: Valsartan blocks the AT1 receptor, reducing vasoconstriction, aldosterone release, and maladaptive remodeling commonly seen in heart failure. See angiotensin II receptor blocker for the broader class.

The combination yields effects intended to improve hemodynamics and ventricular remodeling beyond what ACE inhibitors or ARBs alone can achieve. See ARNI for the broader drug class.

Clinical evidence and guidelines

Key trial: PARADIGM-HF compared sacubitril/valsartan with enalapril in adults with HFrEF and demonstrated a significant improvement in the primary composite outcome of cardiovascular death and heart failure hospitalization. The results supported a shift in guideline recommendations toward including an ARNI in standard therapy for many patients with HFrEF. See PARADIGM-HF for details.
Guideline uptake: Following the trial results, major cardiovascular societies incorporated ARNIs as a recommended therapy in appropriate patients with HFrEF, often as a preferred alternative to an ACE inhibitor in those who can tolerate it. See American College of Cardiology and European Society of Cardiology guidelines for context on referencing and adoption.
Practical considerations: When switching from an ACE inhibitor to sacubitril/valsartan, clinicians typically observe a washout period to minimize the risk of angioedema. See the product labeling and clinical switching discussions for specifics.

Safety and adverse effects

Common adverse effects: Hypotension, dizziness, hyperkalemia, and renal function changes are among the typical considerations when initiating or adjusting therapy.
Angioedema risk: There is a risk of angioedema, particularly in patients with a prior history of this reaction or those of certain ancestries. This risk informs patient selection and monitoring, and a careful washout period is advised when transitioning from an ACE inhibitor.
Cough and bradykinin: While neprilysin inhibition can influence bradykinin pathways, the incidence of cough tends to be lower than with conventional ACE inhibitors, though it can still occur.
Pregnancy and lactation: The drug is generally avoided in pregnancy due to potential fetal harm; contraception and counseling are important in women of childbearing potential who are on therapy.
Renal considerations: Monitoring renal function and potassium is important, with closer observation in patients with preexisting kidney disease or other risk factors for renal impairment.

Dosing, monitoring, and switching considerations

Initiation and titration: Dosing is typically individualized based on blood pressure, renal function, and potassium levels, with gradual titration to target or tolerated doses as per clinical guidelines.
Switching from ACE inhibitors: A recommended washout period (often around 36 hours, though specifics may vary by label and clinician judgment) helps mitigate angioedema risk during transition.
Drug interactions: Careful review of concomitant therapies, particularly other agents affecting renal function or potassium, is essential to avoid adverse interactions.

Economic and policy considerations

Cost and access: As a branded therapy, sacubitril/valsartan has been the subject of discussion about affordability and reimbursement. Proponents emphasize the potential savings from reduced hospitalizations and improved outcomes, while critics focus on the upfront price and payer access barriers.
Value and innovation: From a market-oriented perspective, the drug is seen as an example of pharmaceutical innovation that delivers meaningful health benefits. The accompanying policy debates often center on how best to achieve patient access without stifling ongoing research and development.
Comparators and alternatives: The availability of other heart failure therapies, including ACE inhibitors, ARBs, beta-blockers, mineralocorticoid receptor antagonists, and device therapies, shapes decisions about when and for whom sacubitril/valsartan is most cost-effective. See health economics discussions for broader framing.

Controversies and debates

Pricing versus value: Critics argue that the price can be a barrier to broad access, especially for patients without robust insurance coverage. Advocates contend that the drug’s benefits—reduced hospitalizations and cardiovascular deaths—justify the cost, and that real-world adherence hinges on coverage and affordability.
Population-specific concerns: There is ongoing discussion about how best to apply ARNIs across diverse patient groups, including considerations of race, ethnicity, and comorbidities. The safety profile, including rare risks like angioedema, informs selective use in certain populations.
HFpEF and broader use: Some discussions push for expanding indications to additional heart failure phenotypes, but current evidence robustly supports use in HFrEF. Critics maintain that broader labeling without solid evidence could misallocate resources.
Cultural and policy critiques: Critics who emphasize government activism in drug pricing often argue for broader price negotiations and transparency. From a more market-driven vantage, supporters claim that allowing private and competitive mechanisms, value-based pricing, and payer-driven formulary decisions can preserve incentives for innovation while improving patient access. Critics of what they call "overreach" in social commentary argue that focusing on pricing alone can obscure the drug’s demonstrated clinical value and the responsibility of stakeholders to balance innovation with patient welfare.