Entresto's Effect on Blood Pressure
Entresto (sacubitril/valsartan) consistently lowers blood pressure through dual mechanisms of neprilysin inhibition and angiotensin II receptor blockade, demonstrating superior BP reduction compared to ARBs alone, though it is not currently endorsed by guidelines for routine hypertension treatment outside of heart failure indications. 1
Blood Pressure Lowering Efficacy
Magnitude of BP Reduction
In patients with heart failure and preserved ejection fraction (HFpEF) who have apparent resistant hypertension, sacubitril/valsartan reduced systolic BP by 4.8 mmHg at 4 weeks and 3.9 mmHg at 16 weeks compared to valsartan alone. 2
In patients with apparent MRA-resistant hypertension (uncontrolled despite valsartan, calcium channel blocker, diuretic, AND mineralocorticoid receptor antagonist), sacubitril/valsartan achieved even greater reductions: 8.8 mmHg at 4 weeks and 6.3 mmHg at 16 weeks versus valsartan. 2
In real-world hypertensive patients with heart failure, sacubitril/valsartan reduced systolic BP by 12.8 mmHg and diastolic BP by 7.1 mmHg during follow-up. 3
BP control rates improved substantially: 47.9% of patients with apparent resistant hypertension achieved controlled BP by week 16 with sacubitril/valsartan versus only 34.3% with valsartan alone (adjusted OR 1.78). 2
Mechanisms Beyond Simple BP Lowering
Sacubitril/valsartan reduces sympathetic nervous system activity independent of BP changes, decreasing muscle sympathetic nerve activity burst frequency from 43 to 36 bursts/min after 2 months without changing heart rate or BP. 4
The drug inhibits cardiomyocyte hypertrophy more effectively than valsartan or enalapril despite equivalent BP reductions in animal models, suggesting beneficial cardiac effects beyond hemodynamic changes. 5
Current Guideline Position
Regulatory Status
The 2024 ESC Hypertension Guidelines state that sacubitril/valsartan "awaits supportive evidence from cardiovascular outcomes trials prior to guideline endorsement and routine use in hypertension," though it was initially developed for hypertension and has been studied at higher doses (200-400 mg once daily) for this indication. 1
The drug is FDA-approved for heart failure with reduced ejection fraction, not specifically for hypertension treatment. 6
Sacubitril/valsartan is approved in China and Japan as an antihypertensive agent but not in Europe or the USA for hypertension. 3
Evidence in Heart Failure Populations
In PARADIGM-HF, the BP-lowering effect may have partially mediated the superior reduction in cardiovascular mortality and morbidity compared to enalapril alone. 1
Post-hoc analysis showed sacubitril/valsartan lowered BP in adults with both HFpEF and resistant hypertension. 1
Benefits were consistent across all baseline systolic BP categories (<110-<120-<130-<140, >140 mmHg), indicating low BP should not prevent optimization. 1
Safety Considerations Related to BP
Hypotension Risk
Symptomatic hypotension occurred in 11.1% of PARADIGM-HF patients, while 16.0% experienced asymptomatic hypotension, but efficacy and safety were maintained regardless of hypotension occurrence. 1
In the PIONEER trial of acute heart failure patients, symptomatic hypotension occurred in 15% with sacubitril/valsartan versus 12.7% with enalapril. 1
The ESC guidelines note sacubitril/valsartan causes more symptomatic hypotension than valsartan alone, requiring careful BP monitoring. 6
Paradoxical BP Effects in Low BP Patients
Patients with baseline systolic BP 95-110 mmHg experienced a mild BP increase over follow-up in both sacubitril/valsartan and enalapril arms, though more pronounced with enalapril. 1
In VICTORIA, patients with baseline systolic BP <110 mmHg showed a trend of increasing BP over time in both study arms. 1
Clinical Pitfalls and Practical Considerations
Dosing in Special Populations
Dose adjustment is required in patients with creatinine clearance <30 mL/min or moderate hepatic impairment, starting at 24/26 mg twice daily. 6
Patients with renal dysfunction (eGFR <60 mL/min/1.73 m²) had more adverse events in real-world studies. 3
Lower Doses May Be Effective
- The lower dosage group (<200 mg/day) achieved a higher BP control rate (83.4% vs 75.6%) and better overall improvement in cardiac indicators (61.3% vs 48.0%) compared to higher doses. 3