Sacubitril/Valsartan vs. Valsartan and Symptomatic Hypotension

Quick Takes

  • PARAGLIDE-HF participants experienced symptomatic hypotension at rates of 24% in the sacubitril/valsartan group vs. 15% in the valsartan group.
  • When prescribing sacubitril/valsartan or valsartan for patients diagnosed with HFpEF or HFmrEF, consider patients with higher LVEF (>60%) and lower baseline systolic BP (<120 mm Hg) at higher risk for symptomatic hypotension during treatment.
  • Overall clinical benefits are higher with sacubitril/valsartan vs. valsartan, but warrant close monitoring for adverse effects including symptomatic hypotension.

Study Questions:

Is there an association of sacubitril/valsartan versus valsartan, with symptomatic hypotension among patients who were enrolled in PARAGLIDE-HF trial?


PARAGLIDE-HF was a multicenter, double-blind, randomized, controlled trial with the goal of evaluating the effects of sacubitril/valsartan versus valsartan on N-terminal pro–B-type natriuretic peptide (NT-proBNP), safety, and tolerability following a recent (within 30 days) worsening heart failure (HF) event for patients diagnosed with HF with preserved ejection fraction (HFpEF) or HF with mildly reduced EF (HFmrEF). A case report form was used to collect symptomatic hypotension events in the PARAGLIDE-HF trial and events were investigator-reported. The measurements of blood pressure (BP) occurred at each follow-up visit and symptoms were evaluated by questioning the patient for experiencing lightheadedness, dizziness, feeling faint, blurred vision, auditory disturbances, emesis, or syncope since the last visit. Any subsequent medication changes were then at the discretion of the prescribers. For this review, outcome comparisons were based on baseline systolic BP stratified by the median BP. Endpoints for this review included time-averaged proportional change in NT-proBNP from baseline through weeks 4 and 8. Additional secondary categorized outcome (win ratio) included cardiovascular death, hospitalization for HF and urgent visits, and change in NT-proBNP.


The PARAGLIDE-HF study participants included 466 patients randomized to sacubitril/valsartan versus valsartan and this analysis found that 92 (19.7%) experienced symptomatic hypotension. This included 24% with sacubitril/valsartan and 15.5% with valsartan. The time to first episode of symptomatic hypotension that was classified as serious by the investigators was similar between both groups, with 18 days versus 15 days (p = 0.42). Medication changes or nondrug therapy changes from the investigators occurred in 42.9% with the sacubitril/valsartan arm versus 16.7% with the valsartan arm (p = 0.009). Factors that were associated with symptomatic hypotension included being White (odds ratio [OR], 1.87; 95% confidence interval [CI], 0.31-11.15), having a lower baseline systolic BP (per 10 mm Hg increase: OR, 0.68; 95% CI, 0.55-0.85), or having a left ventricular EF (LVEF) >60% (OR, 2.21; 95% CI, 1.05-4.65). There were no differences in time-averaged changes in NT-proBNP with baseline systolic BP ≥128 mm Hg versus ≤128 mm Hg (interaction p = 0.43).


Patients with HFpEF and HFmrEF were found to have a reduced NT-proBNP and additional clinical benefit when prescribed sacubitril/valsartan versus valsartan in the PARAGLIDE-HF trial. The sacubitril/valsartan group also experienced more episodes of symptomatic hypotension, and this review evaluated associated factors. Among both groups, patients experiencing more episodes of symptomatic hypotension were identified as having higher LVEF (>60%), lower baseline systolic BPs, and White race. Benefits of sacubitril/valsartan may be more significant in patients with higher baseline systolic BP and lower LVEF.


When considering the well-established clinical value of prescribing sacubitril/valsartan and valsartan for HF patients, one must also consider adverse effects. This analysis of HFpEF and HRmrEF PARAGLIDE-HF trial participants provides insight into the importance of close monitoring of HF patients’ BP and increased knowledge of those at risk for symptomatic hypotension. This particular adverse effect creates challenges for the prescriber reaching endpoints of guideline-directed medical therapy and also complicates patient compliance and safety. This analysis should not deter use of sacubitril/valsartan but should be a reminder to have frank discussions with patients, utilize proper BP measurement techniques at home and in-office, monitor BP trends, and continue to have close follow-up with our patients.

Clinical Topics: Cardiovascular Care Team, Heart Failure and Cardiac Biomarkers

Keywords: Hypotension, Heart Failure, Preserved Ejection Fraction

< Back to Listings