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Hypotension With Sacubitril/Valsartan Use in HFrEF
Quick Takes
- In patients with HFrEF, both asymptomatic and symptomatic hypotension while receiving either sacubitril/valsartan or enalapril were associated with poor clinical outcomes.
- Despite the presence of hypotension, the treatment benefit of sacubitril/valsartan over enalapril was maintained.
Study Questions:
Among patients with heart failure and reduced ejection fraction (HFrEF) started on sacubitril/valsartan, what is the association between asymptomatic versus symptomatic hypotension and clinical outcomes?
Methods:
This study is a post hoc analysis of the PARADIGM-HF randomized trial, which demonstrated a benefit of sacubitril/valsartan compared to enalapril in patients with HFrEF for the primary composite outcome of death from cardiovascular (CV) causes or HF hospitalization. Of note, patients with intolerance to angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, symptomatic hypotension, or a systolic blood pressure (SBP) <100 mm Hg at screening (or <95 mm Hg at randomization) were excluded from the trial. A standardized approach was used for the management of hypotension during the trial.
Results:
There were 8,399 patients in the PARADIGM-HF trial. Of these, 936 (11.1%) had at least one episode of symptomatic hypotension and 1,343 (16.0%) had only asymptomatic hypotension (SBP of <100 mm Hg). Patients with symptomatic hypotension were more likely to be older, have New York Heart Association class III or IV symptoms, and have lower estimated glomerular filtration rate, and have more CV comorbidities. Patients with asymptomatic hypotension were more likely to have lower baseline SBPs and have lower left ventricular EFs.
When examining the entire trial cohort, compared to patients without hypotension, those with asymptomatic and symptomatic hypotension experienced a higher adjusted risk for the primary composite outcome as well as a higher risk for CV death, HF hospitalization, and all-cause death. Despite worse outcomes when hypotension is present, the treatment benefit of sacubitril/valsartan over enalapril was not decreased for those with hypotension compared to no hypotension (no hypotension: hazard ratio [HR], 0.80; 95% confidence interval [CI], 0.72-0.89; asymptomatic hypotension: HR, 0.87; 95% CI, 0.70-1.08; symptomatic hypotension: HR, 0.51; 95% CI, 0.38-0.69).
Conclusions:
Any hypotension while receiving treatment with sacubitril/valsartan or enalapril was associated with worse clinical outcomes. However, the treatment benefit of sacubitril/valsartan over enalapril was maintained even when asymptomatic or symptomatic hypotension was present.
Perspective:
The development of hypotension when initiating and titrating HF guideline-directed medical therapies is a significant problem for patients with HFrEF. Hypotension is a known marker for poor prognosis and the presence of hypotension may lead to the reduction or discontinuation of HF therapies (and possibly the loss of potential medication benefits). The results of this study confirm the negative clinical association of hypotension while on either sacubitril/valsartan or enalapril. However, importantly, this does not mean therapies should be stopped, as there still is potential treatment benefit of sacubitril/valsartan over enalapril despite the presence of hypotension.
This study also interestingly highlights differences between asymptomatic and symptomatic hypotension, which may suggest these are different phenotypes. While this study does provide new insights, more research is needed to better define the best approach to management of hypotension in HF and ensure findings like these are generalizable to all HFrEF patients (especially ones that may be at higher risk of symptomatic hypotension and end-organ dysfunction).
Clinical Topics: Heart Failure and Cardiomyopathies
Keywords: Heart Failure, Reduced Ejection Fraction, Hypotension, Valsartan
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