Systolic BP and Outcomes in HF Patients on Sacubitril/Valsartan

Study Questions:

What is the association between systolic blood pressure (SBP) and outcomes on systolic heart failure (HF) patients treated with the angiotensin receptor-neprilysin inhibitor (ARNI) sacubitril/valsartan when compared to enalapril?


The study cohort was comprised of 8,399 systolic HF patients enrolled in the PARADIGM-HF (Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial, as well as the effect of sacubitril/valsartan, compared with enalapril, according to baseline SBP. The study investigators evaluated the effect of treatment on SBP and on the primary composite outcome (cardiovascular mortality or HF hospitalization), its components, and all-cause mortality. Specifically, they analyzed change in SBP from baseline to 4 months, and over the whole duration of follow-up, as well as time-updated SBP during follow-up. They examined baseline SBP as a categorical (<110, 110 to <120, 120 to <130, 130 to <140, and ≥140 mm Hg) and a continuous measure. They examined the association between baseline SBP, change in SBP and time-updated SBP, and the primary endpoint and secondary endpoints described above. They also explored the effect of sacubitril/valsartan, compared with enalapril, on these endpoints according to baseline SBP category and SBP analyzed as a continuous measure. Adverse events according to baseline SBP category are also reported. The effect of sacubitril/valsartan, compared with that of enalapril, on each outcome of interest, according to SBP category, was examined using Cox proportional hazards regression models.


The investigators found that compared to patients with higher SBP, those with lower SBP were younger, more often male, and less likely to have an ischemic etiology or a history of diabetes or hypertension. Patients with a lower SBP also had a lower ejection fraction and slightly lower heart rate and body mass index. They also found that the risk of mortality (all-cause and cardiovascular) and the risk of HF hospitalization is higher in patients with a lower SBP. However, above a SBP of approximately 120 mm Hg, the relationship between SBP and both types of mortality was flat, whereas the risk of HF hospitalization was greater in patients with a higher SBP (approximately <140 mm Hg); i.e., there was a U-shaped relationship between SBP and HF hospitalization, whereas all-cause and cardiovascular mortality rates were highest in patients with the lowest SBP. The benefit of sacubitril/valsartan over enalapril was consistent across all baseline SBP categories for all outcomes—the sacubitril/valsartan versus enalapril hazard ratio for the primary endpoint was 0.88 (95% confidence interval [CI], 0.74–1.06) in patients with a baseline SBP <110 mm Hg, 0.84 (0.70–1.01) for 110 to <120 mm Hg, 0.73 (0.61–0.87) for 120 mm Hg to <130 mm Hg, 0.74 (0.59–0.92) for 130 to <140 mm Hg, and 0.81 (0.65–1.02) for those with a SBP ≥140 mm Hg (p value for interaction = 0.55). They also found that patients with lower BP had more frequent symptomatic hypotension, study drug dose-reduction, and discontinuation.


The study authors concluded that compared to patients with a higher SBP, those with lower SBP may obtain greater absolute benefits from sacubitril/valsartan, but at the expense of more hypotension-related adverse effects.


This is an important study because it demonstrates, what many experienced clinicians have known, that lower SBP is an indicator of a left ventricular ‘squeeze’ that is below par. That is, when comparing two patients with the same left ventricular ejection fraction, the one with the lower SBP is more likely to have a worse outcome. It is heartening to note that the benefit of sacubitril/valsartan is consistent across all SBP categories and should prompt the practicing physician to increasingly consider this therapy for their patients with systolic HF.

Clinical Topics: Heart Failure and Cardiomyopathies, Prevention, Acute Heart Failure, Chronic Heart Failure, Heart Failure and Cardiac Biomarkers, Hypertension

Keywords: Blood Pressure, Body Mass Index, Diabetes Mellitus, Enalapril, Heart Failure, Systolic, Heart Failure, Hypertension, Hypotension, Mortality, Myocardial Ischemia, Neprilysin, Receptors, Angiotensin, Stroke Volume

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