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MRAs, Blood Pressure, and Outcomes in HFrEF
Study Questions:
What are the effects of mineralocorticoid receptor antagonists (MRAs) on systolic blood pressure (SBP) and outcomes according to baseline SBP in patients with heart failure with reduced ejection fraction (HFrEF)?
Methods:
The study cohort was comprised of 4,396 patients with HFrEF randomized in the RALES (Randomized Aldactone Evaluation Study) and EMPHASIS-HF (Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure) trials. Patients were divided into five baseline SBP categories: ≤105, >105 to ≤115, >115 to ≤125, >125 to ≤135, and >135 mm Hg, to ensure equally sized groups across the spectrum of BP values. In the RALES trial, SBP was measured at 1, 2, 3, 6, and 9 months and at 1, 5, and 9 months in the EMPHASIS-HF trial. In this analysis, the 5- and 6-month measurements were considered to have occurred at 6 months. The primary outcome used in this analysis was the composite of cardiovascular death or HF hospitalization. The components of this composite and all-cause death were also examined. The authors also analyzed the occurrence of investigator-reported hypotension, a decrease in SBP ≥30 mm Hg at the 6-month measurement, and decrease of SBP <85 mm Hg at the 1-month, 6-month, and both measurements.
Results:
The study authors found that mean SBP change from baseline to 6 months was +1.4 ± 18.1 mm Hg in the placebo group and -1.2 ± 17.9 mm Hg in the MRA group. The between-treatment difference was 2.6 mm Hg (95% confidence interval [CI], 1.5-3.6; p < 0.001). All outcomes were reduced by MRA therapy overall, with consistent effects across SBP categories (e.g., all-cause mortality, overall hazard ratio [HR], 0.72; 95% CI, 0.64-0.82; p < 0.001; SBP ≤105 mm Hg; HR, 0.72; 95% CI, 0.56-0.94; SBP >105 to ≤115 mm Hg; HR, 0.78; 95% CI, 0.60-1.02; SBP >115 to ≤125 mm Hg; HR, 0.71; 95% CI, 0.53-0.94; SBP >125 to ≤135 mm Hg; HR, 0.79; 95% CI, 0.57-1.10; and SBP >135 mm Hg; HR, 0.67; 95% CI, 0.50-0.90; p for interaction = 0.95). Hypotension was infrequent and not more common with MRA therapy than with placebo, overall (4.6% vs. 3.9%; p = 0.25) or in any SBP category.
Conclusions:
The authors concluded that MRA therapy had little effect on SBP in patients with HFrEF, and the clinical benefits were not modified by baseline SBP. MRA treatment infrequently caused hypotension, even when the baseline SBP was low. The treatment discontinuation rates between MRA and placebo therapy were similar. Low SBP is not a reason to withhold MRA therapy in patients with HFrEF.
Perspective:
The findings of this study are important, given the findings of the recent PATHWAY-2 (Prevention And Treatment of Hypertension With Algorithm based therapY) trial seem to have led to the perception that MRAs are powerful antihypertensive agents and amplified the concern about steep fall in SBP in patients with HFrEF. Patients with HFrEF have a Frank-Starling curve that is more flat than those of normal individuals and therefore up-titration of HF medications is less likely to cause large reductions in SBP. The findings of this study are reassuring to the practitioner who is concerned of hypotension with MRAs.
It must be remembered that applying the overall relative risk reduction of 27% in all-cause mortality with MRA therapy, patients in the lowest SBP category would have the greatest absolute mortality benefit because they had the highest absolute mortality rate. As the study authors point out that specifically, therapy would lead to approximately 11 fewer deaths per 100 patients treated with an MRA drug in the SBP group of ≤105 mm Hg, compared with six fewer deaths per 100 patients in the SBP group of >135 mm Hg.
Clinical Topics: Geriatric Cardiology, Heart Failure and Cardiomyopathies, Prevention, Acute Heart Failure, Hypertension
Keywords: Antihypertensive Agents, Blood Pressure, Blood Pressure Determination, Geriatrics, Heart Failure, Hypertension, Hypotension, Mineralocorticoid Receptor Antagonists, Primary Prevention, Risk, Spironolactone, Stroke Volume
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