Lowest risk of outcomes in HFpEF associated with SBP of 120-129 mmHg
Systolic Blood Pressure in Heart Failure With Preserved Ejection Fraction Treated With Sacubitril/Valsartan
Introduction and methods
Hypertension is common in patients with heart failure with preserved ejection fraction (HFpEF) and can lead to left ventricular hypertrophy, diastolic dysfunction, abnormal ventricular arterial coupling, and end-organ damage. It has been presumed that blood pressure (BP) control could be related to improved outcomes [1-3]. Society guidelines recommend a systolic BP (SBP) of <130 mmHg in patients with HFpEF [4,5]. There is, however, little evidence that supports this recommendation. It has remained unclear to which extend SBP control influences clinical outcomes. Furthermore, it is not known whether BP lowering is associated with clinical benefit and the relationship between BP reduction and biomarkers in HFpEF is not well established. This study assessed the prognostic role of baseline SBP and mean achieved SBP in patients with HFpEF in PARAGON-HF. Moreover, the relationship between SBP reduction with clinical outcomes and biomarkers was investigated, and it was assessed whether the treatment effect of sacubitril/valsartan was mediated by SBP reduction.
PARAGON-HF was a randomized, double-blind, parallel group, event-driven trial that investigated the efficacy and safety of sacubitril/valsartan vs valsartan in patients with HFpEF . In this study data from 4,795 trial participants (average age was 73 ± 8 years, 52% were women, 82% were white) were analyzed. The primary composite outcome of this analysis was total (first and recurrent) hospitalizations for HF, and CV death. Other efficacy outcomes included CV death, total HF hospitalizations, myocardial infarction or stroke, all-cause mortality, and a renal composite outcome (decrease in eGFR of ≥50%, development of end stage renal disease, or death due to renal failure). The safety outcome was dose reduction or discontinuation. Baseline SBP and mean achieved SBP were grouped by quartiles (quartile 1: <120 mmHg; quartile 2: 120 to 129 mmHg; quartile 3: 130 to 139 mmHg; quartile 4: ≥140 mmHg). In addition, quality of life (using the overall summary score on the Kansas City Cardiomyopathy Questionnaire [KCCQ-OSS]), NT-proBNP, and high-sensitivity troponin T were assessed in a subgroup of participants with available data.
- The highest quartile of baseline SBP was independently associated with higher risk for the primary outcome after multivariable adjustment, with quartile 2 as the reference quartile (HR 1.54, 95%CI 1.24-1.91). This was driven by a greater risk in total HF hospitalizations (HR 1.63, 95%CI 1.28-2.09). Quartile 2 of baseline SBP had the lowest risk for all studied outcomes.
- A J-shaped relationship was observed between SBP and the primary outcome (and the other CV outcomes) in an analysis that modeled SBP as a continuous variable.
- The relationship between sacubitril/valsartan and the primary outcome (or any other outcome) was not modified by baseline SBP (interaction P=0.50 for primary outcome; P>0.20 for all interaction terms).
- Next, the relationship between change in SBP and subsequent risk was assessed by analyzing the time-updated mean achieved SBP for all study outcomes, using quartile 2 as referent arm. Quartile 4 was associated with elevated risks of the primary outcome (HR 1.30, 95%CI 1.14-1.47) and total HF hospitalizations (HR 1.39, 95%CI 1.20-1.60) after multivariable adjustment. Quartile 1 was associated with an elevated risk of all-cause mortality (HR 1.29, 95%CI 1.04-1.62). Quartiles 3 and 4 were associated with higher risks of myocardial infarction or stroke (HR 1.39, 95%CI 1.04-1.84 for quartile 3, and HR 1.68, 95%CI 1.26-2.24 for quartile 4), and of the renal composite outcome (HR 1.87, 95%CI 1.04-3.38 for quartile 3, and HR 1.87, 95%CI 1.02-3.43 for quartile 4). Quartile 2 of mean achieved SBP was associated with the lowest risk for all outcomes.
- Sacubitril/valsartan reduced SBP by 5.2 mmHg (95%CI 4.4-6.0), compared with valsartan at 4 weeks. The BP-lowering effect of sacubitril/valsartan was similar across the 4 SBP baseline quartiles at the 4-week visit (interaction P=0.61), but the difference in SBP in the 2 treatment arms diminished over time in the highest quartile. The SBP-lowering effect of sacubitril/valsartan was higher in women (6.3 mmHg, 95%CI 5.2-7.4 mmHg), than in men (4.0 mmHg, 95%CI 2.9-5.1 mm Hg) at the 4-week visit.
- Change in SBP between baseline and the 16- and 48 week visits was not associated with change in KCCQ-OSS or high-sensitivity troponin T, after multivariable-adjusted analysis. Change in SBP was associated with a change in log-transformed NT-proBNP (-3.8% per 10 mmHg lowering in SBP, P<0.001 at week 16, and -2.1% per 10 mmHg lowering in SBP, P=0.027 at week 48).
- The treatment effect of sacubitril/valsartan was not modified by baseline SBP and was similar when adjusting for time-updated SBP, regardless of sex.
Baseline and mean achieved SBP of 120 to 129 mmHg were associated with the lowest risk of adverse outcomes in patients with HFpEF. Sacubitril/valsartan reduced SBP by 5.2 mmHg (95%CI 4.4-6.0), compared with valsartan at 4 weeks and the SBP-lowering effect was higher in women than in men. SBP-lowering was associated with a modest reduction in NT-proBNP. The BP-lowering effect of sacubitril/valsartan did not account for the treatment effects on outcomes.