PARAGON-HF: Lowest risk in HFpEF observed with 120-129 mm Hg systolic BP
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Patients with HF with preserved ejection fraction who had a baseline and mean achieved systolic BP between 120 mm Hg and 129 mm Hg had the lowest risk for CV and other outcomes compared with higher systolic BP, according to new analysis of the PARAGON-HF trial.
The analysis is part of the program of the American College of Cardiology Scientific Session and has been simultaneously published in the Journal of the American College of Cardiology.
As Healio previously reported from the 2019 European Society of Cardiology Congress, sacubitril/valsartan (Entresto, Novartis) did not reduce the rate of hospitalizations for CV-related death and HF in patients with HFpEF, defined as at least 45%. A few months later at the American Heart Association Scientific Sessions, two analyses of the trial were presented, which found that sacubitril/valsartan reduced the risk for HF hospitalization more in women compared with men, and the overall benefit of the treatment was driven by a benefit in patients with chronic HF and a left ventricular ejection fraction below the normal range.
New analysis of PARAGON-HF
In this analysis, Senthil Selvaraj, MD, fellow in the division of cardiovascular medicine at the Hospital of the University of Pennsylvania, and colleagues analyzed data from 4,795 patients (mean age, 73 years; 52% women; mean BP at baseline, 131/74 mm Hg) with available systolic BP information at baseline. Patients were groups by baseline systolic BP: less than 120 mm Hg, 120 mm Hg to 129 mm Hg, 130 mm Hg to 139 mm Hg and 140 mm Hg or greater.
Endpoints of interest included the primary composite outcome of CV death and total HF hospitalizations, individual components of the composite outcome, stroke or MI, all-cause mortality and a renal composite outcome of end-stage renal disease development, decrease in estimate glomerular filtration rate of at least 50%, or death from renal failure and doubling of serum creatinine.
Researchers also assessed the relationship of systolic BP to several endpoints in a subgroup of patients. Endpoints for this included high-sensitivity troponin T, N-terminal pro-B-type natriuretic peptide and quality of life according to the Kansas City Cardiomyopathy Questionnaire.
Patients with a baseline and mean achieved systolic BP between 120 mm Hg and 129 mm Hg had the lowest risk for all outcomes compared with other systolic BP ranges.
At 4 weeks, patients assigned sacubitril/valsartan had a reduction in systolic BP of 5.2 mm Hg (95% CI, 4.4-6) compared with those assigned valsartan alone. This effect was not modified by systolic BP at baseline.
Sacubitril/valsartan resulted in a greater systolic BP reduction in women (6.3 mm Hg; 95% CI, 5.2-7.4) compared with men (4 mm Hg; 95% CI, 2.9-5.1; P for interaction = .005). This was primarily driven by a higher systolic BP in women assigned valsartan alone.
Systolic BP changes was associated with changes in NT-proBNP (P < .001), although this was not seen for Kansas City Cardiomyopathy Questionnaire scores (P = .4) or high-sensitivity troponin T. Each 10 mm Hg lowering in systolic BP was associated with a modest change in log-transformed NT-proBNP at 16 weeks (–3.8%; P < .001). This was also similar at 48 weeks (–2.1%; P = .027).
Systolic BP at baseline did not modify the link between sacubitril/valsartan and the primary outcome (P for interaction = .5). This remained similar after adjusting for time-updated systolic BP regardless of sex.
“Our analyses provide new insight into the relationship of baseline and mean achieved systolic BP and outcomes in HFpEF, and further suggest that systolic BP reduction with sacubitril/valsartan is not responsible for its treatment benefits in HFpEF in both women and men,” the researchers wrote.
Complex relationship
In a related editorial published in JACC, Hector O. Ventura, MD, section head of the Cardiomyopathy and Heart Transplant Center at the Ochsner Clinic Foundation in New Orleans, and colleagues wrote: “What is certain ... is that the relationship and contributions of hypertension to manifest HFpEF are complex, multifactorial and likely go well beyond a simplistic framework of hemodynamic influences. ... The PARAGON-HF investigators weave a compelling story to define the potential dissociation of the hemodynamic effects of pharmacological therapy in determining clinical efficacy while outlining the important role of blood pressure target as a potentially vital prognostic surrogate for determining clinical outcomes.” – by Darlene Dobkowski
References:
Selvaraj S, et al. Heart failure with preserved ejection fraction: Identifying mechanisms and targeting therapy. Presented at: American College of Cardiology Scientific Session; March 28-30, 2020 (virtual meeting).
Selvaraj S, et al. J Am Coll Cardiol. 2020;doi:10.1016/S0735-1097(20)31307-3.
Ventura HO, et al. J Am Coll Cardiol. 2020;doi:10.1016/j.jacc.2020.02.024.
Disclosures: The PARAGON-HF trial was funded by Novartis. Selvaraj reports he received a training grant from the NIH. Ventura reports no relevant financial disclosures. Please see the study and editorial for all other authors’ relevant financial disclosures.
Perspective
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Ali Ahmed, MD, MPH
These findings confirm that baseline systolic BP has no association with total or CV mortality in patients with HFpEF (EF ≥ 45%) enrolled in the PARAGON-HF trial. When compared with systolic BP 120 mm Hg to 129 mm Hg, systolic BP of 140 mm Hg or greater was associated with a 54% higher risk of the primary combined endpoint of total HF hospitalizations or CV death, but it was mostly driven by HF hospitalization. Baseline systolic BP also had no association with CV mortality or HF hospitalization in patients with HFpEF (EF ≥ 45%) in the TOPCAT trial (Selvaraj S, et al. Eur J Heart Fail. 2017;doi:10.1002/ejhf.1060).
We have demonstrated that a normal systolic BP (< 120 mm Hg) is associated with a higher risk of both mortality and readmission in hospitalized older patients with HFpEF (EF ≥ 50%) in the OPTIMIZE-HF registry (Tsimploulis A, et al. JAMA Cardiol. 2018;doi:10.1001/jamacardio.2017.5365).
Taken together, these findings suggest that there is no evidence that a normal (< 120 mm Hg) or lower (< 130 mm Hg) baseline systolic BP is associated with a lower risk of death in patients with HFpEF. The association with HF hospitalization is conflicting (lower risk in PARAGON-HF, null in TOPCAT and higher risk in OPTIMIZE-HF).
What the current study adds new is the role of systolic BP change. In PARAGON-HF, mean baseline systolic BP was 131 ± 16 mm Hg, and by 4 weeks, it was about 5 mm Hg higher in the valsartan group than in the sacubitril/valsartan group. In the current study, the authors examined the association between “time-updated mean achieved systolic BP” and outcomes using 120 mm Hg to 129 mm Hg as a reference, and noted that achieved systolic BP of 140 mm Hg or greater was associated with a 30% higher risk of the primary combined endpoint, which was driven by the HF hospitalization. However, achieved systolic BP of 140 mm Hg or greater was not associated with a higher risk of total mortality. In contrast, achieved systolic BP of less than 120 mm Hg was associated with a 29% higher risk of total mortality. Achieved systolic BP had no association with quality of life.
According to the 2017 update of the 2013 American College of Cardiology/American Heart Association HF guideline (Yancy CW, et al. Circulation. 2017;doi: 10.1161/CIR.0000000000000509), systolic BP in euvolemic patients with HFpEF and persistent hypertension should be lowered to less than 130 mm Hg. Findings from the current study, taken together with the other two studies of systolic BP in HFpEF, suggest that currently there is no evidence that baseline or “achieved” systolic BP of less than 130 mm Hg is associated with improved outcomes and that an achieved systolic BP of less than 120 mm Hg may be associated with a higher risk of total death.
Future studies are needed to prospectively evaluate optimal systolic BP treatment goals in patients with HFpEF.
When similar methodologies are used, observational studies of systolic BP and outcomes in the general population consistently demonstrate that a lower systolic BP is associated with better outcomes. This suggests that the association of systolic BP with outcomes in HFpEF is different from that in the general population, and it is possible that in patients with HFpEF, a lower systolic BP is a marker of underlying pathophysiologic severity. However, in the absence of any evidence of improved outcomes associated with baseline or achieved systolic BP of less than 130 mm Hg and suggestion of possible associated harm at normal systolic BP (< 120 mm Hg), clinicians may not want to aggressively lower systolic BP in patients with HFpEF. Findings from our preliminary data in patients with HFpEF and hypertension suggest that a very high systolic BP may be associated with a higher risk of death and need to be avoided. However, the optimal systolic BP treatment goals in patients with HFpEF will ultimately need to be evaluated in future prospective studies.
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