PARAGON-HF: Optimal Systolic Pressure in HFpEF is 120-129 mmHg

Bruce Jancin

March 18, 2020

A target systolic blood pressure (SBP) of 120-129 mm Hg in patients with heart failure with preserved ejection fraction (HFpEF) proved to be the sweet spot with the lowest rates of major adverse cardiovascular and renal events in a new analysis from the landmark PARAGON-HF trial.

This finding from the largest-ever randomized, controlled study in HFpEF strengthens support for current US joint hypertension guidelines, which call for a target SBP less than 130 mm Hg in patients with HFpEF, a recommendation based upon weak evidence until now. That's because the SPRINT trial, the major impetus for adoption of intensive blood pressure control in the current guidelines, excluded patients with symptomatic HF, Scott D. Solomon, MD, and coinvestigators noted in their new analysis.

The study was published in the Journal of the American College of Cardiology and had been planned for presentation during the joint scientific sessions of the American College of Cardiology (ACC) and the World Heart Federation. ACC organizers chose to present parts of the meeting virtually after COVID-19 concerns caused them to cancel the meeting.

The new analysis from PARAGON-HF (Prospective Comparison of ARNI with ARB Global Outcomes in HFpEF) also ruled out the SBP-lowering effect of sacubitril/valsartan (Entresto, Novartis) as the explanation for the combination drug's demonstrated beneficial impact on outcomes in the subgroup with an SBP of 120-129 mm Hg. That wasn't actually a surprise. Indeed, the new study had two hypotheses: (1) that the relationship between SBP and cardiovascular and renal outcomes in HFpEF would follow a J-shaped curve and (2) that sacubitril/valsartan's blood pressure–lowering effect would not account for the drug's outcome benefits in the subset of HFpEF patients with an SBP in the sweet spot of 120-129 mm Hg. Both hypotheses were borne out, noted Solomon, professor of medicine at Harvard Medical School and director of noninvasive cardiology at Brigham and Women's Hospital, both in Boston, Massachusetts.

"These data strongly support that additional mechanisms other than blood pressure lowering account for the benefit. But this is not surprising. The same can be said for most of the therapies that work in heart failure," he said in an interview.

Take, for example, spironolactone. In TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist), another major trial in which Solomon played a leadership role, the beneficial effect of spironolactone on clinical outcomes also proved unrelated to the drug's blood pressure–lowering effect.

Other known effects of sacubitril/valsartan, a novel angiotensin receptor–neprilysin inhibitor (ARNI), might in theory account for the observed clinical benefits in ARNI-treated patients with an on-treatment SBP of 120-129 mm Hg in PARAGON-HF. These include improved left atrial remodeling, an increase in natriuretic peptides, and improved myocardial relaxation. However, the current lack of understanding of the basic mechanistic processes underlying the varied clinical expressions of HFpEF is a major factor contributing to the lack of any proven-effective therapy for this extremely common and costly disorder, according to Solomon and coinvestigators.

In contrast to HFpEF, for which to date there is no proven treatment, sacubitril/valsartan has a class I recommendation for heart failure with reduced ejection fraction on the strength of its performance in significantly reducing cardiovascular deaths and heart failure hospitalizations in the PARADIGM-HF trial.

PARAGON-HF included 4822 patients with symptomatic HFpEF who were randomized to sacubitril/valsartan at 97/103 mg b.i.d. or valsartan at 160 mg b.i.d. As previously reported, at an average follow-up of 35 months, the primary outcome — a composite of total hospitalizations for heart failure and cardiovascular death — occurred at a rate of 12.8 events per 100 patient-years in the sacubitril/valsartan group and 14.6 per 100 patient-years in the valsartan arm, for a 13% relative risk reduction that narrowly missed statistical significance (P = .059).

However, sacubitril/valsartan showed significant benefit on some prespecified secondary endpoints, including worsening renal function, change in New York Heart Association class, and quality of life. Women, who notably accounted for 52% of study participants, appeared to benefit from sacubitril/valsartan more than men as evidenced by their 27% relative risk reduction in the primary endpoint. Also, in the roughly half of PARAGON-HF participants with a baseline left ventricular ejection fraction of 45%-57%, treatment with sacubitril/valsartan resulted in a statistically significant 22% relative risk reduction in the primary endpoint, compared with valsartan alone.

SBP and Cardiovascular Outcomes in HFpEF

In the new analysis, Solomon and coworkers examined outcomes based on baseline and mean achieved SBP quartiles regardless of treatment arm. In an unadjusted analysis, the primary composite endpoint occurred at a rate of 15.2 events/100 patient-years in HFpEF patients with an achieved SBP below 120 mm Hg, 11.4/100 patient-years at 120-129 mm Hg, 12.2/100 patient-years at 130-139 mm Hg, and 15.6/100 patient-years at 140 mm Hg or more. Further, in a multivariate regression analysis extensively adjusted for atrial fibrillation, sex, race, and numerous other potential confounders, the group with an achieved SBP of 120-129 mm Hg continued to fare best.

The adjusted risks for the primary endpoint were 11% and 21% higher in patients in the first and third quartiles of achieved SBP, compared with those at 120-129 mm Hg, although neither trend reached statistical significance. But patients in the top quartile, with an achieved SBP of 140 mm Hg or more, had a highly significant 56% increase in risk, compared with patients in the second-lowest SBP quartile.

Change in blood pressure from baseline to week 48 had no impact on quality of life or high-sensitivity troponin T. However, each 10–mm Hg lowering of SBP was associated with a modest 2.1% reduction in log-transformed N-terminal of the prohormone brain natriuretic peptide.

Sacubitril/valsartan reduced SBP by an average of 5.2 mm Hg more than valsartan alone at 4 weeks regardless of baseline SBP. And the combo drug had a significantly greater SBP-lowering effect in women than men, by a margin of 6.3 mm Hg vs 4.0 mm Hg. But a Cox regression analysis showed that in women, as in the study population as a whole, sacubitril/valsartan's SBP-lowering effects didn't account for the drug's impact on outcomes.

In an editorial accompanying publication of the new PARAGON-HF blood pressure analysis, Hector O. Ventura, MD, and colleagues at the Ochsner Clinic in New Orleans, Louisiana, observed that the study results "lend some credence to the prognostic relationship of blood pressure in HFpEF, but whether they should serve as a therapeutic target or are merely a prognostic surrogate determined by other pathogenic factors, such as vascular ventricular uncoupling or aortic stiffness on one hand when blood pressure is greater than 140 mm Hg, or a reduced cardiac performance indicated by reduced blood pressure to less than 120 mm Hg, remains uncertain.

"What is certain, however, is that the relationship and contributions of hypertension in manifest HFpEF are complex, multifactorial and likely go well beyond a simplistic framework of hemodynamic influences," they added.

Solomon reported research grants from and serving as a consultant to Novartis, which funded PARAGON-HF, and has similar financial relationships with more than a dozen other pharmaceutical companies. Ventura has disclosed no relevant financial relationships.

J Am Coll Cardiol. Published online March 16, 2020. Article, Editorial

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