NT pro

Baseline N-terminal pro-B natriuretic peptide in patients with HF with preserved ejection fraction accurately predicted HF hospitalizations and CV death, according to an analysis of the PARAGON-HF trial.

In addition, sacubitril/valsartan (Entresto, Novartis) successfully lowered NT pro-BNP over 16 weeks post-randomization, with similar reductions in both men and women and across the range of LV ejection fraction.

As Healio previously reported, in PARAGON-HF, sacubitril/valsartan did not significantly improve clinical outcomes in the overall cohort, but women were more likely to benefit from the treatment than men, and patients with EF of 57% or below were more likely to benefit than those with EF greater than 57%.

According to findings presented at the virtual American College of Cardiology Scientific Session, among a cohort of patients with median NT pro-BNP of 911 pg/mL at baseline, NT pro-BNP level at screening was strongly associated with HF events, defined as total HF hospitalizations and CV death (RR per log increase in NT pro-BNP= 1.68; 95% CI, 1.53-1.85). The results were simultaneously published in JACC Heart Failure.

Moreover, this association was stronger in patients with atrial fibrillation (adjusted RR in AF = 2.33; 95% CI, 1.89-2.87; aRR in patients without AF = 1.58; 95% CI, 1.42-1.75; P for interaction < .001) and weaker in patients with obesity (aRR in obesity = 1.5; 95% CI, 1.31-1.71; aRR in nonobesity = 1.92; 95% CI, 1.7-2.17; P for interaction < .001).

"NT pro-BNP strongly predicted clinical events in HFpEF patients enrolled in PARAGON-HF," Jonathan W. Cunningham, MD, cardiovascular fellow at Brigham and Women's Hospital, said during a presentation. "For a given NT pro-BNP, patients with atrial fibrillation were at lower risk for the primary endpoint than patients without atrial fibrillation. Conversely, obese patients with lower NT pro-BNP were still at moderate risk for hospitalization and death."

Sacubitril/valsartan vs. valsartan

In other findings, NT pro-BNP level at screening did not modify the treatment effect of sacubitril/valsartan compared with valsartan (P interaction = .96)

Researchers determined that sacubitril/valsartan reduced NT pro-BNP by 19% at 16 weeks (95% CI, 14-23; P < .001) and 17% at 48 weeks (95% CI, 11-22; P < .001) compared with valsartan. Similar reductions were observed for both men (20%) and women (18%), and patients with LVEF of 57% or less (20%) and more than 57% (18%).

"Sacubitril/valsartan decreased NT pro-BNP by 19% compared to valsartan," Cunningham said during the presentation. "NT pro-BNP response did not explain differences in apparent treatment benefits between men and women and patients with lower or higher EF. All these subgroups had substantial reduction in NT pro-BNP with sacubitril/valsartan compared with valsartan. Baseline NT pro-BNP did not identify patients who experienced greater reduction in primary endpoint events with sacubitril/valsartan."

Translation to other trials

During a follow-up discussion, Lee R. Goldberg, MD, MPH, section chief advanced heart failure and cardiac transplant and professor of medicine at the Hospital of the University of Pennsylvania, suggested that these findings may speak to difficulties experienced in past HFpEF trials.

"A teaching point is the impact of the interaction between atrial fibrillation, NT pro-BNP and then a better known interaction of obesity. How this does impact how we design future clinical trials and the concept of personalized medicine in terms of looking at risk factors and then the various thresholds or cutoffs for NT-proBNP?" Goldberg said in the discussion. "Is this why some of our trials in HFpEF have been unsuccessful? Because it's a very heterogeneous population and perhaps NT pro-BNP cutoffs are leading to a lot of misclassification."

Sex differences

Cardiology Today Editorial Board Member Mary Norine Walsh, MD, MACC, medical director of the heart failure and cardiac transplantation program and director of nuclear cardiology at St. Vincent Heart Center, program director of the St. Vincent Advanced Heart Failure and Transplantation Fellowship and past president of the ACC, inquired about the sex differences observed in the parent trial.

"There's been a lot of interest in the PARAGON-HF trial on the interaction of sex, as in the benefit in women, demonstrated in the primary endpoint of the trial," Walsh said during the discussion. "I was interested in the fact that there's a pretty significant difference in sex among the four quartiles, which is unusual because there are fewer women in the fourth quartile, when in fact most heart failure trials, we see women having more symptoms, not fewer."

"We've all been trying to unravel, the explanation for the differential effects in the primary trial between men and women, I don't know that this NT pro-BNP substudy gives a clear answer because we did see similar reduction between men and women," Cunningham said in response. "There were moderate differences in the baseline characteristics of NT pro-BNP between men and women, though we didn't see large differences in baseline NT-proBNP, such as between patients with and without AF and patients with and without obesity. We're still looking for the underlying physiological explanation for that interaction, which was very interesting in the primary trial."

A second biomarker is needed

"As with the complex approaches taken to better clinically phenotype HFpEF, it is likely that a simple biomarker strategy will not suffice, given the multiple directions the comorbidities in these patients affect the results," James L. Januzzi, MD, director of the Dennis and Marilyn Barry Fellowship in Cardiology Research at Massachusetts General Hospital and Hutter Family Professor of Medicine at Harvard Medical School, and Peder L. Myhre, MD, PhD, of the division of medicine at Akershus University Hospital, Lørenskog, Norway, wrote in a related editorial in JACC Heart Failure. "Adding a second biomarker that is less confounded to the patient selection criterion in randomized controlled trials may allow for lower NT pro-BNP thresholds without decreasing the specificity and baseline risk in the trial population. A combined biomarker strategy may also be applicable as an enhanced surrogate endpoint to improve the translation to clinical outcome measures. There are several biomarker candidates for such strategy, including cardiac troponins and insulin-like growth factor-binding protein-7. Whether this is a path forward or not, it is worth considering next steps to better manage this complex and challenging population of patients." – by Scott Buzby

Reference:

Cunningham JW, et al. Featured Clinical Research III. Presented at: American College of Cardiology Scientific Session; March 28-30, 2020 (virtual meeting).

Cunningham JW, et al. JACC Heart Fail. 2020;doi:10.1016/j.jchf.2020.03.002.

Januzzi JL, Myhre PL. JACC Heart Fail. 2020;doi:10.1016/j.jchf.2020.03.003.

Disclosure: Cunningham reports no relevant financial disclosures. Please see the full study for all other authors’ relevant financial disclosures. Januzzi reports he is a trustee of the ACC; received grant support from Novartis Pharmaceuticals; received consultant fees from Abbott, Janssen, Merck, Novartis, Pfizer and Roche Diagnostics; and participates in data safety monitoring boards for Abbott, AbbVie, Amgen, Bayer, Siemens and Takeda. Myhre reports served on advisory boards for Novartis and Novo Nordisk and consulted for Amgen, Novartis and Novo Nordisk. The PARAGON-HF trial was sponsored by Novartis.