HFpEF-PH Improves Following Treatment With Sacubitril/Valsartan

Mean pulmonary arterial pressure (mPAP), functional capacity, lung congestion, and quality of life all improved among persons who have heart failure with preserved ejection fraction (HFpEF) and pulmonary hypertension (PH) following treatment with sacubitril/valsartan, an angiotensin receptor-neprilysin inhibitor (ARNI).

These findings from the nonrandomized, single-arm, investigator-initiated, interventional Treatment of PH With Angiotensin II Receptor Blocker and Neprilysin Inhibitor in HFpEF Patients With CardioMEMS Device (ARNIMEMS-HFpEF) study were published in ESC Heart Failure. Data were collected and analyzed during 3 periods after 14 consecutive patients had PAP monitors surgically implanted. These time points were the 6 weeks in between CardioMEMS implantation and sacubitril/valsartan initiation (pre-ARNI; weeks –6 to 0), during 6 weeks of sacubitril/valsartan treatment (ARNI On; weeks 1-6), and during 6 weeks of sacubitril/valsartan withdrawal (ARNI Off; weeks 7-12). Patients uploaded daily data and had visits at weeks 0, 2, 4, 6, and 12, and PAP was evaluated twice weekly.

“Attempts to treat PH in HFpEF-PH have resulted in a succession of failures, despite approaching this problem from different pathobiological angles,” the authors wrote. “There is a paucity of data regarding the hemodynamic effects of sacubitril/valsartan on PH in patients with HFpEF-PH.” Their primary study end point was change in mPAP following sacubitril/valsartan treatment vs the pre-ARNI and ARNI Off periods.

Overall, there were 1717 PAP measurements gathered during the study, for a per-patient mean (SD) of 122.6 (7.8). The fewest measures from a single patient were 96 and the most, 128. The median (IQR) patient age was 79 (72-84) years, and 78.6% were female.

These data show a statistically significant median decline in mPAP of –4.99 (–5.55 to –4.43) mm Hg after treatment was initiated with sacubitril/valsartan. Further, the 7-day mean decline from the day before treatment initiation to day 7 of treatment was –4.14 (5.7) mm Hg. In addition, left ventricular ejection fraction was lower in responders vs nonresponders: 56.5% (5.5%) vs 65.0% (5.9%).

A stark change was seen between the ARNI On and Off periods: During that time, mPAP crept back up by 2.84 mm Hg.

Looking at each week of the ARNI On period compared with the pre-ARNI period, the following mPAP improvements were seen:

• A steady mPAP improvement (decline) was seen from week 0 to week 4: week 0, ­–3.93 mm Hg; week 1, –5.15 mm Hg; week 2, –5.56 mm Hg; week 3, –5.62; week 4, –6.55.
• mPAP continued to improve in weeks 5 and 6, but to a lesser degree: –5.72 and –3.86 mm Hg, respectively.
• All of these findings were considered statistically significant.

When the investigators compared the ARNI On and Off periods, these mPAP changes were seen:

• mPAP increased in weeks 7 and 8: 2.16 and 2.62 mm Hg, respectively.
• mPAP continued to increase in weeks 9, 10, and 11, although not as much as in the preceding weeks: 1.56, 1.00, and 0.06 mm Hg, respectively.

Daily averages of mPAP changes following CardioMEMS implantation were –0.018 mm Hg in the pre-ARNI period, –0.153 mm Hg during ARNI On, and 0.022 mm Hg during ARNI Off.

The 3 most common comorbidities among the study cohort were hypertension (85.7%), hyperlipidemia (78.6%), and atrial fibrillation or flutter (71.4%). Most patient participants also had heart failure in the form of hypertensive cardiomyopathy (57.1%), New York Heart Association class III disease (92.9%), and baseline/study entrant treatment of loop diuretics (100%).

For the secondary study end points, distance on the 6-minute walk test improved from a mean distance of 270.6 (101.3) m in the pre-ARNI period to 298.3 (88.4) m by the end of the ARNI On period. However, a statistically significant decline to 268.5 (109) m was seen at the final ARNI Off period visit. Interestingly, the authors highlighted, “The highest improvement was observed in the patients with the lowest initial functional capacity.”

In addition, lung ultrasounds of changes in the B-lines sum revealed a significant reduction to 4.9 (4.0) B-lines at the final ARNI On visit from 9.3 (6.2) B-lines seen at the first pre-ARNI visit. However, an increase to 6.9 (8.4) B-lines was seen at the final ARNI Off visit.

For the most part, the biomarkers studied did not change. The one exception was a significant rise in hs-TnT and a trend of increase in CA-125 during the ARNI Off period. And the echocardiographies performed in each study period show an overall decrease in left atrial diameter only during the ARNI On period; left ventricular diameter, E/e′, and tricuspid annular plane systolic excursion did not change.

“To our knowledge, ARNIMEMS-HFpEF is the first trial to evaluate the effect of sacubitril/valsartan in the subset of patients with HFpEF-PH monitored with CardioMEMS,” the authors concluded. “Overall, our results highlight the role of sacubitril/valsartan in HFpEF-PH and thereby open a new therapeutic avenue in this patient phenotype.”

References

Codina P, Domingo M, Barceló, et al. Sacubitril/valsartan affects pulmonary arterial pressure in heart failure with preserved ejection fraction and pulmonary hypertension. ESC Heart Fail. 2022;9(4):2170-2180. doi:10.1002/ehf2.13952