Sacubitril-Valsartan Eases PH in Some Heart Failure Patients

Marta Figueiredo, PhD avatar

by Marta Figueiredo, PhD |

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Sacubitril-valsartan — a combination oral therapy approved to treat heart failure — rapidly reduces pulmonary blood pressure in people with pulmonary hypertension (PH) associated with heart failure with preserved ejection fraction (HFpEF), according to data from a Phase 3 clinical trial.

Notably, these benefits were accompanied by reduced lung congestion and improved exercise capacity and quality of life, further supporting sacubitril/valsartan as a therapeutic option for people with HFpEF-associated PH (HFpEF-PH), the researchers noted.

The study, “Sacubitril/valsartan affects pulmonary arterial pressure in heart failure with preserved ejection fraction and pulmonary hypertension,” was published in the journal ESC Heart Failure.

In people with heart failure with reduced ejection fraction, the left side of their heart does not effectively pump blood throughout the body. However, many of these patients also have problems in the right side of the heart, which pumps blood through the vessels in the lungs, called pulmonary arteries.

As such, up to 80% of HFrEF patients have PH — defined by a blood pressure in pulmonary arteries of 25 millimeters of mercury (mmHg) or greater — and show worse quality of life and increased mortality than those without PH.

“Attempts to treat PH in HFpEF–PH have resulted in a succession of failures, despite approaching this problem from different [biological] angles,” the researchers wrote.

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Sacubitril-valsartan, sold under the brand name Entresto, is a fixed-dose combination of both compounds that works by widening blood vessels. While it is approved as a first-line treatment for people with HFpEF, no adequately-controlled study to date has assessed whether the medication lessens PH in those with the condition.

To address this, a team of researchers in Spain launched a Phase 3 trial called ARNIMEMS-HFpEF (NCT04753112). The study evaluated sacubitril/valsartan’s effects in mean pulmonary artery pressure (mPAP), a measure of PH severity, in 11 women and three men with HFpEF-PH.

All participants, enrolled between October 2020 and May 2021 at Germans Trias i Pujol University Hospital, previously had undergone implantation of Abbott’s CardioMEMS HF System, a wireless monitor permanently placed in a specific pulmonary artery to continuously measure pulmonary arterial pressure.

Sacubitril-valsartan was administered for six weeks and daily PAP values were examined during three six-week periods: before, during, and after treatment (withdrawal).

The trial’s main goal was assessing changes in mPAP with and without sacubitril-valsartan, while secondary goals included changes in exercise capacity — measured with the 6-minute walking test — ultrasound-based lung congestion, and quality of life, as assessed with heart failure-specific and non-specific questionnaires.

The dynamics of heart damage biomarkers and echocardiographic parameters also were evaluated.

Patients’ median age was 79 and 1,717 mPAP measurements were recorded throughout the study.

Results showed that patients’ mPAP was significantly reduced by 4.99 mmHg during sacubitril-valsartan treatment and significantly increased by 2.84 mmHg during the withdrawal period.

Notably, a significant mPAP drop of 4.14 mmHg was already observed between the day before sacubitril-valsartan treatment and the seventh day of treatment.

Sacubitril-valsartan also led to significant reductions in lung congestion and significant improvements in exercise capacity, and in both heart failure-specific and nonspecific quality-of-life tests. Quality-of-life improvements were classified as clinically meaningful in half of the patients.

Notably, all these benefits were generally reverted at the end of the six-week withdrawal period.

Only one heart damage biomarker and one echocardiographic parameter showed significant changes between the studied periods; all generally supported sacubitril-valsartan’s beneficial effects.

Also, these effects appeared to be independent of loop diuretics, a type of medication used to lower blood pressure throughout the body, as their mean doses did not differ between periods.

Sacubitril-valsartan was generally well-tolerated, with no reports of adverse events leading to treatment discontinuation or deaths.

These findings highlight that six weeks of treatment with sacubitril-valsartan effectively reduced mPAP and lung congestion in HFpEF-PH patients, while improving exercise capacity and quality of life.

As such, it “may be a therapeutic alternative in HFpEF–PH,” the researchers wrote.

Larger studies are needed to confirm these findings.

The team also noted that combining a pulmonary artery sensor, such as the CardioMEMS device, with a powerful blood vessel-widening agent like sacubitril/valsartan may improve determination of its best dose to reduce mPAP, but not blood pressure throughout the body.