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Heart failure patients unable to reach the target dose of angiotensin receptor/neprilysin inhibitor (ARNI) therapy still reaped gains in health status a year later, according to a post hoc analysis of PROVE-HF.

People taking sacubitril/valsartan (Entresto) for heart failure with reduced ejection fraction (HFrEF) had comparable improvements across tertiles of dosing: low dose (average daily dose 112 mg), moderate dose (342 mg), or high dose (379 mg). Over 12 months, all three doses were associated with consistent changes in:

• Prognostic biomarkers (e.g., NT-proBNP, high-sensitivity cardiac troponin T)
• Kansas City Cardiomyopathy Questionnaire scores
• Reverse cardiac remodeling (e.g., left ventricular ejection fraction, indexed left atrial and ventricular volumes)

"Although achieving target GDMT [guideline-directed medical therapy] doses in HFrEF should always be attempted, these results suggest that for those unable to achieve maximum doses of Sac/Val [sacubitril/valsartan], mechanistic benefits and improvement in health status may be expected, even at lower doses (e.g., 24/26 mg twice daily)," reported James Januzzi, Jr., MD, of Massachusetts General Hospital and Harvard Medical School in Boston, and colleagues in the Oct. 18 issue of the .

In an , Mary Norine Walsh, MD, of Ascension St. Vincent Heart Center in Indianapolis, called these results "very encouraging" and said they "send a very strong and reassuring message for patients -- and their clinicians -- who are unable to tolerate maximum-dose sacubitril/valsartan."

Nonetheless, she cautioned that the study does not answer whether survival is helped by less-than-maximal doses of ARNI therapy.

The PROVE-HF investigators found that the incidence of side effects such as hypotension (27.6%) and dizziness (22.4%) was generally higher in the low-dose group, which may explain why these patients were not titrated higher. There were two adjudicated cases of angioedema, both occurring in this group.

Indeed, real-world sacubitril/valsartan users often do not reach the 97/103 mg twice daily dose that proved superior to enalapril 10 mg twice daily in PARADIGM-HF. Only participants who were able to tolerate target doses of these medications were enrolled in that randomized trial.

In practice, financial barriers have also prevented many ARNI candidates from accessing sacubitril/valsartan. When it is used, the most common dose is 24/26 mg twice daily, which was the starting dose for nearly all patients in the PROVE-HF analysis, Januzzi and colleagues said.

People needing lower doses of sacubitril/valsartan in PROVE-HF tended to be older individuals with a generally higher prevalence of medical conditions and frequency of intolerances.

In contrast, patients who could tolerate higher doses were more likely to be Black men who had higher blood pressure and better kidney function at baseline. As more than 70% of study participants were white, however, analysis by race was limited.

"Even in this nonrandomized, community-enrolled trial, women were underrepresented," Walsh added. "It remains to be seen if the demonstrated benefits extend to more diverse populations and include improved survival."

PROVE-HF was a conducted at 78 U.S. sites.

The present post hoc analysis included 794 HFrEF patients who discontinued any ACE inhibitor or angiotensin II receptor blocker (ARB) treatment. All initiated sacubitril/valsartan and returned for study visits and drug titration approximately every 2 weeks through day 60.

Participants in the highest-dose tertile were generally able to reach ARNI target quickly, within 45 days, maintaining the 97/103 mg twice daily dose over the study period.

Januzzi's team acknowledged that change in other GDMT was not assessed.

"Portal messages from asymptomatic patients concerned about low blood pressure taken multiple times a day, patient cases from primary care physicians reporting in-office blood pressure readings on mutual patients that they deem to be 'too low,' and voicemails from family members reporting patient concerns about being on so many 'heart medicines' -- these are the headwinds we face in providing our patients with lifesaving, quality of life-improving GDMT," Walsh said.

"Even after we have cleared the hurdles of medication expense, prescription benefit manager demands for prior authorization, and helping patients without insurance coverage get access to all medications, we often remain daunted in our efforts to deliver optimal GDMT," she continued.

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