In-hospital vs outpatient sacubitril/valsartan may be riskier for Asian HF patients

Initiation of sacubitril-valsartan combo during hospitalization in Asian patients with heart failure with reduced ejection fraction (HFrEF) appears to lead to a higher incidence of adverse drug reactions (ADRs) and treatment discontinuation when compared with starting the patients on the drug as an outpatient, according to real-world data.

“Nevertheless, the majority of patients in the inpatient cohort tolerated sacubitril/valsartan,” said investigators from the National Heart Centre Singapore.

The analysis included 840 adult HFrEF patients prescribed sacubitril/valsartan in inpatient (n=289) or outpatient (n=551) settings in a tertiary healthcare institution in Singapore. The most common starting dose was 24/26 mg twice a day in both groups (62.6 percent vs 60.6 percent).

Over the follow-up (median duration, 27 days in the inpatient group vs 56 days in the outpatient group), the primary outcome of ADRs occurred with significantly greater frequency among patients who received in-hospital sacubitril/valsartan (34.6 percent vs 22.7 percent; adjusted hazard ratio [HR], 2.28, 95 percent confidence interval [CI], 1.68–3.10; p<0.01). [Heart Lung Circ 2020;doi:10.1016/j.hlc.2020.08.014]

Likewise, there were more incidences of treatment discontinuation in the inpatient vs outpatient group (18.0 percent vs 10.3 percent; adjusted HR, 2.11, 95 percent CI, 1.37–3.26; p<0.01).

Commonly reported ADRs were symptomatic and asymptomatic hypotension, worsening of kidney function, and hyperkalemia. Such events mainly led to discontinuation of sacubitril/valsartan in both groups (16.6 percent inpatient vs 8.9 percent outpatient; p<0.01). Other reasons were death due to other medical causes (stroke, acute myocardial infarction, or ventricular fibrillation), high cost of medications, and patient preferences due to no improvement in HF symptoms.

The safety outcomes were consistent across subgroups defined by age, left ventricular ejection fraction (LVEF), systolic blood pressure (SBP), and estimated glomerular filtration rate (eGFR).

Explaining the difference in safety and tolerability of sacubitril/valsartan between the two patient groups, the investigators pointed to certain baseline patient characteristics. Specifically, the inpatient group had lower SBP (median, 113 vs 115 mm Hg) and LVEF (23 percent vs 26 percent) and higher N-terminal pro-B type natriuretic peptide (5,622 vs 1,739 pg/mL) than the outpatient group.

“This may indicate that patients included in the inpatient cohort were sicker and had more advanced HF. Hence, they may have been less tolerant to the initiation of sacubitril/valsartan and have a higher chance of developing ADRs,” they explained.

The present data are somewhat at odds with those of PIONEER-HF, which have shown that sacubitril/valsartan can be initiated early and safely in patients with HFrEF shortly after an acute HF episode during hospitalization, with lower rates of discontinuation due to adverse event in the predischarge arm than in the current study’s inpatient arm. [Eur J Heart Failure 2019;21:998-1009; New Engl J Med 2019;380:539-548]

However, the investigators pointed out that PIONEER-HF used a different definition for the discontinuation rate. Whereas the current study defined discontinuation rate as temporary discontinuation (as short as 1 day) or permanent discontinuation of sacubitril/valsartan at or before the next follow-up visit, the PIONEER-HF trial defined the discontinuation as permanent discontinuation.

Regardless of the findings, the investigators stated that “in-hospital initiation of sacubitril/valsartan remains feasible when it is initiated under close monitoring.”

There are merits to inpatient initiation of the drug, they added. For the most part, it creates “the opportunity for close monitoring of ADRs and assessment of the tolerability before discharge. Timely management can be provided should there be any ADRs that require immediate medical attention.

“In addition, there will be less patient inertia on new medication initiation during hospitalization because patients will be more open to the use of new evidence-based medication when they are acutely ill,” they said.