Disclosures: The authors report no relevant financial disclosures.
May 11, 2022
3 min read

In HFrEF, early sacubitril/valsartan initiation may improve outcomes, hasten LV remodeling

Disclosures: The authors report no relevant financial disclosures.
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Compared with later initiation, starting sacubitril/valsartan within 3 months of a diagnosis of HF with reduced ejection fraction was tied to better clinical outcomes and earlier left ventricular reverse remodeling, researchers reported.

Despite patients who initiated sacubitril/valsartan (Entresto, Novartis) early having lower baseline LVEF, improvements in the form of LV reverse remodeling were observed in less than 6 months, according to data published in ESC Heart Failure.

“One-year mortality reaches 20% and 5-year mortality reaches 53% to 67% after the diagnosis of HF. The prevalence of HFrEF continues to increase despite advances in therapeutic modalities for cardiovascular diseases and due to an increasingly aging population,” Ji-Hye Oh, MD, of the department of cardiology in the school of medicine and institute for medical science at Keimyung University in Daegu, South Korea, and colleagues wrote. “However, in recent years, the novel sacubitril/valsartan, an angiotensin receptor-neprilysin inhibitor, has been proven safe and effective in the management of patients with HFrEF.”

As Healio previously reported, in the PARADIGM-HF trial, sacubitril/valsartan reduced risk for death and HF hospitalization in patients with HFrEF compared with ACE inhibition with enalapril.

Another prior study, called PIONEER-HF, showed that treatment of acute decompensated HF with sacubitril/valsartan conferred greater reduction in N-terminal pro-B-type natriuretic peptide compared with enalapril.

Moreover, sacubitril/valsartan was also associated with cardiac reverse remodeling with improvements in LV systolic function improvement and reduction in NT-proBNP, according to data published in JAMA.

The researchers assessed whether early sacubitril/valsartan initiation, defined as less than 3 months, after HFrEF diagnosis was more beneficial compared with later initiation, defined as 3 months or more.

A total of 115 patients were enrolled, of whom 67 initiated sacubitril/valsartan early (mean period, 52.1 days) and 48 initiated later (mean period, 201.8 days).

The primary outcome was a composite of HF hospitalization and cardiac death. Secondary outcomes included HF hospitalization, cardiac death, all-cause death, significant ventricular arrhythmia and evidence of cardiac reverse remodeling such as change in LVEF during follow-up.

Participants in the early sacubitril/valsartan group were younger (58 years vs. 65 years; P = .01), heavier (72.1 kg vs. 66 kg; P = .042), had lower occurrences of chronic kidney disease (14.9% vs. 35.4%; P = .011), had more hypertension (56.7% vs. 33.3%; P = .013), had higher mean diastolic BP (73.3 mm Hg vs. 68.2 mm Hg; P = .046), had higher arterial pressure (89.3 mm Hg vs. 84.8 mm Hg; P = .072), had higher hemoglobin levels (14.2 g/dL vs. 13 g/dL; P = .004) and had higher alanine aminotransferase levels (32.7 U/L vs. 20.6 U/L; P = .011) compared with the later group.

In addition, mean EF in the early group was lower compared with the later group (21.3% vs. 24.8%; P = .012); however, researchers found no differences in LV and left atrium chamber sizes.

Improvement in the primary outcome

During a median follow-up of 721 days, the primary outcome occurred in 18.3% of the overall cohort, including in 10.4% of the early sacubitril/valsartan group compared with 29.2% in the later group (P = .01).

Researchers reported that the Kaplan-Meier survival curve indicated better event-free survival during follow-up in the early sacubitril/valsartan group compared with the later group (log-rank P = .017).

Observations regarding secondary outcomes

There were no significant differences in the secondary outcomes of cardiac death (1.5% vs. 2.1%; P = .811), all-cause death (1.5% vs. 4.2%; P = .375) and ventricular arrhythmia (3% vs. 0%; P = .227) between the early and late initiation groups.

Despite a lower baseline LVEF in the early sacubitril/valsartan group, at 6 months, mean LVEF was higher in the early group compared with the later group (35.2% vs. 27.8%; P = .007).

At last follow-up, the groups had similar LVEF (early, 40.7%; late, 39.4%; P = .686).

Left atrial reverse remodeling was less prominent in the later use group during the follow-up period, with a mean final left atrial volume of 43.6 mL/m2 in the late group compared with 55.2 mL/m2 in the early group (P = .011). Other metrics of LV remodeling had similar trajectories in both groups.

“Recent updates of HF guidelines recommend the use of sacubitril/valsartan as an initial treatment after stabilization of acute decompensated HF during hospitalization,” the researchers wrote. “The HF guidelines have class I recommendations regarding the use of adequate doses of the optimal medication. Nevertheless, it is substantial to be discharged from the hospital without sufficient use of the medication due to various factors (patient factor and doctor factor). ... Based on study findings, it is important to start sacubitril/valsartan as soon as possible, even in HF patients who were discharged from the hospital without its use.”