TRANSITION Study: Feasible and Safe to Initiate Sacubitril/Valsartan Pre-discharge in Acute HFrEF

2 Jan, 19

Background

Hospitalizations due to decompensated heart failure (HF) increase the burden of mortality and re-hospitalization in HF patients. This risk is high especially during the initial 2-3 months, when mortality can reach up to 10% in these patients. Hospitalizations thus provide a crucial opportunity to initiate and up-titrate the guideline-recommended therapies to improve post-discharge prognosis. The PARADIGM-HF trial has already demonstrated the superiority of sacubitril/ valsartan over enalapril for reducing mortality and morbidity in ambulatory patients with chronic heart failure with reduced ejection fraction (HFrEF)

Aim

The TRANSITION study aimed to provide the real-world data on safety and tolerability of initiating sacubitril/valsartan in HFrEF patients following hemodynamic stabilization after acute decompensated HF (ADHF) requiring hospitalization.

Patient Profile

Patients with HFrEF, New York Heart Association (NYHA) class II−IV, left-ventricular ejection fraction (LVEF) ≤40% following hemodynamic stabilization* after an episode of ADHF.
Patients were stratified based on their pre-treatment status as follows:

o Receiving an angiotensin-converting enzyme inhibitor (ACEI)

o Receiving an angiotensin receptor blocker (ARB)

o ACEI/ARB-na?ve patients

*Hemodynamic stabilization defined as no need for intravenous diuretics in 24 h prior to screening and systolic blood pressure [SBP] >110 mm Hg for at least 6 h prior to randomization

Methods

Study Design

A randomized, parallel, open-label study comparing pre- versus post-discharge (1–14 days) initiation of sacubitril/valsartan in the study population

Treatment Strategy

Patients were randomized 1:1 within each stratum for initiation of sacubitril/valsartan treatment either pre- or post-discharge (Figure 1)

Figure 1: Treatment Strategy

OMT: Optimized medical treatment

Endpoints

Primary Endpoint

The proportion of patients achieving the target dose of 200 mg sacubitril/valsartan twice daily, at 10 weeks’ post-randomization

Secondary Endpoints

The tolerability of different doses of sacubitril/valsartan (200 mg, 100 mg, or any other dose) maintained for a period of 2 weeks or more, leading to week 10 after randomization
The incidence of permanent discontinuation of sacubitril/valsartan due to adverse events (AEs)

Results

Mean age of the study population at baseline was 67 years and 75% of them were male. Mean LVEF for the study population was 29%, 64% belonged to NYHA Class II and 34% to NYHA III.
There were 286 (29%) cases of new-onset HFrEF and 242 (24%) patients were ACEI/ARB na?ve.
Similar proportion of patients met the primary and secondary endpoints in the pre- and post-discharge initiation arms
At 10 weeks after randomization, there was statistically no significant difference in proportion of patients who achieved the target dosage of 200 mg twice daily between the pre-discharge and the post-discharge arm (45% vs. 50.4%; 95% CI 0.783–1.019; p=0.092) (Figure 2).
Nearly two-thirds of patients initiated on sacubitril/valsartan pre-discharge and post-discharge , achieved and maintained either 100 mg or 200 mg twice daily regimen for at least 2 weeks following 10 weeks of randomization (62.5% and 68%, respectively; p=0.071) (Figure 2)
Majority of patients in pre-discharge and post-discharge arm (86.4% vs. 88.8%,, p=0.262) achieved and maintained any dose of sacubitril/valsartan for at least 2 weeks following 10 weeks of randomization (Figure 2)
The rate of permanent discontinuation of study drug due to adverse events (AEs) was low amongst patients in both, the pre-discharge and post-discharge arms (4.5% vs. 3.5%, RRR; 1.287, p=0.424)

Figure 2: The incidence of primary and secondary endpoints in the study groups

Sac/val: sacubitril/valsartan, b.i.d: twice daily

Hyperkalemia, hypotension, cardiac failure, and dizziness were the most frequently reported AEs in both the study arms and had almost a similar incidence between the two groups. (Table 1)

Table 1: Incidence of adverse effects in the study groups

Adverse Event	Pre-discharge Group	Post-discharge Group
Hyperkalemia	11.1%	11.3%
Hypotension	12.3%	9.1%
Cardiac Failure	6.8%	8.5%
Dizziness	5.6%	4.2%

Nearly 18.9% patients in the pre-discharge arm and 17.7% in the post-discharge arm suffered with serious AEs (SAEs). Of these, cardiac failure was the most common (7.0% vs. 7.7% of patients in the pre- vs. post-discharge group, respectively)
Patients in both the treatment arms had low mortality (2.6% vs. 2.0% in pre- vs. post-discharge arm; p=0.6740). None of the deaths were attributed to the study treatment

Conclusion

Nearly 50% of the HFrEF patients who were hemodynamically stabilized following an ADHF event attained the recommended target dose of 200 mg sacubitril/valsartan twice daily within 10 weeks
Patients in the pre-and post-discharge arms had similar incidence of AEs. The rate of discontinuation of sacubitril/valsartan due to adverse events was also similar in both the study arms.
The patient subgroups that tolerated the up-titration of sacubitril/valsartan to target dose within 10 weeks included; those with fewer comorbidities, higher systolic blood pressure or newly diagnosed HF.
Sacubitril/valsartan was safe and effective in patients stabilized after hospitalization for acute HF regardless of whether they received it in-hospital or after discharge.

Presented at the European Society of Cardiology (ESC) Congress-2018, Aug 25-29, 2018; Munich, Germany