Treatment with Macitentan Reduced the Risk and Rate of Hospitalizations in Patients with PAH

6 Jul, 18

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Introduction

The Study with Endothelin Receptor Antagonist in Pulmonary arterial Hypertension (PAH) to Improve Clinical Outcome (SERAPHIN) trial demonstrated that macitentan, a dual endothelin-receptor antagonist, significantly reduced the mortality and morbidity in the patients with PAH. A composite secondary endpoint of “death due to PAH or hospitalization for PAH” was evaluated. The risk of such events was significantly reduced with macitentan. The results of the trial indicated a considerable impact on the PAH-related hospitalizations.

Aim

This study evaluated the effect of macitentan on the risk, rate, number of hospital days for all-cause and PAH-related hospitalizations. Additionally the risk and causes of hospitalizations unrelated to PAH were also assessed.

Methods

Study design

Multicenter, double-blind, randomized, placebo-controlled, event-driven phase 3 trial
Patients aged 12 years or more, with confirmed PAH and with 6-minute walk distance (6-MWD) of 50 m or more and class II, III or IV according to WHO functional classification were selected
Patients could be treatment na?ve or receiving phosphodiesterase type 5 inhibitors, oral or inhaled prostanoids, calcium channel blockers or L-arginine
The cohort was randomized into 3 groups after screening to receive placebo once daily, macitentan 3 mg once daily or macitentan 10 mg once daily

Endpoints

Time to first all-cause hospitalization
Time to first PAH-related hospitalization upto the end of treatment
Total number of hospital days per patient-year for both all-cause and PAH-related hospitalizations
Time to first non-PAH-related hospitalization and their causes

Results

The overall cohort comprised of 742 patients
250 received placebo, 250 received macitentan 3 mg and 242 received macitentan 10 mg
The cohort was characterized by 76.5% females, mean age of 45.6+16.1 years, 55% had idiopathic PAH
Mean time from PAH diagnosis was 2.7+4.0 years
Overall median duration of treatment was 115 weeks
The rate of all-cause hospitalization at least once during the treatment and % of total all-cause hospitalizations is shown in figure 1

Figure 1. % of patients with all-cause hospitalization at least once and % of total all-cause hospitalizations

The risk of all-cause hospitalization with 3 mg macitentan was reduced by 18.9% (HR=0.811; p=0.1208) and by 32.3% with macitentan 10 mg (HR=0.677; p=0.0051) as compared to placebo
Rates of all-cause hospitalization per 100 patient years across all the groups is shown in figure 2.

Figure 2. Rates of all-cause hospitalization per 100 patient-years

There was a reduction in the macitentan groups as compared to placebo with respect to
- rate of all-cause hospitalization
- number of hospital days
- risk of PAH-related hospitalization
- rate of PAH-related hospitalization
- number of hospital days due to PAH

Figure 3. Reduction in outcomes across all groups

Outcome	Macitentan 3 mg group		Macitentan 10 mg group
	% Reduction	p value	% Reduction	p value
All-cause hospitalization	20.5%	0.0378	33.1%	0.0005
No of hospital days	30.6%	0.0278	31.0%	0.0336
Risk of PAH-related hospitalization	42.7%	0.0015	51.6%	<0.0001
Rate of PAH-related hospitalization	44.5%	0.0004	49.8%	<0.0001
No of hospital days due to PAH	53.3%	0.0001	52.3%	0.0003

There were no significant differences in the risk of non-PAH-related hospitalization between the groups

Conclusion

Treatment with macitentan 10 mg resulted in significant reduction in the risk and rate of all-cause hospitalization in patients with pulmonary arterial hypertension.
Macitentan 10 mg also significantly reduced the duration of hospital stay
The risk and rate of PAH-related hospitalization was also reduced significantly in the patients treated with macitentan

J Am Coll Cardiol HF. 2015;3:1-8.