Pulmonary arterial hypertension (PAH) remains a progressive and ultimately fatal disease despite the availability of a number of new therapies over the past couple of decades. These therapies individually target three signaling pathways known to be involved in the pathogenesis of PAH: the endothelin (ET), nitric oxide, and prostacyclin pathways [1‐3]. The progressive nature of PAH provides a rationale for early and intensive management and the use of combination therapy to target multiple pathways simultaneously. Combination therapy is an important component of current PAH management strategies, which aim for patients to reach or maintain a low risk for mortality, the defined treatment goal in PAH [2, 3].

Until recently, clinical data to support combination therapy were inconsistent and limited to short-term studies, mostly with primary endpoints of change in 6-minute walk distance (6MWD) (reviewed recently by Sitbon and Gaine [4]). However, more robust clinical evidence from long-term randomized controlled trials now exists. The landmark SERAPHIN study (NCT00660179), which evaluated the effect of macitentan, an ET receptor antagonist (ERA), on morbidity and mortality in patients with PAH, was the first study to demonstrate that a PAH therapy could provide clinically meaningful long-term benefits [5]. As the majority of patients in SERAPHIN were receiving background therapy, predominantly a phosphodiesterase type 5 inhibitor (PDE-5i), this study also provided the first evidence from a randomized controlled trial to support the long-term benefits of combination therapy in PAH. Based on the results from SERAPHIN, macitentan 10 mg once daily is approved in more than 55 countries for the long-term treatment of patients with PAH as monotherapy or in combination with other PAH therapies.

The purpose of this review was to comprehensively examine the evidence from the SERAPHIN study, specifically with respect to macitentan 10 mg in patients already receiving a PAH therapy at baseline. In addition, we discuss the combination therapy data from SERAPHIN in the context of other recently completed trials, clinical practice, and PAH treatment guidelines.

The ET pathway has a well-established role in the pathogenesis of PAH [6‐8], and the deleterious effects of ET-1 are mediated by both the ET_A and the ET_B receptors [9]. ET receptors can be targeted with ERAs, and three ERAs are currently approved for the treatment of PAH (macitentan, bosentan, and ambrisentan) [2, 3]. Macitentan is an oral ERA targeting both ET receptors and is indicated for the treatment of PAH to delay disease progression [10, 11]. In pre-clinical studies, macitentan exhibited high binding affinity to both ET receptors, sustained receptor binding, and high tissue penetration [12‐14]. Furthermore, pharmacokinetic data have demonstrated that macitentan and its active metabolite both have a long elimination half-life of approximately 16 and 48 h, respectively, which supports a once-daily dosing regimen [15]. The safety and efficacy of macitentan in patients with PAH have been demonstrated in the SERAPHIN study and its open-label extension [5].

SERAPHIN was a double-blind, event-driven phase III randomized controlled trial designed to investigate the effects of long-term treatment with macitentan compared with placebo in patients with PAH using a composite primary endpoint of morbidity and mortality [5]. The trial enrolled 742 patients with PAH, making it the largest trial conducted in PAH at the time of its completion. The study enrolled patients aged ≥ 12 years, who were randomized to receive macitentan 3 mg (n = 250), macitentan 10 mg (n = 242), or placebo (n = 250) once daily. The baseline demographics showed that the majority were prevalent patients (i.e., they had been diagnosed with PAH at least 6 months prior to baseline), with a mean time since PAH diagnosis of 2.7 years. The majority of patients (63.7%) were receiving a PDE-5i and/or an oral/inhaled prostanoid at enrollment. Patients who were receiving background PAH therapy were required to have been receiving stable doses for 3 months prior to enrollment. As SERAPHIN was a large study, including both treatment-naive patients and patients previously treated with PAH-specific therapy, it provided an opportunity to evaluate the long-term efficacy and safety of macitentan as monotherapy and combination therapy (mostly with a PDE-5i). Furthermore, patients with and without background therapy were pre-specified subgroups for analysis.

The SERAPHIN trial was the first completed long-term trial in PAH and the first trial to use a clinically relevant composite primary endpoint as a measure of PAH progression. The composite endpoint was the time to the first morbidity event related to PAH or death from any cause, the former defined as worsening of PAH, initiation of intravenous or subcutaneous prostanoid therapy, lung transplantation, or atrial septostomy. Worsening of PAH was defined as the occurrence of all three of the following: a decrease in the 6MWD of ≥ 15% from baseline, worsening of PAH symptoms, and the need for additional treatment for PAH. All primary endpoint events were adjudicated by an independent clinical event committee in a blinded fashion. The study showed that macitentan 10 mg reduced the risk of a morbidity/mortality event by 45% versus placebo (97.5% confidence level [CL] 0.39–0.76; p < 0.001). Worsening of PAH was the most frequent primary endpoint event, occurring in 24% of patients treated with macitentan 10 mg and 37% of placebo-treated patients. Changes in exercise capacity, World Health Organization (WHO) functional class (FC), PAH-related death or hospitalization, and health-related quality of life were examined as secondary endpoints. Hemodynamic parameters at baseline and month 6 were analyzed in a sub-study of patients who underwent an additional right heart catheterization (RHC) at month 6 [16]. The main results from SERAPHIN are summarized in Table 1.

As discussed in this review, the SERAPHIN study has provided robust evidence that combination therapy with macitentan and a PDE-5i is beneficial, and it was the first trial to provide evidence that combination therapy improves long-term outcomes in PAH [5]. Since the completion of SERAPHIN, three additional long-term randomized controlled trials have reported results corroborating the importance of combination therapy: AMBITION, COMPASS-2, and GRIPHON ([21, 22, 39] and reviewed by Sitbon and Gaine [4]). Consistent results have been reported in AMBITION, which compared the treatment strategies of initial double combination therapy and monotherapy. Initial combination therapy with ambrisentan and tadalafil resulted in a significantly lower risk of clinical failure events than either drug as monotherapy in a population of treatment-naive newly diagnosed patients (HR 0.50; 95% CL 0.35–0.72; p < 0.001) [21]. The COMPASS-2 trial evaluated the effect of administering bosentan or placebo to patients already receiving stable doses of sildenafil. While the study showed a reduction in the risk of a morbidity/mortality event in patients receiving combination therapy compared with monotherapy, the treatment effect was not significant. However, addition of bosentan did significantly improve 6MWD compared with placebo (+ 21.8 m, 95% CL 5.9–37.8; p = 0.0106), and NT-proBNP levels were stable in patients receiving bosentan but increased in those receiving placebo (p = 0.0003) [39]. Long-term benefits of double and triple combination therapy with the oral selective IP prostacyclin receptor agonist selexipag in combination with an ERA, a PDE-5i, or both, were recently reported in the event-driven GRIPHON trial [22]. This study included patients who were predominantly in WHO FC II or III and were treatment-naive (20.4%) or receiving background therapy at enrollment (79.6%). All patients in GRIPHON who were receiving a PAH therapy at baseline had to have been receiving a stable dose for at least 3 months before enrollment. In the overall study population, selexipag reduced the risk of the morbidity/mortality primary endpoint by 40% (HR 0.60; 99% CL 0.46–0.78; p < 0.001). Pre-specified subgroup analyses by background therapy showed that the treatment effect for patients treated with double and triple combination therapy was consistent with the results in the overall population (PDE-5i background therapy HR 0.58, 99% CL 0.37–0.91; ERA background therapy HR 0.66, 99% CL 0.32–1.35; PDE-5i and ERA background therapy HR 0.63, 99% CL 0.39–1.01) [22]. This study provided the first randomized controlled trial data on the benefits of triple combination therapy in patients with PAH. Together, results from these trials have demonstrated that combination therapy can improve outcomes for patients with PAH and have paved the way for a paradigm shift in the management of PAH. Triple combination therapy is being investigated further in the ongoing TRITON study (NCT02558231), which will assess the efficacy and safety of an initial triple oral combination regimen (macitentan, tadalafil, and selexipag) versus an initial double oral treatment regimen (macitentan and tadalafil).

Disease registries can be helpful in understanding how clinical trial evidence supporting combination therapy has impacted upon clinical practice because they provide insights into the real-world use of combination therapy in PAH. Historically, the use of combination therapy for PAH was not widespread. This is evident from REVEAL, a large multicenter observational registry that enrolled patients with PAH between 2006 and 2009 in the USA, which showed that only 46% of previously diagnosed patients were receiving double combination therapy at enrollment and only 9% were receiving triple combination therapy [40]. More recently, data from an ongoing large US-based registry of patients with PAH who were newly treated with macitentan (the OPUS registry) have suggested that use of combination therapy has increased; 68% of patients in this registry were receiving at least one other PAH therapy at follow-up, with the majority of these patients receiving a PDE-5i (84.8%) [41]. However, a comparison of other recent registries has indicated that the use of initial combination therapy in clinical practice still varies. For example, among newly diagnosed patients, 43% received combination therapy within 3 months of diagnosis in the French registry [30]; in contrast, this figure was only 19% in the COMPERA registry [42]. These data suggest that combination therapy may sometimes still be underutilized in clinical practice.

To ensure that the robust clinical trial data supporting combination therapy translates into changes in clinical practice, it is essential that clear guidance is available on how and when to implement combination therapy. As outlined in the ESC/ERS guidelines, the decision on when to combine therapies must be based on the patient’s risk profile, as determined by comprehensive multi-parameter risk assessments, which should be conducted at baseline and regularly during treatment. An estimated 1-year mortality rate for patients with a low risk status is < 5%, whereas for those with an intermediate or high risk status it is 5–10 or > 10%, respectively. The guidelines recommend treating to achieve a low risk profile, which includes, among others, WHO FC I or II and near-normalization of resting cardiac index and/or NT-proBNP plasma levels [2, 3]. Recent evidence has shown that patients reaching targets associated with low risk status have better prognosis and long-term outcomes than those who do not [16, 30, 42, 43]. Given the importance of reaching a low risk profile, the ESC/ERS guidelines strongly recommend combination therapy [2, 3]. Timely initiation of combination therapy has the potential to increase the likelihood of achieving a low risk status in PAH and thereby improve patient outcomes.

Combination therapy with macitentan is effective and well tolerated in the management of PAH. Efficacy of combination treatment with macitentan and other PAH therapies, primarily a PDE-5i, was demonstrated in the SERAPHIN study for a number of its endpoints [5]. Compared with background therapy alone, macitentan was associated with a reduction in the risk of clinically relevant long-term outcomes, such as morbidity/mortality and hospitalization, as well as with improvement of functional parameters of exercise capacity and functional class, and in cardiopulmonary hemodynamics and health-related quality of life [5, 16, 20, 34]. SERAPHIN contributes long-term data on combination therapy with macitentan to the growing body of evidence for treatment of patients with PAH with multiple treatment modalities. Based on recent evidence from long-term randomized controlled trials and recommendations from the ESC/ERS guidelines for PAH, in the current treatment era, combination therapy regimens, such as those including macitentan and a PDE-5i, are an important treatment option for patients with PAH.