STUDY SUMMARY: Summaries of Combination Therapy Trials in Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH), a condition characterized by increased pressure in the pulmonary arteries, may cause progressive remodeling of the pulmonary vasculature, and if left untreated, may lead to right-sided heart failure and death.1 In PAH, combination therapy targeting multiple mechanisms, such as the prostacyclin, nitric oxide, or endothelin pathways, may benefit patients who do not respond to therapy that targets a single pathway.2 Previous clinical trials have explored the effects of the sequential addition of therapeutic agents in patients with PAH; the effects of combination therapy as a first-line option have not previously been evaluated.2 To assess the effects of initial combination therapy, investigators conducted the Ambrisentan and Tadalafil in Patients with Pulmonary Arterial Hypertension (AMBITION) trial, which evaluated the efficacy and safety of initial combination therapy with ambrisentan and tadalafil in treatment-naïve patients with PAH compared with ambrisentan monotherapy or tadalafil monotherapy. The combination of ambrisentan, a selective endothelin-A receptor antagonist, and tadalafil, a phosphodiesterase type 5 inhibitor, was utilized because these agents have different mechanisms of action and do not pharmacokinetically interact with each other.2

Patients enrolled in the AMBITION trial were randomized in a 2:1:1 ratio to receive ambrisentan and tadalafil combination therapy (n = 253), ambrisentan monotherapy (n = 126), or tadalafil monotherapy (n = 121) for a minimum of 24 weeks.2 A 2:1:1 ratio was utilized to provide a 1:1 ratio when evaluating combination therapy versus pooled monotherapy. The most common types of PAH were idiopathic PAH (iPAH, 53%) and PAH associated with connective tissue disease (CTD-PAH, 37%). Average duration of treatment for all patients was 517 days (550 days in the combination group and 484 days in the pooled monotherapy group).2 The primary end point was the occurrence of the first clinical failure event (defined as death, worsening PAH leading to hospitalization, disease progression, or unsatisfactory long-term clinical response) prior to the final assessment visit.2 For the primary analysis, the exclusion criteria were amended after the start of the trial to reduce the potential of enrolling patients with pulmonary hypertension that was likely secondary to left ventricular dysfunction, which could confound the findings.2 Secondary end points evaluated included improvements from baseline to week 24 in biomarkers and scoring metrics (eg, 6-minute walk distance [6MWD] test, World Health Organization [WHO] functional class and Borg dyspnea index) and the proportion of patients with satisfactory clinical response (defined as an increase of 10% in the 6MWD, with a reclassification to, or maintenance of, WHO functional class I or II and no events of worsening clinical condition).2

The primary end point occurred in 123 patients, which included 46 patients (18%) in the combination therapy group and 77 patients (31%) in the pooled monotherapy group (43 in the ambrisentan group and 34 in the tadalafil group).2 The authors noted that initial combination therapy reduced the risk of experiencing a first clinical failure event by 50% compared with monotherapy with ambrisentan or tadalafil (HR, 0.50; 95% CI, 0.35-0.72; P <.001).2 The greatest benefit of combination therapy versus monotherapy was the observed difference in reduction of hospitalization for worsening PAH.2 Significant differences were also seen in secondary end point results favoring combination therapy (vs pooled monotherapy, P <.001 for change from baseline to week 24 for 6MWD).2 The percentage of patients with a satisfactory clinical response was significantly greater in the combination therapy group compared with the pooled-monotherapy group; however, no significant difference was seen when comparing the combination group with ambrisentan monotherapy.2

The most common adverse events (AEs) in the combination therapy group (≥20% of patients) were peripheral edema, headache, nasal congestion, diarrhea, and dizziness. Discontinuation rates due to AEs were similar across treatment groups (12% of the combination therapy group vs 11% of the pooled monotherapy group).2
The results of the AMBITION study showed that initial combination therapy with ambrisentan and tadalafil in treatment-naïve patients with PAH significantly reduced the risk of experiencing a first clinical failure event versus initial monotherapy with either ambrisentan or tadalafil.2  

AMBITION: Connective Tissue Disease Pulmonary Arterial Hypertension
In a post hoc subgroup analysis of the AMBITION trial, investigators evaluated whether patients with CTD-PAH responded differently to combination therapy than patients with iPAH or hereditary PAH (hPAH). Based on prior reports, patients with CTD-PAH, particularly systemic sclerosis PAH (SSc-PAH), generally have a poorer prognosis and response to certain therapies versus patients with iPAH and hPAH.3 In the AMBITION post hoc subgroup analysis, patients were stratified based on PAH classification: iPAH/hPAH (n = 279) or CTD-PAH (n = 187). Of the patients with CTD-PAH, 63% also had a diagnosis of SSc-PAH, a subtype of CTD-PAH.3

For the post hoc subgroup analysis, investigators evaluated the same primary end point as the original AMBITION trial: occurrence of the first clinical failure event.3 Among patients receiving combination therapy, the rate of first clinical failure event was 19% in the iPAH/hPAH group, 19% in the CTD-PAH group, and 21% in the SSc-PAH subgroup. In comparison, the respective rates in patients receiving monotherapy were 32%, 36%, and 40%. Compared with monotherapy, combination therapy reduced the risk of experiencing a first clinical failure event by 49% in patients with iPAH/hPAH (HR, 0.51; 95% CI, 0.31-0.83), 57% in patients with CTD-PAH (HR, 0.43; 95% CI, 0.24-0.77) and 54% in patients with SSc-PAH (HR, 0.44; 95% CI, 0.22-0.89).3 The greatest benefit of combination therapy compared with monotherapy in patients with CTD-PAH and SSc-PAH was the reduction in occurrence of first hospitalization for worsening PAH. There was a 71% reduction in risk of hospitalization for worsening PAH in the CTD-PAH group (HR, 0.29; 95% CI, 0.12-0.67) and a 64% reduction in risk in the SSc-PAH subgroup (HR, 0.36; 95% CI, 0.13-1.04).3

Based on these findings, the authors concluded that patients with CTD-PAH had a similar response to initial combination therapy versus monotherapy as patients with iPAH or hPAH in terms of clinical failure risk reduction. Thus, patients with CTD-PAH may benefit from initial combination therapy with ambrisentan and tadalafil versus monotherapy.3

AMBITION: Mortality Analysis
In a secondary mortality analysis of the AMBITION trial, investigators evaluated whether use of initial combination therapy of ambrisentan and tadalafil provided mortality benefits versus either agent alone. All-cause mortality data were analyzed for the modified intent-to-treat population; data were included for any patient who received study medication regardless of whether patients withdrew from treatment.1 The amended exclusion criteria utilized for the primary analysis in the original AMBITION trial was not implemented here.
The authors evaluated all-cause mortality from randomization to the end of the study. The median follow-up time was 101 weeks in the combination group and 96 weeks in the pooled monotherapy group.1 No significant difference was observed in all-cause mortality between the groups. Death from all causes occurred in 10% of patients in the combination therapy group (29 of 302) versus 14% of the pooled monotherapy group (41 of 303). Mortality rates in the ambrisentan group (13%) and tadalafil group (15%) were also comparable.1 Despite 29% of the patients (n = 176) withdrawing from treatment before study completion, the rates and reasons for discontinuations were comparable between treatment groups.1 Survival status could not be determined for 34 of the 605 patients enrolled.1

Although there was a slight reduction in all-cause mortality with initial ambrisentan and tadalafil combination therapy versus monotherapy, it is important to note that the AMBITION trial was not designed or powered to detect a difference in all-cause mortality. Larger longitudinal mortality studies are necessary to further evaluate the correlation between combination therapy and mortality.1

Scleroderma-Associated Pulmonary Arterial Hypertension
SSc-PAH is a subset of PAH that affects 10% to 12% of patients with scleroderma. SSc-PAH is one of the leading causes of death in patients with scleroderma. Prior studies have demonstrated that patients with SSc-PAH typically do not respond to therapy as well as patients with iPAH and have poorer survival outcomes.4 Hassoun and colleagues evaluated the tolerability and efficacy of combination therapy with ambrisentan and tadalafil in patients with SSc-PAH. In this small prospective study, 24 treatment-naïve patients with SSc-PAH received combination therapy with ambrisentan 5 mg and tadalafil 20 mg daily, which was titrated up to 10 mg and 40 mg, respectively, daily at week 4. Patients were treated for 36 weeks.4

In this study, investigators elected to evaluate efficacy based on improvement of pulmonary vascular resistance (PVR) and right ventricular (RV) mass from baseline, rather than the 6MWD measure used in other trials because the test was not validated in patients with SSc-PAH given their musculoskeletal impairment.4 Other measured outcomes included changes in hemodynamic markers, such as mean pulmonary arterial pressure, cardiac index, and pulmonary arterial compliance (stroke volume/pulse pressure).4
After the first 4 weeks of combination therapy, 75% (n = 18) of the patients tolerated titration to the 10-mg dose of ambrisentan and 87% (n = 21) tolerated titration to the 40-mg dose of tadalafil.4 A 55% reduction in PVR, from a baseline median of 6.9 Wood units to 3.1 Wood units, was observed after 36 weeks of combination therapy (P <.01). All patients achieved at least a 20% decrease in PVR from baseline and 66.7% achieved a decrease greater than 50% (n = 16). Overall, RV mass was significantly reduced by 14%, from a median of 32.5 to 28.0 g (P <.05).4 A reduction in RV mass of 10% or greater was observed in 62.5% of patients (n = 15). Combination therapy was generally well tolerated; AEs were generally mild and included fluid retention, nasal congestion, headache, abdominal pain, and dyspnea.4

Based on the reductions in PVR and RV mass, the authors hypothesized that tadalafil and ambrisentan combination therapy may aid in RV de-remodeling, thereby improving arterial pressure, blood flow, and cardiac function.4 Thus, the authors concluded that patients with SSc-PAH may benefit from combination therapy; however, larger clinical trials are needed to further evaluate the benefits of RV function.

The results of these 4 studies (summarized in Table1-4) demonstrate the potential benefits of initial combination therapy compared with monotherapy in certain patients with PAH. First-line treatment with ambrisentan and tadalafil combination therapy may improve outcomes in patients with iPAH, hPAH, CTD-PAH, or SSc-PAH. Although there was no significant benefit observed in all-cause mortality, the AMBITION trial may not have been sufficiently powered to detect such a difference. Larger prospective studies are needed to provide additional insight on the potential benefits of combination therapy in terms of mortality.

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