Study Summary: Ambrisentan and Tadalafil Up-Front Combination Therapy in Scleroderma-Associated Pulmonary Arterial Hypertension
Hassoun PM, Zamanian RT, Damico R, et al. Ambrisentan and tadalafil up-front combination therapy in scleroderma-associated pulmonary arterial hypertension. Am J Respir Crit Care Med. 2015;192(9):1102-1110. doi: 10.1164/rccm.201507-1398OC.
Pulmonary arterial hypertension (PAH) affects approximately 10% to 12% of patients with scleroderma and is a leading cause of mortality in this patient population. Scleroderma-associated pulmonary arterial hypertension (SSc-PAH) is characterized by progressive remodeling of the pulmonary vasculature. Pressure in pulmonary circulation as a result of these changes presents a higher workload for the right ventricle (RV), leading to RV failure and, ultimately, death. There is heterogeneity among PAH disorders classified within group 1 of pulmonary hypertension, which leads to great differences in patient response to therapy and overall survival with modern PAH therapies. As several clinical trials and registries have demonstrated, patients with idiopathic PAH have achieved greater responses to therapy when compared with patients with SSc-PAH; therefore, there is a need for effective treatment for patients with SSc-PAH.1
Investigators hypothesized that initial combination therapy with agents that have distinct targets in the pathological mechanism of PAH would improve outcomes in patients with SSc-PAH. Investigators selected 2 FDA-approved agents, tadalafil and ambrisentan, which were previously shown to have therapeutic effect by targeting different intracellular pathways responsible for PAH. Tadalafil is a phosphodiesterase type 5 inhibitor and ambrisentan is an antagonist of the endothelin A. Enrolled patients received combination therapy with 5 mg ambrisentan and 20 mg tadalafil once daily for the first 4 weeks of the study period, followed by uptitrated doses of 10 mg ambrisentan and 40 mg tadalafil once daily, if tolerated, for the duration of the 36-week study.1
The efficacy and safety of the combination therapy was evaluated in a total of 24 patients with SSc-PAH who were naïve to PAH-specific therapy. Patients enrolled had World Health Organization (WHO) functional class II or III symptoms of PAH clinical severity; the majority of the population (65%) had WHO functional class III symptoms. The defining characteristics of PAH include an elevated mean pulmonary arterial pressure (mPAP) of at least 25 mm Hg, and high pulmonary vascular resistance (PVR) greater than 3 Wood units (WU). In this study, patients had a mean baseline mPAP of 42 mm Hg, PVR of 8.4 WU, and elevated right atrial pressure of 7 mm Hg.1
Typically, clinical trials utilize the 6-minute walking distance as a measure of therapeutic efficacy on exercise capacity in patients with PAH. This end point is nonspecific for the population affected by SSc-PAH, because these patients are heavily burdened by musculoskeletal impairments. As an alternative method of measure, investigators evaluated the efficacy of combination therapy for patients with SSc-PAH by monitoring changes from baseline in the coprimary end points of PVR and RV mass over 36 weeks. These coprimary end points reflected ventricular failure and mortality outcomes in patients with SSc-PAH after tadalafil and ambrisentan treatment. Other clinical outcomes included changes in hemodynamic markers of RV structure and function after 36 weeks, including mPAP, cardiac index, PVR, and pulmonary arterial compliance (stroke volume/pulse pressure [SV/PP]). Health function was assessed by change in WHO functional class symptoms, 6-minute walking distance, and dyspnea severity after 36 weeks of combination therapy from baseline measures. The frequency and type of adverse events (AEs) were recorded over the study period to evaluate the safety of the combination treatment in patients with SSc-PAH.1
After 4 weeks of initial combination therapy, 75% (n = 18) of patients tolerated an increased 10 mg dose of ambrisentan; 87% (n = 21) tolerated a dose increase to 40 mg of tadalafil. Nonserious AEs limited the uptitration of study treatment: Hypotension, headache, and nasal congestion prevented the uptitration of tadalafil, and 4 patients experienced fluid retention at 4 weeks, which prevented uptitration of ambrisentan. After 36 weeks, 87% (n = 21) of patients tolerated the maximal dosage of 10 mg ambrisentan and 40 mg tadalafil. However, 12% (n = 3) of patients did not tolerate the combination therapy or maximal dosage of the combination; these 3 patients completed the treatment period with either once daily 40 mg of tadalafil monotherapy, 10 mg ambrisentan monotherapy, or 5 mg of ambrisentan and 20 mg tadalafil combination. The combination was well tolerated and safe overall, with nonserious AEs; the most common AEs included fluid retention (29%), nasal congestion (16%), headache (29%), abdominal pain (12%), and dyspnea (12%).1
Treatment with ambrisentan and tadalafil significantly improved (P <.05) the clinical severity of PAH symptoms defined by WHO functional classification at 36 weeks compared with baseline. Combination therapy allowed a greater percentage of patients to achieve WHO functional class II symptoms compared with baseline measures (57% vs 35%). There was a reduction in the percentage of patients who experienced WHO class III symptoms after treatment compared with baseline symptom burden (39% vs 65%). None of the enrolled patient cohort had WHO functional class I PAH symptoms at baseline measurements of disease; 4% of patients achieved WHO functional class I symptoms after 36 weeks of therapy. Combination therapy also impacted the outcome of exercise capacity, demonstrated by the significant improvement in patients’ 6-minute walking distance (P <.001) and dyspnea severity (P <.02) after completion of treatment.1
After 36 weeks of combination therapy, patients with SSc-PAH achieved significant improvements in the coprimary end points. The PVR was reduced by 55% from a median of 6.9 WU (interquartile range [IQR], 4.0-12.9) at baseline to 3.1 WU (IQR, 2.0-5.7) by the end of the study (P <.01). All patients achieved a decrease in PVR of more than 20% from baseline; 66.7% of patients (n = 16) had a decrease greater than 50%. RV mass was significantly (P <.05) reduced by 14% from a median of 32.5 g (IQR, 23.4-41.4) to 28.0 g (IQR, 20.1-32.8); RV mass was decreased by 10% or greater in 15 patients, but was unchanged in 5 patients and increased in 3 patients. Investigators suggested that combination therapy promoted a decreased pulmonary vascular load and that these PVR improvements contributed to the reduction in RV mass following de-remodeling of the RV.1
RV mass following de-remodeling of the RV was confirmed by improvements from baseline in several other secondary clinical hemodynamic measures after combination therapy. Indeed, there was a significant (P <.01) improvement in mPAP with a 28% reduction after 36 weeks of combination therapy. The mPAP reflects changes in the relationship between cardiac output and PVR, where high mPAP indicates an increased workload. The cardiac index, a measure of circulation, was improved with an increase of 27% after treatment. The RV adapts to increasing vascular load by enhancing contractility to maintain blood flow; the SV/PP ratio estimates the total arterial response of the pulmonary vascular network and indicates the ability for dilation of the vascular network in response to this right ventricular contraction. After 36 weeks of therapy, patients experienced an improvement (P <.001) of 67% from baseline in the outcome of SV/PP ratio.1
Taken together, investigators concluded that combination therapy with tadalafil and ambrisentan had induced RV de-remodeling. This is likely a direct result of decreased pulmonary vascular load, which was supported with a reduction in RV mass, along with functional and hemodynamic improvements in arterial pressure, blood flow, and cardiac function. The tadalafil and ambrisentan combination was well tolerated in patients with SSc-PAH with limited AEs, and treatment improved patient health function and symptom burden.1
1. Hassoun PM, Zamanian RT, Damico R, et al. Ambrisentan and tadalafil up-front combination therapy in scleroderma-associated pulmonary arterial hypertension. Am J Respir Crit Care Med. 2015;192(9):1102-1110. doi: 10.1164/rccm.201507-1398OC.