Analysis Supports Initial Combination Therapy for Patients with PAH, Comorbidities

Patients with pulmonary arterial hypertension (PAH) and one or two cardiac comorbidities experience a similar benefit from initial combination therapy with macitentan (Opsumit) and tadalafil (Cialis) as patients without comorbidities, according to a new analysis.

The findings are important because they call into question existing guidelines for patients with cardiopulmonary comorbidities, which suggest beginning with initial monotherapy with either an endothelin receptor antagonist (ERA; e.g. macitentan) or phosphodiesterase 5 inhibitor (PDE5i; e.g. tadalafil) and then escalating as appropriate based on individual patient responses.

The new analysis comes as the demographics and characteristics of people diagnosed with PAH appear to have shifted in recent decades. For instance, a 2016 study from Sweden found the majority of patients diagnosed with PAH or chronic thromboembolic pulmonary hypertension (CTEPH) were over the age of 65, and tended to have “several” comorbidities, including systemic hypertension, diabetes, ischemic heart disease, and atrial fibrillation.

Similarly, a 2012 report based on a registry of patients with pulmonary hypertension in the United Kingdom and Ireland suggested that patients were being diagnosed at older ages, and that those patients were more likely to have more comorbidities but also better survival. At the time, the investigators said the change might be due to changes in referral patterns, rather than changes in the actual disease.

For instance, they noted an increase in referrals to pulmonary hypertension specialty centers over the years of the study. An alternative cause, they said, could be that there were emerging subtypes of the disease: older patients with more comorbidities and younger patients with fewer comorbidities, higher functional capacity, and more severe hemodynamic impairment.

Vallerie V. McLaughlin, MD, of the University of Michigan, and colleagues, noted that to date there is limited data on the use of initial combination therapy in patients with few comorbidities. In a new study published in the European Journal of Heart Failure, they explain that more data are needed to better understand how to tailor treatment to individual patients and risk profiles.

“While this stepwise approach may particularly resonate for older patients with a high cardiopulmonary comorbidity burden, the question remains whether a more aggressive treatment strategy with initial combination therapy would be beneficial for younger patients with a lower comorbidity burden,” they wrote.

Fortunately, they said data already exist regarding how patients with PAH and 1-2 cardiac comorbidities respond to initial combination macitentan and tadalafil—it just needed to be analyzed. The authors turned to the TRITON and REPAIR studies, both of which included patients who received initial combination therapy. The investigators noted that most trials now exclude patients with pulmonary comorbidities or with 3 or more cardiac comorbidities, but patients with 1-2 cardiac comorbidities are generally included.

McLaughlin and colleagues identified a set of 148 patients between the two studies who weretreated with initial macitentan and tadalafil combination therapy. From that pool, they constructed two subgroups of patients: those with no cardiac comorbidities (62 participants), and those with one or two cardiac comorbidities (78 participants). Overall, patients in the two trials had a median duration of exposure to the combination of 513.0 days, which the authors said was similar between the two subgroups.

From baseline to week 26, both groups benefited from the combination. The no-comorbidity subgroup had an average reduction of pulmonary vascular resistance (PVR) of 55%, an improvement of six-minute walking distance (6MWD) of 67 meters, and a reduction of N-terminal pro-brain natriuretic peptide (NT-proBNP) of 77%.

In the group with one or two comorbidities, participants had a 50% reduction of PVR, 54-meter increase in 6MWD, and 76% decrease in NT-proBNP. Patients in both groups also had improvement inWorld Health Organization functional class, McLaughlin and colleagues found. Both cohorts had similar safety profiles, and their experiences were consistent with previously reported safety data, the authors said.

The investigators said this information should be helpful to clinicians treating newly diagnosed patients, though they cautioned that comorbidity burden should be assessed on an individualized basis.

“It is important to acknowledge that comorbidity burden cannot be measured by simply counting the number of comorbidities; information on severity, duration and controlled/not controlled status must also be considered,” they wrote.

However, they concluded that these data suggest some patients with comorbidities might be good candidates for initial combination therapy.