Revatio, Tracleer Combo Therapy Adds No Benefit to PAH Patients, Phase 4 Trial Shows

Pfizer’s Phase 4 clinical trial (NCT00323297) in pulmonary arterial hypertension (PAH) shows no clinical benefits of adding Revatio (sildenafil) to a stable Tracleer (bosentan) regimen.

The study, “Sildenafil dosed concomitantly with bosentan for adult pulmonary arterial hypertension in a randomized controlled trial,” appeared in the journal BMC Cardiovascular Disorders.

The research team was led by Carmine Dario Vizza, MD, from Universita’ degli Studi di Roma La Sapienza in Rome, Italy, and included scientists from the Czech Republic, the United Kingdom, and the United States.

Therapeutic strategies in PAH include different classes of compounds, such as phosphodiesterase 5 inhibitors (such as Revatio) or endothelin receptor antagonists (including Tracleer).

International guidelines for the treatment of PAH recommend sequential combination therapies using different classes of agents when the response to a monotherapy is inadequate. However, most clinical studies of PAH treatment strategies focus on monotherapies. Also, an oral combination therapy might be more appealing to patients than injectable drugs.

Of note, previous clinical trials have shown improvements in PAH management and promising tolerability data when Revatio was administered to patients on stable treatment with Tracleer.

This study determined the safety and effectiveness of oral Revatio when added to a stable oral Tracleer regimen in patients with PAH.

The trial included adult PAH patients with idiopathic PAH (no identifiable cause) or associated with connective tissue disease (APAH-CTD) taking Tracleer, 62.5 or 125 mg twice a day for at least three months. Patients were assigned randomly to either Revatio (20 mg, three times daily; 50 patients) or placebo (53 patients) groups.

The scientists primarily analyzed changes in exercise capacity at week 12 using the six-minute walk test. An extension study was conducted over 52 weeks that included 91 patients.

The results showed no benefits in exercise capacity at week 12 when adding Revatio in both idiopathic PAH and APAH-CTD patients. Interestingly, more detailed analyses revealed differences when assessing PAH type and duration of Tracleer treatment before the study began, as Revatio-treated patients with APAH-CTD and patients receiving Tracleer for less than one year showed a decline in exercise capacity, whereas placebo-treated patients showed improved functional data.

Researchers also observed no differences in changes in PAH World Health Organization’s functional class, Borg dyspnoea score (which assesses difficulty in breathing), and incidence of clinical worsening comparing Revatio with placebo.

The prevalence of headache, diarrhea, and flushing were higher with Revatio, but the researchers noted that adverse effects with combination therapy were in line with their predictions.

Overall, the study showed that combining Revatio with stable Tracleer therapy did not improve functional capacity at 12 weeks of treatment. Among the possible reasons for the negative results, the authors said, was that “patients were not truly stable on [Tracleer] therapy at the time of randomization to [Revatio] or placebo and that patients did not receive sufficient [Revatio] exposure because of the drug-drug interaction with [Tracleer].” The latter observation is supported by the study’s pharmacological data.

Also, the choice of drugs and the timing of the therapy also may have affected the effectiveness of treatment, the researchers wrote.

The differences in the results compared to previous benefits observed with the same combination therapy in PAH could be due to “different study designs, patient populations (PAH aetiology, functional class), and dosing regimens.”

The authors also suggest that besides exercise capacity at 12 weeks, analysis of other parameters might provide a more complete picture of clinical outcomes with Revatio combined with Tracleer, especially if focusing on longer-term analyses.

Future studies should address the influence of PAH types in effectiveness, duration of background therapy, and whether combination therapies should be initial or sequential, the authors said.