Featured article
Tadalafil monotherapy and as add-on to background bosentan in patients with pulmonary arterial hypertension

https://doi.org/10.1016/j.healun.2010.11.009Get rights and content

Background

Tadalafil 40 mg orally once daily, was shown to be well-tolerated and efficacious for pulmonary arterial hypertension in a 16-week, double-blind, placebo (PBO)-controlled trial. Inclusion criteria included the option for background bosentan. Analyses of tadalafil in treatment-naive patients and as add-on to bosentan were pre-specified. Objectives were to provide safety and efficacy data for both groups.

Methods

Groups analyzed included: treatment-naive + PBO; treatment-naive + tadalafil; background bosentan + PBO; and background bosentan + tadalafil. Patients randomized to tadalafil or PBO (N = 405) were analyzed by bosentan use (yes = 216, no = 189). Treatment differences in 6-minute walk distance (6MWD, PBO-adjusted), functional class (FC), clinical worsening (CW) and adverse events were assessed. Hazard ratios (HRs) with 95% confidence intervals (CIs) are presented for FC and CW.

Results

At Week 16, PBO-adjusted 6MWD increases were 44 m (CI: 20 to 69 m; n = 37) for tadalafil 40 mg in treatment-naive patients and 23 m (CI: −2 to 48 m; n = 42) for tadalafil 40 mg add-on to bosentan. The 6MWD for treatment-naive and background bosentan PBO patients decreased by 3 m and increased by 19 m, respectively, at Week 16 compared with baseline. Two (5%) treatment-naive patients had CW with tadalafil 40 mg vs 8 (22%) with PBO (HR = 3.3, CI: 1.1 to 10.0). Two (5%) background bosentan patients had CW with tadalafil 40 mg add-on vs 5 (11%) for PBO add-on (HR = 1.9, CI: 0.4 to 10.2). Adverse events for tadalafil monotherapy and as add-on were similar.

Conclusion

Tadalafil 40 mg was well-tolerated and provided clinical benefit in patients as monotherapy. It was also well-tolerated when added to background bosentan, but data are insufficient to conclude additional benefit.

Section snippets

Study design

PHIRST-1, a 16-week, randomized, double blind, PBO-controlled study, evaluated tadalafil in PAH. Patients were randomized 1:1:1:1:1 to 5 groups (2.5, 10, 20, 40 mg, or PBO orally once daily). Stratification included background bosentan (yes/no) at enrollment. The trial was conducted at 82 centers in Canada, the USA, Europe and Japan. Patients were enrolled starting on August 18, 2005 with last subject completing the study on August 16, 2007. The study was conducted in accordance with applicable

Results

The disposition of all patients enrolled in PHIRST-1 is presented in Figure 1. Of the 405 patients receiving study drug, 341 (84%) completed the 16-week study. For the data that follows, we have limited results to the patients who received PBO, 20 mg tadalafil or 40 mg tadalafil.

Discussion

Because there is no cure for PAH, treatment goals are to improve quality of life and survival.25 Because monotherapy can be sub-optimal,1, 25 combination therapies, with potentially additive or synergistic effects, are being explored.26, 27, 28, 29

PHIRST-1 was the first PBO-controlled study in which a targeted therapy was evaluated as both monotherapy and as add-on to a background treatment in the same trial.10 Although this study was not powered for safety and efficacy analysis of the

Disclosure statement

The authors thank the sub-investigators, site coordinators, study nurses and investigation-site personnel. Without the combined efforts of all these parties, this study would not have been possible. We thank Melanie Chan for her initial efforts with statistical analyses and providing suggestions and discussion early in the process, and Emel Guldogan, MA (i3 Statprobe, Cary, NC), for her statistical assistance and review.

This study was supported by Eli Lilly and Co. A license agreement exists

References (38)

  • R. Hubbard et al.

    Survival in patients with cryptogenic fibrosing alveolitis: a population-based cohort study

    Chest

    (1998)
  • N. Galie et al.

    New insights into a challenging disease—a review of the Third World Symposium on Pulmonary Arterial Hypertension

    J Am Coll Cardiol

    (2004)
  • D.B. Badesch et al.

    Continuous intravenous epoprostenol for pulmonary hypertension due to the scleroderma spectrum of diseaseA randomized, controlled trial

    Ann Intern Med

    (2000)
  • R.J. Barst et al.

    A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension

    N Engl J Med

    (1996)
  • R.J. Barst et al.

    Sitaxsentan therapy for pulmonary arterial hypertension

    Am J Respir Crit Care Med

    (2004)
  • N. Galie et al.

    Sildenafil citrate therapy for pulmonary arterial hypertension

    N Engl J Med

    (2005)
  • N. Galie et al.

    Ambrisentan for the treatment of pulmonary arterial hypertension: results of the ambrisentan in pulmonary arterial hypertension, randomized, double-blind, placebo-controlled, multicenter, efficacy (ARIES) study 1 and 2

    Circulation

    (2008)
  • N. Galie et al.

    Tadalafil therapy for pulmonary arterial hypertension

    Circulation

    (2009)
  • H. Olschewski et al.

    Inhaled iloprost for severe pulmonary hypertension

    N Engl J Med

    (2002)
  • Cited by (96)

    • Pulmonary pressure recovery in idiopathic, hereditary and drug and toxin-induced pulmonary arterial hypertension: determinants and clinical impact

      2022, Vascular Pharmacology
      Citation Excerpt :

      Indeed, the prognostic role of pulmonary pressure was demonstrated more than three decades ago in the first registry of primary pulmonary hypertension by the United States National Institutes of Health (NIH) [26]. Despite this potentially important prognostic finding, the last two decades have been mainly characterized by oral monotherapy or sequential combination trials, resulting in limited changes in PVR with an even more trivial reduction in mPAP [4–14,27]. However, this modest effect in PVR was able to translate into cardiac output improvement, the key mechanism behind clinical functional benefit as measured by the 6MWD.

    • Efficacy and safety of sequential combination therapy for pulmonary arterial hypertension: A meta-analysis of Randomized-Controlled Trials

      2022, Pulmonary Pharmacology and Therapeutics
      Citation Excerpt :

      SCT was associated with a significant increase in integral and addition of prostacyclin analog subgroup compared with BT (RR 2.30, 95% CI 1.86 to 2.84; p < 0.00001; RR 3.61, 95% CI 2.48 to 5.26; p < 0.00001; Online Appendix Table S4). Adverse events during the trials after receiving sequential PAH-specific agent treatment were reported in all studies [4,11,15,16,24–36]. SCT increased the incidence of flushing (RR 2.83, 95% CI 1.88 to 4.28; p < 0.00001; Table 3), headache (RR 2.00, 95% CI 1.85 to 2.15, p < 0.00001; Table 3), nausea (RR 1.77, 95% CI 1.58 to 1.98; Table 3), diarrhoea (RR 1.89, 95% CI 1.68 to 2.14; p < 0.00001; Table 3), and jaw pain (RR 3.60, 95% CI 2.48 to 5.23; p < 0.00001; Table 3) compared with BT in pooled analyses with low or moderate heterogeneity.

    View all citing articles on Scopus

    See Appendix for investigator listing.

    View full text