Pulmonary Arterial Hypertension and Response to Tadalafil - PHIRST

Jun 08, 2009
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Trial Sponsor:
Eli Lilly and Company
Date Published:
01/01/2009
Date Updated:
06/08/2009
Original Posted Date:
06/08/2009
References

Description:

Sildenafil has been shown to be beneficial in patients with pulmonary arterial hypertension (PAH) in improving exercise capacity and hemodynamic parameters. However, there are no trials studying the role of sildenafil or other similar phosphodiesterase type-5 (PDE-5) inhibitors in patients with PAH who are already on the endothelin receptor antagonist bosentan. Moreover, sildenafil is a three times daily drug. The current study sought to investigate the role of tadalafil in patients with PAH, with and without bosentan.

Hypothesis:

Tadalafil would be associated with a greater improvement in 6-minute walk distance at 16 weeks compared with placebo, in patients with PAH.

Study Design

Study Design:

Patients Screened: 457
Patients Enrolled: 405
Mean Follow Up: 16 weeks
Mean Patient Age: 54 years
Female: 78

Patient Populations:

  • Age >12 years
  • Symptomatic PAH (primary or secondary)

Exclusions:

  • 6-minute walk distance <150 m or >450 m
  • Treatment with intravenous epoprostenol, intravenous or inhaled iloprost

Primary Endpoints:

  • Placebo-correct change in 6-minute walk distance at 16 weeks

Secondary Endpoints:

  • WHO functional class
  • Time from randomization to clinical worsening
  • Borg dyspnea score
  • Quality of life
  • Hemodynamic response (subset)

Drug/Procedures Used:

Patients were randomized to groups receiving one of five treatments (tadalafil 2.5 mg, 10 mg, 20 mg, 40 mg, or placebo once daily) for 16 weeks.

Concomitant Medications:

Bosentan (53.3%)

Principal Findings:

A total of 405 patients were randomized, 82 to placebo, 82 to 2.5 mg, 80 to 10 mg, 82 to 20 mg, and 79 to 40 mg daily of tadalafil. Baseline characteristics were fairly similar between the two groups. The majority of patients had primary PAH, and were more likely to be white women, with relatively recent onset of PAH (<2 years). The mean baseline 6-minute walk distance ranged from 338 to 352 m, with a mean PA pressure of 49-58 mm Hg, and a cardiac index of 2.4-2.6 L/min/m2. The mean baseline pulmonary vascular resistance ranged from 827 to 972 dynes-sec-cm5.

There was a dose-dependent improvement in 6-minute walk distance with taladafil, compared with placebo, although this was statistically significant compared with baseline only in the 40 mg daily arm. This was true in those patients already on bosentan as well, although the effect was blunted when compared with treatment-naive patients. The mean placebo-corrected improvements were 14 m (2.5 mg), 20 m (10 mg), 27 m (20 mg), and 33 m (40 mg), respectively. Clinical worsening was noted less frequently with tadalafil 40 mg (5% vs. 16%, p = 0.04). There was one death each in the placebo, 10 mg, and 20 mg arms. No change in World Health Organization (WHO) functional class or Borg dyspnea score was noted with tadalafil compared with placebo.

Hemodynamic data were available on a subset of the patients. In these patients, tadalafil 20 mg and 40 mg were associated with a significant reduction in mean PA pressure by 8.5 (p < 0.001) and 4.3 (p = 0.01) mm Hg, and in pulmonary vascular resistance by 254 (p = 0.001) and 209 (p = 0.04) dyne-sec-cm5, respectively.

Many side effects, including headache, nausea, back pain, dyspepsia, visual blurring, and chest pain seemed to have a dose-dependent effect, with the highest incidence in the 40 mg tadalafil arm. No changes were noted in mean systemic blood pressure.

Interpretation:

The results of the PHIRST trial indicate that in patients with PAH, 40 mg daily of tadalafil is associated with a significant improvement in 6-minute walk distance, hemodynamic parameters including mean PA pressure and pulmonary vascular resistance, as well as a reduction in patients who clinically worsen, compared with placebo. No differences were noted in subjective dyspnea scores, or in mortality. This was true even in patients already on bosentan, although some subgroup analyses suggested that the response was not as pronounced as in treatment-naive patients.

The results of this trial are interesting, and formed the basis for FDA approval for the use of tadalafil 40 mg daily in patients with PAH. Tadalafil offers a few benefits over the other currently used PDE-5 inhibitor in PAH, sildenafil, including once-a-day dosing (vs. thrice daily dosing).

References:

Galie N, Brundage BH, Ghofrani HA, et al. Tadalafil therapy for pulmonary arterial hypertension. Circulation 2009;119:2894-903.

Keywords: Nausea, Phosphodiesterase 5 Inhibitors, Purines, Blood Pressure, Back Pain, Piperazines, Phosphoric Diester Hydrolases, Dyspnea, Sulfones, Headache, Dyspepsia, Vasodilator Agents, Urological Agents, Receptors, Endothelin, Chest Pain, Carbolines, Hypertension, Pulmonary, Vascular Resistance, Sulfonamides


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