Pulmonary Arterial Hypertension Soluble Guanylate Cyclase–Stimulator Trial 1 - PATENT-1

Aug 07, 2013
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Author/Summarized by Author:
Dharam J. Kumbhani, MD, SM, FACC
Summary Reviewer:
Deepak L. Bhatt, MD, MPH, MBA, FACC
Trial Sponsor:
Bayer HealthCare
Date Published:
01/01/2013
Date Updated:
08/07/2013
Original Posted Date:
08/07/2013
References

Description:

Riociguat is a novel pulmonary vasodilator that acts via stimulation of soluble guanylate cyclase (sGC).The current trial sought to study the safety and efficacy of riociguat in patients with symptomatic pulmonary arterial hypertension (PAH).

Hypothesis:

Riociguat would be superior to placebo in the improvement of symptoms in patients with PAH.

Study Design

  • Placebo Controlled
  • Randomized
  • Blinded
  • Parallel

Patient Populations:

  • Symptomatic PAH
  • 6-minute walk distance of 150-450 m
  • Pulmonary vascular resistance of more than 300 dynes/sec/cm–5
  • Mean pulmonary artery pressure of at least 25 mm Hg

    Number of enrollees: 443
    Number screened: 586
    Duration of follow-up: 12 weeks
    Mean patient age: 51 years
    Percentage female: 79%

Exclusions:

  • Patients on phosphodiesterase-5 inhibitors
  • Use of intravenous prostanoids
  • For patients on endothelin-receptor antagonists and oral prostanoids, to be included, the dose had to be stable for at least 90 days

Primary Endpoints:

  • Change in 6-minute walk distance between baseline and week 12

Secondary Endpoints:

  • Between baseline and week 12, changes in:
    - Pulmonary vascular resistance
    - NT-pro-BNP
    - Symptoms
    - Time to clinical worsening
    - Borg dyspnea scale
    - EuroQol Group 5-Dimension Self-Report Questionnaire score
    - Living with Pulmonary Hypertension questionnaire score

Drug/Procedures Used:

Patients were randomized in a 4:1:2 fashion to receive either oral riociguat adjusted to 2.5 mg TID, 1.5 mg TID, or matching placebo. Riociguat was adjusted from a starting dose of 1 mg three times daily according to systolic systemic arterial pressure and signs or symptoms of hypotension (final range, 0.5-2.5 mg three times daily). The doses reached at the end of the 8-week adjustment phase were considered to be the appropriate dose for the patient, and the patient continued taking the drug at that dose for another 4 weeks.

Concomitant Medications:

Endothelin-receptor antagonists (44%), prostanoids (6%)

Principal Findings:

A total of 443 patients were randomized, 254 to riociguat 2.5 mg TID, 63 to riociguat 1.5 mg TID, and 126 to placebo. Baseline characteristics were fairly similar between the three arms. PAH was idiopathic in 61% of patients, and associated with connective tissue disorders in 25%. The majority of patients had World Health Organization (WHO) class II (42%) or III (53%) symptoms. The baseline 6-minute walk distance was 363 m.

Efficacy comparisons were only made between the riociguat 2.5 mg TID and placebo arms. At week 12, the primary endpoint of 6-minute walk distance was significantly higher in the riociguat arm as compared with placebo (change: 30 m vs. -6 m; least-squares mean difference [LSMD]: 36 m, p < 0.001). Correspondingly, there were significant improvements in pulmonary vascular resistance (LMSD: -223 dynes/sec/cm5, p < 0.001), N-terminal pro-B-type natriuretic peptide (NT pro-BNP) (LMSD: -198 pg/ml, p < 0.001), and the Borg dyspnea score (-0.4 vs. 0.1, p = 0.002). Cardiac output (LMSD: 0.9 L/min, p < 0.001) was also increased; wedge pressure was similar (LMSD 0.4 mm Hg, p = 0.08).

Drug discontinuation due to adverse events was low and similar between the two arms (3% vs. 2%). Common side effects with riociguat were headache, dizziness, dyspepsia, nausea/vomiting, and hypotension.

Interpretation:

The results of the current trial indicate that riociguat, a novel pulmonary vasodilator that works by stimulating sGC, is safe and effective as compared with placebo in the treatment of PAH. Riociguat resulted in improved hemodynamics, as well as improved 6-minute walk distance. When compared with other agents used in PAH, the improvements noted with riociguat were more or less similar. One drawback of the current trial is that <50% of the enrolled patients were already on established therapy for PAH. Thus, the incremental benefit of this drug over currently used medications is not clear. Also, no information is also provided regarding right ventricular performance/metrics at the end of the trial.

References:

Ghofrani HA, Galiè N, Grimminger F, et al. Riociguat for the treatment of pulmonary arterial hypertension. N Engl J Med 2013;369:330-40.

Keywords: Nausea, Vomiting, Pulmonary Wedge Pressure, Follow-Up Studies, Arterial Pressure, Hypotension, Cardiac Output, Pyrimidines, Pyrazoles, Dyspnea, Headache, Dyspepsia, Vasodilator Agents, Guanylate Cyclase, Dizziness, Hypertension, Pulmonary, Vascular Resistance, Natriuretic Peptide, Brain


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