Chronic Thromboembolic Pulmonary Hypertension Soluble Guanylate Cyclase–Stimulator Trial 1 - CHEST-1

Description:

Chronic thromboembolic pulmonary hypertension (CTEPH) is very difficult to treat. The gold standard has been pulmonary thromboendarterectomy, but is offered at very few centers. Although currently available pulmonary vasodilators are sometimes used in this condition, there are no approved medications available for this condition. 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 CTEPH.

Hypothesis:

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

Study Design

  • Parallel
  • Randomized
  • Blinded
  • Placebo Controlled

Patient Populations:

  • Age 18-80 years
  • CPETH that was adjudicated to be technically inoperable or if they had persistent or recurrent pulmonary hypertension after undergoing pulmonary endarterectomy
  • Six-minute walk distance of 150-450 m
  • Pulmonary vascular resistance of more than 300 dyn/sec/cm–5
  • Mean pulmonary artery pressure of at least 25 mm Hg

    Number of enrollees: 261
    Number screened: 446
    Duration of follow-up: 16 weeks
    Mean patient age: 59 years
    Percentage female: 66%

Exclusions:

  • Endothelin-receptor antagonist, prostacyclin analogue, phosphodiesterase type 5 inhibitor, or nitric
    oxide donor within the 3 months before study entry

Primary Endpoints:

  • Change in 6-minute walk distance between baseline and week 16

Secondary Endpoints:

  • Between baseline and week 16, 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 2:1 fashion to receive either riociguat 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 8 weeks.

Concomitant Medications:

N/A

Principal Findings:

A total of 261 patients were randomized, 173 to riociguat and 88 to placebo. Baseline characteristics were fairly similar between the three arms. CTEPH was considered inoperable in 72% of patients; it was postoperative in the other patients. The majority of patients had World Health Organization (WHO) class II (31%) or III (64%) symptoms. The baseline 6-minute walk distance was 347 m.

At week 16, the primary endpoint of 6-minute walk distance was significantly higher in the riociguat arm as compared with placebo (change: 39 m vs. -6 m; least-squares mean difference [LSMD]: 46 m, p < 0.001). Correspondingly, there were significant improvements in pulmonary vascular resistance (LMSD: -246 dynes/sec/cm5, p < 0.001), N-terminal pro-B-type natriuretic peptide (NT-pro-BNP) (LMSD: -444 pg/ml, p < 0.001), and the Borg dyspnea score (-0.8 vs. 0.2, p = 0.004). Cardiac output (LMSD: 0.9 L/min, p < 0.001) was also increased; wedge pressure was similar (LMSD 0.6 mm Hg, p = 0.2).

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, nasopharyngitis, 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 CTEPH. Riociguat resulted in improved hemodynamics, as well as improved 6-m walk distance. Since no other drug is currently approved for treatment of CTEPH, this represents an important advance. However, no information is provided regarding RV performance/metrics at the end of the trial. It is also important to note that the majority of patients in this trial were deemed inoperable, suggesting that results may not be generalizable to patients who are otherwise good candidates for pulmonary thromboendarterectomy.

References:

Ghofrani HA, D’Armini AM, Grimminger F, et al. Riociguat for the treatment of chronic
thromboembolic pulmonary hypertension. N Engl J Med 2013;369:319-29.

Clinical Topics: Anticoagulation Management, Heart Failure and Cardiomyopathies, Invasive Cardiovascular Angiography and Intervention, Pulmonary Hypertension and Venous Thromboembolism, Statins, Heart Failure and Cardiac Biomarkers, Pulmonary Hypertension

Keywords: Nausea, Endarterectomy, Vomiting, Pulmonary Wedge Pressure, Arterial Pressure, Pyrimidines, Hypotension, Cardiac Output, Pyrazoles, Dyspnea, Headache, Dyspepsia, Vasodilator Agents, Guanylate Cyclase, Dizziness, Receptors, Cytoplasmic and Nuclear, Hypertension, Pulmonary, Peptide Fragments, Vascular Resistance, Nasopharyngitis, Natriuretic Peptide, Brain


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