Predictors of long-term outcomes in patients treated with riociguat for pulmonary arterial hypertension: data from the PATENT-2 open-label, randomised, long-term extension trial

Lancet Respir Med. 2016 May;4(5):361-71. doi: 10.1016/S2213-2600(16)30019-4. Epub 2016 Apr 8.


Background: Pulmonary arterial hypertension is a chronic disease associated with poor long-term outcomes. Identifying predictors of long-term outcome in pulmonary arterial hypertension is important to assess disease severity and guide treatment. We investigate associations between efficacy parameters and long-term outcomes in patients with pulmonary arterial hypertension receiving riociguat in the PATENT-2 study. We also present safety and efficacy data from the final data cutoff of PATENT-2, where most patients had received at least 2 years of riociguat treatment.

Methods: Eligible patients from the PATENT-1 study entered the PATENT-2 open-label extension, which will continue until all patients transition to the commercial drug. All patients received riociguat individually adjusted to a maximum dose of 2·5 mg three times a day. The primary endpoint was safety and tolerability, assessed with recording adverse events, serious adverse events, discontinuations, and deaths; exploratory assessments included 6-min walking distance (6MWD), WHO functional class, N-terminal prohormone of brain natriuretic peptide (NT-proBNP)concentrations, Borg dyspnoea score, health-related quality of life (EQ-5D score), survival, and clinical worsening-free survival. Association between efficacy parameters and long-term outcomes was assessed using Kaplan-Meier analyses and a Cox proportional-hazards regression model. PATENT-2 is registered at, number NCT00863681.

Findings: 396 patients entered PATENT-2, of whom 197 patients were receiving riociguat monotherapy and 199 were receiving riociguat in combination with endothelin receptor antagonists or prostanoids, or both. A significant association was noted between 6MWD, NT-proBNP concentration, and WHO functional class and overall survival at baseline (p=0·0006, 0·0225, and 0·0191, respectively), and at follow-up (p=0·021, 0·0056, and 0·0048, respectively). Riociguat was well tolerated in PATENT-2. Serious adverse events were recorded in 238 (60%) of the total population, and 45 (11%) patients discontinued treatment because of an adverse event. Improvements in 6MWD, WHO functional class, and NT-proBNP concentrations were maintained after 2 years of treatment.

Interpretation: These results support the long-term use of riociguat in patients with pulmonary arterial hypertension, and emphasise the prognostic value of 6MWD, WHO functional class, and NT-proBNP concentrations.

Funding: Bayer Pharma AG.

Publication types

  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Antihypertensive Agents / administration & dosage*
  • Double-Blind Method
  • Drug Administration Schedule
  • Drug Therapy, Combination
  • Endothelin Receptor Antagonists / administration & dosage
  • Female
  • Humans
  • Hypertension, Pulmonary / blood
  • Hypertension, Pulmonary / drug therapy*
  • Male
  • Middle Aged
  • Natriuretic Peptide, Brain / blood
  • Prostaglandins / administration & dosage
  • Pulmonary Artery
  • Pyrazoles / administration & dosage*
  • Pyrimidines / administration & dosage*
  • Quality of Life
  • Time*
  • Treatment Outcome
  • Young Adult


  • Antihypertensive Agents
  • Endothelin Receptor Antagonists
  • Prostaglandins
  • Pyrazoles
  • Pyrimidines
  • Natriuretic Peptide, Brain
  • riociguat

Associated data