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

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.

Author information

1
University of Giessen and Marburg Lung Center (UGMLC) and German Centre of Lung Research (DZL), Giessen, Germany; Department of Medicine, Imperial College London, London, UK. Electronic address: Ardeschir.Ghofrani@innere.med.uni-giessen.de.
2
University of Giessen and Marburg Lung Center (UGMLC) and German Centre of Lung Research (DZL), Giessen, Germany.
3
Centre for Pulmonary Hypertension at the Thoraxclinic of University Hospital Heidelberg, Heidelberg, Germany.
4
Department of Cardiology, Guangdong General Hospital and Guangdong Cardiovascular Institute, Guangzhou, Guangdong, China.
5
Clinical Department of Cardiology and Angiology of the First Faculty of Medicine and General Teaching Hospital, Prague, Czech Republic.
6
State Key Laboratory of Cardiovascular Disease, Fu Wai Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.
7
Discipline of Medicine, University of Tasmania, Hobart, Australia.
8
Center for Pulmonary Vascular Disease and Lady Davis Institute, Jewish General Hospital, McGill University, Montreal, Canada.
9
Department III of Internal Medicine and Cologne Cardiovascular Research Center (CCRC), Cologne University Heart Center, Cologne, Germany.
10
Bayer HealthCare Pharmaceuticals, São Paulo, Brazil.
11
Global Clinical Development, Bayer Pharma AG, Wuppertal, Germany.
12
Global Clinical Development, Bayer Pharma AG, Berlin, Germany.
13
Université Paris-Sud, Université Paris-Saclay, Le Kremlin Bicêtre, France; AP-HP, Service de Pneumologie, Hôpital Bicêtre, Le Kremlin Bicêtre, France; Inserm UMR_S 999, Hôpital Marie Lannelongue, Le Plessis Robinson, France.

Abstract

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 ClinicalTrials.gov, 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.

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