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

Summary

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.

Introduction

Pulmonary arterial hypertension is a chronic and progressive disease, characterised by raised pulmonary vascular resistance, that can result in death due to right heart failure.¹ Pulmonary arterial hypertension is a rare condition, with an estimated incidence of 1·1–7·6 cases per million individuals across several EU and US national registries.² The symptoms of pulmonary arterial hypertension, which include shortness of breath, chest pain, and fatigue, have a substantial impact on patients' quality of life.³ There are four approved classes of pharmacological therapy for the treatment of pulmonary arterial hypertension: endothelin receptor antagonists (ERAs), phosphodiesterase type 5 inhibitors, prostanoids, and soluble guanylate cyclase (sGC) stimulators.¹ However, despite these treatments, pulmonary arterial hypertension remains incurable and the long-term prognosis is poor.4, 5

Research has focused on identifying prognostic factors in patients with pulmonary arterial hypertension to identify patients at high risk of clinical deterioration.⁶ Parameters known to be predictive of long-term outcome in pulmonary arterial hypertension include functional assessments such as 6-min walking distance (6MWD) and WHO functional class, and biomarkers such as N-terminal prohormone of brain natriuretic peptide (NT-proBNP).1, 7, 8 Regular assessment of these parameters allows physicians to determine a patient's disease severity and clinical status, how well a patient is responding to therapy, and whether modification or escalation of treatment is required.¹

Riociguat is an sGC stimulator approved for the treatment of pulmonary arterial hypertension. As noted elsewhere,⁹ riociguat targets the nitric oxide–sGC–cyclic guanosine monophosphate (cGMP) pathway with a dual mode of action, sensitising sGC to endogenous nitric oxide and stimulating sGC directly, independently of nitric oxide; this results in increased cGMP production.¹⁰ In the 12-week, phase 3 PATENT-1 study,¹¹ riociguat was well tolerated in treatment-naive and pretreated patients with pulmonary arterial hypertension, and improved a range of clinical endpoints including 6MWD, WHO functional class, and NT-proBNP. These improvements were sustained at 1 year in the PATENT-2 open-label extension study.¹² Riociguat also increased the number of patients achieving clinically relevant responder thresholds in PATENT-1.¹³

Research in context

Evidence before this study

We searched PubMed from inception to Nov 30, 2015, for studies (in English only) investigating the prognostic value of efficacy assessments, and long-term studies of targeted therapy, in patients with pulmonary arterial hypertension. A number of functional, biochemical, and haemodynamic parameters have been shown to predict outcome in patients with pulmonary arterial hypertension, and guidelines recommend regular assessment of these parameters with the aim of achieving a low-risk profile, in which the risk of 1-year mortality is less than 5%. However, the evidence is mixed for the use of on-treatment efficacy parameters to predict long-term outcomes in pulmonary arterial hypertension. Most evidence focuses on the use of 6-min walking distance (6MWD) and WHO functional class as prognostic factors, whereas there are few data about N-terminal prohormone of brain natriuretic peptide (NT-proBNP).

Most of the approved pulmonary arterial hypertension-specific therapies have been assessed in long-term open-label extension studies, and another publication from the PATENT-2 study (median treatment duration 91 weeks) showed that riociguat was well tolerated, and improved exercise and functional capacity at 1 year.

Added value of this study

This study presents data from the final data cutoff of PATENT-2 (median treatment duration 139 weeks), at which most patients had received at least 2 years of riociguat treatment. Using two different methodologies, the analyses presented here show that 6MWD, WHO functional class, and NT-proBNP concentration at baseline and after 12 weeks of riociguat therapy were significantly associated with long-term survival and clinical worsening-free survival. The data also show the long-term tolerability and efficacy of riociguat. Building on the results from the phase 3 PATENT-1 study, the improvements in 6MWD, WHO functional class, and NT-proBNP concentration observed after 12 weeks of riociguat treatment were sustained after 2 years of treatment. Riociguat continued to show a favourable safety profile, with no new safety signals identified.

Implications of all the available evidence

The data published here contribute to the existing evidence for the use of efficacy parameters as predictors of long-term outcome, suggesting that the non-invasive parameters 6MWD, WHO functional class, and concentrations of the biomarker NT-proBNP, can all be used to predict long-term outcomes and guide patient management and treatment decisions. These results also support guidelines recommending the regular assessment of functional and biochemical parameters in patients with pulmonary arterial hypertension, with the aim of reducing the risk of clinical deterioration through early treatment escalation. Furthermore, these results show that patients on long-term riociguat therapy, as monotherapy and in combination with endothelin receptor antagonists or prostanoids, have sustained improvements in clinical and functional status. The results also confirm the known safety profile of riociguat, with no new safety signals identified. This supports the long-term use of riociguat in patients with pulmonary arterial hypertension.

Here we present results from the final data cutoff of the PATENT-2 study, at which most patients had received at least 2 years of treatment with riociguat (median treatment duration 139 weeks; range 0–244 weeks) and some had received over 4 years of treatment. Furthermore, we investigate the associations between baseline and on-treatment efficacy parameters, and long-term survival and clinical worsening-free survival in this patient cohort.