The Safety And Efficacy Of Riociguat Treatment In The Management Of Pulmonary Arterial Hypertension

 

Objective

The soluble form of guanylate cyclase (sGC) stimulator riociguat has been approved for the management of patients with PAH (pulmonary arterial hypertension). It is also approved for the treatment of inoperable or recurrent/persistent chronic thromboembolic pulmonary hypertension after its safety and efficacy were assessed during the phase 3 randomized trials. 

This EXPERT (EXPosurE Registry RiociguaT) study in patients with pulmonary hypertension is designed to assess the long-term safety of this medication in clinical practice.

Methods

EXPERT is an international, non-interventional prospective, multicenter, uncontrolled, cohort study of patients who were administered riociguat. During this study, patients were followed up for at least one year and up to four years from the enrollment or for 30 days after they stopped riociguat treatment. 

The safety outcomes were related to the serious adverse events (SAEs) and adverse events (AEs) coded using Medical Dictionary for the System Organ Classes version 21.0 and Regulatory Activities preferred terms, as collected during routine visits (usually every 3 to 6 months) and collated with the help of case report forms.

Results

In this study, 326 PAH patients were included for the analysis. The common AEs in the patients were cardiac/RV (right ventricular) failure (10.7%), dizziness (11.7%), diarrhea (8.6%), dyspnea (8.0%), edema/peripheral edema (10.7%), and cough (7.7%). 

The common SAEs included cardiac/RV failure (10.1%), syncope (3.4%) and dyspnea (4.0%). The exposure-adjusted rate of pulmonary hemorrhage/hemoptysis was about 2.5 events for every 100 patient-years.

Conclusion

Data from EXPERT have shown that the safety of riociguat was consistent in both clinical practice and clinical trials in patients with PAH. No new safety concerns were identified. A lower exposure-adjusted rate of pulmonary hemorrhage/hemoptysis was observed compared to the long-term extension of the PAH studies in the phase 3 trial.

Introduction

PAH (Pulmonary arterial hypertension) is a form of PH (pulmonary hypertension) characterized by a rise in the PVR (pulmonary vascular resistance) caused due to the progressive remodeling of pulmonary vasculature that can ultimately lead to death by causing right heart failure. 

PAH is also characterized hemodynamically by the precapillary PH, as defined most recently by a mean (PAH) pulmonary arterial pressure more than or equal to 20 mm of Hg as compared to the previous measure of equal to or more than 25 mm of Hg. 

The definition also includes having a pulmonary artery wedge pressure of less than or equal to 5 mm of Hg and PVR more than or equal to 3 Wood units particularly in the absence of other known causes of precapillary PH including PH due to pulmonary diseases, or CTEPH (chronic thromboembolic PH). 

The approved targeted therapies for patients with PAH include prostacyclin analogs, prostacyclin receptor agonists, PDE5i (phosphodiesterase type 5 inhibitors), ERAs (endothelin receptor antagonists), and the soluble guanylate cyclase stimulator - riociguat. 

Calcium channel blockers may be used occasionally for the treatment of some patients with PAH, although these drugs are not as usually described as the PH-targeted drugs. Riociguat has been specifically approved for the treatment of adult patients with PAH and in cases that are inoperable or are characterized by persistent or recurrent CTEPH. 

Results

The evaluable population in this study consisted of 1330 patients among which 326 were diagnosed with PAH, and 956 with CTEPH, with 48 participants with “other forms of PH”. The EXPERT study exceeded the planned enrollment by nearly 400 patients. The differences between CTEPH and PAH in pathophysiology, outcomes, and treatment lead to the decision to analyze and present the results separately for both conditions. This report is focused on patients with PAH. 

PAH patient disposition

The population of patients with PAH in this study consisted of 326 participants among which 182 (55.8%) participants were riociguat-pre-treated while 144 (44.2%) were newly treated with riociguat. Approximately 87% of the participants completed the study. 

Comparison between riociguat-newly treated and riociguat-pre-treated patients

Compared to the patients pre-treated with riociguat, the newly treated patients were found to have a shorter disease duration, a higher risk of WHO FC III/IV diseases, shorter 6MWD, and an increased proportion of incident diseases. 

About 90% of participants in both groups had one or more comorbidities. Approximately 88% of them completed the study. Among the riociguat-newly treated patients, 22.9% (33 participants) had switched from the previous PAH-approved therapy with 31 (21.5%) of them having been switched from PDE5i, 1 (0.7%) from an ERA (a few were switched from more than 1 prior therapy) and 4 (2.8%) from a prostanoid therapy.

One hundred and seven riociguat-newly treated patients (74.3%) and 122 riociguat-pre-treated patients (67.0%) were reported to have developed AEs. SAEs were reported in 78 patients (54.2%) and 74 patients (40.7%) in these groups, respectively. 

SAEs and AEs found in riociguat-newly treated patients were believed to be drug-related leading to drug discontinuation as compared to that in riociguat-pre-treated patients. 

Most SAEs and AEs were frequent in the newly treated patients. The safety results in the switched patients were similar to those in non-switched patients. 

In both riociguat-newly treated and riociguat-pre-treated patients, there was a higher incidence of AEs when combination therapy was administered compared to when monotherapy was administered. 

SAEs and AEs of special interest

SAEs and AEs of special interest were more frequent in the riociguat-newly treated patients compared to that in the riociguat-pre-treated patients. Among the 6 patients with more intense hemoptysis, 3 had been receiving concomitant anticoagulants, 2 were treated with a concomitant prostanoid, and 1 was receiving antiplatelet drugs.

The incidence of hypotension was lower across all these subgroups. No events of hemoptysis were reported in patients receiving therapy with both riociguat as well as a prostanoid, with or without the ERA.

Discussion

Safety findings

EXPERT has provided data on the tolerability and safety of riociguat in more than three hundred patients with PAH in clinical practice. The types of AEs reported were consistent with those reported in PATENT-1 and PATENT-2. 

No new safety signals were identified. The common events such as edema, peripheral edema, hypotension, dizziness, cardiac failure, RV failure, and dyspnea were found to be consistent with vasodilatation by riociguat or the symptoms of the underlying disease. 

Concomitant therapy with anticoagulants, antiplatelets, or prostanoids (having antiplatelet action) might have led to bleeding AEs in some participants. The exposure-adjusted rate of hypotension, pulmonary hemorrhage, and hemoptysis was lower than that reported in PATENT-2. 

In patients receiving a combination regimen with riociguat, the incidence of AEs was higher than that in patients receiving monotherapy. The AEs that were considered to be drug-related by the investigators were more common with monotherapy with riociguat than with combination therapy. This could be because it was easier to link AEs to the treatment when the patient was receiving only 1 drug. 

This data needs to be interpreted with caution as they are not adjusted for the difference between the monotherapy and combination groups. They only refer to the treatment at baseline. Also, the number of patients receiving dual therapy with riociguat and a prostanoid was very small. However, the overall results have indicated the safety of riociguat both as monotherapy and in a combination regimen. 

Comparison with other studies

The disease characteristics and demographics of patients with PAH were similar to those observed in the REVEAL registry as well as the incident group in REVEAL. Patients with PAH were approximately four years older than those in the French National Registry. 

EXPERT was also linked with the COMPERA (Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension), which is one of the largest global PH registries used for academic purposes. This was consistent with the guidance from regulatory authorities to utilize the existing registries. 

The association of COMPERA with EXPERT in which participants are older than those in other registries might have encouraged enrollment of patients from the older age groups.

The estimated one-year survival in patients with PAH was comparable in EXPERT and REVEAL with 91.0% accuracy. 

These registries have provided important information about the efficacy and safety of drugs in clinical practice. They supplement the information discovered from selected populations under closely controlled conditions during clinical trials. They may also help to detect the previously unsuspected signals related to safety. Limitations inherent to registries such as confounding, missing values, lack of randomization, and the risk of generalizing data from registry population to other populations apply to EXPERT. 

Strengths of EXPERT in this study include the relatively longer observation time with a median of 473 days and the larger percentage of patients who completed the study.

Conclusion

Riociguat has been approved for the management of pulmonary arterial hypertension (PAH). Expert studies have evaluated the safety and efficacy of riociguat in clinical settings.

The results available for 326 patients with PAH from 28 countries, followed up for 1 to 4 years, have shown outcomes that are consistent with clinical trials without any new safety concerns being identified.