Millions of Records, One Drug: Global Databases Expose Riociguat’s Hidden Risks

Riociguat, a soluble guanylate cyclase stimulator that has transformed the treatment of chronic thromboembolic pulmonary hypertension and pulmonary arterial hypertension, has now been subjected to one of the most comprehensive post-marketing safety analyses published to date. A team of clinical pharmacists and researchers led by Xuejiao Hong and Shujuan Zhao of Henan Provincial People’s Hospital, affiliated with People’s Hospital of Zhengzhou University, mined two of the world’s largest spontaneous adverse event reporting systems to build a detailed portrait of the drug’s real-world risk profile. Their findings, published in BMC Pharmacology and Toxicology, confirm the safety concerns clinicians already knew about while surfacing unexpected signals that had never emerged from the carefully controlled environment of clinical trials.

The scale of the investigation is striking. The researchers extracted 12,763 adverse event reports involving riociguat from the United States Food and Drug Administration’s Adverse Event Reporting System, known as FAERS, and a further 17,316 reports from VigiAccess, the World Health Organization’s public gateway to global pharmacovigilance data. Together these databases capture hundreds of thousands of reports submitted by healthcare professionals, patients, and manufacturers across dozens of countries, offering a view of drug safety that no single trial can match. Women accounted for the majority of reports in both databases, a pattern consistent with the epidemiology of pulmonary hypertension, which disproportionately affects women, but also a finding that would prove consequential when the team examined sex-specific reactions.

At the heart of the analysis lies a statistical technique called disproportionality analysis, the workhorse of modern pharmacovigilance. Rather than simply counting how often a reaction appears, disproportionality methods ask whether a particular drug-event pair occurs together more often than would be expected by chance, given the overall composition of the database. The team applied multiple established algorithms, including the reporting odds ratio, the proportional reporting ratio, and Bayesian confidence propagation methods, each with defined thresholds for what constitutes a meaningful signal. Requiring agreement across several independent algorithms reduces the risk that a single statistical quirk will be mistaken for a genuine safety concern, a persistent problem in spontaneous reporting data where reporting biases and confounding abound.

The results largely vindicated the drug’s known safety profile. The most frequently reported adverse events were dyspnoea, the medical term for breathlessness, and hypotension, or abnormally low blood pressure. Both are biologically plausible for riociguat: the drug works by enhancing the nitric oxide signalling pathway, relaxing blood vessels and lowering pulmonary vascular resistance, so systemic vasodilation and its consequences are expected effects pushed to an uncomfortable extreme in some patients. The strongest statistical signals included diastolic hypotension and bendopnoea, a subtle symptom in which breathlessness occurs while bending over, such as when putting on shoes. Bendopnoea is increasingly recognized as an early marker of worsening cardiac function, and its emergence as a signal suggests clinicians are documenting it more systematically in this patient population.

The sex-stratified analysis produced some of the study’s most clinically actionable findings. After adjusting for age and body weight, two variables that could otherwise explain differences in drug exposure and metabolism, female patients reported significantly more dyspnoea, headache, nausea, vomiting, and chest pain than male patients. Such gender differences in adverse drug reactions are an area of growing scientific interest, driven by known variations in body composition, hormonal influences, renal and hepatic clearance, and even the historical underrepresentation of women in pivotal trials. For riociguat, the pattern implies that women may need closer monitoring during dose titration, particularly for gastrointestinal intolerance and blood pressure-related symptoms, and that prescribers should not assume trial-derived tolerability data apply uniformly across sexes.

Drug-drug interaction analysis added a second layer of concern. The team identified 30 interaction signals, and the companies of riociguat proved telling: endothelin receptor antagonists accounted for 36.67 percent of the signals and oral anticoagulants for 33.33 percent. Both drug classes are staples of pulmonary hypertension care, meaning the interactions are not exotic edge cases but routine combinations encountered in everyday practice. Endothelin receptor antagonists and riociguat both affect vascular tone, raising questions about additive haemodynamic effects, while anticoagulants are standard in chronic thromboembolic disease and interact with any drug that influences bleeding risk or hepatic metabolism. The authors used multiple signal-detection algorithms for the interaction analysis as well, and their supplementary tables transparently flag which signals were supported by only a single method, an unusually honest approach to the uncertainty inherent in this kind of data mining.

Timing proved to be another revealing dimension. The median time to onset of adverse events was 225 days, with an interquartile range spanning from 47 days to just over 710 days. This long and widely distributed onset window carries a sobering implication: riociguat toxicity is not confined to the initiation period that trials and early monitoring tend to emphasize. A substantial fraction of reactions emerge months or even years into therapy, precisely when patients and clinicians have settled into a sense of security. Sustained vigilance, rather than a brief introductory monitoring burst, appears to be what the data demand, and the late-onset pattern also complicates causal attribution, since comorbid disease progression can mimic drug effects in this progressive illness.

Crucially, the team did not stop at database mining. They cross-validated their pharmacovigilance signals against the safety data from six riociguat clinical trials, finding general concordance between the real-world reports and the trial evidence for established concerns such as hypotension, gastrointestinal disorders, and peripheral edema. But the databases also yielded signals that trials had not flagged, most notably traumatic fractures and pain in the jaw. Traumatic fractures could plausibly reflect falls precipitated by dizziness or syncope from hypotension, an indirect but clinically important chain of harm, while jaw pain raises questions that will require targeted follow-up. These discrepancies illustrate the complementary nature of the two evidence systems: trials establish causation with rigor but limited statistical power for rare events, while spontaneous reports detect rare and unexpected events but cannot by themselves prove causation.

The practical culmination of the study is a pharmacist-led management framework built on the narrative evidence review and the pharmacovigilance findings. The workflow is organized into three phases: pre-treatment evaluation, treatment initiation, and maintenance, with six core responsibilities assigned to pharmacists. These are drug interaction management, safety signal recognition, patient education, efficacy and safety assessment, professional documentation, and quality indicators. The framework reflects a broader shift in hospital practice, in which pharmacists move from dispensing roles into direct therapeutic management, particularly for high-risk medications like riociguat that demand blood pressure monitoring, careful titration, and constant attention to a patient’s full medication list. Given that the interaction signals cluster around drugs pulmonary hypertension patients take routinely, the pharmacist’s cross-checking role becomes not a luxury but a structural safeguard.

The study carries the usual caveats of spontaneous reporting research. FAERS and VigiAccess suffer from underreporting, inconsistent reporting quality, missing denominators that make incidence rates impossible to calculate, and the reporting biases that come with media attention and litigation. The authors were careful to frame their findings as signals warranting attention rather than proven causal effects, and the ethics declarations note that the use of publicly available, anonymized data required no institutional review board approval. Still, the convergence of evidence from two independent global databases, agreement across multiple statistical algorithms, and validation against six clinical trials gives these findings a weight that single-database studies often lack. For the growing population of patients living with pulmonary hypertension, the message is one of informed vigilance: riociguat remains a valuable therapy, but its safety profile is broader, later-emerging, and more sex-dependent than the label alone suggests, and the pharmacist may be the most important person watching for what the label does not say.

Subject of Research: Post-marketing safety evaluation of the pulmonary hypertension drug riociguat using FAERS and VigiAccess pharmacovigilance databases

Article Title: Safety evaluation of riociguat: insights from FAERS and VigiAccess databases, and establishment of pharmacist management framework

Article References: Hong, X., Guo, C., Wang, H., Cai, H., & Zhao, S. (2026). Safety evaluation of riociguat: insights from FAERS and VigiAccess databases, and establishment of pharmacist management framework. BMC Pharmacology and Toxicology. https://doi.org/10.1186/s40360-026-01245-6

Image Credits: AI Generated

DOI: 10.1186/s40360-026-01245-6

Keywords: riociguat, pharmacovigilance, FAERS, VigiAccess, adverse events, pulmonary hypertension, drug-drug interactions, hypotension, pharmacist-led management, drug safety, gender differences, disproportionality analysis