Survival in patients with chronic thromboembolic pulmonary hypertension treated with riociguat versus other medications: a COMPERA analysis

Extract

Current treatment options for patients with chronic thromboembolic pulmonary hypertension (CTEPH) include surgical pulmonary endarterectomy (PEA), interventional balloon pulmonary angioplasty (BPA) and medical therapy [1, 2]. For many years, medical treatment primarily involved off-label use of drugs approved for pulmonary arterial hypertension, despite limited and sometimes inconclusive evidence supporting their effectiveness in CTEPH patients. In 2014, riociguat, a soluble guanylate cyclase stimulator, became the first drug approved for treating patients with inoperable CTEPH or persistent/recurrent pulmonary hypertension (PH) post-surgery [3]. Parenteral treprostinil was subsequently approved for CTEPH [4], although its use has remained limited, likely due to the invasiveness and associated side-effects.

Shareable abstract

This analysis from the COMPERA registry suggests that in medically treated patients with CTEPH, the soluble guanylate cyclase stimulator riociguat may confer a survival benefit over other PH medications https://bit.ly/3Zq3AIu

To the Editor:

Current treatment options for patients with chronic thromboembolic pulmonary hypertension (CTEPH) include surgical pulmonary endarterectomy (PEA), interventional balloon pulmonary angioplasty (BPA) and medical therapy [1, 2]. For many years, medical treatment primarily involved off-label use of drugs approved for pulmonary arterial hypertension, despite limited and sometimes inconclusive evidence supporting their effectiveness in CTEPH patients. In 2014, riociguat, a soluble guanylate cyclase stimulator, became the first drug approved for treating patients with inoperable CTEPH or persistent/recurrent pulmonary hypertension (PH) post-surgery [3]. Parenteral treprostinil was subsequently approved for CTEPH [4], although its use has remained limited, likely due to the invasiveness and associated side-effects.

Recently, the International CTEPH Association (ICA) published registry data showing that riociguat use was linked to a survival benefit in patients with CTEPH when compared to other PH medications [5]. We sought to validate these findings and utilised the COMPERA database to analyse further potential survival differences between CTEPH patients treated with riociguat compared to those treated with other PH therapies.

Details of the COMPERA registry have been published before [6, 7]. In brief, COMPERA is an ongoing, European-based PH registry launched in 2007, which collects data from patients with all forms of PH who receive targeted therapy. For the present analysis, data collected until 31 July 2024 were analysed. From the 12 930 patients enrolled into COMPERA by this time, we selected patients newly diagnosed with CTEPH who had a mean pulmonary artery pressure (mPAP) ≥25 mmHg and a pulmonary artery wedge pressure ≤15 mmHg, who received targeted medical therapy, and who had not undergone BPA prior to initiation of medical therapy. We excluded patients who could have been enrolled into the ICA database to avoid potential double counting. Two groups were defined: the RIO group comprised all patients who received riociguat as initial medical therapy, whereas patients who received other PH medications were included in the No-RIO group. Kaplan–Meier survival analyses with log-rank statistics and Cox proportional hazard analyses (adjusted for age, sex and risk at baseline) were performed from the time of diagnosis. Patients who underwent PEA or BPA after initiation of medical therapy were censored at the time of the first intervention. Patients in the No-RIO group were censored at the start of riociguat therapy during follow-up, if applicable. A sensitivity analysis was performed including only patients who were diagnosed after March 2014, i.e. after market authorisation for riociguat in Europe.

A total of 1451 patients with CTEPH were eligible for this analysis. At baseline, the characteristics of patients in the RIO (n=880, 60.6%) and No-RIO (n=571, 39.4%) groups were comparable regarding age (median 72 and 71 years, respectively), World Health Organization (WHO) functional class III (71.6% and 71.3%), median mPAP (42 and 43 mmHg) and median pulmonary vascular resistance (PVR) (8.2 and 8.6 Wood units), with lower median 6-min walk distance (321 and 299 m), higher proportion of patients with high mortality risk (19.8% and 27.7%) according to the European noninvasive three-stratum risk stratification model [8] and male sex predominance (41.8% and 49.6%), in the No-RIO group. The proportion of patients who had undergone PEA before initiation of medical therapy was low in both groups (5.5% and 3.0%). Medical therapy in the No-RIO group consisted mainly of phosphodiesterase-5 (PDE5) inhibitors (n=407, 71.3%) and endothelin receptor antagonists (ERAs) (n=178, 31.2%), while prostacyclin pathway agents were used infrequently (n=11, 1.9%). Combinations of PH medications were used infrequently (18 (2.0%) patients in the RIO group and 29 (5.1%) in the No-RIO group).

The median observation time was 1.8 years. During follow-up, 22.0% of patients in the RIO group underwent PEA or BPA, compared to 16.3% in the No-RIO group. In the No-RIO group, 122 patients were censored due to the start of riociguat at a median follow-up of 2.4 years. A total of 286 patients died within 5 years after CTEPH diagnosis: 141 (16.0%) out of 880 in the RIO group and 145 (25.4%) out of 571 in the No-RIO group. In the RIO group, the Kaplan–Meier survival estimates at 1, 3 and 5 years were 92.8%, 79.9% and 65.3%, respectively. The corresponding survival estimates in the No-RIO group were 93.1%, 75.0% and 58.6%, respectively (figure 1a). The survival difference between the two groups was statistically significant (p=0.025). Factors associated with mortality by Cox proportional hazard analysis were riociguat treatment (hazard ratio (HR) 0.79, 95% CI 0.63–0.98; p=0.024), age (HR 1.04, 95% CI 1.03–1.05; p<0.001), intermediate risk versus low risk (HR 4.03, 95% CI 1.98–8.2; p<0.001) and high risk versus low risk (HR 10.88, 95% CI 5.26–22.52; p<0.001).

FIGURE 1.

Kaplan–Meier survival estimates of patients with chronic thromboembolic pulmonary hypertension who received riociguat (RIO) versus other medications (No-RIO) used to treat pulmonary hypertension. a) Full analysis set. b) Sensitivity analysis of patients enrolled from April 2014, i.e. after market authorisation of riociguat.

The sensitivity analysis of patients enrolled from April 2014 onwards included 1034 patients: 862 (83.4%) in the RIO group and 172 (16.6%) in the No-RIO group. The patient characteristics of these subgroups matched those of the respective parent groups described above (data not shown). In both groups, a similar proportion of patients underwent PEA or BPA during follow-up (21.8% in the RIO group and 22.7% in the No-RIO group). A total of 164 patients died within 5 years after diagnosis: 139 (16.1%) out of 862 in the RIO group and 25 (14.5%) out of 172 in the No-RIO group. In the RIO group, the Kaplan–Meier survival estimates at 1, 3 and 5 years were 92.6%, 79.5% and 64.4%, respectively. The corresponding survival estimates in the No-RIO group were 95.7%, 70.0% and 56.5%, respectively (figure 1b). The survival difference between these two subgroups was not statistically significant (p=0.23) but Cox proportional hazard analysis revealed the same factors associated with survival as in the entire group, including riociguat treatment (HR for death with riociguat compared to other PH medications 0.61, 95% CI 0.39–0.95; p=0.029).

These data suggest that riociguat treatment might be associated with a survival benefit compared to other PH medications in patients with medically treated CTEPH. It could be argued that a survival advantage in CTEPH patients receiving riociguat is not unexpected, as riociguat remains the only oral treatment to demonstrate significant clinical benefit in a randomised controlled trial [3]. In contrast, PDE5 inhibitors, ERAs and the prostacyclin receptor agonist selexipag have not consistently shown efficacy in this population [1, 9–11]. However, the efficacy of riociguat in the pivotal 16-week CHEST study was primarily limited to improvements in 6-min walk distance (the primary endpoint), as well as reductions in PVR, and improvements in WHO functional class and N-terminal pro-brain natriuretic peptide levels. Similar improvements in exercise capacity and haemodynamics were recently demonstrated in a meta-analysis of eight studies evaluating riociguat as monotherapy [12]. Notably, neither this meta-analysis nor the CHEST trial showed an effect on disease progression or survival [3, 12].

Our analysis has several limitations, most notably that the data were derived from a registry rather than a randomised clinical trial. Although the baseline characteristics of patients in the RIO and No-RIO groups were mostly comparable, and the Cox proportional hazards model was adjusted for age, sex and calculated baseline mortality risk, the possibility of hidden biases, such as uncaptured comorbidities influencing medication choice or country specific reimbursements policies, cannot be ruled out. Moreover, BPA was introduced in Europe around the same time as riociguat. While we censored patients at the time of their first BPA intervention (as we did for PEA), the potential influence of BPA availability on survival outcomes in our cohort remains unclear. Additionally, most patients in the No-RIO group were enrolled before market authorisation of riociguat. A sensitivity analysis including only patients enrolled after riociguat became available showed directionally comparable – albeit statistically nonsignificant – results.

In conclusion, our data align with recent ICA findings suggesting that riociguat may offer a survival benefit for CTEPH patients compared to other PH medications. In the absence of prospective head-to-head studies, we believe that physicians treating patients with CTEPH should be aware of these findings, acknowledging that registry data do not hold to the same scientific rigor as randomised clinical trials.