4. DISCUSSION
The present study evaluated whether patient data from the JADER database could be used for survival analysis to compare the long-term efficacies of PAH-specific vasodilators targeting the same biological pathway in PAH patients. Our study findings indicate that continuous intravenous epoprostenol and oral ERAs were associated with long-term survival in PAH patients. In contrast, sildenafil, a phosphodiesterase 5 inhibitor (PDE5i), did not associate with improvement in PAH mortality in this study. To the best of our knowledge, this is the first report to comprehensively compare the effects of PAH-specific vasodilators on long-term survival using a spontaneous reporting database. Our results suggest that spontaneous reporting databases partially provide useful information about associations between medications and all-cause mortality in limited situations such as analysis for rare diseases.
The demographics of the PAH patients reported in the JADER database were characterized by a high proportion of females, and most of the patients were idiopathic PAH. Similar demographics of PAH patients were reported in studies using RWD, such as patient registries or medical records.16–19 Ogawa et al. conducted a retrospective medical chart review assessing 141 Japanese PAH patients and reported that 40 patients died during the study period, and 21 patients died from heart failure.16 Although the JADER database is a spontaneous adverse event reporting database, the data of PAH patients contain causes of disease-related death, including death from heart failure, as well as just side effects of drugs. In our study population, the percentage of patients whose clinical outcomes were reported as death and the treatment distributions of respective pulmonary vasodilators were similar to the rate of all-cause death and treatments distributions in PAH patients registered in the Japan Pulmonary Hypertension Registry (JAPHR), the largest network of pulmonary hypertension hospitals in Japan.20,21 In the JAPHR, approximately 20% of the registered patients resulted in death from any causes; the most frequently prescribed drugs in each major drug class were epoprostenol, selexipag, tadalafil, and macitentan, in consistency with our results.20,21 The high similarity of our study population to other RWD often used for cohort studies indicates the reliability of our results. In limited situations where representative patient population data in rare diseases, such as PAH, are unavailable, patient data from a spontaneous reporting database, with confirmed similarity of the demographics to the whole patient population, may be alternative data for cohort studies.
The present study showed that among drugs targeting the prostacyclin pathway, epoprostenol was most associated with long-term survival in the PAH patients reported in the JADER database. The 2022 European Society of Cardiology/European Respiratory Society (ESC/ERS) guidelines recommend the addition of epoprostenol or treprostinil to the combination of an ERA and a PDE5i for high-risk PAH patients.12 The effect of epoprostenol on long-term survival has been confirmed in clinical trials;22–24however, there are no clinical trials directly comparing epoprostenol and treprostinil regarding long-term survival. Epoprostenol requires continuous administration via a central venous catheter owing to its short half-life.25 In contrast, treprostinil is chemically stable, and several delivery systems, including implantable pumps, have been developed.26,27 Although the long-term efficacy of treprostinil was not fully confirmed in the present study, treprostinil may be an alternative for PAH patients unsuitable for epoprostenol therapy.
The associations of the use of iloprost, beraprost, and selexipag with improved survival were not observed in the present study. The effects of iloprost and beraprost on improvement in PAH mortality have not been fully elucidated in clinical trials.28,29 The 2022 ESC/ERS guidelines contain no specific recommendations on the use of iloprost and beraprost in the treatment algorithm for PAH.12 The guidelines recommend add-on therapy of selexipag for PAH patients at intermediate risk despite receiving the initial combination therapy of an ERA and a PDE5i.10,12 The JADER database cannot distinguish whether reported drugs are administered as initial or second-line add-on therapy, while 71.1% of the selexipag users were also ERA and PDE5i users in our study (data not shown). The PAH patients reported as selexipag users in the JADER database may include many patients resistant to initial therapy, which might influence our results.
The PAH patients treated with sildenafil were associated with a poor prognosis compared with the patients treated with tadalafil or the non-PDE5i users in the present study. The 2022 ESC/ERS guidelines recommend initial combination therapy with tadalafil and an ERA for PAH patients at low or intermediate risk based on the evidence from a randomized controlled trial that compared the combination of tadalafil and ambrisentan with each monotherapy.11,12 There is little evidence for the superiority of tadalafil over sildenafil. Tadalafil is a long-acting PDE5i with a half-life of 17.5 hours compared with 4 hours for sildenafil.30 The longer half-life of tadalafil contributes to stable hemodynamics in PAH patients, which may be associated with our results. The superiority of riociguat, a soluble guanylate cyclase stimulator, over PDE5is was not fully confirmed in the present study. Although the effect of switching to riociguat from PDE5is has been evaluated,31 initial use of riociguat in newly diagnosed PAH patients should be assessed in future studies.
The PAH patients treated with ERAs, especially macitentan, had significantly better survival than the non-user patients in the present study. There is little information about the comparison of the efficacies of ERAs, while different safety profiles have been observed in clinical trials of each ERA.9,32,33 The use of bosentan was related to dose-dependent increases in liver transaminases and is not strongly recommended in the 2022 ESC/ERS guidelines compared with other ERAs.12,33 Ambrisentan and macitentan had low liver toxicity; however, the clinical trials of ambrisentan or macitentan demonstrated an increased incidence of peripheral edema or anemia, respectively.9,32 Although our data suggest that macitentan was superior to other ERAs for long-term survival, their safety profiles and baseline characteristics of PAH patients should be considered in ERA selection.
Oxygen therapy for PAH patients was not associated with long-term survival in our results. Ulrich et al. reported that oxygen therapy improved exercise capacity in PAH patients.34 Oxygen therapy is effective for PAH patients as a symptomatic treatment. In the present study, the effect of warfarin on improvement in all-cause mortality was observed in only non-epoprostenol users. Similar tendencies were reported by Ogawa et al.16 These findings suggest that PAH patients with epoprostenol therapy do not benefit from anticoagulant therapy with warfarin. The relationship between anticoagulant therapy with DOAC and epoprostenol was not assessed in the present study because of the small sample size of DOAC users. The use of tolvaptan was associated with a poor prognosis in our study. Tolvaptan is used for the treatment of right ventricular failure due to PAH in combination with traditional diuretics such as furosemide.35 Thus, in the present study, PAH patients using tolvaptan potentially have had a poor prognosis owing to the comorbidity of right ventricular failures.
Our study has several limitations. Firstly, high censoring rates were observed in the survival analyses. The JADER database does not include follow-up data for each patient. We used the last-reported date of adverse events as a censoring date to estimate the survival times of the non-death PAH patients. This approach enables large-scale survival analysis using a spontaneous adverse event reporting database, while careful interpretation of the results is needed owing to the tendency to consider non-death patients as censored. Secondly, our study did not assess the effect of combination therapy of PAH-specific vasodilators. We extracted all drug information related to the treatment of PAH from the DRUG table; however, our analyses did not distinguish whether these drugs were administered as mono or combination therapy. The present study performed multivariate analyses to eliminate the influence of covariates including concomitant use of other pulmonary vasodilators. Our results potentially reflect the inherent efficacies of PAH-specific vasodilators as monotherapy. Future clinical trials are required to confirm the effect of combination therapy of PAH-specific vasodilators. Thirdly, the JADER database contains several biases inherent to RWD such as the potential of missing or wrongly entered data and the duplications of patient data. Additionally, the JADER database is a passive reporting system and is influenced by under-reporting which is the problem that not all occurrences of adverse events are reported to the database. Careful application of our data to clinical decision making is needed.