1. INTRODUCTION
Evidence for drug treatment strategies that improve mortality in rare disease patients is essential for clinical decision making. In rare diseases, the use of real-world data (RWD) has become a promising approach for evaluating the effects of medications on long-term survival, as large-scale clinical trials are less feasible.1 Although several RWD sources are available in Japan, the major issue that needs to be resolved is mortality data collection.2 The National Database of Health Insurance Claims and Specific Health Checkups of Japan, the largest database provided by the Japanese government, has limited information on death.2Especially in rare disease patients, efficient approaches for collecting information on death are required to evaluate the long-term survival.
The Japanese Adverse Drug Event Report (JADER) database is a spontaneous adverse event reporting database provided by the Pharmaceuticals and Medical Devices Agency (PMDA).3 In the JADER database, information on clinical outcomes including death is individually reported with an acceptable missing data rate.4 The death reports in the JADER database include disease-related death in addition to death due to drug side effects and have been abundantly accumulated since 2004 when the data collection began.3,5 Patient data reported in spontaneous reporting databases, including the JADER database, are not considered a representative cohort of patients with a particular disease;6 however, we hypothesized that analysis using patient data from the JADER database as a real-world patient cohort might provide useful information about associations between medications and all-cause mortality in limited situations such as analysis for rare diseases.
Pulmonary arterial hypertension (PAH) is a rare, progressive disease characterized by pulmonary arterial remodeling, leading to elevated pulmonary vascular resistance, right ventricular failure, and death.7 Although several PAH-specific vasodilators have been approved over the past two decades, the prognosis of PAH is still poor.8 The effects of some PAH-specific vasodilators on improvement in PAH mortality were partially evaluated in clinical intervention studies that employed a composite endpoint of a PAH-related complication or all-cause death.9,10However, the long-term efficacies of PAH-specific vasodilators remain unclear due to limitations of the study period and evaluation using the composite endpoint.
PAH-specific vasodilators are classified into three categories: drugs targeting the prostacyclin pathway, drugs targeting the nitric oxide (NO) pathway, and drugs targeting the endothelin pathway.8 Combination therapy of PAH-specific vasodilators targeting different biological pathways reduces the risk of PAH-related events, including all-cause death, compared with monotherapy.11 Clinical practice guidelines recommend a dual-combination of drugs targeting the NO and endothelin pathway for PAH patients at low risk of death and the addition of a prostacyclin analogue to the dual-combination for high-risk PAH patients.12 However, there is no consensus on which drug is most associated with long-term survival in PAH patients among pulmonary vasodilators targeting the same biological pathway.13 Although head-to-head trials directly comparing all drugs in the same category are required, it is difficult to comprehensively conduct large-scale clinical trials comparing all PAH-specific vasodilators targeting the same biological pathway due to PAH being a rare disease.14 Exploratory analysis using RWD is an efficient approach for comparing the effects of PAH-specific vasodilators on long-term survival prior to conducting clinical trials.
The purpose of this study was to evaluate whether patient data from the JADER database could be used as a real-world cohort for survival analysis of rare disease patients. Moreover, we compared the effects of PAH-specific vasodilators targeting the same biological pathway on long-term survival using PAH patient data from the JADER database. Also, associations between supportive therapy and survival in the PAH patients were examined.