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.