Changes in the Characteristics and Initial Treatments of Pulmonary Hypertension Between 2008 and 2020 in Japan

Background Pulmonary arterial hypertension (PAH) is a rare, progressive disease. The treatment landscape for PAH in Japan has evolved considerably in recent years, but there is limited knowledge of the changes in treatment practices or patient characteristics. Objectives The aim of this study was to evaluate the changes in characteristics and initial treatments for PAH in Japan over time. Methods This study used data from the Japan Pulmonary Hypertension Registry (JAPHR) to compare patient characteristics and treatment practices between 2008-2015 (n = 316) and 2016-2020 (n = 315). Results The mean ± standard deviation age at diagnosis increased from 47.9 ± 16.7 years in 2008-2015 to 52.7 ± 16.9 years in 2016-2020. The mean pulmonary arterial pressure decreased from 45.4 ± 15.0 to 38.6 ± 13.1 mm Hg. Idiopathic/hereditary PAH was the most common etiology in both periods (50.0% and 51.1%, respectively). The proportion of patients prescribed oral/inhaled combination therapies increased from 47.8% to 57.5%. Oral/inhaled combination therapies were frequently prescribed to patients with congenital heart disease-related PAH (81.8%). There was no significant trend in prescribing practices based on French low-risk criteria: among patients with 0, 1, 2, 3, or 4 criteria, 53.8%, 68.8%, 52.8%, 66.7%, and 39.4% were prescribed oral/inhaled combination therapies, and 0%, 16.7%, 27.0%, 17.3%, and 15.2% were prescribed oral/inhaled monotherapies. Macitentan, tadalafil, selexipag, and epoprostenol were the most frequently prescribed drugs. Conclusions The severity of PAH decreased over time in Japan. Oral/inhaled combination therapies were generally preferred. Physicians generally prescribed therapies after considering the patients’ hemodynamics and clinical severity. (Japan Pulmonary Hypertension Registry [JAPHR]; UMIN000026680)

P ulmonary arterial hypertension (PAH) is a rare, progressive disease with a poor prognosis 1,2 that has devastating effects on patients in terms of excess disability, financial burden, and impaired quality of life. [3][4][5] PAH is defined as a sustained elevation of mean pulmonary arterial pressure (mPAP) of $25 mm Hg at rest, as measured by right heart catheterization. 6 Group 1 PAH is further defined as pulmonary artery wedge pressure #15 mm Hg and pul- hypertension, congenital heart disease, or schistosomiasis. Estimates suggest that the prevalence of PAH ranges from 10 to 52 cases per million people, [8][9][10] and it is w2 to 4 times more common in female subjects than in male subjects. 11,12 Based on reported cases and the population of Japan in 2019, we estimate that the prevalence of PAH in Japan is w32 cases per 1 million people. 13 Indeed, the 5-year survival rate has increased from 34% (95% CI: 24%-44%) for patients diagnosed with PAH between 1981 and 1985 17 to 61.2% for patients diagnosed with PAH between 2006 and 2009. 16 Combination therapy may also improve outcomes; eg, in the AMBITION (Ambrisentan and Tadalafil in Patients with Pulmonary Arterial Hypertension) study, the risk of clinical failure in patients with CTD-PAH was 57% lower in patients who received combination therapy than in those who received monotherapy. 18 After the introduction of novel therapies, the European Society of Cardiology and the European Respiratory Society first introduced guidelines for the clinical management of PAH in 2015. 6 These guidelines encompass a treatment algorithm advocating monotherapy or combination therapy, depending on the patient's diagnosis and functional class. The guidelines also recommend combination therapy and management of pediatric and adult patients at expert referral centers. Another novel aspect is the incorporation of a risk stratification mechanism, whereby risk is classified as low, intermediate, or high, and the ultimate goal is to keep patients in the low-risk group.
However, the applicability of these cut points is still unknown, and further research is needed. Moreover,     Table 2 shows the treatments prescribed in patients stratified into subgroups according to the Values are n (%) or mean AE SD.
6MWD ¼ 6-minute walk distance; BNP ¼ brain natriuretic peptide; CHD-PAH ¼ congenital heart disease-related pulmonary arterial hypertension; CTD-PAH ¼ connective tissue disease-related pulmonary arterial hypertension; IPAH/ HPAH ¼ idiopathic pulmonary arterial hypertension/hereditary pulmonary arterial hypertension; mPAP ¼ mean pulmonary arterial pressure; mRAP ¼ mean right arterial pressure; NYHA ¼ New York Heart Association; PAWP ¼ pulmonary artery wedge pressure; PoPH ¼ portopulmonary hypertension; PVR ¼ pulmonary vascular resistance; SvO2 ¼ mixed venous oxygen saturation.   We observed an increase in the mean age of patients between the 2 study periods, consistent with prior reports. 22 24 and dual therapy was prescribed to 29% and triple therapy to 14% in a Swiss registry. 25 Furthermore, the AMBITION study showed that upfront combination therapy with ambrisentan and tadalafil was superior to monotherapy in treatment-naive patients. 26   The numbers include all patients who received each type of drug; some patients received multiple therapies and are included in multiple categories.
SR ¼ sustained release; other abbreviations as in Figure 2. Study) 29 may explain the greater use of combination therapy and triple therapy in the latter period in our study. Furthermore, we observed a decrease in the proportion of patients prescribed parenteral therapy, possibly caused by the decreased number of severe cases in the latter period.
As might be expected, the treatment patterns for