Long-term treatment of pulmonary arterial hypertension with macitentan in Japanese patients.

Objective: Macitentan, a novel dual endothelin receptor antagonist, was approved for the treatment of pulmonary arterial hypertension (PAH) in Japan. However, long-term effects in Japanese patients of macitentan are currently unavailable. This study sought to assess the long-term efficacy and safety of macitentan in Japanese patients with PAH.Methods: In this multicenter, open-label, clinical extension study (JapicCTI-121986), efficacy was evaluated based on the change from baseline at 24, 48, 72, 96 and 120-week in the 6-minute walk distance (6MWD), World Health Organization (WHO) functional class, and serum N-terminal pro-brain natriuretic peptide (NT-pro-BNP) levels. In addition, the time to a hospitalization related to PAH and a morbidity/mortality event was determined. As for safety, the incidence of adverse events and changes in laboratory data and vital signs were assessed.Results: Macitentan was administered at a once-daily dose of 10 mg in 30 PAH patients with a median treatment period of 2.4 years (range, 229-1037 days). The improvements in 6MWD, WHO functional class and NT-pro-BNP at week 24 were maintained throughout the long-term follow-up. Hospitalization related to PAH occurred in 2 patients. Levels of liver enzyme and hemoglobin remained unchanged throughout the study period.Conclusions: This study suggests that the long-term use of macitentan is well tolerated and effective in Japanese patients with PAH. We concluded that macitentan can be a possible approach to reduce morbidity/mortality in Japanese PAH patients.

Efficacy and Safety of an Orally Administered Selective Prostacyclin Receptor Agonist, Selexipag, in Japanese Patients With Pulmonary Arterial Hypertension.

BACKGROUND: Selexipag is an orally available prostacyclin receptor (IP receptor) agonist with a non-prostanoid structure. In this open-label Phase II trial, the efficacy and safety of selexipag in Japanese patients with pulmonary arterial hypertension (PAH) is examined.Methods and Results:Selexipag was administered at 200 µg twice daily and titrated up to 1,600 µg by increments of 200 µg in 37 subjects to reach the individual maximum tolerated dose. At 16 weeks, in 33 patients comprising the per-protocol set, the pulmonary vascular resistance (PVR; primary endpoint) decreased from 683.2±237.3 to 560.3±238.7 dyn·s/cm5(P<0.0001). For the secondary endpoint, the 6-min walk distance (6MWD) increased from 445.0±102.2 to 459.1±112.8 m (P=0.0324); World Health Organization functional class improved in 4 patients (12.1%), and was maintained in 29 patients (87.9%). A decrease in PVR was also shown in patients treated with selexipag, on top of a phosphodiesterase inhibitor and endothelin receptor antagonist. Most of the commonly reported adverse events were consistent with those reported for other PGI2formulations. Thirty-four patients attained the individual maximum tolerated dose (maintenance dose). CONCLUSIONS: The efficacy and tolerability of selexipag in Japanese PAH patients was confirmed by improvement in pulmonary hemodynamics, exercise capacity, symptoms. Selexipag is an efficacious treatment option for Japanese PAH patients. (Trial registration: JAPIC Clinical Trials Information [JapicCTI-111532].).

Efficacy and Safety of a Novel Endothelin Receptor Antagonist, Macitentan, in Japanese Patients With Pulmonary Arterial Hypertension.

BACKGROUND: Macitentan is a novel, dual endothelin receptor antagonist with sustained receptor binding, used for the long-term treatment of pulmonary arterial hypertension (PAH). In the present study, we assessed the efficacy and safety of macitentan in Japanese patients with PAH. METHODS AND RESULTS: Macitentan was administered at a once-daily dose of 10 mg in 30 patients. The primary endpoint was change in pulmonary vascular resistance (PVR) from baseline to week 24. Change to week 24 in the other hemodynamic parameters, 6-min walk distance (6MWD), World Health Organization (WHO) functional class, and plasmaN-terminal pro-brain natriuretic peptide (NT-pro-BNP), as well as time to clinical deterioration up to week 52 were also assessed as secondary endpoints. In the 28 patients on per-protocol analysis, PVR decreased from 667±293 to 417±214 dyn·sec·cm(-5)(P<0.0001). 6MWD increased from 427±128 to 494±116 m (P<0.0001). WHO functional class improved in 13 patients (46.4%) and was maintained in 15 patients (53.6%), and NT-pro-BNP was reduced by 18% (P<0.0001). The favorable treatment effect on PVR was apparent regardless of concomitant therapy for PAH. CONCLUSIONS: Macitentan was efficacious and well tolerated and improved the hemodynamic parameters, exercise capacity, symptoms, and clinical biomarkers in Japanese PAH patients. Macitentan can be a valuable therapeutic option for Japanese patients with PAH. ( TRIAL REGISTRATION: JAPIC Clinical Trials Information [JapicCTI-121986].) (Circ J 2016; 80: 1478-1483).

Effects of nocturnal oxygen therapy in patients with chronic heart failure and central sleep apnea: CHF-HOT study.

It was previously reported that nocturnal home oxygen therapy (HOT) significantly improved not only sleep disordered breathing (SDB), but also quality of life (QOL) and left ventricular ejection fraction (LVEF) in two trials. To strengthen the statistical reliability of the above efficacies of HOT and to assess the effects of 12-week nocturnal HOT on suppression of ventricular arrhythmias, we combined the two trials and undertook a post hoc analysis. Ninety-seven patients with chronic heart failure (CHF) and central sleep apnea were assigned to receive HOT (45 patients) or not (52 patients). HOT resulted in greater reduction in the apnea-hypopnea index (AHI) (-11.4 ± 11.0 vs. -0.2 ± 7.6 events/h, p < 0.01), which is associated with greater improvement in the Specific Activity Scale (0.8 ± 1.2 vs. 0.0 ± 0.6, p < 0.01), New York Heart Association (NYHA) functional class (p < 0.01), and LVEF (p = 0.06). Median number of premature ventricular contraction (PVC) at baseline was 17 beats per hour in both the HOT and the control groups. Overall improvements of PVCs were not different either in the HOT group or in the control. However, in 12 patients with NYHA >III and AHI >20 events/h, PVC was significantly improved by HOT with a marked reduction in AHI and a substantial increase in LVEF. In conclusion, among patients with CHF and CSA, HOT improves SDB, QOL, and cardiac function. The effectiveness of HOT for ventricular arrhythmias was not observed in the overall analysis, but only in a limited number of patients with severe CHF and SDB. To clarify the effects of HOT on ventricular arrhythmias in patients with CHF and SDB, a further study is needed.

Effects of the endothelin receptor antagonist bosentan on hemodynamics and exercise capacity in Japanese patients with mildly symptomatic pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) trial has mostly enrolled patients with World Health Organization functional class (WHO FC) III or IV. However, PAH is rapidly progressive in nature even in patients with less severe forms at diagnosis. Following the recent studies in Western population, here we assessed the efficacy of bosentan in Japanese patients with WHO FCII PAH. In this open-label trial, bosentan 125 mg twice daily was administered for 12 weeks in 16 patients, and a hemodynamic evaluation was performed. Treatment was continued for a further 12 weeks, where the effect on exercise capacity was assessed in 13 patients. In 16 patients, mean pulmonary arterial pressure decreased from 40.4 ± 10.4 to 35.6 ± 12.6 mmHg (p = 0.018) and cardiac index increased from 2.54 ± 0.73 to 2.96 ± 0.82 L/min/m(2) (p = 0.023). Thus, pulmonary vascular resistance decreased from 792 ± 565 to 598 ± 558 dyn·sec/cm(5) (p = 0.006). In 13 patients followed up for 24 weeks, 6-min walking distance increased from baseline at Week 12 (p = 0.003) and Week 24 (p = 0.011). All patients were mildly symptomatic at baseline with dyspnea index (Borg scale) of 2.50 ± 1.58 and the specific activity scale (SAS) of 5.0 ± 1.4 METs. These values remained unchanged throughout the study. These results suggest that bosentan treatment was beneficial for Japanese patients with WHO FC II PAH and treatment should be started in the early stage of the disease.

Evaluation of a new formulation of epoprostenol sodium in Japanese patients with pulmonary arterial hypertension (EPITOME4).

INTRODUCTION: Pulmonary arterial hypertension (PAH) is associated with poor prognosis despite significant recent advances in its treatment. An intravenous formulation of epoprostenol sodium containing glycine and mannitol (epoprostenol GM; GlaxoSmithKline, London, UK) is widely used to treat PAH. A new formulation of epoprostenol sodium containing arginine and sucrose excipients (epoprostenol AS; Actelion Pharmaceuticals Japan Ltd., Tokyo, Japan) shows better stability at room temperature after preparing diluted solutions. The primary objective of this study was to evaluate the safety and tolerability of switching from epoprostenol GM to epoprostenol AS in Japanese patients with PAH. The authors also evaluated the efficacy and treatment satisfaction after switching formulations. METHODS: This was a two-site, open-label, single-arm, Phase 3b study. Eight adult Japanese PAH patients (seven females) treated with a stable dose of epoprostenol GM for ≥30 days were switched to epoprostenol AS and followed for 12 weeks. Outcomes included safety, changes from baseline to 12 weeks in pulmonary hemodynamic factors (pulmonary vascular resistance, mean pulmonary arterial pressure, and cardiac output), and treatment satisfaction, assessed using the Treatment Satisfaction Questionnaire for Medication (TSQM-9). RESULTS: The mean (range) age and time since diagnosis of PAH were 48 (25-69) years and 6.2 (0.6-13.9) years, respectively. There were no unexpected safety or tolerability concerns after switching formulations. The epoprostenol dose was maintained after switching formulations. There were no significant changes in pulmonary hemodynamic factors from baseline to week 12. Regarding treatment satisfaction, there was a significant improvement in convenience, which is demonstrated in the score of the domain increased from 51.40 ± 10.19 at baseline to 58.33 ± 12.96 at week 12 (P < 0.05). CONCLUSIONS: Switching from epoprostenol GM to the same dose of epoprostenol AS was well tolerated over 12 weeks of treatment, and pulmonary hemodynamics were maintained. Switching to epoprostenol AS was also associated with improvements in treatment satisfaction (convenience). Clinical Trials: JapicCTI-122017.

Prognostic effects of combined treatment with calcium channel blockers and statins in patients with coronary narrowing: from the Japanese Coronary Artery Disease study.

Calcium channel blockers (CCB) and statins are frequently prescribed for patients with coronary artery disease (CAD) complicated by hypertension and/or hypercholesterolemia. CCB have pleiotropic actions beyond their blood pressure-lowering effect, while statins have pleiotropic actions beyond their cholesterol-lowering effect. We assessed the hypothesis that combined treatment with CCB and statins has additional prognostic benefits resulting from potential additive or synergistic pleiotropic actions of both classes of drugs in the Japanese CAD (JCAD) study population. The JCAD study consisted of 13,812 patients with angiographically demonstrable significant coronary narrowing in at least 1 of 3 major coronary arteries who were followed-up for a mean of 2.7 years (follow-up rate, 88.4%). The primary endpoint of the present study was all cardiovascular events. We compared the event rate between patients receiving neither CCB nor statins and those receiving each drug alone or as a combination treatment using propensity score matching analysis. The rate of all events was 62.8 per 1,000 patient-years in the JCAD study. Kaplan-Meier analysis with the log-rank test showed no statistically significant difference in the event rate in each comparison. In conclusion, there may be no additional prognostic benefit beyond the blood-pressure-lowering and cholesterol-lowering effects in the combined treatment with CCB and statins for angiographically documented CAD patients.

Treatment effects of renin-angiotensin system inhibitor and calcium channel blocker in patients with coronary artery narrowing (from the Japanese Coronary Artery Disease Study).

Low-dose antihypertensive drugs in combination are prescribed frequently in clinical practice. Combination treatment is superior to monotherapy with higher doses of each drug in terms of blood pressure reduction and side effects. However, it is unclear whether combination treatment provides additional prognostic benefit beyond the blood pressure lowering effects. We assessed the usefulness of the combined treatment of a renin-angiotensin system inhibitor (RASI) and a calcium channel blocker (CCB) for all cardiovascular events in the Japanese Coronary Artery Disease (JCAD) Study population. In the JCAD Study, which is an observational and non-randomized trial, 13,812 patients with angiographically shown narrowing >50% in ≥1 of 3 major coronary arteries were followed up for a mean of 2.7 years. The primary endpoint of the study was all cardiovascular events. In the present study, baseline covariates possibly influencing the event rate were adjusted between the different treatment groups. There was no statistically significant difference in the event rate between the RASI monotherapy and combined treatment groups, although Kaplan-Meier analysis showed a 23% (p = 0.0003) relative risk reduction with an RASI monotherapy compared with the control group. In conclusion, there may be no additional benefit beyond blood pressure lowering effects in the combination of an RASI and a CCB in patients with angiographically documented CAD.

Coronary collateral growth and its therapeutic application to coronary artery disease.

There is a tremendous body of data concerning the coronary collateral circulation in both experimental animals and humans. The functional importance of a well-developed coronary collateral circulation has now been documented. The paradigm regarding the principal stimulus for coronary collateral growth has shifted from myocardial ischemia to increased shear stress at the site of pre-existing collateral arterioles. Numerous experimental and clinical studies have contributed to elucidation of the mechanisms of coronary collateral growth. Stimulation of coronary collateral growth is an alternative therapeutic approach to patients with intractable angina pectoris who are not indicated for percutaneous coronary intervention and/or coronary artery bypass grafting. Pharmacological and mechanical modulations accelerating coronary collateral growth have been challenged. Because it is conceivable that a well-developed coronary collateral circulation attenuates myocardial ischemia upon exercise, further research addressing coronary collateral growth is needed in both experimental models of myocardial ischemia and human coronary artery disease.

Reappraisal of functional importance of coronary collateral circulation.

Coronary collateral circulation (CCC) is defined as an alternative blood-conveying circuit to the ischemic myocardium supplied by a jeopardized coronary artery. Accumulating evidence on CCC and its functional role has been derived from basic and clinical studies over several decades. Progress in molecular biology and genetic engineering has enabled us to elucidate the mechanisms of collateral growth on the basis of the development of new experimental models and methods for accurate assessment of CCC. These achievements in basic research have been promptly translated into the clinical setting. Interaction between basic and clinical sciences in the fascinating field of CCC will contribute to the establishment of innovative collateral-promoting therapy for severe coronary artery disease.

Improvement of quality of life with nocturnal oxygen therapy in heart failure patients with central sleep apnea.

BACKGROUND: Previously, we reported the benefit of 12 weeks of home oxygen therapy (HOT) in patients with central sleep apnea (CSA) and heart failure (HF). In the present study, we attempted to confirm the sustained efficacy of HOT in the long term treatment. METHODS AND RESULTS: In the present study, 51 patients with CSA and HF (New York Heart Association (NYHA) functional classes II-III) were assigned to receive either nocturnal oxygen (HOT group n=26) or usual breathing (control group n=25) for 52 weeks. In the HOT group, greater reduction in apnea and hypopnea and greater increase in nocturnal oxygen saturation were observed. These changes were associated with greater improvement in the Specific Activity Scale (0.82 +/-1.17 vs -0.11 +/-0.73 Mets, P=0.009) in NYHA functional class (P=0.007) and in ejection fraction (5.45 +/-11.94 vs 1.28 +/-9.77%). There were no significant differences in the cardiac event rates; however, the later divergence favored the HOT group. CONCLUSIONS: The 52-week HOT was well tolerated and the benefit observed in the 12-week trial was sustained over a prolonged period of time. HOT was considered to be a valuable non-pharmacological therapeutic addition for HF patients with CSA.

Efficacy of abciximab for patients undergoing balloon angioplasty: data from Japanese evaluation of c7E3 Fab for elective and primary PCI organization in randomized trial (JEPPORT).

BACKGROUND: The efficacy and safety of abciximab were investigated in Japanese patients undergoing percutaneous coronary intervention (PCI) for acute myocardial infarction (MI) or unstable angina. METHODS AND RESULTS: The 973 patients were randomized into 3 groups: the low-dose group (L group) received bolus injection of 0.20 mg/kg followed by 12-h infusion; the high-dose group (H group) received bolus injection of 0.25 mg/kg followed by 12-h infusion; the placebo group (P group) received bolus and infusion of placebo. The incidence of the primary endpoint (30-day post-PCI coronary events: death, MI or urgent revascularization) was 3.6%, 1.6%, and 4.1% in the P, L, and H groups, respectively, with no significant difference between the P and L groups (P=0.104) or between the P and H groups (P=0.772). The incidence of bleeding tended to increase in a dose-dependent manner. CONCLUSION: No significant difference in the incidence of coronary events was found between the placebo and abciximab groups, so the efficacy of abciximab in preventing post-PCI coronary events in Japanese patients was not confirmed.

Clinical efficacy and cost-benefit analysis of nocturnal home oxygen therapy in patients with central sleep apnea caused by chronic heart failure.

BACKGROUND: There is increasing evidence that both obstructive and central sleep apnea contribute to the progression and prognosis in patients with chronic heart failure (CHF). In the main study of nocturnal home oxygen therapy (HOT) in patients with central sleep apnea because of CHF (CHF-HOT), significant improvements in oxygen desaturation index, apnea - hypopnea index, left ventricular ejection fraction, and specific activity scale were reported following 12 weeks of nocturnal HOT in these patients. METHODS AND RESULTS: The present study is designed to further evaluate the clinical efficacy and cost - benefit of nocturnal HOT according to the results of a follow-up survey on changes in frequencies of hospitalization, emergency visits, and regular outpatient visits by 53 patients undergoing nocturnal HOT for more than 6 month periods. Medical costs were estimated from the DPC-MDC5 charge for hospitalization because of worsening heart failure (HF), and from the standard model case estimation for emergency and regular outpatient visits for HF. To reveal the time-saving benefit following nocturnal HOT, the influence on estimated days spent for hospital-care was also analyzed. The present study revealed significant reduction in frequencies and length of hospitalization (2.1 to 0.5 times/year, 38.7 to 34.6 days, medical cost: -2,686,267 yen), emergency visit (2.5 to 0.7 times/year, -15,984 yen), and regular outpatient visit (17.7 to 12.6 times/year, -6,324 yen) as compared with those before the induction of nocturnal HOT, which resulted in a total medical cost-reduction of 1,854,175 yen/patient/year, even with the additional charge for nocturnal HOT (854,400 yen/patient/year). Furthermore, nocturnal HOT produced a remarkable decline in estimated days spent for hospital-care (88.2 to 21.2 days/patient/year). CONCLUSION: The present analysis calculated a remarkable cost-benefit (1,854,175 yen/patient/year) from the reduction in hospitalization and emergency visits, and also time-saving benefits from an increase in expected days free from hospital-care (67 days/patient/year).

Long-term trial of bosentan monotherapy for pulmonary arterial hypertension in Japanese patients.

OBJECTIVE: To determine the efficacy and safety of long-term bosentan monotherapy in Japanese patients with pulmonary arterial hypertension (PAH). RESEARCH DESIGN AND METHODS: The present study was an extension to a 12-week open-label trial of bosentan in which 21 Japanese patients with PAH received bosentan, 125 mg twice daily. Of the 21 patients in the initial trial, 20 elected to participate in the long-term study and to continue to receive bosentan for up to 3 years. MAIN OUTCOME MEASURES: The primary efficacy measure was comparison of World Health Organization (WHO) functional class for pulmonary arterial hypertension following long-term (> 2.5 years) therapy compared with baseline (prior to initiation of bosentan). Secondary outcomes included time from initiation of bosentan therapy to clinical worsening and safety assessments. RESULTS: Bosentan treatment was continued for a median of 2.7 years (range 0.4-3.0 years); 12 patients received bosentan monotherapy for at least 2.5 years. Following long-term treatment, improvement of WHO functional class compared with baseline was observed in 9/12 patients (75.0%) and in 3/12 patients (25.0%) the functional class remained stable; no patient experienced a worsening of WHO functional class compared with baseline. Overall, long-term treatment with bosentan was well tolerated. CONCLUSIONS: Long-term treatment with bosentan is well tolerated and is associated with sustained clinical improvement in Japanese patients with PAH. Bosentan, therefore, represents a valuable treatment option for Japanese patients with this devastating disease.

[Home oxygen therapy (HOT) for patients with heart failure associated with sleep disturbed breathing].

Recently, there is increasing evidence that sleep apnea may adversely affect pathophysiology and outcomes of congestive heart failure (CHF). Repetitive nocturnal apneas may worsen CHF through a number of mechanisms including the repetitive arterial oxygen desaturation, increased left ventricular afterload, or an activation of sympathetic nervous system. Although central sleep apnea (CSA) is relatively rare, prospective studies revealed that 33 to 82 % of patients with CHF have evidence of CSA and characteristic Cheyne-Stokes respiration (CSR). We assessed an efficacy of nasal O2 therapy at night using a conventional O2 concentrator in ambulatory patients with stable CHF and CSR. O2 resulted in a significant improvement of sleep together with an increase in left ventricular function and quality of life. Therefore, home oxygen therapy(HOT) can be a valuable nonpharmacological option for the treatment of patients with CHF and CSR-CSA.

Effects of nocturnal oxygen therapy on outcome measures in patients with chronic heart failure and cheyne-stokes respiration.

BACKGROUND: The effects of nasal oxygen (O(2)) supply at night using conventional home oxygen therapy (HOT) equipment on quality of life (QOL) and sleep-disordered breathing (SDB) were evaluated in patients with congestive heart failure (CHF). Nasal nocturnal O(2) therapy not only stabilizes SDB but also reduces sympathetic activity, and improves exercise capacity in patients with CHF. However, the effects of oxygen on the cardiac function and QOL of heart failure patients have not been fully elucidated. METHODS AND RESULTS: Fifty-six patients with CHF (New York Heart Association class II - III, left ventricular ejection fraction (LVEF)