Zhi-Cheng Jing

Macitentan and Morbidity and Mortality in Pulmonary Arterial Hypertension

BACKGROUND Current therapies for pulmonary arterial hypertension have been adopted on the basis of short-term trials with exercise capacity as the primary end point. We assessed the efficacy of macitentan, a new dual endothelin-receptor antagonist, using a primary end point of morbidity and mortality in a long-term trial. METHODS We randomly assigned patients with symptomatic pulmonary arterial hypertension to receive placebo once daily, macitentan at a once-daily dose of 3 mg, or macitentan at a once-daily dose of 10 mg. Stable use of oral or inhaled therapy for pulmonary arterial hypertension, other than endothelin-receptor antagonists, was allowed at study entry. The primary end point was the time from the initiation of treatment to the first occurrence of a composite end point of death, atrial septostomy, lung transplantation, initiation of treatment with intravenous or subcutaneous prostanoids, or worsening of pulmonary arterial hypertension. RESULTS A total of 250 patients were randomly assigned to placebo, 250 to the 3-mg macitentan dose, and 242 to the 10-mg macitentan dose. The primary end point occurred in 46.4%, 38.0%, and 31.4% of the patients in these groups, respectively. The hazard ratio for the 3-mg macitentan dose as compared with placebo was 0.70 (97.5% confidence interval [CI], 0.52 to 0.96; P=0.01), and the hazard ratio for the 10-mg macitentan dose as compared with placebo was 0.55 (97.5% CI, 0.39 to 0.76; P<0.001). Worsening of pulmonary arterial hypertension was the most frequent primary end-point event. The effect of macitentan on this end point was observed regardless of whether the patient was receiving therapy for pulmonary arterial hypertension at baseline. Adverse events more frequently associated with macitentan than with placebo were headache, nasopharyngitis, and anemia. CONCLUSIONS Macitentan significantly reduced morbidity and mortality among patients with pulmonary arterial hypertension in this event-driven study. (Funded by Actelion Pharmaceuticals; SERAPHIN ClinicalTrials.gov number, NCT00660179.).

Riociguat for the Treatment of Pulmonary Arterial Hypertension

BACKGROUND Riociguat, a soluble guanylate cyclase stimulator, has been shown in a phase 2 trial to be beneficial in the treatment of pulmonary arterial hypertension. METHODS In this phase 3, double-blind study, we randomly assigned 443 patients with symptomatic pulmonary arterial hypertension to receive placebo, riociguat in individually adjusted doses of up to 2.5 mg three times daily (2.5 mg-maximum group), or riociguat in individually adjusted doses that were capped at 1.5 mg three times daily (1.5 mg-maximum group). The 1.5 mg-maximum group was included for exploratory purposes, and the data from that group were analyzed descriptively. Patients who were receiving no other treatment for pulmonary arterial hypertension and patients who were receiving endothelin-receptor antagonists or (nonintravenous) prostanoids were eligible. The primary end point was the change from baseline to the end of week 12 in the distance walked in 6 minutes. Secondary end points included the change in pulmonary vascular resistance, N-terminal pro-brain natriuretic peptide (NT-proBNP) levels, World Health Organization (WHO) functional class, time to clinical worsening, score on the Borg dyspnea scale, quality-of-life variables, and safety. RESULTS By week 12, the 6-minute walk distance had increased by a mean of 30 m in the 2.5 mg-maximum group and had decreased by a mean of 6 m in the placebo group (least-squares mean difference, 36 m; 95% confidence interval, 20 to 52; P<0.001). Prespecified subgroup analyses showed that riociguat improved the 6-minute walk distance both in patients who were receiving no other treatment for the disease and in those who were receiving endothelin-receptor antagonists or prostanoids. There were significant improvements in pulmonary vascular resistance (P<0.001), NT-proBNP levels (P<0.001), WHO functional class (P=0.003), time to clinical worsening (P=0.005), and Borg dyspnea score (P=0.002). The most common serious adverse event in the placebo group and the 2.5 mg-maximum group was syncope (4% and 1%, respectively). CONCLUSIONS Riociguat significantly improved exercise capacity and secondary efficacy end points in patients with pulmonary arterial hypertension. (Funded by Bayer HealthCare; PATENT-1 and PATENT-2 ClinicalTrials.gov numbers, NCT00810693 and NCT00863681, respectively.).

Efficacy and Safety of Oral Treprostinil Monotherapy for the Treatment of Pulmonary Arterial Hypertension: A Randomized Controlled Trial

Background— Pulmonary arterial hypertension (PAH) is a progressive, fatal disease with no cure. Parenteral and inhaled prostacyclin analogue therapies are effective for the treatment of PAH, but complicated administration requirements can limit the use of these therapies in patients with less severe disease. This study was designed to evaluate the safety and efficacy of the oral prostacyclin analogue treprostinil diolamine as initial treatment for de novo PAH. Methods and Results— Three hundred forty-nine patients (intent-to-treat population) not receiving endothelin receptor antagonist or phosphodiesterase type-5 inhibitor background therapy were randomized (treprostinil, n=233; placebo, n=116). The primary analysis population (modified intent-to-treat) included 228 patients (treprostinil, n=151; placebo, n=77) with access to 0.25-mg treprostinil tablets at randomization. The primary end point was change from baseline in 6-minute walk distance at week 12. Secondary end points included Borg dyspnea index, clinical worsening, and symptoms of PAH. The week 12 treatment effect for 6-minute walk distance (modified intent-to-treat population) was 23.0 m (P=0.0125). For the intent-to-treat population, 6-minute walk distance improvements were observed at peak (26.0 m; P=0.0001) and trough (17.0 m; P=0.0025) plasma study drug concentrations. Other than an improvement in the combined 6-minute walk distance/Borg dyspnea score, there were no significant changes in secondary end points. Oral treprostinil therapy was generally well tolerated; the most common adverse events (intent-to-treat) were headache (69%), nausea (39%), diarrhea (37%), and pain in jaw (25%). Conclusions— Oral treprostinil improves exercise capacity in PAH patients not receiving other treatment. Oral treprostinil could provide a convenient, first-line prostacyclin treatment option for PAH patients not requiring more intensive therapy. Clinical Trial Registration:— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00325403.

Vardenafil in Pulmonary Arterial Hypertension: A Randomized, Double-blind, Placebo-controlled Study

RATIONALE Although the phosphodiesterase type 5 inhibitors sildenafil and tadalafil have demonstrated efficacy in patients with pulmonary arterial hypertension (PAH), monotherapy with these agents has not been conclusively shown to reduce clinical worsening events. OBJECTIVES To evaluate the safety and efficacy of the phosphodiesterase type 5 inhibitor vardenafil in Chinese patients with PAH. METHODS In a randomized, double-blind, placebo-controlled study, 66 patients with PAH were randomized 2:1 to vardenafil (5 mg once daily for 4 wk then 5 mg twice daily; n = 44) or placebo (n = 22) for 12 weeks. Patients completing this phase were then treated with open-label vardenafil (5 mg twice daily) for a further 12 weeks. MEASUREMENTS AND MAIN RESULTS At Week 12, the mean placebo-corrected 6-minute walking distance was increased with vardenafil (69 m; P < 0.001), and this improvement was maintained for at least 24 weeks. Vardenafil also increased the mean placebo-corrected cardiac index (0.39 L·min(-1)·m(-2); P = 0.005) and decreased mean pulmonary arterial pressure and pulmonary vascular resistance (-5.3 mm Hg, P = 0.047; -4.7 Wood U, P = 0.003; respectively) at Week 12. Four patients in the placebo group (20%) and one in the vardenafil group (2.3%) had clinical worsening events (hazard ratio 0.105; 95% confidence interval, 0.012-0.938; P = 0.044). Vardenafil was associated with only mild and transient adverse events. CONCLUSIONS Vardenafil is effective and well tolerated in patients with PAH at a dose of 5 mg twice daily.

Survival of Chinese Patients With Pulmonary Arterial Hypertension in the Modern Treatment Era

BACKGROUND In a previous study of Chinese patients with idiopathic pulmonary arterial hypertension (IPAH) in the nontargeted therapy era (defined as the time before 2006 when new pulmonary arterial hypertension-specific drugs were not available in China), we reported 1- and 3-year survival estimates of only 68% and 39%, respectively. However, it is not yet known whether the survival of patients with pulmonary arterial hypertension is improved in the modern treatment era (defined in China as after 2006). METHODS A retrospective cohort study was undertaken in 276 consecutive patients with newly diagnosed incident IPAH and connective tissue disease-related pulmonary arterial hypertension (CTDPAH) who were referred between 2007 and 2009. Baseline characteristics and survival rates in the two groups were compared. RESULTS The 1- and 3-year survival estimates were 92.1% and 75.1%, respectively, in patients with IPAH, and 85.4% and 53.6%, respectively, in patients with CTDPAH. Patients with CTDPAH had a significantly lower mean pulmonary artery pressure, more pericardial effusion, and more severe impairment of the diffusion capacity of the lung for carbon monoxide than patients with IPAH. A diagnosis of CTDPAH, World Health Organization functional class III or IV, single-breath diffusion capacity of the lung for carbon monoxide < 80% predicted, and the presence of pericardial effusion were independent predictors of mortality. The 1- and 3-year survival rates of male patients were 93.5% and 77.5%, respectively, in those with IPAH, and 71.1% and 47.4%, respectively, in those with CTDPAH. CONCLUSIONS The survival rates of patients with pulmonary arterial hypertension have improved in China in the modern treatment era, despite the high costs of treatment and financial constraints. However, the survival rates of patients with CTDPAH are inferior to those of patients with IPAH. Our study also indicates poorer survival rates in male patients with CTDPAH.

Vardenafil in Pulmonary Arterial Hypertension

RATIONALE Although the phosphodiesterase type 5 inhibitors sildenafil and tadalafil have demonstrated efficacy in patients with pulmonary arterial hypertension (PAH), monotherapy with these agents has not been conclusively shown to reduce clinical worsening events. OBJECTIVES To evaluate the safety and efficacy of the phosphodiesterase type 5 inhibitor vardenafil in Chinese patients with PAH. METHODS In a randomized, double-blind, placebo-controlled study, 66 patients with PAH were randomized 2:1 to vardenafil (5 mg once daily for 4 wk then 5 mg twice daily; n = 44) or placebo (n = 22) for 12 weeks. Patients completing this phase were then treated with open-label vardenafil (5 mg twice daily) for a further 12 weeks. MEASUREMENTS AND MAIN RESULTS At Week 12, the mean placebo-corrected 6-minute walking distance was increased with vardenafil (69 m; P < 0.001), and this improvement was maintained for at least 24 weeks. Vardenafil also increased the mean placebo-corrected cardiac index (0.39 L·min(-1)·m(-2); P = 0.005) and decreased mean pulmonary arterial pressure and pulmonary vascular resistance (-5.3 mm Hg, P = 0.047; -4.7 Wood U, P = 0.003; respectively) at Week 12. Four patients in the placebo group (20%) and one in the vardenafil group (2.3%) had clinical worsening events (hazard ratio 0.105; 95% confidence interval, 0.012-0.938; P = 0.044). Vardenafil was associated with only mild and transient adverse events. CONCLUSIONS Vardenafil is effective and well tolerated in patients with PAH at a dose of 5 mg twice daily.

Iloprost for pulmonary vasodilator testing in idiopathic pulmonary arterial hypertension

The aim of this study was to confirm the utility of aerosolised iloprost for identifying long-term responders to calcium channel blockers (CCBs) in patients with idiopathic pulmonary arterial hypertension (IPAH). While undergoing right heart catheterisation, 74 patients with IPAH sequentially received incremental infusions of adenosine and aerosolised iloprost. The effects of the two vasodilators on haemodynamic parameters were recorded. All acute responders identified by aerosolised iloprost were subsequently treated with high doses of a CCB and were re-evaluated after 12 months. Both adenosine and iloprost produced significant decreases in mean pulmonary arterial pressure and pulmonary vascular resistance, and significant increases in cardiac index. Adverse effects were experienced by 35 out of the 74 patients with adenosine, but by only two with iloprost. Aerosolised iloprost identified more acute responders than infused adenosine (10 versus eight, respectively) according to the criteria recommended in recent consensus guidelines. Nine responders identified by iloprost were followed-up after 12 months of high-dose CCB therapy. Five had normal or near-normal haemodynamics and a World Health Organization functional classification of I or II after 12 months. Aerosolised iloprost is an appropriate new agent to identify long-term responders to CCBs in patients with IPAH. It is as effective in this regard as infused adenosine but is better tolerated.

BMPR2 mutations and survival in pulmonary arterial hypertension: an individual participant data meta-analysis

Summary Background Mutations in the gene encoding the bone morphogenetic protein receptor type II (BMPR2) are the commonest genetic cause of pulmonary arterial hypertension (PAH). However, the effect of BMPR2 mutations on clinical phenotype and outcomes remains uncertain. Methods We analysed individual participant data of 1550 patients with idiopathic, heritable, and anorexigen-associated PAH from eight cohorts that had been systematically tested for BMPR2 mutations. The primary outcome was the composite of death or lung transplantation. All-cause mortality was the secondary outcome. Hazard ratios (HRs) for death or transplantation and all-cause mortality associated with the presence of BMPR2 mutation were calculated using Cox proportional hazards models stratified by cohort. Findings Overall, 448 (29%) of 1550 patients had a BMPR2 mutation. Mutation carriers were younger at diagnosis (mean age 35·4 [SD 14·8] vs 42·0 [17·8] years), had a higher mean pulmonary artery pressure (60·5 [13·8] vs 56·4 [15·3] mm Hg) and pulmonary vascular resistance (16·6 [8·3] vs 12·9 [8·3] Wood units), and lower cardiac index (2·11 [0·69] vs 2·51 [0·92] L/min per m2; all p<0·0001). Patients with BMPR2 mutations were less likely to respond to acute vasodilator testing (3% [10 of 380] vs 16% [147 of 907]; p<0·0001). Among the 1164 individuals with available survival data, age-adjusted and sex-adjusted HRs comparing BMPR2 mutation carriers with non-carriers were 1·42 (95% CI 1·15–1·75; p=0·0011) for the composite of death or lung transplantation and 1·27 (1·00–1·60; p=0·046) for all-cause mortality. These HRs were attenuated after adjustment for potential mediators including pulmonary vascular resistance, cardiac index, and vasoreactivity. HRs for death or transplantation and all-cause mortality associated with BMPR2 mutation were similar in men and women, but higher in patients with a younger age at diagnosis (p=0·0030 for death or transplantation, p=0·011 for all-cause mortality). Interpretation Patients with PAH and BMPR2 mutations present at a younger age with more severe disease, and are at increased risk of death, and death or transplantation, compared with those without BMPR2 mutations. Funding Cambridge NIHR Biomedical Research Centre, Medical Research Council, British Heart Foundation, Assistance Publique-Hôpitaux de Paris, INSERM, Université Paris-Sud, Intermountain Research and Medical Foundation, Vanderbilt University, National Center for Advancing Translational Sciences, National Institutes of Health, National Natural Science Foundation of China, and Beijing Natural Science Foundation.

A global view of pulmonary hypertension

Pulmonary hypertension is a substantial global health issue. All age groups are affected with rapidly growing importance in elderly people, particularly in countries with ageing populations. Present estimates suggest a pulmonary hypertension prevalence of about 1% of the global population, which increases up to 10% in individuals aged more than 65 years. In almost all parts of the world, left-sided heart and lung diseases have become the most frequent causes of pulmonary hypertension. About 80% of affected patients live in developing countries, where pulmonary hypertension is frequently associated with congenital heart disease and various infectious disorders, including schistosomiasis, HIV, and rheumatic heart disease. These forms of pulmonary hypertension occur predominantly in those younger than 65 years. Independently of the underlying disease, the development of pulmonary hypertension is associated with clinical deterioration and a substantially increased mortality risk. Global research efforts are needed to establish preventive strategies and treatments for the various types of pulmonary hypertension.

MicroRNA-134 as a potential plasma biomarker for the diagnosis of acute pulmonary embolism

BackgroundAcute pulmonary embolism (APE) remains a diagnostic challenge due to a variable clinical presentation and the lack of a reliable screening tool. MicroRNAs (miRNAs) regulate gene expression in a wide range of pathophysiologic processes. Circulating miRNAs are emerging biomarkers in heart failure, type 2 diabetes and other disease states; however, using plasma miRNAs as biomarkers for the diagnosis of APE is still unknown.MethodsThirty-two APE patients, 32 healthy controls, and 22 non-APE patients (reported dyspnea, chest pain, or cough) were enrolled in this study. The TaqMan miRNA microarray was used to identify dysregulated miRNAs in the plasma of APE patients. The TaqMan-based miRNA quantitative real-time reverse transcription polymerase chain reactions were used to validate the dysregulated miRNAs. The receiver-operator characteristic (ROC) curve analysis was conducted to evaluate the diagnostic accuracy of the miRNA identified as the candidate biomarker.ResultsPlasma miRNA-134 (miR-134) level was significantly higher in the APE patients than in the healthy controls or non-APE patients. The ROC curve showed that plasma miR-134 was a specific diagnostic predictor of APE with an area under the curve of 0.833 (95% confidence interval, 0.737 to 0.929; P < 0.001).ConclusionsOur findings indicated that plasma miR-134 could be an important biomarker for the diagnosis of APE. Because of this finding, large-scale investigations are urgently needed to pave the way from basic research to clinical utilization.