| Part I:Atorvastatin in pulmonary hypertension studyObjective: Statins have been shown to both prevent and attenuate pulmonary hypertension in animal models. Data in patients with pulmonary hypertension are few. To understand the potential therapeutic benefits of statins as a treatment for pulmonary hypertension patients.Methods: Two hundred and twenty patients with pulmonary arterial hypertension (PAH) or chronic thromboembolic pulmonary hypertension (CTEPH) were randomised, double-blind, to receive atorvastatin 10 mg daily or matching placebo in addition to supportive care. The primary end point was the change from baseline to week 24 in the distance walked in six minutes.Results: Serum low density lipoprotein levels fell significantly on atorvastatin treatment. The mean placebo-corrected treatment effect was -0.4mmol/L (95% confidence interval:-0.6 to -0.2 mmol/L, P<0.0001). However, at 6 months,6-minute walk distance decreased by 16.6 m in the atorvastatin group and 14.1 m in the placebo group. The mean placebo-corrected treatment effect was -2.5 m (95% confidence interval:-38 to 33 m, P =0.96), based on intention to treat. Changes in the Borg dyspnea score did not differ significantly between patients treated with atorvastatin and those receiving placebo. There was no significant difference in the proportion of patients who improved, remained stable or showed a deterioration in WHO functional class between atorvastatin and placebo treatments. A small increase in pulmonary vascular resistance and fall in cardiac index was seen in the atorvastatin groups. These changes did not differ significantly from those patients treated with placebo (P>0.05). There was no significant difference between the atorvastatin and placebo groups in time to clinical worsening (P=0.98).Conclusions:Atorvastatin (10mg/d for six months) has no beneficial effect on exercise capacity, WHO functional class, and hemodynamics in patients with PAH or CTEPH. PartⅡ:The efficacy and safety of sildenafil in patients with pulmonary arterial hypertension associated with different types of congenital heart disease:a prospective multicenter studyObjective:The difference in underlying pathophysiology in different congenital heart disease (CHD) may have an influence on clinical outcome. It remains unclear whether the effect of sildenafil on pulmonary arterial hypertension (PAH) varies in different types of CHD.Methods:In this 12-week, prospective, open label, multicenter trial,55 patients with CHD were divided into the 3 groups:atrial septal defects group (ASD, n=15), ventricular septal defects group (VSD, n=24), and patent ductus arteriosus group (PDA, n=16). Exercise capacity, World Health Organization (WHO) functional class, hemodynamic parameters, and arterial oxygen saturation were assessed at baseline and after sildenafil therapy (25 mg,3 times daily). The primary end point was the change from baseline to week 12 in the distance walked in six minutes.Results:Six-minute walk distance significantly increased from 377.2±68.7 m to 436.0±70.4 m in patients with ASD (P< 0.001), from 371.2±66.0 m to 413.7±83.1 m in VSD (P=0.006), and from 384.3±90.2 m to 440.9±71.8 m in PDA (P=0.006). The WHO functional class improved significantly in both the VSD group and the PDA group. Moreover, sildenafil also improved the pulmonary vascular resistance and pulmonary blood flow index in the 3 groups, whereas no significant changes in systemic vascular resistance and mean systemic arterial pressure were observed. However, arterial oxygen saturation was significantly improved in the ASD group only. There were no significant differences among the 3 groups in terms of changes in six-minute walk distance, WHO functional class, arterial oxygen saturation, and hemodynamics. The incidence of adverse events was similar among the 3 groups.Conclusions:Sildenafil therapy seems to be effective and safe for PAH secondary to ASD, VSD, and PDA, although some clinical and hemodynamic parameters were changed in a different manner among the 3 groups. PartⅢ:Survival in Chinese patients with idiopathic pulmonary arterial hypertension in the modern treatment eraBackground:The survival rates of Chinese patients with IPAH and familial pulmonary arterial hypertension (PAH) on conventional therapy at 1,2,3, and 5 years were 68.0%, 56.9%,38.9%, and 20.8%, respectively. Targeted therapies for PAH have been introduced in China since 2006. Sildenafil, an inhibitor of the enzyme phosphodiesterase type 5, is in fact the first-line therapy for PAH in China. However, it remains unknown whether the survival of patients with PAH is improved in the modern management era. The evidence regarding the impact of sildenafil on survival of patients with IPAH is relatively limited. Therefore, the aim of the present study was to 1) study outcome of Chinese patients with IPAH in the modern treatment era; 2) identify factors that may predict mortality; and 3) investigate the comparative survival in patients with IPAH who received sildenafil therapy and who did not.Methods:In order to study outcome of Chinese patients with IPAH and identify factors that may predict outcome,90 newly diagnosed IPAH patients who admitted to Fu Wai Hospital between March 2006 and November 2009 and who could be followed-up after discharge were retrospectively identified. In order to study the impact of sildenafil on survival in patients with IPAH,11 patients who received other PAH-targeted therapy rather than sildenafil were excluded. To avoid the exaggeration of the impact of sildenafil on survival, eight patients who were not acute vasodilator responders but treated with calcium channel blockers were also excluded. Therefore, seventy-one patients were enrolled in the subgroup analysis. These patients were divided into two groups:23 patients who were treated with conventional therapy alone served as the "conventional group", the 48 patients who received sildenafil served as the "sildenafil group".Results:For the whole patients (90 cases), the female-to-male ratio was 1.7:1. Patients in WHO functional classⅢ/Ⅳaccounted for 56.7%. The mean duration from the onset of symptoms to diagnosis was 38 months. Fifty-nine patients (65.6%) received PAH-targeted therapies during follow-up period. Most of them treated with sildenafil therapy (81.4%). Of the 85 patients who underwent acute vasodilator testing,10.6% had a positive vasoreactivity test. Calcium channel blockers were given to 22.2% of patients. Our survival rates of 84.1% (95% confidence intervals [CI]:76.5% to 91.7%),73.7% (95%CI:62.7% to 84.7%) and 70.6% (95%CI:58.6% to 82.6%) at 1-year,2-year, and 3-year compared favorably with predicted survival based on the National Institutes of Health equation which showed 1-,2-, and 3- year survival rates of 67.7%,55.9%, and 47.0%, respectively. For the patients receiving conventional therapy solely (31 patients, 34.4%), the 1-,2-, and 3-year observed survival rates were 67.0%,57.5%, and 49.3%, respectively. Univariable Cox analysis showed that younger age, lower weight, lower 6-minute walking distance, higher N-terminal brain natriuretic peptide, lower mixed venous oxygen saturation, the presence of pericardial effusion, lower cardiac out, higher mean right atrial pressure, greater pulmonary vascular resistance and the absence of PAH targeted therapy were significantly and negatively associated with survival. Multivariable Cox analysis revealed that younger age, lower weight, the presence of pericardial effusion and the absence of PAH targeted therapy were independently associated with poor outcome.In the subgroup analysis, The baseline characteristics of the sildenafil group were similar to those of the conventional group. The 1- and 3-year survival rates in the sildenafil group were 91.35% and 78.01%, compared with 64.93% and 37.87% in the conventional group (P<0.05). Of the patients in WHO functional class III or IV, the survival rate was significantly higher in the sildenafil group than in the conventional group (P<0.05), such statistical was also observed in patients in WHO functional class I/II (P<0.05).Conclusions:The outcome of Chinese patients with IPAH has been improved in the modern treatment era. Sildenafil therapy was found to be associated with improved survival in patients with idiopathic pulmonary arterial hypertension.
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