Massimiliano Palazzini

A meta-analysis of randomized controlled trials in pulmonary arterial hypertension

Aims There is no cure for pulmonary arterial hypertension, but current approved treatment options include prostanoids, endothelin-receptor antagonists, and phosphodiesterase type-5 inhibitors. The effect on survival of these compounds has not been appropriately assessed in individual trials because of small sample size and short duration. We performed a meta-analysis of all randomized controlled trials with drugs published in this condition. Methods and results Trials were searched in the Medline database from January 1990 to October 2008. The primary analysis included only studies with a placebo comparator arm, the sensitivity analysis also included studies comparing two active treatment arms. The main outcome measure was all-cause mortality. Twenty-one trials were included in the primary analysis (3140 patients) and two additional studies (59 patients) were included in the sensitivity analysis. Average duration of the trials was 14.3 weeks. All-cause mortality rate in the control group was 3.8%. Active treatments were associated with a reduction in mortality of 43% (RR 0.57; 95% CI 0.35–0.92; P = 0.023); the sensitivity analysis confirmed a reduction in mortality of 38% (RR 0.62; 95% CI 0.39–1.00; P = 0.048). Conclusion The results of this meta-analysis suggest an improvement of survival in the patients treated with the targeted therapies approved for pulmonary arterial hypertension.

Fibrinolysis for patients with intermediate-risk pulmonary embolism

BACKGROUND The role of fibrinolytic therapy in patients with intermediate-risk pulmonary embolism is controversial. METHODS In a randomized, double-blind trial, we compared tenecteplase plus heparin with placebo plus heparin in normotensive patients with intermediate-risk pulmonary embolism. Eligible patients had right ventricular dysfunction on echocardiography or computed tomography, as well as myocardial injury as indicated by a positive test for cardiac troponin I or troponin T. The primary outcome was death or hemodynamic decompensation (or collapse) within 7 days after randomization. The main safety outcomes were major extracranial bleeding and ischemic or hemorrhagic stroke within 7 days after randomization. RESULTS Of 1006 patients who underwent randomization, 1005 were included in the intention-to-treat analysis. Death or hemodynamic decompensation occurred in 13 of 506 patients (2.6%) in the tenecteplase group as compared with 28 of 499 (5.6%) in the placebo group (odds ratio, 0.44; 95% confidence interval, 0.23 to 0.87; P=0.02). Between randomization and day 7, a total of 6 patients (1.2%) in the tenecteplase group and 9 (1.8%) in the placebo group died (P=0.42). Extracranial bleeding occurred in 32 patients (6.3%) in the tenecteplase group and 6 patients (1.2%) in the placebo group (P<0.001). Stroke occurred in 12 patients (2.4%) in the tenecteplase group and was hemorrhagic in 10 patients; 1 patient (0.2%) in the placebo group had a stroke, which was hemorrhagic (P=0.003). By day 30, a total of 12 patients (2.4%) in the tenecteplase group and 16 patients (3.2%) in the placebo group had died (P=0.42). CONCLUSIONS In patients with intermediate-risk pulmonary embolism, fibrinolytic therapy prevented hemodynamic decompensation but increased the risk of major hemorrhage and stroke. (Funded by the Programme Hospitalier de Recherche Clinique in France and others; PEITHO EudraCT number, 2006-005328-18; ClinicalTrials.gov number, NCT00639743.).

Management of Pulmonary Arterial Hypertension Associated with Congenital Systemic-to-Pulmonary Shunts and Eisenmenger’s Syndrome

A large proportion of patients with congenital heart disease (CHD), in particular those with relevant systemic-to-pulmonary shunts, will develop pulmonary arterial hypertension (PAH) if left untreated. Persistent exposure of the pulmonary vasculature to increased blood flow, as well as increased pressure, may result in pulmonary obstructive arteriopathy, which leads to increased pulmonary vascular resistance that, if it approaches or exceeds systemic resistance, will result in shunt reversal. Eisenmenger’s syndrome, the most advanced form of PAH associated with CHD, is defined as CHD with an initial large systemic-to-pulmonary shunt that induces severe pulmonary vascular disease and PAH, with resultant reversal of the shunt and central cyanosis.The histopathological and pathobiological changes seen in patients with PAH associated with congenital systemic-to-pulmonary shunts, such as endothelial dysfunction of the pulmonary vasculature, are considered similar to those observed in idiopathic or other associated forms of PAH. A pathological and pathophysiological classification of CHD with systemic-to-pulmonary shunt leading to PAH has been developed that includes specific characteristics, such as the type, dimensions and direction of the shunt, extracardiac abnormalities and repair status. A clinically oriented classification has also been proposed.The prevalence of PAH associated with congenital systemic-to-pulmonary shunts in Western countries has been estimated to range between 1.6 and 12.5 cases per million adults, with 25–50% of this population affected by Eisenmenger’s syndrome.Clinically, Eisenmenger’s syndrome presents with multiple organ involvement, with progressive deterioration of function over time. The signs and symptoms of Eisenmenger’s syndrome in the advanced stages include central cyanosis, dyspnoea, fatigue, haemoptysis, syncope and right-sided heart failure. Survival of patients with Eisenmenger’s syndrome is clearly less than that of the general population, but appears to be better than that of patients with idiopathic PAH in a comparable functional class.The treatment strategy for patients with PAH associated with congenital systemic-to-pulmonary shunts and, in particular, those with Eisenmenger’s syndrome is based mainly on clinical experience rather than being evidence based. General measures include recommendations for physical activity, pregnancy, infections, air travel, exposure to high altitudes and elective surgery, and that psychological assistance be provided as necessary. Phlebotomies are required only when hyperviscosity of the blood is evident, usually when the haematocrit is >65%. The use of supplemental oxygen therapy is controversial and it should be used only in patients in whom it produces a consistent increase in arterial oxygen saturation. Oral anticoagulant treatment with warfarin can be initiated in patients with pulmonary artery thrombosis and absent, or only mild, haemoptysis.The following three classes of drugs targeting the correction of abnormalities in endothelial dysfunction have been approved recently for the treatment of PAH: (i) prostanoids; (ii) endothelin receptor antagonists; and (iii) phosphodiesterase-5 inhibitors. The efficacy and safety of these compounds have been confirmed in uncontrolled studies in patients with PAH associated with corrected and uncorrected congenital systemic-to-pulmonary shunts, as well as in patients with Eisenmenger’s syndrome. One randomized controlled trial reported favourable short- and long-term outcomes of treatment with the orally active dual endothelin receptor antagonist bosentan in patients with Eisenmenger’s syndrome. Lung transplantation with repair of the cardiac defect or combined heart-lung transplantation are options for Eisenmenger’s syndrome patients with a poor prognosis. A treatment algorithm based on the one used in the treatment of PAH patients is proposed for patients with PAH associated with corrected and uncorrected congenital systemic-to-pulmonary shunts and Eisenmenger’s syndrome.

Current era survival of patients with pulmonary arterial hypertension associated with congenital heart disease: a comparison between clinical subgroups

AIMS This study compared the clinical, functional, and haemodynamic characteristics and current era survival of subgroups of patients with pulmonary arterial hypertension associated with congenital heart disease (PAH-CHD): Eisenmenger syndrome (ES); PAH-CHD associated with systemic-to-pulmonary shunts (SPs); PAH with small defects (SDs); and PAH after defect correction (CDs). METHODS AND RESULTS Data from consecutive PAH-CHD patients referred to our centre from 1 January 1998 to 31 May 2011 were collected. A contemporary group of idiopathic PAH patients was utilized for comparison. Treatment was per PAH guidelines, including combination therapy, with approved PAH-specific drugs. Survival was assessed with Kaplan-Meier analysis from the first invasive haemodynamic confirmation of PAH and compared across subgroups by log-rank test. Of 192 patients (mean age 41 ± 17 years; 61% female), 90 had ES (aged 41 ± 16 years); 48 SP (aged 47 ± 18 years); 10 SD (aged 25 ± 21 years); and 44 CD (aged 36 ± 17 years). Patients with ES had the highest baseline pulmonary vascular resistance and the lowest exercise capacity. Seventy-eight per cent were treated with approved PAH-specific drugs, and 44% were treated with combination therapy. Kaplan-Meier survival estimates (95% confidence interval) at 20 years for ES, SP, and CD were 87% (77-93%), 86% (60-96%), and 36% (12-72%, P = 0.0001 vs. ES; P = 0.004 vs. SP), respectively, and at 15 years for SD was 66% (16-91%, P = 0.015 vs. ES; P = 0.016 vs. SP). The survival of the 278 patients with idiopathic PAH appeared to be worse when compared with the PAH-CHD subgroups. CONCLUSION Relevant clinical, functional, haemodynamic, and survival differences were observed among subgroups. In particular, patients with CD and SD had the worst survival. These findings should be considered when planning medical or interventional treatment strategies in PAH-CHD patients.

Pulmonary arterial hypertension associated to connective tissue diseases.

Pulmonary arterial hypertension is a well-known complication of connective tissue diseases such as systemic sclerosis, systemic lupus erythematosus, mixed connective tissue diseases, and to a lesser extent, rheumatoid arthritis, dermatopolymyositis and primary Sjögren’s syndrome. In these patients, pulmonary hypertension may occur in association with left heart disease, interstitial fibrosis or as a result of a isolated pulmonary arteriopathy. The incidence of pulmonary arterial hypertension in the limited form of systemic sclerosis is about 10%. The pathophysiologic mechanisms leading to pulmonary arterial hypertension remain unknown. Symptoms and clinical presentation are very similar to idiopathic pulmonary arterial hypertension but mortality was confirmed to be higher. Echocardiography is the reference investigation for the detection of pulmonary arterial hypertension but the results should be confirmed by right heart catheterization. Treatment appears more complex as compared to idiopathic pulmonary arterial hypertension. Intravenous epoprostenol therapy has been shown to be effective in a special trail. Also, the endothelin receptor antagonists bosentan and sitaxentan, the phosphodyesterase-type-5 sildenafil and subcutaneous treprostinil have shown favourable results.

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.

Pulmonary hypertension and pulmonary arterial hypertension: a clarification is needed

The growing interest in pulmonary hypertension (PH) in many medical specialties including cardiology, rheumatology and respiratory medicine, is possibly due to the recent availability of specific drugs approved for a group of rare conditions defined as pulmonary arterial hypertension (PAH). The terms “pulmonary hypertension” and “pulmonary arterial hypertension” appear to be quite similar, and this has led to confusion and ambiguity in both common clinical practice and the medical literature 1. It is, therefore, important to clarify the different definitions of PH, the relationship between the haemodynamic measurement and the echocardiographic estimate, and the additional diagnostic methods required for the final clinical diagnosis. In addition, it is relevant to highlight the significant role of right heart catheterisation in the diagnostic algorithm of a patient with PH. PH cannot be considered to be a specific “disease”. PH has been defined as an increase in mean pulmonary arterial pressure ( P pa) ≥25 mmHg at rest, as assessed by right heart catheterisation 2–5. Recent re-evaluation of the available data has shown that the normal P pa±sd at rest is 14±3 mmHg with an upper limit of normal of ∼20 mmHg 6, 7. The significance of P pa 21–24 mmHg is unclear. Patients presenting with P pa in this range need further evaluation in epidemiological studies. The definition of PH on exercise as a P pa >30 mmHg, as assessed by right heart catheterisation, is not supported by published data and healthy individuals can reach much higher values 6, 8. Therefore, no definition for PH on exercise as assessed by right heart catheterisation can be provided at the present time. An additional, very important haemodynamic parameter that characterises the definitions of PH is pulmonary capillary wedge pressure ( P pcw). In fact, according to various …

Pulmonary hypertension due to left heart disease: analysis of survival according to the haemodynamic classification of the 2015 ESC/ERS guidelines and insights for future changes

Pulmonary hypertension (PH) is a relevant complication of left heart disease (LHD). The 2015 ESC/ERS PH guidelines report two different haemodynamic subsets of PH due to LHD (PH‐LHD) based on levels of pulmonary vascular resistance (PVR) and diastolic pressure gradient (DPG): isolated post‐capillary PH (Ipc‐PH) and combined post‐ and pre‐capillary PH (Cpc‐PH). The objective of this study is to evaluate the prognostic value of Ipc‐PH and Cpc‐PH.

Combining bosentan and sildenafil in pulmonary arterial hypertension patients failing monotherapy: real-world insights

Pulmonary arterial hypertension is a severe disease with a complex pathogenesis, for which combination therapy is an attractive option. This study aimed to assess the impact of sequential combination therapy on both short-term responses and long-term outcomes in a real-world setting. Patients with idiopathic/heritable pulmonary arterial hypertension, or pulmonary arterial hypertension associated with congenital heart disease or connective tissue disease and who were not meeting treatment goals on either first-line bosentan or sildenafil monotherapy, were given additional sildenafil or bosentan and assessed after 3–4 months. Double combination therapy significantly improved clinical and haemodynamic parameters, independent of aetiology or the order of drug administration. Significant improvements in functional class were observed in patients with idiopathic/heritable pulmonary arterial hypertension. The 1-, 3- and 5-year overall survival estimates were 91%, 69% and 59%, respectively. Patients with pulmonary arterial hypertension associated with connective tissue disease had significantly poorer survival rates compared to other aetiologies (p<0.003). The favourable short-term haemodynamic results and good survival rates, observed in patients receiving both bosentan and sildenafil, supports the use of sequential combination therapy in patients failing on monotherapy in a real-world setting. Bosentan and sildenafil combination therapy improved haemodynamics and exercise in PAH patients failing monotherapy http://ow.ly/LGrPm

Pulmonary hypertension in primary Sjögren’s syndrome: report of a case and review of the literature

A 61-year-old female with a history of vaginal dryness, Raynaud’s phenomenon, xerostomia and xerophthalmia presented with exertional dyspnoea and weakness. Laboratory and instrumental examinations enabled us to make the diagnosis of primary Sjögren’s syndrome, while cardiologic and imaging investigations evidenced isolated pulmonary hypertension and ruled out pulmonary fibrosis. Oral anticoagulant and furosemide therapy induced a partial improvement of exertional dyspnoea and weakness.