Luca Negro

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.

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.

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.

Long-term therapeutic outcomes in pulmonary arterial hypertension

ABSTRACT Background: The prognosis of patients with untreated pulmonary arterial hypertension has historically been poor, but recent advances in our understanding of its pathobiology have led to the development of numerous therapeutic options over the last decade. Methods: Systematic literature review of all randomised studies performed in patients with pulmonary arterial hypertension including long-term extension observations (Medline 1990–2007). Findings: This article provides an overview of the currently available data on the short and long-term effects of emerging agents on exercise capacity, functional capacity, haemodynamics, quality of life, and survival in patients with pulmonary arterial hypertension. Prostanoids, endothelin receptor antagonists, and phosphodiesterase‐5 inhibitors have shown great promise in short-term randomised clinical trials, but the long-term effects of these classes of medication have not been well established to date. Conclusion: Several long-term cohort studies have recently suggested that these drugs can maintain their beneficial effects on important clinical outcomes, but further studies will be needed before definitive conclusions can be drawn regarding the ultimate utility and optimal role of each agent in the therapeutic repertoire.

Left ventricular dimensions in pulmonary arterial hypertension: haemodynamic and exercise correlations

ABSTRACT Background: Remodelling of the heart in patients with pulmonary arterial hypertension (PAH) involves both the right and left ventricles. The objective of the present study was to analyse the dimensions of the right and left ventricles as assessed by echocardiography, and to compare this with haemodynamics and exercise capacity in patients with PAH. Materials and methods: Transthoracic echocardiogram, exercise capacity as assessed by the 6-minute walk test and right-heart catheterization were performed within 1 week in 66 consecutive patients with PAH. Univariate correlation and multiple regression analyses were performed to relate echocardiographic and clinical variables. Results: Left ventricular end-diastolic area index had the best correlation with cardiac index (r = 0.62; p < 0.001) and 6-minute walk distance (r = 0.56; p < 0.001). The ratio of the right to left ventricular area correlated with right atrial pressure (r = 0.62; p < 0.001). Right ventricular percent change in area correlated with cardiac index (r = 0.51; p < 0.001). No correlations were observed between the right and left ventricular dimensions. Conclusions: Left ventricular dimensions and the ratio of the right to left ventricular area correlated with resting haemodynamics and exercise capacity in patients with pulmonary arterial hypertension. These correlations were stronger than those observed with right ventricular dimensions alone. Left ventricular dimensions are important for the non-invasive evaluation of severity of patients with pulmonary arterial hypertension.

Evidence for Kaposi's sarcoma-associated herpes virus infection in patients with idiopathic pulmonary arterial hypertension: a case series and review of the literature

ABSTRACT Background: The pathogenesis of idiopathic pulmonary arterial hypertension (IPAH) is unknown. Recent molecular and immunohistochemical evidence has demonstrated the presence of Kaposis sarcoma-associated herpes virus (KSHV) at high frequency in lung tissue from patients with IPAH, suggesting a possible role for this virus in the pathogenesis of the disease. Materials and methods: Eighty-seven patients with IPAH (n = 45) or other forms of pulmonary hypertension (n = 42) were prospectively assessed for serologic evidence of KSHV, Epstein–Barr virus (EBV) and human cytomegalovirus (HCMV) infection. Immunofluorescence assays specific for antibodies against latency-associated and lytic antigens of KSHV, as well as commercially available kits that detect antibodies against HCMV and EBV nuclear antigens, were employed. Results: Only one patient with IPAH (2.2%) and one of the patients with other forms of pulmonary hypertension tested seropositive for KSHV. In contrast, 100% and more than 90% of patients with both forms of pulmonary hypertension were positive for EBV and HCMV antibodies, respectively. Conclusions: Italian patients with IPAH do not exhibit serologic evidence of KSHV infection despite a normal ability to mount antibody-mediated responses toward human herpes viruses. KSHV is unlikely to play a role in the pathogenesis of IPAH.