Short-Term Hemodynamic Effects of Apelin in Patients With Pulmonary Arterial Hypertension.

Apelin agonism causes systemic vasodilatation and increased cardiac contractility in humans, and improves pulmonary arterial hypertension (PAH) in animal models. Here, the authors examined the short-term pulmonary hemodynamic effects of systemic apelin infusion in patients with PAH. In a double-blind randomized crossover study, 19 patients with PAH received intravenous (Pyr1)apelin-13 and matched saline placebo during invasive right heart catheterization. (Pyr1)apelin-13 infusion caused a reduction in pulmonary vascular resistance and increased cardiac output. This effect was accentuated in the subgroup of patients receiving concomitant phosphodiesterase type 5 inhibition. Apelin agonism is a novel potential therapeutic target for PAH. (Effects of Apelin on the Lung Circulation in Pulmonary Hypertension; NCT01457170).

Clinical trials in pulmonary hypertension: Time for a consortium.

Current and past clinical trials in pulmonary hypertension, while valuable, are limited by the absence of mechanistic aims, by dissatisfaction with endpoints and the inability to share data. Clinical studies in pulmonary hypertension might be enhanced by a consortium approach that utilizes the expertise of academic medicine, the treatment initiatives of the pharmaceutical industry and study design from funding agencies interested in biological mechanisms. A meeting of interested parties, the Pulmonary Hypertension Academic Research Consortium (PHARC), was held from 30 April to 1 May 2012 in Bethesda, Maryland. Members at the conference were from the USA Federal Drug Administration (FDA); pharmaceutical industry (Pfizer, Novartis, Bayer and Gilead); USA National Institutes of Health (NHLBI); the Pulmonary Vascular Research Institute (PVRI), a non-governmental organization (NGO); and research and clinical members of pulmonary hypertension programs of international scope. A recommendation to develop a clinical trials consortium was the product of the working group on academic standards in clinical trials. The working group concluded that clinical trials hold immense promise to move the field of pulmonary hypertension forward if the trials are designed by a consortium with input from multiple groups. This would result in study design, conduct and analysis determined by consortium members with a high degree of independent function. The components of a well-balanced consortium that give it scientific effectiveness are: (1) the consortium can work with multiple companies simultaneously; (2) sponsors with special interests, such as testing biological mechanisms, can add investigations to a study at lower cost than with present granting strategies; (3) data handling including archiving, analysis and future sharing would be improved; (4) ancillary studies supported by the collection and dissemination of tissues and fluids would generate a broader approach to discovery than is now possible; and (5) development of improved endpoints in consultation with regulatory agencies, industry and academia would be possible.

A clinical comparison of slow- and rapid-escalation treprostinil dosing regimens in patients with pulmonary hypertension.

BACKGROUND AND OBJECTIVE: Subcutaneous treprostinil is an effective treatment for pulmonary arterial hypertension (PAH). A previous pivotal study indicated that infusion site pain was dose dependent and resulted in suboptimal dose escalation by week 12 and a reduced clinical benefit. We hypothesized that a rapid-escalation treprostinil dosing regimen would be as safe and effective as a slow-escalation dosing regimen. METHODS: Twenty-three patients received treprostinil to treat PH of various aetiologies and were randomized into two groups. Group 1 (11 patients: seven females and four males, aged 51.7 +/- 15.4 years) received a slow-escalation regimen, and group 2 (12 patients: ten females and two males, aged 51.3 +/- 16.7 years) were exposed to rapid dose escalation. The dose escalation, exercise capacity (a 6-minute walk test [6WT] or a shuttle walk test [SWT]), WHO classification, blood pressure, heart rate, respiration rate, baseline haemodynamics and adverse events were followed up for 12 weeks. RESULTS: Baseline haemodynamics did not differ significantly between the treatment groups. At follow-up, the treprostinil dose reached 12.9 +/- 2.7 ng/kg/min in group 1 and 20.3 +/- 5.8 ng/kg/min in group 2 (p < 0.01). The patients' WHO classification improved significantly (p < 0.05), with no difference between the groups. Improvement of exercise capacity was greater in group 2 (6WT and SWT, p < 0.05). Infusion site pain occurred in 81.8% of group 1 and in 58.3% of group 2 (p < 0.05) patients. Other adverse events and changes in the heart rate, respiration rate and blood pressure were similar in both groups. CONCLUSION: The rapid-dosing regimen is as safe and effective as the slow-escalation regimen and may be associated with even better clinical outcomes. Infusion site pain is not dose dependent.

Ventilation-perfusion scintigraphy is more sensitive than multidetector CTPA in detecting chronic thromboembolic pulmonary disease as a treatable cause of pulmonary hypertension.

UNLABELLED: Pulmonary hypertension (PH) is a progressive disease with a poor prognosis. Identifying chronic thromboembolic pulmonary disease as a cause of PH has major clinical implications as these patients could be potentially offered a surgical cure. Ventilation-perfusion (V/Q) scintigraphy has a high sensitivity to detect embolic disease but its value has been challenged with the emergence of multidetector CT pulmonary angiography (CTPA). We compared the value of V/Q scintigraphy with CTPA in detecting chronic thromboembolic pulmonary disease. METHODS: We retrospectively reviewed the results of V/Q scintigraphy and CTPA performed on patients who had been referred to the Pulmonary Hypertension Service at Hammersmith Hospital between 2000 and 2005. A total of 227 patients (85 males, 142 females; age range, 18-81 y; mean age, 42 y) had all tests done at Hammersmith Hospital and were included in the study. Interpretation of scans was according to the modified PIOPED (Prospective Investigation of Pulmonary Embolism Diagnosis) criteria. CTPA was considered as suggestive of chronic thromboembolic pulmonary disease if it showed visualization of the thrombus or webs, recanalization, perfusion abnormalities, stenosis, or strictures. Standard pulmonary angiography was performed via femoral approach. In 90% of the cases, CTPA and V/Q scintigraphy were performed within 10 d. RESULTS: Seventy-eight patients (group A) had a final diagnosis of chronic thromboembolic pulmonary hypertension (CTEPH) and 149 (group B) had non-CTEPH etiology. Among group A, V/Q scintigraphy was reported as high probability in 75 patients, intermediate probability in 1 patient, and low probability in 2 patients. CTPA was positive in 40 patients and negative in 38 patients. Among group B, V/Q scintigraphy was reported as low probability in 134, intermediate probability in 7, and high probability in 8 patients. CTPA was negative in 148 patients and false-positive in 1 patient. Statistical analysis showed V/Q scintigraphy to have a sensitivity of 96%-97.4% and a specificity of 90%-95%. CTPA showed a sensitivity of 51% and a specificity of 99%. CONCLUSION: Our results demonstrate that V/Q scintigraphy has a higher sensitivity than CTPA in detecting CTEPH as a potential curable cause of PH.