Long-term results of the DelIVery for Pulmonary Arterial Hypertension trial

BACKGROUND: The DelIVery for Pulmonary Arterial Hypertension clinical trial was a multi-center, prospective, single arm, Investigational Device Exemption study utilizing a fully implantable, programmable intravascular delivery system consisting of a pump and a catheter for intravenous treprostinil. The study met its primary endpoint and demonstrated that the intravascular delivery system significantly reduced catheter related complications at 22,000 subject-days of follow-up compared with a predefined objective performance criterion. Here we summarize the results obtained during a 6.4-year follow-up period. METHODS: Throughout study follow-up, participants had clinic visits and medication refills at least every 12 weeks (dependent on the subjects\u27 dose). All adverse events and intravascular delivery system complications were evaluated and recorded. RESULTS: Sixty pulmonary arterial hypertension subjects were followed post device implantation for approximately 282 patient-years (range 87 days to 6.4 years). Of the 60 subjects, 14 died (1 related to intravascular delivery system pump failure), 2 withdrew after lung transplants, and 2 withdrew due to pump pocket infection. No catheter-related bloodstream infections, catheter thrombosis or occlusions, or catheter kinks occurred through 282 patient-years. Two participants had adverse events of abdominal pain, rash, due to subcutaneous treprostinil leaks after one catheter puncture and one catheter laceration during pump refill and replacement, respectively. Eight pump failure events occurred: seven pump motor stalls and one early replacement (faulty battery). CONCLUSION: Delivery of treprostinil with an intravascular delivery system is a safe alternative to an external delivery system, while providing enhanced life experiences. To preserve the risk-benefit ratio, treatment at specialized pulmonary arterial hypertension centers is recommended until training is disseminated at other sites

Late gadolinium enhancement cardiovascular magnetic resonance predicts clinical worsening in patients with pulmonary hypertension

<p>Abstract</p> <p>Background</p> <p>Late gadolinium enhancement (LGE) occurs at the right ventricular (RV) insertion point (RVIP) in patients with pulmonary hypertension (PH) and has been shown to correlate with cardiovascular magnetic resonance (CMR) derived RV indices. However, the prognostic role of RVIP-LGE and other CMR-derived parameters of RV function are not well established. Our aim was to evaluate the predictive value of contrast-enhanced CMR in patients with PH.</p> <p>Methods</p> <p>RV size, ejection fraction (RVEF), and the presence of RVIP-LGE were determined in 58 patients with PH referred for CMR. All patients underwent right heart catheterization, exercise testing, and N-terminal pro-brain natriuretic peptide (NT-proBNP) evaluation; results of which were included in the final analysis if performed within 4 months of the CMR study. Patients were followed for the primary endpoint of time to clinical worsening (death, decompensated right ventricular heart failure, initiation of prostacyclin, or lung transplantation).</p> <p>Results</p> <p>Overall, 40/58 (69%) of patients had RVIP-LGE. Patients with RVIP- LGE had larger right ventricular volume index, lower RVEF, and higher mean pulmonary artery pressure (mPAP), all p < 0.05. During the follow-up period of 10.2 ± 6.3 months, 19 patients reached the primary endpoint. In a univariate analysis, RVIP-LGE was a predictor for adverse outcomes (p = 0.026). In a multivariate analysis, CMR-derived RVEF was an independent predictor of clinical worsening (p = 0.036) along with well-established prognostic parameters such as exercise capacity (p = 0.010) and mPAP (p = 0.001).</p> <p>Conclusions</p> <p>The presence of RVIP-LGE in patients with PH is a marker for more advanced disease and poor prognosis. In addition, this study reveals for the first time that CMR-derived RVEF is an independent non-invasive imaging predictor of adverse outcomes in this patient population.</p

Computational platform for doctor–artificial intelligence cooperation in pulmonary arterial hypertension prognostication: a pilot study

Background Pulmonary arterial hypertension (PAH) is a heterogeneous and complex pulmonary vascular disease associated with substantial morbidity. Machine-learning algorithms (used in many PAH risk calculators) can combine established parameters with thousands of circulating biomarkers to optimise PAH prognostication, but these approaches do not offer the clinician insight into what parameters drove the prognosis. The approach proposed in this study diverges from other contemporary phenotyping methods by identifying patient-specific parameters driving clinical risk. Methods We trained a random forest algorithm to predict 4-year survival risk in a cohort of 167 adult PAH patients evaluated at Stanford University, with 20% withheld for (internal) validation. Another cohort of 38 patients from Sheffield University were used as a secondary (external) validation. Shapley values, borrowed from game theory, were computed to rank the input parameters based on their importance to the predicted risk score for the entire trained random forest model (global importance) and for an individual patient (local importance). Results Between the internal and external validation cohorts, the random forest model predicted 4-year risk of death/transplant with sensitivity and specificity of 71.0–100% and 81.0–89.0%, respectively. The model reinforced the importance of established prognostic markers, but also identified novel inflammatory biomarkers that predict risk in some PAH patients. Conclusion These results stress the need for advancing individualised phenotyping strategies that integrate clinical and biochemical data with outcome. The computational platform presented in this study offers a critical step towards personalised medicine in which a clinician can interpret an algorithm's assessment of an individual patient

Smooth Muscle Myosin Inhibition: A Novel Therapeutic Approach for Pulmonary Hypertension

Pulmonary hypertension remains a major clinical problem despite current therapies. In this study, we examine for the first time a novel pharmacological target, smooth muscle myosin, and determine if the smooth muscle myosin inhibitor, CK-2019165 (CK-165) ameliorates pulmonary hypertension.Six domestic female pigs were surgically instrumented to measure pulmonary blood flow and systemic and pulmonary vascular dynamics. Pulmonary hypertension was induced by hypoxia, or infusion of the thromboxane analog (U-46619, 0.1 µg/kg/min, i.v.). In rats, chronic pulmonary hypertension was induced by monocrotaline.CK-165 (4 mg/kg, i.v.) reduced pulmonary vascular resistance by 22±3 and 28±6% from baseline in hypoxia and thromboxane pig models, respectively (p<0.01 and 0.01), while mean arterial pressure also fell and heart rate rose slightly. When CK-165 was delivered via inhalation in the hypoxia model, pulmonary vascular resistance fell by 17±6% (p<0.05) while mean arterial pressure and heart rate were unchanged. In the monocrotaline model of chronic pulmonary hypertension, inhaled CK-165 resulted in a similar (18.0±3.8%) reduction in right ventricular systolic pressure as compared with sildenafil (20.3±4.5%).Inhibition of smooth muscle myosin may be a novel therapeutic target for treatment of pulmonary hypertension

Survival and Predictors of Mortality in Systemic Sclerosis‐Associated Pulmonary Arterial Hypertension: Outcomes From the Pulmonary Hypertension Assessment and Recognition of Outcomes in Scleroderma Registry

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/106105/1/acr22121.pd

Prevention of bronchial hyperreactivity in a rat model of precapillary pulmonary hypertension

<p>Abstract</p> <p>Background</p> <p>The development of bronchial hyperreactivity (BHR) subsequent to precapillary pulmonary hypertension (PHT) was prevented by acting on the major signalling pathways (endothelin, nitric oxide, vasoactive intestine peptide (VIP) and prostacyclin) involved in the control of the pulmonary vascular and bronchial tones.</p> <p>Methods</p> <p>Five groups of rats underwent surgery to prepare an aorta-caval shunt (ACS) to induce sustained precapillary PHT for 4 weeks. During this period, no treatment was applied in one group (ACS controls), while the other groups were pretreated with VIP, iloprost, tezosentan via an intraperitoneally implemented osmotic pump, or by orally administered sildenafil. An additional group underwent sham surgery. Four weeks later, the lung responsiveness to increasing doses of an intravenous infusion of methacholine (2, 4, 8 12 and 24 μg/kg/min) was determined by using the forced oscillation technique to assess the airway resistance (Raw).</p> <p>Results</p> <p>BHR developed in the untreated rats, as reflected by a significant decrease in ED₅₀, the equivalent dose of methacholine required to cause a 50% increase in Raw. All drugs tested prevented the development of BHR, iloprost being the most effective in reducing both the systolic pulmonary arterial pressure (Ppa; 28%, p = 0.035) and BHR (ED₅₀= 9.9 ± 1.7 vs. 43 ± 11 μg/kg in ACS control and iloprost-treated rats, respectively, p = 0.008). Significant correlations were found between the levels of Ppa and ED₅₀(R = -0.59, p = 0.016), indicating that mechanical interdependence is primarily responsible for the development of BHR.</p> <p>Conclusions</p> <p>The efficiency of such treatment demonstrates that re-establishment of the balance of constrictor/dilator mediators via various signalling pathways involved in PHT is of potential benefit for the avoidance of the development of BHR.</p

Anaesthesiological strategies in elective craniotomy: randomized, equivalence, open trial – The NeuroMorfeo trial

<p>Abstract</p> <p>Background</p> <p>Many studies have attempted to determine the <it>"best" </it>anaesthetic technique for neurosurgical procedures in patients without intracranial hypertension. So far, no study comparing intravenous (IA) with volatile-based neuroanaesthesia (VA) has been able to demonstrate major outcome differences nor a superiority of one of the two strategies in patients undergoing elective supratentorial neurosurgery. Therefore, current practice varies and includes the use of either volatile or intravenous anaesthetics in addition to narcotics. Actually the choice of the anaestesiological strategy depends only on the anaesthetists' preferences or institutional policies.</p> <p>This trial, named NeuroMorfeo, aims to assess the equivalence between volatile and intravenous anaesthetics for neurosurgical procedures.</p> <p>Methods/Design</p> <p>NeuroMorfeo is a multicenter, randomized, open label, controlled trial, based on an equivalence design. Patients aged between 18 and 75 years, scheduled for elective craniotomy for supratentorial lesion without signs of intracranial hypertension, in good physical state (ASA I-III) and Glasgow Coma Scale (GCS) equal to 15, are randomly assigned to one of three anaesthesiological strategies (two VA arms, sevoflurane + fentanyl or sevoflurane + remifentanil, and one IA, propofol + remifentanil). The equivalence between intravenous and volatile-based neuroanaesthesia will be evaluated by comparing the intervals required to reach, after anaesthesia discontinuation, a modified Aldrete score ≥ 9 (primary end-point). Two statistical comparisons have been planned:</p> <p>1) sevoflurane + fentanyl vs. propofol + remifentanil;</p> <p>2) sevoflurane + remifentanil vs. propofol + remifentanil.</p> <p>Secondary end-points include: an assessment of neurovegetative stress based on (a) measurement of urinary catecholamines and plasma and urinary cortisol and (b) estimate of sympathetic/parasympathetic balance by power spectrum analyses of electrocardiographic tracings recorded during anaesthesia; intraoperative adverse events; evaluation of surgical field; postoperative adverse events; patient's satisfaction and analysis of costs.</p> <p>411 patients will be recruited in 14 Italian centers during an 18-month period.</p> <p>Discussion</p> <p>We presented the development phase of this anaesthesiological on-going trial. The recruitment started December 4^th, 2007 and up to 4^th, December 2008, 314 patients have been enrolled.</p

A Review of the Adverse Effects of Peripheral Alpha-1 Antagonists in Hypertension Therapy

BACKGROUND: Doxazosin and its role as an antihypertensive agent have come under recent scrutiny as a result of the early termination of that treatment arm in ALLHAT. It is unclear why the cardiovascular (CV) event rate in this randomized, controlled trial (RCT), especially heart failure, is higher in those treated with a doxazosin-based regimen than with a chlorthalidone based-regimen. There has been little work in the past to summarize information on peripheral alpha-1 antagonists that may be helpful in evaluating the results of this randomized controlled trial. METHODS: Using Medline and the Cochrane databases, we performed a comprehensive review of the literature on the use of peripheral alpha-1 antagonists as antihypertensive agents, focusing on available information that could explain the excess cardiovascular events observed in the Antihypertensive and Lipid-Lowering Treatment to prevent Heart Attack Trial (ALLHAT). RESULTS: Minimal data were available concerning the effects of peripheral alpha-1 antagonists on CV endpoints. A multitude of short-term studies-ranging from small observational studies to short-term moderate-sized RCTs – focused on safety, efficacy, and tolerability, and some studies investigated the physiologic effects of these agents. These previously reported studies reveal associations with weight gain, fluid retention, and neurohormonal changes among various populations of those treated with peripheral alpha-1 antagonists. CONCLUSION: These findings suggest several possible mechanisms by which doxazosin may be inferior to low-dose diuretics as antihypertensive therapy for the prevention of heart failure

New Trial Designs and Potential Therapies for Pulmonary Artery Hypertension

A greater understanding of the epidemiology, pathogenesis, and pathophysiology of pulmonary artery hypertension (PAH) has led to significant advances, but the disease remains fatal. Treatment options are neither universally available nor always effective, underscoring the need for development of novel therapies and therapeutic strategies. Clinical trials to date have provided evidence of efficacy, but were limited in evaluating the scope and duration of treatment effects. Numerous potential targets in varied stages of drug development exist, in addition to novel uses of familiar therapies. The pursuit of gene and cell-based therapy continues, and device use to help acute deterioration and chronic management is emerging. This rapid surge of drug development has led to multicenter pivotal clinical trials and has resulted in novel ethical and global clinical trial concerns. This paper will provide an overview of the opportunities and challenges that await the development of novel treatments for PAH. A greater understanding of the epidemiology, pathogenesis, and pathophysiology of pulmonary artery hypertension (PAH) has led to significant advances over the past 2 decades in treatment of this disorder. However, these treatment options are neither universally available nor always effective, underscoring the need for development of novel therapies and therapeutic strategies. Because PAH is considered an orphan disease that is uniformly progressive and fatal, prior clinical trials evaluating novel therapies were relatively short in duration and were comprised of small populations of affected patients. These studies provided evidence of efficacy, but were limited in evaluating the scope and duration of treatment effects. Accordingly, clinical development of novel therapies for PAH in the future will require trials of larger and perhaps more diverse patient cohorts who are studied for longer periods and with more robust and meaningful efficacy endpoints. The challenges posed by these requirements are substantial, and include From th