Capsaicin 8% patch for treprostinil subcutaneous infusion site pain in pulmonary hypertension patients.

BACKGROUND: Treprostinil sodium improves haemodynamics and symptoms in pulmonary arterial hypertension (PAH) patients, but its subcutaneous (s.c.) administration can produce severe local site pain, and lead to discontinuation of vital treatment. Treprostinil is a prostacyclin analogue which stimulates prostacyclin receptors in skin nociceptor terminals, resulting in pain and cutaneous hypersensitivity, for which current pain remedies have limited effect. Capsaicin 8% patch relieves neuropathic pain for 3 months after a single 60 min cutaneous application; we investigated whether its pre-application can reduce s.c. trepostinil-induced pain. METHODS: A single-centre, double-blind, randomized, placebo-controlled, crossover study was conducted to assess the safety and efficacy of a single capsaicin 8% patch pre-application for s.c. treprostinil pain in 11 PAH patients, relative to control patch with low-dose capsaicin 0.075% cream. RESULTS: The primary efficacy endpoint, mean difference between the two treatment arms in an 11-point numerical pain rating scale from baseline to 2 weeks after patch applications, was significantly lower on the capsaicin 8% patch treatment arm [P=0.01, mean difference=-1.47 units, 95% credible interval (CI): -2. 59 to -0.38] in the patients who completed the study per protocol, although intention-to-treat analysis did not show significant difference (P=0.28). Heat pain thresholds were decreased (P=0.027, mean difference=5.43°C, 95% CI: 0.71-10.21) and laser Doppler flux increased (P=0.016, mean difference=370 units, 95% CI: 612 to 127.9) at the application site immediately after capsaicin 8% patch, confirming activity. CONCLUSIONS: Further investigation of the efficacy of capsaicin 8% patch in this indication is warranted.

Iron deficiency in pulmonary arterial hypertension: a potential therapeutic target.

Iron deficiency is known to be common and detrimental in chronic left heart failure, where parenteral iron treatment has been shown to improve exercise capacity, New York Heart Association functional class and patient wellbeing. There is now increasing interest in the role of iron in the natural history of pulmonary arterial hypertension (PAH). Iron availability influences the pulmonary vasoconstrictor response to hypoxia and accumulating evidence indicates that iron deficiency is prevalent in idiopathic and heritable forms of PAH, iron status being related to exercise capacity, symptoms and poorer survival in patients with idiopathic PAH (IPAH). Potential mechanisms behind iron deficiency in IPAH include inhibition of dietary iron uptake by the master iron regulator hepcidin. High hepcidin levels underlie the anaemia of chronic disease. Possible stimuli of the observed high levels of hepcidin in IPAH include dysfunctional bone morphogenetic protein receptor type II signalling and inflammation. Iron status may influence outcomes through modulation of the pulmonary circulation as well as myocardial and skeletal muscle function. Two parallel studies, from our centre (Hammersmith Hospital, London, UK) and others in the UK and Amsterdam (the Netherlands), investigating the safety and potential benefit of iron supplementation in patients with PAH are currently under way.

Clinical and cost-effectiveness of epoprostenol, iloprost, bosentan, sitaxentan and sildenafil for pulmonary arterial hypertension within their licensed indications: a systematic review and economic evaluation.

OBJECTIVE(S): To investigate the clinical and cost-effectiveness of epoprostenol, iloprost, bosentan, sitaxentan and sildenafil for the treatment of adults with pulmonary arterial hypertension (PAH) within their licensed indications. DATA SOURCES: Major electronic databases (including the Cochrane Library, MEDLINE and EMBASE) were searched up to February 2007. Further data were obtained from dossiers submitted to NICE by the manufacturers of the technologies. REVIEW METHODS: The systematic clinical and economic reviews were conducted according to accepted procedures. Model-based economic evaluations of the cost-effectiveness of the technologies from the perspective of the UK NHS and personal social services were carried out. RESULTS: In total, 20 randomised controlled trials (RCTs) were included in this assessment, mostly of 12-18 weeks duration and comparing one of the technologies added to supportive treatment with supportive treatment alone. Four published economic evaluations were identified. None produced results generalisable to the NHS. There was no consensus in the industry submissions on the most appropriate model structure for the technology assessment. Improvement in 6-minute walk distance (6MWD) was seen with intravenous epoprostenol in primary pulmonary hypertension (PPH) patients with mixed functional class (FC) (mainly III and IV, licensed indication) compared with supportive care (58 metres; 95% CI 6-110). For bosentan compared with supportive care, the pooled result for improvement in 6MWD for FCIII patients with mixed PAH (licensed indication) was 59 metres (95% CI 20-99). For inhaled iloprost, sitaxentan and sildenafil no stratified data for improvement in 6MWD were available. The odds ratio (OR) for FC deterioration at 12 weeks was 0.40 (95% CI 0.13-1.20) for intravenous epoprostenol compared with supportive care. The corresponding values for inhaled iloprost (FCIII PPH patients; licensed indication), bosentan, sitaxentan (FCIII patients with mixed PAH; licensed indication) and sildenafil (FCIII patients with mixed PAH; licensed indication) were 0.29 (95% CI 0.07-1.18), 0.21 (95% CI 0.03-1.76), 0.18 (95% CI 0.02-1.64) and [Commercial-in-confidence information has been removed] respectively. The incremental cost-effectiveness ratios (ICERs) for the technologies plus supportive care compared with supportive care alone, determined by independent economic evaluation, were 277,000 pounds/quality-adjusted life-year (QALY) for FCIII and 343,000 pounds/QALY for FCIV patients for epoprostenol, 101,000 pounds/QALY for iloprost, 27,000 pounds/QALY for bosentan and 25,000 pounds/QALY for sitaxentan. For the most part sildenafil plus supportive care was more effective and less costly than supportive care alone and therefore dominated supportive care. In the case of epoprostenol the ICERs were sensitive to the price of epoprostenol and for bosentan and sitaxentan the ICERs were sensitive to running the model over a shorter time horizon and with a lower cost of epoprostenol. Two RCTs directly compared the technologies against each other with no significant differences observed between the technologies. Combinations of technologies were investigated in four RCTs, with some showing conflicting results. CONCLUSION(S): All five technologies when added to supportive treatment and used at licensed dose(s) were more effective than supportive treatment alone in RCTs that included patients of mixed FC and types of PAH. Current evidence does not allow adequate comparisons between the technologies nor for the use of combinations of the technologies. Independent economic evaluation suggests that bosentan, sitaxentan and sildenafil may be cost-effective by standard thresholds and that iloprost and epoprostenol may not. If confirmed, the use of the most cost-effective treatment would result in a reduction in costs for the NHS. Long-term, double-blind RCTs of sufficient sample size that directly compare bosentan, sitaxentan and sildenafil, and evaluate outcomes including survival, quality of life, maintenance on treatment and impact on the use of resources for NHS and personal social services are needed.

Prognostic and aetiological factors in chronic thromboembolic pulmonary hypertension.

Several prognostic variables have previously been identified in patients with chronic thromboembolic pulmonary hypertension (CTEPH). Specific medical conditions have also been associated with the development and prognosis of CTEPH. Using a national registry, the current authors have assessed the prognostic value of a larger number of variables and have also attempted to validate the clinical importance of previously identified aetiological factors. Baseline information for all 469 CTEPH patients diagnosed in the UK pulmonary hypertension service between January 2001 and June 2006 was collected from hospital records. Although univariate analysis confirmed the prognostic importance of pulmonary resistance, in multivariate analysis gas transfer and exercise capacity predicted pulmonary endarterectomy perioperative mortality. Cardiac index and exercise capacity independently predicted outcome in patients with nonoperable disease. Previous splenectomy was noted in 6.7% of patients, being significantly more common in patients with nonoperable than operable disease (13.7 versus 3.6%). Medical risk factors were not found to predict mortality. In a large national cohort, predictors of outcome in patients with both operable and nonoperable chronic thromboembolic pulmonary hypertension have been identified. These may be useful in planning treatment. The aetiological importance of previously identified medical risk factors has been confirmed, although the current authors were unable to validate their prognostic strength.

Pulmonary veno-occlusive disease presenting with recurrent pulmonary oedema and the use of nitric oxide to predict response to sildenafil.

Pulmonary veno-occlusive disease (PVOD) is a disorder which causes progressive pulmonary hypertension, usually presenting with worsening dyspnoea and right heart failure. Pulmonary oedema induced by pulmonary vasodilator therapy to reduce pulmonary arterial pressure has been well described in PVOD, but here we describe a case of PVOD presenting with recurrent episodes of acute non-cardiogenic pulmonary oedema, in the absence of significant pulmonary hypertension. Concern over the risk of precipitating pulmonary oedema led us to use inhaled nitric oxide to predict the safety and efficacy of sildenafil.

Embolisation of pulmonary arteriovenous malformations: no consistent effect on pulmonary artery pressure.

Increasing evidence supports the use of embolisation to treat pulmonary arteriovenous malformations (AVMs). Most pulmonary AVM patients have hereditary haemorrhagic telangiectasia (HHT), a condition that may be associated with pulmonary hypertension. The current authors tested whether pulmonary AVM embolisation increases pulmonary artery pressure (P(pa)) in patients without baseline severe pulmonary hypertension. P(pa) was measured at the time of pulmonary AVM embolisation in 143 individuals, 131 (92%) of whom had underlying HHT. Angiography/embolisation was not performed in four individuals with severe pulmonary hypertension, whose systemic arterial oxygen saturation exceeded levels usually associated with dyspnoea in pulmonary AVM patients. In 143 patients undergoing pulmonary AVM embolisation, P(pa) was significantly correlated with age, with the most significant increase occurring in the upper quartile (aged >58 yrs). In 43 patients with repeated measurements, there was no significant increase in P(pa) as a result of embolisation. In half, embolisation led to a fall in P(pa). The maximum rise in mean P(pa) was 8 mmHg: balloon test occlusion was performed in one of these individuals, and did not predict the subsequent rise in P(pa) following definitive embolisation of the pulmonary AVMs. In the present series of patients, which excluded those with severe pulmonary hypertension, pulmonary artery pressure was not increased significantly by pulmonary arteriovenous malformation embolisation.

Pulmonary artery-to-pulmonary artery anastomoses: angiographic demonstration in patients with chronic thromboembolic pulmonary hypertension.

AIM: To describe direct pulmonary artery-to-pulmonary artery anastomoses seen at pulmonary angiography in patients with chronic thromboembolic pulmonary hypertension and discuss their possible significance. MATERIALS AND METHODS: Between 1 August 2000 and 31 July 2004 43 patients (male-to-female ratio 25:18) with a diagnosis of chronic thromboembolic pulmonary hypertension (CTEPH) underwent selective pulmonary angiography to assess the extent of disease and suitability for surgical pulmonary endarterectomy. The mean pulmonary artery pressure ranged from 27-84 mmHg (average of 51 mmHg). Selective bilateral digital subtraction pulmonary angiograms performed in all individuals were reviewed for the presence of intrapulmonary collaterals. RESULTS: In 15 of the 43 patients (male-to-female ratio =7:8) definite (n = 12) or probable (n = 3) pulmonary artery-to-pulmonary artery anastomoses were demonstrated. Of the remaining 28 patients in whom intrapulmonary collaterals were not seen it was felt that in 16 the angiograms were of insufficient diagnostic quality (grades 4-5) to exclude their presence. Twelve patients, eight of whom had angiograms of sufficient diagnostic quality (grades 1-3), demonstrated one or more areas of luxury perfusion but intrapulmonary collaterals were not seen. CONCLUSION: Direct pulmonary artery-to-pulmonary artery anastomoses were demonstrated in patients with chronic thromboembolic pulmonary hypertension, which to our knowledge have not been previously described. The importance of these collateral vessels is unclear but they may play a role in the maintenance of pulmonary parenchymal viability in patients with chronic pulmonary embolic disease. The rate of development of these collaterals and their prognostic significance in patients with chronic thromboembolic pulmonary hypertension are areas worthy of further study.

Echocardiographic features and brain natriuretic peptides in patients presenting with heart failure and preserved systolic function.

OBJECTIVE: To characterise patients who appear to fulfil the diagnosis of heart failure with preserved systolic function clinically, echocardiographically, and by concentrations of brain-type natriuretic peptide (BNP). METHODS: 102 new cases of heart failure were identified over 24 months in 213 patients referred to a rapid access heart failure clinic. Patients with heart failure and preserved systolic function with contemporary markers of diastolic function were assessed to evaluate their cardiac status further. RESULTS: Forty patients (39%) had an ejection fraction (EF) < 45% and 62 (61%) had an EF > or = 45%. Of these 62 patients, 30 (48%) fulfilled the case definition of diastolic heart failure. The remaining 32 (52%) had neither an EF < 45% nor abnormalities of diastolic function. Dobutamine stress echocardiography was performed on 26 (42%) patients with EF > or = 45%, which provided an alternative explanation for symptoms in 15 (58%) patients. Concentrations of BNP were higher in patients with diastolic abnormalities (mean (SEM) 101.4 (32.5) pg/ml v 58.4 (6.78) pg/ml, p = 0.042) and with no diastolic abnormalities (199 (37.9) pg/ml v 58.4 (6.78) pg/ml, p < 0.0001) than in patients with no heart failure. CONCLUSION: Among ambulatory patients presenting with suspected heart failure in the community 19% have systolic dysfunction, 14% have diastolic dysfunction, and 15% seemingly have heart failure with neither systolic nor diastolic dysfunction. A new understanding, including alternative parameters of diastolic function, seems to be necessary to classify patients with heart failure and preserved systolic function.

Perioperative beta-blockade (POBBLE) for patients undergoing infrarenal vascular surgery: results of a randomized double-blind controlled trial.

OBJECTIVE: To assess whether a pragmatic policy of perioperative beta-blockade, with metoprolol, reduced the 30-day cardiovascular morbidity and mortality and reduced the length of hospital stay in average patients undergoing infrarenal vascular surgery. METHODS: This was a double-blind randomized placebo-controlled trial that occurred in vascular surgical units in four UK hospitals. Participants were 103 patients without previous myocardial infarction who had infrarenal vascular surgery between July 2001 and March 2004. Interventions were oral metoprolol (50 mg twice daily, supplemented by intravenous doses when necessary) or placebo from admission until 7 days after surgery. Holter monitors were kept in place for 72 hours after surgery. RESULTS: Eighty men and 23 women (median age, 73 years) were randomized, 55 to metoprolol and 48 to placebo, and 97 (94%) underwent surgery during the trial. The most common operations were aortic aneurysm repair (38%) and distal bypass (29%). Intraoperative inotropic support was required in 64% and 92% of patients in the placebo and metoprolol groups, respectively. Within 30 days, cardiovascular events occurred in 32 patients, including myocardial infarction (8%), unstable angina (9%), ventricular tachycardia (19%), and stroke (1%). Four (4%) deaths were reported. Cardiovascular events occurred in 15 (34%) and 17 (32%) patients in the placebo and metoprolol groups, respectively (unadjusted relative risk, 0.94; 95% confidence interval, 0.53-1.66; adjusted [for age, sex, statin use, and aortic cross-clamping] relative risk, 0.87; 95% confidence interval, 0.48-1.55). Time from operation to discharge was reduced from a median of 12 days (95% confidence interval, 9-19 days) in the placebo group to 10 days (95% confidence interval, 8-12 days) in the metoprolol group (adjusted hazard ratio, 1.71; 95% confidence interval, 1.09-2.66; P < .02). CONCLUSIONS: Myocardial ischemia was evident in a high proportion (one third) of the patients after surgery. A pragmatic regimen of perioperative beta-blockade with metoprolol did not seem to reduce 30-day cardiovascular events, but it did decrease the time from surgery to discharge.

Massive pulmonary artery thrombosis with haemoptysis in adults with Eisenmenger's syndrome: a clinical dilemma.

Although the frequency of haemoptysis in Eisenmenger's syndrome is well recognised, the high prevalence of pulmonary artery thrombus has been newly appreciated through the growing use of non-invasive imaging. Three patients with Eisenmenger's syndrome with haemoptysis are reported who underwent computed tomography pulmonary angiography and cardiovascular magnetic resonance. Each patient was found to have aneurysmal dilatation of the right pulmonary artery with large laminar thrombus. These cases illustrate a rising clinical problem in this special population-that is, how to treat and prevent large pulmonary artery thrombosis in the setting of haemoptysis. The authors discuss their approach to these cases and the known literature.

Clinical and haemodynamic effects of sildenafil in pulmonary hypertension: acute and mid-term effects.

AIM: The treatment of patients with pulmonary arterial hypertension remains a challenge. We set out to investigate the use of sildenafil, a selective inhibitor of phosphodiesterase type 5, in patients with this disease. METHODS AND RESULTS: Ten patients (8 females, mean age 34.5+/-3.3 years) with pulmonary hypertension underwent right heart catheterisation with vasodilator testing using incremental doses of intravenous sildenafil without adverse events. All patients were subsequently commenced on oral sildenafil 50 mg t.d.s. Nine patients had repeat right heart catheterisation 3 months after the commencement of oral therapy. There was a significant reduction in mean pulmonary artery pressure (from 55.8+/-5.9 to 50.4+/-6.1 mmHg, p=0.038 ) and pulmonary vascular resistance (from 10.1+/-1.7 to 8.6+/-1.5 Wood units, p=0.009 ), and an increase in cardiac output (from 4.7+/-0.3 to 5.0+/-0.4 l/min, p=0.15 ). Furthermore, there was a significant increase in the 6-minute walk test, a mean of 112 m. In response to a quality-of-life questionnaire, patients indicated marked clinical improvement on sildenafil. Sildenafil was discontinued in 1 patient due to a transient visual disturbance. The only patient previously awaiting transplantation was removed from the active transplantation list. CONCLUSIONS: Sildenafil is well tolerated in its intravenous and oral forms and appears to improve both pulmonary haemodynamics and the clinical status of patients with pulmonary hypertension after 3 months of oral therapy.

A systematic review of the use of opioids in the management of dyspnoea.

BACKGROUND: Opioids are commonly used to treat dyspnoea in palliative medicine but there has been no formal evaluation of the evidence for their effectiveness in the treatment of dyspnoea. A systematic review was therefore carried out to examine this. METHODS: The criteria for inclusion required that studies were double blind, randomised, placebo controlled trials of opioids for the treatment of dyspnoea secondary to any cause. The methods used to identify suitable studies included electronic searching of the literature, hand searching of the literature, and personal contact with relevant individuals and organisations. Random effects meta-analyses were performed on all included studies and on various subgroups (studies involving nebulised opioids or patients with chronic obstructive pulmonary disease (COPD)). Subgroups were compared using meta-regression. Some studies included in the systematic review could not be included in the meta-analysis because insufficient data were presented. RESULTS: Eighteen studies fulfilled the criteria for the review. The meta-analysis showed a statistically significant positive effect of opioids on the sensation of breathlessness (p=0.0008). Meta-regression indicated a greater effect for studies using oral or parenteral opioids than for studies using nebulised opioids (p=0.02). The subgroup analysis failed to show a positive effect of nebulised opioids on the sensation of breathlessness. The results of the subgroup analysis of the COPD studies were essentially similar to the results of the main analysis. CONCLUSION: This review supports the continued use of oral and parenteral opioids to treat dyspnoea in patients with advanced disease. There are insufficient data from the meta-analysis to conclude whether nebulised opioids are effective, but the results from included studies that did not contribute to the meta-analysis suggest that they are no better than nebulised normal saline.