Screening and management of cardiovascular disease in Australian adults with HIV infection.

BACKGROUND: Cardiovascular disease (CVD) is common in HIV infection. With no specific Australian guidelines for the screening and management of CVD in HIV-infected patients, best clinical practice is based on data from the general population. We evaluated adherence to these recommendations by primary care physicians who treat HIV-infected patients. METHODS: Primary care physicians with a special interest in HIV infection were asked to complete details for at least 10 consecutive patient encounters using structured online forms. This included management practices pertaining to blood pressure (BP), blood glucose, electrocardiogram, lipid profile and CVD risk calculations. We assessed overall adherence to screening and follow-up recommendations as suggested by national and international guidelines. RESULTS: Between May 2009 and March 2010, 43 physicians from 25 centres completed reporting for 530 HIV-infected patients, of whom 93% were male, 25% were aged 41-50 years and 83% were treated with antiretrovirals. Risk factors for CVD were common and included smoking (38%), hyperlipidaemia (16%) and hypertension (28%). In men aged >40 years and women aged >50 years without evidence of ischaemic heart disease, only 14% received a CVD risk assessment. Lipid and BP assessments were performed in 87% and 88% of patients, respectively. CONCLUSIONS: This Australian audit provides unique information on the characteristics and management of HIV and CVD in clinical practice. We have found a high burden of risk for CVD in HIV-infected Australians, but current screening and management practices in these patients fall short of contemporary guidelines.

Reducing clinical trial monitoring resource allocation and costs through remote access to electronic medical records.

PURPOSE: With electronic medical records (eMRs), the option now exists for clinical trial monitors to perform source data verification (SDV) remotely. We report on a feasibility study of remote access to eMRs for SDV and the potential advantages of such a process in terms of resource allocation and cost. METHODS: The Clinical Trials Unit at the Peter MacCallum Cancer Centre, in collaboration with Novartis Pharmaceuticals Australia, conducted a 6-month feasibility study of remote SDV. A Novartis monitor was granted dedicated software and restricted remote access to the eMR portal of the cancer center, thereby providing an avenue through which perform SDV. RESULTS: Six monitoring visits were conducted during the study period, four of which were performed remotely. The ability to conduct two thirds of the monitoring visits remotely in this complex phase III study resulted in an overall cost saving to Novartis. Similarly, remote monitoring eased the strain on internal resources, particularly monitoring space and hospital computer terminal access, at the cancer center. CONCLUSION: Remote access to patient eMRs for SDV is feasible and is potentially an avenue through which resources can be more efficiently used. Although this feasibility study involved limited numbers, there is no limit to scaling these processes to any number of patients enrolled onto large clinical trials.

Vascular function and mortality in haemodialysis patients: a pilot study.

BACKGROUND: Haemodialysis patients often have impaired vascular function that can contribute to mortality. Endothelial-dependent and -independent vascular function can be assessed using the brachial artery reactivity (BAR) technique that measures flow-mediated dilatation (FMD) and the response to glyceryl trinitrate (GTN), respectively. AIMS: The aim of this pilot study was to determine whether BAR measurements in haemodialysis patients were associated with mortality. METHODS: Brachial artery responses to FMD and administration of GTN were assessed in consecutive haemodialysis patients. Patients were then followed up to 18 months after BAR measurements. RESULTS: Seventeen patients were included in the study. After 18 months of follow-up, patients were divided into two groups: survived (n=12) and deceased (n=5). Patients who survived had a significantly greater median percentage vasodilatation to GTN than those who died (19.1% vs 8.8%; P=0.04); and a significantly greater median area under the diameter change-time curve (318 vs 146 mm/s; P=0.03). However, there were no significant differences between survivors and deceased in median percentage vasodilation to FMD (6.0% vs 4.3%; P=0.21), time to peak dilation (45 vs 40s; P=0.66) or area under the diameter change-time curve (35.5 vs 20 mm/s; P=0.29). CONCLUSION: In this pilot study in a small group of haemodialysis patients, endothelial-independent vasodilatory response to GTN was associated with mortality and was of better prognostic value than the endothelial-dependent response to FMD. This finding needs to be investigated in a larger cohort.

Pharmacoeconomic evidence of bosentan for pulmonary arterial hypertension.

In this article, we review randomized controlled trials, open-label trials and pharmacoeconomic models of bosentan for the management of patients with pulmonary arterial hypertension. Bosentan consistently improves WHO functional class and quality of life, slows clinical worsening and is associated with improved survival compared with historical treatment. Although head-to-head trials are scarce, data directly comparing bosentan with sildenafil indicate no clinically significant differences between treatments as measured by the 6-min walk distance alone. Compared with historical care, bosentan treatment, over a 15-30-year period, increases the number of quality-adjusted life years (3.49 years). Economic modeling suggests that the cost-effectiveness of bosentan is similar to that of ambrisentan (US$43,725-57,778 per quality-adjusted life year), not as cost effective as sildenafil (at 20 mg three-times daily) and more cost effective than iloprost. More randomized controlled trials of longer duration are required to confirm the results from these economic models.

Hemodynamics in pulmonary arterial hypertension (PAH): do they explain long-term clinical outcomes with PAH-specific therapy?

BACKGROUND: Pulmonary arterial hypertension (PAH) has witnessed dramatic treatment advances over the past decade. However, with the exception of epoprostenol, data from short-term randomized controlled trials (RCTs) have not shown a benefit of these drugs on survival. There remains a need to differentiate between available therapies and current endpoint responses which in turn, could be used to guide treatment selection and provide long-term prognostic information for patients. METHODS: We performed a systematic literature search of MEDLINE and EMBASE databases for RCTs of PAH-specific therapy published between January 1980 and May 2009. Articles were selected if they contained a placebo comparator and described hemodynamic changes from baseline. We applied the weighted mean change in hemodynamic variables to the equation developed by the National Institutes of Health (NIH) Registry to estimate long-term survival with each therapy. RESULTS: Ten RCTs involving 1,635 patients met the inclusion criteria. Suitable hemodynamic data were identified for bosentan, sitaxentan, sildenafil, epoprostenol, beraprost and treprostinil. 77.6% of patients were female and the mean (SD) age was 46.5 +/- 4.9 years. 55.5% of patients had idiopathic PAH (iPAH), 23.9% PAH related to connective tissue disease, and 18.2% PAH related to congenital heart disease. Based on the effects observed in short-term trials and, relative to placebo, all analyzed therapies improved survival. The estimated 1-year survival was 78.4%, 77.8%, 76.1%, 75.8%, 75.2%, and 74.1% for epoprostenol, bosentan, treprostinil, sitaxentan, sildenafil, and beraprost, respectively. These estimates are considerably lower than the 1-year observed survival reported in several open-label and registry studies with PAH-specific therapies: 88% - 97%. CONCLUSION: When applied to the NIH Registry equation, hemodynamic changes from baseline appear to underestimate the survival benefits observed with long-term PAH therapy.

Efficacy, safety and tolerability of bosentan in Chinese patients with pulmonary arterial hypertension.

BACKGROUND: Bosentan has an established role in the management of pulmonary arterial hypertension (PAH). This clinical trial assessed the benefits of bosentan in the Chinese population. METHODS: We investigated the efficacy and safety of bosentan in 92 Chinese citizens (mean +/- standard deviation age, 29.0 +/- 3.8 years) with PAH for a minimum of 12 weeks. All received bosentan (62.5 mg twice daily) for 4 weeks; then, patients who weighed <40 kg received 62.5 mg bosentan twice daily and patients who weighed >40 kg received 125 mg twice daily. All patients were eligible to continue bosentan beyond 12 weeks. The primary end point was a change in exercise capacity from baseline to 12 and 24 weeks. Secondary end points included a change in World Health Organization (WHO) functional class and changes in cardiopulmonary hemodynamics. RESULTS: At baseline, 66 patients (72%) were in WHO functional class III; presentation was 37 (40%) with idiopathic PAH (iPAH), 34 (37%) with PAH related to congenital heart disease (CHD), and 21 (23%) with PAH related to connective tissue disease (CTD). Exercise capacity increased to 67.8 m after 12 weeks and 92.6 m after 24 weeks (p < 0.001). After 24 weeks, WHO functional class decreased (-0.8 +/- 0.6; p < 0.001), mean pulmonary artery pressure and pulmonary vascular resistance decreased (p < 0.01), and cardiac output increased (p < 0.001). Twelve patients (13%) experienced at least 1 adverse event. CONCLUSIONS: Bosentan improved exercise capacity, functional class, and cardiopulmonary hemodynamics in this patient cohort and was well tolerated.

Integrated care and optimal management of pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) may occur as an idiopathic process or as a component of a variety of diseases, including connective tissue diseases, congenital heart disease, and exposure to appetite suppressants or infectious agents such as HIV. Untreated, it is a potentially devastating disease; however, diagnosis can be difficult due to the non-specific nature of symptoms during the early stages, and the fact that patients often present to a range of different medical specialties. The past decade has seen remarkable improvements in our understanding of the pathology associated with the condition and the development of PAH-specific therapies with the ability to alter the natural history of the disease. This article reviews the evidence for screening and diagnosis of susceptible patient groups and discusses treatment selection and recommendations based on data available from randomized controlled trials. In addition, due to the complexity of the diagnostic evaluation required and the treatment options available, this review mandates for a multidisciplinary approach to the management of PAH. We discuss the roles and organizational structure of a specialized PAH center in Perth, Western Australia to highlight these issues.

No relationship between low-density lipoproteins and endothelial function in hemodialysis patients.

BACKGROUND: Relationships between low-density lipoprotein cholesterol and endothelial function in hemodialysis patients have yet to be investigated. Furthermore, current reporting of endothelial function data using flow-mediated dilatation has recognised limitations. The aims of the study were to determine the relationship between low-density lipoproteins and endothelial function in hemodialysis patients and to investigate the validity of determining the area under the curve for data collected during the flow-mediated dilatation technique. METHODS: Brachial artery responses to reactive hyperemia (endothelial-dependent) and glyceryl trinitrate (endothelial-independent) were assessed in 19 hemodialysis patients using high-resolution ultrasound. Lipid profiles and other factors known to effect brachial artery reactivity were also measured prior to the flow-mediated dilatation technique. RESULTS: There were no significant relationships between serum low-density lipoproteins and endothelial-dependent or -independent vasodilation using absolute change (mm), relative change (%), time to peak change (s) or area under the curve (mm x s). In hemodialysis patients with atherosclerosis, area under the curve analysis showed a significantly (p<0.05) decreased endothelial-dependent response (mean+/-S.D.: 19.2+/-17.4) compared to non-atherosclerotic patients (42.3+/-28.6). However, when analysing these data using absolute change, relative change or time to peak dilatation, there were no significant differences between the two groups. CONCLUSIONS: In summary, there was no relationship between low-density lipoproteins and endothelial function in hemodialysis patients. In addition, area under the curve analysis of flow-mediated vasodilatation data may be a useful method of determining the temporal vascular response during the procedure.