Effect of imatinib as add-on therapy on echocardiographic measures of right ventricular function in patients with significant pulmonary arterial hypertension.

AIMS: Imatinib mesylate, as add-on therapy in patients with pulmonary arterial hypertension (PAH) who remain inadequately treated despite receiving at least two PAH-specific drugs, improves exercise capacity and haemodynamics. We evaluated whether 24 weeks of add-on therapy with imatinib compared with placebo also improves right ventricular (RV) function assessed by echocardiography. METHODS AND RESULTS: Echocardiograms were obtained at baseline, 12 weeks, and 24 weeks in 74 patients randomized to imatinib or placebo in the Imatinib in Pulmonary arterial hypertension, a Randomized Efficacy Study (IMPRES) trial. Right ventricular function was assessed by tissue Doppler tricuspid annular peak systolic velocity (TA S'), tricuspid annular plane systolic excursion (TAPSE), RV Tei index, and RV fractional area change. Between-treatment-group differences in the changes from baseline to week-24 were assessed using an ANCOVA with the last observation carried forward. At week-24 patients randomized to imatinib demonstrated greater improvements in TA S' (1.6 ± 2.3 imatinib vs. 0.5 ± 2.4 cm/s placebo, P = 0.007) and RV Tei index (-0.11 ± 0.18 imatinib vs. 0.05 ± 0.18 placebo, P = 0.005) compared with placebo, but not in TAPSE (0.07 ± 0.44 imatinib vs. 0.03 ± 0.32 cm placebo, P = 0.08). Imatinib therapy was also associated with significant reduction in peak tricuspid regurgitation velocity, increase in LV size, and improvement in LV early diastolic relaxation velocity. CONCLUSIONS: Among patients with advanced PAH who remain symptomatic on at least two PAH-specific drugs, treatment with imatinib compared with placebo is associated with significant improvements in echocardiographic measures of RV function, in addition to LV size and LV early diastolic relaxation. CLINICAL TRIAL REGISTRATION: NCT00902174 (Clinicaltrials.gov).

Pharmacokinetic interactions among imatinib, bosentan and sildenafil, and their clinical implications in severe pulmonary arterial hypertension.

AIMS: This study characterized the population pharmacokinetics (PK) of imatinib in patients with severe pulmonary arterial hypertension (PAH), investigated drug-drug interactions (DDI) among imatinib, sildenafil and bosentan, and evaluated their clinical implications. METHODS: Plasma concentrations of imatinib, bosentan and sildenafil were collected in a phase III study and were used to characterize the PK of imatinib in this population. DDIs among the three drugs were quantified using a linear mixed model and log-transformed drug concentrations. RESULTS: The population mean estimates of apparent clearance (CL/F) and volume (V/F) were 10.8 l h(-1) (95% CI 9.2, 12.4 l h(-1) ) and 267 l (95% CI 208, 326 l), respectively. It was estimated that sildenafil concentrations increased, on average, by 64% (95% CI 32%, 103%) and bosentan concentrations by 51% (95% CI 12%, 104%), in the presence of imatinib. Despite increased concentrations of co-medications, treatment differences between imatinib and placebo for change in 6 min walk distance and pulmonary vascular resistance were relatively constant across the entire concentration range for sildenafil and bosentan. Overall, higher concentrations of imatinib and bosentan were not associated with increasing liver enzymes (serum glutamic oxaloacetic transaminases [SGOT]/serum glutamic-pyruvic transaminase [SGPT]). CONCLUSIONS: Population PKs of imatinib in patients with severe PAH were found comparable with those of patients with chronic myeloid leukemia. Imatinib was found effective regardless of the co-medications and showed intrinsic efficacy beyond merely elevating the concentrations of the co-medications due to DDIs. There was no evidence of increased risk of liver toxicity upon co-administration with bosentan.

Two prospective, multicenter studies for the identification of biomarker signatures for early detection of pulmonary hypertension (PH): The CIPHER and CIPHER-MRI studies.

A blood test identifying patients at increased risk of pulmonary hypertension (PH) could streamline the investigative pathway. The prospective, multicenter CIPHER study aimed to develop a microRNA-based signature for detecting PH in breathless patients and enrolled adults with a high suspicion of PH who had undergone right heart catheterization (RHC). The CIPHER-MRI study was added to assess the performance of this CIPHER signature in a population with low probability of having PH who underwent cardiac magnetic resonance imaging (cMRI) instead of RHC. The microRNA signature was developed using a penalized linear regression (LASSO) model. Data were modeled both with and without N-terminal pro-brain natriuretic peptide (NT-proBNP). Signature performance was assessed against predefined thresholds (lower 98.7% CI bound of ≥0.73 for sensitivity and ≥0.53 for specificity, based on a meta-analysis of echocardiographic data), using RHC as the true diagnosis. Overall, 926 CIPHER participants were screened and 888 were included in the analysis. Of 688 RHC-confirmed PH cases, approximately 40% were already receiving PH treatment. Fifty microRNA (from 311 investigated) were algorithmically selected to be included in the signature. Sensitivity [97.5% CI] of the signature was 0.85 [0.80-0.89] for microRNA-alone and 0.90 [0.86-0.93] for microRNA+NT-proBNP, and the corresponding specificities were 0.33 [0.24-0.44] and 0.28 [0.20-0.39]. Of 80 CIPHER-MRI participants with evaluable data, 7 were considered PH-positive by cMRI whereas 52 were considered PH-positive by the microRNA signature. Due to low specificity, the CIPHER miRNA-based signature for PH (either with or without NT-proBNP in model) did not meet the prespecified diagnostic threshold for the primary analysis.

Impact of Proactive Case Management by Multiple Sclerosis Specialist Nurses on Use of Unscheduled Care and Emergency Presentation in Multiple Sclerosis: A Case Study.

BACKGROUND: Multiple sclerosis (MS) affects approximately 100,000 people in the United Kingdom, with rising emergency admissions to the hospital. The multiple sclerosis specialist nurse plays a pivotal role in managing MS care in the United Kingdom, and there is anecdotal evidence that this role can help avoid emergency presentations and unnecessary hospital admissions. METHODS: A retrospective service evaluation took place in one established MS nursing service. The impact of the introduction of proactive nurse-led management and a rapid response service on rates of emergency presentation, hospital admission, and bed use was examined. The primary intervention was the introduction of extra nursing hours (6 hours per week) and the reallocation of some routine administrative duties, which allowed the service to move to a proactive management model aimed at avoiding the need for unplanned care. In addition, a care pathway was implemented in the emergency department for patients with MS who did present. RESULTS: Reduction in utilization was from a mean of 2700 bed-days per year (2002-2006) to a mean of 198 bed-days per year (2007-2013). CONCLUSIONS: During a 10-year period, moving from reactive management to proactive management demonstrated an increase in complex specialist nursing interventions and led to a decrease in emergency presentation and bed use at the local acute-care center.

Impact of lowering pulmonary vascular resistance on right and left ventricular deformation in pulmonary arterial hypertension.

AIMS: As pulmonary arterial hypertension (PAH) is associated with significant morbidity and mortality, particularly among patients with right ventricular (RV) dysfunction, we aimed to determine the impact of therapy to reduce pulmonary vascular resistance (PVR) on RV and LV deformation in PAH. METHODS AND RESULTS: Right ventricular free wall longitudinal strain (FWLS) and LV global circumferential strain (CS) were measured at baseline, 12 weeks, and 24 weeks in 68 patients with advanced PAH randomized to imatinib or placebo in the Imatinib in Pulmonary arterial hypertension, a Randomized Efficacy Study (IMPRES) trial, and compared with 30 healthy controls. Compared with controls, PAH was associated with impaired RV FWLS (-15.9 ± 5.4 vs. -30.8 ± 4.3, respectively; P < 0.0001) and LV septal CS (-24.2 ± 8.2 vs. -31.4 ± 5.3, respectively, P < 0.0001), but not LV global CS. Improvement in PVR and mean pulmonary artery pressure (MPAP) over a 24-week period was significantly associated with improvement in RV FWLS (r = 0.39, P = 0.02; 0.33, P = 0.04 respectively), LV global CS (r = 0.61, P = 0.0001; r = 0.60, P = 0.0001, respectively), and LV septal CS (r = 0.50, P = 0.005; r = 0.56, P = 0.002, respectively). These associations were most robust with LV global and septal CS. Imatinib therapy was associated with improvement in RV FWLS compared with placebo. CONCLUSIONS: PAH is associated with impaired biventricular deformation. Reduction in PVR is associated with improvements in both RV and LV deformation, coupled to improvements in MPAP and stroke volume index, with LV global and septal CS the strongest correlates of these changes. RV FWLS is sensitive to treatment effect, demonstrating greater improvement with imatinib compared with placebo. TRIAL REGISTRATION: NCT00902174.

Developing a community multiple sclerosis nursing service.

Reforms to the NHS following the passing of the Health and Social Care Act 2012 have created new purchaser organisations with responsibility for planning the configuration of healthcare services in their geographic areas. If a community multiple sclerosis (MS) nursing service is to survive in this environment, it must demonstrate its ability to contribute to achieving the purchaser organisations' objectives. Evaluation data, such as hospital admission avoidance and patient satisfaction, will be crucial in demonstrating the community MS nursing service's clinical and economic effectiveness. A strengths, weaknesses, opportunities and threats (SWOT) analysis of the issues facing a community MS service in this environment is provided.