Andrew J. Peacock

Imatinib mesylate as add-on therapy for pulmonary arterial hypertension: results of the randomized IMPRES study.

Background— By its inhibitory effect on platelet-derived growth factor signaling, imatinib could be efficacious in treating patients with pulmonary arterial hypertension (PAH). Methods and Results— Imatinib in Pulmonary Arterial Hypertension, a Randomized, Efficacy Study (IMPRES), a randomized, double-blind, placebo-controlled 24-week trial, evaluated imatinib in patients with pulmonary vascular resistance ≥800 dyne·s·cm−5 symptomatic on ≥2 PAH therapies. The primary outcome was change in 6-minute walk distance. Secondary outcomes included changes in hemodynamics, functional class, serum levels of N-terminal brain natriuretic peptide, and time to clinical worsening. After completion of the core study, patients could enter an open-label long-term extension study. Of 202 patients enrolled, 41% patients received 3 PAH therapies, with the remainder on 2 therapies. After 24 weeks, the mean placebo-corrected treatment effect on 6-minute walk distance was 32 m (95% confidence interval, 12–52; P=0.002), an effect maintained in the extension study in patients remaining on imatinib. Pulmonary vascular resistance decreased by 379 dyne·s·cm−5 (95% confidence interval, −502 to − 255; P<0.001, between-group difference). Functional class, time to clinical worsening, and mortality did not differ between treatments. Serious adverse events and discontinuations were more frequent with imatinib than placebo (44% versus 30% and 33% versus 18%, respectively). Subdural hematoma occurred in 8 patients (2 in the core study, 6 in the extension) receiving imatinib and anticoagulation. Conclusions— Imatinib improved exercise capacity and hemodynamics in patients with advanced PAH, but serious adverse events and study drug discontinuations were common. Further studies are needed to investigate the long-term safety and efficacy of imatinib in patients with PAH. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00902174 (core study); NCT01392495 (extension).Background— By its inhibitory effect on platelet-derived growth factor signaling, imatinib could be efficacious in treating patients with pulmonary arterial hypertension (PAH).nnMethods and Results— Imatinib in Pulmonary Arterial Hypertension, a Randomized, Efficacy Study (IMPRES), a randomized, double-blind, placebo-controlled 24-week trial, evaluated imatinib in patients with pulmonary vascular resistance ≥800 dyne·s·cm−5 symptomatic on ≥2 PAH therapies. The primary outcome was change in 6-minute walk distance. Secondary outcomes included changes in hemodynamics, functional class, serum levels of N-terminal brain natriuretic peptide, and time to clinical worsening. After completion of the core study, patients could enter an open-label long-term extension study. Of 202 patients enrolled, 41% patients received 3 PAH therapies, with the remainder on 2 therapies. After 24 weeks, the mean placebo-corrected treatment effect on 6-minute walk distance was 32 m (95% confidence interval, 12–52; P =0.002), an effect maintained in the extension study in patients remaining on imatinib. Pulmonary vascular resistance decreased by 379 dyne·s·cm−5 (95% confidence interval, −502 to − 255; P <0.001, between-group difference). Functional class, time to clinical worsening, and mortality did not differ between treatments. Serious adverse events and discontinuations were more frequent with imatinib than placebo (44% versus 30% and 33% versus 18%, respectively). Subdural hematoma occurred in 8 patients (2 in the core study, 6 in the extension) receiving imatinib and anticoagulation.nnConclusions— Imatinib improved exercise capacity and hemodynamics in patients with advanced PAH, but serious adverse events and study drug discontinuations were common. Further studies are needed to investigate the long-term safety and efficacy of imatinib in patients with PAH.nnClinical Trial Registration— URL: . Unique identifier: [NCT00902174][1] (core study); [NCT01392495][2] (extension).nn# Clinical Perspective {#article-title-39}nn [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00902174&atom=%2Fcirculationaha%2F127%2F10%2F1128.atomn [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01392495&atom=%2Fcirculationaha%2F127%2F10%2F1128.atom

End points and clinical trial design in pulmonary arterial hypertension.

New and emerging therapies might provide benefit in patients with pulmonary arterial hypertension. Their efficacy and safety will be compared with existing combination therapies in randomized clinical trials. Appropriate end points for these trials need to be identified: these will include exercise testing, the composite end point of time to clinical worsening, and hemodynamic markers, including advanced imaging modalities and biomarkers. Quality-of-life questionnaires are useful and important secondary end points; pulmonary arterial hypertension-specific questionnaires are currently being developed. Advantages and disadvantages of various trial designs, including placebo-controlled monotherapy or add-on trials, noninferiority studies, and withdrawal trials are also discussed.

Predicting survival in pulmonary arterial hypertension in the UK

Contemporary prognostic equations in pulmonary arterial hypertension (PAH) derived from US and French cohorts may not perform as well in the UK as a locally derived scoring scheme. The aim of the study was to develop and validate a UK risk score to predict prognosis in PAH. Baseline mortality predictors identified by multivariate Cox analysis in 182 incident PAH patients were used to derive the Scottish composite score (SCS). Its prognostic performance in an independent UK cohort was compared with the French registry and Pulmonary Hypertension Connection (PHC) registry equations using Brier scores (BS). The SCS based on age, sex, aetiology, right atrial pressure, cardiac output and 6-min walk distance predicted survival in the validation cohort (hazard ratio (HR) 1.7 per point increase; p<0.001) and provided further prognostic stratification in World Health Organization (WHO) functional class III patients (HR 1.8 per point increase; p<0.001). It was more accurate than the French registry equation in predicting 1-yr survival (BS: 0.092 versus 0.146; p=0.001) and 2-yr survival (0.131 versus 0.255; p<0.001). There was no significant difference in BS between the SCS and PHC registry equation. The SCS predicts survival and can be used to supplement WHO functional class in prognostication.

Changes in Right Ventricular Function Measured by Cardiac Magnetic Resonance Imaging in Patients Receiving Pulmonary Arterial Hypertension–Targeted Therapy The EURO-MR Study

Background—Most measures that predict survival in pulmonary hypertension (PH) relate directly to, or correlate with, right ventricular (RV) function. Direct assessment of RV function using noninvasive techniques such as cardiac MRI may therefore be an appropriate way of determining response to therapy and monitoring disease progression in PH. Methods and Results—In this pan-European study, 91 patients with PH (mean pulmonary arterial pressure 46±15 mm Hg) underwent clinical and cardiac MRI assessments at baseline and after 12 months of disease-targeted therapy (predominantly endothelin receptor antagonists [47.3%] or phosphodiesterase type-5 inhibitors [25.3%]). At month 12, functional class had improved in 21 patients, was unchanged in 63 patients, and had deteriorated in 7 patients. Significant improvements were achieved in RV and left ventricular ejection fraction (P<0.001 and P=0.0007, respectively), RV stroke volume index (P<0.0001), and left ventricular end-diastolic volume index (P=0.0015). Increases in 6-minute walk distance were significant (P<0.0001) and correlated with change in RV ejection fraction and left ventricular end-diastolic volume, although correlation coefficients were low (r=0.28, P=0.01 and r=0.26, P=0.02, respectively). Conclusions—On-treatment changes in cardiac MRI–derived variables from left and right sides of the heart reflected changes in functional class and survival in patients with PH. Direct measurement of RV function using cardiac MRI can fully assess potential benefits of treatment in PH.

End-points and clinical trial design in pulmonary arterial hypertension: have we made progress?

There is enormous interest in the treatment of pulmonary arterial hypertension (PAH), so it is appropriate to consider the design of trials of new therapies and the end-points to be measured when trying to decide whether or not a therapy is effective. In May 2003, the first meeting devoted solely to the discussion of end-points and trial design in PAH was held in Gleneagles, UK. At that time, most of the randomised controlled trials in PAH had used 6-min walking distance and/or resting haemodynamics as their primary end-points. The present article considers the progress that has been made since 2003. It deals with aspects of clinical trial design (such as noninferiority, superiority and withdrawal trials), considers end-points used in previous and current studies (such as 6-min walking distance, time to clinical worsening, haemodynamics, imaging and plasma brain natriuretic peptide), and considers what end-points might be used in the future. The second end-points meeting was held in Turnberry, UK, in June 2007. It had a similar format to the first meeting. Much of what is presented here is a summary of the workshops from that meeting. An attempt has been made to both summarise the current state of end-points and trial design and suggest new ways in which they could be improved. The present article forms one of a series being published in the European Respiratory Journal on pulmonary hypertension.

NT-proBNP does not rise on acute ascent to high altitude.

The response of brain natriuretic peptide (BNP) to acute ascent to altitude is of interest as a surrogate for ventricular function and because BNP is involved in the normal homeostasis of the pulmonary vasculature. The structurally related hormone atrial natriuretic pressure (ANP) has been demonstrated to be elevated at altitude and implicated in natriuresis. We measured plasma concentrations of ANP and NT-proBNP (a more stable BNP precursor) in 10 healthy non-HAPE-susceptible lowlanders during acute exposure to 5200 m on the Apex 2 expedition to Bolivia. Systolic pulmonary artery pressure (PASP) was measured using tricuspid regurgitant jet estimation by echocardiography. Despite a significant rise in the PASP, NT-proBNP did not rise. A small decrease in NT-pro BNP occurred after 7 days at high altitude. There was no significant change in ANP levels. The lack of any increase in NT-proBNP in healthy resting subjects supports the view that ventricular function is well preserved and suggests that BNP is not playing a significant role in altered pulmonary artery pressure.

Plasma Metabolomics Implicates Modified Transfer RNAs and Altered Bioenergetics in the Outcomes of Pulmonary Arterial Hypertension.

Background: Pulmonary arterial hypertension (PAH) is a heterogeneous disorder with high mortality. Methods: We conducted a comprehensive study of plasma metabolites using ultraperformance liquid chromatography mass spectrometry to identify patients at high risk of early death, to identify patients who respond well to treatment, and to provide novel molecular insights into disease pathogenesis. Results: Fifty-three circulating metabolites distinguished well-phenotyped patients with idiopathic or heritable PAH (n=365) from healthy control subjects (n=121) after correction for multiple testing (P<7.3e-5) and confounding factors, including drug therapy, and renal and hepatic impairment. A subset of 20 of 53 metabolites also discriminated patients with PAH from disease control subjects (symptomatic patients without pulmonary hypertension, n=139). Sixty-two metabolites were prognostic in PAH, with 36 of 62 independent of established prognostic markers. Increased levels of tRNA-specific modified nucleosides (N2,N2-dimethylguanosine, N1-methylinosine), tricarboxylic acid cycle intermediates (malate, fumarate), glutamate, fatty acid acylcarnitines, tryptophan, and polyamine metabolites and decreased levels of steroids, sphingomyelins, and phosphatidylcholines distinguished patients from control subjects. The largest differences correlated with increased risk of death, and correction of several metabolites over time was associated with a better outcome. Patients who responded to calcium channel blocker therapy had metabolic profiles similar to those of healthy control subjects. Conclusions: Metabolic profiles in PAH are strongly related to survival and should be considered part of the deep phenotypic characterization of this disease. Our results support the investigation of targeted therapeutic strategies that seek to address the alterations in translational regulation and energy metabolism that characterize these patients.

Imaging right ventricular function to predict outcome in pulmonary arterial hypertension

BACKGROUNDnRight ventricular (RV) function is a major determinant of outcome in pulmonary arterial hypertension (PAH). However, uncertainty persists about the optimal method of evaluation.nnnMETHODSnWe measured RV end-systolic and end-diastolic volumes (ESV and EDV) using cardiac magnetic resonance imaging and RV pressures during right heart catheterization in 140 incident PAH patients and 22 controls. A maximum RV pressure (Pmax) was calculated from the nonlinear extrapolations of early and late systolic portions of the RV pressure curve. The gold standard measure of RV function adaptation to afterload, or RV-arterial coupling (Ees/Ea) was estimated by the stroke volume (SV)/ESV ratio (volume method) or as Pmax/mean pulmonary artery pressure (mPAP) minus 1 (pressure method) (n=84). RV function was also assessed by ejection fraction (EF), right atrial pressure (RAP) and SV.nnnRESULTSnHigher Ea and RAP, and lower compliance, SV and EF predicted outcome at univariate analysis. Ees/Ea estimated by the pressure method did not predict outcome but Ees/Ea estimated by the volume method (SV/ESV) did. At multivariate analysis, only SV/ESV and EF were independent predictors of outcome. Survival was poorer in patients with a fall in EF or SV/ESV during follow-up (n=44, p=0.008).nnnCONCLUSIONnRV function to predict outcome in PAH is best evaluated by imaging derived SV/ESV or EF. In this study, there was no added value of invasive measurements or simplified pressure-derived estimates of RV-arterial coupling.

Severe pulmonary hypertension in lung disease: phenotypes and response to treatment

Pulmonary hypertension (PH) due to lung disease (World Health Organization (WHO) group 3) is common, but severe PH, arbitrarily defined as mean pulmonary artery pressure ≥35u2005mmHg is reported in only a small proportion. Whether these should be treated as patients in WHO group 1 (i.e. pulmonary arterial hypertension) with PH-targeted therapies is unknown. We compared the phenotypic characteristics and outcomes of 118 incident patients with severe PH and lung disease with 74 idiopathic pulmonary arterial hypertension (IPAH) patients, all treated with pulmonary vasodilators. Lung disease patients were older, more hypoxaemic, and had lower gas transfer, worse New York Heart Association functional class and lower 6-min walking distance (6MWD) than IPAH patients. Poorer survival in those with lung disease was driven by the interstitial lung disease (ILD) cohort. In contrast to IPAH, where significant improvements in 6MWD and N-terminal pro-brain natruiretic peptide (NT-proBNP) occurred, PH therapy in severe PH lung disease did not lead to improvement in 6MWD or functional class, but neither was deterioration seen. NT-proBNP decreased from 2200 to 1596u2005pg·mL−1 (p=0.015). Response varied by lung disease phenotype, with poorer outcomes in patients with ILD and emphysema with preserved forced expiratory volume in 1u2005s. Further study is required to investigate whether vasodilator therapy may delay disease progression in severe PH with lung disease. Treatment of severe pulmonary hypertension associated with lung disease can improve or stabilise noninvasive outcomes http://ow.ly/Ormp1

Non‐invasive stroke volume measurement by cardiac magnetic resonance imaging and inert gas rebreathing in pulmonary hypertension

Objective:u2002 Right ventricular function determines the prognosis of pulmonary hypertension (PAH). Measurement of stroke volume (SV) non‐invasively could be a promising method to monitor disease progression. Cardiac magnetic resonance (CMR) imaging is recognized as an accurate and reproducible method to measure SV. Inert gas rebreathing (IGR) using acetylene is a validated but cumbersome method for pulmonary blood flow (PBF) measurement in PAH. A more convenient rebreathing technique using rapid photoacoustic analysis of nitrous oxide has been introduced and validated in left heart failure. We investigated the accuracy of CMR imaging and IGR using photoacoustic analysis to measure SV in patients under investigation for PAH.