Trials In Pulmonary Arterial Hypertension Research Articles

Sample Size and Cost Analysis for Pulmonary Arterial Hypertension Drug Trials Using Various Imaging Modalities to Assess Right Ventricular Size and Function End Points

Placebo-controlled trials for pulmonary arterial hypertension are no longer acceptable because new therapies must show clinically significant effects on top of standard treatment. The purpose of this study was to estimate sample sizes and imaging costs for the planning of a hypothetical pulmonary arterial hypertension drug trial using imaging to detect changes in right ventricular size and function in response to combined therapy. Same-day cardiovascular MR (CMR) and 2-dimensional (2D) and 3D transthoracic echocardiography (2DTTE and 3DTTE) were performed in 22 patients with pulmonary arterial hypertension (54±13 years of age) twice, 6 months apart. Short-axis CMR cines and full-volume 3DTTE data sets of the right ventricle were used to measure end-diastolic volume and ejection fraction. Fractional area change was obtained from 2DTTE. Sample size calculations used a 2-sample t test model incorporating differences between baseline and 6-month measurements. Cost estimates were made using the Medicare fee schedule. No significant differences were noted between baseline and follow-up measurements. Large SDs reflected variable progression of disease in individual patients on standard therapy and measurement variability. These sources of variability resulted in intertechnique differences in sample sizes: to detect a change of 5% to 15% in 3DTTE-derived right ventricular ejection fraction and fractional area change or change of 15 to 30 mL in 3DTTE right ventricular end-diastolic volume; sample sizes were 2× to 2.5× those required by CMR. As a result, the total cost of a trial using complete TTE was greater than CMR, which was greater than limited TTE. Because of lower measurement variability, CMR is more cost saving in pulmonary arterial hypertension drug trials than echocardiography, unless limited TTE is used.

Evaluation of the Predictive Value of a Clinical Worsening Definition Using 2-Year Outcomes in Patients With Pulmonary Arterial Hypertension: A REVEAL Registry Analysis

Time to clinical worsening has been proposed as a primary end point in clinical trials of pulmonary arterial hypertension (PAH); however, neither standardized nor validated definitions of clinical worsening across PAH trials exist. This study aims to evaluate a proposed definition of clinical worsening within a large prospective, observational registry of patients with PAH with respect to its value as a predictor of proximate (within 1 year) risk for subsequent major events (ie, death, transplantation, or atrial septostomy).We assessed overall 2-year survival and survival free from major events to determine the relationship between clinical worsening and major events among adults with hemodynamically defined PAH (N = 3,001). Freedom from clinical worsening was defined as freedom from worsening functional class (FC), a ≥ 15% reduction in 6-min walk distance (6MWD), all-cause hospitalization, or the introduction of parenteral prostacyclin analog therapy.In the 2 years of follow-up, 583 patients died. Four hundred twenty-six died after a documented clinical worsening event, including FC worsening (n = 128), a ≥ 15% reduction in 6MWD (n = 118), all-cause hospitalization (n = 370), or introduction of a prostacyclin analog (n = 91). Patients who experienced clinical worsening had significantly poorer subsequent 1-year survival postworsening than patients who did not worsen (P < .001).Clinical worsening was highly predictive of subsequent proximate mortality in this analysis from an observational study. These results validate the use of clinical worsening as a meaningful prognostic tool in clinical practice and as a primary end point in clinical trial design.ClinicalTrials.gov; No.: NCT00370214; URL: www.clinicaltrials.gov.

From short-term benefits to long-term outcomes: the evolution of clinical trials in pulmonary arterial hypertension.

Abstract Over the past 2 decades, major advances in our understanding of pulmonary arterial hypertension (PAH) have led to the development of new targeted therapeutics and management strategies that have provided benefits to patients with this devastating disease. Despite such improvements, no therapies are curative, and PAH remains a progressive disease associated with high morbidity and suboptimal survival in many patients. Clinical research in PAH is currently at a crossroads. To move forward, not only are new therapies needed, but novel approaches to clinical trial design are also required. Trials should be designed to assess the longer-term benefits of investigational therapies in what has become a chronic disease. Moreover, there is a need to consider moving away from short-term trials that use markers such as the 6-minute walk distance as a measure of exercise capacity as primary end points to longer-term, event-driven trials with composite end points made up of clinically relevant measures that better reflect the ultimate goals of reducing morbidity and mortality. A shift in trial design may also be useful in overcoming some of the muted results from recent pivotal phase III studies of combination therapy by allowing the potential of these regimens to be more comprehensively assessed.

Sustained effect of macitentan, a novel oral endothelin receptor antagonist, on exercise capacity and the association of its measure with long-term outcomes in pulmonary arterial hypertension

Purpose: In SERAPHIN ([NCT00660179][1]), a Phase III trial in pulmonary arterial hypertension (PAH), macitentan reduced the risk of morbidity and mortality (primary outcome) and risk of PAH-related death or hospitalisation (PAHDH; secondary outcome). The effect of macitentan on 6-minute walk distance (6MWD) and the association between 6MWD and PAHDH were explored. Methods: 742 PAH patients were randomised to placebo, 3 or 10mg macitentan, once daily. Treatment-by-visit interaction and placebo-corrected treatment effects were calculated using repeated measures analysis on 6MWD change from baseline at Months 3, 6, 12 in the all-randomised set. Hazard ratios were calculated to measure the association between interquartile ranges of baseline 6MWD, 6MWD changes, or values at Month 6 (± adjustment for significant covariates) and PAHDH. This was performed independently of treatment in patients with available data for 6MWD at Month 6 and from Month 6 up to end of treatment for PAHDH Results: Baseline mean±SD 6MWD for placebo (n=249), 3mg (n=248) and 10mg macitentan (n=242) was 352±111m, 364±96m and 363±93m, respectively. No significant treatment-by-visit interaction (p=0.47) suggested that beneficial effects of macitentan on 6MWD (3mg: 21.5m [10.0–33.0]; p=0.0003 and 10mg: 25.4m [13.8–37.0]; p<0.0001 vs placebo) were maintained over 12 months. There were 125 PAHDH events in 595 patients with 6MWD data available. Lower 6MWD at baseline and Month 6 were strongly associated with a risk of PAHDH (Table). Absolute 6MWD at Month 6 lost its association when adjusted for baseline 6MWD and sex. Neither adjusted nor non-adjusted changes in 6MWD from baseline to Month 6 were significantly associated with the risk of PAHDH. View this table: Table 1. Association of 6MWD with risk of PAHDH Conclusions: Macitentan provided sustained improvements in 6MWD over 12 months. No association between 6MWD changes and long-term clinical outcome was demonstrated. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00660179&atom=%2Fehj%2F34%2Fsuppl_1%2F1061.atom

OP0015 Stimulation of soluble guanylate cyclase reduces experimental dermal fibrosis

BackgroundFibrosis of the skin and internal organs is a cardinal feature of systemic sclerosis (SSc). Since it disrupts the physiologic tissue architecture and causes organ failure, fibrosis leads to a...

Cost-Effective Design of Pulmonary Arterial Hypertension Trials To Detect Changes in Right Ventricular Size and Function: 3D Echocardiography Versus Cardiovascular Magnetic Resonance

Purpose Both cardiovascular magnetic resonance (CMR) and 3D transthoracic echocardiography (3DE) can quantify right ventricular (RV) end diastolic volume (EDV) and ejection fraction (EF) accurately. This study was designed to estimate sample sizes and imaging costs to detect changes in RV EDV and EF using 3DE and CMR for future pulmonary arterial hypertension (PAH) drug trials. Methods and Materials Same day CMR and 3DE were performed on 20 PAH patients (age: 53±13 yrs, 19 females) at 0 and 6 months. Consecutive short axis cines spanning the entire RV (Philips 1.5-T scanner) and full-volume acquisitions of the RV (Philips iE33+TomTec 4D RV-Function software) were used to measure EDV and EF. Sample size calculations using two-sample repeated measures to account for changes over time were performed modeling a placebo-controlled trial (Stata v12.1). Cost estimates were made using the 2012 Medicare physician fee schedule. Results No significant differences were noted between 0- and 6-month RV EF and EDV measurements with either CMR or 3DE, but the relatively large SDs reflected variable progression of disease in individual patients on standard therapy. Sample sizes required for 3DE were roughly 3 times greater than CMR. Although the per-study cost of CMR (~$400) is approximately double that of 3DE (~$200), the total cost of a trial using CMR is considerably lower. Conclusions Both CMR and 3DE can be used to detect the effects of new PAH therapies on RV EDV and EF, but CMR is more cost-effective. Population characteristics (average ± SD) Baseline 6 months CMR 3DE CMR 3DE RV EF (%) 34 ± 15 32 ± 12 36 ± 11 33 ± 9 RV EDV (mL) 245 ± 58 195 ± 59 244 ± 71 199 ± 48 Estimated per-group sample sizes (placebo-controlled trial - 90% power) Estimated cost (US$) CMR 3DE CMR 3DE EF: 3% change 54 169 89,000 143,000 EF: 5% change 20 61 33,000 52,000 RVEDV: 20 mL change 44 138 73,000 117,000 RVEDV: 30 mL change 20 61 33,000 52,000

Designing pulmonary arterial hypertension trials for detecting change in right ventricular function using cardiovascular magnetic resonance: what is the appropriate sample size?

Background Right ventricular (RV) failure is a major complication of pulmonary arterial hypertension (PAH). Cardiovascular magnetic resonance (CMR) can accurately quantify RV volume and function. Short-term changes in CMR measurements of RV size and function in PAH patients on individualized therapy have not been extensively studied; therefore, the required sample size for detecting a certain change in RV size and function in response to therapy is unknown. This study was designed to (1) assess changes in RV size and function in patients on individualized PAH treatment, and (2) to estimate sample sizes needed to detect a change in RV function in future PAH drug trials without discontinuing standard therapy.

Assessment of measurement properties of peak VO2in children with pulmonary arterial hypertension

BackgroundThe 6-minute walk test evaluates the effect of pharmacologic intervention in adults with pulmonary arterial hypertension (PAH) but, for reasons of compliance or reliability, may not be appropriate for children at all ages. Thus, peak oxygen consumption (VO2, maximal exercise test) was used instead in a pediatric PAH trial (STARTS-1) to evaluate pharmacologic intervention with sildenafil. This was the first large placebo-controlled trial to use the peak VO2 endpoint in this population. Our working hypothesis was that, as with other populations, percentage changes in peak VO2 in pediatric patients with PAH are reliable and are associated with changes in other clinical endpoints.MethodsUsing data from the subpopulation of 106 patients who were developmentally and physically able to perform exercise testing, all of whom were World Health Organization Functional Class (WHO FC) I, II, or III, reliability was assessed using the intraclass correlation coefficient and Bland-Altman plot on screening and baseline data. Relationships between percentage change in peak VO2 from baseline to end of treatment and other endpoints were evaluated using correlation coefficients and regression analyses.ResultsThe intraclass correlation was 0.79 between screening and baseline peak VO2, an agreement that was supported by the Bland-Altman plot. Percentage change in peak VO2 correlated well (r ≥0.40) and showed responsiveness to a physician global assessment of change and with change in WHO FC (for baseline classes I and III). Percentage change in peak VO2 did not correlate with change in the Family Cohesion of the Child Health Questionnaire (r = 0.04) or with a subject global assessment of change (r = 0.12). The latter may have been influenced by child and parental-proxy response and instrument administration.ConclusionIn pediatric PAH patients who are developmentally and physically able to perform exercise testing, peak VO2 measurements exhibited good reliability and improvements that were associated with improvements in certain other clinical endpoints, such as the WHO FC and a physician global assessment.Trial registrationClinicalTrials.gov identifier NCT00159913.

Old dog, new tricks: Therapeutic potential of the NO pathway in pulmonary hypertension

The NO signaling pathway is of major importance for regulation of pulmonary vascular tone. Inhalation of exogenous NO in patients with pulmonary arterial hypertension (PAH) results in selective pulmonary vasodilation, while limitations of chronic NO therapy in pulmonary hypertension include the need of continuous administration, methaemoglobinemia formation and the fact that NO does not induce pulmonary vasodilation in all PAH patients. A major breakthrough for treatment of PAH was the introduction of the phosphodiesterase (PDE) type 5 inhibitor sildenafil. PDE 5 inhibition stabilizes the second messenger cGMP that is produced by the soluble guanylate cyclase (sGC) upon binding of NO. However, the efficacy of PDE5 inhibitors is critically dependent on the synthesis of cGMP by an intact NO pathway. Reduced cGMP production might be explained by limited NO bioavailability either by reduced biosynthesis (down regulation or dysfunction of eNOS) or increased NO scavenging (e.g. oxidative stress). Therefore, stimulation of the NO/sGC/cGMP pathway downstream to NO seems an appealing therapeutical strategy. Recently, the pharmacological sGC stimulator Riociguat was shown to be a systemic and pulmonary vasodilator. Moreover, this compound has shown to produce beneficial effects in animal models of pulmonary hypertension. Chronic treatment of animals with established pulmonary hypertension with Riociguat could reverse right ventricular hypertrophy and structural remodeling of the lung vasculature. Riociguat has also been investigated clinically in terms of pharmacokinetics, pharmacodynamics, safety, tolerability and efficacy. Based on positive clinical findings, the efficacy of Riociguat is currently addressed in two placebo controlled multicenter phase 3 trials in pulmonary arterial hypertension (PATENT) and chronic thromboembolic pulmonary hypertension (CHEST).

The Minimal Important Difference in the 6-Minute Walk Test for Patients with Pulmonary Arterial Hypertension

Although commonly used as the primary outcome measure of clinical trials in pulmonary arterial hypertension (PAH), the minimal important difference (MID) of the 6-minute walk test (6MWT) has not been well defined for this population of patients. To estimate the MID in the 6MWT in patients with PAH. Study subjects from the clinical trial of tadalafil in PAH, a 16-week, parallel-group, randomized clinical trial of patients who were treatment naive or on background therapy with an endothelin receptor antagonist, were eligible. 6MWT was performed using a standardized protocol. Distributional and anchor-based methods were used to estimate the MID; the latter method used the Physical Component Summary Score (PCS) of the Medical Outcomes Study 36-item short form (SF-36). Four hundred five subjects were analyzed. Domains of the SF-36 were weakly to modestly associated with 6MWT. Change in the PCS of the SF-36 was most strongly associated with change in 6MWT (r = 0.40, P < 0.001) and thus was selected as the anchor for subsequent anchor-based analyses. Distributional analyses yielded estimates of the MID ranging from 25.1 to 38.5 m, whereas anchor-based analyses yielded an estimate of 38.6 m. Using both distributional and anchor-based methods, the estimated consensus MID in the 6MWT for PAH is approximately 33 m. These results have important implications for (1) assessing treatment responses from clinical trials and metaanalyses of specific PAH therapy, and (2) sample size calculations for future study design.

Validation of 6-Minute Walk Distance as a Surrogate End Point in Pulmonary Arterial Hypertension Trials

Nearly all available treatments for pulmonary arterial hypertension have been approved based on change in 6-minute walk distance (Δ6MWD) as a clinically important end point, but its validity as a surrogate end point has never been shown. We aimed to validate the difference in Δ6MWD against the probability of a clinical event in pulmonary arterial hypertension trials. First, to determine whether Δ6MWD between baseline and 12 weeks mediated the relationship between treatment assignment and development of clinical events, we conducted a pooled analysis of patient-level data from the 10 randomized placebo-controlled trials previously submitted to the US Food and Drug Administration (n=2404 patients). Second, to identify a threshold effect for the Δ6MWD that indicated a statistically significant reduction in clinical events, we conducted a meta-regression among 21 drug/dose-level combinations. Δ6MWD accounted for 22.1% (95% confidence interval, 12.1%- 31.1%) of the treatment effect (P<0.001). The meta-analysis showed an average difference in Δ6MWD of 22.4 m (95% confidence interval, 17.4-27.5 m), favoring active treatment over placebo. Active treatment decreased the probability of a clinical event (summary odds ratio, 0.44; 95% confidence interval, 0.33-0.57). The meta-regression revealed a significant threshold effect of 41.8 m. Our results suggest that Δ6MWD does not explain a large proportion of the treatment effect, has only modest validity as a surrogate end point for clinical events, and may not be a sufficient surrogate end point. Further research is necessary to determine whether the threshold value of 41.8 m is valid for long-term outcomes or whether it differs among trials using background therapy or lacking placebo controls entirely.

Emerging therapies for pulmonary arterial hypertension: a review of recently completed and ongoing clinical trials

Pulmonary arterial hypertension (PAH) is a rare, progressive disorder that leads to an inexorable rise in pulmonary vascular resistance, ultimately resulting in right ventricular failure and death if left untreated. Currently available pulmonary vasoremodeling therapy has significantly improved morbidity and mortality in PAH. However, 3-year mortality in PAH is still higher than in many other cardiovascular diseases. Recent and ongoing clinical trials in PAH have evaluated five major avenues of clinical investigation: trials of combination therapy using current US FDA-approved agents; trials of new forms or new delivery systems of existing agents; trials of newly developed agents that target novel steps in existing pathways implicated in the pathogenesis of PAH; trials of agents targeting new pathways that may play a role in PAH; and stem-cell and molecular therapy for PAH. This article reviews evidence for emerging therapies for PAH based on recently completed and ongoing clinical trials.

Clinical safety, pharmacokinetics, and efficacy of ambrisentan therapy in children with pulmonary arterial hypertension

Recent trials in adult PAH revealed the efficacy of ambrisentan. However, in children with PAH, the clinical safety and pharmacokinetics of ambrisentan has not been well studied. Our aim was to investigate the clinical safety, pharmacokinetics, tolerability, and efficacy of endothelin receptor antagonist therapy with ambrisentan in children with pulmonary arterial hypertension (PAH). This retrospective cohort study provides clinical data from pediatric patients with PAH receiving ambrisentan as add-on therapy or transition from bosentan. Safety included evaluation of adverse events including aminotransferase abnormalities. The clinical impact was evaluated by improvement from baseline in clinical variables. A total of 38 pediatric patients with PAH received ambrisentan. Fifteen of 38 patients were switched from bosentan to ambrisentan. The remaining 23 children were treated with ambrisentan as an add-on therapy due to disease progression. In both transition and add-on cases, mean pulmonary artery pressure significantly improved (transition; 55 ± 18 vs. 45 ± 20 mmHg, n = 13, P = 0.04, add-on; 52 ± 17 vs. 45 ± 19 mmHg, n = 13, P = 0.03) during the follow-up. World Health Organization functional class improved in 31% of patients, but one patient required an atrial septostomy due to disease progression during the follow-up period (median, range; 20, 4-44 months). Five patients (13%) discontinued ambrisentan due to severe headache, lack of clinical efficacy, or near syncope. Ten patients (26%) had side effects associated with ambrisentan treatment, including nasal congestion, headache, and flushing. However, no patients had aminotransferase abnormalities and there were no deaths after initiation of ambrisentan during follow-up. Pharmacokinetics were evaluated in sixteen children treated with ambrisentan from 2.5 mg to 10.0 mg; the mean peak plasma concentration was 738 ± 452 ng/ml, mean time to peak plasma concentration was 3.2 ± 2.1 hours, and mean area under the curve plasma concentration was 6657 ± 4246 ng·hour/ml. In conclusion, initial experience with ambrisentan in children suggests that treatment is safe with similar pharmacokinetics to those in adults and may improve PAH in some children.

Research Highlights

Research Highlights

Cell-based therapies in pulmonary hypertension: who, what, and when?

pulmonary hypertension (PH), diagnosed when mean pulmonary arterial pressure exceeds the upper limits of normal (i.e., >25 mmHg) at rest (2), occurs in a variety of clinical situations and is associated with a broad spectrum of histological patterns and abnormalities. PH is currently classified into five distinct World Health Organization (WHO) groups, based on common clinical parameters, potential etiological mechanisms, and responses to treatment (22). Although any form of PH can contribute to increased patient morbidity and mortality, pulmonary arterial hypertension (PAH) (WHO group 1) is a particularly severe and progressive form associated with right heart failure and premature death (1). At present, therapeutic approaches to stabilize or reverse this debilitating condition involve treatment with one or a combination of up to three specific classes of agents, including prostacyclin analogs, endothelin-1 receptor antagonists, and/or phosphodiesterase-5 inhibitors. Retrospective (meta)analyses of these therapeutic strategies have demonstrated a reduction in mortality with their use (7, 12); however, many experts believe that current PAH treatment is inadequate given the persistently high mortality rate and functional hemodynamic impairment in many patients. These observations have led to continued intensive investigation into pathogenetic mechanisms and many proposals for additional alternative new therapies (20, 24). Among the potential new therapies, increasing interest in the role of endothelial progenitor cells (EPCs) as a cell-based therapy has emerged. However, issues remain regarding what group of PH patients are most likely to benefit from treatment, at what point in the disease is treatment most likely to be successful, and what types of cells should be utilized for therapy.

Hemodynamic assessment of pulmonary hypertension

There has been significant progress in our understanding of the pathobiology, epidemiology and prognosis of pulmonary vascular disease and, over the past few years, there has been an explosion of clinical therapeutic trials for pulmonary arterial hypertension (PAH). The increasing number of different conditions now associated with PAH and the appearance of new diagnostic techniques have led to a need for a systematic diagnostic approaches and a new disease classification, which has resulted in notable improvements in the quality and efficacy of clinical care. We appreciate traditional resting right heart catheterization techniques (which still remain the gold standard for diagnosing PAH and managing patients on therapy) and look forward to novel invasive techniques (e.g. intravascular ultrasound) that add greatly to our understanding of right ventricle and pulmonary circulation, and for the interpretation of data from clinical trials as well.

Registries and randomised controlled trials in pulmonary arterial hypertension: are they revealing?

Registries and randomised controlled trials in pulmonary arterial hypertension: are they revealing?

Comparison of 6-min walk test distance and cardiopulmonary exercise test performance in children with pulmonary hypertension

ObjectiveTo assess the relationship between 6-min walk test (6MWT) distance and variables of cardiopulmonary exercise testing (CPET) in children with pulmonary arterial hypertension (PAH).DesignRetrospective study.SettingTertiary hospital.PatientsChildren with PAH.InterventionsCPETs and 6MWTs.Main...

Riociguat for treatment of pulmonary hypertension

Several substances have proven clinical efficacy for the treatment of pulmonary arterial hypertension (PAH). However, clinical worsening does occur, and for some forms of PH no effective systemic treatment exists at all. New compounds that will hopefully improve the prognosis of pulmonary hypertension/pulmonary arterial hypertension (PH/PAH) patients are, therefore, being developed. Promising new substances include riociguat, a stimulator of the soluble guanylate cyclase (sGC). In a multicenter open-label phase II study, riociguat exerted strong and significant effects on pulmonary hemodynamics and exercise capacity in patients with PAH and in patients with chronic thromboembolic pulmonary hypertension (CTEPH). Riociguat is currently being evaluated in phase III clinical trials both in PAH and in CTEPH patients.

Clinical worsening in trials of pulmonary arterial hypertension: results and implications

Time to clinical worsening (TTCW) can be used to assess disease progression associated with pulmonary arterial hypertension (PAH). As a consequence, it is highly relevant to patients, clinicians, and regulatory agencies. The majority of clinical trials of PAH-specific drug therapies have included TTCW as a secondary endpoint; this article summarizes the results of randomized controlled clinical trials in PAH, specifically with respect to the clinical worsening endpoint. Some trials have demonstrated a treatment-related delay in TTCW and others have not. Recent results suggest that TTCW shows particular promise in detecting disease progression, even in mildly affected patients. Definitions of clinical worsening have also varied across clinical trials; although all have agreed on the inclusion of all-cause death and hospitalization due to PAH in the definition, the inclusion of additional parameters defining 'disease progression' has differed. There is a need for a clear and uniform definition of TTCW that can be tailored to the study population being investigated; the endpoint may require adaptation for patients in different functional classes and with different causes. Consistency of event reporting within a trial may be improved by employing a committee to adjudicate events. Trials are beginning to include TTCW as a primary endpoint; the results will be important in establishing the validity of whether this parameter should become the endpoint of choice in PAH trials in the future.