Trials In Pulmonary Arterial Hypertension Research Articles

A systematic review and meta-analysis of health-related quality of life (HRQoL) outcomes in randomised controlled trials for pulmonary arterial hypertension (PAH)

Abstract Introduction ESC guidelines recognise the under use of disease-specific health-related quality of life (HRQoL) instruments. These include CAMPHOR, PAH-SYMPACT, Emphasis-10 and Living with Pulmonary Hypertension (LPH). Patients highly value HRQoL as a treatment outcome in PAH. This is the first meta-analysis to evaluate HRQoL instruments and outcomes in RCTs in pulmonary arterial hypertension (PAH). Purpose To evaluate which PAH-RCT interventions improve HRQoL outcomes and compare the suitability of HRQoL instruments used. Method We searched MEDLINE (Jan 1970 to Dec 2023) and Cochrane Library from Jan 1990 to Dec 2023 (EMBASE, CT.gov, ICTRP, CINAHL) for RCTs in PAH. Abstracts and unpublished studies were excluded and PRISMA reporting structure followed. Trials meeting final selection criteria included HRQoL instruments sufficiently powered to detect a minimal clinically important difference (MCID). Effective sample sizes were calculated in GPower3.1 from a two independent means model for 80% power, 5% significance, one-tailed test. Meta-analysis was performed in SPSSv28.1. Full search criteria are registered on PROSPERO (ID: CRD42024484021). Results After removal of duplicates, 896 records were screened, 43 studies included a HRQoL endpoint. 8 studies were included in the meta-analysis after exclusion for insufficient data (n=10) or power (n=25). 3 of these did not meet the MCID (>33m) for six-minute walk distance (6MWD) and evaluated separately to discriminate accuracy of HRQoL instrument. Instruments available for comparison were Short Form-36(SF-36), EuroQol (EQ-5D-5L) and Living with Pulmonary Hypertension (LPH). Studies not reaching MCID for 6MWD also showed no change in HRQoL (figure 1). Ambrisentan and exercise training demonstrate a significant improvement (p<0.05) in SF-36 physical(P) component (figure 2). This component was anchored to determine 6MWD MCID; other HRQoL values responded variably. Utility weighting to account for geographical variation was not reported with EQ-5D-5L and SF-36 in multicentre studies however AIR 2002 (Iloprost) was significant for both EQ-5D-5L instruments. The total component score of the disease-specific LPH was more sensitive to functional improvements and overall change in HRQoL compared to EQ-5D-5L (p<0.05). Conclusion Fewer than 10% of all RCTs in PAH have adequately considered a HRQoL outcome measure. 8 RCTs were powered to assess HRQoL. Iloprost, ambrisentan, riociguat and exercise training interventions demonstrate significant improvement in HRQoL. LPH was the only PAH-instrument powered to detect change. LPH was more sensitive to HRQoL than generic instruments and is multidimensional. Geographical indexing should be considered for generic instruments such as EQ-5D-5L and SF-36 in multicentre trials. As a highly valued outcome for patients, future studies should prioritise HRQoL as an endpoint.Figure 1Figure 2

Comparison of pulmonary arterial risk assessment tools to predict mortality or morbidity in treatment naive and previously diagnosed patients

Abstract Background Pulmonary arterial hypertension (PAH) risk stratification (1-year prediction of risk) is crucial and should be the most accurate to ensure appropriate aggressiveness of the treatment choices. According to the European guidelines, several risk tools can be used both at baseline and/or follow-up assessment. Yet, a comparison of risk tools performances only in treatment-naïve or only previously diagnosed patients is still missing. Aims To compare the available risk assessment tools performances to predict 1-year mortality but also 1-year clinical worsening in treatment-naïve and previously diagnosed PAH patients. Methods Eight PAH trials (AMBITION, ARIES1, ARIES2, FREEDOM, GRIPHON, PATTENT, PHIRST and SERAPHIN) provided by the FDA were harmonized and treatment-naïve patients were separated from previously diagnosed patients. Outcomes were 1-year mortality and 1-year clinical worsening (i.e., morbidity) either from baseline assessment or at follow-up. Kaplan-Meier and log-rank tests were performed for each of the following risk tools: European 4-strata, REVEAL2.0, REVEAL Lite, noninvasive FRENCH. In each subgroup, their C-indices were calculated and compared using a total of 100 bootstrap samples from the original data, providing a robust method for comparing across the different tools. Results Among the 4,122 patients included, 1,701 (41%) were treatment-naïve and 2,411 (59%) were previously diagnosed patients. Compared to treatment naïve patients, previously diagnosed patients were younger (p<0.001), with lower level of natriuretic peptide (p=0.013), higher 6MWD (p<0.001) and higher mPAP (p<0.001). At 1-year, the mortality rate was the same in the 2 subgroups (5.6% 5.1%, p=0.05) but clinical worsening occurred more often among previously diagnosed patients (19% vs 8.4%, p<0.001). Each of the risk tools were able to predict both 1-year mortality or morbidity in each subgroup, especially among previously diagnosed or at follow-up, with fair to good C-index (Figure 1). Forrest plots of 95%CI for the C-index differences among the 100 bootstrap samples showed that REVEAL 2.0 was the best performer, followed by REVEAL Lite (Figure 2). Conclusions In this large dataset, we showed that all PAH risk tools were able to predict not only 1-year mortality but also 1-year morbidity, both in treatment naïve and previously diagnosed patients. REVEAL 2.0 depicted the higher C-index.Figure 1.C-index for PAH risk toolsFigure 2.Forrest plots of 95%CI

Clinical trial design, end-points, and emerging therapies in pulmonary arterial hypertension.

Clinical trials in pulmonary arterial hypertension (PAH) have led to the approval of several effective treatments that improve symptoms, exercise capacity and clinical outcomes. In phase 3 clinical trials, primary end-points must reflect how a patient "feels, functions or survives". In a rare disease like PAH, with an ever-growing number of treatment options and numerous candidate therapies being studied, future clinical trials are now faced with challenges related to sample size requirements, efficiency and demonstration of incremental benefit on traditional end-points in patients receiving background therapy with multiple drugs. Novel clinical trial end-points, innovative trial designs and statistical approaches and new technologies may be potential solutions to tackle the challenges facing future PAH trials, but these must be acceptable to patients and regulatory bodies while preserving methodological rigour. In this World Symposium on Pulmonary Hypertension task force article, we address emerging trial end-points and designs, biomarkers and surrogate end-point validation, the concept of disease modification, challenges and opportunities to address diversity and representativeness, and the use of new technologies such as artificial intelligence in PAH clinical trials.

Electrocardiographic Abnormalities and Their Association with Outcomes in Randomized Clinical Trials of Pulmonary Arterial Hypertension.

Rationale: Pulmonary arterial hypertension (PAH) is a progressive disease with manifestations including right atrial enlargement, right ventricular dysfunction, dilation, and hypertrophy. Electrocardiography (ECG) is a noninvasive, inexpensive test that is routinely performed in clinical settings. Prior studies have described separate abnormal findings in the electrocardiograms of patients with PAH. However, the role of composite ECG findings reflective of right heart disease (RHD) for risk stratification, clinical trial enrichment, and management of patients with PAH has not been explored. Objectives: To describe a pattern of RHD on ECG in patients with PAH and to investigate the association of this pattern with clinical measures of disease severity and outcomes. Methods: We harmonized individual participant data from 18 phase III randomized clinical trials of therapies for PAH (1998-2013) submitted to the U.S. Food and Drug Administration. RHD was defined as the presence of right ventricular hypertrophy, right axis deviation, right atrial enlargement, or right bundle branch block on ECG. Random effects linear regression, multilevel ordinal regression (cumulative link model), and Cox proportional hazards models were used to assess the association of RHD by ECG with 6-minute walk distance (6MWD), World Health Organization (WHO) functional class, and clinical worsening after a priori adjustment for age, sex, body mass index, and PAH etiology. Effect modification of treatment and ECG abnormalities was assessed by including an interaction term. Results: A total of 4,439 patients had baseline ECG, and 68% of patients had evidence of RHD. RHD on ECG was associated with higher pulmonary vascular resistance (P < 0.001) and higher mean pulmonary artery pressures (P < 0.001). Patients with RHD on ECG had 10 meters shorter 6MWD (P = 0.005) and worse WHO functional class (P < 0.001) at baseline. RHD on baseline ECG was associated with increased risk of clinical worsening (hazard ratio, 1.42; 95% confidence interval; 1.21, 1.67; P < 0.001). Patients with RHD had greater treatment effect in terms of 6MWD, WHO functional class, and time to clinical worsening than those without (P for interaction = 0.03, 0.001, and 0.03, respectively). Conclusions: RHD by ECG may be associated with worse outcomes and potentially greater treatment effect. Electrocardiograms could be an inexpensive, widely available noninvasive method to enrich clinical trial populations in PAH.

Abstract 16736: Comparison of Pulmonary Arterial Hypertension Risk Assessment Tools Using a Harmonized FDA Dataset

Introduction: One-year mortality risk for a pulmonary arterial hypertension (PAH) patient is the most substantial. Accordingly, the initial risk stratification should be the most accurate to ensure appropriate aggressiveness of the primary treatment choices. According to PAH guidelines, the European 3-strata system is recommended at baseline for risk assessment. However, the US REVEAL2.0 and REVEAL Lite risk scores also provide high performances. Yet, comparison of risk assessment performances at baseline in the same dataset of patients is still missing. Hypothesis: REVEAL 2.0 provide higher discrimination performances than the European 3-strata system at baseline. We aim to compare the discrimination power at baseline of the currently available tools. Methods: Treatment naïve PAH patients from 6 PAH trials were provided by the FDA and harmonized (AMBITION n=500, ARIES n=126, PATENT n=221, PHIRST n=77, GRIPHON n=231, and SERAPHIN n=270). Kaplan-Meier and log-rank tests were performed for each of the following tools: noninvasive FRENCH method (FR), European 3-strata system (E3), COMPERA2.0 4-strata (CO), REVEAL2.0 (RE), and REVEAL Lite (RL). Their C-indices were compared. A total of 100 bootstrap samples were obtained from the original data providing a robust method for comparing across the different tools. Results: Among the 1,425 patients, 78% were female, 54% NYHA 3-4 with a median age of 51(38, 64) yo, 6-min walking distance of 365(295, 418)m, mPAP of 49(38, 59) mmHg, PVR 9.3(6.2, 13.5) WU. At baseline, the C-index for FR, CO, E3, RL, and RE were 0.64, 0.67, 0.68, 0.69, 0.73, respectively. Out of the 100 bootstrap samples, 99% led to a better C-index for RE compared to E3, with a statistically significant paired t-test (p&lt;e -40 ) as well as RL compared to E3 (p&lt; e-8 ). Forrest plots of 95%CI for the C-index differences among the 100 bootstrap samples showed that RE was the best performer, followed by RL, while the E3 and FR models were comparable and worse than the others. Conclusions: REVEAL 2.0 and REVEAL Lite risk scores perform better than the European-3 strata, COMPERA-4 strata, and the noninvasive FRENCH models in predicting 1-year survival at baseline and should be considered as the initial stratification scheme in future guidelines.

Evolution and optimization of clinical trial endpoints and design in pulmonary arterial hypertension.

Selection of endpoints for clinical trials in pulmonary arterial hypertension (PAH) is challenging because of the small numbers of patients and the changing expectations of patients, clinicians, and regulators in this evolving therapy area. The most commonly used primary endpoint in PAH trials has been 6-min walk distance (6MWD), leading to the approval of several targeted therapies. However, single surrogate endpoints such as 6MWD or hemodynamic parameters may not correlate with clinical outcomes. Composite endpoints of clinical worsening have been developed to reflect patients' overall condition more accurately, although there is no standard definition of worsening. Recently there has been a shift to composite endpoints assessing clinical improvement, and risk scores developed from registry data are increasingly being used. Biomarkers are another area of interest, although brain natriuretic peptide and its N-terminal prohormone are the only markers used for risk assessment or as endpoints in PAH. A range of other genetic, metabolic, and immunologic markers is currently under investigation, along with conventional and novel imaging modalities. Patient-reported outcomes are an increasingly important part of evaluating new therapies, and several PAH-specific tools are now available. In the future, alternative statistical techniques and trial designs, such as patient enrichment strategies, will play a role in evaluating PAH-targeted therapies. In addition, modern sequencing techniques, imaging analyses, and high-dimensional statistical modeling/machine learning may reveal novel markers that can play a role in the diagnosis and monitoring of PAH.

Pulmonary arterial hypertension trials put to the test: Using the fragility index to assess trials robustness

BackgroundRandomized clinical trials (RCTs) are considered the gold standard for evidence-based medicine. The Fragility Index (FI) is a tool to assess the robustness of RCT results. FI was validated for dichotomous outcomes and recent work expanded its use to continuous outcomes. Studying the robustness of RCTs in Pulmonary Arterial Hypertension (PAH) treatments is crucial due to the severity and mortality risks associated with this rare condition. ObjectivesAnalyze FI and Fragility quotient (FQ) of significant primary outcomes in PAH RCTs and study FI correlation with sample size and journal impact factor. MethodsFI and FQ calculation followed by Spearman correlation to assess the correlation between FI and sample size, and FI and impact factor. ResultsThe median sample size of the 21 trials was 202 patients (IQR 106–267), with 6 trials reporting primary outcomes as dichotomous and 15 reporting continuous primary outcomes. The median FI was 10 (IQR 3–20), and the median FQ was 0.044 (0.026–0.097). A moderate correlation was found between FI and sample size, with r = 0.56; P = 0.008 and FI and journal impact factor (r=0.50; P=0.019). The FI for continuous outcomes was similar to that for dichotomous outcomes. ConclusionsThis study represents the first analysis of the FI and FQ of PAH treatment RCTs, and expands the use of FI to continuous outcomes in this context. The moderate correlation between FI and sample size suggests that increasing sample size alone is partially correlated to a higher FI. The similarity between FI for continuous and dichotomous outcomes supports the broader use of FI in PAH RCTs.

Surrogate endpoints in pulmonary arterial hypertension trials

Why don't you just look at the pulmonary artery pressure? This question is frequently asked when we discuss endpoints in pulmonary arterial hypertension (PAH) trials with colleagues from other disease areas. Trials of antihypertensive drugs simply look at blood pressure changes, whereas pivotal trials in PAH use change in 6-min walk distance or time to clinical worsening as primary outcome measures. Why the difference? It is not just the invasiveness of right heart catheterisation but much more a question of validated surrogate endpoints. The US Food and Drug Administration (FDA) and other regulatory agencies approve drugs when they improve how patients feel, function, or survive. 1 Temple R Are surrogate markers adequate to assess cardiovascular disease drugs?. JAMA. 1999; 282: 790-795 Crossref PubMed Scopus (298) Google Scholar In systemic hypertension, lowering blood pressure predicts reductions in major adverse cardiovascular events including stroke, myocardial infarction, and cardiovascular death, and so authorities accept blood pressure reduction as a surrogate endpoint—ie, a substitute for a clinically meaningful endpoint that is expected to predict the effect of a therapy. 1 Temple R Are surrogate markers adequate to assess cardiovascular disease drugs?. JAMA. 1999; 282: 790-795 Crossref PubMed Scopus (298) Google Scholar In PAH, there is no convincing evidence that reductions in pulmonary artery pressure or pulmonary vascular resistance are directly linked to improved exercise capacity or better survival. Hence, change in 6-min walk distance is being frequently used as a primary endpoint assessing the function part of the FDA paradigm. Time to clinical worsening has been applied as well, a composite endpoint based on death, PAH-related worsening, and prespecified reductions in exercise capacity. However, these endpoints have limitations. Improvement in 6-min walk distance reflects better exercise capacity but is no surrogate of better outcomes. 2 Gabler NB French B Strom BL et al. Validation of 6-minute walk distance as a surrogate end point in pulmonary arterial hypertension trials. Circulation. 2012; 126: 349-356 Crossref PubMed Scopus (185) Google Scholar Time to clinical worsening does not capture clinical improvement, and reducing clinical worsening events does not necessarily lead to better survival. 3 Sitbon O Channick R Chin KM et al. Selexipag for the treatment of pulmonary arterial hypertension. N Engl J Med. 2015; 373: 2522-2533 Crossref PubMed Scopus (607) Google Scholar , 4 Galiè N Barberà JA Frost AE et al. Initial use of ambrisentan plus tadalafil in pulmonary arterial hypertension. N Engl J Med. 2015; 373: 834-844 Crossref PubMed Scopus (750) Google Scholar , 5 Pulido T Adzerikho I Channick RN et al. Macitentan and morbidity and mortality in pulmonary arterial hypertension. N Engl J Med. 2013; 369: 809-818 Crossref PubMed Scopus (981) Google Scholar In addition, studies designed to show improvement in time to clinical worsening require large sample sizes, a challenge in a rare disease like PAH. Hence, there is an ongoing search for surrogate endpoints. Is low-risk status a surrogate outcome in pulmonary arterial hypertension? An analysis of three randomised trialsMulticomponent risk scores have utility for the prediction of outcomes in patients with PAH. Clinical surrogacy for long-term outcomes cannot be inferred from observational studies of outcomes. Our analyses of three PAH trials with long-term follow-up suggest that further study is necessary before using these or other scores as surrogate outcomes in PAH RCTs or clinical care. Full-Text PDF

Is low-risk status a surrogate outcome in pulmonary arterial hypertension? An analysis of three randomised trials

Targeting short-term improvements in multicomponent risk scores for mortality in patients with pulmonary arterial hypertension (PAH) could result in improved long-term outcomes. We aimed to determine whether PAH risk scores were adequate surrogates for clinical worsening or mortality outcomes in PAH randomised clinical trials (RCTs). We performed an individual participant data meta-analysis of RCTs selected from PAH trials provided by the US Food and Drug Administration (FDA). We calculated predicted risk using the COMPERA, COMPERA 2.0, non-invasive FPHR, REVEAL 2.0, and REVEAL Lite 2 risk scores. The primary outcome of interest was time to clinical worsening, a composite endpoint composed of any of the following events: all-cause death, hospitalisation for worsening PAH, lung transplantation, atrial septostomy, discontinuation of study treatment (or study withdrawal) for worsening PAH, initiation of parenteral prostacyclin analogue therapy, or decrease of at least 15% in 6-min walk distance from baseline, combined with either worsening of WHO functional class from baseline or the addition of an approved PAH treatment. The secondary outcome of interest was time to all-cause mortality. We assessed the surrogacy of these risk scores, parameterised as attainment of low-risk status by 16 weeks, for improvement in long-term clinical worsening and survival using mediation and meta-analysis frameworks. Of 28 trials received from the FDA, three RCTs (AMBITION, GRIPHON, and SERAPHIN; n=2508) had the data necessary to assess long-term surrogacy. The mean age was 49 years (SD 16), 1956 (78%) participants were women, 1704 (68%) were classified as White, and 280 (11%) were Hispanic or Latino. 1388 (55%) of 2503 participants with available data had idiopathic PAH and 776 (31%) of 2503 had PAH associated with connective tissue disease. In a mediation analysis, the proportions of treatment effects explained by attainment of low-risk status ranged only from 7% to 13%. In a meta-analysis of trial-regions, the treatment effects on low-risk status were not predictive of the treatment effects on time to clinical worsening (R2 values 0·01-0·19) nor the treatment effects on time to all-cause mortality (R2 values 0-0·2). A leave-one-out analysis suggested that the use of these risk scores as surrogates might lead to biased inferences regarding the effect of therapies on clinical outcomes in PAH RCTs. Results were similar when using absolute risk scores at 16 weeks as the potential surrogates. Multicomponent risk scores have utility for the prediction of outcomes in patients with PAH. Clinical surrogacy for long-term outcomes cannot be inferred from observational studies of outcomes. Our analyses of three PAH trials with long-term follow-up suggest that further study is necessary before using these or other scores as surrogate outcomes in PAH RCTs or clinical care. Cardiovascular Medical Research and Education Fund, US National Institutes of Health.

Heterogeneity of treatment effects by risk in pulmonary arterial hypertension.

It is currently unknown if disease severity modifies response to therapy in pulmonary arterial hypertension (PAH). We aimed to explore if disease severity, as defined by established risk-prediction algorithms, modified response to therapy in randomised clinical trials in PAH. We performed a meta-analysis using individual participant data from 18 randomised clinical trials of therapy for PAH submitted to the United States Food and Drug Administration to determine if predicted risk of 1-year mortality at randomisation modified the treatment effect on three outcomes: change in 6-min walk distance (6MWD), clinical worsening at 12 weeks and time to clinical worsening. Of 6561 patients with a baseline US Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL 2.0) score, we found that individuals with higher baseline risk had higher probabilities of clinical worsening but no difference in change in 6MWD. We detected a significant interaction of REVEAL 2.0 risk and treatment assignment on change in 6MWD. For every 3-point increase in REVEAL 2.0 score, there was a 12.49 m (95% CI 5.86-19.12 m; p=0.001) greater treatment effect in change in 6MWD. We did not detect a significant risk by treatment interaction on clinical worsening with most of the risk-prediction algorithms. We found that predicted risk of 1-year mortality in PAH modified treatment effect as measured by 6MWD, but not clinical worsening. Our findings highlight the importance of identifying sources of treatment heterogeneity by predicted risk to tailor studies to patients most likely to have the greatest treatment response.

Risk assessment in pulmonary arterial hypertension: A step towards clinical implementation based on the 2022 ESC/ERS pulmonary hypertension guidelines.

Risk assessment in pulmonary arterial hypertension: A step towards clinical implementation based on the 2022 ESC/ERS pulmonary hypertension guidelines.

Prognosis in Hispanic patient population with pulmonary arterial hypertension: An application of common risk stratification models.

Pulmonary arterial hypertension (PAH) is a cardiovascular disease with high mortality rate. Current guidelines propose initiation and escalation of PAH-targeted treatment based on a goal-directed approach targeting hemodynamic, functional, and biochemical variables. This approach has been successfully validated in large Caucasian cohorts. However, given the low number of Hispanic patients enrolled in large PAH trials and registries, it is unknown if the same prognostic tools can be applied tothis patient population. We analyzed a single-center outpatient cohort that consisted of 135 Hispanic patients diagnosed with PAH. Baseline characteristics werecalculated based on COMPERA, COMPERA 2.0 and REVEAL 2.0 risk scores before the initiation of PAH-targeted therapies. The survival rateat 1 year after diagnosis was 88% for the entire cohort. The three established risk scores to predict PAH outcomes yielded similar results with reasonable discrimination of mortality in the different risk strata (all p < 0.001). Hispanic patients with PAH have a high mortality rate. Our analysis suggests that guideline proposed risk assessment at baseline yields important prognostic information in this patient population.

No Placebo Effect beyond Regression to the Mean on the Six Minute Walk Test in Pulmonary Arterial Hypertension Trials.

In drug studies, patients are often included when the disease activity is high. This will make any treatment appear to lessen disease activity, although the improvement is biased by selection. This effect is known as regression towards the mean (RTM). We aimed at investigating drug trials in Pulmonary Arterial Hypertension (PAH) using the 6-minute walking distance test (6MWD) as a primary outcome for the phenomenon of RTM. An existing registry of 43 open label studies and 23 randomized controlled trials conducted between 1990 and 2009 was used as the data source. Data analysis was carried out for 18 randomized controlled trials (RCTs) and 24 open label studies out of this registry. Data were analyzed for verum and placebo arms of the RCTs separately, as well as for the open label arms. In the verum arms, the overall effect given as 33.2 m (95% CI: 25.7; 40.6]); 6MWD was slightly lower than the effect in the observational studies, with 44.6 m (95% CI: [25.4; 63.8]). After studying and interpreting the data, we found that regression towards the mean plays only a minor role in PAH studies. In particular, placebo effects in the RCTs were negligibly small, with a mean 6MWD of -2.5 m (95% CI: [-9.8; 4.7]) in the placebo arm. Therefore, our analysis indicates that results of non-randomized observational studies can be regarded as valid tools for gaining valid clinical effects in patients with PAH.

Early selexipag initiation and long-term outcomes: insights from randomised controlled trials in pulmonary arterial hypertension.

Further understanding of when to initiate therapies in pulmonary arterial hypertension (PAH) is important to improve long-term outcomes. Post hoc analyses of GRIPHON (NCT01106014) and exploratory analyses of TRITON (NCT02558231) suggested benefit of early selexipag initiation on long-term outcomes, despite no additional benefit versus initial double combination on haemodynamic and functional parameters in TRITON. Post hoc analyses investigated the effect of early selexipag initiation on disease progression and survival in a large, pooled PAH cohort. Data from newly diagnosed (≤6 months) PAH patients from GRIPHON and TRITON were pooled. Patients on active therapy with selexipag (pooled selexipag group) were compared with those on control therapy with placebo (pooled control group). Disease progression end-points were defined as per the individual studies. Hazard ratios (HR) and 95% CI for time to first disease progression event up to end of double-blind treatment (selexipag/placebo) +7 days and time to all-cause death up to end of study were estimated using Cox regression models. The pooled dataset comprised 649 patients, with 44% on double background therapy. Selexipag reduced the risk of disease progression by 52% versus control (HR: 0.48; 95% CI: 0.35-0.66). HR for risk of all-cause death was 0.70 (95% CI: 0.46-1.10) for the pooled selexipag versus control group. Sensitivity analyses accounting for the impact of PAH background therapy showed consistent results, confirming the appropriateness of data pooling. These post hoc, pooled analyses build on previous insights, further supporting selexipag use within 6 months of diagnosis, including as part of triple therapy, to delay disease progression.

COMPARISON BETWEEN PULMONARY ARTERIAL HYPERTENSION (PAH) RISK ASSESSMENT METHODS, INCLUDING PULMONARY HYPERTENSION OUTCOME RISKS ASSESSMENT (PHORA)

COMPARISON BETWEEN PULMONARY ARTERIAL HYPERTENSION (PAH) RISK ASSESSMENT METHODS, INCLUDING PULMONARY HYPERTENSION OUTCOME RISKS ASSESSMENT (PHORA)

Assessing Daily Life Physical Activity by Actigraphy in Pulmonary Arterial Hypertension: Insights From the Randomized Controlled Study With Selexipag (TRACE)

Reduced daily life physical activity (DLPA) in pulmonary arterial hypertension (PAH) contributes to a poor quality of life. Can actigraphy be used to assess changes in DLPA in patients with PAH receiving selexipag or placebo? Effect of Selexipag on Daily Life Physical Activity of Patients With Pulmonary Arterial Hypertension (TRACE) was a prospective, multicenter, randomized, placebo-controlled, double-blind, exploratory phase 4 study enrolling patients with PAH in World Health Organization functional class II/III, receiving stable endothelin receptor antagonist with/without phosphodiesterase type 5 inhibitor background therapy. Primary end points were change from baseline to Week 24 in actigraphy-assessed DLPA (recorded by using an accelerometer), including daily time spent in nonsedentary physical activity (NSPA), daily time spent in moderate to vigorous physical activity (MVPA), daily volume of activity, and daily number of steps. At baseline, patients (N= 108) were prevalent, on stable background PAH therapy, and at low risk of disease progression. Patients showed high compliance with wear of the accelerometer throughout the study. From baseline to Week 24, mean daily time spent in NSPA increased by 1.1min and decreased by 16.7min in the selexipag and placebo groups (treatment difference [95%CI], 17.8 [-6.0, 41.6] min); mean time spent in MVPA increased by 0.3min and was reduced by 2.0min in the selexipag and placebo groups (treatment difference [95%CI], 2.3 [-10.8, 15.4] min); and mean number of daily steps decreased by 0.3 and 201.9 in the selexipag and placebo groups (treatment difference [95%CI], 201.6 [-243.0, 646.2]). TRACE enrolled a prevalent population on background therapy and at low risk of disease progression. Changes in DLPA were small and highly variable, with no statistically significant differences between treatment groups. This patient-centric study was the first randomized trial in PAH to capture high-quality actigraphy data and to describe DLPA in terms of mean/median and variability, which may inform the design of future studies. ClinicalTrials.gov; No.: NCT03078907; URL: www. gov.

Assessment of Clinical Worsening End Points as a Surrogate for Mortality in Pulmonary Arterial Hypertension: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Clinical worsening (CW) is a composite end point commonly used in pulmonary arterial hypertension (PAH) trials. We aimed to assess the trial-level surrogacy of CW for mortality in PAH trials, and whether the various CW components were similar in terms of frequency of occurrence, treatment-related relative risk (RR) reduction, and importance to patients. We searched MEDLINE, Embase, and the Cochrane Library (January 1990 to December 2020) for trials evaluating the effects of PAH therapies on CW. The coefficient of determination between the RR for CW and mortality was assessed by regression analysis. The frequency of occurrence, RR reduction, and importance to patients of the CW components were assessed. We included 35 independent cohorts (9450 patients). PAH therapies significantly reduced CW events (RR, 0.64 [95% CI, 0.55-0.73]), including PAH-related hospitalizations (RR, 0.61 [95% CI, 0.47-0.79]), treatment escalation (RR, 0.57 [95% CI, 0.38-0.84]) and symptomatic progression (RR, 0.58 [95% CI, 0.48-0.69]), and modestly reduced all-cause mortality when incorporating deaths occurring after a primary CW-defining event (RR, 0.860 [95% CI, 0.742-0.997]). However, the effects of PAH-specific therapies on CW only modestly correlated with their effects on mortality (R2trial, 0.35 [95% CI, 0.10-0.59]; P<0.0001), and the gradient in the treatment effect across component end points was large in the majority of trials. The weighted proportions of CW-defining events were hospitalization (33.5%) and symptomatic progression (32.3%), whereas death (6.7%), treatment escalation (5.6%), and transplantation/atrioseptostomy (0.2%) were infrequent. CW events were driven by the occurrence of events of major (49%) and mild-to-moderate (37%) importance to patients, with 14% of the events valued as critical. PAH therapies significantly reduced CW events, but study-level CW is not a surrogate for mortality in PAH trials. Moreover, components of CW largely vary in frequency, response to therapy, and importance to patients and are thus not interchangeable. URL: https://www.crd.york.ac.uk/PROSPERO; Unique identifier: CRD42020178949.

Long-Term Safety, Tolerability and Survival in Patients with Pulmonary Arterial Hypertension Treated with Macitentan: Results from the SERAPHIN Open-Label Extension.

IntroductionIn SERAPHIN, a long-term, event-driven, double-blind randomised controlled trial in pulmonary arterial hypertension (PAH), macitentan 10 mg significantly reduced the risk of morbidity/mortality compared with placebo. Its open-label extension study (SERAPHIN OL) further assessed long-term safety and tolerability of macitentan 10 mg in PAH patients.MethodsPatients in SERAPHIN who completed the double-blind treatment period or experienced a morbidity event during the study could enter SERAPHIN OL. Patients received macitentan 10 mg once daily, and safety and survival were assessed until end of treatment (+ 28 days). Two overlapping sets were analysed for safety: (1) all patients in SERAPHIN OL (OL safety set); (2) patients randomised to macitentan 10 mg in SERAPHIN (long-term safety/survival set). Survival was evaluated as an exploratory endpoint in the latter set.ResultsOf 742 patients randomised in SERAPHIN, 550 (74.1%) entered SERAPHIN OL (OL safety set); 242 patients were randomised to macitentan 10 mg in SERAPHIN (long-term safety/survival set). Median (min, max) exposure to macitentan 10 mg was 40.1 (0.1, 130.5) months (2074.7 patient-years; OL safety set) and 54.7 (0.1, 141.3) months (1151.0 patient-years; long-term safety/survival set). Safety in both analysis sets was comparable to the known safety profile of macitentan. Kaplan-Meier survival estimates (95% CI) at 1, 5, 7 and 9 years were 95.0% (91.3, 97.1), 73.3% (66.6, 78.9), 62.6% (54.6, 69.6) and 52.7% (43.6, 61.0), respectively (long-term safety/survival set; median follow-up: 5.9 years).ConclusionsThis analysis provides the longest follow-up for safety and survival published to date for any PAH therapy. The safety profile of macitentan 10 mg over this extensive treatment period was in line with that observed in SERAPHIN. As the majority of patients were receiving other PAH therapy at macitentan initiation, our study provides additional insight into the long-term safety of macitentan, including as part of combination therapy.Trial RegistrationClinicalTrials.gov Identifiers: NCT00660179 and NCT00667823.Supplementary InformationThe online version contains supplementary material available at 10.1007/s12325-022-02199-x.

Prognostic value of improvement endpoints in pulmonary arterial hypertension trials: A COMPERA analysis.

The prognostic value of improvement endpoints that have been used in clinical trials of treatments for pulmonary arterial hypertension (PAH) needs to be further investigated. Using the COMPERA database, we evaluated the prognostic value of improvements in functional class (FC) and absolute or relative improvements in 6-min walking distance (6MWD) and N-terminal fragment of pro-brain natriuretic peptide (NT-proBNP). In addition, we investigated multicomponent endpoints based on prespecified improvements in FC, 6MWD and NT-proBNP that have been used in recent PAH trials. Finally, we assessed the predictive value of improvements determined by risk stratification tools. The effects of changes from baseline to first follow-up (3-12 months after initiation of PAH therapy) on consecutive survival were determined by Kaplan-Meier analysis with Log-Rank testing and Cox proportional hazard analyses. All analyses were based on 596 patients with newly diagnosed PAH for whom complete data were available at baseline and first follow-up. Improvements in FC were associated with improved survival, whereas absolute or relative improvements in 6MWD had no predictive value. For NT-proBNP, absolute declines conferred no prognostic information while relative declines by ≥35% were associated with better survival. Improvements in multicomponent endpoints were associated with improved survival and the same was found for risk stratification tools. While sole improvements in 6MWD and NT-proBNP had minor prognostic relevance, improvements in multicomponent endpoints and risk stratification tools based on FC, 6MWD, and NT-proBNP were associated with improved survival. These tools should be further explored as outcome measures in PAH trials.

The Association of N-Terminal Pro-Brain Natriuretic Peptide With Time to Clinical Worsening in Hispanic Patients With Pulmonary Arterial Hypertension.

BackgroundMeasurement of N-terminal pro-brain natriuretic peptide (NT-proBNP) level is an important parameter in the risk assessment of patients with pulmonary arterial hypertension (PAH). Data about the prognostic value of NT-proBNP in the Hispanic PAH population are lacking. Historically, clinical trials in PAH have only included a minority of Hispanic patients. It has been reported that baseline NT-proBNP levels differ between different ethnicities. Furthermore, NT-proBNP levels can be impacted by declining renal function, making its interpretation difficult regarding clinical decision making.MethodsIn a retrospective single-center cohort analysis, Hispanic patients with PAH had a baseline outpatient NT-proBNP level drawn during a period of clinical stability and were followed for 1 year to monitor for time to clinical worsening (TTCW). The association of baseline NT-proBNP and TTCW was assessed in patients with normal and abnormal renal function.ResultsA total of 26 patients (22%) met the clinical endpoint of clinical worsening. Twenty-seven patients (24%) had chronic kidney disease (CKD). At baseline NT-proBNP levels showed a significant inverse correlation with 6-min walk test (6MWD, r = -0.382, P = 0.02), and a significant positive correlation with renal function (r = 0.273, P = 0.05). NT-proBNP levels did not correlate with age (r = 0.19, P = 0.11) or body mass index (BMI) (r = -0.292, P = 0.061). NT-proBNP levels of > 1,415 ng/L were significantly associated with shorter TTCW (P < 0.01) in all patients and in patients with CKD (P = 0.03). A stepwise increase in NT-proBNP levels by 100 ng/L was associated with a higher risk of meeting the clinical endpoint of TTCW in patients with normal renal function (hazard ratio (HR) = 1.8, P < 0.01) and CKD (HR = 1.5, P < 0.01).ConclusionsIn Hispanic patients with PAH, NT-proBNP is a valuable tool to predict 1-year TTCW, independent of renal function.