Contemporary risk scores predict clinical worsening in pulmonary arterial hypertension - An analysis of FREEDOM-EV

Benza, Raymond L.; Gomberg‐Maitland, Mardi; Farber, Harrison W.; Vizza, Carmine Dario; Broderick, Meredith; Holdstock, Louis; Nelsen, Andrew C.; Deng, Chunqin; Rao, Youlan; White, R. James

doi:10.1016/j.healun.2022.08.006

Cited by 13 publications

(10 citation statements)

References 29 publications

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“…4 e, p = 0.001). REVEAL Lite 2 produces an integer score, and on average, the score dropped by 1.2 ± 1.9 ( p < 0.0001); a drop of at least 1 in this continuous, quantitative scoring system is prognostically significant [ 11 ], and most, 39/64 participants, dropped by at least 1 ( p < 0.0001). Tabular data at week 48 is presented as Supplementary Material Table 1 .…”

Section: Resultsmentioning

confidence: 99%

“…The participants in FREEDOM-EV were effectively “early combination therapy” (median time on monotherapy 6 months before randomization), and treatment delay (randomization to placebo) led to a clear increase in CWE and death over the median 55 weeks of careful, quarterly observation explicitly designed to prevent death. Our recent analysis of risk argued for fixed-duration “clinical improvement” studies to synthesize the goals of measuring durable treatment effects and functional benefits [ 11 ], and we believe that the mortality consequences of event-driven studies are another reason to avoid these in the future.…”

Section: Discussionmentioning

confidence: 99%

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Oral Treprostinil is Associated with Improved Survival in FREEDOM-EV and its Open-Label Extension

Grünig,

Rahaghi,

Elwing

et al. 2023

Adv Ther

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Introduction In the event-driven FREEDOM-EV trial, oral treprostinil delayed clinical worsening in patients with pulmonary arterial hypertension (PAH). Open-label extension studies offer additional data about tolerability, efficacy, and survival, especially for those initially assigned placebo. The aim of the current study was to determine if oral treprostinil changed survival when considering the parent and extension study, if treprostinil provides functional benefits for participants initially assigned to placebo, and if the benefits observed for those treated with treprostinil were durable. Methods Both active and placebo participants from FREEDOM-EV could enroll in the FREEDOM-EV open-label extension (OLE) study after experiencing an investigator-assessed clinical worsening event or after parent study closure. All participants in the OLE were offered open-label oral treprostinil. Previously assigned placebo participants titrated to maximally tolerated doses; previously assigned treprostinil participants continued dose titration. We repeated assessments including functional class and 6-min walk distance (6MWD) at 12-week intervals and measured N-terminal pro-brain natriuretic peptide (NT-proBNP) at week 48. Survival was estimated by Kaplan–Meier analysis, and we estimated hazard ratio (HR) using Cox proportional hazards. Results Of 690 FREEDOM-EV participants, 470 enrolled in the OLE; vital status was available for 89% of initial Freedom-EV participants. When considering the combined parent and open-label data, initial assignment to oral treprostinil reduced mortality (HR 0.64, 95% confidence interval 0.46–0.91, p = 0.013); absolute risk reduction was 9%. Participants randomized to placebo who initiated oral treprostinil after clinical worsening and tolerated treatment through week 48 demonstrated favorable shifts in functional class ( p < 0.0001), 6MWD improvements of + 84 m ( p < 0.0001), and a reduction in NT-proBNP of − 778 pg/mL ( p = 0.02), compared to OLE baseline. Modest trends toward benefit were measured for those initially assigned placebo who did not have clinical worsening, and 132/144 (92%) of treprostinil assigned participants without clinical worsening remained on drug at week 48 in the OLE study. Adverse events were consistent with FREEDOM-EV. Conclusion Initial treprostinil assignment improved survival in the entire data set; those who began treprostinil after a clinical worsening in the placebo arm and tolerated drug to week 48 enjoyed substantial functional gains. Clinical Trial Registration ClinicalTrials.gov identifier NCT01560637. Supplementary Information The online version contains supplementary material available at 10.1007/s12325-023-02711-x.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Oral Treprostinil is Associated with Improved Survival in FREEDOM-EV and its Open-Label Extension

Grünig,

Rahaghi,

Elwing

et al. 2023

Adv Ther

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“…It has been shown that PAH patients who maintain a low‐risk status after initial treatment fare better than those who fall into the intermediate‐ and high‐risk categories 14,60,61 and this also represents a valuable assessment of clinical worsening or improvement. In the FREEDOM‐EV study, a 1‐point decrease from baseline at Week 12 in REVEAL 2.0 score predicted a 62% reduction in the relative risk of clinical worsening, while a 1‐point decrease in REVEAL Lite 2 score predicted a 59% reduction in the relative risk of clinical worsening 62 . The use of patient‐reported outcome measures (such as the Pulmonary Arterial Hypertension‐Symptoms and Impact Questionnaire and Minnesota Living with Heart Failure® Questionnaire included in the current study) also provide an insight into treatment effects distinct from those that are purely clinical or mechanistic.…”

Section: Discussionmentioning

confidence: 99%

“…In the FREEDOM-EV study, a 1-point decrease from baseline at Week 12 in REVEAL 2.0 score predicted a 62% reduction in the relative risk of clinical worsening, while a 1-point decrease in REVEAL Lite 2 score predicted a 59% reduction in the relative risk of clinical worsening. 62 The use of patient-reported outcome measures (such as the Pulmonary Arterial Hypertension-Symptoms and Impact Questionnaire and Minnesota Living with Heart Failure® Questionnaire included in the current study) also provide an insight into treatment effects distinct from those that are purely clinical or mechanistic. Understanding hemodynamics at baseline and changes over time is also crucial to guide clinical management of patients with PAH.…”

Section: Adult Congenital Heart Disease (Achd)mentioning

confidence: 99%

CS1, a controlled‐release formulation of valproic acid, for the treatment of patients with pulmonary arterial hypertension: Rationale and design of a Phase 2 clinical trial

Benza,

Adamson,

Bhatt

et al. 2024

Pulm. circ.

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Although rare, pulmonary arterial hypertension (PAH) is associated with substantial morbidity and a median survival of approximately 7 years, even with treatment. Current medical therapies have a primarily vasodilatory effect and do not modify the underlying pathology of the disease. CS1 is a novel oral, controlled‐release formulation of valproic acid, which exhibits a multi‐targeted mode of action (pulmonary pressure reduction, reversal of vascular remodeling, anti‐inflammatory, anti‐fibrotic, and anti‐thrombotic) and therefore potential for disease modification and right ventricular modeling in patients with PAH. A Phase 1 study conducted in healthy volunteers indicated favorable safety and tolerability, with no increased risk of bleeding and significant reduction of plasminogen activator inhibitor 1. In an ongoing randomized Phase 2 clinical trial, three doses of open‐label CS1 administered for 12 weeks is evaluating the use of multiple outcome measures. The primary endpoint is safety and tolerability, as measured by the occurrence of adverse events. Secondary outcome measures include the use of the CardioMEMS™ HF System, which provides a noninvasive method of monitoring pulmonary artery pressure, as well as cardiac magnetic resonance imaging and echocardiography. Other outcomes include changes in risk stratification (using the REVEAL 2.0 and REVEAL Lite 2 tools), patient reported outcomes, functional capacity, 6‐min walk distance, actigraphy, and biomarkers. The pharmacokinetic profile of CS1 will also be evaluated. Overall, the novel design and unique, extensive clinical phenotyping of participants in this trial will provide ample evidence to inform the design of any future Phase 3 studies with CS1.

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“…Studies that applied risk scores to clinical trials as post hoc analyses or exploratory endpoints have previously suggested that risk scores distinguish between treatment arms in clinical trials 15,18,20–22 ; however, an individual patient data meta‐analysis of the SERAPHIN, GRIPHON, and AMBITON clinical trials did not find that risk scores were predictive of long‐term outcomes 23 . REVEAL 2.0 and REVEAL Lite 2.0 have been shown to predict prognosis in individual patients on treatment and have excellent concordance indices (> 0.7), 24–27 demonstrating that they may have the potential to be used in clinical practice. Risk scores can be seen as more clinically meaningful than single endpoints, with a dynamic relationship between changes in score and changes in outcome, a key requirement for surrogate endpoints 28 ; however, further refinement of risk scores may be necessary to infer surrogacy.…”

Section: Composite Endpointsmentioning

confidence: 99%

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

2023

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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.

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Contemporary risk scores predict clinical worsening in pulmonary arterial hypertension - An analysis of FREEDOM-EV

Cited by 13 publications

References 29 publications

Oral Treprostinil is Associated with Improved Survival in FREEDOM-EV and its Open-Label Extension

Oral Treprostinil is Associated with Improved Survival in FREEDOM-EV and its Open-Label Extension

CS1, a controlled‐release formulation of valproic acid, for the treatment of patients with pulmonary arterial hypertension: Rationale and design of a Phase 2 clinical trial

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

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