Evidence map›Paper›PMID 22696079›Full record

SynthesisCirculation2012

Validation of 6-minute walk distance as a surrogate end point in pulmonary arterial hypertension trials.

Nicole B Gabler, Benjamin French, Brian L Strom, Harold I Palevsky, Darren B Taichman, Steven M Kawut, Scott D Halpern

2 registry-linked trialsAbstract readMeta-AnalysisValidation Study
PubMed Full text at PMC Publisher
In one paragraph

Synthesis in Circulation, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to 2 registered trials, which are not on this map. Cited by 103 papers, 11 of them syntheses that pooled it.

0numbers the graph read from it
0cells of the map it votes in
103citing papers in PubMed, 11 pooled it
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

NCT04633538 completednot on this mapstarted 2018, after this paper: background citation

Evaluation of a New 6 Minute Walk Test Smartphone App in Patients With Pulmonary Hypertension (The 6-APP Study)

TypeobservationalSponsorOxford University Hospitals NHS TrustRan2018 to 2020Enrolled30ConditionsPulmonary HypertensionArms6MWT smartphone app
NCT05096819 completednot on this mapstarted 2021, after this paper: background citation

Evaluation of the Usefulness of Adopting Remote, Mobile-based 6MWT Among Hospital Outpatients (the 6-APPnow), Within the Constraints Imposed by the SARS-COV2 Pandemic

TypeobservationalSponsorOxford University Hospitals NHS TrustRan2021 to 2023Enrolled67ConditionsPulmonary HypertensionArmsPatients Using the 6MWT App in the Community, Volunteers for 6MWT distance comparison
3 · Its place in the literature

Who cites it

103 citing papers in PubMed, 11 syntheses or guidelines pooled it.

  1. Parenteral treprostinil in paediatric pulmonary arterial hypertension: a systematic review and meta-analysis.European respiratory review : an official journal of the European Respiratory Society · 2026
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43 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

7 authors.

Nicole B GablerCenter for Clinical Epidemiology and Biostatistics, Philadelphia, PA, USA. gabler@upenn.edu
Benjamin French
Brian L Strom
Harold I Palevsky
Darren B Taichman
Steven M Kawut
Scott D Halpern

Funding

Mentored Patient-Oriented Research in Pulmonary Arterial HypertensionK24HL103844 · NHLBI · UNIVERSITY OF PENNSYLVANIA · PI KAWUT, STEVEN M · 2011 to 2020
$1.6M
NHLBI NIH HHS K24 HL103844
6 · The paper itself

Abstract

backgroundNearly 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. METHODS AND

resultsFirst, 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.

conclusionsOur 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.

Indexed as

WalkingAdultDisability EvaluationDrug MonitoringEndothelin Receptor AntagonistsFamilial Primary Pulmonary HypertensionFemaleHumansHypertension, PulmonaryMaleMiddle AgedPhosphodiesterase InhibitorsProstaglandinsRandomized Controlled Trials as TopicRecovery of FunctionReproducibility of ResultsEndothelin Receptor AntagonistsPhosphodiesterase InhibitorsProstaglandins

Identifiers

PMID22696079
PMCPMC4237273

What OpenQuestion holds

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Read underepoch 390

Registered trials

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.