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Alive and Ventilator Free

A Hierarchical, Composite Outcome for Clinical Trials in the Acute Respiratory Distress Syndrome

Novack, Victor MD, PhD1,2; Beitler, Jeremy R. MD, MPH3; Yitshak-Sade, Maayan PhD1,4; Thompson, B. Taylor MD5; Schoenfeld, David A. PhD6; Rubenfeld, Gordon MD7; Talmor, Daniel MD, MPH2; Brown, Samuel M. MD, MS8

doi: 10.1097/CCM.0000000000004104
Clinical Investigation: PDF Only

Objectives: Survival from acute respiratory distress syndrome is improving, and outcomes beyond mortality may be important for testing new treatments. The “ventilator-free days” score, is an established composite that equates ventilation on day 28 to death. A hierarchical outcome treating death as a worse than prolonged ventilation would enhance face validity, but performance characteristics and reporting of such an outcome are unknown. We therefore evaluated the performance of a novel hierarchical composite endpoint, the Alive and Ventilator Free score.

Design: Using data from four Acute Respiratory Distress Syndrome Network clinical trials, we compared Alive and Ventilator Free to the ventilator-free days score. Alive and Ventilator Free compares each patient with every other patient in a win-lose-tie for each comparison. Duration of mechanical ventilation is only compared if both patients survived. We evaluated power of Alive and Ventilator Free versus ventilator-free days score under various circumstances.

Setting: ICUs within the Acute Respiratory Distress Syndrome Network.

Patients: Individuals enrolled in four Acute Respiratory Distress Syndrome Network trials.

Interventions: None for this analysis.

Measurements and Main Results: Within the four trials (n = 2,410 patients), Alive and Ventilator Free and ventilator-free days score had similar power, with Alive and Ventilator Free slightly more powerful when a mortality difference was present, and ventilator-free days score slightly more powerful with a difference in duration of mechanical ventilation. Alive and Ventilator Free less often found in favor of treatments that increased mortality and increased days free of ventilation among survivors.

Conclusions: A hierarchical composite endpoint, Alive and Ventilator Free, preserves statistical power while improving face validity. Alive and Ventilator Free is less prone to favor a treatment with discordant effects on survival and days free of ventilation. This general approach can support complex outcome hierarchies with multiple constituent outcomes. Approaches to interpretation of differences in Alive and Ventilator Free are also presented.

1Clinical Research Center, Soroka University Medical Center, Beer Sheva, Israel.

2Department of Anesthesia, Critical Care and Pain Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA.

3Center for Acute Respiratory Failure and Division of Pulmonary, Allergy, and Critical Care Medicine, Columbia University College of Physicians and Surgeons, New York, NY.

4Exposure, Epidemiology, and Risk Program, Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA.

5Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA.

6Biostatistics Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA.

7Sunnybrook Hospital Toronto, Toronto, ON, Canada.

8Division of Pulmonary and Critical Care Medicine, Intermountain Medical Center and University of Utah School of Medicine, Salt Lake City, UT.

Drs. Novack, Beitler, and Brown were involved in drafting the work. Drs. Yitshak-Sade, Thompson, Schoenfeld, Rubenfeld, and Talmor were involved in critical revision for important intellectual content. Drs. Novack, Beitler, Yitshak-Sade, and Brown were involved in statistical analysis. All authors were involved in substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work. All authors were involved in final approval of the version to be published. All authors were involved in agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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Supported, in part, by grant from the National Institutes of Health.

Dr. Novack received funding from Cardiomed Consultants LLC. Drs. Beitler’s and Schoenfeld’s institution received funding from the National Institutes of Health (NIH). Drs. Beitler, Thompson, Schoenfeld, and Brown received support for article research from the NIH. Dr. Thompson’s institution received funding from the National Heart, Lung, and Blood Institute (NHLBI) and Department of Defense; reports consulting for Bayer, Boehringer Ingelheim, and GlaxoSmithKline; and authorship for UpToDate, all outside the submitted work. Drs. Talmor (1UM1HL108724) and Beitler (K23HL133489) received funding from NHLBI. The remaining authors have disclosed that they do not have any potential conflicts of interest.

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