Easily applicable multiple testing procedures to improve the interpretation of clinical trials with composite endpoints

TY - JOUR

T1 - Easily applicable multiple testing procedures to improve the interpretation of clinical trials with composite endpoints

AU - Schüler, Svenja

AU - Mucha, Annegret

AU - Doherty, Patrick

AU - Kieser, Meinhard

AU - Rauch, Geraldine

N1 - Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

PY - 2014/7/15

Y1 - 2014/7/15

N2 - BACKGROUND: Cardiology trials often consider composite endpoints as primary efficacy outcomes thereby combining several time-to-event variables in a single time-to-first-event measure. The main motivation to use a composite endpoint is to increase the number of expected events thereby reducing the required sample size. However, interpretation may be difficult as the effect observed for the composite endpoint does not necessarily reflect the effects for the single components. To improve interpretation, it is therefore a current standard to analyze the individual components in a descriptive way. However, a descriptive analysis does not allow a statistical proof of concept. Therefore the gain in information is limited.METHODS: This paper systematically explores multiple testing procedures aimed at improving the interpretation of composite endpoints by confirmatory tests of the components. A simulation study demonstrates, on the basis of a real cardiology clinical trial example, the benefit of these easily applicable multiple testing procedures.RESULTS: By applying adequate multiple testing strategies to assess the components of a composite endpoint there is a high chance to get additional confirmatory evidence on the components without the need to increase sample size. With a moderate increase in sample size, a gain in evidence can often also be ensured with a predefined power.CONCLUSION: The interpretation of composite endpoints can be improved by applying multiple testing procedures that assess the components. The methods discussed here are easy to apply and provide a substantial benefit for clinical interpretation of study results.

AB - BACKGROUND: Cardiology trials often consider composite endpoints as primary efficacy outcomes thereby combining several time-to-event variables in a single time-to-first-event measure. The main motivation to use a composite endpoint is to increase the number of expected events thereby reducing the required sample size. However, interpretation may be difficult as the effect observed for the composite endpoint does not necessarily reflect the effects for the single components. To improve interpretation, it is therefore a current standard to analyze the individual components in a descriptive way. However, a descriptive analysis does not allow a statistical proof of concept. Therefore the gain in information is limited.METHODS: This paper systematically explores multiple testing procedures aimed at improving the interpretation of composite endpoints by confirmatory tests of the components. A simulation study demonstrates, on the basis of a real cardiology clinical trial example, the benefit of these easily applicable multiple testing procedures.RESULTS: By applying adequate multiple testing strategies to assess the components of a composite endpoint there is a high chance to get additional confirmatory evidence on the components without the need to increase sample size. With a moderate increase in sample size, a gain in evidence can often also be ensured with a predefined power.CONCLUSION: The interpretation of composite endpoints can be improved by applying multiple testing procedures that assess the components. The methods discussed here are easy to apply and provide a substantial benefit for clinical interpretation of study results.

KW - Endpoint Determination

KW - Humans

KW - Randomized Controlled Trials as Topic

KW - Sample Size

KW - Statistics as Topic

KW - Journal Article

U2 - 10.1016/j.ijcard.2014.04.267

DO - 10.1016/j.ijcard.2014.04.267

M3 - SCORING: Journal article

C2 - 24861257

VL - 175

SP - 126

EP - 132

JO - INT J CARDIOL

JF - INT J CARDIOL

SN - 0167-5273

IS - 1

ER -