Problems with use of composite end points in cardiovascular trials: systematic review of randomised controlled trials.
OBJECTIVE
To explore the extent to which components of composite end points in randomised controlled trials vary in importance to patients, the frequency of events in the more and less important components, and the extent of variability in the relative risk reductions across components.


METHODS
Systematic review of randomised controlled trials.


METHODS
Cardiovascular randomised controlled trials published in the Lancet, Annals of Internal Medicine, Circulation, European Heart Journal, JAMA, and New England Journal of Medicine, from 1 January 2002 to 30 June 2003. Component end points of composite end points were categorised according to importance to patients as fatal, critical, major, moderate, or minor.


RESULTS
Of 114 identified randomised controlled trials that included a composite end point of importance to patients, 68% (n=77) reported complete component data for the primary composite end point; almost all (98%; n=112) primary composite end points included a fatal end point. Of 84 composite end points for which component data were available, 54% (n=45) showed large or moderate gradients in both importance to patients and magnitude of effect across components. When analysed by categories of importance to patients, the most important components were associated with lower event rates in the control group (medians of 3.3-3.7% for fatal, critical, and major outcomes; 12.3% for moderate outcomes; and 8.0% for minor outcomes). Components of greater importance to patients were associated with smaller treatment effects than less important ones (relative risk reduction of 8% for death and 33% for components of minor importance to patients).


CONCLUSIONS
The use of composite end points in cardiovascular trials is frequently complicated by large gradients in importance to patients and in magnitude of the effect of treatment across component end points. Higher event rates and larger treatment effects associated with less important components may result in misleading impressions of the impact of treatment.
Ferreira-González
Ignacio
I
Departament de Medicina, Universitat Autònoma de Barcelona, and Hospital Vall d'Hebron, Barcelona 08035, Spain.
Busse
Jason W
JW
Heels-Ansdell
Diane
D
Montori
Victor M
VM
Akl
Elie A
EA
Bryant
Dianne M
DM
Alonso-Coello
Pablo
P
Alonso
Jordi
J
Worster
Andrew
A
Upadhye
Suneel
S
Jaeschke
Roman
R
Schünemann
Holger J
HJ
Permanyer-Miralda
Gaietà
G
Pacheco-Huergo
Valeria
V
Domingo-Salvany
Antònia
A
Wu
Ping
P
Mills
Edward J
EJ
Guyatt
Gordon H
GH
D002318:Cardiovascular Diseases / Q000517:prevention & control*; D023381:Endpoint Determination; D006801:Humans; D015588:Observer Variation; D016032:Randomized Controlled Trials as Topic / Q000379:methods / Q000592:standards*; D040242:Risk Reduction Behavior; D013223:Statistics as Topic