DOI: 10.4244/EIJ-D-21-00440R

Reply: Composite endpoints in clinical trials - simplicity or perfection?

Hironori Hara1,2, MD; Yoshinobu Onuma2, MD, PhD; Patrick W. Serruys2,3, MD, PhD

We are grateful for the insightful comments of Lozano et al1 mentioning that a reasonable approach would be a combination of the time-to-first-event method (primary endpoint) and additional appropriate analyses as sensitivity analyses. We agree with their opinion. However, only the time-to-first-event method is commonly applied to the analysis of composite endpoints in current clinical trials. We recently applied the multiple statistical methods for composite endpoints (time-to-first-event, negative binomial regression, Andersen-Gill, win-ratio, and weighted composite endpoint methods) to the GLOBAL LEADERS trial23. The GLOBAL LEADERS trial investigated aspirin-free antiplatelet treatment (experimental arm: 1-month dual antiplatelet therapy [DAPT] followed by 23-month ticagrelor monotherapy vs reference arm: 12-month DAPT followed by 12-month aspirin monotherapy) in an all-comers population. The results were consistent in that ticagrelor monotherapy reduced ischaemic and bleeding events by 5-8%. However, only the results of negative binomial regression and Andersen-Gill analyses demonstrated the statistically significant risk reduction (p-values less than 0.05), while others (time-to-first-event, win-ratio, and weighted composite endpoint methods) did not. We would propose pre-specifying the details for additional methodological analyses in a statistical analysis plan (SAP) to avoid any arbitrariness. First, the methods for counting repeated events should be clarified. In other words, how to handle a sequence of adverse events should be defined. For example, if a patient suffered myocardial infarction and died the next day, should this sequence of events be counted as one event (cardiovascular death) or two events (non-fatal myocardial infarction and cardiovascular death)? Along the same lines, if myocardial infarction caused heart failure on the same day, should these be counted as one event or two events? The method of event counting could influence the results, especially in the analyses of negative binomial regression and Cox-based models for recurrent events (Andersen-Gill and the Wei-Lin-Weissfeld models). Second, the weights of cardiovascular events in previous research are not consistent; the consensus for event severity and weight has not been achieved yet. Event severity and weight could be dependent on patient characteristics and perspectives. The impact of percutaneous coronary intervention could be different in patients with and without previous coronary stenting. Furthermore, an examination of patients’ perspectives regarding composite endpoints reported that disabling stroke was more severe than death4, although death is treated as the most severe event in clinical trials. Therefore, event severity and weight should be discussed in each trial based on the patient’s background, and the event severity and weight should be prespecified. As Lozano et al point out, the sample size calculation in the novel methodological methods is more complex than that in the time-to-first-event analysis. However, dedicated codes for sample size calculation in the novel methodological methods have been developed56, which would support analyses using novel methodological methods in future clinical trials. Applying not only the time-to-first-event method but also other prespecified statistical methods could emphasise the multiple facets of a trial and could result in more appropriate analyses.

Conflict of interest statement

H. Hara reports a grant for studying overseas from the Japanese Circulation Society, a Grant-in-Aid for JSPS Fellows and a grant from the Fukuda Foundation for Medical Technology. The other authors have no conflicts of interest to declare.

Supplementary data

To read the full content of this article, please download the PDF.

Volume 17 Number 13
Jan 28, 2022
Volume 17 Number 13
View full issue


Key metrics

Suggested by Cory

10.4244/EIJ-D-21-00440L Jan 28, 2022
Letter: Composite endpoints in clinical trials - simplicity or perfection?
Lozano I et al
free

10.4244/EIJV11I1A22 May 19, 2015
Novel approaches to composite endpoints in clinical trials
Westerhout C and Bakal J
free

Expert review

10.4244/EIJ-D-19-00953 Apr 2, 2021
Statistical methods for composite endpoints
Hara H et al
free

10.4244/EIJV9I1A3 May 21, 2013
EuroIntervention - Methodology and Statistics Review Board
Boersma E et al
free

10.4244/EIJV16I18A266 Apr 2, 2021
Similar long-term outcome of dissimilar drug-eluting stents: is it time to change the assessment?
von Birgelen C and Ploumen EH
free

Editorial

10.4244/EIJ-E-24-00038 Aug 19, 2024
Impella – a treatment for all STEMI patients with cardiogenic shock? The effect of off-hours admission
Engstrøm T and Madsen J
free
Trending articles
151.43

State-of-the-Art

10.4244/EIJ-D-22-00776 Apr 3, 2023
Computed tomographic angiography in coronary artery disease
Serruys PW et al
free
55.9

Clinical research

10.4244/EIJ-D-22-00621 Feb 20, 2023
Long-term changes in coronary physiology after aortic valve replacement
Sabbah M et al
free
54.9

Expert review

10.4244/EIJ-D-21-01010 Jun 24, 2022
Device-related thrombus following left atrial appendage occlusion
Simard T et al
free
43.75

Clinical Research

10.4244/EIJ-D-21-01091 Aug 5, 2022
Lifetime management of patients with symptomatic severe aortic stenosis: a computed tomography simulation study
Medranda G et al
free
39.95

Clinical research

10.4244/EIJ-D-22-00558 Feb 6, 2023
Permanent pacemaker implantation and left bundle branch block with self-expanding valves – a SCOPE 2 subanalysis
Pellegrini C et al
free
X

The Official Journal of EuroPCR and the European Association of Percutaneous Cardiovascular Interventions (EAPCI)

EuroPCR EAPCI
PCR ESC
Impact factor: 7.6
2023 Journal Citation Reports®
Science Edition (Clarivate Analytics, 2024)
Online ISSN 1969-6213 - Print ISSN 1774-024X
© 2005-2024 Europa Group - All rights reserved