1 Introduction
Choosing the primary endpoint (PE) in a randomized controlled trial (RCT) is a critical decision in the design phase. Composite endpoints are defined as the occurrence of any of the relevant events in trials with binary response and as the time from randomization to the first observed event among all components in timetoevent studies. Some examples are the composite of death or myocardial reinfarction and major adverse cardiovascular events (MACE) generally defined as a composite of cardiovascular death, myocardial infarction, stroke and target vessel revascularization.
What are the reasons for using a CE? On the one hand, taking into account multiple outcomes altogether could provide a broader overview of an intervention’s efficacy (1). On the other hand, if the event rates are too low, it could increase the study power. However, CEs also hide some drawbacks. For instance, the tested intervention should have a similar effect on all the components while none of them should be affected negative (2). Moreover, having more outcomes does not necessarily imply an increase in power: small intervention effects on one component could mask significant effects on others (3) or strong associations may reduce the joint information.
We discuss the gain in efficiency of adding endpoints to form a primary CE rather than simply using a single relevant endpoint. We provide a multitask tool named CompARE that can be freely access through https://cinna.upc.edu/compare/ as an aid for a more wellinformed decision. The code of the functions implemented in this web app is available in GitHub at https://github.com/CompAREComposite/Functions. CompARE allows to check the efficiency of different designs with more than one outcome and provides a calculator to get the required sample size based on several CEs configurations among other features. This will be illustrated through two RCT published in NEJM and European Heart Journal, respectively (4,5).
List of abbreviations ARE: Asymptotic Relative Efficiency , , : Relevant event, ; Additional event, ; Composite event, , defined as or . HR: Hazard Ratio PE: Primary Endpoint OS: Overall survival MI: Myocardial infarction
2 Relative Efficiency of Using Composite Endpoints
Should we use the most relevant endpoint (such as overall survival, OS) as the PE for a twoarm RCT? Or should we base our trial on a CE that includes an additional endpoint (such as myocardial reinfarction)? Both endpoints are capable of measuring the treatment effect in the same direction, are of interest to the investigator but they are not equally efficient.
What does efficiency mean when it refers to an endpoint that may be chosen for testing a therapy or treatment? According to the Oxford dictionary, a system is efficient when it “achieves maximum productivity with minimum wasted effort or expense”. A hypothesis testing procedure based on a given endpoint is efficient when it can be influenced by the treatment achieving maximum power for a given sample size. The efficiency is then a measure of the quality of a given test based on an endpoint, while the relative efficiency between two endpoints is determined by their efficiency ratio. Since often we can only assess the efficiency of a statistical test for large enough sample sizes, we use the asymptotic relative efficiency (ARE) as the principal comparison measure. This measure has been studied in a timetoevent framework (6) as well as in a binary setup (7) and it has been used (8) to assess, in the cardiovascular research area, the characteristics that a potential endpoint should have to be part of the CE leading the trial.
Suppose that, two potential endpoints could satisfactorily answer the study’s primary clinical question: we could use a relevant event, say , or the composite event (), say or , where is some additional endpoint. The ARE measure can be roughly interpreted as the ratio of the required sample sizes using versus to attain the same power for a given significance level (9) yielding the following criterion: whenever ARE 1, choose as PE to guide the study; otherwise, use .
To calculate the ARE we need to anticipate: the frequencies of observing events and in the control group; the relative treatment effect given by either the hazard ratios (HR) –survival outcome– or risk differences –binary outcome– and a measure of the association between components. In very general terms, one should use the CE (ARE1) if the relative effect of treatment on the additional endpoint is greater or about the same as that on the relevant endpoint. Nevertheless, other scenarios such as those for slightly smaller relative effect of treatment on the additional endpoint together with low frequencies of observing the relevant endpoint, might yield ARE1, thus, making the composite endpoint more efficient. Furthermore, as we discuss next, the association between and plays a major role when computing the ARE. The ability to make a wellinformed decision can be aided by a simple and friendly tool, such as CompARE, which allows calculating the ARE in various clinical trial scenarios.
3 Association Between the Components of the Composite Endpoint
The association between and plays a major role when computing the ARE. Two endpoints are positively associated when a large value of one implies a large value of the other, and vice versa.
The association between two binary outcomes can be measured by means of Pearson’s correlation, although the conditional probability of one, given the other, might furnish a more natural and interpretable understanding of association. When we wonder about the percentage of patients ends up suffering a stroke after having a myocardial infarction (MI), the interpretation is quite clear in terms of conditional probability. The positive and linear relationship between the correlation coefficient and the conditional probability allows to use the estimated conditional probability to guess the correlation. For instance, if the frequency of having a MI and suffering a stroke are roughly equal and very low (say, less than 5%), the correlation between them is approximately equal to the proportion of patients having a MI among those that had a stroke.
ARE insights The clinical question could be satisfactorily answered by events and = or , where is some additional endpoint. ARE quantifies how much more efficient the composite endpoint is over as the primary endpoint of the study: If ARE 1, choose to guide the study; If ARE 1, base the study on . To compute ARE, we need to anticipate: frequencies of observing and in the control group, relative treatment effect given by the hazard ratios (in a survival trial) or risk differences (in a binary trial). In the survival setting, additional assumptions should be made. a measure of the association between and .
The association between the timetoevent outcomes for and is a little bit “tricky” in the presence of competing risks, when one outcome could prevent the observation of the other. The ARE method is based on a joint copula model built on the cause specific hazards for times to and and on Spearman’s rho correlation between these times. We strongly remark here that the anticipation of Spearman’s rho is only done for the purpose to obtain precise sample size calculations and not assumed to be used or computed in the analysis phase when it makes no sense to get the association between times to and when one of them is death.
It has been shown (6,7) that the efficiency of using a CE rather than using its more relevant component decreases as the composite components become more associated; or, in other words, the more correlated the components are, the larger the sample size needed for the trial (9) and using the CE might not be worthwhile.
The association between the components of the composite endpoint has a significant impact both on the probability of observing the composite endpoint and on the efficiency of the composite endpoint as a primary endpoint. Therefore, it is of utmost importance to consider how the components of the composite endpoint are associated, quantify this association and report them in all documents and summaries derived from the trials.
4 Case Studies Using Compare
We illustrate the PE decision using two RCTs and with the aid of CompARE, which is useful for different purposes as shown in Figure 1. CompARE is a comprehensive and freely available webtool intended to provide guidance on how to deal with composite endpoints in the planning stage of a randomized controlled trial. CompARE can also be used to:

Choose the best primary endpoint to lead the trial. CompARE computes the ARE to quantify the gain in the efficiency of using –as the primary endpoint– a composite endpoint over one of its components.

Specify the treatment effect for the composite endpoint based on the marginal information of the composite components and to study the performance of the composite parameters according to these. In a survival trial, it can also evaluate the proportional hazards assumption for the composite endpoint.

Determine the sample size for different situations, such as when the association between composite components is unknown or when the hazards are not proportional.

Calculate and interpret the different association measures among the composite components.
The code to reproduce the following two case studies is available in GitHub.
4.1 TUXEDO trial: binary endpoints
The TUXEDO study was a RCT aimed at comparing paclitaxeleluting stents (control group) with everolimuseluting stents (intervention group) (4). The PE was targetvessel failure (), defined as a composite of cardiac death, target vessel MI or ischemiadriven targetvessel revascularization at 1year of followup. The secondary endpoints were, among others, the ischemiadriven targetlesion revascularization (, revascularization for short) and the endpoint of cardiac death or targetvessel MI (, death or MI for short). The TUXEDO protocol was based on the results of the SPIRIT IV trial (10), which faced similar research questions and considered the same PE and that we will use as reference values for illustrative purposes. The association between the different outcomes was not reported, nor was the number of patients who had more than one event.
Would it have been preferable to consider revascularization () instead of the CE of targetvessel failure () as PE? We discuss it considering that the frequency of and in the control group were 5.9% and 3.2%, respectively. Everolimuseluting stents as compared with paclitaxeleluting stents resulted in a 1.96 percentagepoint absolute reduction in and a 0.98 percentagepoint absolute reduction in .
Association  Correlation  Conditional  Conditional  Probability of  Percentagepoint  Total 

probability  probability  observing  absolute reduction  Sample Size  
given  given  
Weak  0.1  0.19  0.1  0.08  2.7  2,187 
Moderate  0.4  0.58  0.31  0.07  2.3  2,561 
Strong  0.7  0.97  0.52  0.06  2.0  3,076 
Table 1 presents three scenarios according to weak, moderate, strong degrees of association between revascularization and death or MI. The strength of association is provided both in terms of the correlation coefficient (0.1, 0.4, 0.7) and as the conditional probability of given a . For each of these scenarios and based on the values provided by the SPIRIT IV trial, the probability of observing in the control group ranges between 6% and 8%; and the expected absolute reduction for takes values between 2.3 and 2.9. Observe that both the probability and the expected effect for decrease as the association increases, and this pattern is always found (11,12). We have also computed the required total sample size for a trial with as PE. Notice that, as the association between the composite components gets larger, the sample size is increasingly higher.
Figure 2 shows that the efficiency of using as PE rather than decreases as the components become more correlated. Indeed, revascularization is preferred over targetvessel failure when and are strongly associated. To study the extent to which adding affects the PE choice, we consider several effect values for : for a given correlation, the ARE increases as the anticipated treatment effect in gets larger.
4.2 OASIS6 trial: timetoevent endpoints
Odlgren et al. (5) tested fondaparinux treatment vs. placebo or unfractionated heparin, in a prespecified subgroup of 2,867 patients not receiving reperfusion treatment in the OASIS6 trial. The primary outcome was the composite endpoint () of death or myocardial reinfarction at 30 days. The observed frequency in the control group was 0.125 for OS () and 0.037 for myocardial reinfarction (), and the estimated HRs were 0.83 for and 0.66 for .
If a new similar study was planned, should we use the composite endpoint () to lead the trial or should we stick to OS as the PE? Figure 3 shows how CompARE can help to discuss the efficiency of using death or myocardial reinfarction as PE (see also Figure 4), to compare sample sizes and to illustrate effect sizes for several scenarios with different HRs (between 0.65 and 0.90) for and several degrees of association.
Figure 4 (selfexplained) shows the influence of correlation on the ARE value and, consequently, can be used as a criterion to choose between OS or the CE formed by death () and Myocardial reinfarction (). The ARE values (vertical axis) depend on the Spearman correlation (horizontal axis) and the treatment effect of the additional endpoint (colored lines). Causespecific hazard function for the time to Myocardial reinfarction () and the time to death () are assumed constant during the followup.
When the PE is based on the time from randomization to , the behavior of the corresponding causespecific hazards has to be as well anticipated. Table 2 presents the ARE and the required sample size under five selected scenarios, assuming constant, increasing or decreasing hazards for each outcome and strong correlation between them. ARE is greater than 1 in all scenarios and hence is always recommended; however sample sizes vary a lot – in a range from 2,682 to 3,381 – exemplifying the impact of the hazard shape over time.
Hazard of death  Hazard of  ARE  Total 

myocardial reinfarction  Sample Size  
Increasing  Decreasing  1.84  3,381 
Constant  Decreasing  1.90  3,278 
Constant  Constant  2.02  3,084 
Constant  Increasing  2.18  2,857 
Decreasing  Increasing  2.32  2,682 
ARE and the required sample size to achieve an 80% power at a significance level of 0.05 for detecting differences in the CE, depending on the causespecific hazard behavior over time for each component: constant (exponential distribution), increasing (Weibull distribution with shape parameter equals 2) or decreasing (Weibull with shape parameter equals 0.5). Other assumed parameters: i) frequencies of 0.125 and 0.05 for death and myocardial reinfarction in the control arm; ii) HRs of 0.83 and 0.66 for OS and myocardial reinfarction; and iii) Spearman’s rho correlation between components equal to 0.7, considering Gumbel copula. Sample size calculations are based on the Freedman formula.
5 Discussion
Composite endpoints are commonly used in clinical trials and observational studies. However, contrary to popular belief, composite endpoints only barely increase total eventprobability and do not necessarily yield higher power.
The design of a randomized controlled trial involving a composite endpoint needs a careful specification of the expected rates, the treatment effects and the correlation between the components. While the frequencies and relative effects of the primary and secondary endpoints in most of the published clinical trials can often be derived from previous studies, the degree of association between them are seldom disclosed. CompARE can be used to explore different scenarios and for each one calculate the treatment effect for the CE and the needed sample size.
Because the association between the composite components plays an important role in the overall expected frequency of the CE, but also in the statistical power of the study, this information is critical in designing a trial, it has a large impact on the design efficiency, notably on the PE choice and, hence, on the trial’s sample size. For example, the SAMPL guidelines (13) enumerate the items to be reported for each type of analysis, but currently do not make any reference to this point. We urge trialists to report, as accurately as possible, all the primary and secondary parameter information as well as a measure of the association between the endpoints considered in the trial.
Acknowledgements
This work is partially supported through grant MTM201564465C21R (MINECO/FEDER, UE) from the Secretaría de Estado de Investigación, Desarrollo e Innovación del Ministerio de Economía y Competitividad (Spain) and through grant 2017 SGR 622 (GRBIO) from the Departament d’Economia i Coneixement de la Generalitat de Catalunya (Spain). Marta Bofill Roig acknowledges financial support from the Spanish Ministry of Economy and Competitiveness, through the María de Maeztu Programme for Units of Excellence in R&D (MDM20140445).
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