# Two-sample win ratio tests of possibly recurrent event and death

## INTRODUCTION

This vignette demonstrates the use of the WR package for two-sample win ratio tests of recurrent event and death (Mao et al., 2022).

### Data

Let $$D$$ denote the survival time and write $$N_D(t)=I(D\leq t)$$. Likewise, let $$T_1<T_2<\cdots$$ denote the recurrent event times and write $$N_H(t)=\sum_{k=1}^\infty I(T_k\leq t)$$. In other words, $$N_H(t)$$ is the counting process for the recurrent event. Since death is a terminal event, we must have that $$N_H(t)=N_H(t\wedge D)$$, where $$b\wedge c=\min(b,c)$$. Let $$\boldsymbol Y(t)=\{N_D(u), N_H(u):0\leq u\leq t\}$$ denote the event history up to time $$t$$. The full outcome data without censoring are thus $$\boldsymbol Y:=\boldsymbol Y(\tau)$$, where $$\tau$$ is the maximum length of follow-up.

### General framework for hypotheses and tests

Use $$a=1$$ to denote the active treatment and $$a=0$$ to denote the control. For all notation introduced above, use the subscript $$(a)$$ to denote the corresponding group-specific quantity. For example, $$\boldsymbol Y^{(a)}$$ represents the outcome data from group $$a$$ $$(a=1, 0)$$. Consider a time-dependent win function of the form $\mathcal W(\boldsymbol Y^{(a)}, \boldsymbol Y^{(1-a)})(t) = I(\mbox{patient in group a wins against that in group 1-a by time t}).$ The specific definition of $$\mathcal W$$ will be discussed later.

Given such a rule of cross-group comparison, the win and loss probabilities for the treatment against control by time $$t$$ are $$w(t)=E\{\mathcal W(\boldsymbol Y^{(1)}, \boldsymbol Y^{(0)})(t)\}$$ and $$l(t)=E\{\mathcal W(\boldsymbol Y^{(0)}, \boldsymbol Y^{(0)})(t)\}$$, respectively. Suppose that we wish to test the null hypothesis that the win and loss probabilities are equal, i.e., $H_0: w(t)=l(t)\hspace{2ex}\mbox{for all }t\in[0, \tau],$ against the alternative hypothesis that the win probability dominates the loss probability, i.e., $$$\tag{1} H_A: w(t)\geq l(t)\hspace{1ex}\mbox{for all }t\in[0, \tau] \mbox{ with strict inequality for some }t.$$$ With censored data, a general way to test such hypotheses is to use a log-transformed two-sample win ratio constructed similarly to Pocock et al. (2012), only with the pairwise rule of comparison replaced by the customized $$\mathcal W(\cdot,\cdot)(t)$$, where $$t$$ is set as the earlier of the two observed follow-up times. A stratified test can also be developed along the lines of Dong et al. (2018).

### Choice of win function

Different choices of $$\mathcal W$$ will lead to different hypotheses and tests. The standard win ratio (SWR) of Pocock et al. (2012) corresponds to the choice of $\mathcal W_S(\boldsymbol Y^{(a)}, \boldsymbol Y^{(1-a)})(t) =I(D^{(1-a)}<D^{(a)}\wedge t)+I(D^{(a)}\wedge D^{(1-a)}>t, T_1^{(1-a)}<T_1^{(a)}\wedge t).$ With recurrent nonfatal event, $$\mathcal W_S$$ fails to fully exploit the data as it draws only on the first occurrence. A more efficient rule is given by the last-event-assisted win ratio (LWR), which compares on the nonfatal event first by its cumulative frequency, with ties broken by the time of its last episode. In other words, \begin{align} \mathcal W_L(\boldsymbol Y^{(a)}, \boldsymbol Y^{(1-a)})(t) &=I(D^{(1-a)}<D^{(a)}\wedge t)+I\{D^{(a)}\wedge D^{(1-a)}>t, N_H^{(a)}(t)<N_H^{(1-a)}(t)\}\\ &\hspace{1ex}+I\{D^{(a)}\wedge D^{(1-a)}>t, N_H^{(a)}(t)=N_H^{(1-a)}(t)=\mbox{ some } k, T_k^{(1-a)}<T_k^{(a)}\}. \end{align} Likewise we can construct a first-event-assisted win ratio (FWR) by replacing the $$T_k^{(a)}$$ with the $$T_1^{(a)}$$, or a naive win ratio (NWR) by removing the tie-breaking third term altogether (see Mao et al. (2022) for details). Nonetheless, it is recommended that the LWR be used as the default, as it makes fuller use of the data and reduces to the SWR when the nonfatal event occurs at most once.

Under the LWR, a simple condition that implies the dominance of win probability in (1) is a joint stochastic order of the event times between the two groups: $$$\tag{2} {P}(D^{(1)}>s, T^{(1)}_{1}>t_1, T^{(1)}_{2}>t_2, \ldots)> {P}(D^{(0)}>s, T^{(0)}_{1}>t_1, T^{(0)}_{2}>t_2, \ldots),$$$ for all $$0\leq t_1\leq t_2\leq\cdots\leq s\leq\tau$$. Expression (2) means that the treatment stochastically delays all events, fatal and nonfatal, jointly as compared to the control. Hence, when (2) is true, the LWR test rejects $$H_0$$ with probability tending to 1 as the sample size increases to infinity.

## BASIC SYNTAX

The basic function to perform the win ratio tests is WRrec(). To use the function, the input data must be in the “long” format. Specifically, we need an ID variable containing the unique patient identifiers, a time variable containing the event times, a status variable labeling the event type (status=2 for recurrent non-fatal event, =1 for death, and =0 for censoring), and, finally, a binary trt variable with 1 indicating the treatment and 0 indicating the control. To perform an unstratified LWR test, use

obj<-WRrec(ID,time,status,trt)

For a stratified test, supply a vector of stratifying (categorical) variable through an additional strata= argument. To get test results from FWR and NWR as well, add the option naive=TRUE. Printing the object obj gives us the $$p$$-values of the tests as well as some descriptive statistics.

## AN EXAMPLE WITH THE HF-ACTION TRIAL

### Data description

To illustrate the win ratio tests, consider the Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training (HF-ACTION) trial. A randomized controlled trial, HF-ACTION was conducted on a cohort of over two thousand heart failure patients recruited between 2003–2007 across the USA, Canada, and France (O’Connor et al., 2009). The study aimed to assess the effect of adding aerobic exercise training to usual care on the patient’s composite endpoint of all-cause death and all-cause hospitalization. The primary analysis of the whole study population showed a moderate and non-significant reduction in the risk of time to the first composite event (hazard ratio 0.93; $$p$$-value 0.13). Here we focus on a subgroup of non-ischemic patients with reduced cardio-pulmonary exercise (CPX) test duration (i.e., $$\leq 9$$ minutes before reporting of discomfort). There are scientific and empirical evidence suggesting that this particular sub-population may benefit more from exercise training interventions than does the average heart failure patient.

The associated dataset hfaction_cpx9 is contained in the WR package and can be loaded by

library(WR)
#>        patid       time status trt_ab age60
#> 1 HFACT00001  7.2459016      2      0     1
#> 2 HFACT00001 12.5573770      0      0     1
#> 3 HFACT00002  0.7540984      2      0     1
#> 4 HFACT00002  4.2950820      2      0     1
#> 5 HFACT00002  4.7540984      2      0     1
#> 6 HFACT00002 45.9016393      0      0     1

The dataset is already in a format suitable for WRrec() (status= 2 for hospitalization and = 1 for death). The time variable is in units of months and trt=0 for usual care (control) and 1 for exercise training. The age60 variable is an indicator of patient age being greater than or equal to 60 years and can potentially serve as a stratifying variable.

### Win ratio tests on recurrent event and death

To perform the win ratio tests between exercise training and usual care stratified by age, use the code

## simplify the dataset name
dat<-hfaction_cpx9
## comparing exercise training to usual care by LWR, FWR, and NWR
obj<-WRrec(ID=dat$patid,time=dat$time,status=dat$status, trt=dat$trt_ab,strata=dat$age60,naive=TRUE) ## print the results obj #> Call: #> WRrec(ID = dat$patid, time = dat$time, status = dat$status, trt = dat$trt_ab, #> strata = dat$age60, naive = TRUE)
#>
#>             N Rec. Event Death Med. Follow-up
#> Control   221        571    57       28.62295
#> Treatment 205        451    36       27.57377
#>
#> Analysis of last-event-assisted WR (LWR; recommended), first-event-assisted WR (FWR), and naive WR (NWR):
#>     Win prob Loss prob WR (95% CI)*      p-value
#> LWR 50.4%    38.2%     1.32 (1.05, 1.66) 0.0189
#> FWR 50.4%    38.3%     1.32 (1.04, 1.66) 0.0202
#> NWR 47%      35%       1.34 (1.05, 1.72) 0.0193
#> -----
#> *Note: The scale of WR should be interpreted with caution as it depends on
#> censoring distribution without modeling assumptions.

We can see from the output above that 57 (25.8%) out of 221 patients died in usual care, with an average of $$571/221=2.6$$ hospitalizations per patient; and that 36 (17.6%) out of 205 patients died in exercise training with an average of $$451/205=2.2$$ hospitalizations per patient. Clearly, those undergoing exercise training are doing much better in terms of both overall survival and recurrent hospitalization.

Following the descriptive statistics are the analysis results by the LWR, FWR, and NWR. Although estimates of overall win and loss probabilities, as well as the win ratio, are provided, their magnitudes are generally dependent on the censoring distribution and should thus be interpreted with caution. On the other hand, the $$p$$-values are from valid tests of the null and alternative hypotheses discussed in the earlier section. We can see that all three tests yield $$p$$-values less than the conventional threshold 0.05, suggesting that exercise training significantly reduces mortality and recurrent hospitalization.

### Comparison with standard win ratio

To compare with the SWR, we first create a dataset where only the first hospitalization is retained.

######################################
## Remove recurrent hospitalization ##
######################################
## sort dataset by patid and time
o<-order(dat$patid,dat$time)
dat<-dat[o,]
## retain only the first hospitalization
datHF<-dat[!duplicated(dat[c("patid","status")]),]
#>         patid       time status trt_ab age60
#> 1  HFACT00001  7.2459016      2      0     1
#> 2  HFACT00001 12.5573770      0      0     1
#> 3  HFACT00002  0.7540984      2      0     1
#> 6  HFACT00002 45.9016393      0      0     1
#> 7  HFACT00007  3.4754098      2      1     1
#> 11 HFACT00007 34.8852459      1      1     1

Then we perform the SWR test by applying the same procedure for the LWR to the reduced dataset (which in this case is equivalent to the SWR).

## Perform the standard win ratio test
objSWR<-WRrec(ID=datHF$patid,time=datHF$time,status=datHF$status, trt=datHF$trt_ab,strata=datHF$age60) ## print the results objSWR #> Call: #> WRrec(ID = datHF$patid, time = datHF$time, status = datHF$status,
#>     trt = datHF$trt_ab, strata = datHF$age60)
#>
#>             N Rec. Event Death Med. Follow-up
#> Control   221        170    57       28.62295
#> Treatment 205        145    36       27.57377
#>
#> Analysis of last-event-assisted WR (LWR):
#>     Win prob Loss prob WR (95% CI)*  p-value
#> LWR 49.5%    39.1%     1.27 (1, 1.6) 0.0494
#> -----
#> *Note: The scale of WR should be interpreted with caution as it depends on
#> censoring distribution without modeling assumptions.

We can see that the test result is only borderline significant, possibly due to less efficient use of the recurrent-event data.

## References

• Dong, G., Qiu, J., Wang, D., & Vandemeulebroecke, M. (2018). The stratified win ratio. Journal of Biopharmaceutical Statistics, 28, 778–796.

• Mao, L., Kim, K., & Li, Y. (2022). On recurrent-event win ratio. Statistical Methods in Medical Research, under review.

• O’Connor, C. M., Whellan, D. J., Lee, K. L., Keteyian, S. J., Cooper, L. S., Ellis, S. J., Leifer, E. S., Kraus, W. E., Kitzman, D. W., Blumenthal, J. A. et al. (2009). “Efficacy and safety of exercise training in patients with chronic heart failure: HF-ACTION randomized controlled trial”. Journal of the American Medical Association, 301, 1439–1450.

• Pocock, S., Ariti, C., Collier, T., and Wang, D. (2012). The win ratio: a new approach to the analysis of composite endpoints in clinical trials based on clinical priorities. European Heart Journal, 33, 176–182.