The competing risk between in-hospital mortality and recovery: A pitfall in COVID-19 survival analysis research

Oulhaj, A.; Ahmed, L. A.; Prattes, J.; Suliman, A.; Al Suwaidi, A.; Al-Rifai, R. H.; Sourij, H.; Van Keilegom, I.

Background Many studies investigating mortality and recovery in COVID-19 have been published recently. The majority of these studies used the standard Cox Proportional Hazards (Cox PH) model without taking into account the presence of competing risks. This study investigates, through extensive simulations, the bias in estimating the hazard ratio (HR) of death due to COVID-19 and the absolute risk reduction (ARR) when competing risks are not taken into consideration, and suggests an alternative method. Methods We simulated data for a fictive clinical trial in COVID-19 patients, to mimic recent trials involving the use of Hydroxychloroquine, Remdesivir, and convalescent plasma therapy for example. The primary outcome is the time from randomization until death due to COVID-19. Six scenarios representing different situations of the effect of treatment on death and its competing event recovery were considered. The HR of death and the 28-day ARR were estimated using the Cox PH model and the Fine and Gray (FG) model which takes competing risks into account. The estimates were then compared to their corresponding true values and the magnitude of misestimation quantified. Results The Cox PH model misestimated the true HR of death in the majority of the scenarios. The magnitude of this misestimation increased when the process of recovery was faster and/or the chance of recovery was higher. In some cases, this model has also incorrectly shown a harmful effect of treatment when it was in fact beneficial. The true 28-day ARR of death was also misestimated, and this misestimation increased in magnitude when the process of recovery was faster. The results obtained from the FG competing risks model are all consistent and show no misestimation or changes in direction for both the HR and the 28-day ARR of death. Conclusion There is a substantial risk of misleading results in COVID-19 research if recovery and death are not considered as competing risk events. We strongly suggest the use of a competing risk approach to re-analyze relevant published data that have used the Cox PH model.