key: cord-1043837-oxp34nnr
authors: Ridker, Paul M; Ortel, Thomas L.; Hochman, Judith S.
title: Equipoise, Trust, and the Need for Cardiologists to Randomly Assign Patients Into Anticoagulation Trials in the Time of COVID
date: 2020-10-15
journal: Circulation
DOI: 10.1161/circulationaha.120.052069
sha: 77ee1ac2ab7196928f15460f79a73a3d0c6f8887
doc_id: 1043837
cord_uid: oxp34nnr

nan

all potential confounders, known and unknown, are equally distributed across study groups and, therefore, that a definitive answer to a life-threatening question can be ascertained. In a time of public health crisis, that honesty about what does and does not work is furthermore a statement of empathy for our communal lack of knowledge, a recognition that we are all in the same situation together, and that we must share the burden and risks of trial participation equably across society.

As clinical trialists, we are intimately aware that the monitoring of safety and efficacy during COVID-19 is complex. Our protocols must be adaptive and allow proven therapies such as remdesivir, proning, and dexamethasone to be used without altering overall equipoise for the novel intervention at hand. Our investigators must have a willingness to alter and rapidly update trial aims, protocols, treatment targets, sample size calculations, and manuals of operation on timetables that challenge long established traditions of deliberative caution. Our institutional review boards must show the flexibility and speed to address the needs of electronicbased consent, low-touch trial designs, and risk-based monitoring. Members of our Data and Safety Monitoring Boards must take on levels of responsibility for trial conduct that, in some instances, can require weekly virtual meetings as data evolve. Our statistical colleagues, many long engaged solely in frequentist approaches, are being asked to address both Bayesian and adaptive trial designs that can incorporate posterior probabilities calculated from accruing data to allow the addition or closure of specific study arms. We are pleased to report that all these innovations are incorporated into many federally sponsored trials addressing the infectious, respiratory, neurological, and cardiovascular complications of COVID-19.

Of utmost importance, however, we cannot lose the trust of our patients. Public reticence to enroll in an intervention trial or to consider a preventive vaccine trial will undermine our ability to know what truth is and how best to apply it to save lives. Consistent and accurate messaging from regulatory agencies and public health officials is crucial to maintaining this trust. At both home and abroad, we need to enroll participants in adequately powered COVID-19 trials as quickly as possible to provide firm clinical evidence for practitioners on what to do, in whom, and when. No obstruction to these goals should be introduced or tolerated.

Patients enter trials not only for themselves but also for the benefit of their neighbors, both those known and unknown. That is the generosity that our patients provide-it needs to be respected, and we need to insist that a strategy is in place to affirm these values during the time of pandemic.

We encourage cardiologists consulting on patients with COVID-19 to consider enrollment in the National Institutes of Health ACTIV trials. ACTIV-1 is addressing the role of immune modulators in hospitalized adults with moderate to severe COVID-19 disease as add-on therapy to remdesivir and dexamethasone. ACTIV-2 is addressing the potential utility of monoclonal antibodies and other novel therapeutics in outpatients with COVID-19, whereas ACTIV-3 is addressing similar questions of efficacy and risk in inpatients with COVID-19. The ACTIV-4 antithrombotic trials discussed above and most relevant to cardiologists are summarized in the Figure. Descriptions of all the ACTIV trials, how to refer potential trial participants, and how to be considered as a study site are available at "COVID-19 Therapeutics Prioritized for Testing in Clinical Trials" on the National Institutes of Health website. 1 

COVID-19 therapeutics prioritized for testing in clinical trials. National Institutes of Health

Active drug and matching placebo for the ACTIV-4B Outpatient and ACTIV-4C Convalescent trials are generously provided by Bristol Myers Squibb and Pfizer, Inc. The institutions where Drs Ridker, Ortel, and Hochman are employed have received or will receive research grants from the National Heart, Lung, and Blood Institute to conduct the ACTIV-4 trials. Dr Ridker has received an investigatorinitiated grant from Pfizer, Inc for research not related to this commentary.