Reference: BMJ 2021 Jun 9;373:n1205
People needing anticoagulants such as warfarin often require a window of time without medicine to undergo procedures where bleeding is a significant risk. Opening and shutting that window is hard with long-acting anticoagulants like warfarin but easier with shorter-acting drugs like low-molecular-weight heparin (LMWH) or direct oral anticoagulants (DOACs). Stopping chronic warfarin and using heparinoids as a temporary “bridge” has long been a way around this problem.
The PERIOP2 study group consisted of researchers from 10 different sites in Canada and India collecting data on patients taking warfarin who needed a procedure with a bleeding risk between 2007 and 2016. The group enrolled 1,471 people on chronic warfarin (79% with atrial fibrillation and a CHADS2 risk factor and 21% with a mechanical heart valve) scheduled for a variety of procedures carrying a risk of significant bleeding. Participants in the trial replaced warfarin with dalteparin (a LMWH) before their procedure, had their procedure, and were randomized to receive warfarin postoperatively with either a dalteparin or placebo injection daily for at least 4 days until warfarin reached a therapeutic level.
The primary outcome was either arterial or venous thromboembolic events. Results failed to demonstrate a difference between postoperative placebo or dalteparin injections for this outcome. Exactly 8 events were observed in both the intervention and standard groups of 650 and 820 patients respectively. You may notice the difference in the size of the two groups - this was the result of one of several concerning protocol issues in this study. An inadvertent randomization error was corrected, but this then affected allocation concealment, leading to important baseline differences between the two arms of this study, including higher percentages of prosthetic valves (23.7% vs. 18.4%, p = 0.01), prior stroke history (25.2% vs. 20.2%, p = 0.02), and intermittent atrial fibrillation (40% vs. 31.3%, p = 0.002) in the placebo vs. dalteparin group. Researchers faced other challenges: a very low event rate - only one primary outcome was recorded in the 304 patients enrolled with mechanical heart valves - and enrollment limited by the increasing replacement of warfarin with DOACs for atrial fibrillation during the study period. In addition, a prophylactic rather than therapeutic dose of dalteparin was used after procedures if the provider felt there was a very high risk of bleeding.
At the end of the day, the problems with randomization, allocation concealment, baseline heterogeneity, and low event rate all represented important threats to internal and external validity. Additionally, the clinical question may no longer be relevant as clinical practice has simply moved on. DOACs are replacing warfarin for most patients with high-risk atrial fibrillation and seem equally effective and actually safer for perioperative anticoagulation. It has been said that the usefulness of clinical information is a product of validity and relevance divided by the work it takes to find and understand the information. The authors state that this was the first randomized trial of perioperative bridging that included patients with mechanical valves, a worthy clinical question. However, this study had significant threats to validity and primarily looked at a population that is rapidly diminishing (i.e. people taking warfarin for atrial fibrillation without a mechanical heart valve), limiting its usefulness.
For more information, see the topic Periprocedural Management of Patients on Long-Term Anticoagulation in DynaMed.
DynaMed EBM Focus Editorial Team
This EBM Focus was written by Dan Randall, MD, Deputy Editor at DynaMed. Edited by Alan Ehrlich, MD, Executive Editor at DynaMed and Associate Professor in Family Medicine at the University of Massachusetts Medical School, Carina Brown, MD, Assistant Professor at Cone Health Family Medicine Residency, Katharine DeGeorge, MD, MS, Associate Professor of Family Medicine at the University of Virginia and Clinical Editor at DynaMed, Tanya Tupper, MM, RT(N), CNMT, PET, Medical Writer at DynaMed, and Vincent Lemaitre, PhD, Medical Writer at DynaMed. Published by Christine Fessenden, Editorial Operations Assistant.