Continuation or interruption of DOAC does not affect hematoma risk at device surgery
BRUISE CONTROL-2 - A Randomized Controlled Trial of Continued versus Interrupted Novel Oral Anti-coagulant at the time of Device Surgery
Presented at ACC.17 Scientific Sessions in Anaheim, CA, USA by David H. Birnie (Ottawa Heart Institute, Ottawa, ON, Canada)
Oral anticoagulant therapy is common among patients who require pacemaker or defibrillator surgery. The BRUISE-CONTROL trial has previously demonstrated 80% reduction of device pocket hematomas when surgery was performed without interruption of warfarin treatment. The use of direct oral anticoagulants (DOACs) has increased since the publication of BRUISE CONTROL and a majority of patients with atrial fibrillation are now treated with DOACs.
It is uncertain how DOACs should be managed perioperatively around device surgery, with regard to balancing the risk of thrombo-embolism and perioperative bleeding. The major DOAC clinical trial have found that brief, temporary interruptions for procedures or surgery are associated with an approximately 3-fold increase in stroke/systemic embolism. Pocket hematomas may have very significant sequelae for patients and they can necessitate prolonged cessation of anticoagulation, which increases the risk of thromboembolism and are associated with a markedly increased risk of serious device system infection.
Since a lack of consensus on peri-operative management of DOACs has been noted, the BRUISE CONTROL-2 trial was conducted. In this multi-center single-blind randomized controlled trial, they specifically hypothesized that performing device surgery without DOAC interruption would result in a reduced hematoma rate. Initially, only dabigatran had post-marketing approval, but as additional DOACs became approved during the trial, the protocol was expanded to included patients on apixaban and rivaroxaban.
Patients with CHA2DS2-VASc score ≥2 were randomized to continued or interrupted DOAC. Investigator blinding was achieved by installing two patient-care teams per center, one unblinded to treatment allocation that was responsible for device implantation, and one blinded team that was responsible for diagnosing, following and making decisions about hematomas.
The primary outcome was clinically significant hematoma, requiring re-operation and/or resulting in prolonged hospitalization and/or requiring interruption of all anticoagulation for >24 hours. The study was powered with 80% to detect a 40% relative risk reduction in the primary end point in the continued DOAC arm (two-sided alpha: 0.05). At the second pre-specified interim analysis, based on data of 590 patients, the DSMB recommended study termination. This analysis refers to 662 patients enrolled between April 9, 2013 and June 1, 2017.
- No significant differences in any baseline variable were seen between groups.
- Regarding operative details, significantly more intrapocket administration of prohemostatic agents was seen in the continued DOAC (21/319, 6.6%) than in the interrupted DOAC (10/328, 3.1%), and pressure dressing applied postoperatively was also seen more often in the continued DOAC group (217/319, 68.0% vs. 197/328, 60.1%) (P=0.035 for both findings).
- Overall, the time between last pre-operative dose and first post-operative dose was 14 hours on average in those on continued DOAC treatment and 72 hours on interrupted DOAC (all DOACs taken together).
- Clinically significant hematoma was seen in 7 patients on continued DOAC (2.1%) and in 7 patients on interrupted protocol (2.1%, P=0.973). Nor were statistically significant differences seen in the occurrence of components of the primary outcome.
- Similar occurrences of the secondary outcomes were seen, including non-clinically significant hematoma (3.4 vs. 3.0%), any hematoma (5.5 vs. 4.8%), all-cause mortality (0.6 vs. 0.3%), pneumothorax (0.6 vs. 0%), hemothorax (0 vs. 0%), cardiac tamponade (0.3 vs. 0%), significant pericardial effusion (0 vs. 0.3%), stroke (both 0.3%) and TIA (both 0).
In this study, continuation or interruption of DOAC treatment during cardiac procedures are associated with similar rates of device pocket hematoma. In both arms, the rate of this feared complication was lower than expected. Despite this being a negative trial, it carries a good message for patients, noted dr. Birnie. The take home message for clinicians is that either strategy may be good, depending on the clinical scenario. Scenarios in which clinical judgement may favor operating with continued DOAC therapy may include when waiting for the anticoagulant effect to dissipate may lead to unacceptable harm, or in case of a high stroke risk.
During the press conference, discussant dr. Mina Chung (Cleveland Clinic, Cleveland, OH, USA) started out by showing the complexity of the decision pathway for peri-procedural management of anticoagulation. These decisions have been made based on observational and anecdotal information, and few randomized trials have now been published. The BRIDGE trial demonstrated higher major and minor bleeding rates with bridging. It is important to note that this trial included some very high risk patients, both high thrombotic and surgical risk for bleeding. The BRUISE CONTROL study also included some high risk patients, and the primary outcome was clinically significant bleeding. The DSMB stopped this trial due to a higher rate of hematoma in the bridging arm, while BRUISE CONTROL 2 was stopped due to a lack of difference in the outcomes.
We now see the broader scope of implications from these studies; to avoid hematomas, continuation with warfarin is preferred over interruption with heparin bridging. With regard to DOACs, both continuation or interruption is acceptable for CIED procedures, as no increase in CVA/TIA was seen with interrupted DOAC, nor an increase in clinically significant hematoma with continued DOAC treatment. Chung noted that the absence of differences in CVA/TIA incidence with holding DOACs for short periods of time compared to continued use may have implications for other procedures. The power of this study was likely limited in this study, also considering its premature stopping. A futility analysis for CVA/TIA endpoints might be helpful. Other remaining questions regarding peri-procedural DOAC management concern other high risk procedures, active device infection/need for lead extraction, GFR <30 and rheumatic valve disease.
- Our reporting is based on the information provided at the AHA 2017 congress -