Cardiac implantable electronic device surgery with interruption of warfarin forgoing post-operative bridging therapy in patients with moderate or high thromboembolic risks

Annually, an estimated 1.25 million pacemaker and 410,000 implantable cardioverter defibrillator (ICD) operations are performed [1]. Between 14 and 37% of patients undergoing cardiac implantable electronic device (CIED) surgeries are on long-term anti-coagulation therapy, and the peri-procedural management of anti-coagulation presents a dilemma to physicians [2‐5]. Interruption of anti-coagulation therapy can transiently increase the risks of thromboembolic events, but continuing anti-coagulation therapy can increase the risk of surgical site hematoma formation. Importantly, there is an association between hematoma formation and subsequent device system infection. For example, patients with device infections were 20-fold and 8-fold more likely to have had postoperative hematomas in the REPLACE registry and the BRUISE CONTROL INFECTION study, respectively [6, 7]. CIED infections frequently necessitate complete system removal, and are associated to increased morbidity, mortality and cost [8].

Randomized trials, most notably the BRUISE CONTROL (INFECTION) study, showed that continuation of warfarin was superior to the previous practice of interruption of warfarin therapy with heparin bridging [9‐11]. However, a strategy of interruption of warfarin without heparin bridging have not been examined in these trials, and there is growing evidence that this may be a better peri-operative strategy. For example, in the BRIDGE randomized trial, patients with atrial fibrillation (AF) who had warfarin therapy interrupted for elective surgeries (not including CIED surgeries) without heparin bridging benefited from fewer bleeding complications with no excessive thromboembolic risks [12].

We sought to examine the risks of thromboembolic events and clinically significant device pocket hematoma with a strategy of warfarin interruption without post-operative heparin bridging in moderate or high risk patients undergoing CIED surgeries.

In this cohort of patients on chronic warfarin therapy undergoing CIED surgery with moderate to high thromboembolic risks, a strategy of warfarin interruption without post-operative bridging therapy were found to have a relatively low risk of all-cause death or thromboembolism (1.2%) and an acceptable risk of device-pocket hematoma (5.8%). Importantly, we included more than 60% patients with mechanical prosthetic valves and showed that the rates of thromboembolism was comparable with patients without mechanical valves.

There is increasing evidence supporting continued warfarin therapy for CIED surgeries. In the BRUISE CONTROL trial including 668 patients with AF, continued warfarin therapy was superior with respect to risks of major bleeding and non-inferior to heparin bridging with respect to arterial thrombo-embolism [9]. This has led to a shift in European and American guidelines towards favoring continued warfarin therapy over interruption with bridging therapy for CIED surgeries [14‐16]. However, there is limited published data on the efficacy and safety of the strategy of warfarin interruption and no post-operative bridging therapy used in our cohort.

According to a European survey, 9.4% patients undergoing CIED surgeries had warfarin interrupted for more than 24 h without bridging therapy, amid a lack of general consensus or clinical evidence [17]. Indirect clinical evidence supporting this practice stems from the setting of elective non-cardiac procedures, where randomized trials (including the BRIDGE trial) and cohort studies showed that warfarin interruption without bridging therapy was superior to with bridging therapy, with lower bleeding risks and no excess risks of thromboembolism [12, 18].. Moreover, in patients undergoing CIED implantations, post-operative LMWH and higher INR on day of CIED implantations were independent predictors of device-related hematoma in a case-control study [19]. Therefore, a strategy of warfarin interruption without post-operative bridging therapy has theoretical advantage in simultaneously addressing both risk factors. This naturally raises concern about thromboembolic risks during the period of warfarin interruption. The rationale of heparin bridging was to leverage the short half-life of LMWH (3–5 h) to maximize protection against thromboembolism during the pre-operative period, given the time period for INR normalization after warfarin interruption is widely variable [20, 21].

To our knowledge, our study is the largest cohort reporting the safety and efficacy in patients who had warfarin interruption for CIED surgeries without post-operative heparin bridging. Ahmed et al. reported data including 114 patients who had warfarin interruption for CIED implantations, and found significantly higher risks of TIA [22]. However pre-operative bridging therapy was not given and none of the patients had irreversible thromboembolic events. Another nation-wide registry included 150 patients with AF who had warfarin interruption for CIED implantations without bridging therapy, and both bleeding and thromboembolic events were very low (< 1%) [23]. A prematurely terminated trial randomized 171 patients and showed that events were similarly infrequent for reduced-dose warfarin vs warfarin interruption with LMWH bridging, including zero thromboembolic events [24]. Although observational in nature, our data suggests that the strategy under study conferred relatively low thromboembolic risks, which were not significantly higher than the study population’s baseline risks. These results should be considered hypothesis-generating for future randomized studies.

The risks of all-cause mortality and non-fatal thromboembolic event in our patients were 0.7 and 0.4% respectively, which were comparable with both arms in the BRUISE CONTROL trial (0 and 0% respectively for the heparin bridging arm, and 1.2 and 0.6% respectively for the continued warfarin arm) [9]. The risks of clinically significant hematoma in our patients were 5.8%, comparable with the reported 4.6% in a meta-analysis of 5978 patients receiving CIED with various combinations of anti-coagulant and/or anti-platelet therapy [25]. Specifically, the risks of bleeding complication in our cohort were much lower than the heparin bridging arm (16%) but numerically higher than the continued warfarin arm (3.5%) in the BRUISE CONTROL trial [9]. This could be attributed to the high portion of patients with valvular heart disease including more than half with at least moderate tricuspid regurgitation. Tricuspid regurgitation is associated with increased venous pressures and could adversely affect wound hemostasis. In addition, the main subcomponent of bleeding events in our patients was prolonged hospitalization secondary to management of hematoma. This endpoint could be affected by local discharge policies, as the pressure to discharge early from hospital is small in a non-insurance funded system. The other two subcomponents of bleeding events, hematoma requiring interruption of anti-coagulation (3.7%) and hematoma requiring evacuation (1.5%), were similar to the continued warfarin arm (3.2 and 0.6% respectively) and much lower than the heparin bridging arm (14.2 and 2.7% respectively) in the BRUISE CONTROL trial [9]. Nonetheless, comparisons across different patient cohorts are inherently limited, and a randomized trial is needed to compare the two strategies.

Importantly, our patients represented a cohort with moderate to high thromboembolic risks. We included 257 (62.5%) patients with mechanical prosthetic valves and a strategy of warfarin interruption without heparin bridging has never been reported in this population. The primary endpoint occurred at similar frequencies for the mechanical valve and no mechanical valve groups, providing preliminary findings that this anti-coagulation strategy in patients with mechanical valves may be considered.

The strengths of the present study include complete follow-up of all patients, large cohort size compared with previous studies that evaluated no bridging therapy, and inclusion of a sizeable proportion of patients with mechanical prosthetic valves whose outcomes with the current strategy have never been reported. The main limitation is the lack of a comparison group of either continued warfarin therapy or interruption of warfarin with bridging therapy. However, the findings arising from this study should serve to inform future randomized non-inferiority studies comparing our strategy of warfarin interruption without post-operative bridging therapy versus continued warfarin therapy.

Warfarin interruption without post-operative bridging therapy for CIED surgery was associated with relatively low thromboembolic risks and bleeding risks comparable to other cohorts. This approach to anti-coagulation management deserves further direct comparison with continued warfarin therapy in randomized controlled trials.