Abstract

Aims

The safety and efficacy of novel oral anticoagulants in patients with atrial fibrillation undergoing pacemaker or implantable cardioverter-defibrillator interventions have not been clearly defined. Therefore, we compared the incidence of bleeding and thrombo-embolic complications following cardiac rhythm device (CRD) implantations under dabigatran vs. rivaroxaban in a real-world cohort.

Methods and results

We analysed 176 consecutive procedures performed in 93 patients treated peri-interventionally with dabigatran and 83 patients with rivaroxaban, respectively. Post-operative bleeding complications and thrombo-embolic events occurring within 30 days were compared. There were no significant differences in baseline characteristics between patients in the dabigatran and the rivaroxaban group. Most of the patients in both the groups received dual chamber or cardiac resynchronization devices (71 vs. 78%) as opposed to single-chamber systems (29 vs. 22%). In the dabigatran group, two (2%) bleeding complications (two pocket haematomas) were observed in comparison with four (5%, three pocket haematomas and one pericardial effusion) in the rivaroxaban group (P = 0.330). Three complications in the rivaroxaban group necessitated surgical intervention as opposed to none in the dabigatran group (P = 0.064). One case of a transient ischaemic attack occurred in the dabigatran group (P = 0.343).

Conclusion

Bleeding and thrombo-embolic complications in patients treated with dabigatran or rivaroxban are rare. Further and larger studies are warranted to define the optimal anticoagulation management in patients with a need for oral anticoagulation and CRD interventions.

What's new?

  • The safety and efficacy of novel oral anticoagulants (NOACs) in patients undergoing cardiac rhythm devices implantation have not yet been well studied.

  • The study presents a comparison of two widely used NOAC, dabigatran and rivaroxaban, in terms of post-interventional bleeding and thrombo-embolic complications.

Introduction

Approximately 25% of patients undergoing implantations of cardiac rhythm devices (CRDs) require a long-term anticoagulation1 leading to increased peri-interventional bleeding rates.2 The optimal peri-procedural management and finding the delicate balance between potential risk of thrombo-embolic event and bleeding is difficult and a common clinical problem with limited evidence insuring optimal treatment.3 While uninterrupted warfarin use in patients undergoing pacemaker (PM) or implantable cardioverter-defibrillator (ICD) implantations has very recently been shown to be superior to bridging therapy with heparin,4 only very limited data exist on the safety and efficacy of novel anticoagulants.5

We present, for the first time, a comparison of peri-interventional bleeding and thrombo-embolic complications of two widely used novel oral anticoagulants (NOACs), dabigatran and rivaroxaban, in a real-world cohort.

Methods

Patients

In this prospective, observational study, 93 consecutive patients who were peri-procedurally treated with dabigatran and 83 consecutive patients treated with rivaroxaban between January 2011 and December 2012 were included. Table 1 shows the baseline characteristics and procedural data of both groups.

Table 1

Comparison of clinical, procedural, and outcome data of patients treated with dabigatran (n = 93) and rivaroxaban (n = 83)

 Dabigatran (n = 93) Rivaroxaban (n = 83) P value 
Clinical characteristics 
 Age, (years ± SD) 72 ± 11 74 ± 9 0.179 
 Male, n (%) 60 (65) 57 (69) 0.560 
 Diabetes mellitus, n (%) 24 (26) 29 (35) 0.187 
 Coronary artery disease, n (%) 28 (30) 22 (27) 0.597 
 Hypertension, n (%) 86 (93) 78 (94) 0.693 
 Median CHA2DS2-VASc score, (IQR) 4 (3–5) 4 (3–5) 0.770 
 Beta-blockers, n (%) 78 (84) 74 (88) 0.323 
 ACE inhibitor/angiotensin receptor blocker, n (%) 80 (86) 77 (93) 0.150 
 Diuretics, n (%) 70 (75) 65 (78) 0.633 
 Aspirin, n (%) 22 (24) 8 (10) 0.015 
 Thienopyridine, n (%) 13 (14) 3 (4) 0.018 
Procedural data 
 Single- and dual-chamber pacemaker, n (%) 60 (65) 48 (58) 0.616 
 Cardiac resynchronization pacemaker, n (%) 2 (2) 5 (6) 
 Single- and dual-chamber ICD, n (%) 14 (15) 15 (18) 
 Cardiac resynchronization ICD, n (%) 17 (18) 15 (18) 
De novo implantation, n (%) 73 (79) 65 (78) 0.924 
 Generator change, n (%) 10 (11) 10 (12) 
 System upgrade, n (%) 10 (10) 8 (10) 
 Procedure time, (min ± SD) 60 ± 30 56 ± 35 0.487 
 Sub-pectoral implantation, n (%) 3 (3) 2 (2) 0.745 
NOAC management 
 NOAC at the admission, n (%) 69 (74) 54 (65) 0.187 
 Post-procedural interruption, [hours, (IQR)] 24 [12–48] 48 [24–48] 0.006 
Outcomes 
 Bleeding, n (%) 2 (2) 4 (5) 0.330 
 Surgical revision, n (%) 0 (0) 3 (4) 0.064 
 Thrombo-embolic event, n (%) 1 (1) 0 (0) 0.343 
 Mean time to discharge, days (IQR) 2 (1–3) 2 (1–3) 0.722 
 Dabigatran (n = 93) Rivaroxaban (n = 83) P value 
Clinical characteristics 
 Age, (years ± SD) 72 ± 11 74 ± 9 0.179 
 Male, n (%) 60 (65) 57 (69) 0.560 
 Diabetes mellitus, n (%) 24 (26) 29 (35) 0.187 
 Coronary artery disease, n (%) 28 (30) 22 (27) 0.597 
 Hypertension, n (%) 86 (93) 78 (94) 0.693 
 Median CHA2DS2-VASc score, (IQR) 4 (3–5) 4 (3–5) 0.770 
 Beta-blockers, n (%) 78 (84) 74 (88) 0.323 
 ACE inhibitor/angiotensin receptor blocker, n (%) 80 (86) 77 (93) 0.150 
 Diuretics, n (%) 70 (75) 65 (78) 0.633 
 Aspirin, n (%) 22 (24) 8 (10) 0.015 
 Thienopyridine, n (%) 13 (14) 3 (4) 0.018 
Procedural data 
 Single- and dual-chamber pacemaker, n (%) 60 (65) 48 (58) 0.616 
 Cardiac resynchronization pacemaker, n (%) 2 (2) 5 (6) 
 Single- and dual-chamber ICD, n (%) 14 (15) 15 (18) 
 Cardiac resynchronization ICD, n (%) 17 (18) 15 (18) 
De novo implantation, n (%) 73 (79) 65 (78) 0.924 
 Generator change, n (%) 10 (11) 10 (12) 
 System upgrade, n (%) 10 (10) 8 (10) 
 Procedure time, (min ± SD) 60 ± 30 56 ± 35 0.487 
 Sub-pectoral implantation, n (%) 3 (3) 2 (2) 0.745 
NOAC management 
 NOAC at the admission, n (%) 69 (74) 54 (65) 0.187 
 Post-procedural interruption, [hours, (IQR)] 24 [12–48] 48 [24–48] 0.006 
Outcomes 
 Bleeding, n (%) 2 (2) 4 (5) 0.330 
 Surgical revision, n (%) 0 (0) 3 (4) 0.064 
 Thrombo-embolic event, n (%) 1 (1) 0 (0) 0.343 
 Mean time to discharge, days (IQR) 2 (1–3) 2 (1–3) 0.722 

Implantation procedure

Patients undergoing all CRD implantations including de novo implantation, generator change or system upgrade of PM, ICD, or cardiac resynchronization therapy device were included. All procedures were performed in inpatients mode. Most procedures were performed with standard techniques for subcutaneous pectoral pocket formation. In five cases (2%), a sub-pectoral pocket preparation was necessary. In all cases, the subclavian vein was used for lead insertion. The ICD leads were mostly positioned at the right ventricular apex, and the right ventricular PM leads were targeted to the interventricular septum. Haemostasis was obtained using bipolar electrocautery preset for 180/80 W, 350 kHz (Erbe Vio 200S). The procedures were performed by 16 different operators with various levels of experience.

The interruption of NOAC prior procedure was protocolized as follows: the last pre-intervention dose of NOAC was omitted meaning that patients with dabigatran received it 24 h and patients with rivaroxaban 36 h prior procedure (12 h NOAC-free interval in case of dabigatran and 24 h in case of rivaroxaban). The scheduled time of first post-interventional anticoagulant administration was left to the discretion of the implanting physician.

All patients provided written informed consent for device intervention and data collection and analysis.

Follow-up

Routine follow-up examinations were performed on the first post-operative day, at hospital discharge and after 1 month. During the follow-up examinations, the incision site was reassessed by two experienced physicians focusing on pocket haematomas and necessity for surgical revisions. Pocket haematoma was defined as clinically recognized bleeding requiring prolongation of hospitalization, discontinuation of the anticoagulant, or transfusion of blood products. Surgical intervention was performed if none of the conservative measures (e.g. discontinuation of anticoagulation, applied sandbag) lead to sufficient reduction of the bleeding.

Furthermore, in all patients (with exclusion of patients undergoing generator change), the existence of pericardial effusion was accessed by cardiac ultrasound.

Any cerebral and systemic thrombo-embolic events, including transient ischaemic attacks, occurring within 30 days were reported.

Statistical analysis

Continuous variables were expressed as mean and standard deviation (SD). Categorical variables were reported as frequencies and percentage. Continuous variables were compared by means of Student's t-test and categorical by χ2 test. A two-tailed P value <0.05 was considered statistically significant. Analysis was performed with SPSS v 20.0 (SPSS Inc.).

Results

Comparison of patient characteristics

There were no significant differences in baseline characteristics between patients in the dabigatran and the rivaroxaban group. The thrombo-embolic risk, defined by the CHA2DS2-VASc score was similar in both the groups [4 (IQR 3–5) vs. 4 (IQR 3–5), P = 0.770]. Patients in the dabigatran group were more frequently co-medicated with aspirin (27 vs. 10%, P = 0.015) and thienopyridine (14 vs. 4%, P = 0.018).

The procedural parameters including mean procedural time (60 ± 30 vs. 56 ± 35 min, P = n.s.), the frequency of sub-pectoral implantations (3 vs. 2%, P = n.s.), and specification of implanted devices (71 vs. 78% of dual chamber or CRT devices, P = n.s.) were also similar in both the groups. In both the groups, the most frequent procedure was de novo implantation (79 vs. 78%, P = n.s.), as compared with generator change (10 vs. 12%, P = n.s.) and system upgrade (10 vs. 10%, P = n.s.).

Peri-procedural novel oral anticoagulant management

In the dabigatran group, anticoagulation was administered for the first time post-procedurally in 24 patients (26%) while the remainder 69 patients (74%) were on dabigatran on admission. Rivaroxaban treatment was started post-procedurally in 29 patients (35%) and 54 patients (65%) were already on rivaroxaban on admission.

The first dose of dabigatran was administered significantly earlier after the procedure than rivaroxaban (37 ± 21 vs. 27 ± 23 h, P = 0.006). In both the groups no bridging with heparin was performed.

Patients were treated with 110 mg (n = 54, 58%) or 150 mg (n = 39, 42%) dabigatran twice-daily according to their creatinine clearance and age (77 ± 26 or 79 ± 27 mL/min/1,73 qm). Forty-one patients (49%) were treated with 15 mg rivaroxaban and 42 (51%) with 20 mg according to their creatinine clearance only (54 ± 23 or 74 ± 21 mL/min/1,73 qm).

Complications

In the rivaroxaban group, we observed four (5%) bleeding complications (three pocket haematomas and one pericardial effusion) compared with two (2%) pocket haematomas in the dabigatran group (P = n.s.). Three complications in the rivaroxaban group (two pocket haematomas and one pericardial effusion) needed surgical intervention as opposed to none in the dabigatran group (P = 0.064).

In dabigatran group, one case of transient ischaemic attack without any lasting neurological deficits occurred while there were no thrombo-embolic events in the rivaroxaban group (P = n.s.).

The detailed complication characteristics are summarized in Table 2.

Table 2

Characteristics of complications

 Gender Age (years) CHA2DS2- VASc score Procedure Pre-procedural anticoagulation Post-procedural interruption of anticoagulation (hours) Complication Revision Aspirin and/or thiopyridine 
Dabigatran (n = 3) Male 73 De novo implantation of single-chamber PM Dabigatran interrupted 12 h prior procedure No Pocket haematoma No Yes 
  Male 76 De novo implantation of dual-chamber PM Interrupted warfarin with INR of 1.3 12 Pocket haematoma No No 
Male 71 De novo implantation of a CRT-D Pre-procedural anticoagulation with aspirin 12 TIA No Yes 
Rivaroxaban (n = 4) Male 58 De novo implantation of a CRT-D Rivaroxaban interrupted 24 h prior procedure 48 Pocket haematoma Yes No 
  Female 84 De novo implantation of dual-chamber PM Pre-procedural anticoagulation with aspirin and thiopyridine 48 Pocket haematoma Yes Yes 
Female 78 De novo implantation of dual-chamber PM Rivaroxaban interrupted 24 h prior procedure 48 Pocket haematoma No No 
Male 79 System upgrade to dual-chamber PM Rivaroxaban interrupted 24 h prior procedure 24 Pericardial effusion Yes No 
 Gender Age (years) CHA2DS2- VASc score Procedure Pre-procedural anticoagulation Post-procedural interruption of anticoagulation (hours) Complication Revision Aspirin and/or thiopyridine 
Dabigatran (n = 3) Male 73 De novo implantation of single-chamber PM Dabigatran interrupted 12 h prior procedure No Pocket haematoma No Yes 
  Male 76 De novo implantation of dual-chamber PM Interrupted warfarin with INR of 1.3 12 Pocket haematoma No No 
Male 71 De novo implantation of a CRT-D Pre-procedural anticoagulation with aspirin 12 TIA No Yes 
Rivaroxaban (n = 4) Male 58 De novo implantation of a CRT-D Rivaroxaban interrupted 24 h prior procedure 48 Pocket haematoma Yes No 
  Female 84 De novo implantation of dual-chamber PM Pre-procedural anticoagulation with aspirin and thiopyridine 48 Pocket haematoma Yes Yes 
Female 78 De novo implantation of dual-chamber PM Rivaroxaban interrupted 24 h prior procedure 48 Pocket haematoma No No 
Male 79 System upgrade to dual-chamber PM Rivaroxaban interrupted 24 h prior procedure 24 Pericardial effusion Yes No 

CRT-D, cardiac resynchronization therapy-defibrillator; PM, pacemaker; TIA, transient ischaemic attack.

The hospitalization time was similar in both the groups [2 (IQR 1–3] vs. 2 (IQR 1–3) days, P = n.s.].

During extended follow-up of 66 ± 86 days, one case of device infection after 30 days was observed in the rivaroxaban group.

Discussion

To the best of our knowledge, this is the first study comparing bleeding and thrombo-embolic complications following CRD implantation under dabigatran vs. rivaroxaban. Overall, the complication rate was lofw and in a comparable range with recent reports.4 Although not statistically significant, there was a trend towards an increased risk of bleeding complications with the need for surgical revision in rivaroxaban-treated patients compared with dabigatran. Interestingly, this finding was observed despite the more frequent use of antiplatelet drugs in dabigatran-treated patients. Those findings are in accordance with recently published data from the RE-LY study population, showing a low incidence of bleeding complications after different surgical procedures and other invasive interventions.6

Considering our and the comparable bleeding rates in the very recently published BRUISE CONTROL study under warfarin,4 NOAC may even be associated with superior safety.

Although the two anticoagulation agents have many similarities concerning pharmacokinetics, low potential for drug interactions, and rapid onset of action, some significant differences may explain our results. The different levels of inhibition of coagulation cascade, factor Xa in case of rivaroxaban and thrombin in case of dabigatran might be crucial: compared with thrombin, factor Xa is more thrombogenic as a primary site of amplification7 and is not associated with protein C-mediated thrombin generation after withdrawal.8 Therefore, deactivation of factor Xa could lead to more aggressive anticoagulation resulting in more bleeding complications,9 even if started after longer interval than dabigatran. In addition, the effective anticoagulation time of single rivaroxaban dose is almost two times longer than that of dabigatran. Although, in our study and clinical practice, this fact was reflected by an extended period of discontinuation, it also may contribute to a higher complication rate. Furthermore, an additional interaction of rivaroxaban with the wound healing processes cannot be excluded and has been suggested recently after orthopedic surgery.10,11

Since surgery may induce a prothrombotic state related to inflammatory reactions, endothelial injury, and transient immobilization,12 an adequate protection in the form of early initiated anticoagulation is advisable. However, despite recent and this investigation in atrial fibrillation (AF) patients,4 the optimal peri-procedural anticoagulation management strategy according to bleeding and (rebound) thrombo-embolic risk is hard to determine.

The novel agents with fast onset are advantageous, but the optimal time of initiation is disputable and more evidence is needed. Perhaps, also the time of discontinuation of NOAC must be re-evaluated as we recently saw it in the case of warfarin where a continuous medication enables a so-called ‘anticoagulant stress test’ where any excessive bleeding is detectable and appropriately managed while the wound is still open, which results in a lower bleeding rate. This question will be possibly soon be answered by an ongoing trial testing the uninterrupted dabigatran regime in CRD implantations (NCT01675076).

Modern anticoagulation agents have been rapidly adopted into ambulatory practice for the treatment of AF and a further rise is to be expected. Therefore, the peri-procedural management of such patients is a rapidly growing and complex clinical problem that requires further careful evaluation.

Limitations

Despite the novelty and so far largest sample size, our study is still limited by heterogeneous anticoagulation management, diverse procedures, and non-randomized design. Although no association between higher dose of dabigatran and bleeding complications was observed in our study, it cannot be excluded that the application of higher dose in countries where the 110 mg dose was not approved may influence bleeding rates. The discontinuation of the NOAC was protocolized but was not adjusted for creatinine clearances as it is was not recommended at the time of the study's beginning. The physicians assessing the incision site were not blinded to the treatment and no ultrasound imaging of the haematoma was conducted. Although, the study design is in accordance with previous trials comparing different anticoagulation regimens,4 an open-label design and observational nature of the study might be a potential source of type 2 error.

Conclusions

Bleeding and thrombo-embolic complications in patients treated with dabigatran or rivaroxban are rare. Further and larger studies are warranted to define the optimal anticoagulation management in patients with a need for oral anticoagulation and CRD interventions.

Conflict of interest: none declared.

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