275 PROFESSIONAL ARTICLE Antithrombotic management in patients undergoing cardiac implantable electronic device implantation Copyright (c) 2023 Slovenian Medical Journal. This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License. Antithrombotic management in patients undergoing cardiac implantable electronic device implantation Antitrombotično zdravljenje pri bolnikih pred vstavitvijo vsadne elektrostimulacijske naprave srca Anja Zupan Mežnar,1 Jan Alatič,2 Juš Kšela,3 Marko Miklič,4 Matevž Jan,3 Franjo Husam Naji,2 Damijan Vokač,2 David Žižek1 Abstract Cardiac implantable electronic devices (CIEDs) are an established treatment option for arrhythmias, sudden cardiac death prevention, and heart failure. Approximately 1000 devices are implanted per million inhabitants in European countries each year. However, the main concern in patients with an indication for CIED implantation is frequently associated with comorbidities requiring antithrombotic medications. The invasive device implantation procedure represents a bleeding risk ranging from pocket hematoma to cardiac tamponade. On the other hand, temporary interruption of antithrombotic therapy increases the risk for thromboembolic events. Implanting CIEDs in patients on antithrombotic medications incites several clinical dilemmas of balancing thromboembolic risk against bleeding risk, as complications are associated with higher mortality rates in both aspects. The most common bleeding complication is pocket haematoma formation, which is associated with a prolonged hospital stay, higher cost, higher risk of pocket infection, and thus higher morbidity and mortality. Studies have shown that the heparin bridging strategy in patients on oral anticoagulants imposes a greater risk for pocket haematoma formation and no benefit in reducing thromboembolic events. Most procedures of CIED implanta- tion can be performed safely with uninterrupted oral anticoagulants. Dual antiplatelet therapy increases the risk of pocket haematoma and should be avoided whenever possible. 1 Department of Cardiology, University Medical Centre Ljubljana, Ljubljana, Slovenia 2 Department of Cardiology, University Medical Centre Maribor, Maribor, Slovenia 3 Department of Cardiovascular Surgery, University Medical Centre Ljubljana, Ljubljana, Slovenia 4 Department of Vascular Diseases, University Medical Centre Ljubljana, Ljubljana, Slovenia Correspondence / Korespondenca: Anja Zupan Mežnar, e: anja.zupanmeznar@gmail.com Key words: cardiac pacemaker; pocket hematoma; perioperative anticoagulation; device complications; antiplatelets Ključne besede: srčni spodbujevalnik; hematom ležišča; perioperativno antikoagulantno vodenje; zapleti vsadne naprave; antiagregacijska zdravila Received / Prispelo: 18. 11. 2022 | Accepted / Sprejeto: 17. 2. 2023 Cite as / Citirajte kot: Zupan Mežnar A, Alatič J, Kšela J, Miklič M, Jan M, Husam Naji F, et al. Antithrombotic management in patients undergoing cardiac implantable electronic device implantation. Zdrav Vestn. 2023;92(5–6)275–82. DOI: https://doi.org/10.6016/ ZdravVestn.3402 eng slo element en article-lang 10.6016/ZdravVestn.3402 doi 18.11.2022 date-received 17.2.2023 date-accepted Cardiovascular system Srce in obtočila discipline Professional article Strokovni članek article-type Antithrombotic management in patients undergoing cardiac implantable electronic device implantation Antitrombotično zdravljenje pri bolnikih pred vstavitvijo vsadne elektrostimulacijske naprave srca article-title Antithrombotic management in patients undergoing cardiac implantable electronic device implantation Antitrombotično zdravljenje pri bolnikih pred vstavitvijo vsadne elektrostimulacijske naprave srca alt-title cardiac pacemaker, pocket hematoma, periop- erative anticoagulation, device complications, antiplatelets srčni spodbujevalnik, hematom ležišča, perioper- ativno antikoagulantno vodenje, zapleti vsadne naprave, antiagregacijska zdravila kwd-group The authors declare that there are no conflicts of interest present. Avtorji so izjavili, da ne obstajajo nobeni konkurenčni interesi. conflict year volume first month last month first page last page 2023 92 5 6 275 282 name surname aff email Anja Zupan Mežnar 1 anja.zupanmeznar@gmail.com name surname aff Jan Alatič 2 Juš Kšela 3 Marko Miklič 4 Matevž Jan 3 Franjo Husam Naji 2 Damijan Vokač 2 David Žižek eng slo aff-id Department of Cardiology, University Medical Centre Ljubljana, Ljubljana, Slovenia Klinični oddelek za kardiologijo, Univerzitetni klinični center Ljubljana, Ljubljana, Slovenija 1 Department of Cardiology, University Medical Centre Maribor, Maribor, Slovenia Kardiološki oddelek, Univerzitetni klinični center Maribor, Maribor, Slovenija 2 Department of Cardiovascular Surgery, University Medical Centre Ljubljana, Ljubljana, Slovenia Klinični oddelek za kirurgijo srca in ožilja, Univerzitetni klinični center Ljubljana, Ljubljana, Slovenija 3 Department of Vascular Diseases, University Medical Centre Ljubljana, Ljubljana, Slovenia Klinični oddelek za žilne bolezni, Univerzitetni klinični center Ljubljana, Ljubljana, Slovenija 4 Slovenian Medical Journallovenian Medical Journal 276 CARDIOVASCULAR SYSTEM Zdrav Vestn | May – June 2023 | Volume 92 | https://doi.org/10.6016/ZdravVestn.3402 1 Introduction Cardiac implantable electronic devices (CIED) are an established treatment option for tachy- and brad- yarrhythmia, sudden cardiac death prevention and heart failure. In the past decades, CIED technology and implantation techniques have improved immense- ly, and approximately 1000 devices are implanted per million inhabitants in European countries each year (1). Notably, patients eligible for the CIED frequently have comorbidities for which they need to take anti- thrombotic medications. For instance, 23-24% of pa- tients with an indication for a permanent pacemaker (PPM) and 32-37% of those eligible for an implantable cardioverter defibrillator (ICD) require antithrom- botic medications (2-4). The main indication for anti- thrombotic therapy is atrial fibrillation (AF), the most common type of arrhythmia and the major risk factor for thromboembolic complications and death (3,5). Antithrombotic therapy combined with an invasive device implantation procedure represents a bleeding risk ranging from pocket haematoma to cardiac tam- ponade (3). On the other hand, temporary interrup- tion of antithrombotic therapy increases the risk for thromboembolic events. This article aims to present the available data and summarise the European Society of Cardiology rec- ommendations on perioperative antithrombotic thera- py management in patients undergoing CIED implan- tation (6). 2 Bleeding and thromboembolic risks in patients undergoing device implantation Implantation of CIEDs in patients on antithrom- botic medications incites several clinical dilemmas of balancing thromboembolic risk on the one hand and bleeding risk on the other, as complications are associ- ated with greater mortality rates in both aspects (3,5,7). The CIED implantation procedure is considered a low-bleeding-risk procedure. Pocket haematoma is the most common bleeding complication, with an average incidence rate of approximately 4% (8). Clinically rele- vant pocket haematoma is defined as one being associ- ated with patient discomfort, prolonged hospitalisation time, need for repeated follow-up visits, and surgical revision (Figure 1) (9). Bleeding risk tends to be higher in more complex devices and upgrades than in de novo implantations. The incidence of pocket haematoma is approximately 2.5% in patients undergoing ICD im- plantation, > 3% in case of cardiac resynchronisation therapy-pacemaker (CRT-P) or defibrillator (CRT-D), and 4.2% when upgrading a device to CRT-P or CRT-D (9). Pocket haematoma significantly affects morbidity and mortality, prolongs hospitalisation, and increas- es costs (8). In the BRUISE CONTROL INFECTION study, clinically significant pocket haematoma was associated with a seven-fold increased risk of device infection within one year after its implantation (10). Other potential bleeding complications in CIEDs im- plantation procedures are rare. Haemothorax resulting Izvleček Vsadne elektrostimulacijske naprave so pomemben del zdravljenja malignih aritmij, srčnega popuščanja in preprečevanja nenadne srčne smrti. Letno se v evropskem prostoru vstavi približno 1.000 naprav na milijon prebivalcev. Glavna težava pri bolnikih, pri katerih je predvidena vstavitev elektrostimulacijske naprave, so pridružene bolezni, pri katerih je potrebno antitrombotično zdravljenje. Poseg pomeni povečano tveganje za krvavitev, ki se pri vsadnih elektrostimulacijskih napra- vah pokaže vse od hematoma v področju ležišča naprave do tamponade srca. Drugi del spektra tveganj pa je nevarnost, da nastopi trombembolični dogodek zaradi prehodne prekinitve antitrombotičnega zdravljenja. Antitrombotično zdravljenje v obdobju ob posegu pa pomeni pomembno klinično dilemo pri obravnavi tovrstnih bolnikov. Najpogostejši zaplet je he- matom v ležišču naprave, ki terja daljšo hospitalizacijo, višje stroške in večje tveganje za okužbo ležišča, kar vodi do večje obolevnosti in smrtnosti. Prvotno so za preprečevanje morebitnih trombemboličnih dogodkov priporočali premostitev antitrombotične terapije s heparinom, vendar so kasneje raziskave pokazale, da ta strategija prinaša večje tveganje za hematom v ležišču naprave v primerjavi ali z neprekinjenim ali s kratkoročno prekinjenim peroralnim antitrombotičnim zdravljenjem. Hkrati niso opažali pomembne razlike v pojavnosti trombemboličnih dogodkov med obema skupinama bolnikov. Trenutno veljavna priporočila odsvetujejo premostitveno zdravljenje s heparini v obdobju ob posegu. Večino vstavitev vsadnih elektrostimulacijskih naprav lahko varno opravimo ob strategiji neprekinitve prejemanja peroralnega antikoagulacijskga zdravljenja. Dvojna antiagregacijska terapija pa je povezana s povečanim tveganjem za hematom leži- šča naprave in se zato odsvetuje v obdobju ob posegu, če je to sploh mogoče. 277 PROFESSIONAL ARTICLE Antithrombotic management in patients undergoing cardiac implantable electronic device implantation from the injury of the vascular access site is anecdotal. Pericardial effusion and cardiac tamponade resulting from lead perforation are reported in 0.3% of cases (8). The thromboembolic risk depends on the anticoag- ulation indication and comorbidities (Table 1). Low- risk patients are those with less than a 5% annual risk of a thromboembolic event without anticoagulation, and high-risk patients are those with more than a 10% risk of thromboembolism per year (11,12). Consider- ing this risk estimate, we can calculate a thromboem- bolic risk of temporary periprocedural discontinuation of an anticoagulant. For example, in a patient with an annual risk of 5% (0.01% daily risk), a five-day with- drawal of anticoagulants before the procedure would translate into a 0,05% periprocedural risk of thrombo- embolism. However, a study of patients that interrupt- ed warfarin therapy for any reason showed that the risk of thromboembolism is highest in the first 90 days after interruption and subsides thereafter (5). Another ob- servational trial of short interruption of warfarin (<5 days) found a 0.7% risk of TE, which is ten times high- er than the calculated risk (7). Data from the Ljubljana registry show a similar increase in TE risk even in the temporary discontinuation of dabigatran and rivarox- aban (13). Thus, it seems likely that the prothrombotic milieu of the postoperative state somewhat increases the thrombotic risk. The traditional approach to periprocedural antico- agulant management during the vitamin K antagonists (VKA) era was the discontinuation of oral anticoag- ulants and bridging with standard or low molecular weight heparin (LMWH). Before a patient underwent CIED implantation, VKA was discontinued five days before the planned procedure and bridged with LM- WH or continuous intravenous (i.v.) heparin three days before the procedure. The procedure was usually performed when the INR level was less than 1.5 and i.v. heparin was stopped four hours before the proce- dure or in case LMWH was prescribed 24 hours before the procedure. The rationale was to minimise the risk of thromboembolic events and facilitate optimal hae- mostasis during the procedure (11,14). Despite sever- al trials that showed increased bleeding risk with this approach, it is still widely adopted in clinical practice. The European snapshot survey on procedural routines for electronic device implantations from 2016 showed that bridging was still used in 20% of patients on VKA and 23% on non-vitamin K antagonist oral anticoag- ulants (NOAC), while antiplatelet drugs were mainly continued (15). 3 Available data on uninterrupted antithrombotic therapy in patients undergoing device implantation 3.1 Vitamin K antagonists The BRUISE CONTROL trial randomised 681 de- vice recipients with at least moderate thromboembolic risk into the warfarin continuation group or interrup- tion with the full heparin bridging group. In the hep- arin bridging group, warfarin was stopped five days before the procedure and three days before the proce- dure heparin was started. Heparin was held 24 h before the procedure and resumed 24 h afterwards. Warfarin was started 12-24 h after the procedure, and heparin was continued until the INR was in the therapeutic range. The median INR in the warfarin continuation group was 2.3. The safety monitoring board terminat- ed the study prematurely due to a significant difference in the primary outcome (clinically significant pocket Figure 1: Clinically relevant pocket haematoma is defined as one being associated with patient discomfort, prolonged hospitalisation time, need for repeated follow-up visits, and surgical revision. Source: personal archive. 278 CARDIOVASCULAR SYSTEM Zdrav Vestn | May – June 2023 | Volume 92 | https://doi.org/10.6016/ZdravVestn.3402 haematoma) between the study groups. Pocket haema- toma occurred in 3.5% of the patients in the continued oral anticoagulation group and 16% of those bridged with heparin (Figure 2). There were no differences in the occurrence of stroke or other adverse events be- tween the groups (16). Furthermore, a meta-analysis Legend: AF – atrial fibrillation; VTE – venous thromboembolism; TIA – transient ischaemic attack; CHA2DS2-VASc – Congestive heart failure, Hypertension, Age >75 years, Diabetes mellitus, Stroke or transient ischemic attack, Vascular disease, Age 65 to 74 years, Sex category. Indication for anticoagulant therapy High thromboembolic risk (> 10% annual risk) Moderate thromboembolic risk (5-10% annual risk) Low thromboembolic risk (< 5 % annual risk) AF • CHADS2 score 5-6 • CHA2DS2-VASc score 7-9 • Recent (within 3 months) stroke or TIA • Rheumatic valvular heart disease • CHADS2 score 3-4 • CHA2DS2-VASc score 5-6 • CHADS2 score 0-2 • CHA2DS2-VASc score ≤ 4 Mechanical heart valve • Any mitral valve prosthesis • Caged-ball or tilting disc aortic valve prosthesis • Recent (within 6 months) stroke or TIA • Bi-leaflet aortic valve prosthesis and 1 or more of the following risk factors: AF, prior stroke or TIA, hypertension, diabetes, congestive heart failure, age > 75 years • Bi-leaflet aortic valve prosthesis without AF and no other risk factors for stroke VTE • Recent (within 3 months) VTE • Severe thrombophilia (e.g. deficiency of protein C, protein S, or antithrombin; antiphospholipid antibodies) • VTE within the past 3 to 12 months • Non-severe thrombophilia (e.g. heterozygous factor V Leiden or prothrombin gene mutation) • Recurrent VTE • Active cancer (treated within 6 months or palliative • VTE > 12 months previous and no other risk factors Table 1: Perioperative thromboembolic risk. Adapted from Douketis JD, et al., 2012 and Doherty JU, et al. 2017 (11,12). Figure 2: BRUISE CONTROL trial- outcomes. Adapted from Birnie DH N et al., 2013 (16). Treatment strategy % Continued warfarin Heparin bridging 0 2 4 6 8 10 12 14 16 18 Clinically significant hematoma (%) Haematoma prolonging hospitalization (%) Haematoma requiring interruption of anticoagulation (%) Haematoma requiring evacuation (%) p < 0.001 p = 0.006 p < 0.001 p = 0.003 279 PROFESSIONAL ARTICLE Antithrombotic management in patients undergoing cardiac implantable electronic device implantation of seven randomised controlled trials that included 2191 patients demonstrated a significantly lower risk of postoperative bleeding in patients on continued VKA compared to heparin bridging with no difference in the risk of thromboembolic events between the two strategies (17). BRIDGE trial was conducted in a population of pa- tients planned for any elective surgical procedure, but it addressed the question of forgoing anticoagulation altogether in the perioperative period. It is important to stress that high thromboembolic risk was an exclu- sion criterion, and the mean CHADS2 score was 2.3. There was no significant difference in the occurrence of stroke or other thrombotic events between the arms (VKA discontinuation without vs. with heparin bridg- ing) (18). While the BRIDGE trial suggested relative safe- ty with anticoagulant cessation in a low-risk patient population, a meta-analysis of 15 studies that includ- ed almost 6000 patients demonstrated an increased thromboembolic risk associated with oral anticoagu- lant cessation without bridging compared with hepa- rin bridging (1.07% vs. 0.50%). However, there was no difference in thromboembolic events when warfarin was continued. Consistent with the results of previous studies, there was a significantly increased risk of pock- et haematoma with heparin bridging and prolonged hospital stay. In addition, warfarin continuation was not associated with increased pocket haematoma com- pared to warfarin discontinuation (19). Evidence shows that bridging VKAs with heparins is associated with significantly increased bleeding risk. In most patients, uninterrupted VKA therapy is safe, while short interruption of oral anticoagulation might be considered in patients whose bleeding risks out- weigh the thromboembolic risk. 3.2 Non-vitamin K antagonist Oral Anticoagulants In patients with non-valvular AF, NOACs are pre- ferred over VKAs for stroke prevention (20,21). The analysis of the RE-LY trial that included patients who underwent CIED implantation during the study’s du- ration showed that interruption of dabigatran was associated with a similar or lower incidence of pock- et haematoma compared with warfarin interruption without or with heparin bridging, respectively (22). The same observations were noted in the ROCKET-AF study with rivaroxaban and ARISTOTLE with apix- aban, respectively (23,24). In the BRUISE CONTROL-2 trial, 662 device recipients with AF (CHA2DS2-VASC score of ≥ 2 ) were randomised to either continued or interrupted NOAC. In the continued NOAC group, anticoagulants were not interrupted; patients received the morning dose on the day of surgery and the next dose as scheduled. For apixaban and dabigatran, 12h passed between the pre- and post-op doses and 24h for rivaroxaban. In the in- terrupted arm, NOACs were stopped two days before the surgery and started 24h after, with 72 hours pass- ing between the pre-and post-operative doses. It was shown that both strategies were associated with sim- ilarly low rates of pocket haematoma and that unin- terrupted NOACs were not associated with any major perioperative bleeding events. In addition, there was no difference in the occurrence of thromboembolic events (Figure 3) (25). Thus, an uninterrupted NOAC strategy seems safe in CIED procedures. Still, patient characteristics, such as age, body weight, kidney function, and concomitant medication, should be considered to determine the op- timal strategy. 3.3 Antiplatelet drugs To the best of our knowledge, there are no prospec- tive randomised trials on the use of antiplatelet drugs in patients undergoing CIED implantation. However, several observational and retrospective studies suggest an increased risk of clinically significant pocket he- matoma in patients receiving dual antiplatelet therapy Figure 3: BRUISE CONTROL-2 trial- outcomes. Adapted from Birnie DH et al., 2018 (25). Legend: NOAC – non-vitamin K oral anticoagulants. Treatment strategy % Interrupted NOACContinued NOAC Clinically significant hematoma (%) Non-clinically significant hematoma (%) 0 0,5 1 1,5 2 2,5 3 3,5 4 p = 0.97 p = 0.79 280 CARDIOVASCULAR SYSTEM Zdrav Vestn | May – June 2023 | Volume 92 | https://doi.org/10.6016/ZdravVestn.3402 Legend: VKA – vitamin K antagonists; NOAC – non-vitamin K oral anticoagulants; OAC – oral anticoagulant; PCI – percutaneous coronary intervention; ACS – acute coronary syndrome; DAPT – dual antiplatelet therapy. * – before the procedure † – in case of interruption: normal kidney function: last dose 24 h before the procedure and resume 24 h afterwards; apixaban/rivaroxaban: CrCl 15-29 ml/min last dose ≥ 36 h before the procedure; dabigatran: CrCl 50-79 ml/min last dose ≥ 36 h before the procedure, CrCl 30-49 ml/min last dose ≥ 48 h before the procedure. VKA NOAC Dual antiplatelet therapy OAC + antiplatelet Thrombotic risk after PCI Intermediate or low > 1 month PCI > 6 months ACS High < 1 month PCI < 6 months ACS Continue (or consider interrupting without heparin bridging if CHA2DS2-VASc ≤ 4) Continue or interrupt as per operator preference and patient thromboembolic risk† Continue Aspirin and discontinue P2Y12 inhibitor: - ticagrelor 3 days* - clopidogrel 5 days* - prasugrel 7 days* Continue DAPT Continue OAC (VKA or NOAC) Discontinue antiplatelet per patient-specific risk/ benefit analysis Table 2: The algorithm for perioperative antithrombotic management. Adapted from Glikson M et al., 2021 and Burri H et al., 2021 (6,29). with or without concomitant oral anticoagulants (26- 28). Since antiplatelet effects typically last about 5-7 days, there is often insufficient time to avoid antiplate- let action during device implantation. In elective pa- tients who are not at increased thrombotic risk, i.e., more than one month after elective percutaneous coro- nary intervention (PCI) or more than six months after acute coronary syndrome (ACS), it should be consid- ered that dual antiplatelet therapy is avoided. In such cases, the P2Y12 inhibitor should be discontinued 3-7 days before the procedure (6,29). 4 Antithrombotic therapy management in patients undergoing device implantation Device implantation is considered to be a low-bleed- ing-risk procedure. The recent 2021 European guide- lines for cardiac pacing include recommendations on perioperative antithrombotic therapy management in patients undergoing standard transvenous CIED im- plant procedures. Epicardial lead placement and lead extractions are procedures with higher bleeding risk, and periprocedural antithrombotic management in these patients is beyond the scope of this paper (6). Heparin bridging in patients receiving VKAs should be entirely avoided. In most patients, the pro- cedure can be safely performed on continued oral anticoagulation with prothrombin times in the thera- peutic range (INR < 3). However, brief discontinuation of VKA without heparin bridging might be considered in patients with high bleeding and low thromboembol- ic risk. In patients receiving NOACs, device implanta- tion can be safely performed with continuous antico- agulation. However, the patient’s characteristics (age, history of bleeding complications, concomitant med- ication, kidney function) and surgical factors should be considered in managing anticoagulation therapy perioperatively. In case of NOAC interruption, the timings should be decided according to kidney func- tion and the type of NOAC. In patients with normal kidney function, the last dose of NOAC should be taken 24 h before the elective procedure. For those pa- tients who are on dabigatran with creatinine clearance (CrCl) of 50-79 ml/min, the last dose should be taken > 36 h before the procedure; in CrCl of 30-49 ml/min, the last dose should be taken > 48 h before the proce- dure. For activated factor Xa inhibitors and CrCl above 30 ml/min, the last dose should be taken > 24h before the procedure, and in those with CrCl of 15-29 ml/ min, the last dose should be taken 36 h or more before surgery. NOACs can be resumed 6-8 h after the proce- dure; generally, it is recommended to resume therapy 24 h post-procedure (21,30). Dual antiplatelet therapy should be avoided where 281 PROFESSIONAL ARTICLE Antithrombotic management in patients undergoing cardiac implantable electronic device implantation possible due to the higher risk of clinically signifi- cant pocket hematoma. However, patients in the first month after PCI or in the first six months after ACS should continue with dual antiplatelet therapy. In oth- ers, P2Y12 inhibitors should be discontinued several days before the planned procedure, depending on the specific medication used (3 days for ticagrelor, 5 days for clopidogrel, and 7 days for prasugrel). A good surgical technique with meticulous atten- tion paid to haemostasis, as described in the recent EH- RA practical guide on optimal implantation technique for conventional pacemakers, should be the norm in all patients. A compressive bandage applied above the device pocket on the day of surgery may be considered to reduce the possibility of pocket haematoma (29). An algorithm of perioperative anticoagulation management in patients undergoing CIED implanta- tion adapted after the ESC guidelines and the EHRA practical guide on optimal implantation technique is shown in Table 2 (6,29). 5 Conclusions Most CIED implantation procedures can be safely performed with uninterrupted VKAs or NOACs. 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