sign in sign up
<<
Home , Anticoagulant, Antithrombotic

World Journal of Urology https://doi.org/10.1007/s00345-020-03078-2

INVITED REVIEW

Perioperative (antiplatelet and ) in urological practice: a critical assessment and summary of the clinical practice guidelines

Konstantinos Dimitropoulos1 · Muhammad Imran Omar1 · Athanasios Chalkias2 · Eleni Arnaoutoglou2 · James Douketis3 · Stavros Gravas4

Received: 11 November 2019 / Accepted: 2 January 2020 © Springer-Verlag GmbH Germany, part of Springer Nature 2020

Abstract Purpose The perioperative management of patients who are receiving antithrombotic (antiplatelet or anticoagulant) therapy and require urologic surgery is challenging due to the inherent risk for surgical and the need to minimize throm- boembolic risk. The aim of this review is to assess the quality and consistency of clinical practice guidelines (CPGs) and clinical practice recommendations (CPRs) on this topic, and to summarize the evidence and associated strength of recom- mendations relating to perioperative antithrombotic management. Methods A pragmatic search of electronic databases and guidelines websites was performed to identify relevant CPGs/CPRs. The AGREE II (Appraisal of Guidelines for REsearch and Evaluation) instrument was used to assess the methodological quality and integrity of the CPGs. Results The CPGs provided by the European Association of Urology (EAU), the American College of Chest Physicians (ACCP) and the European Society of /European Society of Anaesthesiology (ESC/ESA), and the CPRs provided by the International Consultation on Urological Disease (ICUD)/American Urologic Association (AUA) were retrieved and reviewed. The 3 CPGs were critically assessed using the AGREE II instrument. Inconsistent recommendations were pro- vided based on the indication for antithrombotic , the antiplatelet/anticoagulant agent and the type of urological procedure. Based on the AGREE II tool for CPG assessment, the EAU CPGs scored higher (83.3 points) compared to the ESC/ESA (75 points) and ACCP CPG (66.7 points). Conclusion The perioperative management of antithrombotic therapy in urological patients is potentially challenging but inconsistent CPG of varying quality may create uncertainty as to best practices to minimize thromboembolic and bleeding risk.

Keywords Antiplatelet · Anticoagulant · Antithrombotic · Urology · Urological · Perioperative · Surgery · Guidelines

Introduction

Acute or elective management of patients on antithrombotic (antiplatelet or anticoagulant) therapy presents a challenge * Konstantinos Dimitropoulos for surgeons because of the intrinsic risk for intra- and post- [email protected] operative bleeding associated with most urologic surgery 1 Academic Urology Unit, University of Aberdeen, Aberdeen, and the need to minimize thromboembolic risk. With an Scotland, UK aging population, an increasing number of patients are 2 Department of Anaesthesiology, University Hospital receiving anticoagulant therapy for prevention in of Larissa, Larissa, Greece atrial fbrillation (AF) or the management of venous throm- 3 Department of Medicine, McMaster University, Hamilton, boembolism (VTE) and antiplatelet therapy for coronary or ON, Canada peripheral vascular disease. Such patients, typically, have 4 Department of Urology, University Hospital of Larissa, multiple comorbidities that increase thromboembolic risk. Larissa, Greece The rationale for withholding antithrombotic therapy during

Vol.:(0123456789)1 3 World Journal of Urology the perioperative period is to minimize loss during of the currently available main antithrombotic agents. For and after surgery; however, this approach needs to be bal- perioperative, it is important to note that their elimination anced against the risk of perioperative thromboembolism half-lives are 10–14 h (longer for patients taking that may arise after stopping treatment, especially in high- and have impaired renal function) and have a rapid (1–3 h) risk patients. peak anticoagulant efect after oral intake. Among antiplatelet , irreversibly binds to In the urological setting, surgeons will frequently need cycloxygenase (COX)-1, efectively inhibiting thrombox- to decide on the perioperative management of patients on ane ­A2 production and aggregation, whereas ­P2Y12 or antiplatelets undergoing open or endo- receptor inhibitors, comprising , and scopic, acute or elective urological procedures. The number , reduce platelet aggregation by inhibiting the acti- of patients taking antithrombotic agents has increased in vation of the glycoprotein IIb/IIIa receptor complex [1–5]. the past decade, especially as DOAC have become widely , which is typically combined therapeutically used in patients with AF and VTE. Thus, it is critical for with aspirin, inhibits cyclic adenosine monophosphate the surgeon to be aware of the characteristics of antithrom- (cAMP) phosphodiesterase, increases platelet cAMP levels botic agent and their mechanism of action to facilitate deci- and reduces ­A2 activity and platelet aggrega- sion-making such as optimal timing of discontinuation and tion [6, 7]. Less commonly used agents are , epti- restarting as well as antithrombotic reversal, if feasible. fbatide and tirofban, which act on platelet glycoprotein IIb/ In addition and separate to pure clinical knowledge and IIIa receptors to inhibit platelet aggregation by preventing practice, the methodological quality of the available guide- the binding of fbrinogen, , and other lines and recommendations becomes a critical component adhesive molecules [8–10]. of evidence-based patient care in the era of evidence-based Anticoagulant , on the other hand, suppress medicine. To the best of our knowledge, the available recom- formation and propagation by targeting diferent mendations on the perioperative management of antithrom- clotting factors involved in the cascade that cul- botic treatment in the urological setting has not been system- minates with the production of fbrin. As venous thrombi atically reviewed and methodologically assessed. contain high levels of fbrin, anticoagulants mainly reduce The current review will identify the clinical practice the incidence of venous thromboembolic events, but antico- guidelines (CPGs) and clinical practice recommendations agulants are also efective to prevent intracardiac thrombus (CPRs) on the management of antiplatelets and anticoagu- formation in patients with AF, thereby reducing the risk for lants in the acute and elective urological surgical setting, as cardioembolic stroke. provided by four main medical and surgical organizations. Among anticoagulant drugs, decreases blood In addition, the methodological quality of the CPGs will be clotting by blocking reactivation of K1; without objectively assessed with a validated instrument. sufciently active vitamin K1, clotting factors II, VII, IX, and X have decreased clotting ability [11]. Unfractionated binds reversibly to III and greatly Methods accelerates the rate at which it inactivates (fac- tor IIa) and factor Xa. Low-molecular-weight A pragmatic search of the available electronic databases and (LMWHs) bind and activate antithrombin, with a stronger guidelines websites, including PubMed, EMBASE and the afnity to factor Xa than unfractionated heparin and afect National Guideline Clearinghouse (www.guideline.gov​ ) was only the intrinsic coagulation cascade. is a performed. Databases were searched from their inception selective factor Xa inhibitor that prevents the conversion date to March 2019; only English-written guidelines were of prothrombin to thrombin [12]. Direct oral anticoagu- searched and retrieved. Following identifcation of guide- lants (DOACs) include dabigatran and factor Xa inhibi- lines authors reached consensus on internationally endorsed tors. Dabigatran etexilate is an oral prodrug that disrupts CPGs or CPRs with direct clinical relevance to the urologi- the coagulation cascade and inhibits the formation of clots cal surgical practice. by ofering reversible and direct inhibition of direct throm- CPGs/CPRs were reviewed and main recommendations bin [13]. , and are factor were summarized into tables. Two independent trained Xa inhibitors. All DOACs inhibit the formation of circulat- appraisers (KD and MO) used the AGREE II (Appraisal ing and clot-bound thrombin and have no efects on platelet of Guidelines for REsearch and Evaluation) instrument to function [14–18]. With respect to reversibility of action, evaluate the three CPGs. AGREE II is an international, dabigatran can be reversed selectively with , validated instrument that assesses the methodological qual- a humanized monoclonal antibody fragment, while further ity and integrity of the Guidelines and is globally endorsed reversal agents for DOACs are on the horizon. Table 1 sum- by several health care organizations [19]. It consists of 23 marizes the characteristics and pharmacological properties separate items evaluating six diferent domains: (1) scope

1 3 World Journal of Urology

Table 1 Summary of the characteristics of currently available antiplatelet and anticoagulant agents Dose Route of administration Bio-availability Plasma half-life Duration of action Reversibility of platelet inhibition

Antiplatelet agents Aspirin 81–325 mg ­dailya Once daily PO / IV 68% 15–30 min 7–10 days No Clopidogrel 75 mg once daily Once daily PO 50% 8 h 7–10 days No Prasugrel 10 mg once daily Once daily PO 80% 7 h 7–10 days No Ticagrelor 90 mg twice daily Twice daily PO 36% 7 h 5 days Yes Abciximab Variable IV – 10–15 min 12 h Yes Eptifbatide Variable IV – 2.5 h 2–4 h Yes Tirofban Non-ST ­ACSb IV – 2 h 2–4 h Yes Drug Dose Route of Bio-availa- Plasma half-life Duration of action Peak plasma Elimination administration bility (%) concentration

Anticoagulant agents Warfarin Highly variable PO 80 20–60 h 48–96 h Variable UFHc Variable SC / IV 30 1 h Dose dependent 4 h (SC) Reticulo-endothe- (SC) lial system LMWHd Variable SC 90 4 h Dose dependent 3 h Hepatic metabo- lism, 10% renal Fondaparinux Variable SC 100 17 h 48–96 h 2 h Renal Dabigatran 150 mg twice daily PO 6 12–14 h 48 h 2 h 80% renal Apixaban 5 mg twice daily PO 66 8–15 h 24 h 2.5–4 h 25% renal Rivaroxaban 20 mg once daily PO 80 7–10 h 24 h 1–3 h 50% renal, 50% hepatic Edoxaban 30–60 mg once PO 62 10–14 h 24 h 1–2 h 50% renal daily a ± Dipyridamole 75–100 mg every 6 h b Non-ST acute coronary syndrome: 5 mcg/kg IV infused within 5 min, then 0.15 mcg/kg/min for up to 18 h (CrCl ≤ 60 mL/min: decrease post loading dose infusion by 50% to 0.075 mcg/kg/min IV) c Unfractionated heparin d Low molecular weight heparin and purpose (items 1–3); (2) stakeholder involvement (items between high- and poor-quality guidelines; instead, this 4–6); (3) rigor of development (items 7–14); (4) clarity of decision should be made by the AGREE II user. However, presentation (items 15–17); (5) applicability (items 18–21); domain scores can certainly be used for comparisons among and (6) editorial independence (items 22–23). The AGREE diferent CPGs. II instrument uses a 7-point scoring system for each one of these 23 individual items, with a score of 1 indicating no/poor information provided for the appraised item, while Results a score of 7 indicates exceptional quality of reporting. There is also a fnal domain assessing the overall quality Four diferent internationally endorsed CPGs and CPRs of the Guideline (score 1–7) and a separate item pertaining were identifed following the initial search. These included to whether the reviewer would recommend the appraised the CPGs of the European Association of Urology (EAU) guideline for clinical use (Yes, Yes with modifcations, No). published in 2018 [20, 21], the American College of Chest Scores for each domain are calculated by summing up Physicians (ACCP) CPG published in 2012 [22] and the all appraisers’ scores of all individual domain items and European Society of Cardiology/European Society of by scaling the total as a percentage of the maximum pos- Anaesthesiology (ESC/ESA) CPGs published in 2014 [23]. sible score for that domain using the formula (Obtained Finally, the CPRs provided by the International Consultation score–Minimum possible score) × 100/(Maximum possible on Urological Disease (ICUD)/American Urologic Associa- score − Minimum possible score). According to the AGREE tion (AUA) were included in this pragmatic review [24]. The II Consortium, there are no set scores used to diferentiate

1 3 World Journal of Urology overall results of the appraisal of the three CPGs with the be presented and discussed below, separate for antiplatelet use of the AGREE-II instrument are presented in Table 2. and antithrombotic agents. The applicability of the AGREE II instrument to assess the ICUD/AUA publication was also assessed by the review- ers. The AUA/ICUD white paper reported consensus-based Discussion recommendations and as the authors reported in their pub- lication, they focused on constructing a review based on Antiplatelet agents a systematic literature search, instead of developing a full CPG. Thus, to ensure methodological consistency, it was With respect to the management of patients who are using decided that AGREE II would not be used to appraise the antiplatelet agents, most CPGs/CPRs focused on aspirin and AUA/ICUD recommendations which should be regarded as clopidogrel, although additional recommendations regarding CPRs instead of CPGs. the management of patients on ticagrelor or prasugrel also With respect to overall guideline assessment, the EAU were provided. It is noteworthy that all CPGs/CPRs discuss and ESC/ESA CPGs had scores of 83.3, and 75, respectively, the need for the clinician to weigh the risks of perioperative while the ACCP CPGs scored lower (66.7) mainly because bleeding against the risk of thromboembolic complications. they were considered to require revision to ensure updated In general, the main clinical settings discussed in the recommendations. As regards scope and purpose, the ACCP CPGs/CPRs represent the perioperative management of Guidelines had the highest score (88.9) compared to the monotherapy (with aspirin or other antiplatelets) and dual EAU (63.9) and ESC/ESA (52.8) CPGs. The ESC/ESA antiplatelet treatment (with aspirin and one P2Y12 inhibi- Guidelines scored higher in terms of stakeholder involve- tor). While a variety of recommendations is noted in regards ment (55.6 versus 52.8 for both EAU and ACCP CPGs), to the perioperative management of aspirin monotherapy and for applicability (70.8 versus 33.3 for ACCP and 8.3 (EAU advises stopping prior to operation based on recent for EAU). The EAU Guidelines had the highest score as evidence, AUA and ACCP recommend in general continu- regards rigor of development (56.3 versus 55.2 for ESC/ESA ing with aspirin through the time of surgery and ESC/ESA and 43.8 for ACCP Guidelines), clarity of presentation (94.4 advise individualized approach), it is clear that all CPGs/ compared to 83.3 for ACCP and 75.0 for ESC/ESA CPGs), CPRs agree on stopping all remaining antiplatelets (such as while the EAU and ACCP CPGs scored 100 for editorial clopidogrel or ticagrelor) preoperatively. independence compared to 91.7 for those of the ESC/ESA. The challenging management of DAPT in the elective/ For all CPGs, modifcations were deemed necessary to urgent/emergency surgical setting is highlighted across all further improve the quality of their recommendations and four CPGs/CPRs. Deferring any elective procedures until the methods. Whereas a similar pattern of scoring was identifed completion of the DAPT course is clearly the consensus rec- across almost all the examined CPG domains, discrepancies ommendation with the clinicians advised to explore simpler were identifed in applicability, with a range of 62.5 points and less invasive management alternatives for a minimum (8.3–70.8). time period that depends on the original clinical indication Table 3 provides a detailed summary of the CPGs for DAPT (e.g., insertion of bare metal or drug eluting stent). and CPRs relating to the perioperative management of If this is not possible (for example in the case of a clinical antithrombotic agents. For brevity, all recommendations will emergency), then multidisciplinary approach is encouraged by all organizations and diferent recommendations are

Table 2 Assessment of clinical practice guidelines with the use of AGREE II instrument AGREE II domain Overall guideline assessment Guideline 1 2 3 4 5 6 Scope and Stakeholder Rigor of Clarity of Applicability Editorial Inde- Overall score Recommended for use in purpose involvement development presentation pendence clinical practice

EAU 63.9 52.8 56.3 94.4 8.3 100 83.3 Yes, with modifcations ACCP 88.9 52.8 43.8 83.3 33.3 100 66.7 Yes, with modifcations ESC/ESA 52.8 55.6 55.2 75.0 70.8 91.7 75.0 Yes, with modifcations

Average scores from two reviewers EAU European Association of Urology, ACCP American College of Chest Physicians, ESC/ESA European Society of Cardiology/European Society of Anaesthesiology

1 3 World Journal of Urology on an individual decision, which depends on an individual decision, which on the bleeding risk, perioperative weighed the riskagainst complications of thrombotic completion of the full course of DAPT— completion should be Multi-disciplinary approach followed period, 3 (new- a minimum of 1 (BMS) to might be DES) months of DAPT generation of the acute - acceptable, independently of ness of coronary disease. Independently implantation stent the between timeframe therapy anti-platelet single and surgery, with aspirin) should be continued (preferably throughout surgery in hospitals, 24/7 catheterization where patients treat to laboratories available, are athero - in case of perioperative immediately events thrombotic and prasugrel 5 days dogrel and ticagrelor for prior unless there is a surgery to 7 days for high risk of - thrombosis, bridging with therapy intrave should be con - or tirofban, nous eptifbatide LMWH bridgingsidered. in these patients therapy Dual anti-platelet should be avoided. as soon possible aftershould be resumed and, if possible, within 48 h surgery ESC/ESA Stopping/continuing aspirinStopping/continuing should be based For elective operations, delay surgery until surgery delay operations, elective For a longer for be delayed cannot When surgery should be performed procedures surgical Such withhold clopi - In case of clinical emergencies, patients with high riskFor a very of stent - - diac surgery, continue aspirin the around time of surgery diac surgery, surgery before aspirin of stopping 10 days instead 7 to ing aspirin, stop aspirin 7 to 10 days before surgery instead instead surgery before ing aspirin, aspirin stop 10 days 7 to of continuation aspirin aspirin noncar receiving who are and require therapy metal stent and for at least 6 months at least after placement of a and for metal stent drug-eluting of undertaking instead stent within surgery these time periods or within 6 months stent of a bare-metal of placement a drug-eluting therapy continuing dual antiplatelet stent, of stopping instead is suggested thearound time of surgery surgery before 7–10 days therapy dual antiplatelet ACCP Patients at low risk for cardiovascular events who are receiv who are events cardiovascular risk for at low Patients Patients at moderate to high risk for cardiovascular events events cardiovascular high risk to at moderate Patients for Defer surgery for at least 6 weeks after placement of a bare- 6 weeks at least for surgery Defer of placement within 6 weeks surgery In patients who require ondary stroke prevention, especially especially prevention, ondary stroke continue aspirin after stroke, recent through Bridging operation. might be neurological by if directed required, consultation in selected cases tions: Continue through perioperative period. If no medical indications, by be discontinued until directed may team the surgical and procedures prior elective to as soon possible afterresume the procedure - urologi occur before should not within cal procedures 12 months of drug placement or eluting stent within 3 months metal stent of bare placement clopidogrel, prasugrel or ticagrelor and continue with aspirin, if bleeding risks acceptable are periods, multidisciplinary approach of ways is essential consider simpler management AUA/ICUD For patients on antiplatelets for sec - for patients on antiplatelets For indica - cardiac dose Aspirin for Low 7–10 days Discontinue antiplatelets Withdrawal of dual AP therapy of dual AP therapy Withdrawal these limits, discontinue Beyond cases within these time In urgent very high-risk for TE high-riskvery for patients, no alternative required Restart when bleeding is no 4 day a risklonger (usually, post-op) otherwise continue anti - through surgery high risk very patients for (drug-eluting place - stent ment within 6 months, placement metal stent bare TIA or within 6 weeks, within 30 days) stroke EAU Stop antiplatelets in all but antiplatelets Stop Delay surgery, if possible, surgery, Delay Clinical practice guidelines and recommendations on the perioperative management of antiplatelet/anticoagulant agents in the setting urological agents of antiplatelet/anticoagulant on the management guidelines and recommendations Clinical practice perioperative platelet platelet - treat ment (aspri - rin / clopi - dogrel) anti - platelet therapy 3 Table Anti - Dual

1 3 World Journal of Urology 1.5 > 2.0 thedose last - 4] or mechani < ≥ 1.5 is reached ≤ resumed at the pre-procedural dose 1–2 days dose 1–2 days at theresumed pre-procedural depending on the patient’s after surgery, 12 h afterhaemostatic status, but at least the on day VKAs should be resumed procedure. 1 or 2 afteron adequate surgery—depending mainte - haemostasis—with the pre-operative dose of 50% for nance dose plus a boosting the maintenance dose days; consecutive two LMWH thereafter. should be administrated or UFH should be continued until the INR returns therapeutic to levels of LMWH is administered no later than 12 h of LMWH is administered the procedure before of intravenous in favour the evidence valves, solid; thusUFH is more in some centres these hospitalized patients are and treated surgery, hours before with UFH until four withand treatment after UFH is resumed until the INR is withinsurgery the therapeu - tic range to should be given Consideration be checked. theif postponing procedure INR is thrombo-embolism (patients with: AF with a of score CHA2DS2-VASc mended that VKA treatment be stopped mended that be stopped VKA treatment (depending on the surgery before 3–5 days - INR measure type of VKA), with daily ments, until cal prosthetic valves, newly inserted newly heartcal prosthetic valves, or mitral heartbiological prosthetic valves, (within repair 3 months) the past valvular thrombo-embolism (within venous or recent 3 months) or ), discontinuation and theseof VKAs is hazardous patients will need bridging with therapy LMWH with the afterLMWH started discontinuation 1 day or once INR is of warfarin ESC/ESA Following operation, LMWH or UFH is operation, Following In patients with mechanical prosthetic heart prosthetic In patients with mechanical the of the procedure, INR should On the day However, in VKA patients with a high risk of However, For patients at low risk for VTE,- it is recom risk for patients at low For or VTE at: of no bridging instead duringis suggested interruption of VKA therapy and lower is, as in the higher- chosen bridging approach risk patients, based on an assessment of individual patient- factors and surgery-related of bridginginstead anticoagulation during interruption of VKA therapy morning) and when there of or next is adequate (evening of VKAs of later resumption instead ACCP Stop VKAs approximately 5 days before surgery before 5 days VKAs approximately Stop atrial fbrillation, heartIn patients with a mechanical valve, thromboembolism, bridgingHigh risk anticoagulation for thromboembolism, the bridging riskModerate or no- for thromboembolism, no bridging risk is suggested for Low 24 h after 12 to surgery VKAs approximately Resume - farin would be stopped 3 to 5 days 5 days 3 to be stopped would farin and procedure the surgical before if restarted 24 h postoperatively 12 to the bleeding risk is acceptable anticoagulation should be regarding elective ahead of any planned well procedure a procedure is being held before an INR of less than 1.5 should have valve mitral mechanical with any aortic or a mechanical replacement should risk with factor) any valve below be bridged when INR falls surgery) 48 h before 2.0 (typically and theto dose should be adjusted partial an activated throm - achieve 3 times the time of 2 to boplastin value control - and unfraction sible postoperatively ated heparin is continued until INR at least for is in the therapeutic range 48 h sultation regarding with cardiologists anticoagulation is advised AUA/ICUD AF patients war In high risk procedures, surgical Prosthetic valves Prosthetic Expert consultation cardiological patients in whom warfarin TE low-risk TE high risk patients (defned as those as soon pos - is resumed Warfarin con - procedures, elective before Well anticoagulants - antithrombot alternative ics – Restart when bleeding a riskis no longer (usually, post-op) 4 day and then discontinue anti - coagulants pre-operatively possible, continue if not with anticoagulants through the or bridging operation be suggested may Anticoagulation with either heparin or LMWH through rather- than stop surgery, ping anticoagulation before and after surgery on heartprosthetic valves warfarin surgery, to and subsequent rather than discontinuing anticoagulation peri- warfarin (Stop operatively 4 days, D–5, LMWH for of surgery, nothing on Day warfarin recommence and LMWH D1 until INR therapeutic levels) reaches EAU All but very high-riskAll but very on anticoagulants, no Stop VTE episode Recent (1–3 months) surgery Delay thrombophilia Severe High-risk mechanical Bridging with LMWH prior (continued) 3 Table VKAs

1 3 World Journal of Urology direct oran anti-coagulant, oran direct biological half-lives prior surgery to biological half-lives prior surgery to biological half-lives their due to short biological half-lives. sary, this to rule is the patient with An exception high thrombo-embolic risk, whose surgical days several for is delayed intervention comparison with of VKAs), resumption aftershould be delayed treatment surgery until post- 1–2 (in some cases 3–5) days, for bleeding tendency is diminished surgical ESC/ESA Normal bleeding risk procedures 2–3 times their respective for DOAC Stop High bleeding risk procedures 4–5 times their respective for DOAC Stop cases unneces - Bridging is in most surgery to (in of NOACs ‘on’-efect Because of the fast dual antiplatelet, DOAC dual antiplatelet, antiplatelet, AF atrial anticoagulant, AP antiplatelet, fbrillation, ACCP N/R ESC/ESA Physicians, American of Chest International College Disease / American Consultation Association, ACCP on Urological Urologic fed should be discontinued rivaroxaban surgery elective before 2–5 days bridging with some other anticoagu - as heparinlant such is recommended although longer rivaroxaban, for periods be required of bridging may expert consultation with for allow cardiology/hematology/thrombosis services advised with experts is strongly AUA/ICUD Minor bleeding risk procedures be modi - to have use does not NOAC bleeding riskStandard/high procedures and dabigatran apixaban, NOACs procedures Urgent 36 h to 24 to thefor procedure Delay Consultation procedures Emergency anticoagulants no alternative (1–3 days), antithrombotics—restart when bleeding is no longer post- 4 day a risk (usually, op) and then discontinue anti - coagulants pre-operatively– possible, continue If not with anticoagulants through the or bridging operation be suggested may EAU All but very high-riskAll but very on anticoagulants Stop VTE episode Recent (1–3 months) surgery Delay (continued) ​ ICUD/AUA Association of Urology, European not reportedN/R not 3 Table EAU thromboembolic events, AC TE thromboembolic events, VTE thromboembolic events, venous of Anaesthesiology, Society of Cardiology/European Society European heparin, heparin, molecular weight VKA vitamin-K molecular weight DAP antagonist,heparin, UFH unfractionated LMWH low LMWH low DOACs

1 3 World Journal of Urology provided such as continuing with the DAPT perioperatively ofer bridging. AUA also advise consultation with cardiol- (EAU and ACCP), or continuing with single antiplatelet ogy/haematology for urgent/emergency procedures. While treatment with aspirin around the time of surgery with or AUA approaches standard and high risk procedures in the without bridging based on indications and with a 24/7 cath- same way (stop DOAC 2–5 days prior to operation, bridging eterization laboratory available to treat patients in case of might be required) ESC/ESA ofer diferent recommenda- perioperative TEs (ESC/ESA). tions based on the risk of bleeding (stop DOACs preopera- AUA is the only association that provides with procedure- tively for 2–3/4–5 times their biological half-lives for low specifc recommendations. Patients on low-dose aspirin can and high risk procedures, respectively) and in general rec- have prostatic biopsies while remaining on the antiplatelet ommends against bridging except in case surgical interven- drug with a risk of minor bleeding approximately a third tion is delayed for several days. higher than the controls. Laser operations such as ureteros- Of note, ACCP Guidelines do not provide with recom- copy or laser prostatectomy can be safely performed without mendations on the management of DOACs as their use was stopping the AP agent. For more complicated procedures not common when ACCP CPGs were released. Recently, such as PCNL, TURP, or even more invasive operations however, Douketis et al. published the results of the PAUSE (e.g., radical prostatectomy or partial nephrectomy) this is (Perioperative Anticoagulation Use for Surgery Evaluation) not the case, and therefore, AP should be stopped and bridg- study, assessing a simple proposed discontinuation/resump- ing should be ofered prior to the procedure. For ESWL, AP tion strategy for patients with AF on DOACs who were to drugs should be discontinued or reversed prior to the ESWL be ofered various types of elective surgery (not urological, session, although no specifc timings of cessation/reinsti- necessarily) [25]. DOACs were stopped 1 or 2 days before a tution of antiplatelet drugs were provided, as they warrant low- or high-risk procedure, respectively, and were resumed multidisciplinary and case-specifc discussions. 1 day after a low risk procedure or 2–3 days after a high-risk one. In more than 3000 patients included, the rates of major Anticoagulant agents bleeding and arterial thromboembolism were low, regardless of the DOAC agent. Two main categories of anticoagulants are discussed by the CPGs/CPRs discussed in this review: warfarin and the newer Methodological aspects DOACs. It should be noted that the ACCP Guidelines do not address perioperative DOAC management. With respect to With respect to the methodological quality of the CPGs procedure-specifc guidance, the recommendations provided assessed in this review, some critical points need to be dis- by the AUA remain the same with the ones provided in the cussed and clarifed. First, the methodological framework case of APs. of the CPGs discussed in this review is not the same, and In regards to perioperative management of warfarin, all therefore, the processes linking the available evidence to four CPGs/CPRs use a risk stratifcation approach to pro- the provided recommendations can vary signifcantly. In vide with recommendations. For patients on warfarin at low addition, the levels of evidence and strengths of recommen- risk for TEs, warfarin should be stopped 3–5 days prior to dations as presented in the CPGs might not be exactly the procedure; warfarin can be restarted after 1–4 days depend- same as the Guidelines organisations can be using diferent ing on the CPG/CPR. All CPGs/CPRs agree that patients at grading systems, and therefore, interpreting the statements high risk for TEs will need to stop warfarin 5 days before the and comparing the recommendations directly based on their procedure and start bridging with LMWH 4 days before the strength should be approached with extreme caution. operation or once INR < 2.0. ACCP Guidelines encourage a Although AGREE II is a validated instrument that patient/surgery-based approach in patients at moderate risk assesses the methodological quality of health system for TEs, where the clinician can decide on whether bridg- guidelines, there are no pre-defned thresholds to defne ing should or should not be ofered. ESC/ESA CPGs and high, moderate and low quality guidelines due to the lack AUA CPRs tend to favour the use of UFH as bridging agent of empirical basis to defne them. An arbitrary threshold in patients with metallic heart valves, ACCP CPGs discuss of < 30% to defne low quality and > 70% to defne high both LMWH and UFH, while EAU CPGs only recommend quality can be used for the subdomains as users should be LMWH. encouraged to avoid using the overall score as the sole indi- For the management of DOACs, some variation in rec- cator of methodological quality. Moreover, depending on the ommendations is noted reflecting the new practice and primary research aim solitary domains could have a higher constantly evolving evidence. EAU CPGs follow the same weight (e.g., stakeholder involvement and applicability), and approach with warfarin: stop preoperatively with no bridg- therefore, their scores will require diferent interpretation. ing; if the TE is recent, defer operation if possible; if not, Thus, we discourage the readers from preferring a specifc continue with the anticoagulants around the procedure or

1 3 World Journal of Urology guideline over another one based on the AGREE II results Another possible limitation is the fact that AGREE II has only. received criticism that it relies on subjective assessments, its The 3 CPGs assessed in the current SR had high scores domains are not weighted and the main problem is that due in Editorial Independence (best domain for all three) and to the lack of clear cut-of scores, it is very difcult for the Clarity of Presentation and moderate scores in Stakeholder reader to reach clear conclusions on the true quality of the Development and Rigor of Development. In Scope and Pur- assessed guideline [26]. pose, EAU and ESC/ESA CPGs had moderate scores, while To the best of our knowledge, this is the frst pragmatic ACCP CPGs scored fairly high. The most impressive score review to summarise the evidence on the perioperative man- range was detected in Applicability, with EAU CPGs scor- agement of antiplatelet/anticoagulant agents in the urologi- ing very low, ACCP CPGs having low score and ESC/ESA cal setting with a critical assessment of the included CPGs. scoring rather moderate-to-high. We feel that from a clinical perspective this will represent It is clear that the CPGs panel need to work more on iden- a helpful tool, will facilitate the decision-making process, tifying the facilitators and barriers to their Guidelines appli- simplify clinical practice and improve patient care. From cation and on how their recommendations can be applied. In the methodological view, the current review will also high- addition, auditing criteria and processes need to be clearly light to the reader the methodological limitations, chal- provided to further improve the Applicability domain score. lenges and strengths behind the available evidence-based With respect to the Rigour of Development domain, main recommendations. weak points were clear descriptions of the methodology and in specifc the link between recommendations and sup- porting evidence, the external review and the update proce- dures. In Stakeholder Development, clear description of the Conclusions target users of the CPGs was not frequently provided and it was unclear how the views and preferences of patients The perioperative management of antithrombotic therapy were sought and taken into consideration. The lack of clear in urological patients is potentially challenging but incon- descriptions of the health questions, objectives and target sistent CPG of varying quality may create uncertainty as to population covered in the CPGs can explain the rather mod- best practices to minimize thromboembolic and bleeding erate scores in Scope and Purpose. For all 3 CPGs, reviewers risk. Various recommendations have been provided by sev- felt that additional modifcations were necessary to further eral surgical and medical organisations on the perioperative improve the quality of recommendations and methods. management of antiplatelet and antithrombotic agents in the urological feld and are presented in the current review. Cli- Limitations and strengths nicians are encouraged to critically endorse them to develop patient-specifc evidence-based management plans tailored A possible limitation of this review is the fact that only 4 to meet individual needs. On the other hand, this review also CPGs/CPRs were included, presented, assessed and dis- reveals weaknesses and gaps in the quality of the available cussed. Indeed, a more inclusive approach could have been guidelines, highlighting the need for further improvement to followed in this review with a more exhaustive literature the guidelines panels and organisations. search to give the reader a more holistic overview of the available literature and mainly the evidence-derived rec- ommendations. There are a big number of international, Author contribution KD: protocol/project development, data collec- tion or management, data analysis, and manuscript writing/editing. national and departmental guidelines available currently MIO: protocol/project development, data collection or management, but the aim of this review was to discuss the perioperative data analysis, and manuscript writing/editing. AC: data collection management of the antithrombotic agents in the urological or management and manuscript writing/editing. EA: data collection setting in specifc. As a result, it was decided that the rec- or management and manuscript writing/editing. JD: protocol/project development, data collection or management, and manuscript writing/ ommendations provided by the two main international uro- editing. SG: protocol/project development, data collection or manage- logical associations (EAU and AUA) should be discussed. ment, and manuscript writing/editing. The ESC/ESA and ACCP CPGs do not exclusively refer to urological operations but provide with evidence based Compliance with ethical standards recommendations on the general perioperative management of antithrombotic medications and are endorsed by multiple Conflict of interest No fnancial conficts of interest. K. Dimitropoulos medical and surgical societies globally. In addition, their is a Senior Associate of the EAU Guidelines Ofce and a member clinical recommendations represent the main basis for guide- of the EAU Guidelines Ofce Urethral Strictures panel, M.I. Omar is the EAU Guidelines Ofce Methodology Supervisor, S. Gravas is the lines provided by other associations. Chair of the EAU Guidelines Ofce Male LUTS panel and J. Douketis is the frst author of the ACCP Guidelines publication.

1 3 World Journal of Urology

Human animals rights Not applicable. and meta-analysis of subgroups. Thrombosis 2013:640723. https​ ://doi.org/10.1155/2013/64072​3 Informed consent Not applicable. 15. O’Donnell MJ, Eikelboom JW, Yusuf S et al (2016) Efect of apixaban on brain infarction and microbleeds: AVERROES- MRI assessment study. Am Heart J 178:145–150. https​://doi. org/10.1016/j.ahj.2016.03.019 References 16. Potpara TS, Polovina MM, Licina MM et al (2012) Novel oral anticoagulants for stroke prevention in atrial fbrillation: focus on apixaban. Adv Ther 29:491–507. https​://doi.org/10.1007/s1232​ 1. Holbrook A, Schulman S, Witt DM et al (2012) Evidence-based 5-012-0026-8 management of anticoagulant therapy: antithrombotic therapy 17. Granger CB, Alexander JH, McMurray JJV et al (2011) Apixaban and prevention of thrombosis, 9th ed: American college of chest versus warfarin in patients with atrial fbrillation. N Engl J Med physicians evidence-based clinical practice guidelines. Chest 365:981–992. https​://doi.org/10.1056/NEJMo​a1107​039 141:e152S–e184S. https​://doi.org/10.1378/chest​.11-2295 18. Frost C, Wang J, Nepal S et al (2013) Apixaban, an oral, direct 2. Patrono C, Baigent C, Hirsh J, Roth G (2008) Antiplatelet drugs: factor Xa inhibitor: single dose safety, pharmacokinetics, pharma- American college of chest physicians evidence-based clinical codynamics and food efect in healthy subjects. Br J Clin Pharma- practice guidelines (8th edition). Chest 133:199–233. https​://doi. col 75:476–487. https://doi.org/10.1111/j.1365-2125.2012.04369​ ​ org/10.1378/chest​.08-0672 .x 3. DiNicolantonio JJ, D’Ascenzo F, Tomek A et al (2013) Clopi- 19. Brouwers MC, Kho ME, Browman GP et al (2010) AGREE II: dogrel is safer than ticagrelor in regard to bleeds: a closer look advancing guideline development, reporting and evaluation in at the PLATO trial. Int J Cardiol 168:1739–1744. https​://doi. health care. CMAJ Can Med Assoc J J Assoc Med Can 182:E839– org/10.1016/j.ijcar​d.2013.06.135 842. https​://doi.org/10.1503/cmaj.09044​9 4. Wallentin L, Becker RC, Budaj A et al (2009) Ticagrelor versus 20. Tikkinen KAO, Craigie S, Agarwal A et al (2018) Procedure- clopidogrel in patients with acute coronary syndromes. N Engl J specifc risks of thrombosis and bleeding in urological sur- Med 361:1045–1057. https​://doi.org/10.1056/NEJMo​a0904​327 gery: systematic review and meta-analysis. Eur Urol 73:242–251. 5. Tafur A, Douketis J (2018) Perioperative management of anticoag- https​://doi.org/10.1016/j.eurur​o.2017.03.008 ulant and antiplatelet therapy. Heart Br Card Soc 104:1461–1467. 21. Tikkinen KAO, Craigie S, Agarwal A et al (2018) Procedure- https​://doi.org/10.1136/heart​jnl-2016-31058​1 specifc Risks of Thrombosis and Bleeding in Urological Non- 6. Schwarz UR, Walter U, Eigenthaler M (2001) Taming platelets cancer Surgery: systematic review and meta-analysis. Eur Urol with cyclic . Biochem Pharmacol 62:1153–1161. https​ 73:236–241. https​://doi.org/10.1016/j.eurur​o.2017.02.025 ://doi.org/10.1016/s0006​-2952(01)00760​-2 22. Douketis JD, Spyropoulos AC, Spencer FA et al (2012) Perio- 7. Diener HC, Cunha L, Forbes C et al (1996) European stroke pre- perative management of antithrombotic therapy: antithrombotic vention study. 2. Dipyridamole and acetylsalicylic acid in the sec- therapy and prevention of thrombosis, 9th ed: American college ondary prevention of stroke. J Neurol Sci 143:1–13. https​://doi. of chest physicians evidence-based clinical practice guidelines. org/10.1016/s0022​-510x(96)00308​-5 Chest 141:e326S–e350S. https​://doi.org/10.1378/chest​.11-2298 8. Dornbos D, Nimjee SM (2018) Reversal of systemic anticoagu- 23. Kristensen SD, Knuuti J, Saraste A et al (2014) 2014 ESC/ESA lants and antiplatelet therapeutics. Neurosurg Clin N Am 29:537– Guidelines on non-cardiac surgery: cardiovascular assessment and 545. https​://doi.org/10.1016/j.nec.2018.06.005 management: the Task Force on non-cardiac surgery: cardio- 9. Altenburg A, Haage P (2012) Antiplatelet and anticoagulant drugs vascular assessment and management of the European Society of in . Cardiovasc Intervent Radiol 35:30–42. Cardiology (ESC) and the European Society of Anaesthesiology https​://doi.org/10.1007/s0027​0-011-0204-0 (ESA). Eur Heart J 35:2383–2431. https​://doi.org/10.1093/eurhe​ 10. Sedat J, Chau Y, Mondot L et al (2014) Is eptifbatide a safe and artj/ehu28​2 efective rescue therapy in thromboembolic events complicating 24. Culkin DJ, Exaire EJ, Green D et al (2014) Anticoagulation cerebral aneurysm coil embolization? Single-center experience in and antiplatelet therapy in urological practice: ICUD/AUA 42 cases and review of the literature. Neuroradiology 56:145–153. review paper. J Urol 192:1026–1034. https​://doi.org/10.1016/j. https​://doi.org/10.1007/s0023​4-013-1301-3 juro.2014.04.103 11. Ageno W, Gallus AS, Wittkowsky A et al (2012) Oral anticoagu- 25. Douketis JD, Spyropoulos AC, Duncan J et al (2019) Perioperative lant therapy: antithrombotic therapy and prevention of thrombo- management of patients with atrial fbrillation receiving a direct sis, 9th ed: American college of chest physicians evidence-based oral anticoagulant. JAMA Intern Med. https​://doi.org/10.1001/ clinical practice guidelines. Chest 141:e44S–e88S. https​://doi. jamai​ntern​med.2019.2431 org/10.1378/chest​.11-2292 26. Brosseau L, Rahman P, Toupin-April K et al (2014) (2014) A 12. Hackett CT, Ramanathan RS, Malhotra K et al (2015) Safety systematic critical appraisal for non-pharmacological management of venous thromboembolism prophylaxis with fondaparinux of osteoarthritis using the Appraisal of Guidelines Research and in ischemic stroke. Thromb Res 135:249–254. https​://doi. Evaluation II instrument. PLoS ONE 9(1):e82986 org/10.1016/j.throm​res.2014.11.041 13. Levy JH, Douketis J, Weitz JI (2018) Reversal agents for non-vita- Publisher’s Note Springer Nature remains neutral with regard to min K antagonist oral anticoagulants. Nat Rev Cardiol 15:273– jurisdictional claims in published maps and institutional afliations. 281. https​://doi.org/10.1038/nrcar​dio.2017.223 14. Gómez-Outes A, Terleira-Fernández AI, Calvo-Rojas G et al (2013) Dabigatran, rivaroxaban, or apixaban versus warfarin in patients with nonvalvular atrial fbrillation: a systematic review

1 3