PERIPROCEDURAL ANTITHROMBOTIC RECS

• ACRONYMS AND DEFINITIONS

• A fib - Atrial fibrillation
• ACC- American College of Cardiology
• ACCP- American College of Chest Physicians
• ASA - Acetylsalicylic acid (aspirin)
• ASGE - American Society for Gastrointestinal Endoscopy
• AHA - American Heart Association
• CABG - Coronary artery bypass grafting
• CAD - Coronary artery disease
• DAPT - Dual antiplatelet therapy (ASA + P2Y12 inhibitor)
• DVT - Deep vein thrombosis
• GI - Gastrointestinal
• NSAIDs - Nonsteroidal anti-inflammatory drugs
• PE - Pulmonary embolism
• SEC - Spanish Society of Cardiology
• TE - Thromboembolism
• TIA - Transient ischemic attack
• Triple therapy - anticoagulation + P2Y12 inhibitor + aspirin (see triple therapy for more)
• VTE - Venous thromboembolism

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• OVERVIEW

• Periprocedural antithrombotic management can be a conundrum for providers. Guidelines vary between professional organizations and are mostly based on "expert opinion" since there are few randomized controlled trials to help guide decision-making. In addition, every patient scenario isn't covered, and in some cases, recent studies do not support current recommendations.
• The guidelines below are grouped by organization. The Spanish Society of Cardiology guidelines are included because they are the most recent, and they provide recommendations for antiplatelet therapy that are not found in other guidelines.

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• ACCP 2012 RECOMMENDATIONS

ACCP 2012 periprocedural aspirin recommendations
Patients taking aspirin for the PRIMARY prevention of any condition Stop aspirin 7 days before the procedure [2]
Patients taking aspirin for the SECONDARY prevention of cardiovascular disease Minor dental procedures, minor dermatological procedures, and cataract surgery Continue aspirin [1] Noncardiac surgery Patients at moderate to high risk for cardiovascular events Continue aspirin NOTE: A large, randomized controlled trial published in 2014 found that aspirin had no benefit in high-risk patients undergoing noncardiac surgery. See POISE-2 study for more. Moderate to high risk defined as one or more of the following: Patients with ischemic heart disease Compensated or prior congestive heart failure Diabetes mellitus Kidney disease Cerebrovascular disease Other considerations: If the surgery is associated with an increased risk for perioperative cardiovascular events, such as carotid endarterectomy and peripheral artery bypass surgery, then continuing aspirin may be beneficial For surgeries that are associated with an increased risk of bleeding (ex. prostate and intracranial surgery), then the risk/benefit ratio of continuing aspirin should be considered Patients at low risk for cardiovascular events Stop aspirin 7 - 10 days before surgery [1] Coronary artery bypass graft surgery (CABG) Continue aspirin [1] NOTE: A large, randomized controlled trial published in 2016 found that preoperative aspirin had no benefit in high-risk patients who were undergoing CABG. See ATACAS trial for more.

• ^✝The ACCP 2012 guidelines did not give recommendations for Factor Xa inhibitors or dabigatran

ACCP 2012 periprocedural warfarin recommendations✝

Minor dental procedures Two options 1. Continue warfarin and administer oral prohemostatic agent (ex. tranexamic acid) 2. Stop warfarin 2-3 days before the procedure (if INR is between 2 - 3, it should drop to 1.6 - 1.9 at time of procedure) Minor dermatological procedures and cataract surgery Continue warfarin and optimize local hemostasis Other surgeries Patients at high risk for thromboembolism (see risk categories below) Stop warfarin 5 days before surgery Administer bridging therapy (typically with SQ Low Molecular Weight Heparin (LMWH), ex. Lovenox®) Restart warfarin 12 - 24 hours after surgery and when there is adequate hemostasis Patients at moderate risk for thromboembolism (see risk categories below) The decision to administer bridging therapy should be made on an individual basis Patients at low risk for thromboembolism (see risk categories below) Stop warfarin 5 days before surgery Do not administer bridging anticoagulation therapy Restart warfarin 12 - 24 hours after surgery and when there is adequate hemostasis [1]

ACCP 2012 thromboembolism risk categories
Atrial fibrillation High risk CHADS₂ score of 5 or 6 Recent (within 3 months) stroke or TIA Rheumatic valvular heart disease Moderate risk CHADS₂ score of 3 or 4 Low risk CHADS₂ score of 0 - 2, assuming no prior stroke or TIA NOTE: A recent study found no benefit of bridging therapy in patients with an average CHADS2 score of 2.3 (see BRIDGE study for more) Other considerations (these factors may affect decision for bridging therapy) High risk surgeries - certain surgeries carry a higher risk for stroke and thromboembolism (ex. heart valve replacement, carotid endarterectomy, and major vascular surgery) Prior thromboembolism during warfarin interruption Any history of stroke or TIA [1]
Venous thromboembolism High risk Recent (within 3 months) DVT or PE Severe hypercoagulable disorder (Protein C and S deficiency, antithrombin deficiency, antiphospholipid antibodies, multiple abnormalities) Moderate risk DVT or PE within past 3 - 12 months Non-severe hypercoagulable disorder (heterozygous Factor V Leiden or prothrombin gene mutation) Recurrent DVT or PE Active cancer (treated within 6 months or palliative) Low risk DVT or PE greater than 12 months ago and no other risk factors Other considerations (these factors may affect decision for bridging therapy) High risk surgeries - certain surgeries carry a higher risk for stroke and thromboembolism (ex. heart valve replacement, carotid endarterectomy, and major vascular surgery) Prior thromboembolism during warfarin interruption Any history of stroke or TIA [1]
Mechanical heart valve High risk Any mitral valve prosthesis Any caged-ball or tilting disc aortic valve prosthesis Recent (within 6 months) stroke or TIA Moderate risk Bileaflet aortic valve prosthesis and one or more of the following risk factors: Atrial fibrillation Prior stroke or TIA Hypertension Diabetes Congestive heart failure Age > 75 years Low risk Bileaflet aortic valve prosthesis without atrial fibrillation and no other risk factors for stroke Other considerations (these factors may affect decision for bridging therapy) High risk surgeries - certain surgeries carry a higher risk for stroke and thromboembolism (ex. heart valve replacement, carotid endarterectomy, and major vascular surgery) Prior thromboembolism during warfarin interruption Any history of stroke or TIA [1]

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• AHA/ACC RECOMMENDATIONS

AHA 2016 periprocedural recommendations for dual antiplatelet therapy
Elective, noncardiac surgery Drug-eluting stents (DES) < 3 months since DES implantation Delay surgery 3 - 6 months since DES implantation Proceeding with surgery may be considered If having surgery, discontinue DAPT before surgery (aspirin should be continued if possible) After surgery, restart DAPT as soon as possible if still indicated There is no convincing evidence that "bridging therapy" with parenteral antiplatelet/anticoagulant agents is beneficial ≥ 6 months since DES implantation Proceed with surgery Discontinue DAPT before surgery (aspirin should be continued if possible) After surgery, restart DAPT as soon as possible if still indicated There is no convincing evidence that "bridging therapy" with parenteral antiplatelet/anticoagulant agents is beneficial [11] Bare metal stents (BMS) < 30 days since BMS implantation Delay surgery ≥ 30 days since BMS implantation Proceed with surgery If having surgery, discontinue DAPT before surgery (aspirin should be continued if possible) After surgery, restart DAPT as soon as possible if still indicated There is no convincing evidence that "bridging therapy" with parenteral antiplatelet/anticoagulant agents is beneficial [11]
Coronary artery bypass graft surgery (CABG) Urgent on-pump CABG Aspirin - do not stop aspirin before surgery P2Y12 inhibitor: Clopidogrel - stop clopidogrel 24 hours before surgery if possible Ticagrelor - stop ticagrelor 24 hours before surgery if possible [7] Elective CABG Aspirin Do not stop aspirin before surgery P2Y12 inhibitor: Clopidogrel - stop clopidogrel 5 days before surgery Ticagrelor - stop ticagrelor 5 days before surgery Prasugrel - stop prasugrel 7 days before surgery [3]

AHA 2017 periprocedural recommendations for patients with mechanical heart valves

Minor procedures (such as dental extractions or cataract removal) where bleeding is easily controlled Continue warfarin [6] Other invasive or surgical procedures Patients with bileaflet mechanical aortic valve replacement (AVR) and no other risk factors for thrombosis Temporary interruption of warfarin without bridging agents while the INR is subtherapeutic - warfarin is stopped 2 to 4 days before the procedure (so the INR falls to < 1.5 for major surgical procedures) and restarted as soon as bleeding risk allows, typically 12 to 24 hours after surgery [6] Patients with 1) mechanical AVR and any thromboembolic risk factor, 2) older-generation mechanical AVR, or 3) mechanical mitral valve replacement Bridging therapy is reasonable. Risks of bleeding should be weighed against the benefits of thromboembolism prevention. NOTE: Bridging therapy has not been found to be of benefit in A fib trials (see BRIDGE study). This may have implications for bridging anticoagulation in patients with prosthetic valves. [12]

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• ACC 2017 ATRIAL FIBRILLATION GUIDELINES

• Overview
• The American College of Cardiology released periprocedural guidelines for anticoagulation management in patients with nonvalvular atrial fibrillation in 2017
• The recommendations are presented in several elaborate algorithms that are buried inside the publication
• Below is a link to a pdf file of the publication along with the pages where the algorithms and other pertinent information can be found


• 2017 ACC periprocedural anticoagulation recommendations for patients with nonvalvular A fib (pdf)


• Important pages in the document:
• Vitamin K antagonist therapy: algorithm for deciding whether to interrupt therapy - page 10
• Bridging therapy: algorithm for deciding when and how to use bridging therapy - page 14
• Direct thrombin inhibitors and Factor Xa inhibitors: algorithm for deciding whether to interrupt therapy - page 11
• Direct thrombin inhibitors and Factor Xa inhibitors: table with recommended duration for withholding therapy - page 12
• Restarting therapy: algorithm for deciding when to restart therapy - page 20
• Procedural bleeding risk - link to pdf with extensive list of procedures classified by their bleeding risk

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• ASGE 2016 RECOMMENDATIONS FOR ELECTIVE GI ENDOSCOPY

• Reference [4]

ASGE 2016 ANTITHROMBOTIC RECOMMENDATIONS FOR ELECTIVE GI ENDOSCOPY
ANTIPLATELET THERAPY
TE risk	Procedure bleed risk	Recommendation
Low	Low	Continue ASA/NSAIDs Continue P2Y12 inhibitor
Low	High	Continue ASA/NSAIDs Discontinue P2Y12 inhibitors at least 5 days before endoscopy or switch to ASA✝ For patients taking dual antiplatelet therapy, hold P2Y12 inhibitors for at least 5 days and continue ASA✝
High	Low	Continue ASA/NSAIDs Continue P2Y12 inhibitors
High	High	Continue ASA/NSAIDs Discontinue P2Y12 inhibitors at least 5 days before endoscopy or switch to ASA✝ For patients taking dual antiplatelet therapy, hold P2Y12 inhibitors for at least 5 days and continue ASA✝
✝Ticagrelor should be held for 3-5 days, and all other P2Y12 inhibitors should be held for 5-7 days
ANTICOAGULATION THERAPY
TE risk	Procedure bleed risk	Recommendation
Low	Low	Continue anticoagulation
Low	High	Discontinue anticoagulation Restart warfarin on same day as procedure Restart Factor Xa inhibitors and direct thrombin inhibitors once adequate hemostasis is achieved
High	Low	Continue anticoagulation
High	High	Discontinue anticoagulation Bridging therapy Restart warfarin on same day as procedure Restart Factor Xa inhibitors and direct thrombin inhibitors once adequate hemostasis is achieved

• Reference [4]

ASGE THROMBOEMBOLISM RISK CATEGORIES
Nonvalvular atrial fibrillation High risk CHA₂DS₂-VASc score ≥ 2 NOTE: A recent study found no benefit of bridging therapy in patients with an average CHADS2 score of 2.3 (see BRIDGE study for more) Medium risk CHA₂DS₂-VASc score of 1 Low risk CHA₂DS₂-VASc score of 0
Mechanical heart valve High risk Any mitral valve prosthesis Any caged-ball or tilting disc aortic valve prosthesis Recent (within 6 months) CVA or TIA Medium risk Bileaflet aortic valve prosthesis and one or more of the following risk factors: A fib, prior CVA or TIA, hypertension, diabetes, congestive heart failure, age ≥ 75 years Low risk Bileaflet aortic valve prosthesis without A fib and no other risk factors for CVA
Venous thromboembolism (VTE) High risk Recent (within 3 months) VTE Severe thrombophilia (deficiency of protein C, protein S, or antithrombin; antiphospholipid antibodies; multiple abnormalities) Medium risk VTE within the past 3 - 12 months Nonsevere thrombophilia (heterozygous factor V Leiden or prothrombin gene mutation) Recurrent VTE Active cancer (treated within 6 months or palliative) Low risk VTE > 12 months previous and no other risk factors
Recent cardiac stent (antiplatelet therapy) High risk Placement of drug-eluting stent ≤ 12 months Placement of bare metal stent ≤ 1 month Placement of bare metal stent after acute coronary syndrome ≤ 12 months Other conditions that can raise cardiovascular risk include: Prior history of stent occlusion History of acute coronary syndrome or ST-elevation MI Multivessel PCI Diabetes Kidney failure

• Reference [4]

ASGE PROCEDURE BLEEDING RISK CATEGORIES
High bleeding risk
Polypectomy Biliary or pancreatic sphincterotomy Treatment of varices PEG placement (PEG on aspirin or clopidogrel is low risk. DAPT is high risk) Therapeutic balloon-assisted enteroscopy Endoscopic ultrasound (EUS) with FNA (EUS-FNA of solid masses on ASA/NSAIDs is low risk) Endoscopic hemostasis Tumor ablation Cystogastrostomy Ampullary resection Endoscopic mucosal resection (EMR) Endoscopic submucosal dissection Pneumatic or bougie dilation Percutaneous endoscopic jejunostomy
Low bleeding risk
Diagnostic (EGD, colonoscopy, flexible sigmoidoscopy) including mucosal biopsy ERCP with stent (biliary or pancreatic) placement or papillary balloon dilation without sphincterotomy Push enteroscopy and diagnostic balloon-assisted enteroscopy Capsule endoscopy Enteral stent deployment (Controversial) Endoscopic ultrasound (EUS) without FNA Argon plasma coagulation Barrett’s ablation

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• SEC 2018 RECOMMENDATIONS FOR ANTITHROMBOTIC THERAPY

• Reference [12]

SEC RECOMMENDATIONS FOR ANTITHROMBOTIC THERAPY
ANTIPLATELET THERAPY
TE risk	Procedure bleed risk	Recommendation
Low	Low / Moderate	Continue ASA Stop P2Y12 inhibitor✝ and replace with ASA if possible
Low	High	Continue ASA except when contraindicated (e.g. neurosurgery)* Stop P2Y12 inhibitor✝ and replace with ASA if possible
Moderate / High	Low	Continue ASA Continue P2Y12 inhibitors
Moderate / High	Moderate	Individualize therapy based on patient risk factors Continue ASA Assess withdrawal of P2Y12 inhibitor
Moderate / High	High	Individualize therapy based on patient risk factors Continue ASA unless contraindicated* Stop P2Y12 inhibitor✝ and replace with ASA if possible Assess bridging therapy
✝Stop clopidogrel 5 days before surgery; Stop ticagrelor 3 - 5 days before surgery; Stop prasugrel 7 days before surgery *If necessary, withdraw ASA 3 days before surgery Restart antiplatelet therapy within 24 hours of surgery if bleeding risk is low or moderate. Restart 48 - 72 hours when bleeding risk is high NOTE: A large, randomized controlled trial published in 2014 found that aspirin had no benefit in high-risk patients undergoing noncardiac surgery. (see POISE-2 study). Also, a large, randomized controlled trial published in 2016 found that preoperative aspirin had no benefit in high-risk patients who were undergoing CABG (see ATACAS trial for more).
ANTICOAGULATION THERAPY
TE risk	Procedure bleed risk	Recommendation
Low / Moderate / High	Low✝	Continue anticoagulation
Low / Moderate	Low / Moderate / High	Discontinue anticoagulation Do not use bridging therapy
High	Low / Moderate / High	Discontinue anticoagulation Consider bridging therapy
✝Guidelines do not state specifically which procedures are okay to continue anticoagulation. Other guidelines state minor procedures such as dental extractions, minor derm procedures, and cataract surgery are okay for continued anticoagulation. For procedures with a low or moderate bleeding risk, restart anticoagulation 24 hours after surgery and consider bridging therapy in patients taking warfarin with high thromboembolic risk For procedures with a high bleeding risk, restart anticoagulation 48 - 72 hours after surgery without bridge therapy

• Reference [12]

SEC THROMBOEMBOLISM RISK CATEGORIES FOR PATIENTS ON ANTICOAGULANT THERAPY
Atrial fibrillation High risk CHA₂DS₂-VASc score of 7 - 9 Stroke/TIA in last 3 months Rheumatic mitral valve disease Moderate risk CHA₂DS₂-VASc score of 5 - 6 Stroke/TIA > 3 months ago Low risk CHA₂DS₂-VASc score of 1 - 4 No history of stroke/TIA NOTE: A recent study found no benefit of bridging therapy in patients with an average CHADS2 score of 2.3 (see BRIDGE study for more)
Mechanical heart valve High risk Mitral valve Tricuspid valve (including biological valve) Aortic valve (monoleaflet) Stroke/TIA in last 6 months Moderate risk Aortic valve + any of the following risk factors: Atrial fib Stroke/TIA > 6 months ago Diabetes Heart failure Age > 75 years Low risk Aortic valve without other risk factors
Venous thromboembolism (VTE) High risk Recent (within 3 months) VTE Severe thrombophilia (homozygous factor V Leiden, prothrombin 20210A, protein C, protein S, or antithrombin deficiency, multiple defects, antiphospholipid syndrome) Moderate risk VTE within the past 3 - 12 months Nonsevere thrombophilia (heterozygous factor V Leiden or prothrombin 20210A gene mutation) Recurrent VTE VTE + active cancer Low risk VTE > 12 months

• Reference [12]

SEC THROMBOEMBOLISM RISK CATEGORIES FOR PATIENTS ON ANTIPLATELET THERAPY
Heart disease The SEC risk categories for patients with heart disease are broken down into a large number of subgroups based on numerous variables. Those categories are detailed at the link below on page 4 of the pdf. SEC periprocedural antithrombotic recs (pdf)
Cerebrovascular disease High risk Ischemic stroke within 3 months Carotid stent placement within 3 months Moderate risk Ischemic stroke within 3 - 6 months Carotid stent placement within 3 - 6 months Low risk Ischemic stroke > 6 months ago Carotid stent placement > 6 months ago
Peripheral vascular disease High risk Within 3 months of acute peripheral vascular event + revascularization with DES or stents used in chronic occlusions Moderate risk Within 3 - 6 months of acute peripheral vascular event + revascularization with DES or stents used in chronic occlusions Low risk > 6 months since acute peripheral vascular event + revascularization with DES or stents used in chronic occlusions

• SEC procedure bleeding risk categories

• The SEC guidelines provide a supplement that contains a long list of procedures and their associated bleeding risk. The supplement is written in Spanish.
• The ACC also publishes a list of procedures and their associated bleeding risks


• SEC procedure bleeding risk categories (in Spanish)
• ACC procedure bleeding risk categories (in English)

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• WHEN TO HOLD THERAPY

• Aspirin

• Aspirin irreversibly inhibits platelets so platelets must be replenished in order for platelet function to be restored. The maximal antiplatelet effect of aspirin occurs within minutes of consumption.
• In general, 10 - 14% of the normal platelet pool is produced each day which means it takes 7 - 10 days after stopping aspirin for normal platelet function to return
• If aspirin is to be held, most guidelines recommend stopping aspirin 7 - 10 days before a procedure [1,4]



• P2Y12 inhibitors

• P2Y12 inhibitors include the following medications: clopidogrel (Plavix®), prasugrel (Effient®), ticagrelor (Brilinta™), and ticlopidine (Ticlid®)
• Clopidogrel, prasugrel, and ticlopidine irreversibly inhibit platelets. Ticagrelor is a reversible platelet inhibitor.
• Recommendations for holding P2Y12 inhibitors are given in the table below

When to hold P2Y12 inhibitors before procedures
Drug	ASGE / SEC	Manufacturer
Clopidogrel	5 days	5 days
Prasugrel	7 days	7 days
Ticagrelor	3 - 5 days	5 days
Ticlopidine	N/A	10 - 14 days

• Warfarin

• The ACCP and AHA give recommendations for holding warfarin in their respective guidelines (ACCP guidelines, AHA guidelines)
• Holding warfarin for 5 days will cause the INR to decrease to < 1.5 in 93% of patients [4]
• The SEC guidelines give recommendations on stopping warfarin based on the INR value drawn 7 days before the procedure. Those recommendations are detailed in the table below

• Reference [12]

SEC recommendations on holding warfarin before procedures
INR 7 days before procedure	Hold warfarin
> 3	7 days
2 - 3	6 days
< 2	5 days

• Factor Xa inhibitors

• Factor Xa inhibitors include the following medications: apixaban (Eliquis®), betrixaban (Bevyxxa®), edoxaban (Savaysa®), and rivaroxaban (Xarelto®)
• Factor Xa inhibitors are excreted renally and the duration of their effect is dependent on kidney function. The table below gives recommendations from the ACC for stopping apixaban, rivaroxaban, and edoxaban based on the creatinine clearance and surgery bleeding risk. Betrixaban is not included in the recommendation and its manufacturer only states that its anticoagulant effect is expected to last at least 72 hours after the last dose.

• Recommendations are for apixaban, rivaroxaban, and edoxaban only
• Recommendations are from the ACC. Other recommendations may vary.
• Anti-Xa level is a lab that measures the concentration of Factor Xa inhibitors in the blood
• References [13,14]

Recommendations for holding Factor Xa inhibitors (apixaban, rivaroxaban, edoxaban) before procedures
CrCl (ml/min)	Procedure bleeding risk	Hold before procedure
≥ 30	Low	≥ 24 hours
15 - 29	Low	≥ 36 hours
< 15	Low	No data. Consider anti-Xa level and/or ≥ 48 hours.
≥ 30	Moderate / High	≥ 48 hours
< 30	Moderate / High	No data. Consider anti-Xa level and/or ≥ 72 hours.

• Dabigatran

• Dabigatran (Pradaxa®) is a direct thrombin inhibitor.
• Dabigatran is excreted renally and the duration of its effect is dependent on kidney function. The table below gives recommendations from the ACC for holding dabigatran before procedures based on the creatinine clearance and surgery bleeding risk.

• dTT - dilute thrombin time assay (not widely available). A normal aPTT usually excludes clinically relevant levels if a sensitive reagent is used. A normal thrombin time (TT) excludes clinically relevant levels.
• Recommendations are from the ACC. Other recommendations may vary.
• References [13,14]

Recommendations for holding dabigatran before procedures
CrCl (ml/min)	Procedure bleeding risk	Hold before procedure
≥ 80	Low	≥ 24 hours
50 - 79	Low	≥ 36 hours
30 - 49	Low	≥ 48 hours
15 - 29	Low	≥ 72 hours
< 15	Low	No data. Consider dTT and/or ≥ 96 hours.
≥ 80	Moderate / High	≥ 48 hours
50 - 79	Moderate / High	≥ 72 hours
30 - 49	Moderate / High	≥ 96 hours
15 - 29	Moderate / High	≥ 120 hours
< 15	Moderate / High	No data. Consider dTT.

• NSAIDs

• None of the guidelines give specific recommendations for holding NSAIDs
• All NSAIDs besides aspirin reversibly inhibit platelets so their antiplatelet effect is related to their duration of action and half-life
• Most drugs are cleared after 4 - 5 half-lives. Guidelines for holding Factor Xa inhibitors and dabigatran are based on 2 - 3 half-lives for procedures with a low bleeding risk and 4 - 5 half-lives for procedures with a moderate to high bleeding risk (adjusted for renal function). These same principles may be applied to holding NSAIDs, although this has not been validated in clinical trials.
• The table below gives the half-lives of some commonly used NSAIDs

• Drugs are typically cleared after 4 - 5 half-lives
• ^✝The manufacturer states that in trials, celecoxib had no effect on reduction of platelet aggregation or increase in bleeding time
• *The manufacturer states that in trials, nabumetone had little effect on collagen-induced platelet aggregation and no effect on bleeding time
• References [Manufacturer PI]

NSAID half-lives
Drug	Half-life
Ibuprofen (Motrin®, Advil®)	2.2 hours
Naproxen (Aleve®, Anaprox®, etc.)	12 - 17 hours
Meloxicam (Mobic®)	15 - 20 hours
Celecoxib (Celebrex®)✝	11 hours
Indomethacin (Indocin®)	4.5 hours
Ketorolac (Toradol®)	5 - 6 hours
Nabumetone (Relafen®)*	24 hours

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• PROCEDURE BLEEDING RISK

• The ASGE gastrointestinal procedure bleeding risk categories are presented in the table above (see ASGE categories)
• The ACC has published a list of procedures and their associated bleeding risks. It is available at the link below.
• The SEC guidelines provide a supplement that contains a long list of procedures and their associated bleeding risk. The supplement is written in Spanish and is available at the link below.


• ACC procedure bleeding risk categories (in English)
• SEC procedure bleeding risk categories (in Spanish)

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• BRIDGING THERAPY

• Overview
• Bridging therapy is the administration of short-acting anticoagulants (typically unfractionated heparin (UFH) and low molecular weight heparins (LMWH)) during the periprocedural time that anticoagulation is being held. Short-acting anticoagulants help to prevent VTE while anticoagulants are subtherapeutic, and their effect dissipates rapidly so that they may be stopped within 24 hours of surgery. Bridging therapy minimizes the amount of time the patient is without anticoagulation.
• Bridging therapy recommendations vary by organization. A study published in 2015 found no benefit of bridging therapy in patients with A fib who had an average CHADS₂ score of 2.3 (see BRIDGE study for more)
• No short-acting anticoagulants have been FDA-approved for bridging therapy. The regimens presented here are based on expert opinion.

• Reference [1,10,14]

BRIDGING THERAPY RECOMMENDATIONS

Pre-operative Stop warfarin 5 days prior to scheduled surgery. When INR becomes subtherapeutic, start a bridging regimen. If patient is receiving a Factor Xa inhibitor or dabigatran, start bridging regimen after omitting 2 - 3 doses of the drug Bridging regimens Enoxaparin (Lovenox®) 1 mg/kg twice a day OR 1.5 mg/kg once daily Dalteparin (Fragmin®) 100 IU/kg twice a day OR 200 IU/kg once daily IV unfractionated heparin to maintain aPTT 1.5 - 2 X the control aPTT NOTE: When patient has a mechanical heart valve, twice daily LMWH regimens are recommended Before procedure LMWH Twice daily regimen - withhold the last LMWH dose before surgery Once daily regimens - give half the total daily dose the morning of the day before surgery Unfractionated heparin (UFH) Stop UFH 4 - 6 hours before surgery Post-operative Warfarin Restart warfarin 12 - 24 hours after surgery when adequate hemostasis has been achieved In patients who underwent surgery that has a high bleeding risk, resume LMWH or UFH (without bolus dose) 48 - 72 hours after surgery In patients who underwent surgery that has a moderate or low bleeding risk, resume LMWH or UFH (without bolus dose) 24 hours after surgery Continue bridging therapy until INR is therapeutic Factor Xa inhibitors and dabigatran Confirm that adequate hemostasis has been achieved In patients who underwent surgery that has a high bleeding risk, resume medication 48 - 72 hours after surgery In patients who underwent surgery that has a low bleeding risk, resume medication on the day following the procedure Parenteral anticoagulation is generally not required

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• STUDIES

• POISE-2 Study - Stopping vs Continuing Aspirin Before Noncardiac Surgery, NEJM (2014) [PubMed abstract]
• The POISE-2 study enrolled 10,010 patients at increased risk for vascular complications who were scheduled to undergo noncardiac surgery
• Main inclusion criteria: undergoing major vascular surgery or a history of CAD, PVD, or stroke (patients with ≥ 3 risk factors for CVD (e.g. DM, smoking, CHF, HTN, TIA, age ≥ 70 years, etc.) were also eligible)
• Main exclusion criteria: drug-eluting coronary stent < 1 year before surgery | Bare-metal coronary stent < 6 weeks before surgery | Undergoing intracranial surgery, carotid endarterectomy, or retinal surgery
• Baseline characteristics: Average age - 69 years | History of CAD - 23% | History of vascular disease - 33% | Undergoing major surgery - 78% | History of hypertension - 86% | Diabetes - 38%
• Patients were randomized to 1 of 2 groups:
• Group 1 (4998 patients)
• Patients not currently taking aspirin - Aspirin 200 mg just before surgery, then 100 mg a day for 30 days
• Patients currently taking aspirin - Aspirin 200 mg just before surgery, then 100 mg for 7 days, then resume previous aspirin regimen
• Group 2 (5012 patients)
• Patients not currently taking aspirin - Placebo for 30 days
• Patients currently taking aspirin - Placebo for 7 days, then resume previous aspirin regimen
• For all patients who were taking aspirin at randomization, aspirin was required to be stopped at least 3 days before surgery. The median stop time was 7 days before surgery.
• PRIMARY OUTCOME: The primary outcome was a composite of death or nonfatal heart attack 30 days after randomization
• At 30 days, the following was seen:
• Primary outcome: Group 1 - 7%, Group 2 - 7.1%, (HR 0.99, 95%CI [0.86 - 1.15], p=0.92)
• Overall mortality: Group 1 - 1.3%, Group 2 - 1.2%, (HR 1.05, 95%CI [0.74 - 1.49], p=0.78)
• Heart attack: Group 1 - 6.2%, Group 2 - 6.3%, (HR 0.98, 95%CI [0.84 - 1.15], p=0.85)
• Stroke: Group 1 - 0.3%, Group 2 - 0.4%, (HR 0.84, 95%CI [0.43 - 1.64], p=0.62)
• Major bleeding: Group 1 - 4.6%, Group 2 - 3.8%, (HR 1.23, 95%CI [1.01 - 1.49], p=0.04)


• StraightHealthcare analysis:
• The POISE-2 study found that perioperative aspirin did not improve outcomes in high-risk cardiovascular patients undergoing noncardiac surgery. Perioperative aspirin did increase the risk of major bleeding.
• The results of this study contradict current ACCP guidelines which recommend that patients on aspirin who are at "moderate to high risk" for cardiovascular disease continue aspirin when they undergo noncardiac surgery


• ATACAS trial - Stopping vs Continuing Aspirin Before CABG, NEJM (2016) [PubMed abstract]
• The ATACAS trial enrolled 2100 patients at increased risk for complications who were scheduled to undergo CABG (on-pump or off-pump) with or without valve replacement
• Main inclusion criteria: Increased risk for major complications related to age or coexisting conditions | Not taking aspirin regularly before the trial or had stopped taking aspirin at least 4 days before CABG surgery
• Main exclusion criteria: Warfarin or clopidogrel within 7 days of surgery | Thrombocytopenia or bleeding disorder | CrCl < 25 ml/min | History of thromboembolism
• Baseline characteristics: Average age 66 years | Heart attack within 90 days - 7.5% | Received aspirin within 7 days of surgery - 43% | Median number of grafts - 3 | On-pump surgery - 97% | CABG + valve surgery - 20%
• Patients were randomized to 1 of 2 groups:
• Group 1 (1047 patients) - Aspirin 100 mg one to two hours before surgery
• Group 2 (1053 patients) - Placebo
• Aspirin was administered to all patients postoperatively at a median time of 18.5 hours after surgery
• The trial had a 2 X 2 factorial design where half the patients received tranexamic acid (an antifibrinolytic agent)
• PRIMARY OUTCOME: Composite of death and thrombotic events (nonfatal myocardial infarction, stroke, pulmonary embolism, renal failure, or bowel infarction) during the initial 30 postoperative days
• At 30 days, the following was seen:
• Primary outcome: Group 1 - 19.3%, Group 2 - 20.4%, (RR 0.94, 95%CI [0.80 - 1.12], p=0.55)
• Major hemorrhage leading to reoperation: Group 1 - 1.8%, Group 2 - 2.1%, (p=0.75)
• Cardiac tamponade: Group 1 - 1.1%, Group 2 - 0.4%, (p=0.08)
• Blood transfusion within 24 hours after surgery: Group 1 - 43.9%, Group 2 - 42.6%, (RR 1.03, 95%CI [0.93 - 1.14], p=0.57)
• No interaction was observed between aspirin and tranexamic acid either for the primary outcome or bleeding outcomes


• StraightHealthcare analysis:
• The ATACAS trial found no benefit or harm of continuing aspirin before CABG surgery
• The trial had a 2 X 2 factorial design that also compared tranexamic acid (an antifibrinolytic agent) to placebo. This could have affected the results, although no interaction between tranexamic acid and aspirin was observed.
• Aspirin was stopped 4 days before surgery, and it's possible some patients in the placebo group still had some antiplatelet effect from aspirin that was taken prior to 4 days (43% of patients received aspirin within 7 days of surgery). This would bias the study toward the null.
• Although slightly flawed, the ATACAS trial found that preoperative aspirin had no effect on CABG outcomes in patients at increased risk for complications


• BRIDGE study - Periprocedural Bridging Therapy vs No Bridging Therapy in A Fib, NEJM (2015) [PubMed abstract]
• The BRIDGE study enrolled 1884 patients taking warfarin for atrial fibrillation who were to undergo an elective operation or other elective invasive procedure that required interruption of warfarin therapy
• Main inclusion criteria: Chronic (permanent or paroxysmal) atrial fibrillation or flutter | At least one CHADS₂ criteria
• Main exclusion criteria: Mechanical heart valve | Stroke, systemic embolism, or TIA within the previous 12 weeks | Major bleeding within previous 6 weeks; planned cardiac, intracranial, or intraspinal surgery
• Baseline characteristics: Average age 72 years | Average CHADS₂ score - 2.3 | CHADS₂ score of 4 - 10% | CHADS₂ score of 5 or 6 - 3% | Mitral valve heart disease - 16% | Concomitant antiplatelet therapy (aspirin or clopidogrel) - 37%
• Patients were randomized to 1 of 2 groups:
• Group 1 (934 patients) - Bridging therapy
• Group 2 (950 patients) - No bridging therapy
• Bridging therapy - 1. warfarin stopped 5 days before procedure 2. dalteparin 100 U/kg twice a day starting 3 days before procedure and stopping 24 hours before procedure 3. warfarin restarted on the evening of or the day after the procedure 4. dalteparin resumed 12 to 24 hours after a minor (or low-bleeding-risk) procedure and 48 to 72 hours after a major (or high-bleeding-risk) procedure for 5 - 10 days (until INR was ≥ 2)
• No bridging therapy - same as bridging therapy except placebo was given in place of dalteparin
• PRIMARY OUTCOME: Arterial thromboembolism (stroke, systemic embolism, or transient ischemic attack) and major bleeding within 30 days after the procedure
• At 30 days, the following was seen:
• Arterial thromboembolism: Group 1 - 0.3%, Group 2 - 0.4%, (difference 0.1%, 95%CI [-0.6 to 0.8], p=0.73)
• Major bleeding: Group 1 - 3.2%, Group 2 - 1.3%, (RR 0.41, 95%CI [0.20 - 0.78], p=0.005)


• StraightHealthcare analysis:
• The BRIDGE study found no benefit and possible harm of bridging anticoagulation in patients with atrial fibrillation (average CHADS₂ score 2.3) undergoing elective procedures
• One major weakness of the study is that patients at high risk (CHADS₂ score 4 - 6) for thromboembolism were largely underrepresented. The study was therefore underpowered to find a benefit in this group.
• The 2012 ACCP guidelines recommend that patients at high risk for thromboembolism (CHADS₂ score 5 - 6) receive bridging therapy and patients at moderate risk (CHADS₂ score 3 - 4) be considered for therapy. The BRIDGE study confirms their recommendation that low risk patients (CHADS₂ score 0 - 2) should not receive bridging therapy.


• Arthrocentesis and Joint Injection in Patients Receiving Direct Oral Anticoagulants, Mayo Clin Proc (2017) [PubMed abstract]
• Design: Case series (N=1050)
• Exposure: Patients receiving direct oral anticoagulants (DOACs) who underwent joint aspirations and/or injections
• Primary outcome: Bleeding complications
• Findings: In 1050 consecutive procedures, there were no bleeding complications. Arthrocentesis and joint injections in patients receiving DOAC therapy are safe procedures, and there is no need to withhold anticoagulation treatment before the procedure.


• Safety of Lumbar Puncture (LP) Performed on Dual Antiplatelet Therapy (DAPT), Mayo Clin Proc (2018) [PubMed abstract]
• Design: Case series (N=100, length = 3 months)
• Exposure: Patients receiving DAPT who underwent lumbar puncture
• Primary outcome: Number of traumatic and bloody cerebrospinal fluid results as well as the presence of any complications occurring within 3 months of the procedure
• Findings: No serious complications occurred. Cerebrospinal fluid analysis was consistent with a traumatic LP, defined as having at least 100 RBCs/mcl, in 8% of cases. Bloody LP, defined as having 1000 RBCs/mcl, occurred in 4% of cases. The percentage of traumatic or bloody LPs was within the range reported previously for LPs performed in any setting. Although this is a small study and additional review is necessary, performing LPs in the setting of dual antiplatelet therapy may not pose an increased risk of serious complications.

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• BIBLIOGRAPHY

• References:
• 1 - PMID 22315266 - Perioperative Management of Antithrombotic Therapy Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines, Chest (2012)
• 2 - PMID 17650517 - Br Anest GL
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• 4 - PMID 26621548 - ASGE 2016 "The management of antithrombotic agents for patients undergoing GI endoscopy"
• 5 - PMID 24682347 - 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation
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• 11 - PMID 27026020 - 2016 ACC/AHA Guideline Focused Update on Duration of Dual Antiplatelet Therapy in Patients With Coronary Artery Disease
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• 13 - PMID 29203195 - 2017 ACC Expert Consensus Decision Pathway on Management of Bleeding in Patients on Oral Anticoagulants
• 14 - PMID 28081965 - 2017 ACC Expert Consensus Decision Pathway for Periprocedural Management of Anticoagulation in Patients With Nonvalvular Atrial Fibrillation