The Postoperative Management of Patients on Chronic Oral … · 2020-06-10 · The Postoperative...

The Postoperative Management of Patients

on Chronic Oral Anticoagulant Therapy (VKA and DOAC) who Need Elective

Surgery

Alex C. Spyropoulos MD, FACP, FCCP, FRCPC Professor of Medicine

The Donald and Barbara Zucker School of Medicine at Hofstra/Northwell Professor – The Center for Health Innovations and Outcomes Research

The Feinstein Institute for Medical Research System Director – Anticoagulation and Clinical Thrombosis Service

Northwell Health System Manhasset, NY

Presentation includes discussion of the following off-label use of a drug: rivaroxaban, apixaban, dabigtran, edoxaban, enoxaparin, dalteparin

Disclosures of: Alex C Spyropoulos, MD

Employment No conflict of interest to disclose Research support Daichi-Sankyo Scientific advisory board Bayer, Jansen, Pfizer, BMS, Daiichi-

Sankyo, Boehringer-Ingelheim Consultancy Bayer, Jansen, Pfizer, Daiichi-

Sankyo, Boehringer-Ingelheim Speakers bureau No conflict of interest to disclose Major stockholder No conflict of interest to disclose Patents No conflict of interest to disclose Honoraria Jansen Travel support Jansen, Boehringer-Ingelheim Other No conflict of interest to disclose

Summary of 2012 ACCP Guidelines in Surgical Thromboprophylaxis

VTE Risk Bleeding Risk Preferred Very Low Any Early Ambulation

Chest 2012;141;e195S-e226S

VTE Risk Bleeding Risk Preferred Low Any IPC

VTE Risk Bleeding Risk Preferred Moderate Not High LMWH, LDUH or IPC

High IPC

VTE Risk Bleeding Risk Preferred High Not High LMWH or LDUH + IPC

(ASA or Fonda if above contraindicated) High IPC (reevaluate bleeding risk)

Why is periprocedural antithrombotic management relevant?

•  Perioperative management of patients on chronic OAC is common… •  400,000-500,000 patients per year in North America

alone •  ~1 in 6 to 1 in 10 patients receiving long-term

warfarin are assessed for periprocedural management annually

Douketis J et al Chest 2012: 141(2):e326S-e350S

Perioperative Management of Anticoagulation

Patient Risk Factors (congenital and acquired)

Bleeding Thrombosis

Risk Stratification

Surgical Risk Factors

Bleeding Thrombosis

Risk Stratification

Embolic Stroke with Hemorrhagic Transformation

Perinephric Hematoma (transplant kidney)

Thrombotic Risk with Prosthetic Heart Valves

Mitral >> Aortic Position Caged Ball > Tilting Disc > Double Wing Valves

Decreasing Thrombotic Risk

St. Jude Valve Bjork-Shiley Valve Caged-Ball Valve

CHADS Score and Risk for Postoperative Stroke in Patients with Chronic Atrial Fibrillation

CHADS score Annual Risk 30-day Postoperative Risk 0 1.9 (1.2-3.0) 1.01 1 2.8 (2.0-3.8) 1.62 2 4.0 (3.1-5.1) 2.05 3 5.9 (4.6-7.3) 2.63 4 8.5 (6.3-11.1) 3.62

5 12.5 (8.2-17.5) 3.65 6 18.2 (10.5-27.4) 7.35

Kaatz S, et al. J Thromb Haemost 2009

Suggested Thromboembolic Risk Stratification when Discontinuing VKAs

High (Annual ATE >10% ;1 month VTE > 10%) Atrial Fibrillation •  recent (<3 months) stroke/TIA •  CHADS score 5-6 •  rheumatic heart disease Mechanical Heart Valves •  any caged-ball or tilting disc valve in

mitral/aortic position •  any mitral valve prosthesis •  Recent (within 6 mos) stroke/TIA Venous Thromboembolism (VTE) •  VTE within past 3 months •  severe thrombophilia

•  deficiency of protein C, protein S or antithrombin

•  antiphospholipid antibodies •  multiple thrombophilias

Moderate (Annual ATE 5 – 10%;1 month VTE 2 - 10%) Atrial Fibrillation •  CHADS score 3-4 Mechanical Heart Valves •  bileaflet AVR with major risk factors VTE •  VTE within past 3-12 months •  Nonsevere thrombophilia •  Active cancer •  Recurrent VTE Low (Annual ATE <5%; 1 month VTE < 2%) Atrial Fibrillation •  CHADS score 0-2 Mechanical Heart Valves •  bileaflet AVR without major risk factors VTE •  VTE more than 12 months ago Douketis J et al Chest 2008; 133:299-339S

Surgery/Procedure-Related Bleeding Risk HIGH BLEEDING RISK

PROCEDURES (2 day risk of MB 2 - 4%)

LOW BLEEDING RISK PROCEDURES

(2 day risk of MB <2%)

MINIMAL BLEEDING RISK PROCEDURES

(essentially no MB risk)

Major surgery with extensive tissue injury Arthroscopy

Minor dermatologic procedures (excision of basal and squamous cell skin cancers, actinic keratoses, and premalignant or cancerous skin nevi)

Cancer surgery Cutaneous/lymph node biopsies Cataract procedures

Major orthopedic surgery Shoulder/foot/hand surgery Minor dental procedures (dental extractions, restorations, prosthetics, endodontics), dental cleanings, fillings

Reconstructive plastic surgery Coronary angiography Pacemaker or cardioverter-defibrillator device implantation*

Urologic or Gastrointestinal surgery Gastrointestinal endoscopy +/- biopsy Transurethral prostate resection, bladder resection or tumor ablation Colonoscopy +/- biopsy

Nephrectomy, kidney biopsy Abdominal hysterectomy

Colonic polyp resection Laparoscopic cholecystectomy

Bowel resection Abdominal hernia repair Percutaneous endoscopic gastrotomy (PEG) placement, endoscopic retrograde cholangiopancreatography (ERCP)

Hemorrhoidal surgery

Surgery in highly vascular organs (kidneys, liver, spleen) Bronchoscopy +/- biopsy

Cardiac, intracranial, or spinal surgery Epidural injections with INR <1.2 Any major operation (procedure duration >45 minutes)

Spyropoulos et al J of Thromb Haemost 2016; 14(5):875-85

Consequences of Thromboembolism and Major Bleeding

•  arterial thromboembolism •  15% case-fatality for heart valve thrombosis •  70% rate of death or disability in stroke

•  venous thromboembolism •  6% rate of death or permanent disability for DVT; 25% rate

for PE •  major bleeding

•  8-9% case-fatality

Martinelli J et al. Circulation 1991; 84(3) Longstreth JR et al. Neurology 2001: 56:368-75 Douketis JD et al JAMA 1998; 279: 458-62 Linkins L et al Ann Intern Med 2003; 893-900

Hypercoagulability Associated with Surgery: Newer Concepts

•  Surgery increases risk of arterial thromboembolism [Wahl 1998]

•  Perioperative arterial thromboembolic and stroke rates (1.6% and 0.6%) 10-fold higher than modelling suggests (~0.1-0.2% for 8d)

[Dunn A et al Arch Intern Med 2003; White RH, JTH, 2007]

Three Key Questions Regarding Perioperative Management of Patients on Chronic OACs?

•  Should oral anticoagulant therapy be discontinued?

•  When VKA is discontinued, should the patient have perioperative “bridging” therapy with heparin (UFH or LMWH)?

•  What is the optimal periprocedural management of patients on DOACs needing interruption?





BRUISE Control Study for Pacemaker or Defibrillator Surgery

N = 6811

1. Birnie DH et al NEJM 2013; 368(22):2084-93 2. Di Biase L et al Circulation 2014; 129(25):2638-44

COMPARE Trial for Catheter Ablation in AF (N = 1584)2 Warfarin discontinuation/Heparin Bridging emerged as a strong predictor of periprocedural TE (OR 13; 95% CI, 3.1–55.6; P<0.001).

ARISTOTLE Trial: Periprocedural Interruption vs No Interruption

Garcia D et al Blood 2014; 124(25):3692-8

Minimal Bleed Risk Procedures

•  Minor dermatologic, cutaneous, dental, opthalmologic procedures (cataract surgery), pacemaker/cardioverter-defibrillator device implantation

Do not interrupt OAC*

*May consider interrupting DOAC day of procedure









Bridging Therapy: Key Questions

•  The perceived need for bridging therapy is driven by TE risk •  In high TE risk patients, the need to prevent TE

will dominate management irrespective of bleed risk and thus an aggressive strategy (such as bridging) is justified

•  In moderate TE patients, a single strategy is not dominant and management will depend on individual RFs for bleeding/thrombosis

•  In low TE risk patients, the need to prevent TE is less dominant thus strategies to avoid bleeding are justified

Adverse Events Caused or Prevented by Pre- and Post-operative Use of IV Heparin According to the

Indication for Anticoagulation

Indication for Heparin Acute venous thromboembolism* Month 1 Months 2 and 3 Recurrent VTE NVAF NVAF and previous embolism Mechanical heart valve Arterial embolism Month 1

TE Major Bleeding Death

No. of Events per 10,000 patients

-7162† +300 -559 -1328† +300 -93 -332† +300 -13 -2 +300 +12 -4 +300 +11 -3 +300 +12 -65 +300 -26

Values are estimated no of major events caused (+) or prevented (-) if Rx administered † A 100-fold increase in the postoperative rate of VTE with major surgery is assumed

Kearon C et al N Engl J Med 1997; 336: 1506 - 11

Post-Operative Heparin Bridging: PROSPECT Study

•  260 patient study on periop LMWH bridging in patients on chronic OAC •  Invasive procedures, minor Sx, major Sx •  ALL patients received enoxaparin 1.5mg/kg

SQ QD within 12-24hrs post-op •  Results:

•  MB in was 0.7% (95% CI: 0.02–3.7), 0% (95% CI: 0–5.0), and 20.0%(95% CI: 9.1–35.7) in invasive, minor, and major Sx

Dunn A et al JTH 2007; 5:2211-8

Periprocedural Management of Patients on Chronic VKA Based on Patient TE and Procedural Bleed Risk

Classifications

HIGH BLEEDING RISK

PROCEDURES 2 Day Risk 2 – 4%

LOW BLEEDING RISK

PROCEDURES 2 Day Risk 0 – 2%

MINIMAL BLEEDING RISK PROCEDURES

~0% (on OAC) HIGH THROMBOEMBOLIC RISK Annual ATE >10% 1 month VTE > 10%

A B C

INTERMEDIATE THROMBOEMBOLIC RISK Annual ATE 5 - 10% 1 month VTE 2 - 10%

D E F

LOW THROMBOEMBOLIC RISK Moderate Annual ATE <5% 1 month VTE < 2%

F G H

Spyropoulos et al J of Thromb Haemost 2016; 14(5):875-85

•  wait 48-72hrs,

then Rx dose LMWH

•  stepwise Px-

then Rx-dose LMWH

•  no bridging

? Heparin Bridging

TE Risk*

Bleeding

Risk

HighAnnual ATE > 10%

1 month VTE > 10%

ModerateAnnual ATE 5 -10%

1 month VTE 2 -10%

LowAnnual ATE < 5%

1 month VTE <2%

High2 day: 2 – 4%

A B C

Low2 day: 0 – 2%

D E F

• Include theoretical 100-fold postoperative VTE risk and possible 10-fold postoperative ATE risk with major surgery

Douketis J et al Chest 2012: 141(2):e326S-e350S

Bridging suggested (Grade 2C)

No bridging (Grade 2C) Bridging optional

Post-op bridging suggested

Post-op bridging considered

- wait 48-72hrs, then Rx dose LMWH

- stepwise Px- then Rx-dose LMWH

- no bridging

9th ACCP Guidelines: Perioperative Management of Anticoagulation: Overall Strategy

Prospective Cohort Studies Assessing Bridging Therapy after VKA Interruption

Omran, H (2005)

362 59 MHV 303 AF

not specified enoxaparin: 1 mg/kg o.d. or b.i.d.

not specified

0 0

n/a n/a 1

Jaffer, A (2006)

69 20 MHV 27 AF 18 VTE 4 other arterial indications

18 surgical 47 non-surgical

enoxaparin: 1 mg/kg b.i.d. (30 mg b.i.d. post-op after surgical procedures)

1 month 0 0

0 0 2

Spyro-poulos, A (2006)



therapeutic-dose (75%) and prophylactic-dose (25%) UFH or LMWH regimens

1 month 8 2 6 31

Dunn A (2006)

260 176 AF 81 VTE


enoxaparin: 1.5 mg/kg o.d.

1 month 4 1 2 8

Malato, A (2006)



therapeutic-dose (40%) or prophylactic-dose (60%) LMWH regimens

0 3 0

1 0 6

Halbritter, K (2007)

311 55 MHV (29 aortic, 26 mitral) 124 AF 50 dsyfunction 59 VTE 23 other (not specified)


therapeutic-dose LMWH or UFH in 62% of MHV, 47% of AF, and 55% of dysfunction

1 3 4 7

Study Pt. No. Reason for VKA Procedure Type Bridging Regimen F/U ATE VTE Bleed Death

v  7169 patients receiving bridging therapy studied v Three chronic VKA patient groups undergoing bridging therapy: MHV, CAF, VTE v  75% of patients bridged for minor procedures v  Standardized protocols for 65.7% of studies:

v  VKA discontinued 5d prior v  LMWH started D-3 v  Maintenance dose VKA restarted within 24 hrs, LMWH restarted within 12 - 72 hrs based on bleed risk

v  57% of studies used treatment-dose LMWH as bridging therapy, 37% intermediate/ prophylactic-dose LMWH v  Median F/U period - 30d v  Overal TE ~1% v Mean major bleed risk 4.32% Siegel D et al Circulation 2012; 126:1630-39

Thromboembolic Risk: NVAF, MHV, VTE

High

High Bleed Risk: Category A

Bridging: careful post-op

strategy*

Low Bleed Risk: Category B

Bridging

Intermediate

High Bleed Risk: Category C

Bridging**

Low Bleed Risk: Category D

Bridging**

Low

High Bleed Risk: Category E

No Bridging

Low Bleed Risk: Category F

No Bridging

Suggested Periprocedural Heparin Bridging Strategies for Patients on Chronic VKA:

Patient Thromboembolic and Procedural Bleed Risk 9th Edition ACCP Guidelines (all Grade 2C except intermediate risk )

Spyropoulos AC, Douketis JD Blood 2012; 120: 2954-62 Douketis J, Spyropoulos AC et al Chest 2012: 141(2):e326S-e350S

*For high-bleed risk procedures: wait a full 48-72 hours before re-initiating post-procedural heparin (LMWH) bridging (especially treatment-dose); stepwise increase in post-procedural heparin (LMWH) dose from prophylactic dose first 24-48 hours to intermediate/treatment dose; no post-procedural heparin (LMWH) bridging in very high bleed risk procedures (i.e. major neurosurgical or cardiovascular surgeries) but use of mechanical prophylaxis ** Based on individual patient- and procedural-related risk factors for thrombosis and bleeding

Bridging therapy with unfractionated heparin or low-molecularweight heparin (LMWH) is recommended for patients with AF

and a mechanical heart valve undergoing procedures that require interruption of warfarin. Decisions on bridging therapy should

balance the risks of stroke and bleeding. (Level of Evidence: C)

AHA/ACC Practice Guidelines JACC 2014; 64(21): 2246-80

Do We Need To Bridge?

Meta-Analysis and Systematic Review of Bridging vs No-Bridging:

Thromboembolic Events

No risk reduction for TE with heparin bridging; no difference in ATE or VTE risks. No difference in TE risk between full and intermediate/prophylactic dose LMWH. Siegel D et al Circulation 2012;126:1630-39

Meta-Analysis and Systematic Review of Bridging vs No-Bridging:

Major Bleeding

Bridging associated with an increase in major bleeding. Significant heterogeneity noted across studies.

Siegel D et al Circulation 2012;126:1630-39

Periprocedural Bridging vs No-Bridging Studies Study

(N) Year Population Comparators 30-day event (post-

procedure)

ATE or VTE OR

(95% CI)

MB +/- CRNMB

OR (95% CI)

Meta-analysis (N = 12,278) 2012

MHV, AF, VTE

Bridging vs No Bridging

0.80 (0.42, 1.54)

3.60 (1.52, 8.50)

ORBIT-AF (N = 2,200)

139 2014 AF


1.62 (0.95, 2.78)

3.84 (2.07, 7.14)

RELY (N = 1,415) 2014 AF


2.70 (0.38, 19.3)

4.62 (2.45, 8.72)

MVR Study (N = 1,777) 2014 MHV

Rx-dose vs Px-dose Bridging

0.90 (0.37, 2.18)

3.23 (1.58, 6.62)

Kaiser VTE (N = 1,178) 2015 VTE

Bridging vs No Bridging 0 vs 3

17.2 (3.9-75.1)

Background 30d Event Rates in No Bridging Arms: ATE = ~ 0.5 – 1.0% MB = ~ 1.0 – 1.5%

Hypotheses

We hypothesized that in patients with AF on chronic VKA with at least one stroke risk factor undergoing temporary interruption of VKA for an elective procedure: 1. Forgoing bridging anticoagulation would be non-inferior to bridging with low-molecular-weight heparin (LMWH) for the prevention of perioperative arterial thromboembolism (ATE)

- and – 2. Forgoing bridging anticoagulation would be superior to bridging with respect to major bleeding

BRIDGE - Trial Design

Douketis JD, Spyropoulos AC et al N Engl J Med 2015;373(9): 823-33

Primary Outcomes Outcome No. (%)

No Bridging (N=918)

Bridging (N=895)

P Value

ATE 4 (0.4) 3 (0.3)

0.01 (non-inf)

0.73 (sup)

Stroke 2 (0.2) 3 (0.3)

TIA 2 (0.2) 0 (0)

Systemic embolism 0 (0) 0 (0)

Major bleeding 12 (1.3) 29 (3.2) 0.005 (sup)

•  The mean CHADS2 score in patients who sustained a thromboembolic event was 2.6 (range, 1-4) The median time to an arterial thromboembolic event was 19.0 days (IQR, 6.0-23.0 days)

The median time to a major bleeding event after a procedure was 7.0 days (IQR, 4.0-18.0 days)

Secondary Outcomes

Outcome No. (%)

No Bridging (N=918)

Bridging (N=895)

P

Value

Death 5 (0.5) 4 (0.4) 0.88 (sup)

Myocardial infarction 7 (0.8) 14 (1.6) 0.10 (sup)

Deep vein thrombosis 0 (0) 1 (0.1) 0.25 (sup)

Pulmonary embolism 0 (0) 1 (0.1) 0.25 (sup)

Minor bleeding 110 (12.0) 187 (20.9) <0.001 (sup)

Limitations

•  Few patients had a high CHADS2 score (e.g., 5–6) •  Most patients underwent low-risk procedures, such

as colonoscopy or ambulatory surgery •  Overall rate of ATE was lower than expected •  Findings should not be applied to patients with

mechanical heart valves or venous thromboembolism •  Findings are not applicable to patients with AF

treated with a direct oral anticoagulant

Conclusions: The BRIDGE Study

•  For patients with AF who require temporary interruption of warfarin treatment for an elective operation or invasive procedure •  A strategy of forgoing bridging anticoagulation was non-

inferior to perioperative bridging with LMWH for prevention of arterial thromboembolism

•  Forgoing bridging treatment also decreased the risk of major bleeding compared to perioperative bridging with LMWH

•  “Experimental” arm with excellent clinical outcomes: ATE 0.4% and MB 1.3%

Douketis JD, Spyropoulos AC et al N Engl J Med 2015; 373(9): 823-33

MVR Study in MVR: Therapeutic vs Prophylactic-dose Bridging

Mathew J, Spyropoulos AC et al Thromb Haemost 2014; 112:1120-8

Screening visit

warfarin

*

Day -5 Stop warfarin Dalteparin

5000 IU QD

R

High bleeding risk

Low bleeding risk

Placebo

Day -3 Start dalteparin

200 IU/kg QD (morning before surgery

100 IU/kg)

Dalteparin 200 IU/kg QD

Placebo

Day -1 Stop dalteparin

warfarin

Day +90 Major TE(MI) Major bleed Survival

Day +1 Start dalteparin OR placebo

Day +1 Resume warfarin

Procedure

The PERIOP 2 Study - Design

N = 1773

ClinicalTrials.gov Identifier: NCT00432796

Thromboembolic Risk: NVAF, MHV,

VTE

High*

High Bleed Risk

Consider Bridging: careful post-op strategy

Low Bleed Risk

Consider Bridging

Low or Intermediate

No Bridging

The New Paradigm of Periprocedural Heparin Bridging Strategies for Patients on Chronic VKA

* Only for MHV patients, and certain high risk AF patients with recent CVA/TIA within 3 months

Spyropoulos AC et al J of Thromb Haemost 2016;14:875-85

Peri-Procedural Heparin Bridging Approach: Day-to-day Management

Day -7 Day -5 Day -3 Day -1 Day 0 Day +1 Day +4 D/C D/C Start D/C Restart AP, Continue Continue AP, warfarin LMWH LMWH warfarin warfarin heparin obtain (BID) (at least 24°, esp at usual If low-bleed and OAC baseline for QD dosing). dose 12 risk procedure until INR labs (CBC, Obtain INR, if - 24 hrs start heparin therapeutic, creat, INR, >1.5 and <1.8 24hrs. check plt PTT) low-dose vit K If high-bleed

D/C IVUFH 4hr risk procedure start heparin

48-72 hrs***









What is the optimal periprocedural management of

patients on DOACs needing interruption?

Laboratory-based or pharmacokinetic approach?

Tripodi A J of Thromb Haemost 2016;14:1325-7

“laboratory strategy appears superior [over a pharmacokinetic strategy] in terms of patient safety and should be considered in patients [on

DOACs] undergoing surgical or invasive procedures”

Tripodi A J of Thromb Haemost 2016:14:1325-7

Periprocedural DOACs and Drug Concentrations

A 48hr discontinuation of a DOAC does not guarantee <30ng/mL and normal PT and aPTT are flawed to predict this threshold and cannot replace specific assays

Godier A et al Thromb Res 2015; 136:763-8

•  Dabigatran ¡ Rivaraxaban

DOAC Measurements in Periprocedural Settings

•  Despite 6 years of investigation after the approval of the first DOAC, there are no compelling data demonstrating that DOAC level measurements, using either direct drug concentrations or measuring DOAC anticoagulant effects with global or specialized functional assays (such as a dilute thrombin time or DOAC-based anti-factor Xa levels), affect clinical outcomes

“There is no need for biological monitoring when the recommended interruption periods are applied and

there is no additional risk of drug accumulation”

Updated Guidelines on the French Working Group on Perioperative Hemostasis (GIHP) Sept 2015

Anaesth Crit Care Pain Med 2017; 36:73-76

Spyropoulos AC et al J Thromb Haemost 2016; 14(12):2556-2559

Similar PD Profile of Rivaroxaban and Enoxaparin:

Time [h] -24 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24

Ant

i-FX

a ac

tivity

[ng/

mL

Enox

apar

in]

-1

0

1

2

3

4

5

6 Rivaroxaban Enoxaparin Rivaroxaban & Enoxaparin

10 mg rivaroxaban with or without 40 mg Enoxaparin

49

Discontinuation of dabigatran and renal function: AC Activity within 24 to 48 hours

*Simulations based on PK data from a study in subjects with renal impairment and PK/aPTT relationships derived from the RELY study; aPTT prolongation in RE-LY was measured centrally in citrate plasma using PTT Reagent Diagnostics GmbH, Mannheim, Germany. There may be quantitative differences between established methods for aPTT assessment.1

In RELY, CrCl was calculated using the Cockroft-Gault equation.2 Pradaxa® US PI, 2013; 2. Data on file. Boehringer Ingelheim Pharmaceuticals, Inc.

50

•  Activated partial thromboplastin time (aPTT) can be used to estimate the time to get to a particular level of recovery, even when the time since the last dose of dabigatran is not precisely known

80

aPTT

(s)

0

70

60

50

40

30 24 48 72 96

Time (hours)

aPTT Time Course* 150 mg bid when CrCl > 30 mL/min 75 mg bid when CrCl ≤ 30 mL/min

Dabigatran Dose

CrCl ≤ 30 mL/min CrCl > 30 and ≤ 50 mL/min CrCl > 50 and ≤ 80 mL/min CrCl > 80 mL/min

Periprocedural DOAC Outcomes in SPAF Trials

Study DOAC 30-day rate (post-procedure)

stroke/systemic embolism (95% CI)

Major bleeding (95% CI)

RELY (N = 4591)109

dabigatran 1.01%

(0.35-2.87) 1.09%

(0.80-1.49)* ROCKET-AF

(N = 4692) 139

rivaroxaban 0.74%

(0.36-1.50) 1.26%

(0.80-1.49)

ARISTOTLE (N = 5439)

apixaban 0.60%

(0.32-1.12) 0.85%

(0.61-1.12)

* Includes only 150mg non-bridging groups Healey JS et al. Circulation 2012;126:343–8 Sherwood MW et al Circulation 2014; 129(18):1850-9 Garcia D et al Blood 2014; 124(25):3692-8

•  Vast majority of patients underwent minor (non-high bleed risk) procedures •  Majority of patients (~80%) held DOAC 2 – 3 days prior to procedure and restarted within 2 days post-procedure •  Only minority underwent bridging (except RELY)

Perioperative Management of Dabigatran: The Periop Dabigatran Study

•  541 cases using a pre-specified dabigatran protocol •  Timing of last dose based on CrCl and procedure-related bleed risk

•  Last dose 24hr before low bleed risk Sx; 48hr before high bleed risk Sx •  For CrCl 30-50ml/min, add 1d for low bleed risk and 2d for high bleed risk

•  Resumption based on complexity of surgery and consequences of a bleeding complication

•  24hr post-op low bleed risk; 48-72hr high bleed risk

•  Results: •  60% of procedures with standard bleed risk; 46% of cases with last

dose 24hrs before surgery; bridging used in 1.7% of cases post-op •  30-day outcomes:

•  0.2% TE (95% CI, 0 – 0.5%) •  1.8% MB (95% CI, 0.7 – 3.0%)

Schulman S et al Circulation 2015; 132(3):167-73

Clinical Outcomes: Bridged

vs. Non-Bridged in RELY Trial: Periprocedural heparin bridging:

Warfarin 28.5%; Dabigatran 110 mg 15.3%; Dabigatran 150 mg 17%

Clinical Outcome

Bridging Status

Warfarin Group (n = 1,415)

% (N) patients with events

Dabigatran Group (n = 2,691)

% (N) patients with events Major Bleeding

Bridged non-bridged OR (95% CI) bridged vs. non-bridged

6.8 (26) 1.6 (16)

4.62 (2.45-8.72)

P <0.001

6.5 (27) 1.8 (42)

3.68 (2.24-6.04),

P <0.001

P-value for treatment interaction

P = 0.577

Stroke and Systemic Embolism

Bridged non-bridged OR (95% CI) bridged vs. non-bridged

0.5 (2) 0.2 (2)

2.70 (0.38-19.3),

P = 0.321

0.5 (2) 0.3 (6)

1.82 (0.37-9.06),

P = 0.463


P = 0.760

Any Thromboembolism Bridged non-bridged OR (95% CI) bridged vs. non-bridged

1.8 (7) 0.3 (3)

6.39 (1.64-24.8),

P =0.007

1.2 (13) 0.6 (5)

2.11 (0.75-5.95),

P = 0.158


P = 0.204

Douketis JD et al. Thromb Haemost 2015; 113(3):625-32

Spyropoulos AC et al J of Thromb Haemost 2016; 14:875-85

55

Stratify by procedural bleed risk (type, urgency) and renal function

No heparin bridging!

For moderate renal insufficiency: add 1–2 days pre-op

‘Low’ bleed risk: 2–3 half-lives

i.e. 1 – 2 days pre-op

‘High’ bleed risk: 4–5 half-lives

i.e. 2 or more days pre-op

Consider coagulation tests in specific situations aPTT, PT, TT, dTT (e.g. Hemoclot®), ECT

Pay special attention in patients on antiplatelet therapy and those requiring neuraxial anaesthesia

General principles of pre-procedure DOAC discontinuation

Spyropoulos AC et al Blood. 2012;120(15):2954-62 Darvis-Kasem S et al Semin Thromb Hemost. 2012(7):652-60

56

Only after good control of hemostasis

No full-dose heparin bridging! In patients who cannot tolerate orals consider prophylactic doses of heparin for VTE prevention

Wait at least 24 hours after operation to restart NOAC for

minor or “low-bleed” risk procedures

Wait 48–72 hrs after operation to restart NOAC for major or

“high-bleed” risk procedures

Consider initial prophylactic doses of NOAC

General principles of post-procedure DOAC resumption

Dependent on bleeding risk and type of operation

Spyropoulos AC et al Blood. 2012;120(15):2954-62 Darvis-Kasem S et al Semin Thromb Hemost. 2012(7):652-60

Narouze S et al Reg Anesth Pain Med 2015;40: 182–212)

2015 ASRA Guidelines for DOACs

Perioperative Anticoagulant Use for Surgery Trial (PAUSE)

•  Study population: •  AF on a DOAC that require an elective procedure

•  Primary aim: •  Standardized protocol for DOAC (including dabigatran,

rivaroxaban, apixaban) is safe with low rates of major bleeding (1.0%, UL 2.0%) and ATE (0.5%, UL 1.5%)

•  Secondary aim: •  The effect of the pre-operative DOAC interruption protocol on the

level of residual anticoagulation •  Routine coagulation tests (i.e. aPTT) •  DOAC-specific tests (i.e. TT, dTT [e.g. HemoclotTM], anti FXa)

•  N = 3,300; ~15 centers in Canada; July 2014 – July 2017

ClinicalTrials.gov Identifier: NCT02228798 58

PAUSETrial:Post-opera3veProtocolforAllDOACs

DOAC Resumption of DOAC after Surgery/Procedure

Low-bleed Risk High-bleed Risk

dabigatran resume AM post-op day +1 (24 hrs)

resume AM post-op day +2 to +3 (48-72

hrs)rivaroxaban as above as above

apixaban as above as above

ClinicalTrials.gov Identifier: NCT02228798

The Management of Patients on Chronic OAC who Need Elective Surgery

•  Is interruption of OACs indicated? •  COMPARE, BRUISE Control, ARISTOTLE

•  No - PM/defibrillator/catheter ablation and DOACs. Proof of concept studies for strategy of OAC continuation in minimal/low bleed risk procedures

•  Is heparin bridging necessary? •  Large meta-analysis and large observational/sub-study data

•  Over 3-4 fold increased risk of major bleeding and no advantages in TE reduction

•  BRIDGE – landmark Pb controlled RCT in AF patients •  “Proof-of-concept” study of no efficacy and harm of heparin bridging •  Likely can be extended to high risk populations incl MHV (PERIOP-2)

•  Optimal periprocedural management of DOACs •  Large Phase 3 SPAF substudy, outcome study, and registry data

•  Excellent outcomes from simple discontinuation/re-initiation based on PK properties, procedural bleed risk, and patient renal fxn (dabi)

•  Heparin bridging causes harm (>3-fold increase MB risk) •  PAUSE Trial

Guidance and Guidelines, Apps: Periprocedural Management of OACs

10th Edition ACCP Antithrombotic Guidelines 2018

THANK YOU!!!

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