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Perioperative Bridging of Warfarin with Low Molecular Weight Heparin in Atrial Fibrillation:
If everyone else jumped off the BRIDGE, would you?
Chelsea Minor, Pharm.D. PGY1 Pharmacy Resident
South Texas Veterans Health Care System The University of Texas at Austin College of Pharmacy
The University of Texas Health Science Center at San Antonio January 22, 2016
Objectives
1. Describe the pathophysiology and risk factors for thromboembolism (TE) associated withatrial fibrillation (AFib)
2. Review the pharmacology and kinetic properties of various anticoagulation agents3. Classify the severity of and identify the risk factors for bleeding4. Review the evidence supporting current guideline bridging recommendations5. Formulate a recommendation regarding the use of perioperative bridging of warfarin with
low molecular weight heparin (LMWH) in patients with AFib
Minor |1
Background
I. Epidemiology 1. Prevalence of AFib in the United States is expected to reach 12.1 million cases by 2030 1
Figure 1. Projected prevalence of AFib cases in U.S 1
2. Patients with AFib have five times the risk of stroke as their age matched controls 2
3. Each year, 69,165 Americans will have a stroke attributed to AFib 3-5
4. Approximately 41-65% of patients with moderate to high stroke risk are prescribed
oral anticoagulation therapy 3
5. Approximately one in six warfarin treated patients with AFib undergo an electiveprocedure requiring temporary interruption of anticoagulation per year 6-7
Atrial Fibrillation
I. Definition 1. AFib is a supraventricular tachycardia arising from disorganized atrial depolarization2. AFib is characterized by:
a. Extremely rapid atrial rate (400 to 600 beats/min)b. Disorganized atrial activation
Table 1. Classification of AFib 8 Classification Description Paroxysmal AFib that terminates spontaneously or with intervention within
seven days of onset but episodes may recur with variable frequency Persistent Continuous AFib that is sustained > seven days Long-standing persistent Continuous AFib > 12 months duration Permanent Joint decision between patient and clinician to stop further attempts
to restore or maintain sinus rhythm Non-valvular AFib (NVAF) AFib in the absence of rheumatic mitral stenosis, a mechanical or
bioprosthetic heart valve, or mitral valve repair
Minor |2
II. Etiology 8
1. Multifactorial mechanisms of AFib development2. Risk factors contribute to electrical remodeling, structural, and neurohormonal changes
Table 2. Risk factors for AFib 8 Atrial Distension High Adrenergic Tone Chronic hypertension Sepsis Mitral valve disease Hyperthyroidism Cardiomyopathy Binge drinking Congenital defects Alcohol withdrawal Pulmonary embolism (PE) Excessive caffeine Pulmonary hypertension Sympathomimetics Myocardial ischemia Surgery Sleep apnea Emphysema or other lung disease
III. Pathophysiology1. Mechanism 8
a. Histopathological changes, such as atrial fibrosis or loss of atrial muscle mass,lead to electrical remodeling
b. Electrical remodeling results in multiple reentry circuits, rapidly firing atrialfoci, decreased atrial refractoriness, and shortening of action potentials
2. Stroke risk 9-11
a. Ischemic strokes occur commonly due to a cardiac embolus in the left atriumb. Stagnant blood flow in the dysfunctional atria can lead to clot formation in the
atria or atrial appendage, subsequent embolization, and cerebral occlusion
Figure 2. Mechanisms contributing to AFib related stroke 12
Minor |3
IV. Estimating stroke risk1. Epidemiology
a. Ischemic strokes associated with AFib demonstrate greater disability and
mortality compared to other ischemic strokes 13(UTD-S)
b. Strokes associated with AFib have been shown to increase composite risk of
death, disability, and handicap by ~50% at three months 14
2. Validated risk stratification tools are used to predict stroke risk:a. CHADS2 score
Table 3. CHADS2 Score 15 Risk Factor Point Value Score Annual Stroke Rate
Congestive heart failure 1 0 1.9% Hypertension 1 1 2.8% Age > 75 years 1 2 4.0%
Diabetes 1 3 5.9% Previous stroke/TIA 2 4 8.5%
5 12.5% 6 18.2%
TIA: transient ischemic attack
b. CHA2DS2- VASc score
Table 4. CHA2DS2- VASc Score 16 Risk Factor Point Value Score Annual Stroke Rate
Congestive heart failure 1 0 0% Hypertension 1 1 1.3%
Age > 75 2 2 2.2% Diabetes 1 3 3.2%
Previous stroke/TIA 2 4 4.0% Vascular disease 1 5 6.7%
Age 65-74 1 6 9.8% Female gender 1 7 9.6%
8 6.7% 9 15.2%
Vascular disease: myocardial infarction (MI), peripheral arterial disease (PAD), aortic plaque
Figure 3. Rates of death, stroke, and systemic embolism (SSE) in CHADS2 vs. CHA2DS2-VASc 17
Minor |4
c. Limited data validating scoring tools in perioperative setting
Table 5. Proposed stroke risk according to CHADS2 in perioperative setting 18 Score 30 Day Postoperative Stroke Rate (95% CI)
0 1.01 (0.83-1.21) 1 1.62 (1.46-1.79) 2 2.05 (1.87-2.24) 3 2.63 (2.26-3.04) 4 3.62 (2.66-4.80) 5 3.65 (1.83-6.45) 6 7.35 (2.42-16.3)
V. Pharmacologic management of AFib 19 1. Rate control2. Rhythm control3. Stroke prophylaxis
a. Recommendations for antithrombotic therapy are determined by stroke riskb. American College of Chest Physicians (ACCP)
Table 6. CHEST Guidelines 9th Edition (2012) 20 Risk CHADS2 score Prophylaxis Regimen Grade Low 0 No therapy
Aspirin 81-325 mg daily Aspirin 81-325 mg daily + clopidogrel 75 mg daily
IIB
Moderate 1 Oral anticoagulation (IB) If unsuitable consider:
Aspirin 81-325 mg daily Aspirin 81 mg daily + clopidogrel 75 mg daily
IIB
High > 2 Oral anticoagulation a If unsuitable consider:
Aspirin 81-325 mg daily (IB) Aspirin 81 mg daily + clopidogrel 75 mg daily (IB)
IA
aCHEST 2012 recommends dabigatran 150 mg twice daily over VKA therapy in patients with paroxysmal AFib (IIB)
c. American College of Cardiology (ACC)/American Heart Association (AHA)Task Force on Practice Guidelines and the Heart Rhythm Society (HRS)
Table 7. AHA/ASA/HRS Guideline Recommendations (2014) 8 Risk CHA2DS2-VASc score Prophylaxis Regimen Class Low 0 No therapy IIA
Moderate 1 No therapy IIB
High > 2 Oral anticoagulation Warfarin (IA) Dabigatran (IB) Apixaban (IB) Rivaroxaban (IB)
I
Minor |5
Anticoagulation I. Vitamin K antagonists (VKAs)
1. Pharmacology of warfarin 21-22 a. VKAs interfere with the cyclic conversion of vitamin K and vitamin K epoxide by
modulating gamma carboxylation of glutamate residues on the N-terminal regions of vitamin K dependent coagulation factors
b. Inhibits production of vitamin K dependent clotting factors II, VII, IX, and X along with anticoagulant proteins C and S, which require gamma carboxylation for their coagulation activity
Figure 4. Mechanism of action of warfarin 23
2. Pharmacokinetics of warfarin 24
a. Half-life(t1/2) i. R-warfarin: 45 hours
ii. S-warfarin: 29 hours b. Highly protein bound: 99% c. Metabolism
i. R-warfarin: CYP1A2, CYP3A4 ii. S-warfarin: CYP2C9
d. Coagulation factors’ half-lives
Table 8. Half-life of clotting factors Clotting factors t1/2 (h)
Factor VII 4-6
Protein C 8-10 Factor IX 20-30 Factor X 24-40 Protein S 40-60 Factor II 60-100
Minor |6
II. LMWH 25 1. Pharmacology of LMWH
a. Heparin is pentasaccharide, which binds to antithrombin, causes a conformational change, and interacts with thrombin and factor Xa (FXa)
b. Unfractionated heparin (UFH) has equivalent activity against thrombin and FXa c. LMWHs are approximately one-third the molecular weight range of UFH d. LMWH has greater activity against FXa, as it cannot bind to both antithrombin
and thrombin
Figure 5. Mechanism of action of heparin products 25
2. Pharmacokinetics of LMWH
a. Elimination is primarily renal b. Better bioavailability and longer half-life than UFH c. Dose independent clearance
Table 9. Comparison of current LMWH agents 26-29 LMWH (SQ) BA (%) Time to Cmax (h) t1/2 (h) Dalteparin 87 4 3-5 Enoxaparin 100 3-5 7 Nadroparin 89 3-6 2-11.2 Tinzaparin 86.7 4-5 3-4 SQ: subcutaneous; BA: bioavailability; Cmax: concentration max; t1/2: half-life
III. Direct oral anticoagulants (DOACs)
Table 10. Comparison of current DOACs 30-33 DOAC BA (%) Time to Cmax (h) Protein binding (%) t1/2 (h) Renal elimination (%) Dabigatran 3-7 1-2 35 12-17 7 Rivaroxaban 80-100 2-4 92-95 5-9 66 Apixaban 50 3-4 87 12 27 Edoxaban 62 1-2 55 10-14 50
Minor |7
Bleeding Risk I. Classification of bleeding
Table 11. International Society of Thrombosis and Hemostasis bleeding definitions34 Classification Criteria Major bleed (MB) A fall in hemoglobin of > 2.0 g/dL or requiring > two units of blood
transfusions; symptomatic bleeding in a critical organ/region; a fatal bleed
Clinically relevant non-major bleed (CRNM)
Does not meet criteria for MB but prompts a clinical response including: hospital admission, physician guided medical or surgical treatment for bleeding, or a change in antithrombotic therapy
Minor bleed All other non-major bleeds
II. Estimating risk of bleeding 1. ATRIA 35
a. Risk factors for bleeding retrospectively identified in patients with NVAF b. Score > five indicates high bleeding risk
Table 12. ATRIA 35
Risk Factor Points Score Annual hemorrhage rate (%) Anemia 3 0-3 0.76
Severe renal disease 3 4 2.62 Age > 75 years 2 5-10 5.76
Any prior hemorrhage diagnosis 1 Hypertension history 1
Severe renal disease: Defined as eGFR < 30 mL/min or dialysis-dependent
2. HEMORR2HAGES 36 a. Quantified bleeding risk in 3791 Medicare beneficiaries with AFib b. Score ≥ four considered high bleeding risk
Table 13. HEMORR2HAGES 36
Risk Factor Points Score Bleeds per 100 patient-years on warfarin (95% CI)
Hepatic or renal disease 1 (each) 0 1.9 (0.6-4.4) Ethanol use 1 1 2.5 (1.3-4.3) Malignancy 1 2 5.3 (3.4-8.1)
Older age (> 75 years) 1 3 8.4 (4.9-13.6) Reduced platelet count or function 1 (each) 4 10.4 (5.1-18.9)
Re-bleeding 2 ≥ 5 12.3 (5.8-23.1) Hypertension, uncontrolled 1
Anemia 1
Genetic factors 1
Elevated risk of fall 1
Stroke 1 Hepatic disease: cirrhosis, two-fold or greater elevation of AST or ALT, or albumin < 3.6 g/dL; Renal insufficiency: CrCl < 30 ml/min; History of alcohol abuse, recent hospitalization for alcohol-related illness, and worsening liver disease; Recent metastatic cancer; Platelets < 75k; Scheduled use of antiplatelet therapy, NSAID therapy, or blood dyscrasia; Prior hospitalization bleeding; Most recent hematocrit < 30 or hemoglobin < 10 g/dL; CYP2C9*2 and/or CYP2C9*3; Alzheimer's dementia, Parkinson's disease, schizophrenia, or any condition predisposing to repeated falls; Prior ischemic stroke or brain infarct detected by brain imaging
Minor |8
3. HAS-BLED 37 a. Validated with warfarin, not DOACs b. Score > three indicates high bleeding risk
Table 14. HAS-BLED 37
Risk Factor Points Score Annual Bleeding Risk (%)
Bleeding rate (%/year)
Hypertension 1 0 0.9 1.13 Abnormal renal/hepatic function 1 (each) 1 3.4 1.02
Stroke 1 2 4.1 1.88 Bleeding 1 3 5.8 3.74
Labile INRs 1 4 8.9 8.70 Elderly (≥ 65 years) 1 5 9.1 12.50 Drugs or alcohol use 1 (each) 6-9 Insufficient data Insufficient data
Hypertension: SBP > 160 mmHg; Abnormal renal function: chronic dialysis, renal transplantation, or serum creatinine > 2.3 mg/dL; Abnormal liver function: chronic hepatic disease (i.e. cirrhosis), evidence of significant hepatic derangement (i.e. bilirubin > 2 x ULN, AST/ALT > 3 x ULN); Bleeding: prior bleed history and/or predisposition to bleeding (i.e. bleeding diathesis, anemia, etc); Labile INR: unstable/high INR or < 60% time spent in therapeutic range; Drugs/alcohol: concomitant drugs that may increase bleed risk (i.e. antiplatelet agents, NSAIDS, etc) or alcohol abuse
Perioperative Bridging Recommendations
I. Rationale for bridging
1. Patients undergoing an elective procedure may require an interruption of VKA therapy 2. The antithrombotic effect of VKAs takes four to five days to recede after it is stopped
and to establish on re-initiation 3. Patients with AFib are at an increased risk for perioperative TE, such as stroke and
require additional anticoagulation during this period of sub-therapeutic VKA therapy 4. Bridging anticoagulation, typically with a LMWH, can provide adequate anticoagulation
during this perioperative period
Figure 6. Perioperative management of VKA 38
Minor |9
II. Perioperative management of bridging anticoagulation 39
1. Stop warfarin approximately five days before surgery 2. Resume warfarin 12-24 hours after surgery 3. In patients receiving therapeutic subcutaneous LMWH, stop LMWH approximately 24
hours before surgery 4. In patients receiving intravenous UFH, stop UFH 4-6 hours before surgery 5. In patients undergoing a high bleed risk surgery, resume LMWH or UFH 48-72 hours
after surgery
III. ACC/AHA/HRS Guidelines 2014 8 1. Decisions about bridging therapy should balance the risks of stroke, bleeding, and the
duration of time anticoagulation will be interrupted 2. In the following high risk patients, consider bridging with UFH or LMWH:
a. Mechanical valves b. Prior stroke or TIA c. CHA2DS2-VASc score > two
3. Low risk patients, without above risk factors, undergoing procedure with bleed risk: a. Stop warfarin up to one week prior to procedure b. Do not bridge c. Resume warfarin after adequate hemostasis is achieved
4. Consider continuing oral anticoagulation for the following procedures: a. Pacemaker or implantable cardioverter defibrillation (ICD) implantation b. Catheter ablation c. Coronary angiography
Table 15. Summary of evidence from ACC/AHA/HRS 2014 Guidelines 40-42 Trial Objective Study Design Results Birnie, et al Compare the incidence of
device-pocket hematomas in patients continuing warfarin therapy vs. undergoing heparin bridging during pacemaker or ICD implantation
Multicenter, single-blinded, RCT (n=668)
Reduced incidence of device-pocket hematoma in continuation group. No difference in bleeding or TE between groups
Hakalahti, et al Evaluate the safety of therapeutic vs. subtherapeutic oral anticoagulation during ablation
Observational, single center, prospective (n=193)
No significant difference in major or minor bleeding, or thromboembolic events
Lahtela, et al Evaluate the safety and efficacy of uninterrupted anticoagulation compared to bridging therapy in patients with AFib undergoing cardiac stenting
Observational, multicenter, prospective (n=451)
No difference in rates of bleeding complications or major adverse cardiac and cerebral events between groups
RCT, randomized control trial
Minor |10
IV. CHEST Guidelines 2012 39 1. Recommendation to bridge is based on CHADS2 risk score
Table 16. CHEST Guidelines Risk Stratification (2012) 39
Risk Group CHADS2 Score Recommendation Low 0-2a Do not bridge
Moderate 3-4 Recommendation to bridge based on assessment of
individual patient and surgical factors High
5-6b Bridge anticoagulation
a Assumes no prior stroke or TIA; b Stroke or TIA in prior 3 months, or rheumatic valvular heart disease
2. Consider continuing oral anticoagulation for the following procedures:
a. Dental b. Dermatologic c. Cataract surgery
Table 17. Summary of evidence from the CHEST 2012 Guidelines 43-45 Trial Objective Study Design Results Nematullah, et al Evaluate the risk of
bleeding in patients continuing warfarin while undergoing elective dental procedures
Meta-analysis of five RCTs
No difference in clinically significant non-major or minor bleeding
Nelms, et al Evaluate the safety of continuing warfarin in patients, undergoing soft tissue surgery
Retrospective chart review (n=26)
Only one case of postoperative bleeding managed with gentle pressure, intraoperative bleeding well controlled in all cases
Jamula, et al Determine the efficacy and safety of continuing warfarin treatment before and after cataract surgery
Meta-analysis of eleven studies
Pooled incidence of bleeding was not clinically significant
V. Perioperative management of DOACs Table 18. Recommendations for perioperative management of DOACs 30-33
Drug Recommendation Bridging Apixaban Low bleeding risk surgery:
Stop 24 hours prior Mod-high bleeding risk surgery: Stop 48 hours prior
Do NOT bridge
Rivaroxaban Stop at least 24 hours prior N/A Edoxaban Stop at least 24 hours prior N/A Dabigatran CrCl < 50 mL/min:
Stop 3-5 days prior CrCl ≥ 50mL/min: Stop 1-2 days prior
N/A
Minor |11
Literature Review
Malato A, Saccullo G, Lo Coco L, et al. Patients requiring interruption of long-term oral anticoagulant therapy: the use of fixed sub-therapeutic doses of low-molecular-weight heparin. J Thromb Haemost. 2010;81:107-13. 46
Objective To evaluate the efficacy and safety of bridging therapy with fixed dose subcutaneous LMWH in patients on long term VKA therapy undergoing an invasive procedure
Methods Study Design Single center, prospective, intention-to-treat, cohort study Population Inclusion Criteria Exclusion Criteria
Adult outpatients on chronic VKA for mechanical heart valves, AFib, stroke with embolic source, VTE, or other indications
Due to have major surgery or invasive procedure requiring temporary interruption of VKA
Minor surgery or dental procedure Renal insufficiency Previous MB Chronic anemia (Hgb ≤ 10 g/L) Platelets (< 100k/ mm3) Severe comorbidities Receiving other anticoagulants Body weight ≤ 40 kg or ≥ 100 kg
Interventions Preoperatively: In all patients, VKA was discontinued 5 ± 1 days prior to procedure High risk group: When INR < 1.5, LMWH was initiated twice daily at a fixed sub-
therapeutic dose (3800 or 4000 IU of anti-FXa for nadroparin or enoxaparin, respectively) and continued until the night before procedure
Low risk group: INR of ≤ 1.2 was required before surgery. LMWH was initiated once daily at a prophylactic dosage (3800 or 4000 IU of anti-FXa for nadroparin or enoxaparin, respectively) the night before procedure
Postoperatively: LMWH was resumed 12 hours post-op (twice daily in high risk group; once daily
in low risk group) and continued until INR in therapeutic range. Usual dose of VKA resumed one day post-op, unless inadequate hemostasis
Assessments Patients were followed up to one month after surgery (30 ± 2 days) CBC measured every 1-2 days while patients were on LMWH INR measured every 1-2 days for one week post-op
Endpoints Primary efficacy endpoint: perioperative arterial or venous TE Primary safety endpoint: MB Secondary safety endpoint: minor bleeding
Statistical Analyses
Intention-to-treat : all patients who received > one dose of LMWH Primary outcome rates expressed as a proportion with a 95% CI Fisher’s exact test was used for the frequency analysis Expected incidence of perioperative MB of 3%, required a sample size of ≥ 300
patients Results
Enrollment University Hospital of Palermo, in Palermo, Italy Between 2003-2008, 486 patients on chronic anticoagulation were considered 134 were excluded 352 patient were included
24 did not receive study medication 328 received at least one dose of LMWH
Minor |12
Baseline Characteristics
Table 19. Baseline characteristics (n=328) Characteristic Findings Mean age, range (years) 62.3 (25-89) Weight, mean ± SD (kg) 76.3 ± 17.4 AFib without previous stroke, n (%) 122 (37.1) AFib with previous stroke, n (%) 58 (17.6)
Low risk group, n (%) 182 (55.4) High risk group, n (%) 146 (44.6) Non-major invasive procedure, n (%) 225 (69) Major surgery, n (%) 103 (31)
Results
Table 20. Results (n=328)
Endpoint Total
Low risk (n=182)
High risk (n=146)
P-value
TE, n (%) 95% CI
6 (1.8) 0.4 – 3.2
1 (0.54) -0.54 – 1.6
5 (3.4) 0.5 – 6.3
0.092
MB, n (%) 95% CI
7 (2.1) 0.6 – 3.6
1 (2.8) -2.6 – 8.2
6 (8.8) 2.1 – 15.5
0.417
Minor bleeding, n (%) 95% CI
15 (4.6) 6 (3.3) 2.7 – 3.9
9 (6.1) 2.3 – 9.9
Discussion Critique Strengths Limitations
Thirty day follow up Standardized dosing of LMWH
Not randomized Single center Various indications for anticoagulation Did not report CHADS2 scores Excluded patients >100 kg
Implications A standardized bridging anticoagulation regimen with fixed doses of LMWH was associated with a low risk of TE and MB
MB occurred more frequently in the group that underwent major surgery
Douketis JD, Healey JS, Brueckmann M, et al. Perioperative bridging anticoagulation during dabigatran or warfarin interruption among patients who had an elective surgery of procedure: substudy of the RE-LY trial. J Throm Haemost. 2015;113:625-32. 6 Objective Compare perioperative clinical outcomes in patients treated with dabigatran or
warfarin requiring an elective procedure while enrolled in RE-LY Methods
Study Design Pre-specified, retrospective, sub-analysis of RE-LY trial Population Inclusion Criteria Exclusion Criteria
Age > 18 years CHADS2 score > 1 NVAF First interruption of anticoagulation
Urgent surgery or procedure Unspecified surgery or procedure MB or TE 30 days prior
Interventions Perioperative management of warfarin was left to physician discretion Bridging with LMWH or UFH vs. no bridging therapy
Assessments Observed seven days before the procedure and 30 days afterwards
Minor |13
Endpoints MB: Non-life threatening MB, life threatening MB, fatal bleed SSE Any TE: SSE, MI, PE, or vascular death
Statistical Analyses
Fisher’s exact test for categorical data Student’s T test for continuous data Multivariable logistic regression analysis to adjust for covariates
Results Enrollment December 2005 to March 2009
4133 patients included in analysis Baseline Characteristics
Table 21. Baseline characteristics of warfarin-treated patients (n=1424) Characteristic Bridged (n=391) Not bridged (n=1033) Age, mean (years) 71.5 73.1 CHADS2 score, mean 2.1 2.1 CHA2DS2-VASc score, mean 3.6 3.6 HAS-BLED score , mean 1.4 1.3 Prior stroke or TIA, n (%) 81 (20.7) 170 (16.5)
Results
Table 22. Results of warfarin treated patients (n=1424)
Endpoint Bridged (n=383)
Not bridged (n=1032)
OR (95% CI)
P-value
MB, n (%) 26 (6.8) 16 (1.6) 4.62 (2.45 – 8.72) <0.001 SSE, n (%) 2 (0.5) 2 (0.2) 2.70 (0.38 – 19.3) 0.321 TE, n (%) 7 (1.8) 3 (0.3) 6.39 (1.64 – 24.8) 0.007
Discussion Critique Strengths Limitations
Multivariable logistic regression analysis to control for confounders
Balanced baseline characteristics Strong external validity
Not randomized No standardized bridging Small sample size Under powered
Implications MB rates were significantly higher in patients who were bridged arm SSE rates did not differ in patients who were bridged or not bridged Rates of TE were significantly higher in patients who were bridged
Steinberg BA, Peterson ED, Sunghee K, et al. Use and outcomes associated with bridging during anticoagulation interruptions in patients with atrial fibrillation: findings from the outcomes registry for better informed treatment of atrial fibrillation (ORBIT-AF). Circ. 2015;131:488-94. 47
Objective Compare the incidence of interruption of oral anticoagulation for procedures, causes for interruption, patterns of bridging agents, and outcomes for patients in the ORBIT-AF registry who were bridged to those who were not bridged
Methods Study Design Retrospective review of prospective, multicenter, outpatient, ORBIT-AF registry data Population Inclusion Criteria Exclusion Criteria
Age ≥ 18 years ECG documented AFib At least 1 follow-up visit
Life expectancy < six months Transient AFib from reversible condition Not on oral anticoagulation at baseline
Minor |14
Interventions Bridging with LMWH, UFH, fondaparinux, or no bridging Procedures included cardiac catheterization, catheter ablation, endoscopy, cardiac
surgery, non-cardiac surgery, device implantation, dental procedure Assessments Interruptions in anticoagulation therapy for procedures were recorded
Observed for 30 days post-surgery or procedure Endpoints Safety: Any bleeding events, MB
Cardiovascular (CV) events: SSE, MI, or CV hospitalization Composite of MI, SSE, MB causing hospitalization, and death within 30 days
Statistical Analyses
Chi squared test for categorical data Wilcoxon rank-sum test for continuous data
Results Enrollment Patients in ORBIT-AF: 10,132
7372 patients included in cohort Baseline Characteristics
Table 23. Baseline characteristics (n=2200) Characteristic Not bridged
(n=1608) Bridged (n=592)
P value
Age, mean (years) 75 74 0.009 CHADS2 score, mean 2.34 2.53 0.004 CHA2DS2-VASc score, mean 4.03 4.25 0.01 ATRIA score, mean 2.74 2.72 0.9 Prior CVA (%) 15 22 0.0003 Congestive heart failure (%) 34 44 <0.0001 Significant valvular disease (%) 27 34 0.0006 Moderate/severe mitral stenosis (%) 1.1 2.5 0.01 Prior mechanical valve replacement (%) 2.4 9.6 <0.0001 Warfarin (%) 93 96 Dabigatran (%) 6.8 3.7 INR prior to procedure, mean 2.34 2.28 0.3
Results Table 24. Results Unadjusted, n (%) Adjusted Endpoint Not bridged
(n=1724) Bridged (n=503)
P-value OR (95% CI) P value
CV events 43 (2.5) 23 (4.6) 0.02 1.62 (0.95-2.78) 0.07
Bleeding events
22 (1.3) 25 (5.0) <0.0001 3.84 (2.07-7.14) <0.0001
Overall composite
108 (6.3) 64 (13.0) <0.0001 1.94 (1.38-2.71) 0.0001
Discussion Critique Strengths Limitations
Large cohort Strong external validity Adjusted for covariates
Observational study Used ATRIA score No standardized bridging procedure
Implications Bridging anticoagulation was associated with an increased risk of bleeding and CV events
Composite outcome driven by rate of hospitalization in bridged group
Minor |15
Douketis JD, Spyropoulos AC, Kaatz S, et al. Perioperative bridging anticoagulation in patients with atrial fibrillation. N Engl J Med. 2015;373:823-33. 48 Objective To evaluate whether forgoing bridging therapy with LMWH is non-inferior to bridging
with LMWH for the prevention of perioperative arterial TE and superior in regard to MB
Methods Study Design Multicenter, randomized, double bind, placebo-controlled, intention-to-treat analysis Population Inclusion Criteria Exclusion Criteria
> 18 years of age Chronic (permanent or paroxysmal)
AFib/flutter Warfarin therapy for > 3 months Undergoing elective operation or
invasive procedure requiring interruption of warfarin therapy
CHADS2 score ≥ 1
Mechanical heart valve SSE, or TIA within previous 12 weeks MB within the previous 6 weeks CrCl < 30 mL/min Platelets (< 100k/mm3) Planned cardiac, intracranial, or
intraspinal surgery
Interventions Preoperatively: Dalteparin sodium 100 IU/kg SQ BID or placebo Postoperatively: Warfarin restarted evening of or day after procedure LMWH or placebo resumed:
12-24 hours after low bleeding risk procedure 48-72 hours after high bleeding risk procedure
Assessments Final follow-up was 30-37 days post procedure Endpoints MB: non-life-threatening MB, life-threatening MB, and fatal bleed
SSE Any TE: SSE, MI, PE, and any vascular death
Statistical Analyses
Primary efficacy outcome: non-inferiority analysis, one sided test at 0.025 95% CI calculated using Barnard’s test Expected event rate 1.0% for both groups; non-inferiority margin 1.0% Primary safety outcome: two sided test at 0.05; p-value calculated with Fisher’s
mid-P test; expected event rates were 1.0% with no bridging and 3.0% with bridging
90% power for two primary endpoints required sample size of 1882 Results
Enrollment From July 2009 to December 2014 at 108 sites in the U.S. and Canada 1884 patients recruited
Baseline Characteristics
Table 25. Baseline characteristics (n=1884) Characteristic Not bridged
(n=950) Bridged (n=934)
Age, year ± SD 71.8 ± 8.74 71.6 ± 8.88 Caucasian, n (%) 860 (90.5) 849 (90.9) Male, n (%) 696 (73.3) 686(73.4) Mean CHADS2 score, ± SD 2.3 ± 1.03 2.4 ± 1.07 Aspirin, n (%) 324 (34.1) 329 (35.2) Clopidogrel, n (%) 30 (3.2) 21 (2.2) Prior stroke, n (%) 79 (8.3) 99 (10.6)
Minor |16
Results
Table 26. Results
Endpoint Not bridged (n=918)
Bridged (n=895)
P-value
Arterial TE, n (%) 4 (0.4) 3 (0.3) 0.01*, 0.73 MB, n (%) 12 (1.3) 29 (3.2) 0.005 Death, n (%) 5 (0.5) 4 (0.4) 0.88 Minor bleeding, n (%) 110 (12.0) 187 (20.9) <0.001 *Non-inferiority
Discussion Critique Strengths Limitations
Large sample Randomized controlled trial Common procedures well represented
Low event rate Selected non-inferiority margin was
too wide so sample size and power re-calculated during study
Excluded high risk patients Time in therapeutic range not
reported Implications Provided little data for patients with CHADS2 score > 5
Patients with mechanical heart valves, patients undergoing major surgical procedures associated with high rates of arterial TE or bleeding, and CrCl < 30mL/min were excluded, limiting external validity
Forgoing bridging did not increase the risk of TE, but did decrease the risk of bleeding
Conclusions I. Summary
1. Forgoing bridging in low to moderate risk patients does not increase the risk of TE, but decreases the risk of bleeding
2. Data limited to observational studies with only one randomized trial 3. Majority of patients studied had a low to moderate risk of TE
a. Current randomized control trial underway with higher risk patients b. PERIOP2 (NCT00432796): LMWH bridging therapy vs. placebo bridging
therapy for patients on long term warfarin requiring temporary interruption
Minor |17
II. Recommendations 1. Gaps in current literature include patients with the following risk factors:
a. CHADS2 > 5 b. Mechanical valves c. Stroke or TIA within the prior three months
2. Do not bridge patients in the absence of the above risk factors 3. Recommend bridging patients with any of the above risk factors 4. Continue oral anticoagulation in patients undergoing a very low bleeding risk procedure
(see appendix A) Table 27. Criteria for perioperative bridging Criteria Points Very low bleeding risk procedure
-4
CHADS2 > 5
1
Mechanical valve or Stroke or TIA within the prior three months
2
Very low bleeding risk procedures defined in appendix A.
Table 28. Perioperative bridging recommendations Score Recommendation ≤ -1 Recommend continuing oral anticoagulation, without bridging
0 Recommend against perioperative bridging with LMWH, unless significant
clinical factors suggest otherwise ≥ 1 Recommend perioperative bridging with LMWH
The above scoring system has not been prospectively validated and was developed for the purposes of
this lecture. It should not replace clinical judgement.
III. Additional considerations
1. Patients at an increased risk of TE
a. High procedural risk of TE (see appendix B)
b. Prior TE when anticoagulation withheld
c. Secondary indication for anticoagulation
2. Patients at an increased risk for hemorrhage
a. High procedural bleed risk (see appendix A)
b. Patients with high bleeding risk
c. Patients with an increased fall risk
3. Alternative strategies
a. Decreased duration of LMWH pre-operatively
b. Increased time till restarting LMWH post-operatively
c. Unconventional LMWH dosing
1. Fixed sub-therapeutic dosing (i.e. enoxaparin 40mg twice daily)
2. Prophylactic dosing (i.e. enoxaparin 40mg once daily)
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Appendices Appendix A. Associated bleeding risk of surgeries or procedures during perioperative antithrombotic drug administration 8,20,39,49,50 Very Low Low Moderate High Pacemaker or ICD implantation
Colonoscopy ± biopsy Invasive dental procedures
Aortic aneurysm repair
Catheter ablation Endodontics Invasive ophthalmic procedure
Bladder
Coronary angiography Endoscopy ± biopsy Major intraabdominal Bowel polypectomy Dental procedures Restorations Major intrathoracic Coronary artery bypass
grafting Dermatologic procedures
Laparoscopic cholecystectomy
Resection of colon polyps
Heart valve replacement
Cataract surgery Simple extractions Renal biopsy Intracranial Prosthetics Prostate biopsy Major cancer Hernia repair Peripheral artery
bypass or major vascular surgery
Major orthopedic Prostate Reconstructive plastic Spinal surgery/
epidural procedure Appendix B. Incidence of perioperative stroke by surgery type (%) 51-62
Surgery type Stroke risk (%) References General surgery 0.08-1.0 Bateman, 2009 Orthopedic surgery 0.2-0.9 Bateman, 2009 Non-carotid major vascular surgery 0.6 Sharifpour, 2013 Head and neck surgery 0.2-4.8 Nosan, 1993; Thompson, 2004 Carotid endarterectomy 1.4 Gupta, 2011 Coronary artery bypass grafting 1.2-2.3 Sezai, 2015 Valve surgery 1.4-6.5 O'Brien, 2009; Biancari, 2013 Thoracic endovascular aortic surgery 3.8 Ullery, 2012 Open thoracic surgery 5.4-5.8 Quintana, 2014; Higgins, 2014