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Mind the Gap: AF and the Evolving Strategies in Anticoagulation

In Cooperation with

Faculty Disclosures

Fred M. Kusomoto, MD, FACC

Mayo Clinic Consulting Fees/Honoraria: Medtronic

Ralph J. Verdino, MD, FACC

University of Pennsylvania Consulting Fees/Honoraria: Biosense Webster; Biotronic, Inc.; Boston Scientific; Medtronic; St. Jude Medical; Zoll

Officer, Director, Trustee or Other Fiduciary Role:

LifeWatch, Inc.

Acknowledgement

Boehringer Ingelheim Pharmaceuticals, Inc. is a Founding Sponsor for the

Mind the Gap Forums.

“Atrial Fibrillation is the Low Back Pain of Cardiology.”

Mike Crawford

Program Objectives

Upon completion of this session, attendees should be able to — • Implement evidence-based anticoagulation regimens for atrial fibrillation patients based on individual risks and patients’ preferences • Recognize common barriers associated with managing chronic anticoagulation in atrial fibrillation patients

Atrial Fibrillation (AF) in the U.S

2.2 million people have AF – 3.3 million in 2020; 5.6 million by 2050 – Above age 70: 10% incidence – Lifetime risk: 25% – Risk increases with increasing age

Future of Atrial Fibrillation

ATRIA Study

Projected Number of Adults With AF in the US 1995 to 2050

7.0

6.0

5.0

3.0

2.0

2.08

2.26

2.44

2.66

2.94

3.33

3.80

4.34

4.78

5.16

5.42

5.61

1.0

0 1990 1995 2000 2005 2010 2015 2020 2025 2030 2035 2040 2045 2050

Year

Go et al.

JAMA

. 2001;285;2370-2375.

Prevalence Incidence

Ann Int Med 1995

Biennial rate/1000 person exams Age

Benjamin EJ JAMA 1994; Framingham Heart Study

Atrial Fibrillation in the U.S. (Cont.)

Risks/causative factors: – HTN, DM, CHF, age, valvular heart disease, MI, pulmonary embolus, cardiomyopathy, pulmonary disease, hyperthyroidism – Genetics: Most common in “Lone AF” • Connexin-40 • Potassium channels: KCNQ1, KCNE2, KCNJ2, KCNH2 • ANF peptide frame shift mutation

Atrial Fibrillation (AF) and Stroke

• Stroke is the most common and devastating complication of AF 1,2 • Incidence of all-cause stroke in patients with AF is 5% 1 • AF is an independent risk factor for stroke 2 • Approximately 15% of all strokes in the US are caused by AF 3

1. Fuster V, et al. Circulation. 2006;114:e257-354. 2. Benjamin EJ, et al. Circulation. 1998;98:946-52.

3. Lloyd-Jones D, et al. Circulation. 2009;119:e21-181.

Stroke Rates in Placebo-Treated Patients With AF*

AFASAK SPAF BAATAF CAFA SPINAF EAFT † *This represents patients who are not anticoagulated; † Secondary prevention.

Hart et al.

Ann Intern Med.

1999;131:492-501.

Atrial Fibrillation and Stroke (Cont.)

• Risk of stroke increases with age 1 • Ischemic stroke associated with AF is often more severe than stroke of other etiologies 4 • Stroke risk persists even in asymptomatic AF 5 • Asymptomatic AF implicated as a cause of cryptogenic stroke 6

4. Dulli DA, et al. Neuroepidemiology. 2003;22:118-23. 5. Page RL, et al. Circulation. 2003;107:1141-5 6. Bhatt A, et al. Stroke Res Treat. 2011; 2011: 1-5

CHADS

2 Congestive heart failure Hypertension Age >75 years Diabetes mellitus Prior Stroke or TIA (*2 points) Gage, BF, et al.

JAMA

. 2001;285:2864-70

CHADS 2 Score 0 1 2 3 4 5 6

Stroke Risk in AF

ACP/AAFP Guidelines

Adjusted Stroke Rate

(95% CI) 1.9 (1.2-3.0) 2.8 (2.0-3.8

) 4.0 (3.1-5.1) 5.9 (4.6-7.3) 8.5 (6.3-11.1) 12.5 (8.2-17.5) 18.2 (10.5-27.4) * Expected rate of stroke per 100 patient-years CHADS 2 Risk Level Low Low Moderate Moderate High High High

Aspirin Aspirin/Warfari n Warfarin

Snow V, et al. Ann Intern Med. 2003;139:1009-17

CHADS

2 Congestive heart failure Hypertension Age >75 years Diabetes mellitus Prior Stroke or TIA (*2 points) Gage, BF, et al.

JAMA

. 2001;285:2864-70

CHADS

2 Congestive heart failure Hypertension Age >75 years Diabetes mellitus Prior Stroke or TIA (*2 points) CHADS 2 did not consider other important risk factors: – Female gender (not confirmed in all studies) – Thyrotoxicosis – LA size – HOCM – Valvular heart disease Gage, BF, et al.

JAMA

. 2001;285:2864-70

Lip et al Chest 2010

CHADS

CHA

DS

-VASc

Clinical Feature CHF HTN Age ≥ 75 Diabetes mellitus Stroke, TIA, or embolism Female gender Age 65 - 74 Vascular disease (prior MI, PVD, aortic plaque Points 1 1 2 1 2 1 1 1

CHADS

vs. CHA

DS

-VASc

Lip et al Chest 2010

CHA 2 DS 2 VAS c score 0 1 7 8 9 2 3 4 5 6 Adjusted stroke rate (%/year) Recommended antithrombotic therapy 0

ESC Guidelines for

1.3

ASA 75-325mg or no Either oral anticoagulation

Antithrombotic Therapy

2.2

Oral anticoagulation 3.2

4.0

6.7

9.8

9.6

6.7

15.2

Oral anticoagulation Oral anticoagulation Oral anticoagulation Oral anticoagulation Oral anticoagulation Oral anticoagulation Oral anticoagulation Europace 2010; 12: 1360-1420

Warfarin AFASAK BAATAF SPAF CAFA SPINAF

Stroke Prevention: Coumadin

Warfarin/ASA EAFT SPAF II AFASAK

Warfarin: Risk-Benefit Profile

20 15 Ischemic Stroke Intracranial Bleeding 10 5 1 1.0

2.0

3.0

4.0

INR

5.0

6.0

7.0

8.0

Fuster V, et al. Circulation. 2006;114:e257-354

Warfarin and Drug Interactions

Warfarin is metabolized by the hepatic P450 enzyme CYP2C9 Warfarin concentration (and therefore INR) is increased by drugs that inhibit CYP2C9. INR must be closely followed and warfarin dosage decreased CYP2C9 inhibitors include: • Amiodarone • Statins simvastatin and rosuvastatin (not atorvastatin, pravastatin) • • • Fibrates (fenofibrate, gemfibrozil) Antibiotics (sulfamethoxazole/trimethoprim, metronidazole) Azole antifungals (fluconazole, miconazole, voriconazole)

Warfarin and Drug Interactions (Cont.)

Drugs that induce CYP2C9 : warfarin’s effectiveness is decreased, reducing INR - Rifampin • Other drugs interactions not via CYP2C metabolism -

Thyroid hormone

For more information visit www.qtdrugs.org (Arizona CERT) or http://medicine.iupui.edu/clinpharm/ddis/table.asp (Indiana University, Prof D.A. Flockhart)

Quality of Warfarin Control in AF Patients on Chronic Anticoagulation

63% 55% 51%

Only 48% of eligible patients in this analysis received warfarin

Baker WL, et al. J Manag Care Pharm. 2009;15:244-52

Time Spent in Therapeutic INR Range and Clinical Outcomes

• • Groups stratified by time spent in therapeutic INR range (2.0-3.0) All patients had a CHADS 2 score ≥ 2

Morgan CL, et al. Thromb Res. 2009;124:37-41

Warfarin in Eligible Patients

ATRIA Study

<55 55-64 Go et al.

Ann Intern Med

. 1999;131:927-934.

65-74 75-84

Age (years)

 85 Overall

Warfarin in Eligible Patients

ATRIA Study

<55 55-64 Go et al.

Ann Intern Med

. 1999;131:927-934.

65-74 75-84

Age (years)

 85 Overall

ACTIVE-W: Warfarin vs. Dual Antiplatelet Therapy for Prevention of Cardiovascular Events Cumulative risk of primary composite endpoint

a RR = 1.44 (1.18-1.76), P = 0.0003

Time (years) a Stroke, MI, non-CNS systemic embolism, or vascular death .

ACTIVE Investigators. Lancet. 2006;367:1903-12

ACTIVE-A: Dual Antiplatelet Therapy Reduces the Incidence of Vascular Events in AF When Warfarin Therapy Is “Unsuitable ” Primary Composite Endpoint a

P = 0.01

Stroke

P < 0.001

Time (years) Time (years) a Stroke, MI, non-CNS systemic embolism, or vascular death

ACTIVE Investigators. N Engl J Med. 2009;360:2066-78

12 10 8 6 4 2 0 ACTIVE-A: Dual Antiplatelet Therapy Increases the Risk of Bleeding

Bleeding Events

P<0.001

Major Bleeding ASA Minor Bleeding ASA+clopidogrel Any Bleeding

2011 Focused Update Recommendation • Class IIb (New Recommendation) • The addition of clopidogrel to aspirin (ASA) to reduce the risk of major vascular events, including stroke, might be considered in patients with AF in whom oral anticoagulation with warfarin is considered unsuitable due to patient preference or the physician’s assessment of the patient’s ability to safely sustain anticoagulation. (Level of Evidence: B) • Single reference: ACTIVE A 2011 ACCF/AHA/HRS Focused Update on the Management of Patients with Atrial Fibrillation (Updating the 2006 Guideline). Circulation 2011;123:104-123 .

New Pharmacologic Approaches for Stroke Reduction in AF

Oral direct thrombin inhibitors – Fixed-dose, no monitoring • Dabigatran Oral factor Xa inhibitors – Fixed-dose, no monitoring • Apixaban • Edoxaban • Rivaroxaban

Antithrombotic Therapy in Atrial Fibrillation. Circulation 2011;75:1539-1547 .

Direct Thrombin Inhibitors

Ximelagatran – Tested in Stroke Prevention Using an Oral Thrombin Inhibitor in Atrial Fibrillation (SPORTIF) III (open label) and V (double blind) – Ximelagatran as effective as warfarin with lower risk of bleeding – Did not make it to market due to liver toxicity

RE-LY:

Randomized Evaluation of Long term Anticoagulation Therapy • 18,113 patients with atrial fibrillation randomized to dabigatran (110 mg or 150 mg twice daily) versus warfarin (INR target 2.0-3.0) • Mean CHADS 2 score = 2.1

• By intention-to-treat analysis dabigatran 110 mg was non-inferior (p < 0.001) while dabigatran 150 mg was superior( p<0.001) to warfarin • INR was in the therapeutic range 64% of the time NEJM 10.1056

RE-LY

“ High risk” AF patients: – At least one of: • Prior CVA or TIA • LVEF < 40%; • NYHA Class I or greater CHF • Age >75 yrs • Age 65-74 and on of: – DM – HTN – CAD Exclusions: “severe valve disease;” CVA <14 days or “severe CVA” <6 months; increased bleeding risk; active liver disease; CrCl <30; pregnancy

RE-LY: Dabigatran Reduces the Risk of Stroke in AF Patients

Time (months

)

Connolly SJ, et al. N Engl J Med. 2009;361:1139-51

RE-LY: Safety Outcomes with Dabigatran

Event Major bleeding Life threatening Gastrointestinal bleeding Major or minor bleeding Intracranial bleeding Dabigatran 110 mg vs. Warfarin RR (95% CI) P value 0.80 (0.69-0.93) 0.003

0.68 (0.55-0.83) < 0.001

1.10 (0.86-1.41) 0.43

0.78 (0.74-0.83) 0.31 (0.20-0.47) < 0.001

< 0.001

Dabigatran 150 mg vs. Warfarin RR (95% CI) P value 0.93 (0.81-1.07) 0.31

0.81 (0.66-0.99) 0.04

1.50 (1.19-1.89) < 0.001

0.91 (0.86-0.97) 0.40 (0.27-0.60) 0.002

< 0.001

Modified from Connolly SJ, et al. N Engl J Med. 2009;361:1139-51

FDA Approval for Dabigatran:

• Dabigatran 150 was superior to warfarin and dabigatran 110 mg for stroke prevention; • Dabigatran 150 mg was similar to warfarin for bleeding risk but inferior to dabigatran 110 mg.

• Among the elderly (40% of Re-Ly patients over age 75), thromboembolism risk was lower with dabi-150 than with dabi-110, but bleeding risk was higher. Because bleeding is “less undesirable” than stroke, dabi-110 not felt to be advantageous.

Beasley BN, Unger EF, Temple R. Anticoagulant Options – Why the FDA Approved a Higher but Not a Lower Dose of Dabigatran. NEJM 2011 (online first).

•

FDA Approval for Dabigatran:

75 mg q12h Among pts with impaired renal function (CrCl 30-50), stroke risk for dabi-150 was 1/2 that of dabi-110 but bleeding risk was not higher.

==> dabi-110 was not felt to offer any advantage, and it was felt that most patients should receive the higher dosage.

• The decision to approve the 75 mg q12h dose was based on pharmacokinetic and pharmacodynamic modeling; there is no safety or efficacy data.

Beasley BN, Unger EF, Temple R. Anticoagulant Options – Why the FDA Approved a Higher but Not a Lower Dose of Dabigatran. NEJM 2011 (online first).

Antithrombotic Therapy in Atrial Fibrillation. Circulation 2011;75:1539-1547 .

Apixaban: AVERROES Trial

5599 patients with AF deemed “unsuitable” for warfarin randomized to apixaban (5mg twice daily) or aspirin (81-324mg daily) Primary endpoint: stroke or systemic embolism Trial terminated early due to superiority of apixaban Apixaban Aspirin

P<0.001

P=0.07

1.6

3.7

stroke/embolism 3.5

4.4

Death

P=0.57

12.6

15.9

1.4

1.2

major bleeding CV hospitalization Connolly et al. NEJM 2011 364: 806-17

ROCKET-AF:

Rivaroxaban for the Prevention of Stroke and Non-CNS Embolism • 14,264 patients with atrial fibrillation randomized to rivaroxaban (20mg once daily) versus warfarin (INR target 2.5) • Mean CHADS 2 score = 3.5

• By intention-to-treat analysis rivaroxaban was non-inferior (p < 0.0001) but not superior ( p =0.12) to warfarin • INR was in the therapeutic range only 55 percent of the time • Currently before the FDA for AF indication • Safety: overall similar bleeding rates with less life threatening (fatal or intracranial) hemorrhage NEJM 10.1056

2011 ACCF/AHA/HRS Focused Update on the Management of Patients with Atrial Fibrillation (Update on Dabigatran)

Case 1

– 76-year-old Female with Dyspnea

• HPI – Shortness of breath and DOE for several months – Denies palpitations, chest pain, or dizziness • PMH – Obesity, diabetes, HTN, chronic kidney disease, hyperlipidemia, DJD – Does not smoke or drink – Meds: diltiazem, celecoxib, metformin, pravastatin

• PE – VS: BP 164/92, HR 94 – CV: irregularly irregular, no murmurs • Data – ECG: atrial fibrillation with controlled VR, LVH by voltage – BUN/Cr: 36/2.1, other labs incl LFTs nl – CXR: mild cardiomegaly, o/w normal – Stress echo: nl LV function, mild LVH, no sig valve dz, no ischemia

Question

What is her risk of stroke?

a) High (~8-18%) b) Medium (~4-6%) c) Low (~2-3%)

CHADS 2 Score 0 1 2 3 4 5 6

Stroke Risk in AF

ACP/AAFP Guidelines

Adjusted Stroke Rate

(95% CI) 1.9 (1.2-3.0) 2.8 (2.0-3.8) 4.0 (3.1-5.1) 5.9 (4.6-7.3) CHADS 2 Risk Level Low Low Moderate Moderate 8.5 (6.3-11.1) 12.5 (8.2-17.5) 18.2 (10.5-27.4) High High High

Aspirin Aspirin/ Warfarin Warfarin

* Expected rate of stroke per 100 patient-years Snow V, et al.

Ann Intern Med

. 2003;139:1009-17

CHA

DS

-VASc

Clinical Feature CHF HTN Age ≥ 75 Diabetes mellitus Stroke, TIA, or embolism Female gender Age 65 - 74 Vascular disease (prior MI, PVD, aortic plaque) Points 1 1 2 1 2 1 1 1

ESC Guidelines for Antithrombotic Therapy

CHA 2 DS 2 VAS c score 0 1 7 8 9 2 3 4 5 6 Adjusted stroke rate (%/year) Recommended antithrombotic therapy 0 ASA 75-325mg or no therapy. No therapy

ESC Guidelines for

1.3

Either oral anticoagulation

Antithrombotic Therapy

anticoagulation preferred 2.2

3.2

4.0

6.7

9.8

9.6

6.7

15.2

Oral anticoagulation Oral anticoagulation Oral anticoagulation Oral anticoagulation Oral anticoagulation Oral anticoagulation Oral anticoagulation Oral anticoagulation Europace 2010; 12: 1360-1420

Question

What is her risk of bleeding with anticoagulation?

a) High b) Medium c) Low

HAS-BLED Sc ore

Clinical Feature SBP ≥ 160 mmHg Abnormal renal function Abnormal liver function Prior CVA Bleeding Labile INRs Age > 65 Taking antiplatelets/NSAIDs Alcohol intake 1 1 1 1 Points 1 1 1 1 1 HAS BLED score ≥3 indicates increased one year risk of intracranial bleed, bleed requiring hospitalization, or drop in hemoglobin ≥2gm/L or requiring transfusion .

HAS-BLED score in the SPORTIF cohort

Lip et al JACC 2011 Score

Question

What is her risk of stroke/bleeding?

a) CHADS 2 score=3 (annual stroke risk=5.9%) b) CHADS2VASc=5 (annual stroke risk=6.7%) c) 3. HASBLED score=4 (annual bleeding risk=5.6%)

Question

Which anticoagulation regimen is most appropriate for her?

a) Aspirin b) Warfarin c) Dabigatran 75mg twice daily d) Dabigatran 150 mg twice daily e) Aspirin/clopidogrel

AF and Strokes

• • • 15% of ischemic strokes are due to cardioemboli => 75,000 events/year 45% of cardioemboli are due to atrial fibrillation Risk of stroke 5-7x increased in patients with atrial fibrillation

Which Anticoagulation Regimen is Most Appropriate for Her?

http://www.vhpharmsci.com/sparc/

Which Anticoagulation Regimen to Use?

http://www.vhpharmsci.com/sparc/

Which Anticoagulation Regimen to Use?

http://www.vhpharmsci.com/sparc/

• •

Case 1 Teaching Points

When using oral anticoagulants, balancing the risks of bleeding vs the risks of stroke can be difficult.

Scoring systems that predict risk (CHADS 2 , CHA 2 DS 2 Vasc, HASBLED) can help with decision making.

Questions and Answers

Case 2 – 59-year-old Man Presents with Acute Chest Pain

Past History

10 years ago first diagnosed with hypertension - 5 years ago acute inferior MI Cath showed - 95% RCA 70% LAD 90% OM1 Underwent CABG x3 - 6 month f/u - EF 40% by echo with inferior and posterior severe hypokinesia

Past History (Cont.)

4 years ago nuclear stress showed EF 35-40%, inferior and posterior scar without ischemia diminished functional status - 6 months ago maintained on Lisinopril 40 mgqd, Carvedilol 20 q12h, Aspirin 81mgqd, Simvastatin 40 mgqd, NYHA Class III CHF symptoms - 3 months ago presented on OV with atrial fibrillation with controlled rate; warfarin begun

Present Coronary Anatomy

Native coronaries 100% RCA 95% prox LAD 100% OM1 95% proximal LCx stenosis - Patent LIMA and LAD, graft to PDA - Occluded graft to OM1 - Placed on clopidogrel full dose aspirin and underwent PCI of LCx with bare metal stent

Question

What would you do next?

a) Continue warfarin indefinitely with aspirin, clopidogrel for one year b) Substitute dabigatran with aspirin, clopidogrel for one year c) Stop warfarin, aspirin and clopidogrel for one month and resume warfarin d) Stop warfarin, aspirin and clopidogrel for one month then add dabigatran

Triple Rx:

Bleeding and Mortality in a Danish Registry after MI Sorensen et al Lancet 2009

Question

What would you do next?

Guidelines for the Management of Atrial Fibrillation. European Heart Journal 2010; 31: 2369 - 2429 .

Risk Management: Stent Thrombosis vs. Bleeding vs. Stroke Faxon et al Hemostasis and Thrombosis 2011 .

• • •

Managing Risk

• • • Stent Thrombosis Discontinuing DAPT Procedural: TIMI < 3,

Discontinuing DAPT, residual dissection, bifurcations stents, incomplete stent apposition, stent length, proximal dz

Patient:

Malignancy, diabetes, renal failure

• Bleeding HAS-BLED • Stroke CHADS 2 or CHA 2 DS 2 -VASc

Risk Management: Stent Thrombosis vs. Bleeding vs. Stroke Faxon et al Hemostasis and Thrombosis 2011 .

• • •

Randomized Trials on Triple Therapy

ISAR-TRIPLE:

600 patients after DES will be randomized to either a short course (6 weeks) or long course (6 months), followed by aspirin and warfarin. 1 ° : Composite of death, MI, definite stent thrombosis, or major bleeding at 9 months

WOEST:

496 patients randomized oral anticoagulation and clopidogrel or triple therapy. 1 ° : Bleeding at 1 year

MUSICA-2:

304 patients (CHADS≤ 2) randomized to DAPT or triple Rx

Case 2 Teaching Points

• Choose BMS if patient will require anti thrombotic therapy long term • Presentation with ACS implies that patient should ideally be treated with dual anti-platelet therapy for 1 year but needs to be judged relative to bleeding risk • Data on triple therapy is limited • No data on dabigitran in this setting and nothing in guidelines

Questions and Answers

Mind the Gap: Summary

• Atrial fibrillation is going to become more common • Stroke is the most devastating complication of atrial fibrillation • Old and new options • Managing patients in “real life” is difficult

Case 3 – 80-year-old Male with Renal Cell Cancer

HPI Renal cell cancer recently diagnosed Nephrectomy is planned Urologic surgeon requests peri-op cardiac management PMH Permanent atrial fibrillation for > 5 years, managed with metoprolol and warfarin Meds: metoprolol, warfarin, lisinopril, pravastatin, aspirin

Physical Exam

VS: BP 134/68, HR 78 irreg irreg CV: irregularly irregular, no murmurs Data ECG: atrial fibrillation with controlled VR INR 2.3

Question In preparation for surgery, you should:

a)Admit the patient to the hospital, stop warfarin and administer IV heparin until the morning of surgery b)Stop warfarin 5 days prior to surgery and initiate LMWH until the morning of surgery c)Stop warfarin 5 days prior to surgery without bridging anticoagulation

Risks Associated with Temporary Discontinuation of Warfarin

• After warfarin is stopped, it takes about 4 days for the INR to reach 1.5.

• Once the INR is 1.5 surgery can be safely performed.

• Therefore, if warfarin is held 4 days before surgery and treatment is started as soon as possible after surgery, patients can be expected to have a subtherapeautic INR for two days before and two days after surgery.

ACC/AHA/ESC 2006 Guidelines for Perioperative Management of Atrial Fibrillation

• • Anticoagulation may be interrupted for a period of up to one week for surgery.

In high risk patients (prior stroke, TIA, or systemic embolism) unfractionated or low-molecular-weight heparin may be used.

ACCP 8 th Edition Evidence-Based Clinical Practice Guidelines: Managing Non-therapeutic INRs For patients with INRs of ≥ 5.0 but < 9.0 and no significant bleeding: –Omit the next one or two doses of warfarin –Monitor more frequently –Resume therapy at an appropriately adjusted dose when the INR is at a therapeutic level (Grade 1C) –Alternatively, omit a dose and administer 1 to 2.5 mg oral vitamin K, particularly if the patient is at increased risk of bleeding (Grade 2A)

Ansell J, et al. Chest. 2008;133:160S-98S

Peri-operative Management of Dabigatran • With normal kidney function, miss two doses of dabigatran before surgery.

• With impaired kidney function, miss 3-4 doses of dabigatran before surgery.

• If surgery carries a high risk of bleeding, consider stopping dabigatran 2 days before surgery with normal renal function and 3-5 days with impaired renal function.

Question

What would you do?

a) Initiate a rhythm control drug b) Discharge on beta-blocker alone

• •

Case 3 Teaching Points

Most patients, unless they have had prior stroke, TIA, or systemic embolism do not require bridging of anticoagulation.

Warfarin can be stopped for 5 days prior to surgery while dabigatran can be stopped just 1 2 days prior to surgery.