Mind the Gap: AF and Evolving Strategies in Anticoagulation

Fred M. Kusumoto, MD, FACCMayo Clinic

Tracy Y. Wang, MD, MHS, FACCDuke Clinical Research InstituteDuke University Medical Center

Faculty Disclosures

Fred M. Kusumoto, MD, FACCNothing to disclose

 Tracy Y. Wang, MD, FACCConsultant Fees/Honoraria: AstraZeneca; Medco Health Solutions

Research/Research Grants: Gilead; Canyon Pharmaceuticals; Daiichi Sankyo, Inc./Eli Lilly and Company; The Medicines Company

Acknowledgement

This activity is sponsored by Boehringer Ingelheim Pharmaceuticals, Inc. and Janssen Pharmaceuticals, Inc. 

Course 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

The Anticoagulation Initiative

• A multidisciplinary effort to identify and address gaps in the quality of anticoagulation care

• Purpose is to facilitate a greater understanding of AF treatments and practice patterns, particularly with the introduction of several new anticoagulants into the marketplace 

• This initiative is building on existing resources (i.e., the AFib Toolkit) and creating new resources (i.e., anticoagulation mobile app)

AnticoagEvaluator: An ACC Risk Assessment Tool

• Tool for estimating risk of stroke and benefits and risks of antithrombotic therapy in patients with chronic atrial fibrillation

• Combination risk calculator using CHADS2, CHA2DS2-VASc and HAS-BLED

• Enter patient characteristics and get individualized annual risk of ischemic stroke and thromboembolism with concurrent annual risk of major bleed

AnticoagEvaluator: An ACC Risk Assessment Tool

• Output presents antithrombotic therapy options including novel oral anticoagulants based on clinical trials (RE-LY, ROCKET-AF, ARISTOTLE)

• Email individual patient results after completing risk calculator tool 

• Based on the SPARCtool (http://sparctool.com/)

AnticoagEvaluator: Calculators

Enter patient characteristics into single screen to calculate risk of stroke and major bleed:

AnticoagEvaluator: Results Screen

Review risk assessment for each antithrombotic therapy option based on individual patient characteristics entered:

Instructions to Download

• Search “AnticoagEvaluator” in your app store or visit http://CardioSource.org/apps

• Available on iPad, iPhone and Android devices

• Anticoagulation Management Clinical Community

– Will feature relevant news articles, case challenges, hot topics, basics of anticoagulation, videos, interactive discussion, and more

– Launch in July 2013

The Anticoagulation Initiative: Coming Soon

The Anticoagulation Initiative: Coming Soon

• Atrial Fibrillation Shared Decision Making Tool – Patient-centered decision aid being developed in 

partnership with the Informed Medical Decisions Foundation

– Launching in Fall 2013

• Visit http://CardioSource.org/anticoagulation for more information

How many patients with atrial fibrillation do you typically see each week?

a) Fewer than 5b) 5-10c) 10-20d) More than 20

Question 1

What anticoagulants/antiplatelet agents do you most frequently use to prevent thromboembolic complications?

a) Aspirinb) Aspirin/clopidogrelc) Clopidogrel aloned) NOACs (novel oral anticoagulant)e) Warfarinf)  Other

Question 2

Over the last nine months, when appropriate for your atrial fibrillation patients, have you found yourself making any of the following changes? a) Switching some patients’ medication to a newer agentb) Switching most patients from existing medication to a newer agent

c) No change in prescribing pattern, current medication successful in treatment

d) No change in prescribing pattern, waiting for more data on newer agents

Question 3

What is the primary thing you might do differently in treating your AF patients? a) Increase my utilization of long-term anticoagulation in my at-risk atrial fibrillation patients

b) Work to better assess the thromboembolic risk in my atrial fibrillation patients

c) Explain to my patients the pros and cons of different anticoagulation agents

d) Better communicate the risk of stroke to my atrial fibrillation patients and the importance of anticoagulation

e) Nothing – I feel my level of patient care is appropriate

Question 4

What might impede you most from making this change? a) Time constraintsb) Low priority compared to other patient management issuesc) Difficulty in changing patient behavior d) Difficulty in getting patients to accept the benefits of long-term anticoagulation

e) Cost of medicationf) Cost of monitoring (blood tests, dosage adjustments) for patients on anticoagulation

g) Lack of data on or experience with newer agentsh) No change necessary

Question 5

A 72-year-old male with a history of persistent atrial fibrillation for the past five (5) years is currently being treated with warfarin anticoagulation and a beta blocker for rate control. He comes to you to ask about switching to a new anticoagulant drug that does not require INR monitoring.  

 

Question 6

Given the following patient characteristics, in which setting would switching from warfarin to a Novel Oral Anticoagulant (NOAC) be appropriate and supported by clinical data?

a) Ejection fraction of 30% with Class II heart failure

b) Normal functioning mechanical MVR 

c) LVH with EF 55%; chronic renal insufficiency with creatinine clearance 10 ml/min

Question 6 (Cont.)

• 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

Atrial Fibrillation (AF) in the U.S.

Ann Int Med 1995

Prevalence

Benjamin EJ JAMA 1994; Framingham Heart Study

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.

Atrial Fibrillation and Stroke

• 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

• Risk of stroke increases with age1

• Ischemic stroke associated with AF is often more severe than stroke of other etiologies4

• Stroke risk persists even in asymptomatic AF5

• Asymptomatic AF implicated as a cause of cryptogenic stroke6

Atrial Fibrillation and Stroke (Cont.)

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

CHADS2

• Congestive heart failure• Hypertension• Age >75 years• Diabetes mellitus• Prior Stroke or TIA (*2 points)

Gage, BF, et al. JAMA. 2001;285:2864-70

Stroke Risk in AF ACP/AAFP Guidelines

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

*Expected rate of stroke per 100 patient-years

CHA2DS2-VASc

ESC Guidelines for Antithrombotic Therapy

Europace 2010; 12: 1360-1420European Heart Journal (2012) 33, 2719–2747

Stroke Prevention: Coumadin

Warfarin

•AFASAK

•BAATAF

•SPAF

•CAFA

•SPINAF

Warfarin/ASA

•EAFT

•SPAF II

•AFASAK

Warfarin: Risk-Benefit Profile

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)

•     

Quality of Warfarin Control in AF Patients on Chronic Anticoagulation

Baker WL, et al. J Manag Care Pharm. 2009;15:244-52.Only 48% of eligible patients in this analysis received warfarin

Time Spent in Therapeutic INR Range and Clinical Outcomes

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

Warfarin and Novel Anticoagulant Mechanisms of Action

Courtesy of David Garcia, MD*This information includes a use that has not been approved by the U.S. FDA

Case 1

67-year-old Female with Dyspnea

• HPI– Shortness of breath and DOE for several months– Denies palpitations, chest pain or dizziness

• PMH– Obesity, carotid artery disease s/p CEA, hyperlipidemia, 

DJD– Does not smoke or drink– Meds: diltiazem, celecoxib, pravastatin, aspirin

• PE– VS: BP 134/72, HR 94 – CV: irregularly irregular, no murmurs

• Data– ECG: atrial fibrillation with controlled VR– BUN/Cr: 36/2.1, GFR 23 ml/min, other labs incl LFTs nl– CXR: mild cardiomegaly, o/w normal– Stress echo: nl LV function, mild LVH, no sig valve dz, no 

ischemia

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

What is her risk of stroke?

Question

Stroke Risk in AFACP/AAFP Guidelines

*Expected rate of stroke per 100 patient-years

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

CHA2DS2-VASc

ESC Guidelines for Antithrombotic Therapy

Europace 2010; 12: 1360-1420European Heart Journal (2012) 33, 2719–2747

a) Highb) Mediumc) Low

What is her risk of bleeding with anticoagulation?

Question

HAS-BLED Score

HAS-BLED score ≥3 indicates increased one year risk of intracranial bleed, bleed requiring hospitalization, or drop in hemoglobin ≥2gm/L or requiring transfusion.

Impact of the CHA2DS2-VASc Score on Anticoagulation Recommendations for Atrial FibrillationPamela K. Mason, MD, Douglas E. Lake, PhD, John P. DiMarco, MD, PhD, John D. Ferguson, MBChB, MD, J. Michael Mangrum, MD, Kenneth Bilchick, MD, Liza P. Moorman, RN, ACNP-BC, J. Randall Moorman, MD University of Virginia Health System, Charlottesville.

Figure 2 Anticoagulation recommendations by CHADS2 and CHA2-DS2-VASc scores in women (A) and men (B).The American Journal of Medicine 2012 125, 603.e4

What is her risk of stroke/bleeding?

a) CHADS2 score = 0 (annual stroke risk = 1.9%)b) CHA2DS2VASc = 3 (annual stroke risk = 3.2%)c) HASBLED score = 3 (annual bleeding risk = 5.6%)

Question

Which anticoagulation regimen is most appropriate for her?

a) Aspirinb) Warfarinc) NOACd) Aspirin/clopidogrel

Question

Which Anticoagulation Regimen Is Most Appropriate for Her?

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

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

Which Anticoagulation Regimen to Use?

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

Which Anticoagulation Regimen to Use?

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 (CHADS2, CHA2DS2-VASc, HAS-BLED) can help with decision making

Practice Innovation and Clinical Excellence (PINNACLE) Registry

• 9,113 patients from 20 practices in 51 office locations

• Mean CHADS2 score: 2.5 (moderate-to-high risk)

• All eligible for warfarin

Chan PS, et al. Am J Cardiol. 2011;108:1136-1140.

PINNACLE Results

• 55.1% treated with warfarin regardless of CHADS2 score

• 44.9% not treated with warfarin:

– 50.8% treated with aspirin only

– 4.4% treated with thienopyridine alone

– 10.1% treated with aspirin and thienopyridine

– 34.7% received no antithrombotic treatment

Chan PS, et al. Am J Cardiol. 2011;108:1136-1140.

PINNACLE: Percent of Patients on Warfarin (Practice Level)

52Chan PS, et al. Am J Cardiol. 2011;108:1136-1140.

PINNACLE Coverage by Zip Code

US Population Density

Records from 1,000+ physicians at 280+ sites

Florida practice performance varies with national averages

• 7,618 patients with non-valvular AF documented in most recently available 12 months

• 53.8% performance on anticoagulation for afib patients (compared with 49.5% nationally) Overall representation

- 8 data-submitting practices- 17 clinical care locations - 69 providers- Record type

 

Questions and Answers

ACTIVE-W: Warfarin vs. Dual Antiplatelet Therapy for Prevention of Cardiovascular Events

Cumulative risk of primary composite endpointa

aStroke, 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”

aStroke, I, non-CNS systemic embolism or vascular death

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

ACTIVE-A: Dual Antiplatelet Therapy Increases the Risk of Bleeding

P<0.001

• 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.

2011 Focused Update Recommendation

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• Rivaroxaban• (Edoxaban)

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 CHADS2  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

• AF Patients with 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)

Cum

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

RE-LY: Safety Outcomes with Dabigatran

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

FDA Approval for Dabigatran:

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).

• 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

FDA Approval for Dabigatran:75 mg q12h

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).

• 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

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

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 CHADS2  score = 3.5

• By intention-to-treat analysis rivaroxaban was non-inferior (p < 0.0001) but not superior (p = 0.12) to warfarin

NEJM 10.1056

Cumulative Rates of the Primary End Point (Stroke or Systemic Embolism) in the Intention-to-Treat Population

ROCKET-AF: Rivaroxaban for the Prevention of Stroke and Non-CNS Embolism

• INR was in the therapeutic range only 55 percent of the time

• Approved by FDA 

• Safety: overall similar bleeding rates with less life-threatening (fatal or intracranial) hemorrhage

• Phase III randomized, double-blind trial

• Apixaban 5 mg bid vs warfarin for stroke prevention in 18,201 patients with AF and at least 1 additional risk factor for stroke

• Randomized to apixaban 5 mg bid (n = 9120) or warfarin (target INR 2.0-3.0) (n = 9081)

• Primary efficacy outcome – stroke or systemic embolism

• Primary safety outcome – major bleeding

Granger CB et al. N Engl J Med 2011 Aug 27. [Epub ahead of print] 

ARISTOTLE

Primary OutcomeStroke (ischemic or hemorrhagic) or systemic embolism

No. at RiskApixaban 9120 8726 8440 6051 3464 1754Warfarin 9081 8620 8301 5972 3405 1768

Granger CB et al. N Engl J Me 2011 Aug 27. [Epub ahead of print]   Duke Clinical Research Institute and Uppsala Clinical Research Center

Efficacy Outcomes

* Part of sequential testing sequence preserving the overall type I errorGranger CB et al. N Engl J Med 2011 Aug 27. [Epub ahead of print] 

  Duke Clinical Research Institute and Uppsala Clinical Research Center

Major BleedingISTH definition

No. at RiskApixaban 9088 8103 7564 5365 3048 1515Warfarin 9052 7910 7335 5196 2956 1491

Granger CB et al. N Engl J Med 2011 Aug 27. [Epub ahead of print]   Duke Clinical Research Institute and Uppsala Clinical Research Center

Bleeding Outcomes

* Part of sequential testing sequence preserving the overall type I error

Granger CB et al. N Engl J Med 2011 Aug 27. [Epub ahead of print]   Duke Clinical Research Institute and Uppsala Clinical Research Center

Conclusions

Treatment with apixaban as compared to warfarin in patients with AF and at least one additional risk factor for stroke:

• Reduces stroke and systemic embolism by 21% (p=0.01)

• Reduces major bleeding by 31% (p<0.001)

• Reduces mortality by 11% (p=0.047)

with consistent effects across all major subgroups and with fewer study drug discontinuations on apixaban than on warfarin, consistent with good tolerability.

Granger CB et al. N Engl J Med 2011 Aug 27. [Epub ahead of print]   Duke Clinical Research Institute and Uppsala Clinical Research Center

Summary of Clinical Trials

New Anticoagulant Therapies Compared to WarfarinStroke or Systemic Embolism

Connolly S et al NEJM 2009; Patel M et al NEJM 2011; Granger CB et al NEJM 2011

New Anticoagulant Therapies Compared to WarfarinMajor Bleeding

Connolly S et al NEJM 2009; Patel M et al NEJM 2011; Granger CB et al NEJM 2011

New Anticoagulant Therapies Compared to WarfarinIntracranial Hemorrhage

Connolly S et al NEJM 2009; Patel M et al NEJM 2011; Granger CB et al NEJM 2011

Conclusion

• Compared to warfarin, the novel oral anticoagulants are at least as good at preventing stroke, have half the rate of ICH, appear to have 10% lower mortality and are easier to use

• But many practical issues are important in their safe use, including

– Adjusting for renal dysfunction

– Understanding how to measure their effect 

– Understanding how to manage procedures

– Understanding how to manage bleeding

– Avoiding aspirin without clear indication 

• Having protocols in place to guide rationale use of the novel drugs is a high priority

www.escardio.org/guidelines

European Heart Journal 2012; 33:2719-2747 – doi:10.1093/eurheartj/ehs253

European Society of Cardiology Recommendations

Case 2

80-year-old Male with Cholelithiasis

HPI

Cholelithiasis recently diagnosed

Cholecystectomy is planned

Surgeon requests peri-op cardiac management

PMH

Permanent atrial fibrillation for > 5 years, managed with 

metoprolol and dabigatran

Meds:  metoprolol, dabigatran, lisinopril, pravastatin

VS: BP 134/68, HR 78 irreg irreg

CV: irregularly irregular, no murmurs

ECG: atrial fibrillation with controlled VR

BUN/Cr – 34/1.2 (estimated creatinine clearance = 70)

Physical Exam

In preparation for surgery, you should:

a) Admit the patient to the hospital, stop dabigatran and administer IV heparin until the morning of surgery

b) Stop dabigatran 7 days prior to surgery and check INR on the morning of surgery

c) Stop dabigatran 2 days prior to surgery and check aPTT on the morning of surgery

Question

Pharmacokinetics of Dabigatran

• Disappearance curve of drug depends upon CrCl

• When CrCl >80 ml/min drug effect mostly gone at 24 hours with 150 mg dose as reflected by PTT

• When CrCl <30 ml/min drug effect about 50% at 48 hours at 75mg dose

• Disappearance of drug can be followed by aPTT

• Time for discontinuation depends upon nature of surgery

• Can be dialysed with removal of 60% of drug in 2-3 hours

• No specific antidote

Copyright American Heart AssociationWeitz J I et al. Circulation 2012;126:2428-2432

Average Time Course for Effects of Dabigatran on Activated Partial Thromboplastin Time (aPTT), Following Dabigatran Dosing Regimens in Patients with Normal Renal Function and Various Degrees of Renal Impairment

Weitz J I et al. Circulation 2012;126:2428-2432Copyright © American Heart Association

Proposed Algorithm for Periprocedural Management of Dabigatran

* In some countries, dabigatran is contraindicated in patients with CrCl <30 mL/min

Now let’s assume that the patient is taking warfarin instead of dabigatran…

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

Question

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

Outcomes of Temporary Interruptions

Adverse Events Caused or Prevented by Intravenous Heparin

Kearon C, Hirsh J. N Engl J Med 1997;336:1506-1511.

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

Case 2 Teaching Points Warfarin

• 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

Case 2 Teaching Points Dabigatran• With normal kidney function, omit 2-3 doses for low risk 

surgery and 4-5 doses for higher risk surgery

• With GFR 30-50, omit for 1.5-2 days (3-4 doses) for low risk surgery 

• With GFR 30-50, omit for 3-4 days (6-8 doses) for higher risk surgery

Guide to the Management ofBleeding in Patients Taking NOAC

Hankey GJ and Eikelboom JW. Circulation. 2011; 123: 1436-1450

Circulation. 2011;124:1573-1579

Rivaroxaban Dabigatran

 

Questions and Answers

A 72-year-old male with a history of persistent atrial fibrillation for the past five (5) years is currently being treated with warfarin anticoagulation and a beta blocker for rate control. He comes to you to ask about switching to a new anticoagulant drug that does not require INR monitoring.   

Question 6 - Post Test Question

Given the following patient characteristics, in which setting would switching from warfarin to dabigatran, rivaroxaban or apixaban be appropriate and supported by clinical data? a) Ejection fraction of 30% with Class II heart failure

b) Normal functioning mechanical MVR 

c) LVH with EF 55%; chronic renal insufficiency with creatinine clearance 10 ml/min

Question 6 (Cont.)

The RE-LY trial showed that:• dabigatran 150 mg BID was superior to warfarin in terms of 

embolic events• dabigatran 110 mg BID dose was superior to warfarin in 

terms of major bleeding

The Rocket-AF trial showed that:• rivaroxaban was non-inferior to warfarin by intention-to-

treat and superior by on treatment analysis in preventing embolic events

• bleeding risk was similar

ARISTOTLE showed that:• apixaban was superior to warfarin in preventing embolic 

events with a reduced bleeding risk

Rationale

 Rationale

ANSWER A: Ejection fraction of 30% with Class II heart failure is the correct answer

− Patients in the three trials included those with a low ejection fraction and heart failure

− Patients with a mechanical MVR were excluded and thus efficacy of  novel anti-coagulants is not known in these patients

− Patients with a creatinine clearance of 10 ml/min should not have these drugs since they are excreted by the kidney

− Patients with liver dysfunction and an elevated prothrombin time should not be given these agents due to high risk of bleeding 

 

Questions and Answers

Case 2

80-year-old Male with Cholelithiasis

HPI

Cholelithiasis recently diagnosed

Cholecystectomy is planned

Surgeon requests peri-op cardiac management

PMH

Permanent atrial fibrillation for > 5 years, managed with 

metoprolol and dabigatran

Meds:  metoprolol, dabigatran, lisinopril, pravastatin

VS: BP 134/68, HR 78 irreg irreg

CV: irregularly irregular, no murmurs

ECG: atrial fibrillation with controlled VR

BUN/Cr – 34/1.2 (estimated creatinine clearance = 70)

Physical Exam

In preparation for surgery, you should:

a) Admit the patient to the hospital, stop dabigatran and administer IV heparin until the morning of surgery

b) Stop dabigatran 7 days prior to surgery and check INR on the morning of surgery

c) Stop dabigatran 2 days prior to surgery and check aPTT on the morning of surgery

Question

Pharmacokinetics of Dabigatran

• Disappearance curve of drug depends upon CrCl

• When CrCl >80 ml/min drug effect mostly gone at 24 hours with 150 mg dose as reflected by PTT

• When CrCl <30 ml/min drug effect about 50% at 48 hours at 75mg dose

• Disappearance of drug can be followed by aPTT

• Time for discontinuation depends upon nature of surgery

• Can be dialysed with removal of 60% of drug in 2-3 hours

• No specific antidote

Copyright American Heart AssociationWeitz J I et al. Circulation 2012;126:2428-2432

Average Time Course for Effects of Dabigatran on Activated Partial Thromboplastin Time (aPTT), Following Dabigatran Dosing Regimens in Patients with Normal Renal Function and Various Degrees of Renal Impairment

Weitz J I et al. Circulation 2012;126:2428-2432Copyright © American Heart Association

Proposed Algorithm for Periprocedural Management of Dabigatran

* In some countries, dabigatran is contraindicated in patients with CrCl <30 mL/min

Copyright © American Heart AssociationGallego P et al. Circulation 2012;126:1573-1576

Bridging Algorithm for New Oral Anticoagulants

Now let’s assume that the patient is taking warfarin instead of dabigatran…

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

Question

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

Outcomes of Temporary Interruptions

Adverse Events Caused or Prevented by Intravenous Heparin

Kearon C, Hirsh J. N Engl J Med 1997;336:1506-1511.

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 8th 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.

Copyright © American Heart AssociationGallego P et al. Circulation 2012;126:1573-1576

Bridging Algorithm for Vitamin K Antagonists

Case 2 Teaching Points Warfarin

• 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

Case 2 Teaching Points Dabigatran• With normal kidney function, omit 2-3 doses for low risk 

surgery and 4-5 doses for higher risk surgery

• With GFR 30-50, omit for 1.5-2 days (3-4 doses) for low risk surgery 

• With GFR 30-50, omit for 3-4 days (6-8 doses) for higher risk surgery

Guide to the Management ofBleeding in Patients Taking NOAC

Hankey GJ and Eikelboom JW. Circulation. 2011; 123: 1436-1450

Circulation. 2011;124:1573-1579

Rivaroxaban Dabigatran

Weitz J I et al. Circulation 2012;126:2428-2432*Recommendations are based on limited nonclinical data only.

Proposed Algorithm for Management of Moderate-to-Severe Bleeding and Life-Threatening Bleeding Episodes in Patients Treated with Dabigatran

 

Questions and Answers

Case 3

55-year-old Man with Hypertension and

NIDDM Who Presents with Palpitations

• Echo – mildly dilated LA

• Mild LVH

• Mild diastolic dysfunction

• Patient cardioverted to NSR after TEE demonstrated no thrombus

• Started on warfarin, switched from amlodipine to metoprolol for BP control and AF suppression

Noted to Have AF with Rapid Rate

• Cardioverted and begun on Sotalol 80 mg q/12

• Metoprolol stopped, Amlodipine restarted

• One month f/u admitted with recurrent atrial fibrillation and in retrospect complains of severe fatigue

• After weighing options, patient underwent Pulmonary Vein Isolation for atrial fibrillation                             

• Remained on Sotalol for 2 months which was then stopped 

• He returns to your office and wishes to be taken off warfarin

3 Months Later, Patients with Rapid AF

a) Do a 24 hr Holter and if negative for atrial fibrillation stop warfarin

b) Do a 2 week ambulatory telemetry monitor and if negative stop warfarin

c) Urge him strongly to continue warfarind) Substitute newer agent

What would you do?

Question

Rhythm Control

≠

Anticoagulation/Stroke Prevention

Case 3 Teaching Points

• Discontinuation of warfarin is potentially hazardous in such patients since they may be minimally symptomatic or asymptomatic and remain at risk of stroke

 

Questions and Answers

Case 4

55-year-old Woman with

3-year History of Atrial Fibrillation

• Echo – normal• Not hypertensive, diabetic, pft’s normal• Discharged with ambulatory cardiac telemetry device• Noted to have multiple episodes of asymptomatic atrial 

fibrillation up to 4 hours in duration  • Atrial fibrillation burden 20% of monitoring period

3 Years Ago Presented with TIA Noted to Be in NSR

a) Initiate a rhythm control drug

b) Discharge on beta-blocker alone

What would you do?

Question

Patient begun on beta-blocker, warfarin, no symptomatic

episode, 24-hour Holter showed no atrial fibrillation

What would you do?

a) Stop anticoagulation

b) Stop beta-blocker

c) Continue regimen

Question

In reviewing INR’s – they vary widely and she complains that

blood tests are inconvenient and generally shows up once a

month for INR’s

What would you do?

a) Attempt rhythm control drug and eliminate A/C

b) Recommend a point of service monitor

c) Stop A/C since she had no current TIA’s

d) Consider dabigatran, rivaroxaban or apixaban

Question

What do you think the barriers are to regular INR testing?

a) Fear of testing

b) Remembering

c) Understanding importance

d) Inconvenience

e) Cost

f) Other

Question

What Do You Think the Barriers Are to Regular INR Testing?

Warfarin Control Is Improved with the Use of an Internet-Based Patient Self-Testing System

Ryan F, et al. J Thromb Haemost. 2009;7:1284-90.

Case 4 Teaching Points

• 24 Hour Holter Monitor is hardly adequate to assure she’s free of AF

• AF was asymptomatic to begin with• Rhythm control drug doesn’t assure stroke risk has 

been eliminated nor does the lack of recurrent TIAs

 

Questions and Answers