Anticoagulation for Atrial Fibrillation: Who, When, and How?

August 17, 2013Elaine M. Hylek, MD, MPH

Boston University School of Medicine

Disclosures

Employment No conflict of interest to disclose

Research support NIH/NINDS, NIH/NHLBI; Bristol-Myers Squibb-Executive Steering Committee; ARISTOTLE trial; Janssen-Executive Steering Committee; ORBIT-AF Registry

Scientific advisory board Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Johnson & Johnson, Pfizer

Consultancy No conflict of interest to disclose

Speakers bureau No conflict of interest to disclose

Major stockholder No conflict of interest to disclose

Patents No conflict of interest to disclose

Honoraria Bayer, Boehringer-Ingelheim, Pfizer

Travel support No conflict of interest to disclose

Other No conflict of interest to disclose

Disclosures of Elaine Hylek

Hesse, B. et al. Circulation 2006;113:e456-457e

TEE depicting a large LAA thrombus attached to the lateral wall

Stanford Stroke Center, Albers G

Stanford Stroke Center, Albers G

Prevalence of AF by Age

Feinberg WM. Arch Intern Med. 1995;155(5):469–473

HAZARDS OF WARFARIN

Budnitz D et al. N Engl J Med 2011;365:2002–12

HAZARDS OF WARFARIN

Budnitz D et al. N Engl J Med 2011;365:2002–12

Efficacy and Safety Data for

Target-Specific Oral Anticoagulants

0.01

0.02

0.03

0.05

0.04

Cum

ulat

ive

haza

rd r

ates

RR 0.91(95% CI: 0.74–1.11)

p<0.001 (noninferiority)p=0.34 (superiority)

RR 0.66(95% CI:

0.53–0.82)p<0.001

(superiority)

Years0 0.5 1.0 1.5 2.0 2.5

0.0

WarfarinDabigatran etexilate 110 mgDabigatran etexilate 150 mg

RE-LY: Time to First Stroke/SEE

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

RRR34%

1.11%

1.69%

1.53%

RE-LY Primary Efficacy Outcome Stroke and non-CNS Embolism

Connolly SJ., et al. NEJM Aug 30th 2009. DOI 10.1056/NEJMoa0905561

RR 0.26 (95% CI: 0.14–0.49)p<0.001 (sup)

Hemorrhagic stroke

Connolly SJ., et al. NEJM published online on Aug 30th 2009. DOI 10.1056/NEJMoa0905561

RR 0.31 (95% CI: 0.17–0.56)p<0.001 (sup)

Num

ber o

f eve

nts

6,015 6,076 6,022

1412

45

0

10

20

30

40

50

D110 mg BID D150 mg BID Warfarin

0.10%

0.38%RRR69%

RRR74%

0.12%

Dabigatran Etexilate vs Warfarin (RE-LY)

October 19, 2010

FDA Approves Pradaxa to Reduce the Risk of Stroke in Patients with Non-Valvular Atrial

Fibrillation

PRADAXA 150 mg BID-higher rate of major (GI) bleeds and any GI bleeds compared to warfarin.

In patients ≥75 years of age, the risk of major bleeding may be greater with PRADAXA than with

warfarin.

  Rivaroxaban Warfarin    Event Rate

Event Rate

HR(95% CI) P-value

On TreatmentN= 14,143

1.70 2.15 0.79 (0.65,0.95)  0.015

ITTN= 14,171 2.12 2.42 0.88 

(0.74,1.03)  0.117

Rivaroxabanbetter

Warfarinbetter

ROCKET-AF Primary Efficacy Outcome Stroke and non-CNS Embolism

Event Rates are per 100 Patient-yearsBased on Safety on Treatment or Intention-to-Treat thru Site Notification

PopulationsPatel et al. NEJM 2011;365:883-91

Key Secondary Efficacy OutcomesRivaroxaban Warfarin

Event Rate Event Rate HR (95% CI) P-value

Vascular Death, Stroke, Embolism 3.11 3.63 0.86 (0.74, 0.99) 0.034

Stroke Type Hemorrhagic Ischemic Unknown Type

0.261.340.06

0.441.420.10

0.59 (0.37, 0.93)0.94 (0.75, 1.17)0.65 (0.25, 1.67)

0.0240.5810.366

Non-CNS Embolism 0.04 0.19 0.23 (0.09, 0.61) 0.003

Myocardial Infarction 0.91 1.12 0.81 (0.63, 1.06) 0.121

All Cause Mortality Vascular Non-vascular Unknown Cause

1.871.530.190.15

2.211.710.300.20

0.85 (0.70, 1.02)0.89 (0.73, 1.10)0.63 (0.36, 1.08)0.75 (0.40, 1.41)

0.0730.2890.0940.370

Patel et al. NEJM 2011;365:883-91

Rivaroxaban WarfarinEvent Rate or N (Rate)

Event Rate or N (Rate)

HR (95% CI)

P-value

Major >2 g/dL Hgb drop Transfusion (> 2 units)

Critical organ bleeding Bleeding causing death

3.602.771.650.820.24

3.452.261.321.180.48

1.04 (0.90, 1.20)1.22 (1.03, 1.44)1.25 (1.01, 1.55)0.69 (0.53, 0.91)0.50 (0.31, 0.79)

0.5760.0190.0440.0070.003

Intracranial Hemorrhage 55 (0.49) 84 (0.74) 0.67 (0.47, 0.94) 0.019

Intraparenchymal 37 (0.33) 56 (0.49) 0.67 (0.44, 1.02) 0.060

Intraventricular 2 (0.02) 4 (0.04)

Subdural 14 (0.13) 27 (0.27) 0.53 (0.28, 1.00) 0.051

Subarachnoid 4 (0.04) 1 (0.01)

Event Rates are per 100 patient-years Based on Safety on Treatment Population

Safety Outcomes Rivaroxaban

Primary OutcomeStroke (ischemic or hemorrhagic) or systemic embolism

Apixaban 212 patients, 1.27% per year Warfarin 265 patients, 1.60% per yearHR 0.79 (95% CI, 0.66–0.95); P (superiority)=0.011

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

P (non-inferiority)<0.00121% RRR

Granger C et al. NEJM 2011;365:981–92

Efficacy Outcomes

Outcome

Apixaban(N=9120)

Warfarin(N=9081)

HR (95% CI) P ValueEvent Rate

(%/yr)Event Rate

(%/yr)Stroke or systemic embolism* 1.27 1.60 0.79 (0.66, 0.95) 0.011

Stroke 1.19 1.51 0.79 (0.65, 0.95) 0.012

Ischemic or uncertain 0.97 1.05 0.92 (0.74, 1.13) 0.42

Hemorrhagic 0.24 0.47 0.51 (0.35, 0.75) <0.001

Systemic embolism (SE) 0.09 0.10 0.87 (0.44, 1.75) 0.70

All-cause death* 3.52 3.94 0.89 (0.80, 0.998) 0.047

Stroke, SE, or all-cause death 4.49 5.04 0.89 (0.81, 0.98) 0.019

Myocardial infarction 0.53 0.61 0.88 (0.66, 1.17) 0.37

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

Granger C et al. NEJM 2011;365:981–92

Bleeding Outcomes

Outcome

Apixaban(N=9088)

Warfarin(N=9052)

HR (95% CI) P ValueEvent Rate(%/yr)

Event Rate(%/yr)

Primary safety outcome: ISTH major bleeding* 2.13 3.09 0.69 (0.60, 0.80) <0.001

Intracranial 0.33 0.80 0.42 (0.30, 0.58) <0.001

Gastrointestinal 0.76 0.86 0.89 (0.70, 1.15) 0.37Major or clinically relevant

non-major bleeding4.07 6.01 0.68 (0.61, 0.75) <0.001

GUSTO severe bleeding 0.52 1.13 0.46 (0.35, 0.60) <0.001

TIMI major bleeding 0.96 1.69 0.57 (0.46, 0.70) <0.001

Any bleeding 18.1 25.8 0.71 (0.68, 0.75) <0.001

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

CHADS 2 score = 0 No therapy rather than antithrombotic therapy (Grade 2B)

CHADS 2 score = 1 Oral anticoagulation rather than no therapy or antiplatelet therapy (Grade 1B)

CHADS 2 score = 2 Oral anticoagulation rather than no therapy or other therapies (Grade 1A)

For recommendations in favor of oral AC, we suggest dabigatran 150 mg twice daily rather than VKA therapy (Grade 2B)

You JJ et al. Chest 2012;141(2 Suppl):e531S-75S. PMID: 22315271

ACCP Recommendations for Stroke Prevention Therapy

ESC 2012UPDATE

GUIDELINESFor

ATRIALFIBRILLATION

Camm J et al. Eur Heart J 2012;33:2719–47

2011 ACCF/AHA/HRS Focused Update

Dabigatran is useful as an alternative to warfarin for the prevention of stroke in patients with AF.

• Selection of patients with AF and ≥1 risk factor for stroke who could benefit from treatment with dabigatran as opposed to warfarin should consider individual clinical features, including the ability to comply with twice-daily dosing, availability of an anticoagulation management program, patient preferences, cost, and other factors

Because of the twice-daily dosing and greater risk of non-hemorrhagic side effects with dabigatran, patients already taking warfarin with excellent INR control may have little to gain by switching to dabigatran.

Wann LS et al. Heart Rhythm 2011;8:e1–e8

Hylek, EM. J Cardiovasc Med 2009;10:605-09

Effect of TTR on Primary Endpoints In RELY

Wallentin, et al. Lancet 2010

0.540.590.911.21

10% increase in center algorithm-consistent warfarin dosing predicted a 6.12% increase in TTR (95% CI 5.65-6.59%), and an 8% decrease in rate of the composite clinical outcome (HR 0.92, 95% CI 0.85-1.00).

Translating the Results of Clinical Trials into Clinical Practice

Patient selection

Therapeutic implementation        Environment of the healthcare delivery system    

Nallamothu, et al. Circulation 2008;118:1294–303

Will we be able to translate trial results to real-world practice?

Property Dabigatran Rivaroxaban Apixaban Edoxaban

Route of admin Oral Oral Oral Oral

Target Thrombin FXa FXa FXa

Dosing Twice daily Once daily Twice daily Once daily

Monitoring required No No No No

Half-life (hrs) 12–17 9–12 8–15 8–11

Mode of elimination Renal 80% Renal ~36% Renal ~25% Renal ~35%

New Oral Anticoagulants: Summary

Definitions:Chronic Kidney Disease and Renal Insufficiency

www.ckdsite.com

I MILD I MOD I SEVERE I

Renal Insufficiency Classification

Kidney Disease Outcomes Quality Initiative (KDOQI) of the National Kidney Foundation

Slide courtesy of C Cove

Randomized Trial Age Baseline CrCl

Exclusion CrCl

ARISTOTLE

Apixaban 5 mg bid 70 83% ≥50 <25 ml/min

Warfarin 70 83% ≥50

ROCKET AFRivaroxaban 20 mg qd 73 67 (median) < 30 ml/min

Warfarin 73 67 (median)

RE-LYDabigatran 150 mg bid 72 68 (median) <30 ml/min

Warfarin 72 69 (median)

Pharmacokinetics with Varying Levels of Renal Dysfunction

Kaatz S et al. Am J Hematol 2012 Suppl 1:S141-5. PMID: 22473649

  Apixaban Dabigatran Rivaroxaban

Elimination half life with CrCl >80 ml/min 7.6 hr 13.8 hr 8.3 hr

Elimination half life with CrCl 50–79 ml/min 7.3 hr 16.6 hr 8.7 hr

Elimination half life with CrCl 30–49 ml/min 17.6 hr 18.7 hr 9.0 hr

Elimination half life with CrCl <30 ml/min 17.3 hr 27.5 hr 9.5 hr

Periodically assess renal function as clinically indicated (i.e., more frequently in clinical situations that may be associated with a decline in renal function) and adjust therapy accordingly.

Discontinue dabigatran in patients who develop acute renal failure and consider alternative therapy.

In patients with moderate renal impairment (CrCl 30–50 mL/min), concomitant use of the P-gp inhibitor dronedarone or systemic ketoconazole can be expected to produce drug exposure similar to that observed in severe renal impairment. Consider reducing the dose.

JANUARY 2012 UPDATE DABIGATRAN PACKAGE INSERT

Property Dabigatran Rivaroxaban Apixaban Edoxaban

Route of admin Oral Oral Oral Oral

Target Thrombin FXa FXa FXa

Dosing Twice daily Once daily Twice daily Once daily

Monitoring required No No No No

Half-life (hrs) 12–17 9–12 8–15 8–11

Mode of elimination Renal 80% Renal ~36% Renal ~25% Renal ~35%

New Oral Anticoagulants: Summary

Polypharmacy and Non-adherence

• Strongest predictor of non-adherence is the # of medications

• Non-adherence rates estimated 25–50%• Intentional about 75% of the time

Changes in regimen made by patients to:

– increase convenience – reduce adverse effects or – decrease refill expense

Recommended Structured Follow-upFirst month and subsequent 3 month intervals

Pradaxa (dabigatran etexilate mesylate): Drug Safety Communication – Safety Review of Post-Market Reports of Serious Bleeding EventsUPDATED 11/02/2012.

… bleeding rates associated with new use of Pradaxa do not appear to be higher than bleeding rates associated with new use of warfarin, which is consistent with observations from the large clinical trial used to approve Pradaxa (the RE-LY trial). FDA is continuing to evaluate multiple sources of data in the ongoing safety review of this issue.

HAS-BLED Bleeding Risk Score

– Hypertension (SBP>160mmHg)

– Abnormal renal/liver fxn (1 pt for each)

– Stroke– Bleeding history or prone– Labile INR (if on warfarin)– Elderly (>65 years)– Drugs (ASA, NSAIDS)/alcohol

(1 pt for each)

• Increasing score associated with ISTH major bleeding (C-index 0.72)

Pisters R et al. Chest 2010;138:1093–100

Hemorrhage Thrombosis

Optimizing Benefit and Reducing Risk

AF stroke associated with a 30-day mortality of 24%.

Swedish AF Cohort; Circulation 2011; 125: 2298-2307

Dabigatran visits,%

2010Q4

2011Q1

2011Q2

2011Q3

2011Q4

Atrial fibrillation 92 72 75 71 63

Venous thromboembolism

0 4 8 3 5

Hypertensive heart disease

8 13 5 15 14

Coronary artery disease 0 3 9 3 6

CVA/TIA 0 0 0 3 3

Valvular disorders 0 0 0 3 0

Kirley K et al. Circ Cardiovasc Qual Outcomes 2012;5:615–21

Effective Use of TSOACs in Clinical Practice

1. Patient selection – ADHERENCE

2. Dose selection – creatinine clearance

3. Determine interval follow-up

4. Assess stability of renal function

5. Blood pressure control

6. Avoidance of concomitant antiplatelet therapy

7. Package insert – avoid potent drug interactions, guidance on transitions

Procedural Management based on Bleeding Risk of Surgery

DABIGATRAN APIXABAN/RIVAROXABAN

Novel Anticoagulants

1. Dabigatran 150 mg BID reduced ischemic stroke

2. Dabigatran 80% renal clearance

3. Dabigatran is associated with small risk of MI, but reduced cardiovascular mortality

4. Dabigatran and rivaroxaban increase GI bleeding

5. Rivaroxaban is once per day and approved Rx for VTE

6. Apixaban reduced stroke, major hemorrhage, and mortality

7. Well-controlled warfarin is associated with low rate of adverse events

Gaps: Practical Considerations

Translation across indication

Atrial fibrillation and valvular heart disease

Atrial fibrillation and ACSAtrial fibrillation and DVT or PE

Select situations in which monitoring would be desirable

Reversibility-trauma, urgent surgery, life-threatening hemorrhage

Guide to the Management ofBleeding in Patients Taking NOAC

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

Patients with bleeding on NOAC therapy

Mild bleeding Moderate-Severebleeding

Life-threateningbleeding

• Delay next dose or discontinue treatment as appropriate

• Mechanical compression

• Surgical intervention• Fluid replacement and

hemodynamic support• Blood product

transfusion• Oral charcoal • Hemodialysis• ? Prothrombin Complex

Concentrate?(Circulation 2011;124:1573-9)

• Consideration of rFVIIa or PCC

• Charcoal filtration• ? Prothrombin

Complex Concentrate

(Circulation 2011;124:1573-9)

47

WILL THERE BE A CONTINUING ROLE

FOR WARFARIN?

1. Mechanical heart valves2. Cost3. Pregnancy4. Severe renal impairment 5. Drug Interactions6. Lack of acceptance of no monitoring7. Reversal?8. Nonadherence9. Intolerant of novel anticoagulant drug

• Novel anticoagulants may be safer in the elderly population due to their wider therapeutic index, shorter t1/2, lack of dietary interference, and fewer drug interactions.

• Older individuals with AF are at the highest risk of stroke, the highest risk of hemorrhage, and the highest risk of stopping therapy.

• Further research is needed to inform commonly encountered clinical situations to optimize the effectiveness of these novel agents in routine practice.