Anticoagulation: A Changing Landscape Kelly Matsuda Pharm.D. July - - PowerPoint PPT Presentation

Kelly Matsuda Pharm.D. July 16, 2011 Anticoagulation: A Changing Landscape

Kelly Matsuda Pharm.D. July 16, 2011

Objectives

• Review epidemiology of stroke/TIA and

atrial fibrillation.

• Review of warfarin and in Stroke and

atrial fibrillation.

• Published Clinical Data with the new and

agents studied in atrial fibrillation.

Atrial Fibrillation: A Risk Factor for Vascular Events

Atherosclerosis/Atherothrombosis MI AF CHF

Wolf PA et al. Arch Intern Med 1987; 147: 1561-1564 Leckey R et al. Can J Cardiol 2000; 16: 481-485

RISK FACTORS: THROMBOSIS

• Hypertension
• Hyperlipidemia
• Age
• Diabetes Mellitus
• Smoking

Atherosclerosis/Atherothrombosis Stroke, MI, Vascular Death MI AF CHF

AF Prevalence: Age and Gender

JAMA 2001; 285: 2370

Prevalence of AF increases with age; men > women

Age, years Prevalence, percent

Wolf et al. Stroke 1991; 22: 983-988

The Percentage of Strokes Attributable to AF Increases with Age

%

AF prevalence Strokes attributable to AF

Age Range (years)

Framingham Study

10 20 30 50–59 60–69 70–79 80–89

Mortality Rates in AF

• Double the overall age and gender

matched population

• No reduction in past two decades
• Mortality 9-fold higher during 1st 4

months after diagnosis

Miyasaka Y, et al. JACC 2007; 49: 986-992

Disturbed Flow (left atrium) Stroke Risk Blood Flow in Atrial Fibrillation

Tissue Factor Kallikren XIa XI

Intrinsic Pathway Extrinsic Pathway

HMW Kininogen XIIa XII Pre-kallikren IX IXa VIII VIIIa IXa VIIa Ca++ X Xa Tissue Injury VII VIIa X VIIa Tissue Factor Ca++ Tenase

Fibrinogen Fibrin Xa Va Ca++ Prothrombinase

Common Pathway

Prothrombin Thrombin

Properties Benefits Orally active Ease of administration Rapid onset of action Obviates need for overlap with parenteral anticoagulant No food drug interaction or drug drug interactions Simplified dosing

Predictable anticoagulant effect No routine anticoagulation monitoring Extra renal clearance Safe in patients with renal insufficiency Rapid offset of action Simplifies management in case of bleed or intervention Safe antidote Useful in case of major bleed Favorable net clinical benefit risk Treatment benefit outweighs risk

Properties of an Ideal anticoagulant

WARFarin trivia

• utbreak1920s cattle bled from minor procedure or spontaneously

1921 -Dr. Schofield, cattle ingesting moldy silage made from sweet clover. repeat experiment in rabbits, one with damaged clover and one with undamaged clover, nothing happened to undamaged group, damaged group died 1929- Dr. Rodrick demonstrated it was lack of functioning prothrombin 1933 U Wisconsin- -Dr. Link and students (campbell and stahmann) 4-hydroxy-coumarin later named dicoumarol. Dicoumarol is plant product of coumarin from spoiled sweet clover 1948 Dr link went on to develop rodenticides which coumarin was used in a potent form. WARF stems from Wisconsin Alumi Research Foundation , the ARIN is a link with coumarin. Widely used anticoagulant today

Fuster V , et al. Eur Heart J 2006;27:1979.

Antithrombotic Therapy for Atrial Fibrillation ACC/AHA/ESC Guidelines 2006

Risk Category Recommended Therapy

No risk factors

CHADS2 = 0 Aspirin, 81-325 mg qd

One moderate risk factor

CHADS2 = 1 Aspirin, 81-325 mg/d or Warfarin

Any high risk factor or >1 moderate risk factor

CHADS2 >2

• r mitral stenosis

Warfarin

(INR 2.0-3.0, target 2.5) Prosthetic valve

Warfarin

(INR 2.5-3.5, target 3.0)

Tissue factor Plasma clotting cascade Prothrombin

Thrombin (IIa)

Fibrinogen Fibrin Thrombus Platelet aggregation Platelet activation Collagen Thromboxane A2 ADP AT AT Aspirin Clopidogrel Prasugrel Eptifibatide Abciximab Tirofiban (GPB) Bivalirudin Hirudin Argatroban Dabitgatran Factor Xa Heparin LMWHs Fibrinolytics Fondaparinux Rivaroxaban Apixaban endoxaban AT

Sites of Antithrombotic Action

Why do we need another warfarin management lecture?

• Warfarin therapy is:

– Highly effective – Complex to manage – Underutilized – When utilized, managed poorly … but effective solutions have evolved.

properties Warfarin UFH LMWH fondaparinux Mode of Action Vitamin K antagonist Indirect factor IIa and Xa inhibitor Indirect factor Xa and minor IIa inhibitor Indirect Xa inhibitor Bioavailability 100 % 100% 100% 100% Peak action ( t max) 4-5 days Iv: immediate Sq: 20-60 min Sq 2-4 hours enox Sq 2.9 hours dalt Sq 4 hours tinz Sq 2-4 hours Elimination half life ( t1/2) ) 36- 42 hours 1-1.5 hours 3-4 hours 17-21 hours Route of elimination Multiple Reticulendothel ial system > 80% renal 100% renal Involvement of CYP Yes No No No

UFH=unfractionated heparin, LMWH= low molecular weight heparin ( enox=enoxaparin, dalt=dalteparin,nz=tinz=tinzaparin

Conventional Anticoagulants

J Douketis, Curr pharma design 2010:16:3426

Properties Fondaparinux Argatroban lepirudin Mode of action Xa IIa IIa Bioavailability 100% 100% 100% Peak action 2-4 hours 1-3 hours Elimination half life (t1/2) 17-21 hours 0.5- 1 hours 1 hour Route of elimination 100% renal 100% hepatic 100% Involvement

• f CYP

no Minor cyp majority thru hydroxylation aromatization no

Conventional anticoagulants

Problems with Warfarin

• 1. Delayed onset/offset
• 2. Unpredictable dose response
• 3. Narrow therapeutic index
• 4. Drug-drug, drug-food interactions
• 5. Problematic monitoring
• 6. High bleeding rate
• 7. Slow reversibility

Hylek, et al, studied the risk of intracranial hemorrhage in outpatients treated with

• warfarin. They determined that an intensity of anticoagulation expressed as a

prothrombin time ratio (PTR) above 2.0 (roughly corresponding to an INR of 3.7 to 4.3) resulted in an increase in the risk of bleeding.

Adapted from: Hylek EM, Singer DE, Ann Int Med 1994;120:897-902

Risk of Intracranial Hemorrhage in Outpatients

Hylek EM, et al. NEJM 1996;335:540-546.

INR below 2.0 results in a higher risk of stroke

Lowest Effective Intensity for Warfarin Therapy for Stroke Prevention in Atrial Fibrillation

Therapeutic Range for Warfarin INR Values at Stroke or ICH

Odds Ratio

5.0 6.0 8.0

INR

1.0 2.0 3.0 4.0 7.0 5.0 15.0 10.0

Stroke

1.0

Fuster et al. J Am Coll Cardiol. 2001;38:1231-1266.

Intracranial Hemorrhage

Anticoagulation in Atrial Fibrillation Stroke Risk Reductions

Hart R, et al. Ann Intern Med 2007;146:857.

Warfarin Better Control Better AFASAK SPAF BAATAF CAFA SPINAF EAFT 100% 50%

• 50%
• 100%

Aggregate

Anticoagulation in Atrial Fibrillation The Standard of Care for Stroke Prevention

Warfarin Better Control Better AFASAK SPAF BAATAF CAFA SPINAF EAFT 100% 50%

• 50%
• 100%

Aggregate Terminated early Double-blind; Men only Unblinded Unblinded Unblinded 2o prevention; Unblinded

Hart R, et al. Ann Intern Med 2007;146:857.

New Anticoagulants

Properties Dabigatran Rivaroxaban Apixaban Mode of action Direct factor IIA (thrombin inhibitor) Direct factor Xa inhibitor Direct factor Xa inhibitor Bioavailability 6.5% 80% 80% Peak action 1-3 hours 1-3 hours 1-3 hours Elimination half life (t½) 14-17 hours 9-15 hours 9-14 hours Route of elimination 100% renal 65% renal 25% renal Involvement of CYP Minor Minor Minor J Douketis, Curr pharma design 2010:16:3426

Tissue factor Plasma clotting cascade Prothrombin

Thrombin (IIa)

Fibrinogen Fibrin Thrombus Platelet aggregation Platelet activation Collagen Thromboxane A2 ADP AT AT Aspirin Clopidogrel Prasugrel Eptifibatide Abciximab Tirofiban (GPB) Bivalirudin Hirudin Argatroban Dabitgatran Factor Xa Heparin LMWHs Fibrinolytics Fondaparinux Rivaroxaban Apixaban endoxaban AT

Sites of Antithrombotic Action for Thrombin inhibitors

Baseline Characteristics

Characteristic Dabigatran 110 mg Dabigatran 150 mg Warfarin Randomized 6015 6076 6022 Mean age (years) 71.4 71.5 71.6 Male (%) 64.3 63.2 63.3 CHADS2 score (mean) 0-1 (%) 2 (%) 3+ (%) 2.1 32.6 34.7 32.7 2.2 32.2 35.2 32.6 2.1 30.9 37.0 32.1 Prior stroke/TIA (%) 19.9 20.3 19.8 Prior MI (%) 16.8 16.9 16.1 CHF (%) 32.2 31.8 31.9 Baseline ASA (%) 40.0 38.7 40.6 Warfarin Naïve (%) 49.9 49.8 51.4

Stroke or Systemic Embolism

0.50 0.75 1.00 1.25 1.50

Dabigatran 110 vs. Warfarin Dabigatran 150 vs. Warfarin

Non-inferiority p-value

<0.001 <0.001

Superiority p-value

0.34 <0.001

Margin = 1.46

HR (95% CI) Warfarin better

Dabigatran better

10 Outcome: Superiority Analysis

D 110mg D 150mg warfarin D 110mg vs. Warfarin D 150mg vs. Warfarin Annual rate Annual rate Annual rate RR 95% CI P* RR 95% CI P Stroke or systemic Embolism 1.5 % 1.1 % 1.7 % 0.91 0.74-1.11 0.34 0.66 0.53-0.82 <0.001 Stroke 1.4 % 1.0 % 1.6 % 0.92 0.74-1.13 0.41 0.64 0.51-0.81 <0.001

Hemorrhagic Stroke

D 110 mg vs. Warfarin D 150 mg vs. Warfarin RR = 0.31 95% CI =0.17-0.56 P <0.001 RR =0.26 95% CI =0.14-0.49 P <0.001

Years of Follow-up Cumulative Hazard Rates 0.0 0.01 0.02 0.03 0.04 0.5 1.0 1.5 2.0 2.5 Dabigatran110 Dabigatran150 Warfarin

Bleeding

D 110mg D 150mg warfarin D 110mg vs. Warfarin D 150mg vs. Warfarin Annual rate Annual rate Annual rate RR 95% CI p RR 95% CI p Total 14.6% 16.4% 18.2% 0.78 0.74-0.83 <0.001 0.91 0.86-0.97 0.002 Major 2.7 % 3.1 % 3.4 % 0.80 0.69-0.93 0.003 0.93 0.81-1.07 0.31 Life- Threatening major 1.2 % 1.5 % 1.8 % 0.68 0.55-0.83 <0.001 0.81 0.66-0.99 0.04 Gastro- intestinal Major 1.1 % 1.5 % 1.0 % 1.10 0.86-1.41 0.43 1.50 1.19-1.89 <0.001

MI, Death and Net clinical Benefit

D 110mg D 150mg warfarin D 110mg vs. Warfarin D 150mg vs. Warfarin Annual rate Annual rate Annual rate RR 95% CI p RR 95% CI p MI 0.7% 0.7 % 0.5 % 1.35 0.98-1.87 0.07 1.38 1.00-1.91 0.048 Death 3.8 % 3.6 % 4.1 % 0.91 0.80-1.03 0.13 0.88 0.77-1.00 0.05 Net Clinical Benefit 7.1 % 6.9 % 7.6 % 0.92 0.84-1.02 0.10 0.91 0.82-1.00 0.04

Net Clinical Benefit includes vascular events, death and major bleed

Permanent Discontinuation

Years of Follow-up Stopping Rates 0.0 0.1 0.2 0.3 0.4 0.5 1.0 1.5 2.0 2.5 Dabigatran110 Dabigatran150

Warfarin

Years of Follow-up Cumulative Risk 0.0 0.01 0.02 0.03 0.04 0.5 1.0 1.5 2.0 2.5 Dabigatran110 Dabigatran150 Warfarin

ALT or AST >3x ULN

Adverse events occurring in >5% of any group Dabigatran 110 mg % Dabigatran 150 mg % Warfarin % Dyspepsia * 11.8 11.3 5.8 Dyspnea 9.3 9.5 9.7 Dizziness 8.1 8.3 9.4 Peripheral edema 7.9 7.9 7.8 Fatigue 6.6 6.6 6.2 Cough 5.7 5.7 6.0 Chest pain 5.2 6.2 5.9 Arthralgia 4.5 5.5 5.7 Back pain 5.3 5.2 5.6 Nasopharyngitis 5.6 5.4 5.6 Diarrhea 6.3 6.5 5.7 Atrial fibrillation 5.5 5.9 5.8 Urinary tract infection 4.5 4.8 5.6 Upper respiratory tract infection 4.8 4.7 5.2

Common Adverse Events

*Occurred more commonly on dabigatran p<0.001

Conclusions

• Dabigatran 150 mg significantly reduced stoke

compared to warfarin with similar risk of major bleeding

• Dabigatran 110 mg had a similar rate of stroke as

warfarin with significantly reduced major bleeding

• Both doses markedly reduced intra-cerebral, life-

threatening and total bleeding

• Dabigatran had no major toxicity, but did increase

dyspepsia and GI bleeding

Tissue factor Plasma clotting cascade Prothrombin

Thrombin (IIa)

Fibrinogen Fibrin Thrombus Platelet aggregation Platelet activation Collagen Thromboxane A2 ADP AT AT Aspirin Clopidogrel Prasugrel Eptifibatide Abciximab Tirofiban (GPB) Bivalirudin Hirudin Argatroban Dabitgatran Factor Xa Heparin LMWHs Fibrinolytics Fondaparinux Rivaroxaban Apixaban endoxaban AT

Sites of Antithrombotic Action for Thrombin inhibitors

Kenneth W. Mahaffey, MD and Keith AA Fox, MB ChB

• n behalf of the ROCKET AF Investigators

Rivaroxaban Once-daily oral direct factor Xa inhibition Compared with vitamin K antagonism for prevention

• f stroke and Embolism Trial in Atrial Fibrillation

Rivaroxaban Warfarin

Primary Endpoint: Stroke or non-CNS Systemic Embolism

INR target - 2.5 (2.0-3.0 inclusive) 20 mg daily

15 mg for Cr Cl 30-49 ml/min

Atrial Fibrillation

Randomize Double Blind / Double Dummy (n ~ 14,000)

Monthly Monitoring Adherence to standard of care guidelines

Study Design

* Enrollment of patients without prior Stroke, TIA or systemic embolism and only 2 factors capped at 10%

Risk Factors

• CHF
• Hypertension
• Age  75
• Diabetes

OR

• Stroke, TIA or

Systemic embolus

At least 2 or 3 required*

Statistical Methodologies

 Sample Size

 Warfarin event rate ~2.3  Type 1 error 0.05 (2-sided)  405 events; >95% power  ~14,000 patients

Primary Efficacy Evaluation: Stroke or non-CNS

Embolism

 Non-Inferiority: Protocol Compliant on treatment  Superiority: On Treatment and then by Intention-to-Treat

 Primary Safety Evaluation: Major or non-Major Clinically Relevant Bleeding

1.0 1.46 Superiority Non-inferiority Inferiority

Rivaroxaban Better Warfarin Better

Rivaroxaban (N=7081)

Warfarin (N=7090) Age (years)

73 (65, 78)

73 (65, 78) Female (%)

40

40 Race (%) White Black Asian

83 1 13

83 1 13 Region (%) North America Latin America Asia-Pacific Central Europe Western Europe

19 13 15 38 15

19 13 15 38 15 Creatinine Clearance (ml/min) (%) 30 - <50 50 - ≤80 > 80

21 47 32

21 48 31

Values are median (IQR) Based on Intention-to-Treat Population

Baseline Demographics

Rivaroxaban (N=7081) Warfarin (N=7090) CHADS2 Score (mean) 2 (%) 3 (%) 4 (%) 5 (%) 6 (%) 3.48 13 43 29 13 2 3.46 13 44 28 12 2 Prior VKA Use (%) 62 63 Congestive Heart Failure (%) 63 62 Hypertension (%) 90 91 Diabetes Mellitus (%) 40 39 Prior Stroke/TIA/Embolism (%) 55 55 Prior Myocardial Infarction (%) 17 18

Based on Intention-to-Treat Population

Baseline Demographics

Primary Efficacy Outcome

Stroke and non-CNS Embolism

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

1 2 3 4 5 6 120 240 360 480 600 720 840 960

• No. at risk:

Rivaroxaban 6958 6211 5786 5468 4406 3407 2472 1496 634 Warfarin 7004 6327 5911 5542 4461 3478 2539 1538 655

Warfarin HR (95% CI): 0.79 (0.66, 0.96) P-value Non-Inferiority: <0.001 Days from Randomization Cumulative event rate (%) Rivaroxaban

Rivaroxaban Warfarin Event Rate 1.71 2.16

Rivaroxaban Warfarin Event Rate Event Rate HR (95% CI) P-value On Treatment

N= 14,143

1.70 2.15 0.79 (0.65,0.95) 0.015 ITT

N= 14,171

2.12 2.42 0.88 (0.74,1.03) 0.117

Rivaroxaban better Warfarin better

Primary Efficacy Outcome

Stroke and non-CNS Embolism

Event Rates are per 100 patient-years Based on Safety on Treatment or Intention-to-Treat thru Site Notification populations

Key Secondary Efficacy Outcomes

Rivaroxaban 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 0.26 1.34 0.06 0.44 1.42 0.10 0.59 (0.37, 0.93) 0.94 (0.75, 1.17) 0.65 (0.25, 1.67) 0.024 0.581 0.366 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 1.87 1.53 0.19 0.15 2.21 1.71 0.30 0.20 0.85 (0.70, 1.02) 0.89 (0.73, 1.10) 0.63 (0.36, 1.08) 0.75 (0.40, 1.41) 0.073 0.289 0.094 0.370

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

Rivaroxaban Warfarin Event Rate

• r N (Rate)

Event Rate

• r N (Rate)

HR (95% CI) P- value Major >2 g/dL Hgb drop Transfusion (> 2 units) Critical organ bleeding Bleeding causing death 3.60 2.77 1.65 0.82 0.24 3.45 2.26 1.32 1.18 0.48 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) 0.576 0.019 0.044 0.007 0.003 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

Primary Safety Outcomes

Adverse Events and Liver Enzyme Data

Values are N (%) Based on Safety Population

Rivaroxaban (N=7111) Warfarin (N=7125) Any Adverse Event Any Serious Adverse Event AE leading to study drug discontinuation 82.4 37.3 15.7 82.2 38.2 15.2 Epistaxis Peripheral edema Dizziness Nasopharyngitis Cardiac failure Bronchitis Dyspnea Diarrhea 10.1 6.1 6.1 5.9 5.6 5.6 5.3 5.3 8.6 6.2 6.3 6.4 5.9 5.9 5.5 5.6 ALT Elevation >3 x ULN >5 x ULN >3 x ULN and T Bili > 2 x ULN 2.9 1.0 0.4 2.9 1.0 0.5

Summary

 Efficacy:

 Rivaroxaban was non-inferior to warfarin for prevention of stroke and non-CNS embolism.  Rivaroxaban was superior to warfarin while patients were taking study drug.  By intention-to-treat, rivaroxaban was non-inferior to warfarin but did not achieve superiority.

 Safety:

 Similar rates of bleeding and adverse events.  Less ICH and fatal bleeding with rivaroxaban.

 Conclusion:

 Rivaroxaban is a proven alternative to warfarin for moderate or high risk patients with AF.

Tissue factor Plasma clotting cascade Prothrombin

Thrombin (IIa)

Fibrinogen Fibrin Thrombus Platelet aggregation Platelet activation Collagen Thromboxane A2 ADP AT AT Aspirin Clopidogrel Prasugrel Eptifibatide Abciximab Tirofiban (GPB) Bivalirudin Hirudin Argatroban Dabitgatran Factor Xa Heparin LMWHs Fibrinolytics Fondaparinux Rivaroxaban Apixaban endoxaban AT

Sites of Antithrombotic Action for Thrombin inhibitors

AVERROES Design

36 countries , 522 centres

AF and ≥ 1 risk factor and demonstrated or expected unsuitable for VKA

Apixiban 5 mg bid

2.5 mg bid in selected patients

R Double Blind ASA 81-324 mg / d 5600 patients

Baseline Characteristics

Characteristics Apixaban ASA Age ( mean and SD) 70± 10 years 70± 10 years Male ( years) 59 58 CHADS2 score (mean and SD) 0-1 2 3+ 2.1± 1.1 36 37 27 2.1± 1.1 37 34 29 Prior stroke/TIA 14% 13% Diabetes 19% 20% Hypertension 86% 87% CHF 40% 38% Baseline ASA 76% 74% Unsuitable for VKA VKA used and discontinued VKA expected unsuitable 39% 61% 40% 60%

AVERROES

Apixaban vs. Aspirin: The AVERROES Trial Primary and Secondary Endpoints

Outcomes Apixaban (n=2809) Aspirin (n=2791) Relative risk (95% CI)

Stroke or systemic embolism

1.6 3.6 0.46 (0.33–0.64)

Stroke, embolism, MI, or vascular death

4.1 6.2 0.66 (0.53–0.83)

MI

0.7 0.8 0.85 (0.48–1.50)

Vascular death

2.5 2.9 0.86 (0.64–1.16)

Cardiovascular hospitalization

11.8 14.9 0.79 (0.68–0.91)

Total death

3.4 4.4 0.79 (0.62–1.02)

Connolly S. European Society of Cardiology, Stockholm, August 31, 2010

Apixaban vs. Aspirin: The AVERROES Trial

Bleeding Events

Outcomes Apixaba n (n=2809 ) Aspirin (n=2791) Relative risk (95% CI)

Major bleeding 1.4 1.2 1.14 (0.74–1.75) Fatal bleeding 0.1 0.1 0.84 (0.26–2.75) Intracranial 0.4 0.3 1.09 (0.50–2.39) Clinical relevant non-major bleeding 3.0 2.6 1.18 (0.88–1.58) Minor bleeding 5.2 4.1 1.27 (1.01–1.61)

Connolly S. European Society of Cardiology, Stockholm, August 31, 2010

What about other trials?

• Apixaban ARISTOTLE trial
• Edoxaban

ENGAGE trial

Challenges with New Oral Anticoagulants

►will Costs be high – who will pay? ►How will we assess compliance? ►How will we treat bleeds?

Challenges for New Anticoagulants

►New oral anticoagulants are poised to replace warfarin for stroke prevention in AF ►Dabigatran is the first, but others will soon follow ►How the new agents compare with each

• ther remains to be determined

ESC AF Guidelines: September, 2010

ESC AF Guidelines: September, 2010 New ESC Guidelines for AF

►OACs, such as a VKA, should be adjusted to an intensity range of INR 2.0–3.0 (target 2.5). ►New OAC drugs [DTIs and factor Xa inhibitors] which may be viable alternatives to a VKA, may ultimately be considered. —Where oral anticoagulation is appropriate therapy, dabigatran may be considered, as an alternative to adjusted dose VKA therapy . . . dabigatran 150 mg b.i.d. may be considered, in view of the improved efficacy in the prevention of stroke and systemic embolism (but lower rates of intracranial haemorrhage and similar rates of major bleeding events, when compared with warfarin)

Europace (2010) 12, 1360–1420 doi:10.1093/europace/euq350, p. 16