Atrial Fibrillation- Anticoagulation

Atrial Fibrillation, Anticoagulation

and Vitamins for Homocysteine

Prof. J. David Spence M.D.

CCS guidelines

•Compared to placebo/control,

the risk reduction with warfarin is 64%

•Patients need anticoagulants if they have AF

31Based on Hart Ann Int Med 1999; 131: 492

It is a mistake to use antiplatelet agents for AF

•The elderly benefit from anticoagulation more than younger patients1, 2

•It would take 295 falls to equal the risk of not anticoagulating in AF3

•Risk of serious bleeding is not higher on anticoagulation than on antiplatelet agents4

1. van Walraven C, et al. Stroke. 2009; 40: 1410-6 2. Spence JD. Nat Rev Cardiol. 2009; 6: 448-50

3. Man-Son-Hing M et al. Arch Intern Med 1999; 159: 677–685

324. Flaker GC, et al. Stroke. 2012; 43: 3291-7

Controlling the INR matters

Annual stroke risk

SPORTIF III 2.3%

SPORTIF V 1.16%

P=0.0004

33Hylek EM et al. Stroke 2008; 39: 3009-3014

Atrial Fibrillation, Anticoagulation

and Vitamins for Homocysteine

Prof. J. David Spence M.D.

Warfarin is impossible to use well

•In clinical trials, time in target INR only 60%

•In the real world:

‒Only 35% of patients with AF on warfarin

‒Of those only 50% of the time in target INR1

•One trick to reduce INR turbulence is to use a small dose of vitamin K daily2

1. Samsa GP et al. Arch Intern Med 2000; 160: 967–973

342. Rombouts EK et al. J Thromb Haemost 2007; 5: 2043–2048

Drug interactions with warfarin

35Spence JD J Neural Transm 2013; 120: 1447-1451

Real-world warfarin bleeding,

Gomes T et al. CMAJ. 2013; 185: E121-7

Atrial Fibrillation, Anticoagulation

and Vitamins for Homocysteine

Prof. J. David Spence M.D.

Under-anticoagulation doesn’t work

•69 yo woman

with mitral stenosis

•Stroke from AF

•INR 1.5 x 22 days

•Surgical removal of thrombus

at day 54

37Tsuda Y et al. Stroke 1990; 21; 1375-1376

Seek AF, and ye shall find it1

In cryptogenic stroke with no AF at baseline

•1-4 months of telephonic ECG turned up AF in 9.2%2

•7-day loop recorder at 0, 3 and 6 months: AF in 26%3

•Continuous monitoring in stroke unit better than Holter4

•30-day monitoring 11%5

•EMBRACE study 3% on Holter, 16% long-term (30 day)

•Implantable monitor 3 years: 23%

1.Tayal AH, Callans DJ. Neurology 2010; 74: 1662–1663

2.Gaillard N et al. Neurology 2010; 74: 1666–1670

3.Wallman D et al. Stroke 2007; 38: 2292–2294

4.Rizos T et al. Stroke. 2012; 43: 2689-2694

385. Flint AC et al. Stroke. 2012; 43: 2788-2790

EMBRACE study intervention

•Event-triggered loop recorder (Braemar Inc., ER910AF)

–Automatically records AF

–Memory storage capacity: 30 minutes

–Programmed to record up to 11 events, max. 2.5 minutes per event

•Accuheart electrode belt (Cardiac Bio-Systems Inc.)

–Dry electrode technology (without adhesive skin-contact electrodes)

•Worn for 30 days or until AF detected

•Data handling

–Recorded data transmitted trans-telephonically to central station

–ECG tracings of all events printed and interpreted centrally by one physician blinded to clinical information

39– Results report sent to patient’s study physician

Atrial Fibrillation, Anticoagulation

and Vitamins for Homocysteine

Prof. J. David Spence M.D.

EMBRACE trial

•527 patients with cryptogenic stroke

•Age 73 years; 54% male; automated recorder belt vs. repeat Holter

•At 3 months, 16.1% with AF vs. 3.2% p = 0.001

40Gladstone D et al. N Engl J Med 2014; 370: 2467-77

CRYSTAL AF study

•441 patients with cryptogenic stroke

•63% male, age 61.5 years; implantable device

•6 months rate with an implantable device was ~ 10%

•After 36 months it was just above 30%

•Many patients with cryptogenic stroke in whom we suspect a cardio-embolic stroke, have undetected intermittent AF

41Based on: Sanna T et al. N Engl J Med. 2014; 370: 2478-86

CCS guidelines

The CHADS2 score is useful in deciding which patient needs anticoagulation therapy

•If a patient had a stroke and his CHADS2 score is > 2, he needs anticoagulation therapy

•If the CHADS2 score is 6 the adjusted rate of stroke/year is 18%

•These patients should not get anti-platelet agents

42www.ccs.ca

Atrial Fibrillation, Anticoagulation

and Vitamins for Homocysteine

Prof. J. David Spence M.D.

CCS guidelines (2)

Recommendations – antithrombotic for AF

When OAC therapy is indicated, most patients should receive (NOA) in preference to warfarin

(Conditional recommendation. High quality evidence)

43www.ccs.ca

Most thrombi in left atrial appendage

>90% of thrombi in non-valvular AF are in the atrial appendage

44

Other approaches

•Prophylactic removal of atrial appendage during cardiac surgery

•Thoracoscopic removal of LA appendage

•Insertion of device in LA appendage

45Onalan O, Crystal E. Stroke 2007; 38; 624-630

Atrial Fibrillation, Anticoagulation

and Vitamins for Homocysteine

Prof. J. David Spence M.D.

Protect - AF trial

• AF patients randomized to conventional warfarin vs. Watchman device

After 900 patient-years:

•32% of primary outcome: absence of ischemic & hemorrhagic stroke, CV /unexplained death, systemic embolism

BUT:

•>25% of patients did not take warfarin

•Implantation only successful in 90%

•12.3% had serious complications

–4 had to have device removed

–2.2% required surgery

–Higher risk in low-volume centres

46Maisel WH. N Engl J Med. 2009 Jun 18; 360(25): 2601-3

PLAATO device

•In feasibility studies n=108

•Successful implantation in 97%;

•65% reduction of stroke

•Trial under way

47Onalan O, Crystal E. Stroke 2007; 38; 624-630

European PLAATO study

180 patients with AF and TIA/Stroke or CHADS > 2 and contraindications to warfarin

•Successful occlusion of atrial appendage in 90%

•2 deaths

•6 cardiac tamponade, 2 requiring surgery

•1 device too small and embolized to aorta; snared successfully

•2.3% strokes per year vs. expected 6.6% for CHADS 2

48Bayard YL et al. EuroIntervention. 2010 Jun; 6(2): 220-6

Atrial Fibrillation, Anticoagulation

and Vitamins for Homocysteine

Prof. J. David Spence M.D.

New era in anticoagulation

Intracranial bleeding?

Apixaban

Rivaroxaban

Dabigatran

49Atarashi H. Circ J. 2011; 75: 1819-20

Novel oral anticoagulants – pharmacological properties

P-gp = P glycoprotein

501. Xarelto® PM, July 18, 2012; 2. Pradaxa ® PM November 12, 2012;

3. Eliquis® PM November 27, 2012; 4. Goette Trends Cardiovasc Med. 2013; 23: 128-34

Dabigatran vs. warfarin in atrial fibrillation

n =18,113 Median follow up 2yrs

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

Atrial Fibrillation, Anticoagulation

and Vitamins for Homocysteine

Prof. J. David Spence M.D.

Dabigatran plasma concentration and outcomes

52Reilly PA et al. J Am Coll Cardiol. 2014; 63: 321-8

Therapeutic range for dabigatran

53Reilly PA et al. J Am Coll Cardiol. 2014; 63: 321-8

New oral anticoagulants: total drug exposure

(AUC) with declining renal function

AUC ratio vs. Normal renal function

1. Xarelto® PM, July 18, 2012; 2. Pradaxa ® PM November 12, 2012; 3. Goette Trends Cardiovasc Med. 542013 [Epub ahead of print]; 4. Eliquis® PM November 27, 2012

Atrial Fibrillation, Anticoagulation

and Vitamins for Homocysteine

Prof. J. David Spence M.D.

Need for blood levels of dabigatran

•Only 3-7% bioavailable

•Subject to large effects of:

–Drug interaction

–Renal function

55Moore TJ et al. BMJ 2014; 349: g4517

Rivaroxaban vs. warfarin in AF

•Stroke or systemic embolism occurred in:

–188 patients in the rivaroxaban group (1.7% per year)

–241 patients in the warfarin group (2.2% per year)

(hazard ratio in the rivaroxaban group, 0.79;

95% confidence interval [CI], 0.66 to 0.96; P<0.001 for noninferiority)

1 outcome HR 0.79 p=0.001

Apixaban vs. warfarin in AF

•The primary outcome of stroke or systemic embolism:

–212 patients in the apixaban group (1.27% per year)

–265 patients in the warfarin group (1.60% per year)

(hazard ratio in the apixaban group, 0.79; 95% confidence interval [CI], 0.66 to 0.95;

P<0.001 for noninferiority and P = 0.01 for superiority)

•Major bleeding (defined according to ISTH criteria):

–327 patients in the apixaban group (2.13% per year)

–462 patients in the warfarin group (3.09% per year)

Atrial Fibrillation, Anticoagulation

and Vitamins for Homocysteine

Prof. J. David Spence M.D.

ICH in ROCKET

58Hankey GJ et al. Stroke 2014; 45: 1304-1312

New oral anticoagulants vs. warfarin in atrial fibrillation; apixaban, dabigatran, rivaroxaban

Reversal of Xa inhibitor

with prothrombin complex concentrate (PCC)

60Eerenberg ES et al. Circulation. 2011; 124: 1573-9