Main Title

1
New Oral Anticoagulants Guidelines and
tips Starting/stopping Switching/swapping Measurin
g/monitoring
Philip Teal MD FRCPC Sauder Family Heart and
Foundation Professor of Stroke Neurology Universit
y of British Columbia
2
Disclosures

• Honorariums (past 5 years)
• Steering Committees, advisory boards, sponsored
  talks
• Boehringer Ingelheim
• Sanofi Aventis
• BMS
• Bayer
• Roche Canada
• Pfizer
• Servier
• Clinical trial participation
• Sanofi Aventis
• Boehringer Ingelheim
• Bayer

3
Objectives

• Risk stratification schemes
• 2012 Canadian Atrial Fibrillation Guidelines
• Starting OAC post stroke
• Monitoring the new OACs
• Starting/ Stopping

4
The Stroke Service Perspective on AF

• Patients referred for advise on primary or
  secondary stroke prevention in atrial
  fibrillation (outpatients)
• Unrecognized, undiagnosed atrial
  fibrillation-first recognition on presentation
  with a major stroke
• Recognized atrial fibrillation, untreated or
  undertreated presenting with a first or recurrent
  stroke
• Intracerebral hemorrhage on anticoagulation
• Poor outcomes with acute stroke therapies in
  atrial fibrillation challenges for acute
  reperfusion therapies
• Cryptogenic strokes that subsequently are
  attributed to unrecognized paroxysmal Afib

5
The Stroke Service Perspective on AF

• Shortcomings of traditional antithrombotic
  therapies ASA, warfarin, dilemmas with NOACs (new
  oral anticoagulants)
• Errors in stratification of patients into low,
  medium, high stroke risks
• Stroke Severity in atrial fibrillation
• Intracerebral hemorrhage on anticoagulation
• Poor outcomes with acute stroke therapies in
  atrial fibrillation

6
VGH Stroke Service Week of Aug 19th

• YY 80 year old man Afib, untreated

• JH 56 year old man with afib and MAVR. sub
  therapeutic

7
VGH Stroke Service Week of Aug 19th

• YD 62 year old man with AF, stopped warfarin

• HG 86 year old woman with AF. falls

8
VGH Stroke Service Week of Aug 19th

• JT 71 year old woman with Afib, untreated

• PT 81 year old man with Afib procedural stop

9
VGH Stroke Service Week of Aug 19th

• GM 66 year old man post cardioversion, no Rx

• PS 59 year old man post gastroscopy, procedural
  stop

10
Hyperdense MCA Sign
11
Large territory strokes in Afib
12
Quantifying the Risk
13
CCS 2012 Guidelines We recommend that all
patients with AF or AFL (paroxsymal, persistent,
or permanent), should be stratified for Stroke
(e.g. CHADS2) and for risk of bleeding (e.g.
HAS-BLED), and that most patients should receive
either an oral anticoagulant or ASA (Strong
Recommendation, High quality Evidence)
Candian Journal of Cardiology 28 (2012) 125-136
14
AF Is Classified By Episode Duration Andthe
Ability To Return To Sinus Rhythm
1st Detected
Recurrent if 2 episodes
Persistent(not self-terminating)
Paroxysmal(self-terminating usually within 7
days)
Permanent (Refractory to cardioversion and/or
accepted)
ACC/AHA/ESC 2006 guidelines. J Am Coll Cardiol
200648854-906.
15
Prediction of Stroke in AF CHADS2
Risk Factor Score
C CHF 1
Hhypertension 1
A age 75 1
D diabetes 1
S stroke/TIA 2
Stroke / yr
CHADS2 score
Adapted from Cairns JA, et al. Can J Cardiol.
2011 277490.
16
CHA2DS2-VASc Score
Patients with a CHADS2 score of 0 or 1 may still
be at increased risk of stroke. The CHA2DS2-VASc
score may be useful in these patients to ensure
consideration of all stroke risk factors
CHA2DS2-VASc Score Stroke Rate per Year (/yr) Recommended Therapy
0 0 ASA
1 1.3 OAC or ASA
2 2.2 OAC
3 3.2 OAC
4 4.0 OAC
5 6.7 OAC
6 9.8 OAC
7 9.6 OAC
8 6.7 OAC
9 15.2 OAC
CHA2DS2-VASc Score Sum Of Points
Congestive Heart Failure / Left Ventricular Dysfunction 1
Hypertension 1
Age 75 Years 2
Diabetes Mellitus 1
Prior Stroke or TIA or Systemic Embolism 2
Vascular Disease 1
Age gt 65 but lt 75 1
Sex Category Female 1
Lip Chest 2010137263 Camm Eur Heart J
2010312369
17
Bleeding Risk HAS-BLED Score
Letter Clinical Characteristic Points
H Hypertension 1
A Abnormal Liver or Renal Function 1 point each 1 or 2
S Stroke 1
B Bleeding 1
L Labile INRs 1
E Elderly (age gt 65 yr) 1
D Drugs or Alcohol 1 point each 1 or 2
Maximum 9 points
Pisters R et al. Chest. 2010 Nov1381093-100
18
Warfarin-associated ICH INR 2.7
INR 2.2
19
74 year old, minor fall. On warfarin INR 2.1
20
Predictors of CNS Bleeding on OAC

• Advanced age gt 75 years
• Hypertension (systolic BP gt 160)
• History of cerebrovascular disease
• Intensity of anticoagulation
• Agents used - new OACs vs VKA
• Concomitant ASA / clopidogrel
• Leukoariosis on CT/MRI
• Microbleeds of T2/GRE/SWI MRI sequences

21
New Oral Anticoagulants vs. Warfarin All-Cause
Stroke or Systemic Embolism
P Value
P 0.01
P 0.30
P lt 0.001
P 0.12
Warfarin Better
Data obtained from intention-to-treat analysis
Not intended as cross-trial comparison
Not approved in Canada for stroke prevention in
AF patients P value superiority
Connolly SJ, et al for the RE-LY Steering
Committee and Investigators. N Engl J Med.
2009361(12)1139-51 Connolly SJ, et al for
the RE-LY Investigators. N Engl J Med.
2010363(19)1875-6 (updated) Patel MR, et al
and the ROCKET AF Steering Committee for the
ROCKET AF Investigators. N Engl J Med.
2011365(10)883-91 Granger CB, et al for the
ARISTOTLE Committees and Investigators. N Engl J
Med. 2011365(11)981-92.
22
New Oral Anticoagulants vs. Warfarin
Intracranial Hemorrhage
P Value
P lt 0.001
P lt 0.001
P lt 0.001
P 0.02
0.50
0.25
0.75
Data obtained from intention-to-treat analysis
Not intended as cross-trial comparison
Not approved in Canada for stroke prevention in
AF patients P value superiority
Connolly SJ, et al for the RE-LY Steering
Committee and Investigators. N Engl J Med.
20093611139-51 Patel MR, et al and the ROCKET
AF Steering Committee for the ROCKET AF
Investigators. N Engl J Med. 2011365883-91 Gran
ger CB, et al for the ARISTOTLE Committees and
Investigators. N Engl J Med. 2011 365981-92.
23
New Oral Anticoagulants vs. Warfarin All-Cause
Mortality
P Value
P 0.047
P 0.13
P 0.051
P 0.073
0.75
Not intended as cross-trial comparison Not
approved in Canada for stroke prevention in AF
patients P value superiority
Connolly SJ, et al for the RE-LY Steering
Committee and Investigators. N Engl J Med.
20093611139-51 Patel MR, et al and the ROCKET
AF Steering Committee for the ROCKET AF
Investigators. N Engl J Med. 2011365883-91 Gran
ger CB, et al for the ARISTOTLE Committees and
Investigators. N Engl J Med. 2011 365981-92.
24
RE-LY ICH subgroup analysis sites/rates of ICH
dabigatran 110 mg BID vs warfarin1

• Significantly lower rates of ICH, intracerebral,
  and subdural haematoma with dabigatran 110 mg BID

Dabigatran 110 mg BID vs warfarin
N/rate (/yr) N/rate (/yr)
D 110 mg BID Warfarin
All ICH (n154) 27/0.23 90/0.76
Intracerebral (n71) 14/0.12 46/0.39
Subdural (n70) 10/0.08 36/0.31
Subarachnoid (n13) 3/0.03 8/0.06
RR (95 CI) P value
0.30 (0.19, 0.45) Plt0.001
0.30 (0.16, 0.54) Plt0.001
0.27 (0.12, 0.55) Plt0.001
0.37 PNS
0.5
1.0
1.5
0
2.0
Dabigatran better
Warfarin better

• BID twice daily CI confidence interval D
  dabigatran ICH intracranial haemorrhage NS
  non-significant RR relative risk

1. Hart RG et al. Intracranial hemorrhage in atrial
   fibrillation patients during anticoagulation with
   warfarin or dabigatran the RE-LY trial. Am Heart
   J 2012 4-5

25
CCS Atrial Fibrillation Guidelines 2012
Prevention of Stroke and Systemic Thromboembolism
in Atrial Fibrillation and Flutter

• John A Cairns, MD, FRCPC,
• Stuart Connolly, MD, FRCPC,
• Gordon Gubitz, MD, FRCPC
• Sean McMurtry, MD, PhD, FRCPC,
• Mario Talajic, MD, FRCPC
• Carl Van Walraven, MD, FRCPC, MSc

26
(No Transcript)
27
Assessing the Risk of Stroke
Any other risk factor for stroke?

• gt Age 65?

Prior stroke?
Diabetes?
Anticoagulant indicated
Anticoagulant indicated
Hypertension?
Female with vascular disease?
28
AF Guidelines Recommendations

• We recommend that all patients with AF or AFL
  (paroxysmal, persistent, or permanent), should be
  stratified using a predictive index for stroke
  (e.g., CHADS2) and for the risk of bleeding
  (e.g., HAS-BLED), and that most patients should
  receive either an oral anticoagulant or ASA.
  (Strong Recommendation, High Quality Evidence)

• We suggest, that when OAC therapy is indicated,
  most patients should receive dabigatran or
  rivaroxaban or apixaban in preference to
  warfarin. (Conditional Recommendation, High
  Quality Evidence)

Once approved by Health Canada.
29
AF Guidelines Recommendations

• Values and Preferences This recommendation
  places a relatively high value on comparisons to
  warfarin showing that dabigatran and apixaban
  have greater efficacy and rivaroxaban has similar
  efficacy for stroke prevention dabigatran and
  rivaroxaban no more major bleeding and apixaban
  has less dabigatran, rivaroxaban, and apixaban
  have less intracranial haemorrhage and all three
  new OACs are much simpler to use.

30
New Oral Anticoagulants Drug Interactions
DABIGATRAN RIVAROXABAN APIXABAN
P-gp inhibitors (e.g., ketoconazole verapamil, quinidine, amiodarone) Potent CYP3A4 and P-gp inhibitors (e.g., ketoconazole, itraconazole, voriconazole, posaconazole, and HIV protease inhibitors ritonavir) Potent CYP3A4 and P-gp inhibitors (e.g., ketoconazole, itraconazole, voriconazole, posaconazole, and HIV protease inhibitors)
P-gp inducers (e.g., Rifampicin carbamazepine, St. Johns Wort) Potent CYP3A4 and P-gp inducers (e.g., rifampicin, and the anticonvulsants phenytoin, carbamazapine, phenobarbitone) Potent CYP3A4 and P-gp inducers (e.g., rifampicin, and the anticonvulsants phenytoin, carbamazapine, phenobarbitone)
P-gp inhibitors may be expected to decrease systemic exposure to dabigatran, rivoraxaban and apixaban P-gp inducers reduce plasma concentrations of dabigatran, rivaroxaban and apixaban Combined potent CYP3A4 and P-gp inhibitors is expected to increase exposure to rivoraxaban and apixaban Combined potemt CYP3A4 and P-gp inducers is expected to reduce plasma concentrations of rivaroxaban and apixaban P-gp inhibitors may be expected to decrease systemic exposure to dabigatran, rivoraxaban and apixaban P-gp inducers reduce plasma concentrations of dabigatran, rivaroxaban and apixaban Combined potent CYP3A4 and P-gp inhibitors is expected to increase exposure to rivoraxaban and apixaban Combined potemt CYP3A4 and P-gp inducers is expected to reduce plasma concentrations of rivaroxaban and apixaban P-gp inhibitors may be expected to decrease systemic exposure to dabigatran, rivoraxaban and apixaban P-gp inducers reduce plasma concentrations of dabigatran, rivaroxaban and apixaban Combined potent CYP3A4 and P-gp inhibitors is expected to increase exposure to rivoraxaban and apixaban Combined potemt CYP3A4 and P-gp inducers is expected to reduce plasma concentrations of rivaroxaban and apixaban
Note Concomitant administration of NSAIDs,
aspirin or clopidogrel may increase bleeding time
for rivaroxaban, dabigatran and
apixaban. Apixaban not yet approved in Canada for
stroke prevention in patients with atrial
fibrilliation.

1. Pradax (Dabigatran Etexilate Capsules) Product
   Monograph, 2012, Boehringer Ingelheim Canada Ltd.
2. Xarelto (Rivaroxaban tablet) Product Monograph,
   February 2012, Bayer Inc.
3. Granger C, et al. N Engl J Med 2011365981-992.

31
When to Start OAC Post-Stroke ?
32
Spontaneous Hemorrhagic Transformation 7 days
post stroke
33
Starting OCA post-Stroke

• Pre-treatment CT scan on all symptomatic
  patients.
• TIAs may start immediately after ICH excluded
• Minor/mod strokes may start within 3-7 days
• Major strokes the bigger the stroke the longer
  you wait (2-4 weeks)
• New OACs wait at least 2 weeks post-stroke
  prior to starting

http//www.esostroke.org/pdf/ESO20 Guidelines
update Jan 2009
34
Antithrombotic and Thrombolytic Therapyfor
Ischemic StrokeAntithrombotic Therapy and
Prevention of Thrombosis,9th ed American
College of Chest PhysiciansEvidence-Based
Clinical Practice Guidelines

• We recommend initiation of oral anticoagulation
  therapy within 2 weeks of a cardioembolic stroke
  however, for patients with large infarcts or
  other risk factors for hemorrhage, additional
  delays are appropriate.

CHEST 2012 141(2)(Suppl)e601Se636S
35
Selecting the Optimal Patient

• Consider for
• Those with unexplained poor warfarin control
• Unavoidable drug-drug interactions
• New patients with atrial fibrillation
• Avoid in
• Patients well-controlled on warfarin (TTR 65)
• Renal failure (CrCl lt 30 mL/min)
• Mechanical heart valve replacement
• Combination of GI disease elderly
• Poor adherence
• Cost concerns

Schulman Crowther. Blood 20121193016-23
36
Important Patient Characteristics

• Age
• Be aware of dose adjustment gt age 80

• Extremes of weight
• Limited data on if / how dose should be adjusted

• Renal Function
• AVOID in patients with CrCl lt 30 mL/min
• CAUTION - ? dose adjustment needed in patients
  with CrCl 30-50mL /min

37
Switching patients from warfarin to newer
anticoagulants

• Assess the patients renal function
• Estimated creatinine clearance must be 30 ml/min
  to consider using dabigatran or rivaroxaban
• Stop warfarin and monitor INR
• Initiate dabigatran or rivaroxaban when INR 2.0
• Dabigatran Twice daily dosing
• Rivaroxaban In the morning or evening with a
  meal
• Evaluate risk factors for bleeding on dabigatran
  or rivaroxaban
• Low body weight (e.g., lt50 kg)
• Older age (e.g., 75 years)
• Concomitant use of ASA, clopidogrel or NSAID
• Use dabigatran 150 mg BID regimen unless there is
  increased risk for bleeding in that case use
  dabigatran 110 mg BID
• Use rivaroxaban 20 mg once daily for patients
  with increased risk for bleeding use 15 mg once
  daily, including in patients with estimated
  creatinine clearance between 30-49 mL/min

38
Clinical Monitoring
The lack of required monitoring is convenient,
however

• Remember!
• Clinical status
• Reinforce adherence
• Drug interactions
• Patient education for bleeding

39
Lab Monitoring When Is It Needed ?
Suspected underdose or overdose
Acute thromboembolic event
Bleeding
Pre-procedure safety elective and urgent,
particularly in the setting of renal dysfunction
40
Renal Function Monitoring

• Depends on age, pre-existing renal function,
  co-morbidities, other medications and choice of
  NOAC

CrCl
Monitoring
gt 50

• Yearly
• with clinical deterioration

30 - 50

• Q6 months
• with clinical deterioration

lt 30

• Contraindicated

41
Dabigatran
Hemoclot TT Assay linear dose response
aPTT curvilinear dose response
van Ryn. Thromb Haemost 20101031116-27
42
Rivaroxaban
PT / INR
Tripodi. J Thromb Haemost 20119226-8
43
Lab Monitoring Summary
Assessment of Reversal
Monitoring of Drug Level
44
Pre-Procedure Use of Dabigatran
Renal function(CrCl, mL/min)
Timing of last dose pre-procedure
Half-life (hr) (range)
High risk
Standard risk
50
15 (12-34)
1 day
2 days
30 - 49
18 (13-23)
2 days (consideraPTT pre)
4 days (consider aPTT pre)
lt 30
gt 27 (22-35)
4 days (aPTT pre)
6 days (aPTT pre)
Use of dabigatran contraindicated
Schulman Crowther. Blood 20121193016-23
45
Pre-Procedure Use of Rivaroxaban
Renal function(CrCl, mL/min)
Timing of last dose pre-procedure
Half-life (hr) (range)
High risk
Standard risk
30
12 (11-13)
1 day
2 days
lt 30
Unknown
2 days (INR pre)
4 days (INR pre)
Use of rivaroxaban contraindicated
Schulman Crowther. Blood 20121193016-23
46
Reversing Anticoagulation
XII
XI
IX
VII
VIII
X

• Oral Xa inhibitor
• Rivaroxaban
• Apixaban

V
II

• Oral IIa inhibitor
• Dabigatran

I
Fibrin clot
47
Potential Considerations in Selection of OAC

• Age
• Gender
• Diabetes
• Prior stroke history
• Moderate or excellent renal function
• CHADS2 score
• HASBLED score
• Cost
• Personal preference

48
Patients unsuitable for new anticoagulants
(Dabigatran, rivaroxaban)

• AF patients not recommended for therapy with new
  anticoagulant agents approved for stroke
  prevention include
• Patients with valvular heart disease
• Patients with mechanical valves
• Patients with advanced renal impairment (CrCllt30
  mL/min)
• Patients with active bleeding

1. Pradax (Dabigatran Etexilate Capsules) Product
   Monograph, 2012, Boehringer Ingelheim Canada Ltd.
2. Xarelto (Rivaroxaban tablet) Product Monograph,
   February 2012, Bayer Inc.

49
Summary of 2010 CCS AF GuidelinesPatients
Requiring Surgery
Cairns et al. Can J Card 2011 2774-90
50
Perioperative Management of Anticoagulant Therapy

• Alteration of oral anticoagulant regimen may not
  be necessary for most patients undergoing low
  risk procedures
• Dental procedures, joint and soft tissue
  injections and arthrocentesis, cataract surgery,
  and upper endoscopy or colonoscopy with or
  without biopsy
• For other invasive and surgical procedures, oral
  anticoagulation needs to be withheld
• Decision whether to pursue an aggressive strategy
  of perioperative administration of intravenous
  heparin or subcutaneous low molecular-weight
  heparin should be individualized based on an
  estimation of the patients risks of
  thromboembolism and bleeding and the patients
  preference

Douketis J, et al. Chest 2008133299S-339S Dunn
AS and Turpie AGG. Arch Intern Med
2003163901-908
51

Surgical / Diagnostic ProceduresSummary of 2010
Canadian Cardiovascular Society (CCS) Guidelines

• Patients with Low to Moderate Stroke Risk (CHADS2
  2)
• Discontinue antithrombotic therapy before
  procedure
• ASA or clopidogrel for 7-10 days
• Warfarin for 5 days if INR within 2-3 range
• Dabigatran for 2 days
• Rivaroxaban for 2 days
• Reinstate antithrombotic therapy once
  post-procedure hemostasis restored ( 24 hrs)

Cairns et al. Can J Card 2011 2774-90
52
Acute Stroke in Setting of Dabigatran

• Obtain aPTT and/or thrombin time
• If normal treat as if not on dabigatran
• If elevated assume therapeutic level of
  anticoagulation
• No IV TPA
• Consider intra-arterial treatment based on
• Availability/experience
• Deficit warrants intervention
• Demonstrable arterial occlusion
• /- mismatch

53
Thank you

54
Timing of Discontinuation After LAST Dose of
Dabigatran Before Surgery
Creatinine Clearance Timing of discontinuation after last dose of dabigatran before surgery Timing of discontinuation after last dose of dabigatran before surgery
Creatinine Clearance Standard risk of bleeding High risk of bleeding
gt 50 mL/min 24 hours 2 4 days
gt 30 mL/min 50 mL/min At least 48 hours 4 days
30 mL/min 2 5 days gt 5 days
Adapted from Van Ryn Thomb Haemost 20101031116