Download P - Western Stroke Conference

New Oral Anticoagulants
Guidelines and tips
Starting/stopping
Switching/swapping
Measuring/monitoring
Philip Teal MD FRCPC
Sauder Family & Heart and Foundation
Professor of Stroke Neurology
University of British Columbia
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
Objectives
•
•
•
•
•
Risk stratification schemes
2012 Canadian Atrial Fibrillation Guidelines
Starting OAC post stroke
Monitoring the new OACs
Starting/ Stopping
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
4
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
5
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
6
VGH Stroke Service – Week of Aug 19th
YD 62 year old man with AF,
stopped warfarin
HG 86 year old woman with
AF. “falls”
VGH Stroke Service – Week of Aug 19th
JT 71 year old woman with
Afib, untreated
PT 81 year old man with Afib
procedural stop
VGH Stroke Service – Week of Aug
GM 66 year old man post
cardioversion, no Rx
th
19
PS 59 year old man post
gastroscopy, procedural stop
Hyperdense MCA Sign
Large territory strokes in Afib
Quantifying the Risk
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
AF Is Classified By Episode Duration And
the Ability To Return To Sinus Rhythm
1st
Detected
Recurrent if ≥2 episodes
Paroxysmal
Persistent
(self-terminating —
usually within 7 days)
(not self-terminating)
Permanent
(Refractory to cardioversion and/or accepted)
ACC/AHA/ESC 2006 guidelines. J Am Coll Cardiol 2006;48:854-906.
Prediction of Stroke
in AF: CHADS2
Score
C= CHF
1
H=hypertension
1
A= age ≥ 75
1
D= diabetes
1
S= stroke/TIA
2
% Stroke / yr
Risk Factor
CHADS2 score
Adapted from Cairns JA, et al. Can J Cardiol. 2011; 27:74–90.
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:
Points
CHA2DS2VASc
Score
Stroke
Rate per
Year
(%/yr)
Recommended
Therapy
Congestive Heart Failure / Left
Ventricular Dysfunction
1
0
0
ASA
1
1.3
OAC or ASA
Hypertension
1
2
2.2
Age ≥ 75 Years
2
3
3.2
Diabetes Mellitus
1
4
4.0
Prior Stroke or TIA or Systemic
Embolism
2
5
6.7
Vascular Disease
1
6
9.8
Age > 65 but < 75
1
7
9.6
Sex Category – Female
1
8
6.7
9
15.2
CHA2DS2-VASc Score
Sum Of:
OAC
Lip Chest 2010;137:263; Camm Eur Heart J 2010;31:2369
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 > 65 yr)
1
D
Drugs or Alcohol
1 point each
1 or 2
Maximum 9 points
Pisters R et al. Chest. 2010 Nov;138:1093-100
INR 2.2
Warfarin-associated ICH INR 2.7
74 year old, minor fall. On warfarin INR 2.1
Predictors of CNS Bleeding on OAC
•
•
•
•
•
•
•
•
Advanced age > 75 years
Hypertension (systolic BP > 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
New Oral Anticoagulants vs. Warfarin†
All-Cause Stroke or Systemic Embolism
TRIAL
OAC Agent
ARISTOTLE
Relative Risk (95% CI)
P Value#
Apixaban* 5mg BID
P = 0.01
Dabigatran 110mg BID
P = 0.30
Dabigatran 150mg BID
P < 0.001
RE-LY
ROCKET-AF Rivaroxaban 20mg QD
P = 0.12
0.5
1
Novel Anticoagulant
Better
2
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. 2009;361(12):1139-51;
Connolly SJ, et al; for the RE-LY Investigators. N Engl J Med. 2010;363(19):1875-6 (updated);
Patel MR, et al; and the ROCKET AF Steering Committee for the ROCKET AF Investigators. N Engl J Med. 2011;365(10):883-91; Granger
CB, et al; for the ARISTOTLE Committees and Investigators. N Engl J Med. 2011;365(11):981-92.
New Oral Anticoagulants vs. Warfarin†
Intracranial Hemorrhage
TRIAL
ARISTOTLE
Relative Risk (95% CI)
OAC Agent
P Value#
Apixaban* 5mg BID
P < 0.001
Dabigatran 110mg BID
P < 0.001
Dabigatran 150mg BID
P < 0.001
RE-LY
ROCKET-AF Rivaroxaban 20mg QD
P = 0.02
0.25
0.50
Novel Anticoagulant
Better
0.75 1
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. 2009;361:1139-51;
Patel MR, et al; and the ROCKET AF Steering Committee for the ROCKET AF Investigators. N Engl J Med. 2011;365:883-91;
Granger CB, et al; for the ARISTOTLE Committees and Investigators. N Engl J Med. 2011; 365:981-92.
New Oral Anticoagulants vs.
All-Cause Mortality
Relative Risk (95% CI)
†
Warfarin
P Value#
TRIAL
OAC Agent
ARISTOTLE
Apixaban* 5mg BID
P =0.047
Dabigatran 110mg BID
P = 0.13
Dabigatran 150mg BID
P = 0.051
ROCKET-AF Rivaroxaban
.
20mg QD
P = 0.073
RE-LY
0.5
0.75
1
Novel Anticoagulant
Better
2
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. 2009;361:1139-51;
Patel MR, et al; and the ROCKET AF Steering Committee for the ROCKET AF Investigators. N Engl J Med. 2011;365:883-91;
Granger CB, et al; for the ARISTOTLE Committees and Investigators. N Engl J Med. 2011; 365:981-92.
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
Atrial Fibrillation Guidelines
Assessing the Risk of Stroke
Any other risk
factor for stroke?
> Age 65?
Prior stroke?
Anticoagulant
indicated
Diabetes?
Anticoagulant
indicated
Hypertension?
Female with
vascular disease?
AF Guidelines Recommendations
2012 UPDATE
• 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.
New Oral Anticoagulants: Drug Interactions
DABIGATRAN
RIVAROXABAN
APIXABAN
P-gp
(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. John’s 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)
inhibitors*
*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 2011;365:981-992.
When to Start OAC Post-Stroke ?
Spontaneous Hemorrhagic
Transformation – 7 days post stroke
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/ESO%20 Guidelines update Jan 2009
Antithrombotic and Thrombolytic Therapy
for Ischemic Stroke
Antithrombotic Therapy and Prevention of Thrombosis,
9th ed: American College of Chest Physicians
Evidence-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):e601S–e636S
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 < 30 mL/min)
• Mechanical heart valve replacement
• Combination of GI disease + elderly
• Poor adherence
• Cost concerns
Schulman & Crowther. Blood 2012;119:3016-23
Important Patient Characteristics
Age
• Be aware of dose adjustment > age 80
Extremes of weight
• Limited data on if / how dose
should be adjusted
Renal Function
• AVOID in patients with CrCl < 30 mL/min
• CAUTION - ? dose adjustment needed
in patients with CrCl 30-50mL /min
:
Switching patients from warfarin to newer
anticoagulants
Assess the patient’s 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., <50 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
Clinical Monitoring
The lack of “required” monitoring is convenient, however:
Remember!
• Clinical status
• Reinforce adherence
• Drug interactions
• Patient education for bleeding
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
Renal Function Monitoring
• Depends on age, pre-existing renal function, comorbidities, other medications and choice of
NOAC
CrCl
Monitoring
> 50
• Yearly
• + with clinical deterioration
30 - 50
• Q6 months
• + with clinical deterioration
< 30
• Contraindicated
Dabigatran
Hemoclot® TT Assay:
linear dose response
aPTT: curvilinear dose response
van Ryn. Thromb Haemost 2010;103:1116-27
Rivaroxaban
PT / INR
• Dose response
(sensitivity) varies
by PT reagent
• INR is not linear at
therapeutic drug
levels
• ISI of the reagent
must be calibrated
for rivaroxaban,
not warfarin*
*Tripodi. J Thromb Haemost 2011;9:226-8
Lab Monitoring Summary
Assessment of “Reversal”
Dabigatran
aPTT
Rivaroxaban & apixaban
PT / INR
Monitoring of Drug Level
Dabigatran
Hemoclot®
Rivaroxaban & apixaban
Anti-Xa
Pre-Procedure Use of Dabigatran
Timing of last dose
pre-procedure
Renal
function
(CrCl,
mL/min)
Half-life
(hr) (range)
Standard risk
High risk
≥ 50
15 (12-34)
1 day
2 days
30 - 49
18 (13-23)
2 days (consider
aPTT pre)
4 days (consider
aPTT pre)
< 30*
> 27 (22-35) 4 days
(aPTT pre)
* Use of dabigatran contraindicated
Schulman & Crowther. Blood 2012;119:3016-23
6 days
(aPTT pre)
Pre-Procedure Use of Rivaroxaban
Timing of last dose
pre-procedure
Renal
function
(CrCl,
mL/min)
Half-life
(hr) (range)
Standard risk
High risk
≥ 30
12 (11-13)
1 day
2 days
< 30*
Unknown
2 days
(INR pre)
4 days
(INR pre)
* Use of rivaroxaban contraindicated
Schulman & Crowther. Blood 2012;119:3016-23
Reversing Anticoagulation
XII
XI
IX
1. The further down
the cascade the
anticoagulant acts,
the harder to reverse
2. Inhibitors are harder
to reverse than
deficiencies
VII
VIII
X
Oral Xa inhibitor
• Rivaroxaban
• Apixaban
V
II
I
Fibrin clot
Oral IIa inhibitor
• Dabigatran
Potential Considerations in
Selection of OAC
•
•
•
•
•
•
•
•
•
Age
Gender
Diabetes
Prior stroke history
Moderate or excellent renal function
CHADS2 score
HASBLED score
Cost
Personal preference
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 (CrCl<30
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.
Summary of 2010 CCS AF Guidelines:
Patients Requiring Surgery
Cairns et al. Can J Card 2011 27:74-90
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 molecularweight heparin should be individualized based on an estimation of the
patient’s risks of thromboembolism and bleeding and the patient’s
preference
Douketis J, et al. Chest 2008;133:299S-339S;
Dunn AS and Turpie AGG. Arch Intern Med 2003;163:901-908
Surgical / Diagnostic Procedures:
Summary 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 27:74-90
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
Thank you
Timing of Discontinuation After LAST
Dose of Dabigatran Before Surgery
Creatinine Clearance
> 50 mL/min
> 30 mL/min ≤ 50 mL/min
≤ 30 mL/min
Timing of discontinuation after last
dose of dabigatran before surgery
Standard risk of
bleeding
High risk of
bleeding
24 hours
2 – 4 days
At least 48 hours
4 days
2 – 5 days
> 5 days
Adapted from Van Ryn Thomb Haemost 2010;103:1116