Transcript Slide 1

Freeport Physicians’ C.M.E. Day
Waterloo – May 6, 2009
Antithrombotic
Therapy in the Elderly
Bill Geerts, MD, FRCPC
Thromboembolism Specialist
Sunnybrook Health Sciences Centre
Professor of Medicine, U. of Toronto
National Lead, VTE Prevention, Safer Healthcare Now!
Disclosures
Personal/family
investments
none
Grants/program
support
Bayer, Boehringer Ingelheim,
Pfizer, Sanofi Aventis
Advisory boards,
consultancies
Bayer, Boehringer Ingelheim,
Covidien, Daiichi Sankyo,
Pfizer, Sanofi Aventis
Honoraria for
education
Bayer, Boehringer Ingelheim,
Leo Pharma, Pfizer, Sanofi
Aventis
Humor in my
presentation
I wish there was more
Guess Who’s 50 this Year?
Antithrombotic Therapy in the
Elderly: Objectives
1. The Problem: thrombosis and
anticoagulants in the elderly
2. Treatment of VTE
3. Starting and maintaining oral
anticoagulation
4. Thromboprophylaxis: implications for
geriatric patients / long-term care
Antithrombotic Therapy in the
Elderly: Summary
1. Thrombosis is very common in the elderly
(AF, VTE, etc)
2. Anticoagulants are under-utilized in the
elderly (esp in AF and VTE prophylaxis)
3. Treatment of VTE: warfarin or LMWH
4. Warfarin management must be obsessive
5. Prophylax elderly with acute VTE risks – hip
fracture, stroke, acute medical illness
Prevalence, %
Prevalence of Atrial Fibrillation
by Age and Sex
12
11
10
9
8
7
6
5
4
3
2
1
0
11.1
Women
Men
10.3
9.1
7.3
5.0
3.0
1.7
0.1 0.2
<55
0.4
0.9
55-59
5% age >65
10% age >80
7.2
5.0
3.4
1.7
1.0
60-64
65-69
70-74
75-79
80-84
>=85
Age, yr
Go - JAMA 2001;285:2370
Potentially Preventable Strokes
 Prospective data from 12 Ontario stroke centers 2003-7
 All 597 patients with a 1st ischemic stroke
+ known high risk AF
Best case
+ no contraindication to anticoagulation
scenario
+ living independently
 Excluded patients with new AF, mechanical heart valve
Stroke Outcome:
Disabling
60%
Fatal
20%
Gladstone – Stroke 2009;40:235
Potentially Preventable Strokes
Ischemic stroke + high risk AF
+ no contraindication to
anticoagulation (n=597)
Warfarin
use
40%
Warfarin
therapeutic
10%
Antiplatelet
therapy
30%
No
antithrombotic
29%
Warfarin
subtherapeutic
29%
Gladstone – Stroke 2009;40:235
Potentially Preventable Strokes
Ischemic stroke + high risk AF + no
contraindication to anticoagulation
+ previous TIA (n=323)
Warfarin
use
57%
Warfarin
therapeutic
18%
Antiplatelet
therapy
28%
No
antithrombotic
15%
Warfarin
subtherapeutic
39%
Gladstone – Stroke 2009;40:235
Potentially Preventable Strokes
 Patients with ischemic stroke
 Ideal candidates for anticoagulation
Any
Therapeutic
warfarin anticoagulation
Above patients
40%
10%
+ previous TIA
57%
18%
Gladstone – Stroke 2009;40:235
Anticoagulant Control & Outcomes in AF
 SPORTIF trials (mean follow-up 17 mos)
 No difference for age, gender, risk factors for stroke
Warfarin Control
Poor Moderate Good
% of time INR 2-3  <60%
60-75% >75%
No.
1190
1207
P*
1190
Stroke
2.1%/yr > 1.3%/yr > 1.1%/yr
Mortality
4.2
> 1.8
> 1.7
<0.01
Bleeding
43.6
>41.8
>34.1
<0.01
3.9
> 2.0
> 1.6
<0.01
Major bleeding
*Poor vs good control
0.02
White – Arch Intern Med 2007;167:239
Anticoagulant Control & Outcomes in AF
Among patients with atrial
fibrillation taking warfarin, good
INR control resulted in REDUCED:
 stroke or systemic embolism
 MI
 death
 bleeding
White – Arch Intern Med 2007;167:239
Recommendations for
Antithrombotic Therapy in AF
HIGH RISK
• prev TIA/stroke
• mitral stenosis
OR 2 or more of:
• age > 75
• hypertension
• diabetes
• LV dysfunction
MODERATE RISK
ONE or more of:
• age > 75
• hypertension
• diabetes
OVKA
INR 2-3
OVKA INR 2-3
over ASA
•
•
LOW RISK
age < 75 AND
no additional
risk factors
LV dysfunction
ASA
Singer – Chest 2008;133:546S
Annual Incidence of VTE
 residents of Worcester, MA
Anderson - Arch Intern Med 1991;151:933
Top 10 Drugs in Long-Term Care
Resulting in Adverse Events
 prospective overall rate = 1 per 10 resident-months
Drug class
Warfarin
Atypical antipsychotics
Loop diuretics
Opioids
Antiplatelets
ACE inhibitors
Antidepressants
Benzodiazepines
Insulin
Total (815)
15 %
11 %
8%
6%
6%
6%
5%
5%
5%
Preventable (338)
12 %
12 %
10 %
8%
7%
8%
7%
9%
5%
Gurwitz – Am J Med 2005;118:251
Antithrombotic Therapy in the
Elderly: Objectives
1. The Problem: thrombosis and
anticoagulants in the elderly
2. Treatment of VTE
3. Starting and maintaining oral
anticoagulation
4. Thromboprophylaxis: implications for
geriatric patients / long-term care
CASE: Mrs. LK
 75 year old woman in long-term care
 Mild cognitive impairment
Previous PUD
Hypertension
Stroke 6 yrs ago, residual Lt hemiparesis
 Mobility: bed-chair, walk with assistance
 Now: increased swelling and
discomfort Lt calf and thigh
Case: Mrs. LK
Doppler ultrasound:
DVT in the popliteal and femoral veins
Case: Mrs. LK (popliteal-femoral DVT)
Which ONE of the following management
options would you select?
A. Transfer to hospital for IV heparin  warfarin
B. Transfer to hospital for SC LMWH 
warfarin
C. LTC treatment with LMWH  warfarin
D. LTC treatment with warfarin alone
Low Molecular Weight Heparin
(dalteparin or Fragmin®; enoxaparin or Lovenox®;
tinzaparin or Innohep®)
Advantages:
- more predictable response
- no dosage adjustment
- no need for lab monitoring
- more effective than heparin
- safer than heparin
- most patients can be Rx’d as OP
- cheaper than using heparin
Disadvantages: - subcutaneous injection daily
- accumulation in renal dysfunction
Long-term Treatment of DVT/PE:
2 options
1
LMWH S/C
Oral Anticoagulation (INR 2.0 - 3.0)
5-7 d
3 mosindefinite
Case: Mrs. LK (popliteal-femoral DVT)
Which of the following management
options would you select?
A. Transfer to hospital for IV heparin  warfarin
No reason to admit or to use heparin
B. Transfer to hospital for SC LMWH  warfarin
No reason to admit to hospital
C. LTC treatment with LMWH  warfarin
YES = treatment of choice
D. LTC treatment with warfarin alone
Never for proximal DVT
Long-term Treatment of DVT/PE:
2 options
1
LMWH S/C
Oral Anticoagulation (INR 2.0 - 3.0)
3 mosindefinite
5-7 d
2 LMWH S/C
?
• pregnancy, uncontrolled adenocarcinoma, failed therapeutic
warfarin, high bleeding risk
Case: Mrs. LK (popliteal-femoral DVT)
What else would you do?
A. Bedrest until pain & swelling decreases
B. Do hypercoagulability testing
C. Look for occult cancer
D. Repeat the Doppler US at 3 months to
look for resolution of the DVT
Case: Mrs. LK (popliteal-femoral DVT)
What else would you do?
A. Bedrest until pain & swelling decreases
No
B. Do hypercoagulability testing
No
C. Look for occult cancer
No
D. Repeat the Doppler US at 3 months to
look for resolution of the DVT
No
2. Treatment of VTE
• Acute treatment of VTE: LMWH (most as OPs)
• Long-term treatment of VTE:
1) warfarin INR 2-3
2) LMWH – active adenocarcinoma, high bleeding
risk, pregnancy
• Encourage patients to remain active (do not
restrict mobility)
Antithrombotic Therapy in the
Elderly: Objectives
1. The Problem: thrombosis and
anticoagulants in the elderly
2. Treatment of VTE
3. Starting and maintaining oral
anticoagulation
4. Thromboprophylaxis: implications for
geriatric patients / long-term care
There is a 50-fold
variation in warfarin
maintenance dose!
(0.5 mg/day – 25 mg/day)
• 100 Sunnybrook Anticoagulation Clinic Patients
Starting Warfarin: 4 Easy Steps
1. Estimate the maintenance dose based on:
age
weight
race
nutritional status
other drugs
liver function
2. Give 1½ x estimated maintenance dose x 2 days
(or estimated maint. dose x 3-4 days if no rush)
3. INR day 3
4. INR < 1.2 (slow responder) -  dose
INR > 1.5 (rapid responder) -  dose
INR 1.2-1.5 – continue estimated maint. dose
Maintaining Warfarin in Elderly
• Obsessive longitudinal record of doses, INR
results using a warfarin dosing sheet
• INR at least once a month
• Automatic alerts for missed INRs
• Instruct patients/staff to report  meds, acute
illness, bleeding
• Don’t over-react to single INR value - use longterm trends
• Use an anticoagulation clinic, if possible, or
pharmacist-run management, or obsessive care
Bleeding and Risk of Falls
 decision analysis in elderly with atrial fibrillation
 Risk of falling is not an important factor in
decision re antithrombotic therapy
 With an average risk of stroke from AF
(5%/yr), benefit:risk favors anticoagulation
unless the person falls > 300 times/yr!
Man-Son-Hing - Arch Intern Med 1999;159:677
Hypertension and Intracranial Bleeding
• BP > 160/95  7 x  risk of ICB
Brott - Stroke 1986;17:1078
Saloheimo - Stroke 2001;32:399
Qureshi - NEJM 2001;344:1450
• Hypertension  risk of intracerebral bleed in
patients taking oral anticoagulants
Hylek - Ann Intern Med 1994;120:897
SPAF - Arch Intern Med 1996;156:409
Diet and Warfarin Use
 Do NOT advise restriction of vitamin
K-containing food = associated with
less stable INR values
 Encourage foods high in vitamin K
(broccoli, spinach, brussels sprouts)
 “Let me know if you plan a major
change in your usual diet.”
ASA and Warfarin Use
• Generally AVOID
• No additional benefit for most patients
• Definite increase in bleeding risk
• There must be a good reason for the
ASA e.g. coronary artery stent; high-risk
mechanical heart valve; TIA despite INR >2
• Therefore, the combination of an
antiplatelet agent and warfarin must be an
ACTIVE decision
Case: Mrs. LK (popliteal-femoral DVT)
What duration of anticoagulation
would you provide?
A. 3 months
B. 6 months
C. 12 months
D. Until the DVT resolves
E. Indefinite
Treatment Duration for VTE
• idiopathic
• active cancer
Anticoagulation
• some thrombophilia
(APLAS, AT def)
• big residual clot
Recurrent
VTE
• secondary
0
Time
Duration of Treatment for VTE
1st Episode:
Transient, reversed risk
Idiopathic
3 - 6 mos
12 mos  indefinite*
Continuing risk (unresolved
cancer, AT deficiency, APLA)
indefinite*
Recurrent Episodes:
indefinite*
Duration of Treatment for VTE
1st Episode:
Transient, reversed risk
Idiopathic
3 - 6 mos
12 mos  indefinite*
Continuing risk (unresolved
cancer, AT deficiency, APLA)
indefinite*
Recurrent Episodes:
indefinite*
*Periodic reassessment re:
1) New patient risk factors for bleeding, thrombosis
2) New knowledge
3) Patient preference
Case: Ms. LK (popliteal-femoral DVT)
What duration of anticoagulation
would you provide?
A. 3 months
B. 6 months
C. 12 months
D. Until the DVT resolves
E. Indefinite – unless important bleeding risk
> recurrent thrombosis risk
3. Starting and maintaining oral anticoagulation
1. Most patients with AF should be on warfarin
2. INR 2.0-3.0 (2.5-3.5 for high risk mechanical
heart valve)
3. Need an obsessive system to monitor OAC –
it makes a difference to outcomes
(+ remember CMPA)
4. Avoid combined antiplatelet agent and
warfarin unless a very good reason
5. Manage hypertension well
6. Encourage vitamin K intake
Antithrombotic Therapy in the
Elderly: Objectives
1. The Problem: thrombosis and
anticoagulants in the elderly
2. Treatment of VTE
3. Starting and maintaining oral
anticoagulation
4. Thromboprophylaxis: implications for
geriatric patients / long-term care
Thromboprophylaxis Summary
Patient
Options
Group
Medical illness • Low Mol Wt Heparin
Duration
Discharge
• Low dose heparin
• Low Mol Wt Heparin
General
surgery, gyne, • Low dose heparin
Discharge
urol
Hip, knee
replacement
14-28 days
Hip fracture
• Low Mol Wt Heparin
• Fondaparinux
• rivaroxaban, dabigatran
• Fondaparinux
• Low Mol Wt Heparin
14-28 days
Hospital Readmisions for VTE
Following THR / TKR
THR
3 months
Thromboembolic events (%)
3.5
THR
TKR
3.0
2.5
2.0
1.5
1.0
TKR
1 month
0.5
0.0
0
7
14
21
28
35
42
49
56
63
70
77
84
91
Days
N=43,645
White - Arch Intern Med (1998)
How long should prophylaxis be given?
Until ambulating = NO!
Until discharge
 most medical/surgical patients
After discharge
 THR
 TKR
 hip fracture surgery
14-28 days
How long should prophylaxis be given?
Patients awaiting placement (ALC)
 As for similar patients (just a bit
longer)
Long term care patients with acute
illness
 As if they were in acute care
Orthopedic Surgery Prophylaxis
Acute care
1
2
3
Discharge or Rehab
Oral rivaroxaban or dabigatran
LMWH / fondaparinux
Warfarin INR 2.0-3.0*
14-35 days
*requires an excellent hospital-based monitoring system
4. Thromboprophylaxis in LTC
• Many geriatric and almost all LTC patients are at
increased risk of VTE
• BUT NO evidence prophylaxis benefit > harm
• When LTC patients are transferred to acute care,
they should almost all receive
thromboprophylaxis in acute care
• And SOME require continuation of prophylaxis
briefly on return from acute care
• Major orthopedic surgery prophylaxis:
- 2-4 weeks of LMWH, fondaparinux,
rivaroxaban, dabigatran
Thrombosis Management in
Geriatrics & Long-term Care
Venous Thromboembolism
in the Elderly
Ratio of incidence in
age >70 vs younger
DVT
4.7
PE
6.2
Stein – Arch Intern Med 2004;164:2260
Risk Factors for VTE in the Elderly
 Age
 Reduced mobility
 Active cancer
 Heart failure
 Previous VTE
 Surgery
 Acute medical illness
 Underuse of prophylaxis
Alikhan – Blood Coag Fibrinolysis 2003;14:341
DiMinno - J Thromb Haemost 2004;2:1292
Weill-Engerer – J Am Geriatr Soc 2004;52:1299
1. The Problem: thrombosis and anticoagulants
in the elderly
In the elderly:
• Thromboembolism (AF, stroke, VTE,
cardiomyopathy, etc) is very common
• Anticoagulants are very effective in
preventing thrombosis
• Physicians tend to underuse anticoagulants
• Bleeding risk increased
• Anticoagulants can be dangerous
Prophylactic and treatment doses
of LMWHs are NOT the same
• For a 75 kg patient with normal renal function
LMWH
Prophylaxis
dose
Treatment
dose
dalteparin
(Fragmin®)
5,000 U QD
15,000 U QD
(200 U/kg QD*)
enoxaparin
(Lovenox®)
30 mg bid or
40 mg QD
120 mg QD
(1.5 mg/kg QD*)
tinzaparin
(Innohep®)
4,500 U QD
13,125 U QD
(175 U/kg QD*)
*no maximum
8th ACCP
Guidelines on
Antithrombotic
Therapy
2008;133:67S-968S
8th ACCP Guidelines on
Antithrombotic Therapy
• Anticoagulants: heparin, LMWH, warfarin
• Antiplatelet agents
• New antithrombotic drugs
• Complications of antithrombotic therapy: bleeding, HIT
• Prevention of venous thromboembolism
• Treatment of venous thromboembolism
• Peri-procedure management
• Arterial disease: AF, CAD, stroke, PAD, valvular disease
• Pregnancy and pediatric thrombotic issues
8th ACCP Guidelines on the Prevention of VTE (2008)
Thromboembolism Risk Groups
• General surgery
• Vascular surgery
• Gynecologic surgery
• Urologic surgery
• Thoracic surgery
• Bariatric surgery
• Laparoscopic surgery
• Cor. bypass surgery
• Hip arthroplasty
• Knee arthroplasty
• Knee arthroscopy
• Hip fracture surgery
• Spine surgery
• Lower extremity injuries
• Neurosurgery
• Major trauma
• Spinal cord injuries
• Burn patients
• Medical patients
• Cancer patients
• Central venous catheters
• Critical care patients
• Long distance travel
Geerts – Chest 2008;133:381S
ACCP Guidelines on Thromboprophylaxis
For each patient group:
1. risks of VTE
2. prophylaxis evidence
3. graded recommendations
Mechanical Methods of Prophylaxis
1. Graduated compression stockings
(TEDS™, elastic stockings)
2. Intermittent pneumatic compression
devices (SCDs™, leg squeezers)
3. Foot pumps
Mechanical Methods of Prophylaxis
1. Graduated compression stockings
(TEDS™, elastic stockings)
2. Intermittent pneumatic compression
devices (SCDs™, leg squeezers)
3. Foot pumps
• If used properly, these methods work in
some patients, but
• They generally don’t work as well as
anticoagulants, and
• They require a big effort to work at all.
Mechanical Methods of Prophylaxis
Using Mechanical Prophylaxis:
1. Ensure they fit properly
2. Start ASAP
3. Have on ~24 hours/day – only remove
- for leg washing
- when patient actually walking
4. Don’t stop when patient starts to walk
8th ACCP Conference on Antithrombotic Therapy
1.4.3 Mechanical prophylaxis used primarily:
- in patients at high risk of bleeding
[Grade 1A],
- or possibly in addition to anticoagulant
prophylaxis
[Grade 2A]
Recommend careful attention to proper use of
and optimal compliance with mechanical
prophylaxis
[Grade 1A]
Geerts – Chest 2008;133:381S
Pharmacologic (anticoagulant)
Methods of Prophylaxis
1. Low dose heparin / minidose heparin
heparin 5,000 U SC Q12H or Q8H
2. Low molecular weight heparin
enoxaparin (Lovenox) 40 mg SC QD or 30 mg SC Q12H
dalteparin (Fragmin) 5,000 U SC QD
tinzaparin (Innohep) 3,500 or 4,500 U SC QD
3. Fondaparinux (Arixtra) 2.5 mg SC QD
4. Warfarin (Coumadin)
5. New oral Factor Xa and Factor IIa Inhibitors
Pharmacologic (anticoagulant)
Methods of Prophylaxis
Using anticoagulant prophylaxis:
1. Start ASAS (safe) once bleeding stopped
- usually day of or after admission or
surgery
2. Try to avoid missing a dose
- don’t hold for most procedures
- consider routine qhs dosing
3. Continue at least until discharge
Which Orthopedic Patients
Should Get DVT Prophylaxis?
Definitely in all
•
•
•
•
THR, TKR, hip fracture
Major trauma – pelvis, femur/multiple LE #
Spine surgery for cancer or with paresis
Amputation
Generally not (or individualize)
• Arthroscopy
• Isolated below-knee fractures
• Upper extremity surgery
Post-Discharge Prophylaxis
In-hospital
After discharge
~1 week
~6 weeks
LMWH
THR
R
LMWH
Prophylaxis after Discharge
Reduces DVT in THR
30
Extended prophylaxis
Prevalence (%)
9 studies
N=3,999
20
19.6%
Risk
reduction
51%
10
Eikelboom –
Lancet 2001;358:9
Not extended
9.6%
0
Venographic DVT
Prophylaxis after Discharge
Reduces DVT and Symptomatic
VTE after THR
30
Extended prophylaxis
Prevalence (%)
9 studies
N=3,999
Not extended
20
19.6%
Risk
reduction
51%
10
9.6%
Risk
reduction
61%
3.3%
1.3%
0
Eikelboom - Lancet 2001;358:9
Venographic DVT Symptomatic VTE
Extended Prophylaxis Reduces DVT
in Hip Fracture Surgery
35
33%
Placebo
Fondaparinux
30
25
%
20
Risk
Reduction
96%
15
10
5
1.4%
0
Venographic DVT
Eriksson – Arch Intern Med 2003;163:1337
Extended Prophylaxis Reduces Both
Asymptomatic DVT and Symptomatic
VTE in Hip Fracture Surgery
35
33%
Placebo
Fondaparinux
30
25
%
20
15
Risk
Reduction
96%
Risk
Reduction
89%
10
5
1.4%
2.7%
0.3%
0
Venographic DVT Symptomatic VTE
Eriksson – Arch Intern Med 2003;163:1337
Use of Post-discharge Prophylaxis
Associated with Reduced Mortality
after Hip/Knee Arthroplasty
•
10,744 patients discharged home after
THR/TKR from 64 Quebec hospitals
Post-discharge
prophylaxis
Mortality
@ 3 mos
No (81%)
2.4%
Yes (19%)
0.7%
* Hazard ratio for death = 0.34 [0.20-0.57]
Rahme, Kahn – CMAJ 2008;178:1545
Post-discharge Prophylaxis and Mortality
LOS < 7 days
LOS 8-14 days
LOS 15-30 days
Rahme, Kahn – CMAJ 2008;178:1545
Use of Post-discharge Prophylaxis
after Hip/Knee Arthroplasty
Conclusions:
• Only 19% of patients >65, discharged home after
THR/TKR, received post-discharge prophylaxis
• Use of post-discharge prophylaxis was associated
with > 3-fold decrease in mortality at 3 months
• When patients with cancer, AF, CHF, IHD were
excluded, the association was even stronger
Rahme, Kahn – CMAJ 2008;178:1545
The Future of Thromboprophylaxis
1. Oral route
2. One drug/one dose for (almost) all
patients at risk
3. Relatively inexpensive
4. Used routinely for duration of risk
Simplified Coagulation System
TF / VIIa
X
IX
VIIIa
IXa
Va
Xa
II
IIa
Fibrinogen
Fibrin
Blood Clot
Current Anticoagulants = Multiple Targets
ORAL
PARENTERAL
TF / VIIa
X
IX
VIIIa
Warfarin
XIa
XIIa
IXa
Va
AT
Xa
Heparin
LMWH
II
IIa
Fibrinogen
Fibrin
Blood Clot
New Anticoagulants = Single Targets
ORAL
TF / VIIa
X
IX
VIIIa
IXa
Va
Rivaroxaban
Xa
II
Dabigatran
Fibrinogen
IIa
Fibrin
Blood Clot
Rivaroxaban: Oral Direct FXaI
Producer
Bayer Healthcare/Johnson & Johnson
Bioavailability
> 80%
Peak level
2-4 hours
Half life
6-9 hours (11-13 hrs in elderly)
Elimination
2/3 renal; 1/3 biliary
Drug interactions  levels with potent CYP3A4 inhibitors
(ketoconazole, HIV protease inhibitors)
 levels with potent CYP3A4 inducers
(rifampin)
Age
Weight
small  half-life in elderly
<50 kg or >120 kg 
little difference
No dose
alteration
Rivaroxaban Clinical Trial Program
Phase II
Orthopedics
ODIXa-Hip1
RECORD1
ODIXa-Hip2
RECORD2
ODIXa-Knee
RECORD3
ODIXa-OD-Hip
RECORD4
Medical prophylaxis
VTE treatment
Phase III
Magellan
ODIXa-DVT
Einstein-DVT
Einstein-DVT
Einstein-PE
Einstein-extension
Atrial fibrillation
Acute cor syndrome
No. patients
ROCKET AF
ATLAS
~8,000
~60,000
Rivaroxaban Phase III
Orthopedic Studies (RECORD)
 12,383 patients undergoing THR or TKR surgery
R
S
U
R
G
E
R
Y
Rivaroxaban 10 mg od
6–8 hours post-surgery
Bilateral Follow-up
venography
Enoxaparin 40 mg od
Enoxaparin 30 mg bid
Evening before surgery (1-3)
Day 1
Day 42+5
RECORD1-4: Pooled Analysis
Outcome
Enoxaparin Rivaroxaban
P
N=6,200
N=6,183
Symptomatic VTE
+ death
101 (1.6%)
50 (0.8%)
<0.001
Death
25 (0.4%)
13 (0.2%)
0.055
Major bleeding
17 (0.3%)
27 (0.4%)
0.135
Any bleeding
415 (6.7%)
452 (7.3%)
0.207
Death + MI +
stroke + symptom.
VTE + major
bleeding
139 (2.2%)
96 (1.6%)
0.004
Turpie – Blood 2008;112:36A
Dabigatran: Oral Direct
Thrombin Inhibitor
Producer
Boehringer Ingelheim
Bioavailability
4-6.5 %
Peak level
2 hours
Half life
11 hours (14-17 hrs in elderly)
Elimination
85% renal
Drug interactions No CYP450 effect
 levels with potent P-gp inhibitors
(verapamil, clarithromycin, quinidine)
 levels with potent P-gp inducers
(rifampin, St. John’s wort)
Dabigatran Clinical Trial Program
Phase II
Orthopedics
BISTRO
Phase III
RE-NOVATE (THR)
RE-MODEL (TKR)
RE-MOBILIZE (TKR)
Hip fracture surgery
Other surgical groups
Medical patients
VTE treatment
Atrial fibrillation
Acute cor syndrome
RE-COVER
RE-MEDY
RE-SONATE
PETRO
RE-LY
RE-DEEM
Post-AMI
No. of patients
~34,000
Dabigatran Phase III
Orthopedic Studies
 8,209 patients undergoing THR or TKR surgery
R
S
U
R
G
E
R
Y
*
dabigatran 150 mg od
*
dabigatran 220 mg od
Evening before
surgery in 2 trials
Bilateral
venography
Follow-up
enoxaparin 40 mg od
or 30 mg BID
Day 1
*1/2 dose 1-4 hrs after surgery
3 months
Dabigatran Orthopedic Trials Pooled
Analysis: Efficacy Outcomes
Enoxaparin Dabigatran
150 mg
Dabigatran
220 mg
No.
1,409
1,400
1,383
Total VTE
+ mortality
Major VTE
20.3%
24.7%
21.3%
3.3%
3.8%
3.0%
Rivaroxaban vs Dabigatran
Feature
Bioavailability
Target
Half life
Rivaroxaban
Dabigatran
>80%
<6%
Factor Xa
Factor IIa
6-13 hrs
11-17 hrs
Drug interactions Few (CYP
3A4)
Few (P-gp)
Renal excretion
<35%
85%
Administration
1 tablet
2 capsules
Efficacy
> LMWH
< LMWH
New Oral Anticoagulants in
Orthopedic Prophylaxis: Strengths
• Oral route
• No lab monitoring
• Rapid onset
Greater patient
convenience
• Potential for more patients to get appropriate
prophylaxis for the appropriate duration
• Will lead to getting rid of warfarin as prophylaxis
• Overall costs may be ~ to LMWH and warfarin
New Oral Anticoagulants in
Orthopedic Prophylaxis: Limitations
• No hip fracture, trauma data
• Uncertainty about impact of: renal function,
age, patient weight, use of epidural
• What if patient is NPO?
• New drugs - ? unexpected adverse effects with
more widespread use
• Uncertainty about reimbursement
• Temptation to use off-label = DON’T
Prophylaxis in Hip or Knee
Arthroplasty – start postop
Admit
OR
Discharge
or rehab
• Low molecular weight heparin
• Rivaroxaban (or dabigatran)
• Obsessive, hosp supervised warfarin
0 1 2 3 4 5 6 7 8 9 10
days
14
21
28
Prophylaxis in Hip Fracture
Surgery - start preop
Admit
OR
Discharge
or rehab
LMWH
• Low molecular weight heparin
• Obsessive, hosp supervised warfarin
0 1 2 3 4 5 6 7 8 9 10
days
14
21
28
Simplifying Thromboprophylaxis
(
2009)
Patient group
Prophylaxis
Duration
Medical
LMWH
discharge
General surgical
LMWH
discharge
Orthopedics
LMWH
rivaroxaban
disch +10d
15 d
Trauma/SCI
LMWH
rehab d/c
ICU
LMWH
discharge
High bleeding risk
TEDS until risk   LMWH
Factors Contributing to Patient
Variability in Warfarin Dose
 Age
 Weight
 Race
 Liver disease
 Heart failure
 Genetics
 Alcohol intake
 Nutritional status
 Diet
 Activity level
 Drug interactions
- cytochrome P450 2C9 polymorphisms (CYP 2C9)
- vitamin K epoxide reductase (VKOR) polymorphisms
 Patient compliance
 Who’s supervising anticoagulation
Therapeutic Window for OVKA
Stroke risk increases at INR < 2
Bleeding risk increases at INR >3
Hylek - NEJM 1996;335:540
Atrial Fibrillation and Stroke
 30-year follow-up of Framingham cohort
Age
Prevalence Strokes/
Strokes/
of AF
1000 pt-yr 1000 pt-yr
(no AF)
(AF)
RR
60-69
1.8%
4.5
21
4.7
70-79
4.7%
9
49
5.4
80-89
10.2%
14
71
5.0
Wolf – Arch Intern Med 1987;147:1561
Risk of Stroke in AF: CHADS2 Score
 1,733 patients with atrial fibrillation age 65-95
points
• prior stroke/TIA
• age >75
• hypertension
• diabetes
• recent CHF
2
1
1
1
1
Gage – JAMA 2001;285:2864
CHADS2 score stroke rate/
100 pt-years
0
1.9 [1.2-3.0]
1
2.8 [2.0-3.8]
2
4.0 [3.1-5.1]
3
5.9 [4.6-7.3]
4
8.5 [6.3-11.1]
5
12.5 [8.2-17.5]
6
18.2 [10.5-27.4]
ASA vs Warfarin in Elderly with AF
 BAFTA = Birmingham Atrial Fibrillation Treatment of
the Aged (>75 years)
Warfarin ASA 75
(INR 2-3) mg/d
p
Fatal/disabling
stroke, ICH,
systemic embolism
1.8%/yr
3.8%/yr
Ischemic stroke
0.8%/yr
2.5%/yr 0.0004
Hemorrhagic
stroke
0.5%/yr
0.4%/yr
0.003
0.83
Mant – Lancet 2007;370:493
Inadequacies of AF Treatment
 660 patients with atrial fibrillation
100%
80%
65%
60%
40%
15%
20%
13%
6%
0
No
warfarin
INR in
range
INR
low
INR
high
Samsa – Arch Intern Med 2000;160:967
Target INR with Mechanical Heart
Valves
Position
Risk factors
Target INR
2.5 (2.0-3.0)
Either
Tilting disc or
bileaflet
Tilting disc or
bileaflet
Caged ball or disc
Either
AF, poor LV, LAE
3.0 (2.5-3.0)
+ ASA
Aortic
Mitral
3.0 (2.5-3.5)
3.0 (2.5-3.5)
Salem – Chest 2008;133:593S
Vitamin K Content of Selected
Foods
Food
Quantity Vit K Content
Broccoli, cooked
½ cup
92 g
Spinach, cooked
½ cup
444 g
Collard greens
½ cup
418 g
Brussels sprouts
5 sprouts
168 g
Soybean oil
7 TBSP
134 g
USDA – www.ars.usda.gov/ba/bhnrc/nd
NSAIDs and Warfarin Use
• Generally NOT a problem
• Not anticoagulants; minimal platelet inhibition
• Effect on INR unpredictable
• Like all meds, there should be a good reason
for the NSAID
• If starting regular NSAID use, check INR 4-7
days later (if using PRN, don’t bother)
• High-risk elderly, consider adding PPI
Anticoagulant-Related Bleeding in
Older Persons with AF
• systematic review of factors that  bleeding in
elderly on OAC
NO: - previous, resolved UGI bleed
- risk of falls
- age a mild risk factor vs  thrombosis risk
YES: - uncontrolled hypertension
- head trauma
- high INR
- alcohol abuse
- poor compliance
- poor monitoring
Man-Son-Hing - Arch Intern Med 2003;163:1580
Anticoagulation Rule No. 5:
If the INR value is not what you
expected, ask the question, “Why
did this happen?”
INR Higher than Expected
• Miscommunication about dosing or change in
dosing (doctor or patient)
“Tell me what doses you’ve taken since the last INR”
• New medication – antibiotics, high dose
acetaminophen, amiodarone, NSAIDs, statins,
omeprazole, OTC, herbals
• Substantial alcohol excess
• Stopped medication – phenytoin
• Intercurrent illness
• Nutrition change – decrease vitamin K intake
INR Lower than Expected
• Compliance
• Compliance
• Compliance
• Miscommunication about dosing or change in
dosing (doctor or patient)
“Tell me what doses you’ve taken since the last INR”
• Nutrition change – increase vitamin K
• New medication – ginseng, green tea
Anticoagulation Rule No. 6:
Don’t over-react to small changes
in INR value
and
Generally make small changes in
dose (unless dangerous to do so)
- e.g. 5-10% of weekly dose
Target INR:
2.0-3.0
INR < 2.0
Increase by
5-10%
INR 3.1-3.5 INR 3.6-4.0
Decrease by
0-10%
INR > 4.0
Hold 1 dose
Hold 1-2
doses
Decrease by
5-10%
Decrease by
10-20%
Anticoagulation Rule No. 7:
Don’t do INRs too often
- half-life of drug ~ 36 hours
- steady state > 1 week
High INRs on Oral Anticoagulants
• Is there bleeding / high risk of bleeding?
• Why did this happen?
High INRs on Oral Anticoagulants
• Is there bleeding / high risk of bleeding?
• Why did this happen?
No Bleeding
1. omit 1 or more dose(s) of warfarin
2. + small dose of vitamin K (~1 mg PO) if INR >5
3. restart warfarin when INR < 3.5
Mild Bleeding
1. omit 1 or more dose(s) of warfarin
2. small dose of vitamin K (~1 mg PO)
Major Bleeding
1. hold oral anticoagulant
2. vitamin K 10 mg IV
3. PCC or FFP (15 mL/kg) 2-6 U
Peri-procedure Management of
Patients on Long-term
Anticoagulation
Peri-procedure Interruption of
Anticoagulation: Issues
• risk of thromboembolism off
anticoagulants – per day
• risk of bleeding
• hassles, costs
Anticoagulation in Patients Requiring
1 Surgery with Very Low Bleeding Risk
warfarin
3.0
INR
2.0
1.5
1.0
-5
-4
-3
-2
-1
OR
DAYS
1
2
3
4
5
6
1
Patients with Very Low
Bleeding Risk
• Cataract surgery
• Most dental procedures
• Upper GI endoscopy + biopsy
• Colonoscopy without polypectomy
• Removal of most skin lesions
• Thora-, para-, arthro- centesis
Anticoagulation in Usual (i.e. low)
TE Risk Patients Requiring Surgery
2
warfarin
warfarin
3.0
? DVT prophylaxis
INR
2.0
1.5
1.0
-5
-4
-3
-2
-1
OR
DAYS
1
2
3
4
5
6
2
“Usual” (i.e. low) TE Risk
Patients
• Atrial fibrillation (most)
• DVT/PE > 3 months ago
• Mechanical aortic valve
with no additional risks
Higher Risk Patients Requiring
Surgery - “Bridging Therapy”
3
warfarin
warfarin
3.0
full-dose
LMWH
LMWH - full-dose
or prophylaxis
INR
2.0
1.5
1.0
-5
-4
-3
-2
-1
OR
DAYS
1
2
3
4
5
6
“Higher” Risk TE Patients →
3
Bridging Anticoagulation
• DVT < 3 months ago
• All mechanical mitral valves
• Mechanical aortic valve with
additional risk factors
• New cardiac thrombus
• Special cases: retired lawyer, AF,
Grade IV LV, TIA after colonoscopy
Bridging Anticoagulation for Surgery - 1
Day Action
-5
last day of warfarin
-4
no warfarin
-3
no warfarin
full-dose LMWH in AM
-2
no warfarin
full-dose LMWH in AM
-1
no warfarin
full-dose LMWH in AM
+ INR  if INR > 1.6, vitamin K 1-2.5 mg PO
Bridging Anticoagulation for Surgery - 2
Day Action
OR
no LMWH
restart warfarin at 1.5 X usual dose
1
LMWH at full-dose (if low bleeding risk
prophylaxis (if high bleeding risk)
warfarin 1.5 X usual dose
2,3
LMWH full-dose or prophylaxis
warfarin usual dose
4-5
LMWH full-dose or prophylaxis
+ INR  adjust warfarin
stop LMWH when INR > 2
Perioperative Management of
Patients on Oral Anticoagulants
Special Situations
Dentistry
• No interruption for fillings, cleaning, scaling, root
canal, single extractions
• Interrupt for dental surgery, multiple extractions
Cataracts
• No interruption
Colonoscopy – 2 options
1. Interrupt everyone (just in case), or
2. No routine interruption; if big polyp found, reverse
warfarin and then repeat colonoscopy
Anticoagulation in the Elderly:
The Important Concerns
1. Frequently indicated
2. And under-utilized
3. Elderly more sensitive to warfarin
4. Narrow therapeutic index drug
5. Multiple comorbidities
6. Polypharmacy
7. Nutritional - low vitamin K