Freeport Physicians’ C.M.E. Day Waterloo – May 6, 2009 Antithrombotic Therapy in the Elderly...

Freeport Physicians’ C.M.E. DayWaterloo – May 6, 2009

Antithrombotic Therapy in the

ElderlyBill Geerts, MD, FRCPC

Thromboembolism Specialist Sunnybrook Health Sciences CentreProfessor of Medicine, U. of Toronto

National Lead, VTE Prevention, Safer Healthcare Now!

Disclosures

Personal/family none investments

Grants/program Bayer, Boehringer Ingelheim, support Pfizer, Sanofi Aventis

Advisory boards, Bayer, Boehringer Ingelheim, consultancies Covidien, Daiichi Sankyo,

Pfizer, Sanofi Aventis

Honoraria for Bayer, Boehringer Ingelheim, education Leo Pharma, Pfizer, Sanofi Aventis

Humor in my presentation I wish there was more

Guess Who’s 50 this Year?

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: Objectives

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

0.1

1.7

3.0

5.0

9.1

7.2

5.0

3.4

1.71.0

0.4

7.3

11.1

10.3

0.90.2

0123456

789

101112

<55 55-59 60-64 65-69 70-74 75-79 80-84 >=85

Age, yr

Pre

vale

nce

, %

Women Men

Go - JAMA 2001;285:2370

5% age >6510% age >80

Prevalence of Atrial Fibrillation by Age and Sex

Potentially Preventable Strokes

Gladstone – Stroke 2009;40:235

Prospective data from 12 Ontario stroke centers 2003-7 All 597 patients with a 1st ischemic stroke

+ known high risk AF + no contraindication to anticoagulation+ living independently

Excluded patients with new AF, mechanical heart valve

Stroke Outcome:

Disabling 60%

Fatal 20%

Best casescenario



Ischemic stroke + high risk AF + no contraindication to anticoagulation (n=597)

Warfarin therapeutic

10%

Warfarin subtherapeutic

29%

Antiplatelettherapy

30%

No antithrombotic

29%

Warfarin use40%



Ischemic stroke + high risk AF + no contraindication to anticoagulation

+ previous TIA (n=323)

Warfarin therapeutic

18%

Warfarin subtherapeutic

39%

Antiplatelettherapy

28%

No antithrombotic

15%

Warfarin use57%



Patients with ischemic stroke Ideal candidates for anticoagulation

Any Therapeutic warfarin anticoagulation

Above patients 40% 10%

+ previous TIA 57% 18%

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% P*

No. 1190 1207 1190

Stroke 2.1%/yr 1.3%/yr 1.1%/yr 0.02

Mortality 4.2 1.8 1.7 <0.01

Bleeding 43.6 41.8 34.1 <0.01

Major bleeding 3.9 2.0 1.6 <0.01

White – Arch Intern Med 2007;167:239*Poor vs good control

>

>

>

> >

>

>

>

Anticoagulant Control & Outcomes in AF

White – Arch Intern Med 2007;167:239

Among patients with atrial fibrillation taking warfarin, good INR control resulted in REDUCED:

stroke or systemic embolism

MI

death

bleeding

HIGH RISK• prev TIA/stroke

• mitral stenosisOR 2 or more of:

• age > 75

• hypertension

• diabetes

• LV dysfunction

MODERATE RISK

ONE or more of:

• age > 75

• hypertension

• diabetes

• LV dysfunction

LOW RISK

• age < 75 AND no additional risk factors

Recommendations for Antithrombotic Therapy in AF

OVKA INR 2-3

OVKA INR 2-3over ASA

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 Total (815) Preventable (338)

Warfarin 15 % 12 % Atypical antipsychotics 11 % 12 % Loop diuretics 8 % 10 % Opioids 6 % 8 % Antiplatelets 6 % 7 % ACE inhibitors 6 % 8 % Antidepressants 5 % 7 % Benzodiazepines 5 % 9 % Insulin 5 % 5 %

Gurwitz – Am J Med 2005;118:251


2. Treatment of VTE




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 optionsLMWH S/C

Oral Anticoagulation (INR 2.0 - 3.0)

5-7 d 3 mos-indefinite

1


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 optionsLMWH S/C

Oral Anticoagulation (INR 2.0 - 3.0)

5-7 d 3 mos-indefinite

LMWH S/C?

1

2• pregnancy, uncontrolled adenocarcinoma, failed therapeutic warfarin, high bleeding risk


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


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)


2. Treatment of VTE




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 long-term 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 ICBBrott - Stroke 1986;17:1078Saloheimo - Stroke 2001;32:399Qureshi - 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


What duration of anticoagulation would you provide?

A. 3 months

B. 6 months

C. 12 months

D. Until the DVT resolves

E. Indefinite

Recurrent

VTE

Anticoagulation

Time

Treatment Duration for VTE

0

• secondary

• idiopathic• active cancer• some thrombophilia (APLAS, AT def)• big residual clot

Duration of Treatment for VTE

Recurrent Episodes: indefinite*

1st Episode:

Transient, reversed risk 3 - 6 mos

Idiopathic 12 mos indefinite*

Continuing risk (unresolved cancer, AT deficiency, APLA) indefinite*

Duration of Treatment for VTE

Recurrent Episodes: indefinite*

1st Episode:

Transient, reversed risk 3 - 6 mos

Idiopathic 12 mos indefinite*

Continuing risk (unresolved cancer, AT deficiency, APLA) 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

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



2. Treatment of VTE




Thromboprophylaxis Summary

Patient Group

Options Duration

Medical illness • Low Mol Wt Heparin• Low dose heparin

Discharge

General surgery, gyne, urol

• Low Mol Wt Heparin• Low dose heparin

Discharge

Hip, knee replacement

• Low Mol Wt Heparin• Fondaparinux• rivaroxaban, dabigatran

14-28 days

Hip fracture • Fondaparinux• Low Mol Wt Heparin

14-28 days

Hospital Readmisions for VTE Following THR / TKR

Hospital Readmisions for VTE Following THR / TKR

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

0 7 14 21 28 35 42 49 56 63 70 77 84 91

Days

Th

rom

bo

emb

olic

eve

nts

(%

) THR TKR

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

0 7 14 21 28 35 42 49 56 63 70 77 84 91

Days

Th

rom

bo

emb

olic

eve

nts

(%

) THR TKR

White - Arch Intern Med (1998)

TKR 1 month

THR 3 months

N=43,645

How long should prophylaxis be given?

most medical/surgical patients

Until ambulating = NO!

THR TKR hip fracture surgery

Until discharge

After discharge

14-28 days

How long should prophylaxis be given?

As for similar patients (just a bit longer)

Patients awaiting placement (ALC)

As if they were in acute care

Long term care patients with acute illness

Orthopedic Surgery Prophylaxis

Acute care Discharge or Rehab

1

2

*requires an excellent hospital-based monitoring system

14-35 days

Warfarin INR 2.0-3.0*3

LMWH / fondaparinux

Oral rivaroxaban or dabigatran

• 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

4. Thromboprophylaxis in LTC

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

Alikhan – Blood Coag Fibrinolysis 2003;14:341DiMinno - J Thromb Haemost 2004;2:1292

Weill-Engerer – J Am Geriatr Soc 2004;52:1299

Age

Reduced mobility

Active cancer

Heart failure

Previous VTE

Surgery

Acute medical illness

Underuse of prophylaxis


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

Thromboembolism Risk Groups8th ACCP Guidelines on the Prevention of VTE (2008)

• 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

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.


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


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]

8th ACCP Conference on Antithrombotic Therapy

Geerts – Chest 2008;133:381S

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

Pharmacologic (anticoagulant) Methods of Prophylaxis

Which Orthopedic Patients Should Get DVT Prophylaxis?

• THR, TKR, hip fracture• Major trauma – pelvis, femur/multiple LE #• Spine surgery for cancer or with paresis• Amputation

Definitely in all

Generally not (or individualize)

• Arthroscopy• Isolated below-knee fractures• Upper extremity surgery

Post-Discharge Prophylaxis

THR R

~1 week ~6 weeks

In-hospital After discharge

LMWH

LMWH

Prophylaxis after Discharge Reduces DVT in THR

9 studiesN=3,999

0

10

20

30

Venographic DVT

Pre

vale

nce (

%)

Not extended

Extended prophylaxis

0

10

20

30

Venographic DVT

Pre

vale

nce (

%)

Not extended


Eikelboom – Lancet 2001;358:9

19.6%

9.6%

Risk reduction

51%

Prophylaxis after Discharge Reduces DVT and Symptomatic

VTE after THR

9 studiesN=3,999

0

10

20

30

Venographic DVT Symptomatic VTE

Pre

vale

nce (

%)

Not extended


0

10

20

30


Pre

vale

nce (

%)

Not extended


Eikelboom - Lancet 2001;358:9

19.6%

9.6%

1.3%3.3%

Risk reduction

51%

Risk reduction

61%

Extended Prophylaxis Reduces DVT in Hip Fracture Surgery

Eriksson – Arch Intern Med 2003;163:1337

%

35

30

25

20

15

10

5

0

33%

1.4%

Risk Reduction

96%

Venographic DVT

PlaceboFondaparinux

Extended Prophylaxis Reduces Both Asymptomatic DVT and

Symptomatic VTE in Hip Fracture Surgery

Eriksson – Arch Intern Med 2003;163:1337

%

35

30

25

20

15

10

5

0

33%

1.4%

Risk Reduction

96%

2.7% 0.3%

Risk Reduction

89%


PlaceboFondaparinux

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 Mortality prophylaxis @ 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

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

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

Xa

IIa

TF / VIIa

X IX

IXaVIIIa

Va

II

FibrinFibrinogen Blood Clot

Current Anticoagulants = Multiple Targets

HeparinLMWH

ORAL PARENTERAL

Xa

IIa

TF / VIIa

X IX

IXaVIIIa

Va

II

FibrinFibrinogen

ATWarfarin

Blood Clot

XIa XIIa

New Anticoagulants = Single Targets

Rivaroxaban

Dabigatran

ORAL

Xa

IIa

TF / VIIa

X IX

IXaVIIIa

Va

II

FibrinFibrinogen Blood Clot

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 small half-life in elderly

Weight <50 kg or >120 kg little difference

Rivaroxaban: Oral Direct FXaI

No dose alteration

Rivaroxaban Clinical Trial Program Phase II Phase III

Orthopedics ODIXa-Hip1 RECORD1

ODIXa-Hip2 RECORD2

ODIXa-Knee RECORD3

ODIXa-OD-Hip RECORD4

Medical prophylaxis Magellan

VTE treatment ODIXa-DVT Einstein-DVT

Einstein-DVT Einstein-PE

Einstein-extension

Atrial fibrillation ROCKET AF

Acute cor syndrome ATLAS No. patients ~8,000 ~60,000

Bilateralvenography

Rivaroxaban Phase III Orthopedic Studies (RECORD)

12,383 patients undergoing THR or TKR surgery

Day 42+5

R

Enoxaparin 40 mg od Enoxaparin 30 mg bid

Rivaroxaban 10 mg od

Evening before surgery (1-3)

6–8 hours post-surgery

Day 1

Follow-up

SURGERY

RECORD1-4: Pooled Analysis

Outcome EnoxaparinN=6,200

RivaroxabanN=6,183

P

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

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: Oral Direct Thrombin Inhibitor

Dabigatran Clinical Trial Program Phase II Phase III

Orthopedics BISTRO RE-NOVATE (THR) RE-MODEL (TKR)

RE-MOBILIZE (TKR)

Hip fracture surgery

Other surgical groups

Medical patients

VTE treatment RE-COVER RE-MEDY RE-SONATE

Atrial fibrillation PETRO RE-LY

Acute cor syndrome RE-DEEM

Post-AMI No. of patients ~34,000

Bilateralvenography

8,209 patients undergoing THR or TKR surgery

3 months

R

enoxaparin 40 mg od or 30 mg BID

dabigatran 150 mg od

Evening beforesurgery in 2 trials

Day 1

Follow-up

Dabigatran Phase III Orthopedic Studies

dabigatran 220 mg od

*1/2 dose 1-4 hrs after surgery

SURGERY

*

*

Dabigatran Orthopedic Trials Pooled Analysis: Efficacy Outcomes

Enoxaparin Dabigatran 150 mg

Dabigatran 220 mg

No. 1,409 1,400 1,383

Total VTE + mortality

20.3% 24.7% 21.3%

Major VTE 3.3% 3.8% 3.0%

Rivaroxaban vs Dabigatran

Feature Rivaroxaban Dabigatran

Bioavailability >80% <6%

Target Factor Xa Factor IIa

Half life 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

• 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

Greater patient convenience

• 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

New Oral Anticoagulants in Orthopedic Prophylaxis:

Limitations

0 1 2 3 4 5 6 7 8 9 10 14 21 28days

• Low molecular weight heparin• Rivaroxaban (or dabigatran)

• Obsessive, hosp supervised warfarin

Admit

ORDischargeor rehab

Prophylaxis in Hip or Knee Arthroplasty – start postop

0 1 2 3 4 5 6 7 8 9 10 14 21 28days

• Low molecular weight heparin• Obsessive, hosp supervised warfarin

Admit

ORDischargeor rehab

Prophylaxis in Hip Fracture Surgery - start preop

LMWH

Simplifying Thromboprophylaxis( 2009)

Patient group Prophylaxis Duration

Medical LMWH discharge

General surgical LMWH discharge

Orthopedics LMWH disch +10d rivaroxaban 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 - cytochrome P450 2C9 polymorphisms (CYP 2C9) - vitamin K epoxide reductase (VKOR) polymorphisms

Alcohol intake Nutritional status Diet Activity level Drug interactions

Patient compliance Who’s supervising anticoagulation

Therapeutic Window for OVKA

Stroke risk increases at INR < 2Bleeding risk increases at INR >3

Hylek - NEJM 1996;335:540

Atrial Fibrillation and Stroke 30-year follow-up of Framingham cohort

Age Prevalence of AF

Strokes/ 1000 pt-yr

(no AF)

Strokes/ 1000 pt-yr

(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

Gage – JAMA 2001;285:2864

1,733 patients with atrial fibrillation age 65-95

points

• prior stroke/TIA 2

• age >75 1

• hypertension 1

• diabetes 1

• recent CHF 1

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 (INR 2-3)

ASA 75 mg/d

p

Fatal/disabling stroke, ICH, systemic embolism

1.8%/yr 3.8%/yr 0.003

Ischemic stroke 0.8%/yr 2.5%/yr 0.0004

Hemorrhagic stroke

0.5%/yr 0.4%/yr 0.83

Mant – Lancet 2007;370:493

Inadequacies of AF Treatment

100%

80%

60%

40%

20%

0

65%

15% 13%6%

No INR in INR INR warfarin range low high

Samsa – Arch Intern Med 2000;160:967

660 patients with atrial fibrillation

Target INR with Mechanical Heart Valves

Salem – Chest 2008;133:593S

Position Risk factors Target INR

Aortic Tilting disc or bileaflet

2.5 (2.0-3.0)

Mitral Tilting disc or bileaflet

3.0 (2.5-3.5)

Either Caged ball or disc 3.0 (2.5-3.5)

Either AF, poor LV, LAE 3.0 (2.5-3.0) + ASA

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 gUSDA – 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


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 INR 3.1-3.5 INR 3.6-4.0 INR > 4.0

Increase by5-10%

Decrease by0-10%

Hold 1 doseHold 1-2

doses

Decrease by5-10%

Decrease by10-20%


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

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

• Is there bleeding / high risk of bleeding?• Why did this happen?

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

Surgery with Very Low Bleeding Risk3.0

2.0

1.0

INR

-5 -4 -3 -2 -1 OR 1 2 3 4 5 6

warfarin

DAYS

1.5

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

1

Anticoagulation in Usual (i.e. low)

TE Risk Patients Requiring Surgery

3.0

2.0

1.0

INR

-5 -4 -3 -2 -1 OR 1 2 3 4 5 6

warfarin warfarin

DAYS

? DVT prophylaxis

1.5

2

“Usual” (i.e. low) TE Risk Patients

• Atrial fibrillation (most)

• DVT/PE > 3 months ago

• Mechanical aortic valve with no additional risks

2

Higher Risk Patients Requiring Surgery - “Bridging Therapy”

3.0

2.0

1.0

INR

-5 -4 -3 -2 -1 OR 1 2 3 4 5 6

warfarin warfarin

DAYS

LMWH - full-dose or prophylaxis

full-dose LMWH

1.5

3

“Higher” Risk TE Patients →

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

3

Bridging Anticoagulation for Surgery - 1

Day Action

-5 last day of warfarin

-4 no warfarin

-3 no warfarinfull-dose LMWH in AM

-2 no warfarinfull-dose LMWH in AM

-1 no warfarinfull-dose LMWH in AM+ INR if INR > 1.6, vitamin K 1-2.5 mg PO

Bridging Anticoagulation for Surgery - 2Day Action

OR no LMWHrestart 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 prophylaxiswarfarin usual dose

4-5 LMWH full-dose or prophylaxis+ INR adjust warfarin

stop LMWH when INR > 2

Perioperative Management of Patients on Oral AnticoagulantsSpecial SituationsDentistry

• 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 Concerns1. 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

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Freeport Physicians’ C.M.E. Day Waterloo – May 6, 2009 Antithrombotic Therapy in the Elderly...

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