Freeport Physicians’ C.M.E. Day Waterloo – May 6, 2009 Antithrombotic Therapy in the Elderly Bill Geerts, MD, FRCPC Thromboembolism Specialist Sunnybrook.

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 none investments Grants/program Bayer, Boehringer Ingelheim, support Pfizer, Sanofi Aventis Advisory boards, Bayer, Boehringer Ingelheim, consultancies Covidien, Daiichi Sankyo, Pfizer, Sanofi Aventis Honoraria forBayer, 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

Go - JAMA 2001;285:2370 5% age >65 10% 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 1 st ischemic stroke + known high risk AF + no contraindication to anticoagulation + living independently  Excluded patients with new AF, mechanical heart valve Stroke Outcome: Disabling 60% Fatal20% Best case scenario

Potentially Preventable Strokes Gladstone – Stroke 2009;40:235 Ischemic stroke + high risk AF + no contraindication to anticoagulation (n=597) Warfarin therapeutic 10% Warfarin subtherapeutic 29% Antiplatelet therapy 30% No antithrombotic 29% Warfarin use 40%

Potentially Preventable Strokes Gladstone – Stroke 2009;40:235 Ischemic stroke + high risk AF + no contraindication to anticoagulation + previous TIA (n=323) Warfarin therapeutic 18% Warfarin subtherapeutic 39% Antiplatelet therapy 28% No antithrombotic 15% Warfarin use 57%

Potentially Preventable Strokes Gladstone – Stroke 2009;40:235  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  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 stenosis OR 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 2-3 over 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

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 LMWH S/C Oral Anticoagulation (INR 2.0 - 3.0) 5-7 d 3 mos- indefinite 1

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 LMWH 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

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)

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: ageweight racenutritional status other drugsliver 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 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

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* 1 st 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* 1 st 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 3. Starting and maintaining oral anticoagulation

Thromboprophylaxis Summary Patient Group OptionsDuration 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 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 careDischarge 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 DVT4.7 PE6.2 Stein – Arch Intern Med 2004;164:2260

Risk Factors for VTE in the Elderly Alikhan – Blood Coag Fibrinolysis 2003;14:341 DiMinno - 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

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 LMWHProphylaxis 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

8 th 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 Groups 8 th 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. 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 Mechanical Methods of Prophylaxis

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-hospitalAfter discharge LMWH

Prophylaxis after Discharge Reduces DVT in THR 9 studies N=3,999 Eikelboom – Lancet 2001;358:9 19.6% 9.6% Risk reduction 51%

Prophylaxis after Discharge Reduces DVT and Symptomatic VTE after THR 9 studies N=3,999 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 Placebo Fondaparinux

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% Venographic DVT Symptomatic VTE Placebo Fondaparinux

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 Rahme, Kahn – CMAJ 2008;178:1545 LOS < 7 daysLOS 8-14 days LOS 15-30 days

Use of Post-discharge Prophylaxis after Hip/Knee Arthroplasty Rahme, Kahn – CMAJ 2008;178:1545 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 IXa VIIIa Va II FibrinFibrinogen Blood Clot

Current Anticoagulants = Multiple Targets Heparin LMWH ORAL PARENTERAL Xa IIa TF / VIIa X IX IXa VIIIa Va II FibrinFibrinogen AT Warfarin Blood Clot XIaXIIa

New Anticoagulants = Single Targets Rivaroxaban Dabigatran ORAL Xa IIa TF / VIIa X IX IXa VIIIa 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 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

Bilateral venography 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 SURGERYSURGERY

RECORD1-4: Pooled Analysis OutcomeEnoxaparin N=6,200 Rivaroxaban N=6,183 P Symptomatic VTE + death 101 (1.6%)50 (0.8%)<0.001 Death25 (0.4%)13 (0.2%) 0.055 Major bleeding17 (0.3%)27 (0.4%) 0.135 Any bleeding415 (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

Bilateral venography  8,209 patients undergoing THR or TKR surgery 3 months R enoxaparin 40 mg od or 30 mg BID dabigatran 150 mg od Evening before surgery in 2 trials Day 1 Follow-up Dabigatran Phase III Orthopedic Studies dabigatran 220 mg od *1/2 dose 1-4 hrs after surgery SURGERYSURGERY * *

Dabigatran Orthopedic Trials Pooled Analysis: Efficacy Outcomes EnoxaparinDabigatran 150 mg Dabigatran 220 mg No.1,4091,4001,383 Total VTE + mortality 20.3%24.7%21.3% Major VTE3.3%3.8%3.0%

Rivaroxaban vs Dabigatran FeatureRivaroxabanDabigatran Bioavailability>80%<6% TargetFactor XaFactor IIa Half life6-13 hrs11-17 hrs Drug interactionsFew (CYP 3A4) Few (P-gp) Renal excretion<35%85% Administration1 tablet2 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 28 days Low molecular weight heparin Rivaroxaban (or dabigatran) Obsessive, hosp supervised warfarin Admit OR Discharge or rehab Prophylaxis in Hip or Knee Arthroplasty – start postop

0 1 2 3 4 5 6 7 8 9 10 14 21 28 days Low molecular weight heparin Obsessive, hosp supervised warfarin Admit OR Discharge or 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 3 Hylek - NEJM 1996;335:540

Atrial Fibrillation and Stroke  30-year follow-up of Framingham cohort AgePrevalence of AF Strokes/ 1000 pt-yr (no AF) Strokes/ 1000 pt-yr (AF) RR 60-691.8%4.5214.7 70-794.7%9495.4 80-8910.2%14715.0 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] 512.5 [8.2-17.5] 618.2 [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%/yr3.8%/yr0.003 Ischemic stroke 0.8%/yr2.5%/yr0.0004 Hemorrhagic stroke 0.5%/yr0.4%/yr0.83 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 PositionRisk factorsTarget INR AorticTilting disc or bileaflet 2.5 (2.0-3.0) MitralTilting disc or bileaflet 3.0 (2.5-3.5) EitherCaged ball or disc3.0 (2.5-3.5) EitherAF, poor LV, LAE3.0 (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  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 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 < 2.0INR 3.1-3.5INR 3.6-4.0INR > 4.0 Increase by 5-10% Decrease by 0-10% 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 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 Risk 3.0 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 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 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 DayAction -5last day of warfarin -4no warfarin -3no warfarin full-dose LMWH in AM -2no warfarin full-dose LMWH in AM -1no warfarin full-dose LMWH in AM + INR  if INR > 1.6, vitamin K 1-2.5 mg PO

Bridging Anticoagulation for Surgery - 2 DayAction ORno LMWH restart warfarin at 1.5 X usual dose 1LMWH at full-dose (if low bleeding risk prophylaxis (if high bleeding risk) warfarin 1.5 X usual dose 2,3LMWH full-dose or prophylaxis warfarin usual dose 4-5LMWH 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

Freeport Physicians’ C.M.E. Day Waterloo – May 6, 2009 Antithrombotic Therapy in the Elderly Bill Geerts, MD, FRCPC Thromboembolism Specialist Sunnybrook.

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Freeport Physicians’ C.M.E. Day Waterloo – May 6, 2009 Antithrombotic Therapy in the Elderly Bill Geerts, MD, FRCPC Thromboembolism Specialist Sunnybrook.

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Presentation on theme: "Freeport Physicians’ C.M.E. Day Waterloo – May 6, 2009 Antithrombotic Therapy in the Elderly Bill Geerts, MD, FRCPC Thromboembolism Specialist Sunnybrook."— Presentation transcript:

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