Acute MI: Public Health Issues

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Anticoagulation Perioperative Bridging
Reginald E. Smith, Pharm.D. Clinical Specialist,
Cardiac Services Thrombosis Clinic Royal
Jubilee Hospital Clinical Researcher, Victoria
Heart Institute
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Disclosures
Investigator In Clinical Trials Sponsored By
Boehringer Ingelheim, Sanofi-Aventis, Pfizer Have
Received Research Fellowship Grants From Leo
Pharma, Pfizer Special Disclosure I did not buy
stock in Vasogen in 2003 when we were doing a
clinical trial on their device for treating heart
failure
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NAIVETEK
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Outline

• Case 1 Presentation
• Vancouver Island Health Authority Statistics
• Stopping Warfarin Using UFH LMWH
• Who Should Be Bridged
• Case 2
• Bleeding Risk Epidural Anaesthesia
• Pending Studies In Bridging
• Interruption of Antiplatelet Agents When Bare
  Metal Drug Eluting Stents Present

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Case 1Presentation
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Case Presentation 1

• Patient is a 73 yr old female with a mechanical
  mitral valve
• Normal Sinus Rhythm
• Had elective surgery 1 week ago
• (ENT)
• Surgeon instructs patient to discontinue warfarin
  10 days prior to surgery
• No Anticoagulation Bridging

Not Real Photo
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Case Presentation
Not Real Photo

• She presents to ER in extreme distress with
  pulmonary edema, shortness of breath and
  Hypotension
• Urgent Transesophageal Echo Obtained

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Not Real Photo
Case Presentation

• Large Thrombus Is Occluding Medial Prosthetic
  Valve Disk. Lateral Disk Is Partially Occluded
• Surgical Opinion Obtained For Urgent Valve
  Replacement
• She Is Quoted A Surgical Risk Of 60 Mortality Or
  Major Morbidity Due To Stroke
• Streptokinase 100,000 U/hr X 48 hrs Is Initiated
  After 48 hrs SK Stopped IV Heparin Is Started
  And Surgical Booking Made

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Stopping Warfarin Using LMWH UFH
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Warfarin Discontinuation INR Curve
Vitamin K Can Cause Warfarin Resistance 1-3 mg
PO/SQ Will Normalize A Therapeutic INR In 24 Hours
3.5
3.0
INR
2.5
2.0
1.0
5
6
3
DAYS
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LMWH/Heparin Overlap
3.5
Therapeutic Dose
3.0
Prophylactic Dose In High Bleeding Risk
INR
2.5
2.0
1.0
4-5 Days Post Op
2-3 Days Preop
OR Day No Anticoagulants
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6
3
DAYS
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AnticoagulationBridging Options
Initial Daily Low-Dose LMWH After Surgery (During
High Bleeding Risk) Tinzaparin 75 U/Kg
SC Nadroparin 38 U/Kg SC Tinzaparin 4500 U SC
q24h Enoxaparin 30 mg SC Dalteparin 5000 U
SC Fondaparinux 2.5 mg SC (Not a heparin
pentasaccharide) Full Anticoagulation LMWH Dose
Post Surgery Tinzaparin 175 U/Kg SC
q24h Nadroparin 171 U/Kg SC q24h Enoxaparin 1
mg/Kg BID SC Dalteparin 100 U/Kg SC
BID Enoxaparin 1.5 mg/Kg SC q24h Weight Based
Heparin IV Infusion With Therapeutic pTT
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About Royal Jubilee Hospital Anticoagulation
Clinic
Royal Jubilee Hospital Victoria
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Royal Jubilee Hospital AC Clinic

• Approx 1650 Clinic Visits/yr Patients Acute
  DVT/PE/Stroke/Cardiac
• Principally warfarin induction and stabilization
• Perioperative Anticoag Management/Bridging Approx
  300 Cases Per Year
• Clinical Research
• Preoperative DVT Risk Assessments/Prophylaxis

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July 2006 June 2007 257 Patients 288 Procedures
Perioperative Bridging Referral Statistics
175/257 (68.1)
50/257 (19.5)
42/257 (16.3)
10/257 (3.9)
Mechanical Valve
Atrial Fib
Venous Thrombosis
Mech Valve Atrial Fib
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July 2006 June 2007 257 Patients 288 Procedures
Stroke Risk Factors Atrial Fib Patients
62/175 (35.4)
20/175 (11.4) Deemed Low Risk No Bridging
33/175 (19.1)
29/175 (16.6)
12/175 (7)
10/175 (5.7)
CHF
Diabetes
Hypertension
gt 75 Yrs
Prior Stroke/TIA Or Embolism
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July 2006 June 2007 257 Patients 288 Procedures
Stroke Death Complications

• 62 year Old Male With Chronic AFib Bridged For
  Major Urological Surgery
• - History Of Stroke (CHADS2 2)
• - No Diabetes, No Hypertension
• No CHF or Known Valve Disease
• Catastrophic Stroke Death POD3 despite bridging

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LMWH Provided At No Cost To Patient If It Will
Reduce Duration of Hospital Stay
2800 day
20 - 50/day
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Surgeons offices send consult requests in
advance Patients Brought Into Clinic In Advance
Of Admission, Provided With LMWH (Tinzaparin) and
Taught To Self Inject Bridging Strategy Is
Decided
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Anticoagulation Bridging

• Who Should Be Bridged?
• - Prosthetic Heart Valves
• Atrial Fibrillation
• Venous Thromboembolism

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Risk Versus Benefit Of Bridging
Problems MVR vs AVR Additive Risk Factors
NEJM 1997 336(21)1506-1511
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Risk Versus Benefit Of Bridging
Rebound Hypercoaguability With Temporary
Discontinuation and Initiation of
Anticoagulation Hypercoaguability Associated
With Surgical Procedures Long Term Clinical
Trial Event Rates (Afib/Prosthetic Valves) May
Not Reflect Actual Short Term Thromboembolic Risk
Problems MVR vs AVR Additive Risk Factors
NEJM 1997 336(21)1506-1511
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Coagulation Factor Decline With Warfarin
Factor VII (T/2 4-6 hrs) Factor IX (T/2 24
hrs) Factor X (T/2 48 hrs) Factor II (T/2 60
hrs) 5 Half-Lives To Steady State
Protein C S
X
II
VII
IX
1 2 3 4
5
Warfarin
DAYS
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Patients With Mechanical Heart Valve (Douketis
JD, Woods K, Crowther MA 2005)
Risk Factors For StrokeAtrial Fibrillation, Left
Ventricular Dysfunction,Age gt 75 Years,
Hypertension, Diabetes
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CHADS2 SCORE Stroke Risk In Atrial
Fibrillation JAMA 2001 (285) 2864-70
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Annual Risk of Stroke
13
9
6
4
3
2
Score 0 1 2
3 4 5
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C Recent CHF (1) HHypertension
(1) AAgegt75(1) D Diabetes (1) S Previous
Stroke/TIA (2)
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Patients With Atrial Fibrillation (Douketis JD,
Woods K, Crowther MA 2005)
Risk Factors For Stroke Atrial Fibrillation,
Previous Stroke or TIA, Left Ventricular
Dysfunction, Age gt 75 Years, Hypertension,
Diabetes
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Pulmonary Vein Ablation
Cancelled With Single Subtherapeutic INR In
Previous Month Bridge In No Preprocedure Echo
(Approx 50-60 Cases) Bridge Out (Approx 75
Cases)
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Bridging Trials
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Uncontrolled Bridging Trials Using LMWH
Study n Follow Up LMWH Indication
ATE Maj Bleed Douketis 650 0.5
Months Dalteparin AF, MHV 0.6 1.0 Kovacs
224 3 Dalteparin AF, MHV 1.3 6.9 Dunn
200 1 Enoxaparin AF 2.3 3.5 Spyro
- 595 1 Tinzaparin AF,
MHV 0.6 3.3 Poulos Dalteparin Enoxapari
n Turpie 220 3 Enoxaparin MHV 0.5 3
.5
(Douketis JD, Woods K, Crowther MA 2005)
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Periop 1 Trial
224 Patients Prosthetic Valves/Afib with one
major RF
Prospective Multicenter Single Arm Cohort
Invasive Procedure
Bridging
Endpoints Thromboembolism/ Bleeding To 3 Months
Kovacs MJ, Kearon C, Rodger M, et al Circulation
20041101658-1663
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Invasive Procedure
Periop 1 Trial
0
1 2 3 4 5
-6 -5 -4 -3 -2 -1
Last Dose Warfarin
Dalteparin 200 U/Kg/d POD 1 Min 4 days till INR
gt 1.9 (or 5000/d if bleeding risk)
Restart Warfarin 2x dose
Dalteparin 200 U/Kg
Dalteparin 100 U/Kg
Dalteparin 200 U/Kg
Kovacs MJ, Kearon C, Rodger M, et al Circulation
20041101658-1663
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Arterial Thromboembolic Events
75 of Embolic Events While Holding
Anticoaulants For Bleeding
8 / 224
6 / 224
Total Embolisms In Setting of Bleeding (15
total Episodes of Major Bleeding)
Kovacs MJ, Kearon C, Rodger M, et al Circulation
20041101658-1663
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Bleeding RiskCase Presentation2

• Multiple Dental Extraction

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Case 2 Presentation
65 year old male with a mechanical mitral valve.
No previous stroke/TIA, normal sinus
rhythm Multiple broken teeth, some dental
abscesses. Requires multiple dental
extraction. Referral from Cardiology
Oral/Maxillofacial Surgery For Perioperative
Anticoagulation Management
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Case 2 Presentation

• Booked for Day Surgery 24 hr Bed
• Anticoag Plan d/c Warfarin 5 days preop
• Therapeutic LMWH start 3 days preop, warfarin
  start POD1, Therapeutic LMWH until INRgt 2.5
• Therapeutic LMWH start 3 days preop, warfarin
  start POD1, keep in for IV heparin until INR gt
  2.5
• Therapeutic LMWH start 3 days preop, warfarin
  start POD5, prophylactic dose LMWH POD1, 2, 3,
  Therapeutic Dose LMWH POD4 until INR gt 2.5

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Dental Surgery
Case 2 Presentation
0
1 2 3 4 5
-6 -5 -4 -3 -2 -1
Last Dose Warfarin
Restart Warfarin
Tinzaparin 4500 U/d
Tinzaparin 175 U/Kg
Tinzaparin 175 U/Kg
Tinzaparin 175 U/Kg
Tinzaparin 175 U/Kg
Tinzaparin 175 U/Kg 14,000 PF Syringe
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Evening of POD7 Presents to Emergency Has
Significant Bleeding of Both Gums Which Started
Several Hours Ago Has Been Swallowing Blood For
Hours, Cant Lay Down. 20-30 g drop in Hgb INR
1.3 ER Applies Packing Page Goes Out At 2 am
Unstoppable Hemorrhage Oral Surgeon Reoperates
Readmitted For 2 days with Pressure Dressings
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Bleeding Risk Stratification
High Bleeding Risk Low-Moderate
Neurosurgery Cataract Extraction Prostatectomy
Lap Cholecytectomy Bladder Tumor
Resection Single Dental Extract Cardiac
Surgery Most Cutaneous Surg Solid Organ
Biopsy Hernia Repair Cervical Cone Biopsy Bowel
Polypectomy Pacemaker
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Epidural Anaesthesia
Drug Last Dose Prior To Restart Drug
After Insertion/Removal Removal/Insertion Pro
phylactic gt 8-12 hrs 2 hrs UFH/LMWH Therapeuti
c LMWH gt 18-24 hrs 2 hrs Therapeutic IV UFH gt 4
hrs 2 hrs Warfarin INR lt 1.5 Only if
catheter in lt 2 days Clopidogrel/ Ticlopid
ine gt 5 14 days ASA/NSAIDS Do Not Appear To
Cause Hematoma
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Upcoming Studies InPerioperative Bridging
Periop 2
Principle Investigators Dr. M. Kovacs, Victoria
Hospital, Dr. M. Rodgers, Ottawa Co-Investigators
Dr. D. Anderson QEII, Halifax Dr. L. Vickars,
St. Pauls, Vancouver Dr. P. Wells, Ottawa
Hospital Dr. E. Yeo, Toronto General Dr. C.
Kearon, Hamilton Dr. S. Solymoss, St. Marys
Hospital Dr. S. Schulman, Hamilton Dr. L.
Desjardin, U Quebec, PAV CHUL Dr. S. Bates,
Hamilton Dr. M. Blostein, Jewish General,
Montreal Dr. S. Kahn, Jewish General,
Montreal Dr. R. Smith, Victoria Heart Institute,
BC
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Periop 2
Dalteparin Bridging
Placebo Bridging
1773 Patients With Prosthetic Heart Valve or
Atrial Fibrillation 1 Risk Factor
Elective Non-Cardiac Surery or Invasive Procedure
Major Thromboembolic or Hemorrhagic Events To 90
Days
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Perioperative Management of Patients With
Coronary Stents on Dual Antiplatelet Therapy
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ACC AHA Scientific Advisory
If Patients With A DES lt 12 Months Having
A Procedure That Has Bleeding Risk Consider
Holding Clopidogrel And Continuing ASA Restart
Clopidogrel ASAP
Grines CL, Bonow RO, Casey DE, et al. JACC Jan
17, 2007
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Canadian Cardiovascular Pharmacists Network
CCPN Going Home Patient Discharge
Kit Distributed To Canadian Cardiac Centers
April 2008
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Canadian Cardiovascular Pharmacists Network
CCPN Going Home Patient Discharge
Kit Distributed To Canadian Cardiac Centers
April 2008
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