What’s New
in the World of
Anticoagulation
Angela Lambing, MSN, ANP-c, GNP-c
Hemophilia & Thrombosis Treatment Center
Henry Ford Health System
Detroit, MI
Objectives
 Understand the coagulation cascade and
risks of VTE
 Identify the variety of current
anticoagulants available
 2012 CHEST guidelines
 To bridge or not to bridge
Disclosures
 Speaker’s Bureau:
 GSK Pharmaceuticals
 Novartis
 Nursing Advisory Boards
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Pfizer
Baxter
Bayer Health Care
CSL Behring
Octapharma
 I have no current affiliation or financial arrangement with any
grantor or commercial interests that might have direct interest
in the subject matter of this CE program
Pathophysiology of a Thrombosis

Abnormalities of vessel wall
 atherosclerosis (arterial)
 trauma, erosion
 deficient fibrinolysis, venous hypotonia
(pregnancy)

Abnormalities of blood flow
 hypertension, turbulence
 hyper-viscosity
 stasis, deficient clearance of coagulation
factors

Abnormalities of blood
 quantitative platelet abnormalities
 thrombocytosis
 decrease of inhibitors, activation of
coagulation hypercoagulability
 Protein C Def, Protein S Def, Antithrombin III
Def
Vessel wall
Virchow’s Triad
Statistics
 Incidence of Venous Thromboembolism exceeds 1
per 1000 cases
 Over 200,000 cases reported annually in the USA
 30% pts die within 30 days of diagnosis
 1/5th pts sudden death due to PE
 30% survive to develop recurrent VTE within 10 yrs
- greatest risk in 1st yr (5-15%) then 1%/yr
 28% of cases develop venous stasis syndrome
within 20 yrs
Heit et al, 2001
 Incidence increases with age from 1:1,000
people/year to 1%/year in old age
Rosendal,1999
Padua Prediction Score Risk
 8 fold risk of VTE
 50-75% of VTE
events in hospitalized
medical pts
Hi Risk > 4
Spyropoulos et al. Chest 2011
Heit et al. Arch In Med, 2000
Heit et al. Arch Int Med, 2002
Why Anticoagulate?
 Thrombosis
 Arterial
 Venous
 Stroke
 Ineffective management with antiplatelet
medications
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Atrial Fibrillation
Cardiomyopathy
Prosthetic valves
Prophylaxis during cancer therapy
Reproduced with permission from: Rao. Am J Med Sci
1998;316:69.
How Does Blood Clot - Overview
History of Anticoagulants
Coumadin© (Warfarin)
Advantages:
Disadvantages:
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Inhibits production of Vit K
needed for production of
thrombin, factors II, VII, IX, X,
protein C & S
No ceiling to dosing
Monitored by INR; 2-3.0 (normal
range 0.8-1.2)
Dosing amount can decrease
with age
Inexpensive- 5 mg tabs, #30 =
$22.00
Easy to reverse;
 vitamin K

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Requires regular blood test
monitoring
Interactions with multiple
medications
Can be affected by oral vitamin K
food intake
Bleeding risk 1%/year long term
use
Can be difficult to regulate
Can cause tissue necrosis if
used without concomitant
heparin initially after
thrombosis
Botanicals with Potential Anticoagulant &
Interactive Effects with Coumadin©*
Alfalfa
Dong Quai
Arnica
ASA
Boldo
Bucho
Cassia
Celery
Dandelion
Fenugreek
Horseradish
Licorice
Nettle
Parsley
Prickly Ash
Quassia
Woodruff
Tonka Beans
Wild Carrot
Wild Lettuce
Sweet CloverSweet
Aniseed
Bogbean
Capsicum
Chamomile
Horse Chestnut
Meadowsweet
Passion Flower
Red Clover
Bladder Wrack
Foetida
*Non-exhaustive list
ALWAYS check formulary
Botanicals than contain Salicylates or
Antiplatelet Properties
Agrimony
Aloe Gel
Black Cohosh
Black Haw
Cassia
Clove
Feverfew
Garlic
Gingo Biloba
Ginseng
Meadowsweet Policosanol
Poplar
Senega
Willow
Wintergreen
German Sarsaparilla
Aspen
Bogbean
Dandelion
Ginger
Licorice
Onion
Tamarind
Botanicals with Coagulant
Properties
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Agrimony
Goldenseal
Mistletoe
Yarrow
Affected by warfarin
Injectable Anticoagulants
 Enoxaparin (Lovenox©) - LMWH
 1 mg/kg Q12,
 1.5 mg/kg/day
 Dalteparin (Fragmin©) - LMWH
 200 IU/kg daily
 Tinzaparin (Innohep©) - LMWH
 175 units/kg/day
 Fondaparinux (Arixtra©) - Direct Anti Xa inhibitor
 7.5 mg, sq daily
 5.0 mg for < 50 kg
 10 mg > 100 kg
 Renal Dosing
Injectable Anticoagulant Properties
Advantages:
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Predictable pharmacokinetic
properties and drug interactions
Can be effective in recurrent VTE
while on warfarin
Poor GI absorption not a concern
Therapeutic dosage based on
patient’s weight
Lab monitoring not routinely
needed
Rapid onset of action and
predictable clearance
 convenient for frequent
interruptions due to procedures
Disadvantages:
 Cost
 Must perform sq injection
 Difficult to use for patients with
decreased GFR
 Many medical personnel do not
understand pharmacokinetics
Injectable anticoagulants
Anticoagulant
½ life
Measurement
Lovenox (Enoxaparin©)
12 hours
Heparin x assay – 4 hours post
injection
Fragmin (Dalteparin©)
19 hours
Heparin x assay– 4 hours post
injection
Innohep (Tinzaparin©)
19 hours
Heparin x assay– 4 hours post
injection
Arixtra (Fondaparinux©)
19 hours
Arixtra drug trough levels – just
prior to next dose
**All injectables are cleared through the renal
system
Affected by UFH
Low molecular
weight heparins
Direct Factor Xa
Inhibitor (Arixtra)
New Oral Anticoagulants
 Rivaroxaban --- Xarelto©
 Affects Xa
 Hip and knee prophylaxis of DVT
 Stroke in NVAF
 November 2, 2012 treatment of DVT/PE
 Apixaban --- Eliquis©
 Affects Xa
 FDA December 2012 to decrease the number of stokes and
dangerous blood clots in NVAF
 Dabigatran --- Pradaxa©
 Direct Thrombin inhibitor: affects IIa
 FDA October 10, 2010 approval
 Stroke prevention in NVAF
Pharmacology
Characteristic
Warfarin©
Rivaroxaban
Apixaban ©
Dabigatran ©
Target
Vitamin K
factors
Factor Xa
Factor Xa
Thrombin
Bioavailability
100%
60-80%
60%
6%
Dosing
OD
OD (BID)
BID
BID (OD)
Time to peak
effect
4-5 day
2-4 hours
1-2 hours
1-3 hours
Half life
40 hours
7-11 hours
12 hours
8-15 hours
Renal
clearance
None
33%
25%
80%
Monitoring
Yes
No
No
No
Interactions
Multiple
3A4/P-gp
3A4/P-gp
P-gp
©
Oral direct thrombin inhibitors
Advantages
Disadvantages
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½ life of 19 hours
Oral medication
No need for blood testing
Side effects: GI upset, diarrhea,
Renal clearance of the drug
 monitor renal/liver function
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Drug-drug interactions
No reversal drug
 Prothrombin complex concentrates
(PCC)
 Feiba©; Bebulin©, Profilnine ©;
FFP, Factor VIIa;
 Dialysis

Lack of understanding mechanism
Direct thrombin
inhibitors: Arixtra (sq)
Dabigatran(PO)
Direct Factor Xa
Inhibitor: Apixaban
Rivaroxaban
CHEST
Guidelines
2012
ACCP Guidelines: Chest 2012
 Patients on vitamin K antagonists
(warfarin) undergoing minor dental
procedures:
 Continuation of warfarin around the time of
procedure
 Co-administration of oral pro-hemostatic
agents
[Grade 1C]
ACCP Guidelines: 2012
 Patients who require a temporary interruption
of a warfarin before surgery and require a
normal INR for surgery:
 Stop warfarin 5 days before procedure (1B)
 Use of LMWH with last dose 24 hr before
surgery at ½ recommended dose (1C)
 Resume warfarin 12 – 24 hours after surgery
(1C)
 Resume LMWH 24 hr after procedure (1C)
ACCP Guidelines: 2012
 Mechanical heart valve or atrial fibrillation
or current VTE
 High risk for recurrent VTE;
 Bridging with therapeutic LMWH of IV UFH
 Low risk for recurrent VTE:
 Low dose LMWH or no bridging with LMWH/UFH
[Grade 2C]
ACCP Guidelines: 2012
 Bare metal coronary stent who require surgery
within 6 weeks of stent placement:
 Continuation of ASA and clopidogrel in the perioperative period
 Drug-eluting coronary stent who require
surgery within 12 months of stent placement:
 Continuation of ASA and clopidogrel in the perioperative period
[Grade 2C]
ACCP Guidelines: 2012
 Patients who require temporary
interruption of ASA or clopidogrel before
surgery:
 Stop 7-10 days before procedure
 Resume agents 24 hours after procedure
(2C)
CHADS score
 Indication: Assess risk of stroke with AFib
 Criteria
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A. Congestive Heat Failure (1point)
B. Hypertension (1 point)
C. Age > 75 years (1 point)
D. Diabetes (1 point)
E. Stroke or TIA history (2 points)
 Recommendations:
 CHADS score > 2, consider bridging if on warfarin
Gage. Circulation 2004
Bridge Therapy
“Shift from oral, long-acting anticoagulants
to parenteral, short-acting anticoagulants
during sub-therapeutic levels of oral
anticoagulant in the perioperative period”
Spyropoulos et al. (2004)
Bridging Therapy
 Advantages
 Provides continued anticoagulation
 Minimal window without anticoagulation
 Cost savings for hospitalizations: ~ >$13,000
 Disadvantages
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Use of LMWH for 8-10 days, SQ self injection
Plan ahead
Prior insurance authorization may be needed
Requires coordination of care
Can be costly (approx. cost 10 syringes =$600$1,000)
Bridging Therapy Process Steps: Lovenox©
1.
2.
3.
4.
5.
6.
7.
8.
Hold warfarin 5 days prior to procedure
Start LMWH q12h, 4 days prior to procedure
Check INR/Platelet level day before procedure
Lovenox dose day before procedure in am ½ the
usual dose; Hold LMWH night before procedure
Restart both warfarin and LMWH q12-24 hr
hours after procedure provided there are no signs of
bleeding
Check INR on the 4th day - goal of INR > 2.0
Stop LMWH when INR >2.0
Expect to be on LMWH for 8-10 days
Bridging Therapy Process Steps:
Using longer ½ life injectables (Arixtra©)
1.
2.
3.
4.
5.
6.
7.
8.
Hold coumadin 5 days prior to procedure
Start injectable daily sq, 4 days prior to procedure
Last dose of injectable 2 days prior to event (3 ½
lives of the drug)
Check INR/Platelet level day before procedure
Restart both warfarin and injectable anticoagulant
q12-24 hr hours after procedure provided there are
no signs of bleeding
Check INR on the 4th day - goal of INR > 2.0
Stop injectable anticoagulant when INR >2.0
Expect to be on injectable anticoagulant for 8-10 days
Procedure
Date
Injectable
anticoagulant
Anticoagulated
5 days
~4-5 days
Warfarin
Normal Coagulation
Check INR
Platelet ct
Coumadin© induced tissue necrosis
 Re-initiation of Coumadin©
 Coumadin© causes decrease of Protein C & S
as part of the coagulation system when
initially started
 potentially allows coagulation cascade to go
unchecked with increased formulation of thrombin
 Onset of thrombosis also causes decreases in
Protein C & S
 RESULT: Increases risk of thrombosis
Bridging process: oral agents
Xarelto©, Pradaxa©
 Hold 48 hours prior to procedure
 Restart 12-24 hours after procedure
Procedure
Date
1 day
Anticoagulated
2 days
Oral direct
thrombin
Normal Coagulation
Challenges
 Injectables are now generic
 Less availability for support programs & educational materials
 Still costly
 Insurance approvals
 Injectables
 New agents
 Lack of understanding
 Medications
 Testing
 Interactions
 Bridging
Summary
 Review risk/benefit of holding any form of
anticoagulation
 Thrombosis vs bleeding risk
 Individualized treatment
 Co-ordination of care with:
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Patients &/or family caregivers
Hematology; HTC
Anticoagulation clinic
Primary physician
 Monitor patient during process
 Check INR (as indicated)
 Bleeding/bruising
 Platelet count (as indicated)
Question #1
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Patient is on warfarin for atrial fibrillation
Need to extract one tooth
Should warfarin be held?
Questions to ask…..
 CHADS score; if high, should not stop warfarin
 What is latest INR testing?; must be between 2-3
 Nature of the procedure…. Increased risks?
Question #2
 Patient is taking Lovenox© every 12
hours for history of pulmonary embolus
 History of active colon cancer receiving
chemotherapy
 Pt requires port placement
 Questions to ask….
 Should lovenox be held?
 How?
Question #3
 Patient is on Pradaxa© for atrial fibrillation
 Requires 5 teeth extracted
 Questions to ask….
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CHADS score? Increased risk of VTE?
Amount of bleeding?
½ life of the medication
Stop Pradaxa© 2 days prior to procedure
Restart 12-24 hours after the procedure
NO injectable anticoagulant needed
Question #4
 Pt on long term Arixtra© for history of recurrent
VTE
 Pt history of recurrent VTE on therapeutic
warfarin
 Allergy to Lovenox© itching, rash
 Needs colonoscopy for Hx of polyps
 Questions to ask?
 Hold Arixtra©?
 How?
Angela Lambing, MSN, NP-C
Hemophilia & Thrombosis
Treatment Center
Henry Ford Health System
alambin1@hfhs.org
313-916-9094