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Anti-coagulants
Principles and practice
Gary Greenberg, MD, MPH
Open Door Clinic
Urban Ministries of Wake Co.
NC Assoc. Free Clinics
May, 2011
1
Disclaimer / Alerts
• I’m an internist at Urban Ministries Wake Co, and
once-upon-a-time, a faculty practitioner at Duke
Med. Ctr. x 18 years
• Only I am responsible for recommendations, and
your mileage may vary
• Topics do include off-label and non-guideline-based
care.
• Talk stresses new ideas, so potential truth-flux
• I have no conflicts of interest to disclose.
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Aims & Limitations
• Mechanisms (briefly)
• Clinical, evidence-based, logistical, tactical
• Website: tinyurl.com/AntiCoag or
www.OpenDoorDocs.org/AntiCoag.html
Documents
References
Calculators
Tools
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Platelet Activation Blockers
• Clinical use is for arterial effects, preventing
“white” emboli, arising across rapid flow
• Stroke prevention, not venous thrombosis
prevention (or treatment)
• Effect can be irreversible for the individual
platelet (aspirin) or dose-related (others)
4
Platelet Activation Blockers
Useful / Common
Narrow use, show-off list
• Aspirin
•
•
•
•
 High (325 mg) v low (81 mg) dose
•
•
•
•
•
Clopidogril (Plavix®)
Ticlopidine (Ticlid®)
Prasugrel (Effient®)
Cilostazol (Pletal®)
Aggrenox® (combines aspirin
Tirofiban (Aggrastat®)
Dipyridamole (Persantine®)
Anagrelide (Agrylin®)
Eptifibatide (Integrilin®, IV
only)
with dipyridamole)
5
Uses for platelet aggregation
antagonists
• CNS / embolic protection
 Threatened stroke / TIA
 Post-stroke secondary prevention
 Atrial fibrillation
• Coronary, direct thrombosis protection





Interrupt an MI
Post MI
Post coronary re-vascularization (esp. stent placement)
High vascular risk status (DM+ or P.A.D.)
Primary prevention
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Pharmacology
Drug
Class
Evidencebased Uses
Comment
Interactions
Aspirin
Cyclo-oxygenase
inhibitor (COX-I)
Native CAD
Stent protection
CVA
PAD
Permanently acetylates
cyclooxygenase
prostaglandin
synthetase
Action blocked by nonacetylated salicylates
(maybe Pepto), maybe
ibuprofen, but not
naproxen
Plavix®
Clopidogril
ADP receptor
P2Y12 inhibitor
Stent protection
CVA
PAD (for CAD/CVA
risk)
Ticlid®
Ticlopidine
ADP receptor
P2Y12 inhibitor
Stent protection
Prasugrel
Effient®
ADP receptor
P2Y12 inhibitor
Stent protection
Dipyridamole
Thromboxane
inhibitor
CVA
PAD (direct effect)
(in Aggrenox® and
Persantine®)
Metabolic activation
blocked by proton-pump
inhibitors (except
pantoprazole = Protonix)
No effect in aggregated
clinical trials
First platelet agent to
show effectiveness in
women
No interaction with PPI’s
Also vasodilator, used
for ‘stress’ coronary
testing
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Aspirin
• Cheap, well accepted
• “Children’s aspirin” 81 is never for children!
 Aspirinita
• Duration of effect is life of platelet
• Direct gastric irritant may make it riskier
• Relative efficacy/ safety for 325 v 81 is
unclear, maybe even paradoxical
• Ibuprofen, other salicylates may block effect
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Plavix® Clopidogril
• 75 mg daily = $170 / month
• Required for stents, especially drug-eluting stents, for at least
a year
• Demonstrable reduction in CVA & MI for patients with PAD
(as seen on TV)
• Altered activation with co-administration of
• No generic (now). But: both previous & soon (November,
2011)
• Pt-Assistance requires Social Security Number (but BristolMyers Squibb/Sanofi website says only: “Must live in the U.S.”
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Ticlopidine (used to be Ticlid®)
•
•
•
•
250 mg BID = $80 / month
Earliest aspirin replacement, now only generic
Proven efficacy for stent protection
In addition to TTP & hemorrhage
 Bone marrow effects include aplastic anemia
 Requires q 2 week CBC monitoring for prompt
discontinuation, for at least 3 months
 Needs informed consent regarding unique risks and
additional lab responsibilities
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Effient® Prasugrel
•
•
•
•
10 mg daily = $187 / mo
New competitor to Plavix®
Equally effective for stent protection
Patient Assistance Program seems not to require SSN
(“must be a US resident”)
• No evidence for CAD or CVA prophylaxis in PAD pts
• May be sampling, since a new agent
• No salicylate or ibuprofen or PPI interactions
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Aggrenox®
• Combination capsule: i BID = $200 / mo
 Aspirin 25 mg, Dipyridamole 200 mg,
• Demonstrably effective CVA prevention (esp.
used for patients who stroked while on ASA)
• Pkg: “not interchangeable” with separate
ingredients
 Combination is brand-name only
 Generic dipyridamole comes in 75 mg tab, so
“replacement” is iii BID, #180/mo = $155
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Pharmacology
Drug
Class
Evidencebased Uses
Comment
Interactions
Aspirin
Cyclo-oxygenase
inhibitor (COX-I)
Native CAD
Stent protection
CVA
PAD
Permanently acetylates
cyclooxygenase
prostaglandin
synthetase
Action blocked by nonacetylated salicylates
(maybe Pepto), maybe
ibuprofen, but not
naproxen
Plavix®
Clopidogril
ADP receptor
P2Y12 inhibitor
Stent protection
CVA
PAD (for CAD/CVA
risk)
Ticlid®
Ticlopidine
ADP receptor
P2Y12 inhibitor
Stent protection
Prasugrel
Effient®
ADP receptor
P2Y12 inhibitor
Stent protection
Dipyridamole
Thromboxane
inhibitor
CVA
PAD (direct effect)
(in Aggrenox® and
Persantine®)
Metabolic activation
blocked by proton-pump
inhibitors (except
pantoprazole = Protonix)
No effect in aggregated
clinical trials
First platelet agent to
show effectiveness in
women
No interaction with PPI’s
Also vasodilator, used
for ‘stress’ coronary
testing
13
Atrial Fibrillation
• Effects




Embolic stroke is main risk
Congestive failure (“10%” of cardiac output)
Syncope
Palpitations
• Treatment to rate or correction of rhythm seems
nearly equally effective (or ineffective)
• Intermittent is not necessarily safer than continuous
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Anticoagulation Decision
CHADS-2
Criterion
Score
History of Congestive Heart Failure
1
History of Hypertension
1
Age over 75 y/o
1
History of Diabetes
1
Stroke or TIA history
2
Score
Risk /
year
1
2.8%
2
4.0%
Risk for embolic event, if no treatment:
3
5.9%
1-2: aspirin, 3+ consider ‘full’ anticoagulation
4
8.5%
5
12.5
6
18.2%
Total
Chest. 2008 Jun;133(6 Suppl):546S-592S. Antithrombotic therapy in atrial
fibrillation: American College of Chest Physicians Evidence-Based Clinical
Practice Guidelines (8th Edition).
http://www.vhpharmsci.com/sparc/
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Anticoagulation Decision
CHA2DS2-VASc
Criterion
Score
History of Congestive Heart Failure
1
History of Hypertension
1
Age over 75 y/o
2*
Age 65-74 y/o *
Score
Risk /
year
1*
1
1.5%
History of Diabetes
1
2
3.0%
Stroke or TIA history
2
3
4.4%
Vascular Dx (MI, aortic placque, PAD) *
1
Female *
1
4
6.7%
5
10.5%
6
12.9%
7
13.9%
8
14.1%
9
16.1%
Risk for embolic event,
if no treatment:
Total
1-2: aspirin, 3+ consider ‘full’ anticoagulation
Chest. 2010 Feb;137(2):263-72. Refining clinical risk stratification for
predicting stroke and thromboembolism in atrial fibrillation using a novel
risk factor-based approach: the euro heart survey on atrial fibrillation.
http://www.vhpharmsci.com/sparc/
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Warfarin Issues
• Myths about “thinning”, so I say “clot-blocking”
 Tired, cold-sensitive, pale, low-flow
• Delayed onset is not pharmacological “loading”, it’s earlier
Factor VII wearing out
• Evening dosing allows more rapid dose adjustment
• Medical Mutual of NC provides an informed consent contract
and a tracking flow-sheet
• Every patient needs to have a phone, good literacy (or
designate someone to supervise both medication use and
communication)
• 7-day pill organizers help
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Warfarin Issues
Drug interactions include many mechanisms
• Metabolic breakdown of warfarin (EtOH, macrolides, St.
John’s wort)
• Enteral kinetics for vitamin K (antibiotics)
• Protein binding for warfarin (salsalate)
• Increased risk for GI irritation (NSAIDs, EtOH)
• Platelet inhibition (NSAIDs)
Dietary issues are about vitamin K
• Outrageous fear, where education is for total avoidance
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About Vitamin K
• 1st reported in German as Koagulationsvitamin
• Necessary for manufacture of hepatic-sourced
clotting factors. Longest-lived of these is VII
• Sources are vegetables (green, leafy) spinach,
broccoli, but also onions, spices
• Patients learn to fear these, resulting in
occasional intake with increased variability
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SUPPLEMENTING Vitamin K?!
• Patient’s dietary variability is reduced in proportionate impact
• Warfarin dose will need to be increased to measurable effect
• Patients need to understand that skipping or stopping the
vitamin pill predictably causes dangerous warfarin overdose
• To synchronize compliance, needs to be taken together
• CostCo “Premium” multivitamins have 100% RDA (80
microgram daily). Studies used 100, 150, 200 μg
• Patients need to understand that this is NOT a common
clinical practice
Vitamin K supplementation can improve stability of anticoagulation for patients with
unexplained variability in response to warfarin
Blood, 2007 109:2419-2423
Vitamin K1 supplementation to improve the stability of anticoagulation therapy with
vitamin K antagonists: a dose-finding study
Haematologica, 2011 96: 583-589
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Modified Warfarin Tracking Page
Located at
TinyUrl/AntiCoag
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Warfarin Dose Calculations
• Use proportionate intervals (small steps for
small doses, bigger steps for larger ones)
• Use just one pill-size
• Smoothe the regimen across the week
• Patient reads back their regimen
• Calculator and tracking form and contract are
all at tinyurl.com/AntiCoag
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Warfarin Dose
Adjustment Calculator
Located at
TinyUrl/AntiCoag
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Patient Take-Home Worksheet
Located at
TinyUrl/AntiCoag
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Duration of Therapy
• Atrial Fibrillation, until need to stop
• Pulmonary emboli or venous thrombosis (VTE)
 Single episode, Reversible cause: at least 3-6 months
 Injury, immobility, pregnancy, medication (BCP’s), hospitalization
 Recurrent VTE: at least 12 months
 Idiopathic: unknown, perhaps 12 months
 Both recurrent and idiopathic (or irreversible): indefinite
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Intensity of Therapy
Usual case, INR 2.0 – 3.0
• Venous thromboembolism
• Atrial Fibrillation
High intensity, INR 2.5 – 3.5
• Mechanical prosthetic valve
Low intensity (soft recommendation), INR 1.5 – 2.0
• High risk patient, recurrent VTE
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Other options:
Enoxaparin (Lovenox®)
Advantages
Disadvantages
• Compared to heparin drip
• Injectable, local bruising
• Cost:




Out-patient
Intermittent, calculated dose
Rarer platelet antibodies
No monitoring
 100 mg BID, $3,400/mo
 60 mg BID, $2,050/mo
 But: Pt Assistance available
• Compared to warfarin




Instantly on, quickly gone
No monitoring
Predictable dose
More effective in cancer pts
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Other options:
Vena Cava Filter (“umbrella”)
• Only for prevention of pulmonary emboli, not for
cardiac valves or atrial fibrillation
 Patients still have clots in their legs, with pain, edema
• Effective immediately, but invasively
• Need to discuss if permanent is desired, many are
permanent (or require open, surgical removal)
• Allows discontinuation of anticoagulation during GI
bleed or stroke urgency
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Other options:
Dabigaltran Pradaxa®
• Direct thrombin inhibitor, licensed 10/20/10
• Effective in 12 hours
• No monitoring, no dose-calculation, no injection, no
dietary issues, (almost) no interactions
• Only licensed for Atrial Fibrillation, but published
articles show advantages for venous thromboembolism, too
• Usual dose: 150 BID, $220/mo (renal dose reduction)
• Patient assistance is available
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Other options:
Rivaroxaban (soon more?)
• Direct thrombin (factor Xa) inhibitor
• Derived from 2 Mexican leach anticoagulants
• New class of agent, several collectively called
“xabans” (get it?)
• Daily flat oral dosing, without monitoring, dietary
effects, many drug interactions (except statins via
cytochrome CYP3A4)
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References
Online sites
• ePocrates.com
• DestinationRx.com
• NeedyMeds.com
• DailyMed.nlm.nih.gov
• Guidelines.gov
Peer-reviewed Publications
(avail online)
• Mgmt of VTE: A Clinical Practice
Guideline from Amer. Coll. of
Physicians & Amer. Acad. of Fam.
Physicians (2007) Ann Intern Med
2007 146:204-210
• New Anticoagulants and the
Future of Cardiology Rev Esp
Cardiol. 2010; 63 :1223-9
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I’m not just a speaker / doctor…
Just like Cy Sperling,
President of the “Hair Club for Men” (& a member)

(no endorsement intended)
My personal medical history





Remote ankle surgery, mild permanent venous insufficiency
Ipsilateral distal DVT, 20 yrs later
Pulmonary embolus 2 years later
Negative thrombophilia evaluation, now (+) Family History spont DVT
Lifelong “full” anticoagulation
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