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Thrombosis Update
Tom DeLoughery MD FACP FAWM
Oregon Health and Sciences University
DISCLOSURE
Current Relevant Financial Relationship(s)
Speaker Bureau – None
What I am Talking About
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Antiplatelet agents
Antithrombotics
Atrial fibrillation
Venous thrombosis
Anticoagulation
• Patients with hematological
malignancies not immune to thrombosis
• DVT 3-5%
– Line – 3-15%
• PICC > Central
• Coronary artery disease:
– 45-64: 5%
– > 65: > 15%
Issues
• Antiplatelet agents
• Antithrombotic
– Atrial fibrillation
– Valves
– Venous thrombosis
Antiplatelet Agents
• Increase risk of bleeding with
counts < 50,000/ul
– Hemophilia studies
– Massive bleeding studies
MI: Primary and
Secondary Prevention
• Primary prevention
– Minimal short term effect
– Halt aspirin for duration
• Secondary prevention
– 22% reduction in new events
– Stop and restart at 50,000/ul
Coronary Stents
• Stent thrombosis devastating
– 30-50% fatal MI
• Highest Risk
– Placed for AMI
– Bare metal – 4 weeks
– Drug eluting – 12 months
• Dual antiplatelet therapy for high risk
period
Drug Eluting Stents
• Drugs inhibits restenosis by
inhibiting cell proliferation
• Inhibits endothelialization of
stent
• Increasing reports of late
thrombosis even 18 months
Stent Management
• Outside “risk period”
– Bare Metal > 4 weeks
– Drug eluting > 12 months
• Aspirin until platelets < 20,000/uL
Stent Management
• Risk Period
– Bare metal < 4 weeks
– Drug eluting < 12 months
• Cardiology input
• Continue dual antiplatelet
therapy unless severe bleeding
Acute Coronary Syndrome
• Aspirin beneficial even with
severe thrombocytopenia
• Further therapy guided by
catheterization
– Angioplasty with no stenting
– Short course of heparin
Antithrombotic Therapy
• UF Heparin
– Short T1/2 0.5-1 hours
• LMWH
– Longer T1/2 4 hours
– Reversible by protamine
– Need to adjust for renal disease
• Fondaparinux
– Longest T1/2 17-19 hours
– Not reversible by protamine
– Contraindicated in renal failure
General LMWH Plan
• Change warfarin patients to LMWH
• Continue full dose until platelets
<50,000/uL
• “Prophylactic” dose until platelet
<20,000/uL
– Enoxaparin 40mg/day
– Several studies have shown this dose
effective for treatment
Dabigatran
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Oral Thrombin Inhibitor
Bioavailability: 6.5%
Onset of action: 2-3 hours
Half-life : 12-14 hours
Renal excretion: 80%
Drug interactions: p-glycoprotein
Dabigatran: Bottom Line
• Superior to warfarin in stroke
prevention
• GI side effects 15%
• 1.3x increase risk of MI – outweighed
by benefit
• CrCl > 50
• Effects aPTT
Drug Interactions
• Contraindicated
– Dronedarone, azoles, rifampin, St
John’s wort, carbamazepine
• Caution with renal disease or use of
multiple of these drugs
– Verapamil, amiodarone, quinidine,
clarithromycin
Rivaroxaban
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Oral Xa Inhibitor
Bioavailability: 80-100%
Onset of action: 2.5-4 hours
Half-life : 5-9 hours
Renal excretion: ~66%
Drug interactions: CYP 3A4
Rivaroxaban
• Approved 10mg daily for DVT
prophylaxis in TKR and THR
• Approved 20mg daily for afib
– 15mg if CrCl 15-50mL/m
– Contraindicated < 15mL/m
• Approved for DVT
– 15mg BID x 3 weeks
– 20mg daily
Drug interactions
• Ketoconazole, itraconazole,
lopinavir/ritonavir, ritonavir,
indinavir/ritonavir, and conivaptan
• Potential with renal insufficiency
– CSA, Erythromycin, azithromycin,
diltiazem, verapamil, quinidine,
ranolazine, dronedarone, amiodarone,
and felodipine
Rivaroxaban: Bottom Line
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Effective in stroke prevention
Superior in prevention of VTE
Safer in treatment of VTE
CrCl > 15 (15mg < 50)
Once a day drug
– BID x 3 weeks in acute VTE
• INR to monitor
Apixaban
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Oral Xa Inhibitor
Bioavailability: 66%
Onset of action: 1-3 hours
Half-life : 8-15 hours
Renal excretion: 25%
Drug interactions: CYP 3A4
– Multiple other pathways
Drug interactions
• Ketoconazole, itraconazole,
clarithromycin,
lopinavir/ritonavir, ritonavir,
indinavir/ritonavir, and
conivaptan
– Cut to 2.5 mg BID
• Avoid due to decrease effect
– Carbamazepine, phenytoin, rifampin, St.
John’s wort
Apixaban: Bottom Line
• Superior in stroke prevention
with less bleeding
• Superior in prevention of VTE
• Safer in therapy of VTE
• BID drug
• CrCl > 15
• Does not effect INR/PTT
Comparing Trials
Atrial Fibrillation
Drug
Stroke
Bleeding
Apixaban
Better
Safer
Dabigatran
Better
Equal
Rivaroxaban
Equal
Equal
Warfarin: $4/month + monitoring ($20-50/visit)
Apixaban: $320/month
Dabigatran: $235/month
Rivaroxaban: $247/month
ICH – Atrial Fibrillation
Stroke
Intracranial Hemorrhage
Events/
100
years
RR
Events/
100 years
RR
Dabigatran
110
1.53
0.91 (0.74-1.11))
0.23
0.31 (0.20-0.47)
Dabigatran
150
1.11
0.66 (0.53-0.82)
0.30
0.40 (0.27-0.60)
Rivaroxaban
1.76
0.79 (0.66-0.96)
0.49
0.67 (0.47-0.94)
Apixaban
1.19
0.79 (0.65-0.95)
0.33
0.42 (0.30-0.58)
Potential for 10-12,000 less ICH in USA
Atrial Fibrillation
• Dabigatran
– Robust trial data for all CHADS2
• Apixaban
– More effective than warfarin
– Better in patients at risk for bleeding
– Safer – “the sweet spot”
• Rivaroxaban
– Effective
Venous Thrombosis
Drug
Thrombosis
Bleeding
Apixaban
Equal
Safer
Dabigatran
Equal
Equal
Rivaroxaban
Equal
Safer
Warfarin: $4/month + monitoring ($20-50/visit)
LMWH: $100-120/day
Apixaban: $320/month
Rivaroxaban: $247/month
Dabigatran: $235/month
Venous Thrombosis
• Rivaroxaban – FDA approved
– Cost effective for acute DVT
– Safer
• Dabigatran with robust data
– Two trials and extended therapy
• Apixaban
– Effective and safer DVT treatment
Reversal
• Drugs we have no antidote for:
– Low molecular weight heparin,
fondaparinux, aspirin, clopidogrel,
ticagrelor, prasugrel, dabigatran,
rivaroxaban, apixaban
What We Do
• Life or limb threatening bleeding
• 50 units/kg of 4 factor PCC
(kcentra)
Atrial Fibrillation
• Leading indications for warfarin
anticoagulation
• Warfarin reduced risk of stroke
from 5%/yr to 1%/yr
• Risk predicated by CHADS2
score
CHADS2
CHADS2
Score
0
Stroke/yr
Risk Level
1.9
Low
1
2.8
Low/moderate
2
4.0
Moderate
3
5.9
Moderate
4
8.5
High
5
12.5
High
6
18.2
High
Management
• CHAD2 <1: nothing
• >1: LMWH protocol or new
anticoagulant
• Highest risk
– Previous stroke
– CHADS2>4
– Cardiac thrombus
Cardiac Valves
• Bioprosthetic
– Asprin until platelets < 50,000/uL
• Mechanical
– New drugs absolutely contraindicated!!!
– Aortic bileaflet – LMWH protocol
– Higher risk
• Monitored LMWH
• Continue until platelets < 30,000/uL
–Prophylactic throughout
Venous Thrombosis
• On anticoagulants
• > 3 months since thrombosis
– Hold anticoagulation
– Prophylaxis
• < 3 months since thrombosis
– LMWH protocol
New Thrombosis
• Calf vein/Muscular vein
– Thrombocytopenic
• Doppler 3 days and then weekly
until resolved or 4 weeks
– Not thrombocytopenia
• Muscular – 10 days
• Calf – 6 weeks
Proximal Vein/PE
• New proximal thrombosis
– IVC filter controversial
• Yes if extensive leg DVT
• Can be nidus for thrombosis
• Pulmonary embolism
– Filter if leg thrombosis
Prophylaxis?
• Range of DVT is 1.2-5.8%
• Would mandate prophylaxis in
other situations!
• Stockings?
• Pharmacologic?
Upper Extremity DVT
• No RCT
• Lower incidence of
– PE
– Recurrence
– Recannulization
– Thrombophilia
• Higher incidence of
– Underlying vascular lesions
Catheter Related DVT
• Common with PICCs
– Less with tunneled catheters
• High risk of thrombosis
– 3-8% symptomatic
– 20-50% asymptomatic
• No benefit of prophylaxis
Catheter Related DVT
• Therapy: High rates of bleeding!
– By definition PICC placed in sick
patients
– RCT 4% incidence life threatening
bleeding
– OHSU 25% halted due to bleeding
Catheter Related DVT
• Increasing interest in conservative
approach
– NeuroICU study > 75% no
anticoagulation
– OHSU – anticoagulation made no
difference in outcomes
– NCCN
• No anticoagulation if at risk for
bleeding
Catheter Related DVT
• Suggested approach
– Pull line
– No new one for 10 days
– Consider anticoagulation if
• Patient very symptomatic
• No bleeding risk factors
What I Talked About
•
•
•
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Antiplatelet agents
Antithrombotics
Atrial fibrillation
Venous thrombosis