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Thrombosis Update
Tom DeLoughery MD FACP FAWMOregon Health and Sciences University
DISCLOSURE
Current Relevant Financial Relationship(s)
Speaker Bureau – None
What I am Talking About
• 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• 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• 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 • 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• 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/monthDabigatran: $235/monthRivaroxaban: $247/month
ICH – Atrial FibrillationStroke 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/dayApixaban: $320/monthRivaroxaban: $247/monthDabigatran: $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
CHADS2CHADS2
ScoreStroke/yr Risk Level
0 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
• Antiplatelet agents
• Antithrombotics
• Atrial fibrillation
• Venous thrombosis