Thrombosis Update Tom DeLoughery MD FACP FAWM Oregon Health and Sciences University
Dec 17, 2015
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