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