Primary prevention of VTE. RATIONALE FOR THROMBOPROPHYLAXIS IN HOSPITALIZED PATIENTS - 1 High prevalence of VTE –Almost all hospitalized patients have

Primary prevention of VTE

RATIONALE FOR THROMBOPROPHYLAXIS IN HOSPITALIZED PATIENTS - 1

High prevalence of VTE– Almost all hospitalized patients have one or more risk

factors for VTE– The incidence of DVT is as high as 80% in some

hospitalized patient groups – Hospital-acquired DVT and PE are usually clinically

silent– It is difficult to predict which at-risk patients will develop

symptomatic thromboembolic complications– Screening at-risk patients using physical examination or

noninvasive testing is neither cost-effective nor effective


Adverse consequences of unprevented VTE– Symptomatic DVT and PE: postop VTE second

most common medical complication– Fatal PE: PE is the most common cause of

preventable hospital death– Costs of investigating symptomatic patients– Risks and costs of treating unprevented VTE – Increased future risk of recurrent VTE– Chronic postthrombotic syndrome


Efficacy of thromboprophylaxis– Thromboprophylaxis is highly efficacious at

preventing DVT and proximal DVT– Thromboprophylaxis is highly effective at

preventing symptomatic VTE and fatal PE– The prevention of DVT also prevents PE– Cost-effectiveness of thromboprophylaxis has

repeatedly been demonstrated

RISK FACTORS FOR VTE - 1

• Surgery• Trauma (major trauma or lower-extremity injury)• Immobility, lower-extremity paresis• Obesity• Increasing age• Cancer (active or occult)• Cancer therapy (hormonal, chemotherapy,

angiogenesis inhibitors, radiotherapy)• Venous compression (tumor, hematoma, arterial

abnormality)• Previous VTE

RISK FACTORS FOR VTE

• Pregnancy and the postpartum period• Estrogen-containing oral contraceptives or

hormone replacement therapy• Selective estrogen receptor modulators• Erythropoiesis-stimulating agents• Acute medical illness• Inflammatory bowel disease• Nephrotic syndrome• Myeloproliferative disorders• Paroxysmal nocturnal hemoglobinuria• Central venous catheterization• Inherited or acquired thrombophilia• Family history of VTE

THROMBOPHILIA• Inherited

– Antithrombin deficiency– Protein C deficiency– Protein S deficiency– Factor V Leiden (heterozygous or homozygous)– Prothrombin G20210A gene mutation

• Acquired– Antiphospholipid syndrome

Highest risk: Antithrombin deficiency, homozygous Factor V Leiden or compound heterozygotes, antiphospholipid syndrome

Predictive value of family history as good as that of lab testing

Most thrombotic events occur after hospital discharge

RISK OF DVT IN HOSPITALIZED PATIENTS NOT RECEIVING PROPHYLAXIS

DRUG REGIMENS TO PREVENT VTE• Low dose unfractionated heparin (5000 U q 8-12h) • Low molecular weight heparin (dalteparin 2500 U q

12-24h; enoxaparin 30 mg q 12h or 40 mg daily)• Fondaparinux (2.5 mg sq once daily)• Warfarin: Adjust to target INR 2-3• Low-dose ASA• New oral agents: dabigatran, rivaroxaban, apixaban

THROMBOPROPHYLACTIC DRUGS

Agent Advantages Disadvantages

Heparin Cost HIT riskShorter half-life

LMWH Lower risk of HITOnce daily dosing option

CostHigh blood levels in renal failure

Warfarin Oral administrationCostNo HIT risk

Variable dose-responseDelayed onset of effectNeed for monitoring

Fondaparinux Efficacy? (vs LMWH)Once daily dosingMinimal HIT risk

CostHigher bleeding risk?High blood levels in renal failure

Relative efficacy of various thromboprophylactic regimens following THR: meta-analysis

Treatment All DVT (%) Prox DVT (%) Bleeding (%)

None 47 23 0.3

Aspirin 36 16 0.4

UFH 24 14 2.6

LMWH 17 6 1.8

Stockings 18 13 0

Warfarin 24 5 1.3

JAMA 1994;271:22

Unfractionated heparin in general surgery

• Meta-analysis of 46 RCTs comparing UFH and placebo or no treatment

• UFH reduced DVT rate from 22% to 9%• Reduced symptomatic PE rate from 2.0% to 1.3%• Reduced fatal PE rate from 0.8% to 0.3%• Reduced all cause mortality from 4.2% to 3.2%

(one less death per 97 patients treated)• Increased bleeding rate from 3.8% to 5.9% (most

bleeds minor)

N Engl J Med 1988; 318:1162

LMWH in surgery

• General surgery:– LMWH reduces risk of asymptomatic DVT and

symptomatic VTE by over 70% vs no treatment– Roughly equivalent to UFH in terms of efficacy

and safety

• LMWH appears superior to UFH in high-risk orthopedic surgery

• No study has shown clear superiority of one form of LMWH over another

2008 ACCP guidelines

FONDAPARINUX

• Selective Xa inhibitor (does not inhibit thrombin)• Long half-life (once daily dosing), no antidote• Equivalent or slightly superior to LMWH for

prevention of postoperative VTE– Slightly higher bleeding risk

FONDAPARINUX VS ENOXAPARIN IN ORTHOPEDIC SURGERY

Pooled results from four pivotal trials

Outcome Fondaparinux Enoxaparin Odds Ratio(95% CI)

All VTE 6.8% 13.7% 0.45 (0.37-0.54)

Proximal DVT 1.3% 2.9% 0.43(0.27-0.64)

Major Bleed 2.7% 1.7% 1.54(1.11-2.16)

Lancet 2002;359:1710

MECHANICAL THROMBOPROPHYLAXISGraded compression stockings

–Knee- or thigh-high

Intermittent pneumatic compression

Venous foot pump

Mechanical thromboprophylaxis• Advantages

– No bleeding risk– Demonstrated efficacy (but limited evidence)– Enhance efficacy of anticoagulant prophylaxis– Reduce leg swelling

• Disadvantages– Less well-studied than anticoagulants– Less well-standardized– Not all devices have been evaluated in trialsLess effective in high-risk groupsLess effective in preventing proximal DVTNot shown to prevent PE or death– Compliance issues

Thromboprophylaxis in acutely ill medical patients2012 ACCP recommendations

• Patients with increased VTE risk:– LMWH, low-dose UFH or fondaparinux

• Patients with low VTE risk:– No prophylaxis

• Patients who are bleeding or at high risk for bleeding:– No anticoagulant prophylaxis– Mechanical prophylaxis if VTE risk high

Chest 2012;141:7S-47S

VTE Risk in Surgery: Rogers Score

J Am Coll Surg 2007;204:1211

VTE Risk in Surgery: Caprini Score

Dis Mon 2005; 51:70

VTE Risk in Surgery

• Very low risk (< 0.5%): – Rogers score < 7– Caprini score 0

• Low risk (~ 1.5%)– Rogers score 7-10– Caprini score 1-2

• Moderate risk (~ 3%)– Rogers score > 10– Caprini score 3-4

• High risk (≥ 6%)– Caprini score ≥ 5

Thromboprophylaxis in non-orthopedic surgical patients2012 ACCP recommendations

• Very low VTE risk:– No prophylaxis, early ambulation

• Low VTE risk:– Mechanical prophylaxis (IPC preferred)

• Moderate VTE risk, not high bleeding risk:– LMWH, low dose UFH, or mechanical prophylaxis

• Moderate VTE risk, high bleeding risk– Mechanical prophylaxis (IPC)

• High VTE risk, not high bleeding risk:– LMWH or low dose UFH, plus mechanical prophylaxis

Chest 2012;141:7S-47S

Thromboprophylaxis in non-orthopedic surgical patients2012 ACCP recommendations (2)

• Cancer surgery, not high bleed risk:– Extended duration LMWH (4 weeks)

• High VTE risk, high bleed risk:– Mechanical prophylaxis (IPC), pharmacologic

prophylaxis once bleed risk diminishes• High VTE risk, LMWH and UFH contraindicated, not high

bleed risk:– Low dose ASA, fondaparinux, or mechanical

• IVC filter should NOT be used for primary VTE prevention

Chest 2012;141:7S-47S

Thromboprophylaxis in orthopedic surgical patients2012 ACCP recommendations

• Total hip or knee arthroplasty:– LMWH (preferred), low-dose UFH, fondaparinux, adjusted-

dose warfarin, apixaban, dabigatran, rivaroxaban, aspirin (controversial), plus IPC

• Hip fracture surgery:– LMWH (preferred), low-dose UFH, fondaparinux, adjusted-

dose warfarin, aspirin (controversial), plus IPC• LMWH should be given at least 12 hours pre-op or 12 hours

post-op rather than closer to the time of surgery• Prophylaxis should be continued for a minimum of 10-14

days• IPC only if high bleeding risk; IVC filter if there is

contraindication to IPCChest 2012;141:7S-47S

Prolonged Thromboprophylaxis Decreases VTE Risk in Major Orthopedic Surgery

• Meta-analysis of 8 randomized controlled trials• Prolonged prophylaxis (≥ 21 days, vs 7-10 days)

decreased VTE risk:– 86% reduction in risk of PE– 74% reduction in risk of symptomatic DVT– 71% reduction in risk of proximal DVT

• 2.4-fold increase in risk of minor bleeding with prolonged prophylaxis

Ann Intern Med 2012;156:720

KNEE ARTHROSCOPY

• Symptomatic DVT rate < 1% without prophylaxis

Routine thromboprophylaxis not recommendedProphylaxis (eg, LMWH) recommended for

patients with prior hx of VTE


SPINAL OR EPIDURAL ANESTHESIA

• Reports of perispinal hematomas in patients receiving LMWH– Exact prevalence unknown– Few reports with low dose UFH as well

• Risk factors: – coagulopathy – anatomic spine abnormalities – difficult insertion/repeated attempts– higher doses of anticoagulant– continuous epidural catheter – older age

SPINAL OR EPIDURAL ANESTHESIARECOMMENDATIONS

• Avoid in patients with known coagulopathy• D/C clopidogrel (Plavix) at least 5 days before

– ASA safer?• Needle insertion and epidural catheter removal at least 8

hours after last dose of LMWH if twice daily, or 18 h after last dose if once daily

• Wait at least 2h before restarting LMWH, longer if CSF bloody

• Do not use continuous epidural anesthesia for more than 2 days if pt taking warfarin; INR should be < 1.5 when catheter removed

• Fondaparinux not recommended (long half-life, little data) • Monitor for signs of cord compression


Variables That Should Be Considered In Choice Of Thromboprophylaxis

2012 ACCP recommendations

“In choosing the specific anticoagulant drug to be used for pharmacoprophylaxis, choices should be based on patient preference, compliance, and ease of administration (eg, daily vs bid vs tid dosing), as well as on local factors affecting acquisition costs (eg, prices of various pharmacologic agents in individual hospital formularies)”

Chest 2012;141:7S-47S

Treatment of acute VTE

Principles of VTE Treatment• Adequate treatment of VTE requires administration of a rapid-

acting anticoagulant• This drug should be given in doses sufficient to achieve a

systemic anticoagulant effect, eg:– UFH: 70-80 U/kg loading dose, 15-18 U/kg/h infusion with

aPTT monitoring– Enoxaparin: 1 mg/kg sq twice daily– Dalteparin: 100 U/kg sq twice daily– Fondaparinux: 7.5 mg sq daily

• Initial treatment should be given for a minimum of 5 days• Failure to administer sufficient doses of a rapid-acting

anticoagulant may increase risk of recurrent VTE for up to three months

No routine monitoring

Heparin is superior to a vitamin K antagonist for initial treatment of acute DVT

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22

Weeks

0

2

4

6

8

10

12

14

Cu

mu

lati

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ailu

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Heparin + acenocoumarol

Acenocoumarol alone

Brandjes et al, NEJM 1992;327:1485

HEPARIN SHOULD BE DOSED ACCORDING TO BODY WEIGHT

OutcomeStandard

doseWeight-based

doseP value

First aPTT > 1.5 x control, % 32 86 <0.001

aPTT > 1.5 x control within 24 hours, %

77 97 0.002

Minor bleeding, % 3.8 3.2 NS

Major bleeding, % 1.9 0 NS

Recurrent DVT/PE, % 25 5 0.02

A randomized, controlled trial in 115 patients with thromboembolism or unstable angina (Ann Intern Med 1993;119:874)

Weight-based starting dose: 80 U/kg bolus, 18 U/kg/hrStandard starting dose: 5000 U bolus, 1000 U/hr

HEPARIN "RESISTANCE"

• Inadequate dose (large patient) Solution: weight-based dosing

• aPTT prolongation less than expected despite therapeutic heparin level (base aPTT short) Solution: monitor heparin level (anti-Xa activity)

• Heparin neutralized by PF4 released during clot formation Solution: LMWH/fondaparinux

• Low plasma antithrombin level (very rarely a cause) Solution: antithrombin concentrate or FFP infusion

• Heparin antibodies (may cause thrombocytopenia and thrombosis) Solution: direct thrombin inhibitor (lepirudin, etc) or

fondaparinux

Causes and solutions

LOW MOLECULAR WEIGHT HEPARINAdvantages over standard heparin

• Better bioavailability• Longer half-life allows once or twice daily dosing

– Facilitates outpatient treatment• Most patients do not need monitoring• Less likely than to cause HIT• Less bone mineral loss, lower fracture risk

• Disadvantages– Accumulates in renal failure– Not neutralized as well by protamine

ENOXAPARIN LEVEL VS CREATININE CLEARANCEJ Clin Pharmacol 2003;43:586-590

Patients treated with enoxaparin 1 mg/kg q12hConclusion: monitoring warranted when CrCl < 30

STANDARD VS LMW HEPARIN FOR TREATMENT OF DVT

meta-analysis of 10 published trials

Arch Intern Med 1995;155:601-7

Outcome% Risk reduction

with LMWH95% CI

Symptomatic thromboembolism

53 18-73

Clinically important bleeding

68 31-85

Mortality 47 10-69

LMWH vs UFH

• Low molecular weight heparin is at least as effective as unfractionated heparin in the treatment of acute VTE

• Low molecular weight heparin has significant practical advantages over unfractionated heparin

• 2012 ACCP Guidelines prefer once-daily LMWH or fondaparinux over UFH for initial treatment of acute VTE

Warfarin for prevention of recurrent VTE

• Takes minimum of 4-5 days to establish anticoagulant effect

• INR does not reflect anticoagulant effect for first 2-3 days

• Target INR 2-3• Utility of “loading dose” questionable

It takes at least 4-5 days for warfarin to achieve an adequate anticoagulant effect

Clotting factor levels after starting warfarin

New Oral Anticoagulants

New anticoagulant drug targets

VII

Fibrin clot

XV

II

IXVIII

XI

Dabigatran

RivaroxabanApixaban(More to come)

New oral anticoagulants• Dabigatran (Pradaxa®) – thrombin inhibitor

– FDA approval 2010: stroke prevention in non-valvular Afib; approved 2014 for VTE treatment

• Rivaroxaban (Xarelto®) – Xa inhibitor– FDA approval 2010/11: postop VTE prophylaxis, stroke

prevention in Afib, treatment of VTE• Apixaban (Eliquis®) – Xa inhibitor

– FDA approval 2012: stroke prevention in Afib; approved 2014 for VTE prophylaxis after major orthopedic surgery

– FDA approval for VTE treatment 2014• Edoxaban – Xa inhibitor

– Not yet FDA approved

Anticoagulant drug mechanisms

Ansell, 2011 HTRS meeting

Indirect inhibitors

Direct inhibitors

Pharmacology of oral anticoagulant drugs

Warfarin New agentsBioavailability 99% 6-80% (some active drug

in large bowel)

Tmax 72-96 hours 2-4 hours

Half-life 40 hours 5-17 hours

Metabolism Cytochrome P450 Biliary/Renal

Drug Interactions Many Not so many

Food Interactions Yes No

Genetic Variation Major effects Minor effects (?)

Monitoring PT/INR None

Reversal Vit K/PCC/FFP PCC?Dialysis?

Cost per month of oral anticoagulants

• Rivaroxaban (20 mg/day) : $290

• Dabigatran (150 mg bid): $290

• Apixaban (5 mg bid): $147

• Warfarin (7.5 mg/day): $31

Source: UWHC Pharmacy

Dabigatran• Dose

– Stroke prevention in A fib: 110-150 mg bid• 110 mg dose not available in US• For patients with CrCl 15-30: 75 mg bid• Not recommended for CrCl < 15 or dialysis dependent

– Postop VTE prophylaxis*: 150-220 mg once daily– VTE treatment/prevention of recurrent VTE: 150 mg bid

• Less than 10% absorbed; relatively high rate of GI side effects• Crosses the placenta – do not use during pregnancy• Drug may degrade over time after exposure to air – must be kept

in original packaging

Unused tablets should be discarded after 90 days

* Not FDA-approved indication

Rivaroxaban• Dose:

– Stroke prevention in Afib: 15-20 mg once daily– Post op VTE prophylaxis: 10 mg once daily– Acute VTE treatment: 15 mg twice daily– Secondary prevention of VTE: 20 mg once daily– Acute coronary syndrome*: 2.5-5 mg twice daily

• Use with caution in moderate renal impairment (CrCL 30-49); 15 mg/day dose recommended– Avoid use if CrCl < 30 (not dialyzable)

• Avoid use in severe liver disease

*Not FDA-approved indication

Apixaban

• Dose: – Stroke prevention in Afib: 5 mg bid

• 2.5 mg bid if age >80, weight < 60 kg, or serum creatinine > 1.5

– Post op VTE prophylaxis: 2.5 mg bid– Treatment of acute VTE*: 10 mg bid– Secondary prevention of VTE*: 2.5 - 5 mg bid

• Avoid use in severe liver disease (75% biliary excretion)

*Not FDA-approved indication

RESULTS OF AF TRIALS WITH NEW ORAL AGENTS

• Main result: New agents at least as effective as warfarin, can be given without routine monitoring

• Other findings:– Reduction in intracranial bleeding– Slightly higher MI rates– Higher rates of GI bleeding (active drug in lower

intestine)– Extracranial bleeding risk higher in older patients

Dabigatran vs warfarin for acute VTEThe RE-COVER trial

Treatment VTE recurrence Major bleeding Any bleeding

Dabigatran 2.4% 1.6% 16.1%

Warfarin 2.1% 1.9% 21.9%

NEJM 2009; 361: 2342

Conclusion: A fixed dose of dabigatran is as effective and safe as warfarin for treatment of acute venous thromboembolism

Rivaroxaban for acute VTEThe EINSTEIN-DVT trial

Treatment Recurrent VTE Bleeding

Rivaroxaban 2.1% 8.1%

Standard treatment 3.0% 8.1%

NEJM 2010; 363: 2499

Conclusion: rivaroxaban is as effective and safe as standard treatment for acute VTE

Rivaroxaban for Pulmonary EmbolismThe EINSTEIN-PE trial

NEJM 2012; 366: 1287

Treatment Recurrent VTE Bleeding Major Bleeding

Rivaroxaban 2.1% 10.3% 1.1%

Standard treatment 1.8% 11.4% 2.2%

Conclusion: rivaroxaban as effective as standard treatment for initial and extended treatment of pulmonary embolism, may be safer

Dabigatran vs enoxaparin prophylaxis after total knee or hip arthroplasty

RE-MODELJ Thromb Haemost 2007;5:2178

RE-NOVATELancet 2007;370:949

Surgery knee hip

# pts 2076 3494

Drug doses Dab: 150 or 220 qdEnox: 40 mg qd

Dab: 150 or 220 qdEnox: 40 mg qd

Duration (d) 6-10 28-35

VTE or death(%)

D150: 40.5D220: 36.4E: 37.7

D150: 8.6D220: 6.0E: 6.7

Major Bleeding(%)

D150: 1.5D220: 1.3E: 1.3

D150: 1.3D220: 2.0E: 1.6

Both trials showed dabigatran (either dose) had similar efficacy and safety compared to enoxaparin

Rivaroxaban vs enoxaparin prophylaxis after total knee or hip arthroplasty: the RECORD trials

RECORD 1NEJM 2008;358:2775

RECORD 2Lancet 2008;372:31

RECORD 3NEJM 2008;358:2776

RECORD 4Lancet 2009;373:1673

Surgery hip hip knee knee

# pts 4541 2509 2531 3148

Duration (d) 35 Riv: 31-35Enox: 10-14

14 11-15

VTE or death(%)

R: 1.1E: 3.7

R: 2.0E: 9.3

R: 9.6E: 18.9

R: 6.9E: 10.1

Bleeding(%)

R: 0.3E: 0.1(major bleed)

R: 6.6E: 5.5(any bleed)



All trials with rivaroxaban 10 mg/d vs enoxaparin 40 mg/dAll had mandatory venography All showed rivaroxaban had superior efficacy vs

enoxaparin with similar safety

Apixaban vs enoxaparin prophylaxis after total knee or hip arthroplasty: the ADVANCE trials

ADVANCE 1NEJM 2009;361:594

ADVANCE 2Lancet 2010;375:807

ADVANCE 3NEJM 2010;363:2487

Surgery knee knee hip

# pts# evaluable for efficacy

31952287

30571973

54073866

Duration (d) 10-14 10-14 35

VTE or death(%)

A: 9.0E: 8.8

A: 15E: 24

A: 1.4E: 3.9

Bleeding(%)

A: 2.9E: 4.3

A: 4E: 5

A: 4.8E: 5.0

Meta-analysis of data from ADVANCE-1 and ADVANCE-2 shows that apixaban is non-inferior to enoxaparin with respect to efficacy, and has a “considerable” safety advantage (Huang et al, Thromb Haemost 2011;105: 245)

Effect of dabigatran on PT and aPTT

Thromb Haemost 2010;103:1116

• Neither assay is adequately sensitive in the range of concentrations expected in patients on chronic oral therapy

• Sensitivity to drug level is reagent-dependent, will vary among laboratories

Trough levels: 32-225 ng/mlPeak levels: 64-443 ng/ml

• No specific antidote for any of the new OACs• Activated charcoal will reduce drug absorption

if administered within a few hours of ingestion• Rivaroxaban & apixaban effect may be

reversed by giving prothrombin complex concentrate (PCC)

• Dabigatran is dialyzable• Case reports suggest that recombinant factor

VIIa (NovoSeven™) is ineffective vs dabigatran (Thromb Haemost 2012;108:585)

When to stop drug before surgery

CrCl, mL/min Approx half-life, h

Standard risk surgery

High risk surgery

>80 13 24 h 2 days

50-80 15 24h 2 days

30-50 18 2 days 4 days

<30 27 4 days 6 days

Dabigatran

CrCl, mL/min Approx half-life, h

Standard risk surgery

High risk surgery

>30 12 24 h 2 days

<30 ? 2 days 4 days

Rivaroxaban

Documents

Primary prevention of VTE. RATIONALE FOR THROMBOPROPHYLAXIS IN HOSPITALIZED PATIENTS - 1 High prevalence of VTE –Almost all hospitalized patients have