View
224
Download
2
Category
Preview:
Citation preview
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
RATIONALE FOR THROMBOPROPHYLAXIS IN HOSPITALIZED PATIENTS - 2
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
RATIONALE FOR THROMBOPROPHYLAXIS IN HOSPITALIZED PATIENTS - 3
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
• 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
2012 ACCP guidelines
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
2008 ACCP guidelines
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
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
ve f
ailu
res
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 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
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)
R: 0.6E: 0.5(major bleed)
R: 0.7E: 0.3(major 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
Recommended