Download Prevention and Treatment of VTE

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
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
RISK OF DVT IN HOSPITALIZED PATIENTS
NOT RECEIVING PROPHYLAXIS
Most thrombotic events occur after hospital discharge
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 risk
Shorter half-life
LMWH
Lower risk of HIT
Once daily dosing option
Cost
High blood levels in renal
failure
Warfarin
Oral administration
Cost
No HIT risk
Variable dose-response
Delayed onset of effect
Need for monitoring
Fondaparinux
Efficacy? (vs LMWH)
Once daily dosing
Minimal HIT risk
Cost
Higher 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 THROMBOPROPHYLAXIS
Graded 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 trials
 Less effective in high-risk groups
 Less effective in preventing proximal DVT
 Not shown to prevent PE or death
– Compliance issues
Thromboprophylaxis in acutely ill medical patients
2012 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 patients
2012 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 patients
2012 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 patients
2012 ACCP recommendations
• Total hip or knee arthroplasty:
– LMWH (preferred), low-dose UFH, fondaparinux, adjusteddose warfarin, apixaban, dabigatran, rivaroxaban, aspirin
(controversial), plus IPC
• Hip fracture surgery:
– LMWH (preferred), low-dose UFH, fondaparinux, adjusteddose 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 IPC
Chest 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 recommended
 Prophylaxis (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 ANESTHESIA
RECOMMENDATIONS
• 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
Treatment of acute VTE
Principles of VTE Treatment
• Adequate treatment of VTE requires administration of a rapidacting 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
No routine monitoring
– 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
Heparin is superior to a vitamin K antagonist for
initial treatment of acute DVT
14
Heparin + acenocoumarol
Cumulative failures
12
Acenocoumarol alone
10
8
6
4
2
0
1
2
3
4
5
6
7
8
9 10 11 12 13 14 15 16 17 18 19 20 21 22
Weeks
Brandjes et al, NEJM 1992;327:1485
HEPARIN SHOULD BE DOSED ACCORDING
TO BODY WEIGHT
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/hr
Standard starting dose: 5000 U bolus, 1000 U/hr
Outcome
Standard Weight-based
P value
dose
dose
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
HEPARIN "RESISTANCE"
Causes and solutions
•
•
•
•
•
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
LOW MOLECULAR WEIGHT HEPARIN
Advantages 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 CLEARANCE
J Clin Pharmacol 2003;43:586-590
Patients treated with enoxaparin 1 mg/kg q12h
Conclusion: monitoring warranted when CrCl < 30
STANDARD VS LMW HEPARIN FOR
TREATMENT OF DVT
meta-analysis of 10 published trials
Outcome
% Risk reduction
with LMWH
95% CI
Symptomatic
thromboembolism
53
18-73
Clinically important
bleeding
68
31-85
Mortality
47
10-69
Arch Intern Med 1995;155:601-7
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 23 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
XI
Dabigatran
VIII
IX
V
X
II
Fibrin clot
VII
Rivaroxaban
Apixaban
(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
Indirect inhibitors
Direct inhibitors
Ansell, 2011 HTRS meeting
Pharmacology of oral
anticoagulant drugs
Warfarin
New agents
Bioavailability
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 3049); 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 VTE
The RE-COVER trial
Treatment
VTE recurrence
Major bleeding
Any bleeding
Dabigatran
2.4%
1.6%
16.1%
Warfarin
2.1%
1.9%
21.9%
Conclusion: A fixed dose
of dabigatran is as
effective and safe as
warfarin for treatment of
acute venous
thromboembolism
NEJM 2009; 361: 2342
Rivaroxaban for acute VTE
The EINSTEIN-DVT trial
Treatment
Recurrent VTE
Bleeding
Rivaroxaban
2.1%
8.1%
Standard treatment
3.0%
8.1%
Conclusion:
rivaroxaban is
as effective and
safe as standard
treatment for
acute VTE
NEJM 2010; 363: 2499
Rivaroxaban for Pulmonary Embolism
The EINSTEIN-PE trial
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
NEJM 2012; 366: 1287
Dabigatran vs enoxaparin prophylaxis
after total knee or hip arthroplasty
RE-MODEL
RE-NOVATE
J Thromb Haemost 2007;5:2178
Lancet 2007;370:949
Surgery
knee
hip
# pts
2076
3494
Drug doses
Dab: 150 or 220 qd
Enox: 40 mg qd
Dab: 150 or 220 qd
Enox: 40 mg qd
Duration (d)
6-10
28-35
VTE or death
(%)
D150: 40.5
D220: 36.4
E: 37.7
D150: 8.6
D220: 6.0
E: 6.7
Major Bleeding
(%)
D150: 1.5
D220: 1.3
E: 1.3
D150: 1.3
D220: 2.0
E: 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 1
RECORD 2
RECORD 3
RECORD 4
NEJM 2008;358:2775
Lancet 2008;372:31
NEJM 2008;358:2776
Lancet 2009;373:1673
Surgery
hip
hip
knee
knee
# pts
4541
2509
2531
3148
Duration (d)
35
Riv: 31-35
Enox: 10-14
14
11-15
VTE or death
(%)
R: 1.1
E: 3.7
R: 2.0
E: 9.3
R: 9.6
E: 18.9
R: 6.9
E: 10.1
Bleeding
(%)
R: 0.3
R: 6.6
R: 0.6
R: 0.7
E: 0.1
E: 5.5
E: 0.5
E: 0.3
(major bleed) 10
(anymg/d
bleed)vs enoxaparin
(major bleed) 40
(major
bleed)
rivaroxaban
mg/d
All trials with
All 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 1
ADVANCE 2
ADVANCE 3
NEJM 2009;361:594
Lancet 2010;375:807
NEJM 2010;363:2487
Surgery
knee
knee
hip
# pts
3195
3057
5407
# evaluable for efficacy
2287
1973
3866
Duration (d)
10-14
10-14
35
VTE or death
(%)
A: 9.0
E: 8.8
A: 15
E: 24
A: 1.4
E: 3.9
Bleeding
(%)
A: 2.9
E: 4.3
A: 4
E: 5
A: 4.8
E: 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
Trough levels: 32-225 ng/ml
Peak levels: 64-443 ng/ml
• 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
Thromb Haemost 2010;103:1116
• 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
Dabigatran
CrCl, mL/min Approx halflife, 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
Rivaroxaban
CrCl, mL/min Approx halflife, h
Standard
risk surgery
High risk
surgery
>30
12
24 h
2 days
<30
?
2 days
4 days