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1
Learning Objectives
After participating in this activity, participants should
be able to:
 Assess the impact of risk factors and comorbidities on
the development of VTE
 Evaluate current clinical trial evidence for the use of
anticoagulant treatments
 Implement current guideline-based recommendations for
VTE prevention and treatment
 Develop strategies for meeting standards set by the Joint
Commission/National Quality Forum
2
Disclosure Statement
The Network for Continuing Medical Education requires that
CME faculty disclose, during the planning of an activity, the
existence of any personal financial or other relationships
they or their spouses may have with the commercial
supporter of the activity or with the manufacturer of any
commercial product or service discussed in the activity.
3
Faculty Disclosure
4
Venous Thromboembolism
Annual incidence of VTE in the US:
• Approximately 600,000 cases of VTE1,2
• Estimated 180,000 deaths due to DVT/PE1
Annual number at risk for VTE in US hospitals:
• 7.7 million medical service inpatients3
• 4.3 million surgical service inpatients3
31% of US
hospital discharges
• 2/3 of VTE cases and deaths are hospital-acquired1
PE is the leading preventable cause of hospital death4
1. US Dept of Health and Human Services. The Surgeon General’s Call to Action to Prevent
Deep Vein Thrombosis and Pulmonary Embolism. Bethesda, MD: September 2008.
2. Anderson FA Jr, et al. Arch Intern Med. 1991;151(5):933-938.
3. Anderson FA Jr, et al. Am J Hematol. 2007;82(9):777-782.
4. Geerts WH, et al. Chest. 2008;133:381S-453S.
5
Rising Incidence of
VTE in Hospitalized Patients
VTE rates are rising because
– The population is getting older
– The US obesity epidemic continues to grow
– Patients are surviving longer with chronic disease
associated with the risk of VTE
6
VTE in Hospitalized Patients
Not Just a Surgical Problem
 50%-70% of symptomatic VTEs occur in
nonsurgical patients1
 70%-80% of fatal PEs occur in nonsurgical patients1
 DVT was detected by ultrasound in 33% of medical
patients in the ICU during an 8-month screening study2
 PE: most preventable cause of hospital death and the
number one strategy to improve patient safety in
hospitals1
1. Geerts WH, et al. Chest. 2008;133:381S-453S.
2. Hirsch DR, et al. JAMA. 1995;274:335-337.
7
DVT-FREE Registry:
Distribution by Age and Gender
800
Men (n=2559)
Women (n=2892)
700
Patients, n
600
500
400
300
200
100
0
≤20
21-30 31-40 41-50 51-60 61-70 71-80 81-90
>90
Age, y
Reprinted with permission from Goldhaber SZ, Tapson VF; for the DVT FREE Steering
Committee. Am J Cardiol. 2004;93:259-262.
8
DVT-FREE Registry:
Distribution by BMI and Gender
800
Men (n=2095)
Women (n=2344)
Patients, n
700
600
500
400
300
200
100
0
≤20
21-25
26-30
31-35
>35
Body Mass Index, kg/m2
Reprinted with permission from Goldhaber SZ, Tapson VF; for the DVT FREE Steering
Committee. Am J Cardiol. 2004;93:259-262.
9
DVT-FREE Registry: Time From Most Recent
Surgery to Diagnosis of DVT by Patient Status
40
Outpatients (n=718)
Inpatients (n=1351)
Patients, %
35
30
25
20
15
10
5
0
0-5
6-10
11-15
16-20
21-25
26-30
>31
Time, d
Reprinted with permission from Goldhaber SZ, Tapson VF; for the DVT FREE Steering
Committee. Am J Cardiol. 2004;93:259-262.
10
Outpatient and Inpatient
VTE Are Linked
An observational study of 1897 patients with a confirmed episode of
VTE found that
– 74% of patients developed VTE in the outpatient setting
 Among those 74%, 60% were hospitalized (23%
surgical; 37% medical) in the past 3 months
• Of those 60%, 67% experienced VTE within 1
month of hospital discharge
– Among 516 patients with a recent hospitalization who
subsequently developed VTE, less than half (43%) had
received anticoagulant prophylaxis during their hospital stay
Spencer FA, et al. Arch Intern Med. 2007;167(14):1471-1475.
11
Potential Mechanisms by Which
Clinical Conditions Facilitate VTE
Increased baseline
propensity
for thrombosis
Hypercoagulability
Direct vessel injury
Blood stasis
Acute insult
Hypercoagulability
Direct vessel injury
Blood stasis
Lopez JA, et al. Hematology. 2004;1:439-456.
12
Risk Factors for VTE
• Surgery
• Estrogen-containing OCs or HRT
• Trauma (major trauma or
lower-extremity injury)
• Erythropoiesis-stimulating agents
• Immobility, lower-extremity
paresis
• Inflammatory bowel disease
• Cancer (active or occult)
• Cancer therapy
• Venous compression
• Previous VTE
• Increasing age
• Pregnancy/postpartum
period
• Smoking
• Acute medical illness
• Nephrotic syndrome
• Myeloproliferative disorders
• Paroxysmal nocturnal
hemoglobinuria
• Obesity
• Central venous catheterization
• Inherited or acquired
thrombophilia
Adapted from Geerts WH, et al. Chest. 2008;133(6 suppl):381S-453S.
13
Acute Respiratory Disease and CHF
Increase the Risk of VTE
• The prevalence of thromboembolic disease in patients hospitalized
for respiratory disease is estimated at 8%-25%1
• COPD patients with DVT are older, more likely to be inpatients,
more likely to be in the ICU and mechanically ventilated, and more
often have concomitant PE2
• CHF has long been associated with an increased risk of VTE3
– One of the few studies to quantify the risk of DVT in patients
with CHF did find increased risk, with an OR of 1.84
• VTE is an underestimated cause of morbidity and mortality in
patients with CHF3
1.
2.
3.
4.
Shetty R, et al. J Throm Thrombolysis. 2008;26:35-40.
Fraisse F, et al. Am J Respir Crit Care Med. 2000;161:1109-1114.
Howell MD, et al. J Clin Epidemiol. 2001;54(8):810-816.
Cogo A, et al. Arch Int Med. 1994;154:164-168.
14
DVT/PE Risk
The Importance of DVT Prophylaxis
in Congestive Heart Failure
38.3 x
greater
1.7
X
greater
LVEF >45%
2.8
X
greater
LVEF 20-44%
LVEF <20%
LVEF = left ventricular ejection fraction.
Howell MD, et al. J Clin Epidemiol. 2001;54:810-816.
15
Joint Commission/NQF Draft
VTE Measures for 2009
• 6 VTE measures were endorsed by the NQF in May 2008
– VTE prophylaxis
– ICU VTE prophylaxis
– VTE patients with anticoagulation overlap therapy
– VTE patients UFH dosages/platelet count monitoring by protocol
(or nomogram)
– VTE discharge instructions
– Incidence of potentially preventable VTE
• Measures will be available for data collection and reporting for
discharges beginning autumn 2009
• Complete measure specifications available spring 2009
National Quality Forum. http://www.qualityforum.org/news/releases/051508-endorsedmeasures.asp. Accessed November 6, 2008.
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Surgical Care Improvement Project
• SCIP is a unique partnership between multiple organizations,
including the American Academy of Orthopedic Surgeons,
American Hospital Association, American College of Surgeons,
Joint Commission, AHRQ, Centers for Disease Control and
Prevention, and VA, among others
• The goal is to reduce the incidence of surgical complications
nationally by 25% by the year 2010
• VTE Performance Measures
– Surgery patients with recommended VTE prophylaxis ordered
– Surgery patients who received appropriate VTE prophylaxis
within 24 hours prior to surgery to 24 hours after surgery
MedQIC – Surgical Care Improvement Project.
http://www.qualitynet.org/dcs/ContentServer?cid=1137346750659&pagename=Medqic/Content/Par
entShellTemplate&parentName=TopicCat&c=MQParents. Accessed November 6, 2008.
17
2008 ACCP Prevention of Venous Thromboembolism Practice Guidelines
Strategies for Prevention of VTE
• Pharmacologic
• Mechanical
– LMWH (eg, enoxaparin,
dalteparin)
– Intermittent pneumatic
compression
– Low-dose UFH
– Graduated elastic
compression stockings
– Fondaparinuxa
– Vitamin K antagonist
(eg, warfarin)
aFondaparinux
is not approved by the FDA for VTE prophylaxis in medical patients.
Geerts WH, et al. Chest. 2008;133(6 suppl):381S-453S.
18
Emerging Anticoagulants for the
Management of VTE
• Indirect FXa inhibitor
– Idraparinux
• Oral direct FXa inhibitors
– Rivaroxaban
– Apixaban
• Oral direct thrombin inhibitor
– Dabigatran
19
2008 ACCP Prevention of Venous Thromboembolism Practice Guidelines
Key ACCP 2008 Practice Guideline
Recommendations
• Every hospital should develop a formal strategy that
addresses the prevention of VTE (Grade 1A)
• Aspirin should not be used alone as thromboprophylaxis
for any patient group (Grade 1A)
• Mechanical methods of thromboprophylaxis should be
used primarily for patients at high bleeding risk (Grade 1A)
or possibly as an adjunct to anticoagulant
thromboprophylaxis (Grade 2A)
Geerts WH, et al. Chest. 2008;133(6 suppl):381S-453S.
20
2008 ACCP Prevention of Venous Thromboembolism Practice Guidelines
Key ACCP 2008 Practice Guideline
Recommendations (cont)
 In patients admitted to the hospital with an acute medical
illness, thromboprophylaxis with LMWH, low-dose UFH, or
fondaparinuxa is recommended (Grade 1A)
 On admission to the ICU, all patients should be assessed for
their risk of VTE, and most should receive thromboprophylaxis
(Grade 1A)
aFondaparinux
is not approved by the FDA for VTE prophylaxis in medical patients.
Geerts WH, et al. Chest. 2008;133(6 suppl):381S-453S.
21
Thromboprophylaxis Recommendations for Hospital
Patients — Balancing the Risk of Bleeding
Bleeding Risk
VTE Risk
Recommendation
Low
Moderate
LMWH or LDUH
Low
Higha
LMWH and/or
fondaparinux, with or
without GCS or IPC
High
Moderate
GCS or IPC, LMWH
or LDUH when risk
decreases
High
Higha
GCS or IPC, LMWH
when risk decreases
aHigh-risk
patients include those who have had major trauma or spinal cord injury, major hip or
knee surgery, or major surgery for cancer.
Adapted from Geerts WH, et al. J Crit Care. 2002;17:95-104.
22
Primary Prevention
of VTE in Hospitalized
Medical Patients
23
Risk of VTE in Hospitalized
Medical Patients
 Patients hospitalized for acute medical illness have more than
a 10-fold increased risk for VTE1
 Nursing home residents are more than twice as likely as
nonresidents to develop DVT/PE2
 VTE prophylaxis remains underutilized or inadequate in
hospitalized medical patients3,4
– Underuse often occurs because of unwarranted
safety concerns5
1.
2.
3.
4.
5.
Heit JA, et al. Arch Intern Med. 2000;160(6):809-815.
Heit JA, et al. Arch Intern Med. 2002;162(11):1245-1248.
Goldhaber SZ, Tapson VF. Am J Cardiol. 2004;93(2):259-262.
Anderson FA Jr, et al. Ann Intern Med. 1991;115(8):591-595.
US Dept of Health and Human Services. The Surgeon General’s Call to Action to Prevent Deep
Vein Thrombosis and Pulmonary Embolism. Bethesda, MD: September 2008.
24
Recommendations for Prophylaxis
in Medical Patients
ACCP 2008 and IUA 2006 Guidelines
• In acutely ill medical patients who have been admitted to the
hospital with:1,2
– congestive heart failure or severe respiratory disease
– Or who are confined to bed and have ≥1 additional risk factors, including
active cancer, previous VTE, sepsis, acute neurologic disease, or
inflammatory bowel disease
• LMWH (Grade 1A; IUA: enoxaparin 40 mg qd or dalteparin 5000 qd)
• Low-dose UFH (Grade 1A; IUA: 5000 IU tid)
• Fondaparinux (Grade 1A)*
* Fondaparinux is not approved by the FDA for prophylaxis in medical patients.
1.
2.
International Consensus Statement. Int Angiol. 2006;25:101-161.
Geerts WH, et al. Chest. 2008;133:381S-453S.
25
VTE Prophylaxis in Acutely Ill Medical Patients
Primary Efficacy End Points:
Implications for Clinical Practice
Trial
VTE
MEDENOX1
Distal and proximal
venographic DVT
+ symptomatic VTE
+ fatal PE
Compression
ultrasonographic DVT
+ symptomatic VTE
+ fatal PE
Distal and proximal
venographic DVT
+ symptomatic VTE
+ fatal PE
PREVENT2
ARTEMIS3
RRR
# Needed to Treat
63%
10
45%
45
47%
20
1. Samama MM, et al. N Engl J Med. 1999;341(11):793-800.
2. Leizorovicz A, et al. Circulation. 2004;110(7):874-879.
3. Cohen AT, et al. BMJ. 2006;332(7537):325-329.
26
VTE Prophylaxis in Hospitalized
Medical Patients: 3 Meta-analyses
 Dentali et al1: 9 randomized trials (N=19,958) comparing anticoagulant prophylaxis
with no treatment
– Anticoagulation significantly reduced any PE by 57% and fatal PE by 62%,
and reduced symptomatic DVT by 53% (nonsignificant)
 King et al2: 12 randomized trials (N=7978) comparing bid with tid UFH
– The combined DVT + PE event rate was 2.34 per 1000 patient days with bid
UFH and 0.86 per 1000 patients days with tid UFH (P=.05)
– The risk for major bleeding was significantly increased with tid UFH (P<.001)
 Wein et al3: 36 randomized trials comparing the efficacy and safety of various
prophylaxis agents
– Both UFH and LMWH were associated with a reduced risk of DVT and PE;
UFH tid was more effective than UFH bid for reducing the risk of DVT (RR
0.27 vs RR 0.52, respectively)
– When directly compared with UFH, LMWH was associated with a lower risk
of DVT (RR 0.68)
1. Dentali F, et al. Ann Intern Med. 2007;146(4):278-288.
2. King CS, et al. Chest. 2007;131(2):507-516.
3. Wein L, et al. Arch Intern Med. 2007;167(14):1476-1486.
27
Is Duration of VTE Prophylaxis Analogous to
Duration of a Course of Antibiotics?
Indication
Average LOS, d
Duration of Prophylaxis
Acute medical illness
3-5
6-11 d
Abdominal surgery
2-10
7-10 d
Hip replacement
2-6
7-10 d or 3 wk
Knee replacement
2-5
7-10 d
Antibiotic
Organism
1.
2.
3.
4.
Process Components:
Failure to give the antibiotic
“Resistance” of the organism
Initial timing of the antibiotic
Duration of treatment
28
EXCLAIM: Extended-duration Enoxaparin
Prophylaxis in High-risk Medical Patients
End points
Extended
prophylaxis
n=2013 (%)
Placebo
n=2027
(%)
RR
P value
reduction
(%)
VTE events
2.8
4.9
44
.001
Symptomatic
0.3
1.1
73
.004
No symptoms
2.5
3.7
34
.032
NNT = 46 patients to avoid one VTE event.
NNT = 224 to result in one major bleeding event.
Hull RD, et al. Abstract presented at: ISTH, July 8-11, 2007, Geneva, Switzerland.
29
Prevention of VTE After Acute Ischemic
Stroke: PREVAIL Study
NIHSS Score <14
NIHSS Score ≥14
Occurrence (95% CI)
P
Occurrence (95% CI)
P
8.3% (5.90-10.70)
.004
16.3% (10.53-21.97)
.004
VTE
Enoxaparin
UFH
14.0% (10.91-17.02)
29.7% (22.94-36.49)
DVT
Enoxaparin
UFH
8.1% (5.73-10.48)
13.6% (10.54-16.58)
.005
16.3% (10.53-21.97)
.005
29.1% (22.41-35.88)
NIHSS = National Institutes of Health Stroke Scale.
Reprinted with permission from Sherman DG, et al. Lancet. 2007;369:1347-1355.
30
Prevention of VTE in Patients With Heart
Failure or Severe Respiratory Disease
Percentage of Thrombolic Events
18
16
Enoxaparin
14
UFH
12
10
8
6
4
2
0
All Patients
Resp Dis
HF
HF = heart failure.
Kleber F-X, et al. Am Heart J. 2003;145:614-621.
31
Prevention of VTE in High-Risk Hospitalized
Medical Patients: THE PRIME Study
Intention-to-treat
Per-protocol
Enoxaparin
(n=442)
Heparin
(n=443)
Enoxaparin
(n=393)
Heparin
(n=377)
1 (0.2%)
6 (1.4%)
1 (0.3%)
5 (1.3%)
DVT
1
2
1
2
DVT + PE
0
2
1
2
PE
0
2
0
2
Thromboembolic events
Test for superiority
P=.1235
P=.1164
Test for equivalence
P=.0000048
P=.00000306
Reprinted with permission from Lechler E, et al. Haemostasis. 1996;26(suppl 2):49-56.
32
Conclusions: THE PRIME Study
• Enoxaparin is at least as efficacious as standard heparin for
DVT prophylaxis in high-risk hospitalized medical patients
• Treatment with enoxaparin resulted in fewer major bleeds and
adverse events
– Only 3 bleeds were considered to be treatment related;
all occurred in the heparin group
– Hematomas at the injection site exceeding 5 cm in diameter
were recorded 22 times (4.6%) in the enoxaparin group and
52 times (10.8%) in the heparin group (P<.001)
– Liver enzymes were significantly more often elevated
with heparin compared with enoxaparin
Lechler E, et al. Haemostasis. 1996;26(suppl 2):49-56.
33
The Importance of DVT Prophylaxis
in Patients With Cancer
• VTE is one of the leading causes of death in cancer patients,
occurring in 4% to 20% of patients
• Hospitalized patients with cancer and cancer patients receiving
active therapy are at greatest risk for VTE
– Cancer increased the risk of VTE 4.1-fold
– Chemotherapy increased the risk 6.5-fold
• Major risk factors include older age, comorbid conditions, recent
surgery or hospitalization, active chemotherapy or hormonal therapy
• All hospitalized cancer patients should be considered for prophylaxis
• Patients with cancer undergoing surgery should be considered for
prophylaxis
• LMWH is the preferred drug
Lyman GH, et al. J Clin Oncol. 2007;25:5490-5505.
34
2008 ACCP Prevention of Venous Thromboembolism Practice Guidelines
Prophylaxis in Cancer Patients
 Cancer patients undergoing surgical procedures: routine
thromboprophylaxis that is appropriate for the type of surgery
(Grade 1A)
 Cancer patients who are bedridden with an acute medical illness:
routine thromboprophylaxis as for other high-risk medical patients
(Grade 1A)
 Cancer patients receiving chemotherapy or hormonal therapy:
recommend against the routine use of thromboprophylaxis for the
primary prevention of VTE (Grade 1C)
 Cancer patients overall: recommend against the routine use
of primary thromboprophylaxis to try to improve survival
(Grade 1B)
Geerts WH, et al. Chest. 2008;133(6 suppl):381S-453S.
35
Despite Evidence, Medical Patients
at Risk Remain Unprotected
ENDORSE1
IMPROVE2
Medical
Surgical
United
States
Other
Countries
37,356
30,827
3,410
11,746
At risk for
VTE
42%
64%
Receiving
ACCP Tx
40%
59%
No. of
patients
No. of
patients
VTE
prophylaxis
1852 (54%) 5788 (49%)
LMWH
476 (14%) 4657 (40%)
UFH
717 (21%) 1014 (9%)
1. Cohen AT, et al. Presented at: 2007 Congress of the International Society on Thrombosis
and Haemostasis; July 6-12, 2007; Geneva, Switzerland.
2. Tapson VF, et al. Chest. 2007;132(3):936-945.
36
Electronic Alerts to Prevent VTE in
Hospitalized Patients
Freedom From DVT
or PE (%)
100
98
96
Intervention group
94
92
Control group
90
P<.001
0
0
30
1255
1251
977
976
No. at Risk
Intervention group
Control group
Days
60
90
900
893
853
839
P<.001 by the log-rank test for the comparison of the outcome between groups at 90 days.
Reprinted with permission from Kucher N, et al. N Engl J Med. 2005;352:969-977.
37
Primary Prevention of VTE in
Surgical Patients
38
2008 ACCP Prevention of Venous Thromboembolism Practice Guidelines
General Surgery Recommendations
• Low-risk patients, minor procedure, no additional risk factors:
recommend against specific thromboprophylaxis other than early
and frequent ambulation (Grade 1A)
• Moderate-risk patients, major procedure for benign disease:
LMWH, LDUH, or fondaparinux (Grade 1A)
• Higher-risk patients, major procedure for cancer: LMWH,
LDUH 3 times/day, or fondaparinux (Grade 1A)
• Patients with multiple risk factors who are thought to be at high
risk: LMWH, LDUH 3 times/day, or fondaparinux with GCS and/or
IPC (Grade 1C)
Geerts WH, et al. Chest. 2008;133(6 suppl):381S-453S.
39
2008 ACCP Prevention of Venous Thromboembolism Practice Guidelines
General Surgery Recommendations (cont)
• Patients with high risk of bleeding: GCS or IPC (Grade 1A);
pharmacologic therapy substituted or added to mechanical
thromboprophylaxis once high bleeding risk decreases (Grade 1C)
• For patients undergoing major general surgery, continue
thromboprophylaxis until discharge (Grade 1A)
• Selected high-risk patients, including some who have undergone
major cancer surgery or have had VTE previously, continue
thromboprophylaxis after discharge; consider LMWH for up to
28 days
Geerts WH, et al. Chest. 2008;133(6 suppl):381S-453S.
40
UFH vs LMWH in Colorectal Surgery:
A Meta-analysis
• In a meta-analysis that included 19 randomized controlled or
clinical controlled trials comparing prophylactic interventions in
patients who underwent colorectal surgery
– UFH and LMWH (4 studies) were equally effective
(POR 1.01)
– The combination of graduated compression stockings and
LMWH is better than LMWH alone (2 studies) (POR 4.17)
• The investigators concluded that graduated compression
stockings + low-dose UFH or LMWH is the optimal
thromboprophylaxis in colorectal surgery
POR, Peto Odds ratio.
Borly L, et al. Colorectal Dis. 2005;7(2):122-127.
41
Efficacy of LMWH in Patients Undergoing
Cancer Surgery: ENOXACAN Results
ENOXACAN I1
16
14
12
18.2a
17.6
14.7
UFH
Enoxaparin
14.4
10
8
6
4
2.9
4.1
16
14
12
10
8
6
4
Placebo
Enoxaparin
12.0b
10.2
4.8
4.2
2
0
2
0
Total VTE
a 95%
20
18
Percent of Patients
Percent of Patients
20
18
ENOXACAN II2
DVT
Major
Bleeding
0.0 0.4
All VTE
Distal
DVT
Major
Bleeding
CI -9.2–2.3; b P=.02.
1. ENOXACAN Study Group. Br J Surg. 1997;84(8):1099-1103.
2. Bergqvist D, et al. N Engl J Med. 2002;346(13):975-980.
42
Efficacy of Dalteparin in Cancer Surgery:
Rate of Clinically Significant DVT or PE
P=.016
Patients With DVT/PE, %
12
10.5
P=.009
10
Dalteparin
UFH
P=.25
8.9
7.7
8
6
4
2
2.9
1.2
0
0
All Patients
Pneumoboots
No Pneumoboots
Treatment Arm
Reprinted with permission from DeBernardo RL Jr, et al. Obstet Gynecol. 2005;105(5 Pt 1):1006-1011.43
Guidelines for VTE Prophylaxis
in Orthopedic Patients
ACCP1
IUA2
AAOS3
Total hip
replacement
LMWH,
fondaparinux,
warfarin
LMWH,
fondaparinux,
warfarin, IPC or
FIT
Aspirin, LMWH,
fondaparinux, warfarin
Total knee
replacement
LMWH,
fondaparinux,
warfarin
LMWH or warfarin
Aspirin, LMWH,
fondaparinux, warfarin
LMWH for higherrisk patients
LMWH or IPC if
contraindications
to LMWH
LMWH or IPC
LMWH or IPC if
contraindications
to LMWH
Note that the ACCP
and IUA specifically
recommend against the
use of aspirin alone as
thromboprophylaxis
Arthroscopic knee
surgery
Multiple trauma
FIT, foot impulse technology; IPC, intermittent pneumatic compression.
1. Geerts WH, et al. Chest. 2008;133(6 suppl):381S-453S.
2. International Consensus Statement. Int Angiol. 2006;25(2):101-161.
3. American Academy of Orthopaedic Surgeons Clinical Guideline, 2007.
http://www.aaos.org/Research/guidelines/PE_guideline.pdf. Accessed October 24, 2008.
44
VTE After Orthopedic Surgery
 VTE is common after major orthopedic surgery1
 Without prophylaxis, approximately 60% of patients have
evidence of DVT at hospital discharge1
 Prevalence of asymptomatic DVT is greater than
2-fold higher after knee replacement than hip replacement
7 to 10 days after surgery2
 In patients who receive short-duration LMWH, the prevalence
of DVT is 16% after hip replacement and 31% after knee
replacement1
 Use of estrogen therapy increases the risk of VTE3
1. Geerts WH, et al. Chest. 2001;119(1 suppl):132S-175S.
2. Douketis JA, et al. Arch Intern Med. 2002;162(13):1465-1471.
3. US Dept of Health and Human Services. The Surgeon General’s Call to Action to Prevent
Deep Vein Thrombosis and Pulmonary Embolism. Bethesda, MD: September 2008.
45
VTE Incidence Following Hip
and Knee Replacement
Time of Onset of DVT After
Incidence of VTE Complications
During 3 Mo After Surgery2
THR1
30
3
All VTE
% Incidence
25
20
Total
Proximal
15
10
2
1
Primary Hip
Primary Knee
5
0
0
2
4
6
8
10
Post-op Day
12
14
16
14
28
42
56
70
84
Days
The incidence of thromboembolic events does not
stabilize until approximately 10 weeks after THR
1. Reprinted with permission from Sikorski JM, et al. J Bone Joint Surg. 1981;63(2):171-177.
2. Reprinted with permission from White RH, et al. Arch Intern Med. 1998;158(14):1525-1531.
46
Prevention of VTE After Major Orthopedic
Surgery: Rivaroxaban vs Enoxaparin
Percent of Patients
2
Meta-analysis of 3 RECORD pivotal trials
P<.001
Rivaroxaban
Enoxaparin
1.3
P=.005
1
0.8
0.4
0.5
P=NS
P=NS
0.3
0.2 0.2
0
2 Weeks
End of Period
Symptomatic VTE and Death
2 Weeks
0.2
End of Period
Major Bleeding
Turpie AG, et al. Presented at: American College of Chest Physicians 74th Annual
Scientific Assembly (CHEST 2008); October 27, 2008; Philadelphia, PA.
47
Thromboprophylaxis With Rivaroxaban vs
Enoxaparin 30 mg q12h: RECORD4
12
P=.012
10.1
Rivaroxaban 10 mg once daily
10
Incidence, %
Enoxaparin 30 mg q12h
8
6.9
6
4
2.0
2
1.2
0.7
1.2
0.7
0.3
0
Total VTE
Major VTE
Symptomatic
VTE
Turpie AG, et al. Presented at: the American Academy of Orthopaedic Surgeons
(AAOS) 2009 Annual Meeting; February 27, 2009; Las Vegas, NV.
Major Bleeding
48
VTE Prevention
After Hip Fracture Surgery
Incidence of VTE by Day 11
Percent of Patients
30
Fondaparinux
25
Enoxaparin
19.1
20
18.8
15
15
10
8.3
7.9
6.7
4.3
5
0.9
0
VTE
Any DVT
Proximal DVT
Distal DVT
P<.001 for all fondaparinux vs enoxaparin comparisons.
Eriksson BI, et al. N Engl J Med. 2001;345(18):1298-1304.
49
2008 ACCP Prevention of Venous Thromboembolism Practice Guidelines
Neurosurgery Recommendations
 Routine use of prophylaxis in all patients undergoing major
neurosurgery (Grade 1A)
– Optimal use of IPC (Grade 1A)
– Acceptable alternatives to IPC: post-op LMWH (Grade
2A) or LDUH (Grade 2B)
 In patients with particularly high thrombosis risk, combine
mechanical and pharmacologic method
(GCS and/or IPC; post-op LMWH or LDUH) (Grade 2B)
Geerts WH, et al. Chest. 2008;133(6 suppl):381S-453S.
50
2008 ACCP Prevention of Venous Thromboembolism Practice Guidelines
Trauma Recommendations
 All major trauma patients should receive prophylaxis
(Grade 1A)
 Initiate LMWH as soon as possible in the absence of
major contraindications (Grade 1A)
 Use GCS +/- IPC when LMWH prophylaxis is delayed or
contraindicated (Grade 1B)
 Consider extended prophylaxis with LMWH or VKA in
major immobility (Grade 2C)
Geerts WH, et al. Chest. 2008;133(6 suppl):381S-453S.
51
Management of VTE in
Special Patient Populations
52
LMWH and Bleeding in
Patients With Severe Renal Insufficiency:
A Meta-analysis
• In a meta-analysis that included 18 studies using 3 preparations of LMWH
– Peak anti-Xa levels measured 4 hours after a SC injection were
statistically significantly higher in patients with a CrCl ≤30 mL/min
compared with those with a CrCl >30 mL/min in studies that used a
standard therapeutic dose of enoxaparin but not in studies of
empirically dose-adjusted enoxaparin
– LMWH was associated with a statistically significant increase in the risk
for major bleeding in patients with a CrCl ≤30 mL/min compared with
those with a CrCl >30 mL/min (P=.013)
– When analyzed according to LMWH preparation, major bleeding was
increased when a standard therapeutic of enoxaparin was used (8.3%
vs 2.4%) but may not be increased when an empirically adjusted dose
of enoxaparin is used (0.9% vs 1.9%; P=.23)
Lim W, et al. Ann Intern Med. 2006;144(9):673-684.
53
2008 ACCP Prevention of Venous Thromboembolism Practice Guidelines
Renal Impairment Recommendations
 Consider renal function when making decisions about the use
and/or dose of LMWH, fondaparinux, and other antithrombotic
drugs cleared by the kidneys (Grade 1A)
– Particularly important in elderly patients, patients with
diabetes mellitus, those at high risk for bleeding
 Depending on circumstances, options include (Grade 1B):
– Avoid anticoagulants that bioaccumulate in the presence
of renal impairment
– Use a lower dose of the agent
– Monitor the drug level or its anticoagulant effect
Geerts WH, et al. Chest. 2008;133(6 suppl):381S-453S.
54
Patients With VTE Eventsa, %
Efficacy of Fixed Low-Dose Dalteparin
in Obese vs Nonobese Patients
10
Obese Patients
8
RR, 0.64; 95% CI, 0.32-1.28
6
RR, 0.53; 95% CI, 0.34-0.82
5.2
4.3
4
Nonobese Patients
2.8
2.8
2
0
Placebo
Dalteparin
Placebo
Dalteparin
NOTE: Fixed low-dose dalteparin was not effective in reducing the primary end point
in patients with a BMI ≥40 kg/m2.
aPrimary
end point: symptomatic VTE, fatal PE, sudden death, or asymptomatic proximal DVT by day 21
55
Kucher N, et al. Arch Intern Med. 2005;165(3):341-345.
2008 ACCP Prevention of Venous Thromboembolism Practice Guidelines
Inpatient Bariatric Surgery
Recommendations
• Use routine thromboprophylaxis with LMWH, LDUH 3 times daily,
fondaparinux, or the combination of 1 of these pharmacologic
methods with optimally used IPC (Grade 1C)
• It is suggested that higher doses of LMWH or LDUH than usual
for nonobese patients be used (Grade 2C)
Geerts WH, et al. Chest. 2008;133(6 suppl):381S-453S.
56
Treatment of VTE
57
2008 ACCP Antithrombotic Therapy for VTE Disease Practice Guidelines
Initial Management of DVT
 Short-term treatment with SC LMWH, IV UFH, or SC fondaparinux
(Grade 1A)
– LMWH SC once or twice daily over UFH as an outpatient if
possible (Grade 1C) and as an inpatient if necessary
(Grade 1A), unless renal failure (Grade 2C)
– IV UFH: continuous infusion with aPTT monitoring (Grade 1C)
 If clinical suspicion of DVT is high, treatment should be initiated while
awaiting results of diagnostic tests (Grade 1C)
 Treat for at least 5 d with LMWH, UFH, or fondaparinux until the INR
≥2.0 for 24 h (Grade 1C)
 Start warfarin on first treatment day together with LMWH, UFH, or
fondaparinux (Grade 1A)
Kearon C, et al. Chest. 2008;133(6 suppl):454S-545S.
58
Treatment With LMWH vs UFH
• LMWH vs UFH1
(based on a meta-analysis)
– LMWH is more effective than UFH for initial treatment of VTE
– LMWH significantly reduces the occurrence of major
hemorrhage during initial treatment and overall mortality
at follow up
• LMWH use is amenable to home therapy2
(based on a meta-analysis)
– Lower VTE recurrence rate than hospital treatment
– Lower mortality
– Lower major bleeding rate
1. van Dongen CJ, et al. Cochrane Database Syst Rev. 2004 Oct 18;(4):CD001100.
2. Othieno R, et al. Cochrane Database Syst Rev. 2007 Jul 18;(3):CD003076.
59
2008 ACCP Antithrombotic Therapy for VTE Disease Practice Guidelines
Initial Treatment of PE
Anticoagulant Therapy
• For objectively confirmed PE, short-term treatment with SC LMWH,
IV UFH, or SC fondaparinux (Grade 1A)
• For acute nonmassive PE, LMWH recommended over IV UFH
(Grade 1A)
• If clinical suspicion of PE is high, treatment should be initiated while
awaiting outcome of diagnostic tests (Grade 1C)
• Treat for at least 5 d with LMWH, UFH, or fondaparinux and until
the INR is ≥2.0 for at least 24 h (Grade 1C)
• Start warfarin on first treatment day together with LMWH, UFH, or
fondaparinux (Grade 1A)
Kearon C, et al. Chest. 2008;133(6 suppl):454S-545S.
60
2008 ACCP Antithrombotic Therapy for VTE Disease Practice Guidelines
Initial Treatment of PE (cont)
Thrombolytic Therapy
• All PE patients should undergo rapid risk stratification (Grade 1C)
– When evidence of hemodynamic compromise, use thrombolytic
therapy unless there are major contraindications owing to bleeding
risk (Grade 1B)
– In selected high-risk patients without hypotension judged to have a
low risk of bleeding, use of thrombolytic therapy is recommended
(Grade 2B)
• The decision to use thrombolytic therapy depends on the clinician’s
assessment of PE severity, prognosis, and risk of bleeding
– For the majority of patients with PE, thrombolytic therapy is not
recommended (Grade 1B)
Kearon C, et al. Chest. 2008;133(6 suppl):454S-545S.
61
Outpatient VTE Protocol
Clinical Exclusionary Criteria
Based on compendium of RCTs and observational studies
Absolute
Relative
• Active bleeding or positive stool guiac
• Thrombocytopenia <100K
• Major surgery/trauma or CVA
<2 weeks
• Phlegmasia
• Symptomatic PE
• Severe renal dysfunction
• Recent GI bleeding
• Hypertensive emergency
• History of heparin sensitivity or HIT
• Active or major comorbid illness
• History of familial bleeding disorder
• Morbid obesity
• Iliofemoral DVT
•
•
•
•
Pregnancy
Underlying liver disorder
Aged >75 y
Acquired or congenital
hypercoagulable state
CVA, cerebrovascular accident; HIT, heparin-induced thrombocytopenia.
Spyropoulos AC. Am J Manag Care. 2000;6(20 suppl):S1034-S1044.
62
Case Study 1
Thromboprophylaxis in a Patient
Undergoing Total Joint Replacement
History and Examination:
• 74-year-old woman scheduled for elective total hip
replacement
• Otherwise healthy and no previous history of vascular
or venous disease
• Currently uses oral estrogen therapy
• Laboratory evaluation at hospital admission was
normal, as were a chest x-ray and ECG
63
Case Study 1
Thromboprophylaxis in a Patient
Undergoing Total Joint Replacement
Risk of DVT:
• Complications associated with total hip replacement
are PE and postphlebitic syndrome
• Fatal PE occurs in 1 in 500 patients undergoing total
hip replacement
• Asymptomatic DVT is much more common, occurring
in 40% to 60% of patients; asymptomatic VTE occurs
in 2% to 5%
64
Case Study 1
Thromboprophylaxis in a Patient
Undergoing Total Joint Replacement
Treatment:
• Adjusted dose warfarin with a target INR of 2.0 to
3.0, LMWH, or fondaparinux
• Treatment usually begins on the day of surgery
(fondaparinux started after surgery) and continues
for up to 35 days
• Risk of bleeding with prophylactic therapy is much
lower than with therapeutic anticoagulation
• Early mobilization and compression stockings also
may be used as adjunctive measures
• Use of estrogen therapy increases the risk of VTE
65
Case Study 2
Thromboprophylaxis in a
Hospitalized Medical Patient
History and Examination:
• 79-year-old woman in a skilled nursing facility
• History of CHF
• Reports shortness of breath over the past 24-48 hours
• Transferred to the ED
• Diagnostic evaluation revealed no PE on CT scan, but
chest x-ray revealed pneumonia in right lung
• Vital signs: RR 24, HR 96, BP 156/76, normal temp
• Levofloxacin was begun for pneumonia
66
Case Study 2
Thromboprophylaxis in a
Hospitalized Medical Patient
Risk of DVT:
• Inadequate or omitted VTE prophylaxis in
hospitalized medical patients is common
• The majority of DVT develops in hospitalized
medical rather than surgical patients
• VTE prophylaxis remains underutilized
• Ineffective regimens are often used
• Underuse often occurs because of
inappropriate safety concerns
67
Case Study 2
Thromboprophylaxis in a
Hospitalized Medical Patient
Treatment:
• Prompt evaluation of the need for VTE prophylaxis is
essential
• Pharmacological therapy is first-line therapy
• Results from the EXCLAIM study show that extended
duration anticoagulation is appropriate in high-risk
medical patients
• Appropriate options in this patient include:
– Mechanical prophylaxis with IPC
– LMWH
– Fondaparinux*
– UFH
68
* Fondaparinux is not approved by the FDA for prophylaxis in medical patients.
Case Study 3
Treatment in a Patient With Cancer
History and Examination:
• 68-year-old woman with Stage II breast cancer
• Post lumpectomy 3 months ago
• Now with left lower extremity proximal DVT
• Labs with normal hemogram and platelet count
of 180K
• CrCl >50 cc/min
• Otherwise healthy and taking tamoxifen
69
Case Study 3
Treatment in a Patient With Cancer
Risk of DVT:
• Patients with cancer have a 6-fold increased risk of VTE
compared to those without cancer
– Cancer also increases risk of recurrent VTE and
hemorrhagic complications
70
Case Study 3
Treatment in a Patient With Cancer
Treatment
• First-line therapy options:
– LMWH heparin bridge to dose-adjusted VKA
– Dalteparin 200 IU/kg q d  1 month, then 150 IU/kg q d
– Enoxaparin 1 mg/kg q 12 h or 1.5 mg/kg q d, extended
therapy
– Fondaparinux 5 mg q d, extended therapy
• Continue treatment for at least 3 to 6 months
71
Question-and-Answer Session
72
Thank you for participating!
73