1. 2 Learning Objectives After participating in this activity, participants should be able to: ...

1

2

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

3

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.

Disclosure Statement

4

Faculty Disclosure

5

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

• 2/3 of VTE cases and deaths are hospital-acquired1

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.

PE is the leading preventable cause of hospital death4

31% of US hospital discharges

6

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

7

VTE in Hospitalized PatientsNot 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.

8

DVT-FREE Registry: Distribution by Age and Gender

Reprinted with permission from Goldhaber SZ, Tapson VF; for the DVT FREE Steering Committee. Am J Cardiol. 2004;93:259-262.Reprinted with permission from Goldhaber SZ, Tapson VF; for the DVT FREE Steering Committee. Am J Cardiol. 2004;93:259-262.

800

700

600

500

400

300

200

100

0≤20

Pat

ien

ts, n

Age, y

Men (n=2559)Women (n=2892)

21-30 31-40 41-50 51-60 61-70 71-80 81-90 >90

9

DVT-FREE Registry:Distribution by BMI and Gender


800

700

600

500

400

300

200

100

0≤20 31-3521-25 26-30 >35

Pat

ien

ts, n

Body Mass Index, kg/m2

Men (n=2095)Women (n=2344)

10

DVT-FREE Registry: Time From Most Recent Surgery to Diagnosis of DVT by Patient Status


40

35

30

25

20

15

10

0

0-5

Pat

ien

ts, %

Time, d

Outpatients (n=718)Inpatients (n=1351)

6-10 11-15 16-20 21-25 26-30 >31

5

11

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.

12

Potential Mechanisms by Which Clinical Conditions Facilitate VTE

HypercoagulabilityDirect vessel injury

Blood stasis

HypercoagulabilityDirect vessel injury

Blood stasisAcute insult

Increased baseline propensity

for thrombosis

Lopez JA, et al. Hematology. 2004;1:439-456.

13Adapted from Geerts WH, et al. Chest. 2008;133(6 suppl):381S-453S.

Risk Factors for VTE• Surgery

• Trauma (major trauma orlower-extremity injury)

• Immobility, lower-extremity paresis

• Cancer (active or occult)

• Cancer therapy

• Venous compression

• Previous VTE

• Increasing age

• Pregnancy/postpartum period

• Smoking

• Estrogen-containing OCs or HRT

• Erythropoiesis-stimulating agents

• Acute medical illness

• Inflammatory bowel disease

• Nephrotic syndrome

• Myeloproliferative disorders

• Paroxysmal nocturnal hemoglobinuria

• Obesity

• Central venous catheterization

• Inherited or acquired thrombophilia

14

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. Shetty R, et al. J Throm Thrombolysis. 2008;26:35-40.2. Fraisse F, et al. Am J Respir Crit Care Med. 2000;161:1109-1114.3. Howell MD, et al. J Clin Epidemiol. 2001;54(8):810-816. 4. Cogo A, et al. Arch Int Med. 1994;154:164-168.

15

The Importance of DVT Prophylaxisin Congestive Heart Failure

38.3 xgreater

1.7 X greater

2.8 X greater

LVEF >45% LVEF 20-44% LVEF <20%

DV

T/P

E R

isk

LVEF = left ventricular ejection fraction.

Howell MD, et al. J Clin Epidemiol. 2001;54:810-816.

16

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-endorsed-measures.asp. Accessed November 6, 2008.

17

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/ParentShellTemplate&parentName=TopicCat&c=MQParents. Accessed November 6, 2008.

18Geerts WH, et al. Chest. 2008;133(6 suppl):381S-453S.

Strategies for Prevention of VTE

• Pharmacologic

– LMWH (eg, enoxaparin, dalteparin)

– Low-dose UFH

– Fondaparinuxa

– Vitamin K antagonist (eg, warfarin)

• Mechanical

– Intermittent pneumatic compression

– Graduated elastic compression stockings

aFondaparinux is not approved by the FDA for VTE prophylaxis in medical patients.

2008 ACCP Prevention of Venous Thromboembolism Practice Guidelines

19

Emerging Anticoagulants for the Management of VTE

• Indirect FXa inhibitor

– Idraparinux

• Oral direct FXa inhibitors

– Rivaroxaban

– Apixaban

• Oral direct thrombin inhibitor

– Dabigatran

20

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.


21

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.

22

Thromboprophylaxis Recommendations for Hospital Patients — Balancing the Risk of Bleeding

aHigh-risk patients include those who have had major trauma or spinal cord injury, major hip or knee surgery, or major surgery for cancer.

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

Adapted from Geerts WH, et al. J Crit Care. 2002;17:95-104.

23

Primary Prevention of VTE in Hospitalized

Medical Patients

24

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. Heit JA, et al. Arch Intern Med. 2000;160(6):809-815.2. Heit JA, et al. Arch Intern Med. 2002;162(11):1245-1248.3. Goldhaber SZ, Tapson VF. Am J Cardiol. 2004;93(2):259-262.4. Anderson FA Jr, et al. Ann Intern Med. 1991;115(8):591-595.5. 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.

25

Recommendations for Prophylaxis in Medical Patients

• 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. International Consensus Statement. Int Angiol. 2006;25:101-161.2. Geerts WH, et al. Chest. 2008;133:381S-453S.

ACCP 2008 and IUA 2006 Guidelines

26

VTE Prophylaxis in Acutely Ill Medical PatientsPrimary Efficacy End Points:

Implications for Clinical Practice

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.

# Needed to Treat

10

45

20

Trial VTE RRR

MEDENOX1 Distal and proximal 63%venographic DVT+ symptomatic VTE+ fatal PE

PREVENT2 Compression 45%ultrasonographic DVT+ symptomatic VTE+ fatal PE

ARTEMIS3 Distal and proximal 47%venographic DVT+ symptomatic VTE+ fatal PE

27

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.

28

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

Process Components:

1. Failure to give the antibiotic

2. “Resistance” of the organism

3. Initial timing of the antibiotic

4. Duration of treatment

29Hull RD, et al. Abstract presented at: ISTH, July 8-11, 2007, Geneva, Switzerland.

EXCLAIM: Extended-duration Enoxaparin Prophylaxis in High-risk Medical Patients

End points Extended prophylaxis n=2013 (%)

Placebo n=2027

(%)

RR reduction

(%)

P value

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.

30

Prevention of VTE After Acute Ischemic Stroke: PREVAIL Study

NIHSS = National Institutes of Health Stroke Scale.

Reprinted with permission from Sherman DG, et al. Lancet. 2007;369:1347-1355.

NIHSS Score <14 NIHSS Score ≥14

Occurrence (95% CI) P Occurrence (95% CI) P

VTE

Enoxaparin 8.3% (5.90-10.70) .004 16.3% (10.53-21.97) .004

UFH 14.0% (10.91-17.02) 29.7% (22.94-36.49)

DVT

Enoxaparin 8.1% (5.73-10.48) .005 16.3% (10.53-21.97) .005

UFH 13.6% (10.54-16.58) 29.1% (22.41-35.88)

31

Prevention of VTE in Patients With Heart Failure or Severe Respiratory Disease

HF = heart failure.

Kleber F-X, et al. Am Heart J. 2003;145:614-621.

Per

cen

tag

e o

f T

hro

mb

oli

c E

ven

ts

0

2

4

6

8

10

12

14

16

18

All Patients Resp Dis HF

Enoxaparin

UFH

32

Prevention of VTE in High-Risk Hospitalized Medical Patients: THE PRIME Study

Reprinted with permission from Lechler E, et al. Haemostasis. 1996;26(suppl 2):49-56.

Intention-to-treat Per-protocol

Enoxaparin

(n=442)

Heparin(n=443)

Enoxaparin

(n=393)

Heparin(n=377)

Thromboembolic events 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

Test for superiority P=.1235 P=.1164

Test for equivalence P=.0000048 P=.00000306

33

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.

34

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.

35

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)



36

Despite Evidence, Medical Patients at Risk Remain Unprotected

Medical Surgical

No. of patients

37,356 30,827

At risk for VTE

42% 64%

Receiving ACCP Tx

40% 59%

ENDORSE1

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.

IMPROVE2

United States

Other Countries

No. of patients

3,410 11,746

VTE prophylaxis

1852 (54%) 5788 (49%)

LMWH 476 (14%) 4657 (40%)

UFH 717 (21%) 1014 (9%)

37

Electronic Alerts to Prevent VTE in Hospitalized Patients

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.

0

92

94

98

100

30

Fre

edo

m F

rom

DV

T

or

PE

(%

) 96

60 900Days

90

Intervention group

Control group

P<.001

No. at RiskIntervention group 1255 977 900 853Control group 1251 976 893 839

38

Primary Prevention of VTE in Surgical Patients

39

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)



40

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



41

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

Borly L, et al. Colorectal Dis. 2005;7(2):122-127.

POR, Peto Odds ratio.

42

Efficacy of LMWH in Patients Undergoing Cancer Surgery: ENOXACAN Results

a 95% 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.

ENOXACAN I1 ENOXACAN II2

18.2a17.6

2.9

14.7 14.4

4.1

0

2

4

6

8

10

12

14

16

18

20

Total VTE

DVT MajorBleeding

Per

cen

t o

f P

atie

nts

UFHEnoxaparin

12.0b

10.2

0.0

4.8 4.2

0.40

2

4

6

8

10

12

14

16

18

20

All VTE Distal DVT

Major Bleeding

Per

cen

t o

f P

atie

nts

PlaceboEnoxaparin

43

Efficacy of Dalteparin in Cancer Surgery: Rate of Clinically Significant DVT or PE

Reprinted with permission from DeBernardo RL Jr, et al. Obstet Gynecol. 2005;105(5 Pt 1):1006-1011.

12

10

8

6

4

2

0

8.9

1.2

7.7

2.9

10.5

0Pa

tie

nts

Wit

h D

VT

/PE

, %

All Patients Pneumoboots No Pneumoboots

Treatment Arm

DalteparinUFH

P=.009

P=.25

P=.016

44

Guidelines for VTE Prophylaxis in Orthopedic Patients

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.

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

Arthroscopic knee surgery

LMWH for higher-risk patients

LMWH or IPC if contraindications

to LMWH

Note that the ACCP and IUA specifically

recommend against the use of aspirin alone as thromboprophylaxis

Multiple trauma LMWH or IPC LMWH or IPC if contraindications

to LMWH

45

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.

46

3

2

1

0%

Inci

den

ce14 28 42 56 70 84

Days

VTE Incidence Following Hip and Knee Replacement

Time of Onset of DVT After THR1

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.

Incidence of VTE Complications During 3 Mo After Surgery2

0

5

10

15

20

25

30

2 4 6 8 10 12 14 16

Post-op Day

Total

Proximal

All VTE

Primary HipPrimary Knee

The incidence of thromboembolic events does notstabilize until approximately 10 weeks after THR

47

Prevention of VTE After Major Orthopedic Surgery: Rivaroxaban vs Enoxaparin

Meta-analysis of 3 RECORD pivotal trials

Turpie AG, et al. Presented at: American College of Chest Physicians 74th Annual Scientific Assembly (CHEST 2008); October 27, 2008; Philadelphia, PA.

0.4 0.5

0.20.3

0.8

1.3

0.2 0.2

0

1

2

2 Weeks

Symptomatic VTE and Death Major Bleeding

End of Period

Pe

rce

nt

of

Pa

tien

ts

Rivaroxaban

Enoxaparin

2 WeeksEnd of Period

P=.005

P<.001

P=NSP=NS

48

10.1

Thromboprophylaxis With Rivaroxaban vs Enoxaparin 30 mg q12h: RECORD4

0

2

4

6

8

10

12

Inci

den

ce,

%

Enoxaparin 30 mg q12h

Rivaroxaban 10 mg once daily

6.9

2.01.2 1.2

0.7 0.30.7

Total VTE Major VTE Major Bleeding

P=.012

SymptomaticVTE

Turpie AG, et al. Presented at: the American Academy of Orthopaedic Surgeons (AAOS) 2009 Annual Meeting; February 27, 2009; Las Vegas, NV.

49

VTE Prevention After Hip Fracture Surgery

Incidence of VTE by Day 11

Eriksson BI, et al. N Engl J Med. 2001;345(18):1298-1304.

P<.001 for all fondaparinux vs enoxaparin comparisons.

8.3 7.9

0.9

6.7

19.1 18.8

4.3

15

0

5

10

15

20

25

30

VTE Any DVT Proximal DVT Distal DVT

Per

cen

t o

f P

atie

nts

Fondaparinux

Enoxaparin

50

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)



51

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)



52

Management of VTE in Special Patient Populations

53

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.

54

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



55

Efficacy of Fixed Low-Dose Dalteparin in Obese vs Nonobese Patients

Kucher N, et al. Arch Intern Med. 2005;165(3):341-345.

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

RR, 0.64; 95% CI, 0.32-1.28

4.3

2.8

0

2

4

6

8

10

Placebo Dalteparin Pat

ien

ts W

ith

VT

E E

ven

tsa ,

%

Obese Patients

5.2

2.8

Placebo Dalteparin

Nonobese Patients

RR, 0.53; 95% CI, 0.34-0.82

56

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)



57

Treatment of VTE

58

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.

2008 ACCP Antithrombotic Therapy for VTE Disease Practice Guidelines

59

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.

60

Initial Treatment of PE

• 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)



Anticoagulant Therapy

61

Initial Treatment of PE (cont)

• 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)


Thrombolytic Therapy


62

Outpatient VTE ProtocolClinical Exclusionary Criteria

Absolute• 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

Relative• History of familial bleeding disorder

• Morbid obesity

• Iliofemoral DVT

• Pregnancy

• Underlying liver disorder

• Aged >75 y

• Acquired or congenital hypercoagulable state

Based on compendium of RCTs and observational studies

CVA, cerebrovascular accident; HIT, heparin-induced thrombocytopenia.

Spyropoulos AC. Am J Manag Care. 2000;6(20 suppl):S1034-S1044.

63

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

64

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%

Case Study 1

Thromboprophylaxis in a Patient Undergoing Total Joint Replacement

65

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

Case Study 1

Thromboprophylaxis in a Patient Undergoing Total Joint Replacement

66

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

67

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

Case Study 2


68

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

Case Study 2


* Fondaparinux is not approved by the FDA for prophylaxis in medical patients.

69

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

Case Study 3

Treatment in a Patient With Cancer

70

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

Case Study 3


71

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

Case Study 3


72

Question-and-Answer Session

73

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