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Prevention of DVT & PEPrevention of DVT & PEArthur P. Wheeler, M.D.
Associate Professor of MedicineDirector MICU, Co-chair P&T
Director, Vanderbilt Clinical Trials CenterDivision of Allergy, Pulmonary and Critical Care Medicine
Vanderbilt Medical CenterDisclosures:
Consultant: Sanofi-Aventis, Boehringer-IngleheimResearch support: NIH-NHLBI, Eli Lilly,
Stockholder: Cumberland pharmaceuticals
Copyright A.P. Wheeler 2008
Thromboembolism epidemiologyThromboembolism epidemiology
5 million DVT’s
900,000 PE’s
290,000 fatalities
Heit J. Blood. 2005;106:910.
Thromboembolism is a disease of Thromboembolism is a disease of hospitalized patientshospitalized patients
1
10
100
1000
Hospitalized Community
Cases / 10,000 person years
Heit Mayo Clin Proc 2001; 76:1102Goldhaber Am J Cardiol 2004; 93:259
50% in nursing homes or50% in nursing homes or<90 days post-discharge<90 days post-discharge
71% received no prophylaxis71% received no prophylaxis in prior 30 daysin prior 30 days
Virchow’s triadVirchow’s triad
Veno
us S
tasis
Veno
us S
tasis
Hypercoagulable StateHypercoagulable StateEndothelial Injury
Endothelial Injury
Advancing ageImmobilizationStroke - cord injuryAnesthesiaHeart or lung failureHyperviscosity
SurgeryPrior DVTVenous accessTraumaSepsisVasculitis
CancerEstrogenFamily historySepsisHIT
Protein C, S or AT III deficiency Activated protein C resistance (Leiden)HyperhomocystenemiaAntiphospholipid antibodyProthrombin 20210 mutation
DVT Incidence absent prophylaxisDVT Incidence absent prophylaxis
0 20 40 60 80 100
General Medical
Acute MI
General Surgery
MICU
Stroke
Cord Injury
Geerts WH. Chest. 2008;133:381S-453S
Mismetti 2000
Nicolaides 1997
Nicolaides 1997
Gallus 1994
Handley 1972
Hirsch 1995
TreatmentTreatment Follow-up Follow-up
Placebo
Enoxaparin 20 mg QD
Enoxaparin 40 mg QD
Day 1
RandomizationRandomizationn=1102n=1102
Day 6-14
BilateralBilateralVenographyVenography
Day 83-110
Day -3
LMWH prophylaxis in medical LMWH prophylaxis in medical patients: study designpatients: study design
Samama NEJM 1999;341:793.
Respiratory failureRespiratory failureCHFCHFInfectionsInfections
LMWH prophylaxis in medical LMWH prophylaxis in medical patients: thrombosis to day 14patients: thrombosis to day 14
0
5
10
15
20
All VTE Proximal DVT PE
Placebo
Enoxaparin 20 mg
Enoxaparin 40 mg
P=0.0370
NS
P=0.0002
Patients(%)
Samama NEJM 1999;341:793
Risk stratification in surgeryRisk stratification in surgery
Geerts WH. Chest. 2008;133:381S-453S
Calf DVT
%
Proximal DVT %
Clinical PE %
Fatal PE%
Low < 2 0.4 0.2 .002
Moderate 10-20 2-4 1-2 .1-.4
High 20-40 4-8 2-4 04-1
Very High 40-80 10-20 4-10 0.2-5
Medical prophylaxis: placebo Medical prophylaxis: placebo controlled trialscontrolled trials
0
5
10
15
20
25
30
Percent VTE
Halkin 1982 Gardlund1996
Dahan1986
Samama1999
Caulin1989
Fraisse2000
placebo
heparin
n=1358 n=2474n=270n=11,693 n=1102 n=223
5000 UFHq12
p=NS
Nadro7500 U qd
p=NS
Enox40 mg qdp<0.001
Enox60 mg qd
p=0.04
5000 UFHq12
p=NS
Nadro3800-5700 U qd
p=0.05
Prophylaxis LMWH vs. UFH:Prophylaxis LMWH vs. UFH:lower risk groupslower risk groups
0
2
4
6
8
10
Percent VTE
Harenberg 1990 Lechler 1995 Bergman 1996 Harenberg 1996
UFH LMWH
n=166 n=442n=959 n=1968
Nadro 1500 QD5000 UFH q12
p=NS
Enox 20mg QD5000 UFH q12
p=NS
Enox 40mg QD5000 UFH q8
p=NS
Nadro 3600 QD5000 UFH q8
p=0.01
DVT prophylaxis: DVT prophylaxis: Important, not perfectImportant, not perfect
0 10 20 30 40 50 60 70 80
ASA
Stockings
ICD
UFH tid
LMWH / FPX
DVT Relative Risk Reduction
Geerts WH. Chest. 2008;133:381S-453S.
$ 1
$ 100
$ 150
$ 2-13
$ 16
“Should not be used”: 1A
Use in high bleeding risk 1C oras adjunct to anticoagulants 2A
Use in cancer, CHF or respiratory failure orreduced mobility & 1 other risk factor: 1A
Meta-analysisMeta-analysis UFH Prophylaxis: q 12h vs q 8h UFH Prophylaxis: q 12h vs q 8h
King CS. Chest. 2007;131:507-516.
Effect Size Weight q 12h
Cade (1982) 3.6 (1.2, 8.3) 5.7
Zawilska (1989) 5.7 (.7, 20.5) 1.0
Gardlund (1996) 2.7 (2.3, 3.3) 21.8
Bergmann (1996) 0.9 (0.1, 3.2) 14.7
Cade (1982) 3.1 (0.6, 9.1) 4.4
Subtotal 2.34 (1.3, 3.3)
q 8h
Harenberg (1990) 4.1 (1.9, 17.9) 1.4
Gallus (1973) 2.5 (0.06, 13.7) 1.9
Pitney (1980) 2.7 (0.7, 14.9) 1.6
Lechler (1996) 1.8 (0.7, 3.9) 14.4
Harenberg (1996) 0.6 (.2, 1.4) 21.2
Belch (1981) 5.0 (0.6, 17.9) 1.2
Kleber (2003) 2.0 (0.5, 5.0) 10.6
Subtotal 0.86 (0.3, 1.4)
- 0 -20.5Per 1000 patient days
VTE Prophylaxis: LMWH vs UFHVTE Prophylaxis: LMWH vs UFH
Wein L. Arch Intern Med. 2007;167:1476-1486.
Meta-analysis of 36 trials of LMWH or UFH
DVT Study Risk Ratio (95% CI)
Weight, %
Harenberg et al, 1990 0.70 (0.16-3.03) 3.4
Turpie et al, 1992 0.29 (0.10-0.81) 11.2
Dumas et al, 1994 0.74 (0.38-1.43) 14.4
Bergmann and Neuhart et al, 1996
0.94 (0.39-2.26) 8.1
Harenberg et al, 1996 2.89 (0.30-27.71) 0.8
Lechler et al, 1996 0.25 (0.03-2.23) 3.3
Hillborn et al, 2002 0.55 (0.31-0.98) 20.5
Kleber et al, 2003 0.77 (0.43-1.38) 19.4
Diener et al, 2006 0.76 (0.43-1.38) 18.9
Overall (95% CI) 0.68 (0.52-0.88)
-1 1 10Risk Ratio
LMWH Better LMWH Worse
Risk stratification in surgeryRisk stratification in surgery
Geerts WH. Chest. 2008;133:381S-453S
Calf DVT
%
Proximal DVT %
Clinical PE %
Fatal PE%
Low < 2 0.4 0.2 .002
Moderate 10-20 2-4 1-2 .1-.4
High 20-40 4-8 2-4 04-1
Very High 40-80 10-20 4-10 0.2-5
LMWH, LDUH, FPX (1A)
LMWH, LDUH q8h, FPX (1A)
LMWH, LDUH q8h, or FPX with GCS +/- IPC (1C)
Early ambulation (1C)
AAOS guidelinesAAOS guidelines
• Prioritize fatal PE.• Reject the idea that DVT
and PE are linked.• Ignore evidence that
prophylaxis prevents DVT and PE.
• Contain numerous non-evidence based recommendations
Eikelboom JW, Chest 2009; 135:513PEP Trial Lancet 2000; 355:1295
VTE Prophylaxis for Patients VTE Prophylaxis for Patients Recommended to Receive itRecommended to Receive it
Tapson V. Chest 2007;132:936
3
47
40
9
0.2
7
13
2221
14
33
0
5
10
15
20
25
30
35
40
45
50
Total LMWH UFH IPC Stockings ASA
Pro
ph
yla
xis
Ra
tes
(%)
USNon-US
N=15,156
Physician response to prompts & Physician response to prompts & overall prophylaxis rateoverall prophylaxis rate
0%
10%
20%
30%
40%
50%
Control Neutral Educational Risk
Total Prophylaxis Rate
*
Conner Chest 118: 162S, 2000
Prophylaxis following consistent Prophylaxis following consistent remindersreminders
Computerized prophylaxis promptsComputerized prophylaxis prompts
0
5
10
15
20
25
30
35
Prophylaxis rates VTE indicence
Percent
ControlPrompted
Kucher N NEJM 2005; 352:969
Δ 41 %
63% had risk score >4
Electronic Alerts to Prevent VTE Electronic Alerts to Prevent VTE
Kucher N. 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
Prophylaxis approaches
• Prophylaxis poor if recommendations passively disseminated.
• Computer and paper based reminders work
• Audit and feedback important
Tooher R, Ann Surg 2005; 241:397
National initiativesNational initiatives• Leapfrog: A preventable cause of death in US hospitals• ACCP: Grade 1A for pharmacological DVT prophylaxis in
patients with VTE risk factors.• SCIP: Prophylaxis ordered on admission, given +/-24 hr
from surgery.• AHRQ: 1 of 8 “major patient safety concerns “ “Appropriate
VTE prophylaxis in patients at risk.”• NQF/JCAH: “Evaluate each patient upon admission, and
regularly thereafter, for the risk of developing DVT/VTE.” • CMS: 2009 “Never event”, VTE within 30 days non-
reimbursed
Venous thromboembolismVenous thromboembolism
~50%~50%
~50%~50%
~10%~10%
90%90%5-30%?5-30%?
63-70% of fatal PE’s63-70% of fatal PE’s unsuspected during lifeunsuspected during life
Stein Chest 1995; 110:978Sandler J R Soc Med 1989; 82:203
Quality of Life after VTEQuality of Life after VTE
• Post-thrombotic syndrome develops in 25-40% of DVTs.
• DVT recurs in ~30% after anticoagulation stopped
• Permanent disability for 15 million Americans
90 day costs to care for DVT90 day costs to care for DVT
de Lissovoy G Arch Intern Med. 2000;160:3160
MeanCost ($)
$12,146 $12,166 $11,558
0
2,500
5,000
7,500
10,000
12,500
15,000
UFH(n=104)
Enoxaparin QD(n=112)
Enoxaparin q12h(n=123)
ConclusionsConclusions
• DVT is common and > 50% preventable.• Prophylaxis is underused. • DVT results in a 30-50% incidence of PE.• Long-term leg vein sequelae are common.• DVT and PE are expensive to treat.
LOVENOX® (enoxaparin sodium injection) Indications and Usage
• LOVENOX® is indicated for the prophylaxis of DVT, which may lead to PE:
– In patients undergoing abdominal surgery who are at risk for thromboembolic complications
– In patients undergoing hip replacement surgery, during and following hospitalization
– In patients undergoing knee replacement surgery
– In medical patients who are at risk for thromboembolic complications due to severely restricted mobility during acute illness
• LOVENOX® Injection is indicated for:– The inpatient treatment of acute DVT with or without PE, when administered in
conjunction with warfarin sodium
– The outpatient treatment of acute deep vein thrombosis without PE when administered in conjunction with warfarin sodium
LOVENOX® (enoxaparin sodium injection) Prescribing Information. Sanofi-aventis, U.S. LLC. June 2007.
Please see full prescribing information for enoxaparin, including boxed WARNING, available at this meeting
LOVENOX® (enoxaparin sodium injection) Indications and Usage (cont’d)
• LOVENOX® is indicated for the prophylaxis of ischemic complications of unstable angina and non–Q-wave myocardial infarction, when concurrently administered with aspirin
• LOVENOX® is indicated for the treatment of acute ST-segment elevation myocardial infarction (STEMI)– LOVENOX® has been shown to reduce the rate of the combined
endpoint of recurrent myocardial infarction or death in patients with acute STEMI receiving thrombolysis and being managed medically or with percutaneous coronary intervention (PCI)
LOVENOX® (enoxaparin sodium injection) Prescribing Information. Sanofi-aventis, U.S. LLC. June 2007.
Please see full prescribing information for enoxaparin, including boxed WARNING, available at this meeting
Important Safety Information
WARNING: SPINAL/EPIDURAL HEMATOMAS
• When neuraxial anesthesia (epidural/spinal anesthesia) or spinal puncture is employed, patients anticoagulated or scheduled to be anticoagulated with low molecular weight heparins or heparinoids for prevention of thromboembolic complications are at risk of developing an epidural or spinal hematoma which can result in long-term or permanent paralysis.
• The risk of these events is increased by the use of indwelling epidural catheters for administration of analgesia or by the concomitant use of drugs affecting hemostasis such as nonsteroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, or other anticoagulants. The risk also appears to be increased by traumatic or repeated epidural or spinal puncture.
• Monitor patients for signs and symptoms of neurological impairment. If neurologic compromise is noted, urgent treatment is necessary.
• Consider the potential benefit versus risk before neuraxial intervention in patients anticoagulated or to be anticoagulated for thromboprophylaxis (see WARNINGS and PRECAUTIONS [5.1] and Drug Interactions [7]).
LOVENOX® (enoxaparin sodium injection) Prescribing Information. Sanofi-aventis, U.S. LLC. June 2007.
Please see full prescribing information for enoxaparin, including boxed WARNING, available at this meeting
Important Safety Information (cont’d)
• LOVENOX® (enoxaparin sodium injection) cannot be used interchangeably with other low molecular weight heparins or unfractionated heparin, as they differ in their manufacturing process, molecular weight distribution, anti-Xa and anti-IIa activities, units, and dosage.
• As with other anticoagulants, use with extreme caution in patients with conditions that increase the risk of hemorrhage. Dosage adjustment is recommended in patients with severe renal impairment. Unless otherwise indicated, agents that may affect hemostasis should be discontinued prior to LOVENOX® therapy. Bleeding can occur at any site during LOVENOX® therapy. An unexplained fall in hematocrit or blood pressure should lead to search for a bleeding site (see WARNINGS and PRECAUTIONS).
• In the STEMI pivotal trial, the rates of major hemorrhages (defined as requiring 5 or more units of blood for transfusion, or 15% drop in hematocrit or clinically overt bleeding, including intracranial hemorrhage) at 30 days were 2.1% in the LOVENOX® group and 1.4% in the unfractionated heparin group. The rates of intracranial hemorrhage at 30 days were 0.8% in the LOVENOX® group and 0.7% in the unfractionated heparin group. The 30-day rate of the composite endpoint of death, myocardial infarction or ICH (a measure of net clinical benefit) was significantly lower in the LOVENOX® group (10.1%) as compared to the unfractionated heparin group (12.2%).
LOVENOX® (enoxaparin sodium injection) Prescribing Information. Sanofi-aventis, U.S. LLC. June 2007.
Please see full prescribing information for enoxaparin, including boxed WARNING, available at this meeting
• Thrombocytopenia can occur with LOVENOX® (enoxaparin sodium injection). In patients with a history of heparin-induced thrombocytopenia, LOVENOX® should be used with extreme caution. Thrombocytopenia of any degree should be monitored closely. If the platelet count falls below 100,000/mm3, LOVENOX® should be discontinued. Cases of heparin-induced thrombocytopenia have been observed in clinical practice. (See WARNINGS.)
• The use of LOVENOX® has not been adequately studied for thromboprophylaxis in pregnant women with mechanical prosthetic heart valves. (See WARNINGS.)
• LOVENOX® is contraindicated in patients with hypersensitivity to enoxaparin sodium, heparin, or pork products, and in patients with active major bleeding.
LOVENOX® (enoxaparin sodium injection) Prescribing Information. Sanofi-aventis, U.S. LLC. June 2007.
Important Safety Information (cont’d)
Please see full prescribing information for enoxaparin, including boxed WARNING, available at this meeting
Dosing for LOVENOX® (enoxaparin sodium injection)
Indications DosageVTE ProphylaxisAbdominal surgery 40 mg SC once daily (7–10 days)*
Hip replacement surgery 30 mg SC q12h† or 40 mg SC once daily‡ (7–10 days)
Hip replacement (extended) 40 mg SC once daily (up to 21 days following initial phase of thromboprophylaxis)
Knee replacement surgery 30 mg SC q12h† (7–10 days)Medical patients with acute illness and restricted mobility 40 mg SC once daily (6–11 days)
Ischemic complications (UA/NSTEMI) 1 mg/kg SC q12h (2–8 days)§
Acute STEMI Treatment (<75 y) (≥75 y)
VTE Treatment ||
30 mg IV bolus + 1 mg/kg SC followed by 1 mg/kg SC q12h§
0.75 mg/kg SC q12h
Inpatient DVT with/without PE 1 mg/kg SC q12h or 1.5 mg/kg SC once dailyOutpatient DVT without PE 1 mg/kg SC q12h
*Initial dose given 2 hours prior to surgery; †started 12-24 hours after surgery; ‡started 12±3 hours prior to surgery; §given in conjunction with aspirin; ||when administered in conjunction with warfarin sodium.
LOVENOX® (enoxaparin sodium injection) Prescribing Information. Sanofi-aventis, U.S. LLC. June 2007.
Please see full prescribing information for enoxaparin, including boxed WARNING, available at this meeting
LOVENOX® (enoxaparin sodium injection) in Patients With Mild or Moderate Renal Impairment
• Mild renal impairment (CrCl 50-80 mL/min) – No adjustment in dose necessary– Physician should observe for signs/symptoms of bleeding
• Moderate renal impairment (CrCl 30-50 mL/min) – No adjustment in dose necessary– Physician should observe for signs/symptoms of bleeding
LOVENOX® (enoxaparin sodium injection) Prescribing Information. Sanofi-aventis, U.S. LLC. June 2007.
Please see full prescribing information for enoxaparin, including boxed WARNING, available at this meeting
LOVENOX® (enoxaparin sodium injection) Dosing Regimens
Severe Renal Impairment* (Does Not Apply to Hemodialysis Patients)
*CrCl <30 mL/min; †when concurrently administered with aspirin; ‡when administered in conjunction with warfarin sodium.
Indication Dosage
Prophylaxis
Abdominal surgery 30 mg SC once daily
Hip or knee replacement surgery 30 mg SC once daily
Medical patients with acute illness and restricted mobility 30 mg SC once daily
Ischemic complications of UA/NSTEMI† 1 mg/kg SC once daily
TreatmentAcute STEMI (<75 y) (≥75 y)
30 mg IV bolus + 1 mg/kg SC followed by 1 mg/kg SC once daily
1 mg/kg SC once daily Inpatient DVT with/without PE‡ 1 mg/kg SC once dailyOutpatient DVT without PE‡ 1 mg/kg SC once daily
LOVENOX® (enoxaparin sodium injection) Prescribing Information. Sanofi-aventis, U.S. LLC. June 2007.
Please see full prescribing information for enoxaparin, including boxed WARNING, available at this meeting
LOVENOX® (enoxaparin sodium injection) Prescribing Information
• After repeated 1.5-mg/kg SC once-daily enoxaparin, the mean AUC of anti-Factor Xa activity is marginally higher at steady state in obese healthy volunteers (BMI 30-48 kg/m2) compared to nonobese control subjects, while Amax is not increased
• When non–weight-adjusted dosing was administered, it was found after a single SC 40-mg dose that anti-factor Xa exposure is 52% higher in low-weight women (<45 kg) and 27% higher in low-weight men (<57 kg) when compared to normal-weight control subjects
Weight
LOVENOX® (enoxaparin sodium injection) Prescribing Information. Sanofi-aventis, U.S. LLC. June 2007.
US.ENO.07.11.025
Please see full prescribing information for enoxaparin, including boxed WARNING, available at this meeting
Risk of Major Bleeding after LMWH in Risk of Major Bleeding after LMWH in patients with CrCl ≤30patients with CrCl ≤30
Lim W, et al. Ann Intern Med. 2006;144:673-684.
Study, Year Patients With Renal Insuff,
n/n
Patients With No Renal Insuff,
n/n
Peto OR (95% CI)
Weight, %
Peto OR (95% CI)
Collet, 2001 0/28 1/83 2.01 0.26 (0.00-23.94)Pautas, 2002 0/51 3/149 6.02 0.26 (0.02-3.50)Siguret, 2000 0/17 0/13 Not estimableChow, 2003 0/5 0/13 Not estimableKhazan (adjusted), 2003
0/10 3/42 4.78 0.28 (0/01-5.16)
Khazan (prophylactic), 2003 3/36 3/47 14.77 1.33 (0/25-7.05)Khazan (therapeutic), 2003 2/17 3/61 8.62 3.09 (0.35-27.31)Spinler, 2003 5/69 74/3432 15.93 10.05 (2.02-49.98)Green, 2005 1/18 0/20 2.66 8.26 (0.16-418.42)Kruse, 2004 0/50 1/120 2.22 0.24 (0.00-17.90)Macie, 2004 2/7 6/201 2.68 977.78
(19.61-48752.07)Peng, 2004 0/7 0/43 Not estimableThorevska, 2004 7/65 11/171 35.56 1.85 (0.63-5.40)Bazinet, 2005 1/36 2/160 4.75 2.74 (0.15-51.73)Total (95% CI) 416 4555 100.00 2.25 (1.19-4.27)Total event: 21 (renal insufficiency), 107 (no renal insufficiency)Test for heterogeneity: Chi-square=20.17 (P=.03), F=50.4%Test for overall effect: Z=2.49 (P=.01)
0.01 0.1 10 1001Favors Reduction in Bleeding Favors Increase in Bleeding
ACCP Recommendations:ACCP Recommendations:Renal ImpairmentRenal Impairment
• 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
• 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. Chest. 2008;133:381S-453S.
Conclusions: Renal Impairment Conclusions: Renal Impairment and the Use of LMWHand the Use of LMWH
• Anticoagulants may accumulate in renal impairment1
• Renal impairment increases bleeding risk1
• Enoxaparin data suggests a correlation between increased anti-Xa levels and bleeding risk and CrCl ≤30 mL/min2
• Standard, weight-adjusted doses of enoxaparin should be avoided in patients with CrCl ≤30 mL/min2
– Consult manufacturer dosing guidelines for any anticoagulant cleared by the kidneys1
• Insufficient data are available to draw conclusions about the use of tinzaparin, dalteparin, or other LMWHs when is CrCl ≤30 mL/min1
1. Geerts WH. Chest. 2008;133:381S-453S.2. Lim W. Ann Intern Med. 2006;144:673-684.
Obesity ConclusionsObesity Conclusions
• Obesity is an independent risk factor for VTE1,2
• Prophylaxis1,2
– Use LMWH at nonobese doses with multimodal therapy
» No apparent increased risk for bleeding
• Treatment– LMWH, fondaparinux, or UFH may be used in
obese patients at “non-obese” doses– No increased risk of bleeding detected
1. Davidson BL. J Thromb Haemost. 2007;5:1191-1194. 2. Kucher N. Arch Intern Med. 2005;165:341-345.
VTE in Obese PatientsVTE in Obese Patients
Cohen AT Vasc Med. 2007;12:123-127.Kucher N Arch Intern Med. 2005;165:341-345.
Primary end point: VTE = symptomatic DVT, symptomatic PE, and asymptomatic proximal DVT or
sudden death at day 21
Relative risk, 0.64; 95% confidence interval, 0.32-1.28
4.3
2.8
0
2
4
6
8
10
Placebo Dalteparin
Pe
rce
nt
of
Pa
tien
ts
Recommended