Transcript The DVT & PE Treatment Revolution

Prevention of DVT & PE
Arthur P. Wheeler, M.D.
Associate Professor of Medicine
Director MICU, Co-chair P&T
Director, Vanderbilt Clinical Trials Center
Division of Allergy, Pulmonary and Critical Care Medicine
Vanderbilt Medical Center
Disclosures:
Consultant: Sanofi-Aventis, Boehringer-Ingleheim
Research support: NIH-NHLBI, Eli Lilly,
Stockholder: Cumberland pharmaceuticals
Copyright A.P. Wheeler 2008
Thromboembolism epidemiology
5 million DVT’s
900,000
PE’s
290,000 fatalities
Heit J. Blood. 2005;106:910.
Thromboembolism is a disease of
hospitalized patients
1000
71% received no prophylaxis
in prior 30 days
100
50% in nursing homes or
<90 days post-discharge
Cases / 10,000
person years
10
1
Hospitalized
Heit Mayo Clin Proc 2001; 76:1102
Goldhaber Am J Cardiol 2004; 93:259
Community
Virchow’s triad
Advancing age
Immobilization
Stroke - cord injury
Anesthesia
Heart or lung failure
Hyperviscosity
Surgery
Prior DVT
Venous access
Trauma
Sepsis
Vasculitis
Hypercoagulable State
Cancer
Estrogen
Family history
Sepsis
HIT
Protein C, S or AT III deficiency
Activated protein C resistance
(Leiden)
Hyperhomocystenemia
Antiphospholipid antibody
Prothrombin 20210 mutation
DVT Incidence absent prophylaxis
Cord Injury
Nicolaides 1997
Stroke
Nicolaides 1997
MICU
Hirsch 1995
General Surgery
Gallus 1994
Acute MI
Handley 1972
General Medical
Mismetti 2000
0
Geerts WH. Chest. 2008;133:381S-453S
20
40
60
80
100
LMWH prophylaxis in medical
patients: study design
Treatment
Follow-up
Placebo
Respiratory failure
CHF
Infections
Enoxaparin 20 mg QD
Day -3
Enoxaparin 40 mg QD
Day 1
Day 6-14
Randomization
n=1102
Bilateral
Venography
Samama NEJM 1999;341:793.
Day 83-110
LMWH prophylaxis in medical
patients: thrombosis to day 14
P=0.0002
Placebo
20
Enoxaparin 20 mg
Enoxaparin 40 mg
15
P=0.0370
10
5
NS
0
All VTE
Samama NEJM 1999;341:793
Proximal DVT
PE
Risk stratification in surgery
Calf DVT
%
Proximal
DVT %
Clinical
PE %
Fatal PE
%
<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
Low
Geerts WH. Chest. 2008;133:381S-453S
Medical prophylaxis: placebo
controlled trials
Nadro
3800-5700 U qd
p=0.05
30
25
20
Percent
15
VTE
placebo
heparin
5000 UFH
q12
p=NS
Enox
40 mg qd
p<0.001
5000 UFH
q12
p=NS
Nadro
7500 U qd
p=NS
Enox
60 mg qd
p=0.04
10
5
0
Halkin 1982 Gardlund
1996
n=1358
n=11,693
Dahan
1986
n=270
Samama
1999
Caulin
1989
n=1102
n=2474
Fraisse
2000
n=223
Prophylaxis LMWH vs. UFH:
lower risk groups
UFH
LMWH
10
8
Percent
VTE
Nadro 1500 QD
5000 UFH q12
p=NS
Enox 40mg QD
5000 UFH q8
p=NS
Enox 20mg QD
5000 UFH q12
p=NS
Nadro 3600 QD
5000 UFH q8
p=0.01
Lechler 1995
Bergman 1996
Harenberg 1996
n=442
n=1968
6
4
2
0
Harenberg 1990
n=166
n=959
DVT prophylaxis:
Important, not perfect
LMWH / FPX
$ 16
Use in cancer, CHF or respiratory failure or
reduced mobility & 1 other risk factor: 1A
$ 2-13
UFH tid
ICD
$ 150
Use in high bleeding risk 1C or
as adjunct to anticoagulants 2A
$ 100
Stockings
$1
ASA
0
“Should not be used”: 1A
10
20
30
40
50
60
DVT Relative Risk Reduction
Geerts WH. Chest. 2008;133:381S-453S.
70
80
Meta-analysis
UFH Prophylaxis: q 12h vs q 8h
-
Effect Size
Weight
q 12h
Cade (1982)
Zawilska (1989)
Gardlund (1996)
Bergmann (1996)
Cade (1982)
Subtotal
3.6 (1.2, 8.3)
5.7 (.7, 20.5)
2.7 (2.3, 3.3)
0.9 (0.1, 3.2)
3.1 (0.6, 9.1)
5.7
1.0
21.8
14.7
4.4
q 8h
Harenberg (1990)
Gallus (1973)
Pitney (1980)
Lechler (1996)
Harenberg (1996)
Belch (1981)
Kleber (2003)
Subtotal
4.1 (1.9, 17.9)
2.5 (0.06, 13.7)
2.7 (0.7, 14.9)
1.8 (0.7, 3.9)
0.6 (.2, 1.4)
5.0 (0.6, 17.9)
2.0 (0.5, 5.0)
0
Per 1000 patient days
2.34 (1.3, 3.3)
1.4
1.9
1.6
14.4
21.2
1.2
10.6
0.86 (0.3, 1.4)
-20.5
King CS. Chest. 2007;131:507-516.
VTE Prophylaxis: LMWH vs UFH
Meta-analysis of 36 trials of LMWH or UFH
DVT Study
Risk Ratio
(95% CI)
0.70 (0.16-3.03)
0.29 (0.10-0.81)
0.74 (0.38-1.43)
0.94 (0.39-2.26)
Harenberg et al, 1990
Turpie et al, 1992
Dumas et al, 1994
Bergmann and Neuhart et al,
1996
Harenberg et al, 1996
Lechler et al, 1996
Hillborn et al, 2002
Kleber et al, 2003
Diener et al, 2006
Overall (95% CI)
2.89 (0.30-27.71)
0.25 (0.03-2.23)
0.55 (0.31-0.98)
0.77 (0.43-1.38)
0.76 (0.43-1.38)
0.68 (0.52-0.88)
-1
1
10
Risk Ratio
LMWH Better
LMWH Worse
Wein L. Arch Intern Med. 2007;167:1476-1486.
Weight, %
3.4
11.2
14.4
8.1
0.8
3.3
20.5
19.4
18.9
Risk stratification in surgery
Calf DVT
%
Proximal
DVT %
Clinical
PE %
Fatal PE
%
<2
(1C)
0.4Early ambulation
0.2
.002
Moderate
10-20
LMWH, LDUH,
(1A)
2-4
1-2 FPX .1-.4
High
20-40
LMWH,
LDUH
(1A)
4-8
2-4q8h, FPX
04-1
Low
Very High
40-80
Geerts WH. Chest. 2008;133:381S-453S
LMWH, LDUH q8h, or FPX
10-20
4-10
with GCS +/IPC (1C)0.2-5
AAOS guidelines
• Prioritize fatal PE.
• Reject the idea that DVT
and PE are linked.
• Ignore evidence that
prophylaxis prevents
DVT and PE.
• Contain numerous nonevidence based
recommendations
Eikelboom JW, Chest 2009; 135:513
PEP Trial Lancet 2000; 355:1295
VTE Prophylaxis for Patients
Recommended to Receive it
47
Prophylaxis Rates (%)
50
45
40
35
40
US
Non-US
33
30
25
20
22
21
N=15,156
14
15
9
10
5
7
0.2
3
3
1
0
Total
LMWH
Tapson V. Chest 2007;132:936
UFH
IPC
Stockings
ASA
Physician response to prompts &
overall prophylaxis rate
50%
40%
*
Total Prophylaxis Rate
30%
20%
10%
0%
Control
Neutral
Conner Chest 118: 162S, 2000
Educational
Risk
Prophylaxis following consistent
reminders
Computerized prophylaxis prompts
35
Control
Prompted
30
25
Percent
20
15
Δ 41 %
10
5
0
Prophylaxis rates
VTE indicence
63% had risk score >4
Kucher N NEJM 2005; 352:969
Electronic Alerts to Prevent VTE
Freedom From DVT
or PE (%)
100
98
96
Intervention group
94
92
Control group
90
P<.001
0
0
No. at Risk
Intervention group
Control group
1255
1251
Kucher N. N Engl J Med. 2005;352:969-977.
30
Days
977
976
60
90
900
893
853
839
Prophylaxis approaches
• Prophylaxis poor if
recommendations
passively
disseminated.
• Computer and paper
based reminders work
• Audit and feedback
important
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














Tooher R, Ann Surg 2005; 241:397
National 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 nonreimbursed
Venous thromboembolism
5-30%?
90%
~50%
~50%
~10%
63-70% of fatal PE’s
unsuspected during life
Stein Chest 1995; 110:978
Sandler J R Soc Med 1989; 82:203
Quality 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 DVT
15,000
$12,166
$12,146
12,500
$11,558
10,000
7,500
5,000
2,500
0
UFH
(n=104)
Enoxaparin QD
(n=112)
de Lissovoy G Arch Intern Med. 2000;160:3160
Enoxaparin q12h
(n=123)
Conclusions
•
•
•
•
•
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
Please see full prescribing information for enoxaparin, including boxed WARNING, available at this meeting
LOVENOX® (enoxaparin sodium injection) Prescribing Information. Sanofi-aventis, U.S. LLC. June 2007.
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)
Please see full prescribing information for enoxaparin, including boxed WARNING, available at this meeting
LOVENOX® (enoxaparin sodium injection) Prescribing Information. Sanofi-aventis, U.S. LLC. June 2007.
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]).
Please see full prescribing information for enoxaparin, including boxed WARNING, available at this meeting
LOVENOX® (enoxaparin sodium injection) Prescribing Information. Sanofi-aventis, U.S. LLC. June 2007.
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%).
Please see full prescribing information for enoxaparin, including boxed WARNING, available at this meeting
LOVENOX® (enoxaparin sodium injection) Prescribing Information. Sanofi-aventis, U.S. LLC. June 2007.
Important Safety Information (cont’d)
• 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.
Please see full prescribing information for enoxaparin, including boxed WARNING, available at this meeting
LOVENOX® (enoxaparin sodium injection) Prescribing Information. Sanofi-aventis, U.S. LLC. June 2007.
Dosing for
LOVENOX® (enoxaparin sodium injection)
Indications
VTE Prophylaxis
Abdominal surgery
Hip replacement surgery
Hip replacement (extended)
Knee replacement surgery
Medical patients with acute illness and
restricted mobility
Ischemic complications (UA/NSTEMI)
Acute STEMI Treatment
(<75 y)
(≥75 y)
VTE Treatment ||
Inpatient DVT with/without PE
Outpatient DVT without PE
Dosage
40 mg SC once daily (7–10 days)*
30 mg SC q12h† or 40 mg SC once daily‡ (7–10 days)
40 mg SC once daily (up to 21 days following initial phase of
thromboprophylaxis)
30 mg SC q12h† (7–10 days)
40 mg SC once daily (6–11 days)
1 mg/kg SC q12h (2–8 days)§
30 mg IV bolus + 1 mg/kg SC followed by 1 mg/kg SC q12h§
0.75 mg/kg SC q12h
1 mg/kg SC q12h or 1.5 mg/kg SC once daily
1 mg/kg SC q12h
Please see full prescribing information for enoxaparin, including boxed WARNING, available at this meeting
*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.
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
Please see full prescribing information for enoxaparin, including boxed WARNING, available at this meeting
LOVENOX® (enoxaparin sodium injection) Prescribing Information. Sanofi-aventis, U.S. LLC. June 2007.
LOVENOX® (enoxaparin sodium injection)
Dosing Regimens
Severe Renal Impairment*
(Does Not Apply to Hemodialysis Patients)
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†
Treatment
Acute STEMI
(<75 y)
(≥75 y)
Inpatient DVT with/without PE‡
Outpatient DVT without PE‡
1 mg/kg SC once daily
30 mg IV bolus + 1 mg/kg SC followed by 1 mg/kg SC
once daily
1 mg/kg SC once daily
1 mg/kg SC once daily
1 mg/kg SC once daily
Please see full prescribing information for enoxaparin, including boxed WARNING, available at this meeting
*CrCl <30 mL/min; †when concurrently administered with aspirin;
‡when administered in conjunction with warfarin sodium.
LOVENOX® (enoxaparin sodium injection) Prescribing Information. Sanofi-aventis, U.S. LLC. June 2007.
LOVENOX® (enoxaparin sodium injection)
Prescribing Information
Weight
• 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
Please see full prescribing information for enoxaparin, including boxed WARNING, available at this meeting
LOVENOX® (enoxaparin sodium injection) Prescribing Information. Sanofi-aventis, U.S. LLC. June 2007.
US.ENO.07.11.025
Risk of Major Bleeding after LMWH in
patients with CrCl ≤30
Study, Year
Collet, 2001
Pautas, 2002
Siguret, 2000
Chow, 2003
Khazan (adjusted),
2003
Khazan (prophylactic), 2003
Khazan (therapeutic), 2003
Spinler, 2003
Green, 2005
Kruse, 2004
Macie, 2004
Patients With Patients With
Renal Insuff, No Renal Insuff,
n/n
n/n
0/28
1/83
0/51
3/149
0/17
0/13
0/5
0/13
0/10
3/42
Peto OR
(95% CI)
Weight,
%
2.01
6.02
Peto OR (95% CI)
4.78
0.26 (0.00-23.94)
0.26 (0.02-3.50)
Not estimable
Not estimable
0.28 (0/01-5.16)
3/36
2/17
3/47
3/61
14.77
8.62
1.33 (0/25-7.05)
3.09 (0.35-27.31)
5/69
1/18
0/50
2/7
74/3432
0/20
1/120
6/201
15.93
2.66
2.22
2.68
10.05 (2.02-49.98)
8.26 (0.16-418.42)
0.24 (0.00-17.90)
977.78
(19.61-48752.07)
Not estimable
1.85 (0.63-5.40)
2.74 (0.15-51.73)
2.25 (1.19-4.27)
Peng, 2004
0/7
0/43
Thorevska, 2004
7/65
11/171
Bazinet, 2005
1/36
2/160
Total (95% CI)
416
4555
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 1
Favors Reduction in Bleeding
Lim W, et al. Ann Intern Med. 2006;144:673-684.
35.56
4.75
100.00
10 100
Favors Increase in Bleeding
ACCP Recommendations:
Renal 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
and 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.
2.
Geerts WH. Chest. 2008;133:381S-453S.
Lim W. Ann Intern Med. 2006;144:673-684.
Obesity 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.
2.
Davidson BL. J Thromb Haemost. 2007;5:1191-1194.
Kucher N. Arch Intern Med. 2005;165:341-345.
VTE in Obese Patients
Percent of Patients
10
Primary end point: VTE = symptomatic DVT,
symptomatic PE, and asymptomatic proximal DVT or
sudden death at day 21
8
Relative risk, 0.64; 95% confidence interval, 0.32-1.28
6
4.3
4
2.8
2
0
Placebo
Cohen AT Vasc Med. 2007;12:123-127.
Kucher N Arch Intern Med. 2005;165:341-345.
Dalteparin