Prevention of DVT & PE Arthur P. Wheeler, M.D. Associate Professor of Medicine Director MICU,...

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


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


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)



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]).



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%).



• 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.


Important Safety Information (cont’d)


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) 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) 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

• 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


US.ENO.07.11.025


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

Prevention of DVT & PE Arthur P. Wheeler, M.D. Associate Professor of Medicine Director MICU,...

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Transcript of Prevention of DVT & PE Arthur P. Wheeler, M.D. Associate Professor of Medicine Director MICU,...