1. DVT Prophylaxis of the Medical Patient Nicole Artz, MD David Lovinger, MD August, 2006

2. Case Mr. Smith- 71 y/o man admitted to general medicine ward service. Mr. Smith- 71 y/o man admitted to general medicine ward service. –HPI: gradually increased sob over 3 days assoc. with new productive cough, rhinorrhea, and fatigue. –PMH: COPD, CHF (LVEF 35%), CRI (creat 2.5) –ROS: No h/o DVT/PE. –PE: VSS with SPO2 93% on RA  Barrel chested, b/l expiratory wheezes, prolonged expiratory phase,  CXR: hyperexpanded, no infiltrate, consolidation or edema. –DX: COPD Exacerbation

3. Does this man need DVT prophylaxis? Why worry about VTE in inpatients? Why worry about VTE in inpatients? What is the prevalence of DVT/PE in hospitalized medical patients? What is the prevalence of DVT/PE in hospitalized medical patients? Is this man at risk for venous thromboembolism? Is this man at risk for venous thromboembolism? What are effective methods of prophylaxis? What are effective methods of prophylaxis? What adjustments need to be made based on his history of renal insufficiency? What adjustments need to be made based on his history of renal insufficiency?

4. Importance What % of all hospital related deaths due to fatal PE? What % of all hospital related deaths due to fatal PE? –7-10% What % of these pts had NO premorbid symptoms? What % of these pts had NO premorbid symptoms? –70-90% 200,000 potentially preventable annual deaths due to PE in the US 200,000 potentially preventable annual deaths due to PE in the US Sandler DA JR Soc Med 1989; 82, Lindblad B Br Med J 1991; 302.

5. Prevalence in Medical Pts 3 large-scale randomized studies (5500 medically ill patients) 3 large-scale randomized studies (5500 medically ill patients) –DVT identified w/ screening studies Patients receiving no prophylaxis: Patients receiving no prophylaxis: –VTE 11-15% of patients –Proximal DVT- 4-5% of patients Rates similar to moderate-high risk general surgery patients. Rates similar to moderate-high risk general surgery patients. Samana, MM NEJM, 1999; Leizorovicz, A Circulation 2004; Cohen, AT J Thromb Haemost, 2003.

6. Prevalence ACCP Guidelines, Chest. 2005.

7. Prevalence Pendleton, R. Amer J. Hematology 2005.

8. Prevalence 3 out of 4 hospital pts dying from PE have NOT had recent surgery… 3 out of 4 hospital pts dying from PE have NOT had recent surgery… 2.5% of medical patients immobilized with multiple clinical problems suffer fatal PE. 2.5% of medical patients immobilized with multiple clinical problems suffer fatal PE. National DVT Free Registry National DVT Free Registry –60% of patients dx with acute DVT were in the peri-hospitalization period –60% of cases were in non-surgical patients! Haas, S. Seminars in Thrombosis and Haemostasis, 2002; Goldhaber, SZ Am J Cardiol 2004.

9. Risk Factors Heterogeneous population! Heterogeneous population! Need to consider: Need to consider: –Acute medical condition (MI, pneumonia, etc.) –Underlying risk factors (h/o VTE, estrogen use, etc.) –Medical interventions (central venous catheters, chemotherapy, etc.) Relative contribution of various risk factors still being defined. Relative contribution of various risk factors still being defined.

10. Risk Factors Acute medical conditions well accepted as high risk: Acute medical conditions well accepted as high risk: –MI (24% VTE risk) –Decompensated CHF (40% VTE risk) –Acute Stroke (30-75% VTE risk) –Spinal Cord Injury (up to 100%) –MICU admission (13-33*% VTE risk, *½ of these were proximal leg vein thromboses) –Central venous catheters (25-46% VTE risk) –Malignancy Haas, S. Seminars in Thrombosis and Hemostasis, 2002; Pendleton, Amer J Hematology, 2005.

11. Abstracted from Pendleton, R. Amer J Hemat 2005.

12. Current Rates of Prophylaxis IMPROVE study IMPROVE study –Ongoing multinational observational cohort study in acutely ill medical patients –Only 34% of potentially at risk patients are receiving any prophylaxis!  Only ½ of patients who would have met criteria used for MEDENOX study received any VTE prophylaxis. Anderson FA, IMPROVE; Blood 2003.

13. Current Rates of Prophylaxis University of Utah University of Utah –Pre and post intervention study –Pts stratified into high and low risk groups based on risk factors –Pre-intervention group  75% of patients admitted to medical service were high risk  Only 43% received prophylaxis of any type. Stinnett, J American Journal of Hematology 2005.

14. How Are We Doing at UCH? Retrospective chart review by Linda Nahlik, Pharm- D, 2005. Retrospective chart review by Linda Nahlik, Pharm- D, 2005. 98 pts admitted to gen med service NOT on therapeutic anticoagulation. 98 pts admitted to gen med service NOT on therapeutic anticoagulation. –20% of pts had a contraindication to prophylaxis (active bleeding) –Only 4% had no risk factors for prophylaxis –29% of pts had 1 major or 2 minor risk fxs, no contraindications, and yet had NO prophylaxis.

15. What Should We Use for Prophylaxis? Mechanical compression devices? (compression stockings, IPC devices) Mechanical compression devices? (compression stockings, IPC devices) Unfractionated heparin BID? Unfractionated heparin BID? Unfractionated heparin TID? Unfractionated heparin TID? Low Molecular Weight Heparin? (Enoxaparin, Daltaparin) Low Molecular Weight Heparin? (Enoxaparin, Daltaparin) Fondaparinux? Fondaparinux?

16. What are the most common regimens in the US? What are the most common regimens in the US? –UFH BID, mechanical compression devices Which regimens have the least data to support them? Which regimens have the least data to support them? –UFH BID, mechanical compression devices What are characteristics of the ideal prophylaxis regimen? What are characteristics of the ideal prophylaxis regimen? –Effective –Safe –Cost-effective What Do We Know About Prophylaxis?

17. Key VTE Prevention Trials Pendleton, R. Amer J. Hemat. 2005 ** MEDENOX study included 20 mg enoxaparin arm which was no more effective than placebo.

19. *Remember that MEDENOX found enoxaparin 20 mg no more effective than placebo, therefore calling into doubt efficacy of bid heparin dosing.

20. Complications of Prophylaxis Bleeding Bleeding –Major bleeding rates no different from placebo in major trials w/ enoxaparin, dalteparin, and fondaparinux (rates 0.2-1.7%) HIT HIT –Develops in 1.4% of medically ill pts exposed to preventive doses of UFH. –Potentially catastrophic- thrombosis rates as high as 60%. –LMWH’s 8-10X’s less likely to cause HIT. –Fondaparinux does not cause HIT. Girolami, B. Blood 2003; Warkentin TE, Br J Haematol 2003. Pendleton, R. Am J Hematol 2005.

21. Special Populations Obesity Obesity Renal Insufficiency Renal Insufficiency Elderly Elderly

22. Obesity Anti Xa levels with fixed dose LMWH regimens correlate negatively with BMI in critically ill patients. (Priglinger U, 2003) Anti Xa levels with fixed dose LMWH regimens correlate negatively with BMI in critically ill patients. (Priglinger U, 2003) Standard prophylactic regimens twice as likely to fail in orthopedic pts with BMI >32. Standard prophylactic regimens twice as likely to fail in orthopedic pts with BMI >32. –BMI >32 VTE rate 32% vs 17% for BMI 32 VTE rate 32% vs 17% for BMI <32. (Samama, MM, 1995) Non-randomized study in bariatric surg pts- suggested decreased DVT rates w/ enoxaparin 40 mg bid vs 30 mg bid. (Scholten, DJ, 2002) Non-randomized study in bariatric surg pts- suggested decreased DVT rates w/ enoxaparin 40 mg bid vs 30 mg bid. (Scholten, DJ, 2002) No data to guide adjustments in therapy. No data to guide adjustments in therapy. Options include: Options include: –Use standard dose –Add mechanical measures –Empiric dose adjustments

23. Renal Insufficiency Delayed renal clearance of LMWH’s and Fondaparinux problematic. Delayed renal clearance of LMWH’s and Fondaparinux problematic. Lack of outcomes based data. Lack of outcomes based data. FDA approved enoxaparin 30 mg qd for pts with creat clearance <30 ml/min based on pharmacokinetic data alone. FDA approved enoxaparin 30 mg qd for pts with creat clearance <30 ml/min based on pharmacokinetic data alone. Additional options include UFH, mechanical devices. Additional options include UFH, mechanical devices.

24. Patients with HIT Avoid UFH or LMWH’s. Avoid UFH or LMWH’s. ? Fondaparinux? Trials ongoing. ? Fondaparinux? Trials ongoing. Mechanical compression devices +/- duplex US surveillance. Mechanical compression devices +/- duplex US surveillance.

25. Elderly Patients Mahe et al. monitored anti-Xa levels in 68 consecutive hospitalized elderly patients (mean age 82) receiving enoxaparin for prophylaxis. Mahe et al. monitored anti-Xa levels in 68 consecutive hospitalized elderly patients (mean age 82) receiving enoxaparin for prophylaxis. By day 2 over half had levels in the therapeutic range. By day 2 over half had levels in the therapeutic range. Lack of safety data with use of UFH as well. Lack of safety data with use of UFH as well. Lack of outcomes data. Lack of outcomes data. –Consider empiric dose reduction or use of mechanical devices alone for elderly patients with low body weight and/or marginal creatinine clearance (30-60 ml/min). Mahe, I, Pathophysiol Haemost Thromb 2002., Pendleton R, Am J Hemat 2005.

26. Take Home Points The majority of hospitalized medical patients are at increased risk for VTE. The majority of hospitalized medical patients are at increased risk for VTE. In the absence of contraindicatons, prophylaxis should be provided for patients based on assessment of risks. In the absence of contraindicatons, prophylaxis should be provided for patients based on assessment of risks. Safe and Effective preventive regimens include: Safe and Effective preventive regimens include: –Enoxaparin 40 mg SC daily –Daltaparin 5000 IU SC daily –Fondaparinux 2.5 mg sc daily –UFH 5000 units SC every 8hrs *Must use clinical judgement for unique patient groups with lack of data.