1. Preventing Venous Thromboembolism in Surgical and Medical Patients Susan Kahn MD MSc Director, JGH Thrombosis Program March 2011

2. Learning Objectives To understand the importance of thromboprophylaxis in hospitalized patients To be aware of the most recent ACCP consensus guidelines on venous thromboembolism (VTE) prevention 2008

3. VTE: a very important and costly complication of hospitalization 70% of all VTE in the community is attributable to recent hospitalization!! 2 nd most common cause of excess length of stay 3 rd most common cause of excess mortality Doubles LOS and costs

4. Autopsy: Fatal Pulmonary Embolism

5. Rationale for VTE prophylaxis 1. High frequency in most hospitalized patients 2. Adverse consequences of unprevented VTE are numerous (PE death, PE, recVTE, PTS, complications of AC) 3. Thromboprophylaxis is effective, safe and cost-effective

6. Risk of DVT in Hospitalized Patients (no thromboprophylaxis, and routine screening for DVT) Patient groupDVT prevalence, % Medical patients10-20 General Surgery15-40 Major gynecologic surgery15-40 Major urologic surgery15-40 Neurosurgery15-40 Stroke20-40 Hip, knee arthoplasty, hip fracture 40-60 Major trauma40-80 Spinal cord injury60-80 Moderate risk High risk

7. Copyright ©2009 BMJ Publishing Group Ltd. Sweetland, S. et al. BMJ 2009;339:b4583 Fig 1 Relative risk of venous thromboembolism by time since inpatient surgery and since day case surgery

8. Thromboprophylaxis What is the evidence?… Hundreds of RCTs show that thromboprophylaxis reduces: DVT PE Fatal PE All-cause mortality Costs

9. Thromboprophylaxis Ranked number 1 of >75 strategies to improve patient safety in hospitalized patients More than 25 published evidence-based guidelines since 1986 show clear evidence of benefit and safety ACCP Guidelines: Every hospital should have a formal thromboppx protocol

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12. Thromboembolism risk groups addressed by ACCP guidelines General surgery Vascular surgery Gynecologic surgery Urologic surgery Thoracic surgery Laparoscopic surgery CABG Knee arthoplasty Hip arthoplasty Knee arthoscopy Hip fracture surgery Spine surgery Lower extremity injuries Neurosurgery Major trauma Spinal cord injuries Burn patients Medical patients Cancer patients CVCs Critical care patients Long distance travel Geerts-Chest 2008;133:381S

13. Recommendation Grades Grade 1 (strong recommendation) Desirable effects clearly outweigh undesirable effects or vice versa (secondary side effects, costs, patient inconvenience) Can apply to most patients in most to many circumstances Grade 2 (weak recommendation: “suggestion”) Desirable and undesirable effects closely balanced Best action may differ depending on patient circumstances or society values Guyatt GH et al. Grades of recommendation for antithrombotic agents. Chest 2008; 133:123S-131S

14. Quality of Evidence QUALITYMETHODOLOGY Strong (A) One or more well-designed and well- executed RCT Well-done observational studies with very large effects (RRR>=80%) Moderate (B) RCTs with important limitations Well-done observational studies with large effects (RRR>=50%) Weak (C) RCTS with very serious limitations Observational studies yielding modest effects Guyatt GH et al. Grades of recommendation for antithrombotic agents. Chest 2008; 133:123S-131S

15. Choose best thromboprophylaxis for: 80 yo F obese post hip # surgery 35 yo M appendectomy 72 yo F for ovarian cancer resection, recent GI bleed 68 yo for colon cancer resection; MVR with prior embolic TIA

16. PREVENTION OF VTE GENERAL RECOMMENDATIONS (I) Mechanical methods of thromboprophylaxis be used primarily in patients at high risk of bleeding (Grade 1A), or possibly as an adjunct to anticoagulant-based thromboprophylaxis (Grade 2A). Graduated compression stockings Intermittent pneumatic compression Venous foot pump Recommend against use of aspirin alone as thromboprophylaxis for any patient group (Grade 1A) Renal function should be considered when making decisions about the use and/or dose of LMWH, fondaparinux, and other ACs cleared by the kidney, especially in elderly patients, diabetics, or if high risk of bleeding. One of the following is recommended (Grade 1B): Avoid use of AC that bioaccumulates with renal impairment, OR Use lower dose OR Monitor drug level or AC level Geerts WH et al. Prevention of venous thromboembolism Chest 2008;133:381S-453S. Increase venous outflow and/or reduce venous stasis

17. Mechanical prophylaxis Can be used in high risk bleeding patients Efficacy demonstrated in a number of patient groups May enhance effectiveness of AC thromboprophylaxis May reduce leg swelling Not as intensively studied as pharmacologic strategies (fewer studies and smaller) No established standards Many devices never tested in RCTs Almost all RCTs unblinded In high risk groups, less effective then AC thromboprophylaxis Greater effect on reducing calf DVT than proximal DVT Effect on PE or death unknown Compliance by patients and staff often poor Cost associated with purchase, storage, dispensing and cleaning, ensuring optimal compliance AdvantagesDisadvantages

18. IPC: Sequential Compression Device (SCD) IPC: Foot pump Anti-embolic (TED) stocking

19. Geerts WH et al. Prevention of venous thromboembolism Chest 2008;133:381S-453S. VTE prophylaxis: Risk groups and recommended thromboppx

20. UFH BID vs. TID

21. Patient-specific high risk features for VTE Previous VTE Increasing age Obesity Immobility, lower-extremity paresis Cancer (active or occult) Cancer therapy (hormonal, chemotherapy, angiogenesis inhibitors, radiotherapy) Venous compression (tumor, hematoma, arterial abnormality) Central venous catheterization Acute medical illness Pregnancy and the postpartum period Estrogen-containing oral contraceptives or hormone replacement therapy Selective estrogen receptor modulators Erythropoiesis-stimulating agents Inflammatory bowel disease Nephrotic syndrome Myeloproliferative disorders Paroxysmal nocturnal hemoglobinuria Inherited or acquired thrombophilia Trauma (major trauma or lower- extremity injury) Geerts WH et al. Prevention of venous thromboembolism Chest 2008;133:381S-453S.

22. Low risk of VTE Patient group: Medical – fully mobile, brief admission Surgical – procedure < 30 min, mobile, and no additional VTE risk factors Laparoscopic surgeries (gynecologic, gen Sx) Transurethral procedures Endoscopic procedures Recommendations:  No specific prophylaxis  mobilization Geerts-Chest 2008;133:381S

23. Moderate Risk: General Surgery Recommendation/SuggestionGrade Major procedure for benign disease LMWH LDUH bid Fondaparinux 1A Major procedure for cancer related surgery LMWH LDUH tid Fondaparinux 1A Major and multiple RFs for VTE LMWH + mechanical method LDUH tid + mechanical method Fondaparinux + mechanical method 1C High risk of bleeding Properly fitted GCS or IPC. When risk of bleeding decreases, AC be substituted or added 1A 1C ACCP Antithrombotic and Thrombolytic therapy: CHEST 133, June2008 For most patients, prophylaxis until discharge (and not mobilization) (grade 1A) For selected high risk general surgery patients (cancer surgery, previous VTE), consider LMWH for 28 days (grade 2A)

24. Moderate Risk: Gynecologic Surgery Recommendation/SuggestionGrade Entirely laparoscopic surgery in whom there are additional VTE risk factors LMWH LDUH bid IPC GCS 1C Major open procedure for benign disease LMWH LDUH bid IPC just before surgery and used continuously while patient not ambulating 1A 1C Major open procedure for cancer or multiple RFs for VTE LMWH LDUH tid IPC just before surgery and used continuously while patient not ambulating Any of above pharmacologic strategies with GCS or IPC 1A 1C For most patients, prophylaxis until discharge (not mobilization) (grade 1A) For selected high risk general surgery patients (cancer surgery, previous VTE), consider LMWH for 28 days (grade 2C)

25. Moderate Risk: Urologic Surgery Recommendation/SuggestionGrade Major open procedure LDUH bid or tid IPC just before surgery and used continuously while patient not ambulating LMWH Fondaparinux Any of above pharmacologic methods with optimal use of GCS or IPC 1B 1C Major open procedure at high risk of bleeding Properly fitted GCS or IPC. When risk of bleeding decreases, pharmacologic thromboprophylaxis be substituted or added 1A 1C For most patients, prophylaxis until discharge (and not mobilization) (grade 1A) For selected high risk general surgery patients (cancer surgery, previous VTE), consider LMWH for 28 days (???)

26. Moderate Risk: Laparoscopic Surgery Recommendation/SuggestionGrade Routine No prophylaxis Mobilization 1B Additional VTE risk factors LMWH LDUH bid Fondaparinux Mechanical methods 1C Considerable uncertainty VTE rates appear to be low: 0%-5% screened DVT; 0.03%-0.06% symptomatic VTE Pneumoperitoneum and reverse Trendelenburg may impact VTE risk Only 3 RCTs (LMWH vs placebo or mechanical) of thromboprophylaxis (very small studies, heterogenous, venogram endpoints): no difference Society of American Gastrointestinal Endoscopic Surgeons recommends the use of similar thromboprophylaxis options as for the equivalent open surgical procedures.

27. Moderate Risk: Bariatric Surgery Recommendation/SuggestionGrade Inpatient bariatric surgery LMWH LDUH tid Fondaparinux Mechanical methods with any of the above pharmacologic methods 1C For most patients, prophylaxis until discharge (and not mobilization) (grade 1A) For selected high risk general surgery patients (cancer surgery, previous VTE), consider LMWH for 28 days (???) VTE rates vary widely (0.2%-2%); Fatal PE (0.2%) Optimal dose, timing and duration unknown Only 1 small RCT of thromboprophylaxis (nadroparin 5700 IU vs 9500 IU; no difference (no events at 3 and 6 months)) Higher doses than usual

28. Moderate Risk: Neurosurgery Recommendation/SuggestionGrade Major neurosurgery Optimal use of IPC Post-operative LMWH LDUH 1A 2A 2B If high risk of thrombosis (eg. cancer) Mechanical method be combined with LDUH or post-operative LMWH 2B Intracranial (vs spinal), malignancy, prolonged procedures, leg weakness are important RFs for VTE in neurosurgery Glioma patients carry a post-operative VTE risk of 15-25% at 3 months Mechanical thromboprophylaxis most studied in this population (RRR 68% compared to no thromboprophylaxis) GCS alone not as effective as IPC GCS alone is not as effective as combination LDUH and GCS Concerns of bleeding with preoperative or early postoperative LMWH in craniotomy patients (2-fold higher risk of bleeding at any site vs. mechanical or no thromboprophylaxis)

29. High risk of VTE: Elective hip replacement SituationRecommendationGrade All THR patients LMWH  High risk dose 12 h pre-op or 12-24 h post-op  Half dose 4-6 h post-op then high dose following day Fondaparinux 2.5 mg 6-24 h post-op VKA INR 2.5 1A Use of: ASA or Dextran or LDUH GCS or VFP Do not use as sole method of thromboprophylaxis 2A If high risk of bleeding When bleeding risk decreases VFP or IPC Add or substitute pharmacological prophylaxis 1A 1C Geerts-Chest 2008;133:381S

30. SituationRecommendationGrade HFS: routine prophylaxis Fondaparinux LMWH Adjusted VKA INR 2.5 LDUH 1A 1B Use of ASAAgainst use of ASA alone1A If surgery delayed LMWH or LDUH during time between admission and surgery 1C If high risk of bleeding When bleeding risk decreases VFP (Venous foot pump) or IPC Add or substitute pharmacological prophylaxis 1A 1C High risk of VTE: Hip fracture surgery Geerts-Chest 2008;133:381S

31. High risk of VTE: Elective knee replacement SituationRecommendationGrade Routine prophylaxis Fondaparinux LMWH Adjusted VKA INR 2.5 1A Alternative optionOptimal use of IPC1B Use of: ASA or LDUH Against use as only method of thromboprophylaxis 1A 1B If high risk of bleeding When bleeding risk decreases IPC VFP  Add or substitute pharmacological prophylaxis 1A 1B 1C Geerts-Chest 2008;133:381S

32. Duration of prophylaxis and orthopaedics SituationRecommendationGrade THR, TKR, HFSAt least 10 days1A THR Extend from 10 up to 35 days LMWH VKA Fondaparinux 1A 1B 1C TKR Extend from 10 to up to 35 days LMWH VKA Fondaparinux 1B 1C HFS Extend from 10 to up to 35 days Fondaparinux LMWH VKA 1A 1C Geerts-Chest 2008;133:381S

33. Knee arthoscopy SituationSuggestionGrade No additional VTE risk factors No prophylaxis Early mobilization 2B Additional risk factorsLMWH 1B Geerts-Chest 2008;133:381S

34. RECORD3: TKR patients, 10 days Rx Total VTE Major bleeding 20 Incidence (%) 0 Major VTE 5 10 15 NS RRR 49% RRR 62% Symptomatic VTE Rivaroxaban 10 mg od Enoxaparin 40 mg od RRR 65% 0.5%0.6%18.9%9.6%2.6% 1.0% 2.0%0.7% Rivaroxaban: oral direct Factor Xa inhibitor

35. RECORD1: THR patients, 35 days Rx Incidence (%) Total VTE Major bleeding Enoxaparin 40 mg once daily Rivaroxaban 10 mg once daily 0 1 2 3 4 5 0.5% 0.3% 0.1% 0.3% Symptomatic VTE RRR 70% 2.0% 0.2% Major VTE RRR 88% 1.1%3.7%

36. Patients with Renal impairment  No dose adjustment required in patients with mild (CrCl >50 mL/min) or moderate (CL CR : 30-49 mL/min) renal impairment  Subjects with CL CR <30ml/min excluded from clinical trial program. Limited clinical data: rivaroxaban levels sig increased in such patients

37. Moderate risk: Patients hospitalized for a medical condition Recommendation/suggestionGrade 1. Congestive heart failure 2. Severe respiratory disease 3. Confined bed rest with one or more of: Active cancer Previous VTE Acute neurologic disease Inflammatory bowel disease LMWH or LDUH bid or Fondaparinux 1A For some patients if contraindication to anticoagulation prophylaxis Mechanical thromboprophylaxis with GCS or IPC 1A 50-70% of symptomatic VTE and 70-80% of fatal PE occur in hospitalized medical patients Geerts-Chest 2008;133:381S

38. Optimal duration remains unclear (EXCLAIM study) 4000 ill medical patients Enoxaparin 6-14 days vs. 28 days VTE at 1 month (enox 4.9% vs. extended enox 2.8%) (p<0.05) Major bleeding (1.1% extended enox vs. 0.3% enox) (p<0.05) No impact on all-cause mortality Moderate risk: Patients hospitalized for a medical condition Geerts-Chest 2008;133:381S

39. VTE risk varies considerably Most ICU patients have multiple risk factors Some acquired RFs include: pharmacologic paralysis, CVC lines, surgical procedures sepsis, mechanical ventilation vasopressor use, renal dialysis Also, have risk factors for bleeding Trauma Surgery Low platelets Liver disease Moderate risk: Critical Care patients Geerts-Chest 2008;133:381S

40. Moderate risk: Critical Care patients Recommendation/SuggestionGrade Any admitted patient Assessment for VTE risk Routine prophylaxis in most 1A Moderate risk of VTE (medically ill or postoperative general surgery) LMWH or LDUH bid1A High risk of VTE (major trauma or orthopedic surgery) LMWH (extrapolate from major trauma and orthopedics population) 1A If high risk of bleeding When bleeding risk decreases GCS and / or IPC Add or substitute LMWH / LDUH 1A 1C Geerts-Chest 2008;133:381S

42. High risk: Hospitalized cancer patients Recommendation/SuggestionGrade Surgery Appropriate for the type of surgery LWMH=LDUH tid 1A Bedridden with an acute medical illness Thromboprophylaxis as for other high risk medical patients 1A Chemotherapy or hormonal therapy No role for prophylaxis1C Indwelling CVCs No role for prophylactic doses of LMWH or mini-dose warfarin 1B Ambulating, non- hospitalized No role for prophylaxis to improve survival 1B Geerts-Chest 2008;133:381S

43. Basic principles Think about VTE prophylaxis in each and every patient Assess risk of VTE Determine if contraindications present Assess if patient is in a higher than usual risk group that might require more aggressive approach (stepped up dose, dual modality, longer duration): e.g. previous VTE, cancer, prolonged immobilization REMEMBER to prescribe thromboprophylaxis Assess ongoing need for thromboprophylaxis (or resolution of contraindications) regularly Low threshold to investigate if symptoms/signs VTE occur Think HIT if VTE (MI, stroke) occurs in patient who received heparin or LMWH

44. Choose best thromboprophylaxis for: 80 yo F obese post hip # surgery 35 yo M appendectomy 72 yo F for ovarian cancer resection, recent GI bleed 68 yo for colon cancer resection; MVR with prior embolic TIA

45. Gaps in knowledge Chronically immobilized nursing home or rehab patients Value of extended thromboprophylaxis after hospitalization for medical illness Post C section thromboprophylaxis Thromboprophylaxis after non- hip lower extremity fracture (e.g. ankle, tibfib)