The basics about thromboprophylaxis by misale haile

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1. Thromboprophylaxis

2. Introduction PTE is the most common preventable cause of hospital death. 10% of inpatient death Responsible for 150K-200K deaths per year in US VTE occurs in 10-80% of hospitalized medical and surgical patients 60% VTE cases occur in hospitalized, recently discharged (within3 months) or nursing home patients Hospitalization has 130 times more risk of VTE

3. Risk factors for VTE in medical patients Age >60 years Previous VTE, Cancer , Prolonged Immobility , Inherited or acquired hypercoagulable states ICU admissions Medical conditions like heart failure, stroke, COPD, sepsis, IBD Pregnancy

4. Risk assessment Low, Moderate, High risk Padua prediction score IMPROVE risk score – IMPROVE study

5. Padua prediction score Prospective cohort, 1180 medical patients followed up to 90 days, 2007-2008, Padua, Italy Primary outcome: risk of VTE in low and high risk patients, risk of VTE in high risk patients given adequate thromboprophylaxis in comparison with those who did not. Findings Low risk – 0.3% risk of VTE High risk receiving adequate thromboprophylaxis – 2.2% risk of VTE High risk not receiving adequate thromboprophylaxis – 11% risk of VTE Conclusion: adequate thromboprophylaxis in high-risk patients during hospitalization leads to longstanding protection against thromboembolic events with a low risk of bleeding Barbar S , et al. A risk assessment model for the identification of hospitalized medical patients at risk for venous thromboembolism: the Padua Prediction Score . J Thromb Haemost .  2010 Nov;8(11):2450-7

6. Padua prediction score

7. Padua prediction score Padua score <4  low risk Pharmacologic thromboprophylaxis not strongly indicated Consider mechanical thromboprophylaxis Padua score ≥4  high risk Pharmacologic thromboprophylaxis indicated Use mechanical thromboprophylaxis if high risk of bleeding

8. IMPROVE study Prospective cohort study of physician practices in the provision of prophylaxis against venous thromboembolism (VTE) in hospitalized 15,000 medical patients from 56 hospitals in 11 countries, 2001-2005 Key endpoints: type and duration of prophylaxis, death, clinically apparent VTE, and bleeding within 3 months of hospital discharge

9. IMPROVE study The rate of VTE within 90 days of admission 0.4 - 0.5% if none of these risk factors was present 8 – 11% in those with the highest risk scores In-hospital bleeding risk Scored 0 to 15 In-hospital bleeding risk Score 1 0.5% Score 4 1.6% Score 7 4.1% Score 10 9.7% Score 15 14%

10. IMPROVE  VTE risk score calculator and bleeding risk score calculator

11. Prevention of VTE Primary prophylaxis Pharmacologic or mechanical methods to prevent VTE Secondary prophylaxis Early detection and treatment of subclinical DVT Objective screening tests However, no single screening method ( eg , contrast venography, venous ultrasound, MRI venography) has found universal acceptance for secondary prevention.

12. Rationale for thromboprophylaxis VTE is common in hospitalized patients VTE is fatal VTE is preventable safely and inexpensively VTE prevention is a standard of care

13. VTE prophylaxis Cost effective method of preventing VTE Appropriate VTE prophylaxis not often offered

14. VTE prophylaxis Reduces VTE in hospitalized patients Reduces mortality in surgical patients Do not reduce overall mortality in medical patients Comorbidities

15. VTE prophylaxis indications ICU admissions Medical patients older than 40 years of age who have limited mobility for ≥3 days, and have at least on thrombotic risk Congestive heart failure, Acute exacerbations of chronic pulmonary disease, Stroke with paralysis, Sepsis Inflammatory bowel disease, High degree of immobility, Age >75 years, Cancer Previous episode of VTE

16. Ideal VTE prophylactic methods Ease of administration Effective Safety Cost effective No need for laboratory monitoring Good compliance by physicians, patients

17. VTE prophylaxis options Low dose unfractionated heparin, Low molecular weight (LMW) heparins, Fondaparinux Intermittent pneumatic compression (IPC) and/or graduated compression stockings ( GCS) Oral factor Xa or factor IIa (thrombin) inhibitors

18. DVT prophylaxis Prevention better than treatment 40 – 60% efficacy Mechanical methods Early postop ambulation, Physiotherapy Graded compression stockings Intermittent pneumatic leg compression Anticoagulants. Low-dose UFH or LMWH is the most common form of in-hospital prophylaxis UFH 7500 unit SC BID, or 5000 unit SC TID LMWH

19. Pharmacologic thromboprophylaxis UFH, LMW heparin and fondaparinux are all superior to placebo in preventing venous thromboembolism (VTE )

20. Heparins Compared with placebo, UFH was associated with a significantly reduced risk of DVT (risk ratio [RR] 0.33; 95% CI 0.26-0.42) and PE (RR 0.64; 95% CI 0.50-0.82 ) Compared with placebo, LMW reduces risk of DVT ( RR 0.56; 95% CI 0.45-0.70) and PE (RR 0.37; 95% CI 0.21-0.64) When directly compared with UFH, LMW heparin was associated with a significantly lower risk of DVT (RR 0.68; 95% CI 0.52-0.88) and injection site hematoma (RR 0.47; 95% C, 0.36-0.62) Neither UFH nor LMW heparin reduced mortality . Has similar risk of bleeding or thrombocytopenia

21. Heparins Reduce DVT by 60% Reduce PTE by 42% Treatment with the heparin preparations resulted in a significant increase in major hemorrhage (RR 2.18; 95% CI 1.28-3.72) and minor hemorrhage (RR 1.74; 95% CI 1.26-2.41) when compared with placebo or no treatment

22. UFH When compared with placebo, UFH given in a dose of 5000 units three times daily was significantly more effective in preventing DVT (RR 0.27; 95% CI 0.20-0.36) than UFH given in a dose of 5000 units twice daily (RR 0.52; 95% CI 0.28-0.96 )

23. Dalteparin PROTECT trial Dalteparin 5000 units/day was not superior to unfractionated heparin (5000 units twice daily) in the prevention of proximal DVT, but the incidence of PE was significantly reduced in the dalteparin -treated group. The incidence of major bleeding and of death was similar in the two groups Cook D, Meade M, et al . Dalteparin versus unfractionated heparin in critically ill patients. PROTECT trial. N Engl J Med 2011; 364:1305.

24. Extended duration prophylaxis 4 weeks vs standard regimen EXCLAIM trial Enoxaparin 40mg SC daily for 28 days Vs placebo after 10 days of standard thromboprophylaxis Extended duration prophylaxis has significant reduction of VTE (2.5% Vs 4%) Significant increase in major bleeding events (0.8 Vs 0.3) Benefit observed in F, age >75, immobilized ADOPT trial Apixaban 2.5mg BID for 3 days Vs enoxaparin 40mg SC daily for 6-14 days Efficacy is not different (2.7% for apixaban group Vs 3.06% in enoxaparin group, RR 0.87, 95% CI 0.63-1.25) Major bleeding in apixaban group (0.47% Vs 0.19%, RR 2.58, 95% CI 1.02-7.24) MAGELLAN study Enoxaparin 40mg SC daily for 10 days followed by placebo Vs extended prophylaxis with rivaroxaban 10mg daily for 35 ± 4 days Efficacy outcome event less in Rivaroxaban group Safety outcome event more in rivaroxaban group Conclusion: routine administration of post-discharge prophylaxis is not likely to be beneficial to the patients admitted for medical illness Hull RD, Schellong SM, Tapson VF, et al. Extended-duration venous thromboembolism prophylaxis in acutely ill medical patients with recently reduced mobility: a randomized trial. Ann Intern Med 2010; 153:8. Goldhaber SZ, Leizorovicz A, Kakkar AK, et al. Apixaban versus enoxaparin for thromboprophylaxis in medically ill patients. N Engl J Med 2011; 365:2167. Cohen AT, Spiro TE, Büller HR, et al. Rivaroxaban for thromboprophylaxis in acutely ill medical patients. N Engl J Med 2013; 368:513. Sharma A, Chatterjee S, Lichstein E, Mukherjee D. Extended thromboprophylaxis for medically ill patients with decreased mobility: does it improve outcomes? J Thromb Haemost 2012; 10:2053. Albertsen IE, Larsen TB, Rasmussen LH, et al. Prevention of venous thromboembolism with new oral anticoagulants versus standard pharmacological treatment in acute medically ill patients: a systematic review and meta-analysis. Drugs 2012; 72:1755.

25. Warfarin Not recommended Anticoagulant effect is delayed Drug interactions with antibiotics and other drugs Achieving target INR difficult in hospitalized medical patients due to comorbidities (liver dysfunction)

26. Aspirin Reduces VTE by 20% Not recommended

27. Mechanical methods Indicated for patients with high risk of bleeding or have bleeding lesions like ICH, bleeding peptic ulcer Shift to pharmacologic methods as soon as possible Intermittent pneumatic compression (IPC ) Graduated compression stockings (GCS) Venous foot pump (VFP)

28. Intermittent pneumatic compression Enhance blood flow in the deep veins  prevent venous stasis Reduces plasminogen activator inhibitor-1 ( PAI-1)  increasing endogenous fibrinolytic activity Contraindication: ischemic PAD

29. Graduated compression stockings GCS in medical patients, with or without low dose low molecular weight (LMW) heparin , found no added mortality benefit with the use of LMW heparin Kakkar AK, Cimminiello C, Goldhaber SZ, et al. Low-molecular-weight heparin and mortality in acutely ill medical patients. N Engl J Med 2011; 365:2463.

30. Recommendations For hospitalized medical patients without obvious risk factors for VTE, we suggest that anticoagulation not be employed ( Grade 1B ) For most patients who are hospitalized with an acute medical illness, have at least one risk factor for VTE, and do not have an increased risk of bleeding, we recommend the use of prophylactic anticoagulation ( Grade 1B ) VTE prophylaxis should typically continue until the patient is discharged from the hospital. We suggest against extending the duration of thromboprophylaxis beyond the period of the acute hospital stay ( Grade 2B )