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1 Slide 1 Current Approaches to Venous Thromboembolism Prevention in Orthopedic Patients Hujefa Vora, MD Maria Fox, RN June 9, 2017 Slide 2 Slide 3 Outline of This Presentation Pathophysiology of venous thromboembolism (VTE) Problem Overview Surgical Risk Groups Primary VTE Prophylaxis Some Data What to discuss with your patients

2 Slide 4 What Is Deep Vein Thrombosis? Deep vein thrombosis is the formation of a blood clot in one of the deep veins of the body, usually in the leg. Three primary components of DVT are venous stasis, hypercoagulability, and endothelial injury Slide 5 Virchow s Triad Venous stasis Hypercoagulable state Endothelial damage Slide 6 Venous stasis prolonged bed rest (4 days or more) A cast on the leg Limb paralysis from stroke spinal cord injury extended travel in a vehicle

3 Slide 7 Hypercoagulability Surgery and trauma - 40% of all thromboembolic disease Malignancy increased estrogen Inherited disorders of coagulation -Deficiencies of protein-s, protein-c, anti-thrombin III. Acquired disorders of coagulation- Nephrotic syndrome, Anti-phospholipid antibodies Slide 8 Endothelial Injury Trauma Surgery Invasive procedure Iatrogenic causes central venous catheters Subclavian Internal jugular lines Slide 9 So this is what it looks like

4 Slide 10 The Coagulation Cascade Slide 11 Incidence US Healthcare Cost and Utilization Project estimated about 8 million surgical discharges in (Old data) Based on ACCP guidelines for risk stratification, 15, 24, and 17% were at moderate, high, or very high risk for VTE. 150 to 200 thousand hospital deaths per year due to pulmonary embolism, making this the most common preventable cause of hospital death. The Surgical Care Improvement Project (SCIP) and CMS consider VTE prophylaxis a core quality measure for this reason. Slide 12 Surgical Risk Assessment

5 Slide 13 Without prophylaxis the incidence of deep vein thrombosis is about 14% in gynecological surgery 22% in neurosurgery 26% in abdominal surgery 45%-60% in patients undergoing hip and knee surgeries. 15% to 40% Urologic surgery. Slide 14 Thromboprophylaxis in Major Orthopedic Surgery Major orthopedic surgery including total hip replacement (THR), total knee replacement (TKR), and hip fracture surgery carries a risk for venous thromboembolism (VTE). Without prophylaxis, historic data suggest deep vein thrombosis (DVT) occurs in percent of cases in the 7 14 days following surgery. With routine use of thromboprophylaxis, symptomatic VTE in patients within 3 months of surgery is approximately percent. Prophylactic strategies may decrease the risk of VTE, DVT, and pulmonary embolism. The main limitation of pharmacological VTE prophylaxis is the risk of bleeding, which historically occurs in 1 3 percent of THR and TKR surgeries. American Academy of Orthopaedic Surgeons. Guideline on preventing venous thromboembolic disease in patients undergoing elective hip and knee arthroplasty. Available at Slide 15 Preventing Venous Thromboembolic Events in Major Orthopedic Surgery Pharmacological Oral antiplatelet agents (Aspirin) Injectable low-molecular-weight heparins (Lovenox) Injectable unfractionated heparin Injectable or oral factor Xa inhibitors (Arixtra, Xarelto, Eliquis) Injectable or oral direct thrombin inhibitors (Desirudin, Angiomax, Pradaxa) Oral vitamin K antagonists (Warfarin) Mechanical modalities Graduated compression Intermittent pneumatic compression Venous foot pump Combinations of these

6 Slide 16 The Coagulation Cascade Slide 17 Establishing the Need for a Systematic Review of VTE Prophylaxis in Orthopedic Surgery The magnitude of benefit and harms in contemporary practice and evaluation of pharmacological agents or devices available within the United States amongst the orthopedic surgery population is not well known. Additionally, the influence of these factors in contemporary practice needs to be systematically evaluated: The impact of duration of prophylaxis on outcomes Whether dual prophylactic therapy is superior to singlemodality therapy The comparative effectiveness of different pharmacological or mechanical modalities The risks of VTE, PE, and DVT and the causal link between DVT and PE. American Academy of Orthopaedic Surgeons. Guideline on preventing venous thromboembolic disease in patients undergoing elective hip and knee arthroplasty. Available at Slide 18 Baseline Postoperative Risk of Venous Thromboembolism and Bleeding Outcomes in Contemporary Practice

7 Slide 19 Rating the Strength of Evidence From the Comparative Effectiveness Review The strength of evidence was classified into four broad categories: High There is high confidence that the evidence reflects the true effect. Further research is very unlikely to change our confidence in the estimate of effect. Moderate Low Insufficient Moderate confidence that the evidence reflects the true effect. Further research may change our confidence in the estimate of effect and may change the estimate. Low confidence that the evidence reflects the true effect. Further research is likely to change our confidence in the estimate of effect and is likely to change the estimate. Evidence either is unavailable or does not permit estimation of an effect. AHRQ. Methods Guide for Effectiveness and Comparative Effectiveness Reviews. April Available at products/60/318/methodsguide_prepublication-draft_ pdf. Slide 20 Baseline Postoperative Risks of VTE Outcomes in the Absence of Pharmacological Prophylaxis Most of the literature evaluated total hip and total knee replacement surgeries with very little evaluation of hip fracture surgery. The baseline risk of venous thromboembolism and bleeding outcomes in the absence of pharmacological prophylaxis are as follows: Outcome Pulmonary embolism Deep vein thrombosis Total Hip Replacement Strength of Evidence (THR) Total Knee Replacement 6% Low 1% Low 39% Low 46% Low Major bleeding 1% Moderate 3% Low Strength of Evidence (TKR) Minor bleeding 5% Low 5% Moderate Slide 21 Comparative Effectiveness of Pharmacological or Mechanical Thromboprophylaxis Versus No Thromboprophylaxis Pharmacological versus no pharmacological prophylaxis Mechanical versus no thromboprophylaxis

8 Slide 22 Comparative Effectiveness of Pharmacological Prophylaxis Versus No Pharmacological Prophylaxis Outcome Magnitude of Effect RR/OR (95% CI), Strength NNT/NNH of Evidence Moderate DVT Decreases risk by 44% RR 0.56 (0.47 to 0.68), NNT 3 to 33 Proximal DVT Decreased risk by 47% RR 0.53 (0.39 to 0.74), High NNT 4 to 213 Distal DVT Decreased risk by 41% RR 0.59 (0.42 to 0.82), High NNT 8 to 35 Asymptomatic DVT Decreased risk by 48% RR 0.52 (0.40 to 0.69), Moderate NNT 4 to 6 Symptomatic VTE NR Major VTE Decreased risk by 79% RR 0.21 (0.05 to 0.95), Low NNT 19 to 22 PE No difference OR 0.38 (0.13 to 1.07) Low Abbreviations: 95% CI = 95-percent confidence interval; NNH = number needed to harm (the calculated range); NNT = number needed to treat (the calculated range; NR = not reported or insufficient evidence to permit conclusions; OR = odds ratio; RR = relative risk Slide 23 Comparative Effectiveness of Pharmacological Prophylaxis Versus No Pharmacological Prophylaxis: Adverse Effects Outcome Magnitude of Effect RR/OR (95% CI), NNT/NNH Strength of Evidence Major Bleeding No difference RR 0.74 (0.36 to 1.51) Moderate Minor Bleeding Relative risk is higher for pharmacological prophylaxis by 67% RR 1.67 (1.18 to 2.38), NNH 30 to 75 Abbreviations: 95% CI = 95-percent confidence interval; NNH = number needed to harm; NNT = number needed to treat; OR = odds ratio; RR = relative risk High Slide 24 Comparative Effectiveness of Mechanical Prophylaxis Versus No Thromboprophylaxis Mechanical prophylaxis significantly decreased deep vein thrombosis (DVT; results from one randomized controlled trial; strength of evidence not rated). The risk for proximal or distal DVT was not significantly different (results from one randomized controlled trial; strength of evidence not rated). Data are not available to evaluate the comparative effect of mechanical prophylaxis versus no prophylaxis on other outcomes.

9 Slide 25 Comparative Effectiveness of Pharmacological and Mechanical Prophylaxis Agents Slide 26 Comparative Effectiveness of Pharmacological Prophylaxis Agents: LMWH Versus UFH Magnitude of Effect; Risk/Odds (95% CI), NNT/NNH (SOE) Comparators DVT Proximal DVT Symptomatic VTE PE Major Bleeding Minor Bleeding Heparininduced Thrombocytopenia LMWH Decreased Decreased NR Decreased Decreased odds No Decreased risk by 20%; risk by 40%; odds by by 35%; difference; odds by vs. UFH RR 0.80 (0.65 RR %; OR 0.57 (0.37 RR %; OR to 0.99), (0.38 to OR 0.48 to 0.88), (0.63 to 0.12 (0.03 NNT 12 to 0.93), (0.24 to NNT ) to 0.43), 100 NNT 14 to 0.95), (SOE = High) (SOE = NNT 34 to (SOE = 50 NNT 8 Moderate) 202 Moderate) (SOE = High) (SOE = (SOE = Moderate) Moderate) Abbreviations: 95% CI = 95-percent confidence interval; DVT = deep vein thrombosis; LMWH = low-molecular-weight heparin; major bleeding = for example, bleeding leading to greater transfusion requirements and/or reoperation; minor bleeding = for example, surgical site bleeding, bleeding leading to infection, or bleeding leading to transfusion but not reoperation; NNH = number needed to harm (the calculated range); NNT = number needed to treat (the calculated range); NR = not reported or insufficient evidence to permit conclusions; OR = odds ratio; PE = pulmonary embolism; RR = relative risk; SOE = strength of evidence rating; UFH = unfractionated heparin; VTE = venous thromboembolism LMWH=Lovenox UFH=unfractionated heparin Slide 27 Comparative Effectiveness of Pharmacological Prophylaxis Agents: Enoxaparin Versus Fondaparinux Magnitude of Effect; Risk/Odds (95% CI), NNT/NNH (SOE) Comparators DVT Proximal DVT Symptomati c VTE PE Major Bleeding Minor Bleeding Enoxaparin Relative Odds are No difference; No Decreased Decreased vs. risk is higher for OR 0.70 difference odds by odds by fondaparinux higher for enoxaparin (0.48 to 1.02) ; 35%; 43%; enoxaparin by 219%; (SOE = Low) OR 3.34 OR 0.65 OR 0.57 by 99%; OR 2.19 (0.58 to (0.48 to (0.35 to RR 1.99 (1.52 to 19.32) 0.89), 0.94), (1.57 to 3.16), (Not NNT 74 to NNT 31 to 2.51), NNH 44 to rated) NNH 13 to 122 (SOE = (SOE = Low) 26 (SOE = Low) Moderate) (SOE = Moderate) Abbreviations: 95% CI = 95-percent confidence interval; DVT = deep vein thrombosis; major bleeding = for example, bleeding leading to greater transfusion requirements and/or reoperation; minor bleeding = for example, surgical site bleeding, bleeding leading to infection, or bleeding leading to transfusion but not reoperation; NNH = number needed to harm (the calculated range); NNT = number needed to treat (the calculated range); OR = odds ratio; PE = pulmonary embolism; RR = relative risk; SOE = strength of evidence rating; VTE = venous thromboembolism LMWH=Lovenox Fondaparinux=Arixtra

10 Slide 28 Comparative Effectiveness of Pharmacological Prophylaxis Agents: LMWH Versus Warfarin Magnitude of Effect; Risk/Odds (95% CI), NNT/NNH (SOE) Comparators DVT Proximal Symptomatic PE Major Minor DVT VTE Bleeding Bleeding LMWH Decreased No No No difference; Odds are Relative risk is vs. warfarin risk difference; difference; OR 1.11 higher for higher for by 34%; RR 0.63 OR 1.00 (0.57 to 2.19) LMWH LMWH RR 0.66 (0.39 to (0.69 to 1.46) (SOE = by 92%; by 23%; (0.55 to 1.00) (SOE = Low) Moderate) OR 1.92 RR ), (SOE = (1.27 to (1.06 to 1.43), NNT 6 to 13 Low) 2.91), NNH 18 to 218 (SOE = Low) NNH 57 to (SOE = 220 Moderate) Abbreviations: 95% CI = 95-percent confidence interval; DVT = deep vein thrombosis; LMWH = low-molecular-weight (SOE = High) heparin; major bleeding = for example, bleeding leading to greater transfusion requirements and/or reoperation; minor bleeding = for example, surgical site bleeding, bleeding leading to infection, or bleeding leading to transfusion but not reoperation; NNH = number needed to harm (the calculated range); NNT = number needed to treat (the calculated range); OR = odds ratio; PE = pulmonary embolism; RR = relative risk; SOE = strength of evidence rating; VTE = venous thromboembolism Slide 29 Comparative Effectiveness of Pharmacological Prophylaxis Agents: UFH Versus Desirudin Magnitude of Effect; Risk/Odds (95% CI), NNT/NNH (SOE) Comparators DVT Proximal Symptomatic PE Major Minor DVT VTE Bleeding Bleeding UFH Relative risk is Odds are NR No difference; NR NR vs. higher for UFH higher for OR 3.23 desirudin by 231%; UFH by (0.56 to 18.98) RR %; (SOE = Low) (1.34 to 4.00), OR 4.74 NNH 5 to 11 (2.99 to (SOE = Moderate) 7.49), NNH 11 (SOE = Moderate) Abbreviations: 95% CI = 95-percent confidence interval; DVT = deep vein thrombosis; major bleeding = for example, bleeding leading to greater transfusion requirements and/or reoperation; minor bleeding = for example, surgical site bleeding, bleeding leading to infection, or bleeding leading to transfusion but not reoperation; NNH = number needed to harm (the calculated range); NR = not reported or insufficient evidence to permit conclusions; OR = odds ratio; PE = pulmonary embolism; RR = relative risk; SOE = strength of evidence rating; UFH = unfractionated heparin; VTE = venous thromboembolism UFH=unfractionated heparin Desirudin=Thrombin inhibitor Slide 30 Comparative Effectiveness of Pharmacological and Mechanical Prophylaxis Warfarin decreased the risk of proximal deep vein thrombosis (DVT) by 63 percent when compared with mechanical prophylaxis. Strength of Evidence = Moderate Patients on aspirin had higher rates of DVT when compared with those using only mechanical prophylaxis. Strength of Evidence = Moderate Pharmacological plus mechanical prophylaxis reduced the risk of DVT by 52 percent when compared with pharmacological prophylaxis alone. Strength of Evidence = Moderate

11 Slide 31 Comparative Effectiveness of Prolonged ( 28 Days) Versus Standard (7 10 Days) Pharmacological Prophylaxis Slide 32 Prolonged ( 28 Days) Versus Standard (7 10 Days) Pharmacological Prophylaxis: Clinical Outcomes Prolonged Versus Magnitude of Effect Risk/Odds (95% CI) NNT/NNH Strength Standard-Duration of Prophylaxis Evidence Symptomatic VTE Decreased RR 0.38 NNT 8 to 54 Moderate risk by 62% (0.19 to 0.77) PE Decreased OR 0.13 NNT 24 to High odds by 87% (0.04 to 0.47) 232 Nonfatal PE Decreased odds by OR 0.13 (0.03 to 0.54) NNT 58 Moderate 87% DVT Decreased risk by 63% RR 0.37 (0.21 to 0.64) NNT 5 to 32 Moderate Asymptomatic DVT Decreased risk by 52% RR 0.48 (0.31 to 0.75) NNT 8 to 65 High Symptomatic DVT Decreased odds by OR 0.36 (0.16 to 0.81) NNT 27 to 79 High 64% Proximal DVT Decreased RR 0.29 NNT 9 to 71 High risk by 71% (0.16 to 0.52) Slide 33 Prolonged ( 28 Days) Versus Standard (7 10 Days) Pharmacological Prophylaxis: Adverse Effects Prolonged Versus Standard-Duration Prophylaxis Magnitude of Effect Risk/Odds (95% CI) NNT/NNH Strength of Evidence Major Bleeding No difference OR 2.18 (0.73 to 6.51) Low Minor Bleeding Odds are higher for prolonged prophylaxis by 244% OR 2.44 (1.41 to 4.20) NNH 11 to 118 High Abbreviations: 95% CI = 95-percent confidence interval; major bleeding = for example, bleeding leading to greater transfusion requirements and/or reoperation; minor bleeding = for example, surgical site bleeding, bleeding leading to infection, or bleeding leading to transfusion but not reoperation; NNH = number needed to harm (the calculated range); NNT = number needed to treat (the calculated range); OR = odds ratio

12 Slide 34 Patient or Surgical Characteristics That May Affect the Risk of Venous Thromboembolism Slide 35 Characteristics That May Affect Risk of Venous Thromboembolism: Results Patients who receive general anesthesia may have a higher risk of deep vein thrombosis (DVT) than those who receive regional anesthesia; however, there were no differences in proximal or symptomatic DVT. Strength of Evidence = Low No difference in risk of DVT or proximal DVT was found among patients receiving cemented versus noncemented arthroplasty. Strength of Evidence = Low Observational data suggest that patients with congestive heart failure were at an increased risk for symptomatic, objectively confirmed venous thromboembolism when compared with those without it. Strength of Evidence = Moderate Slide 36 Spine Surgeries The Special Case Incidence of DVT varies according to length of procedures. Mechanical prophylaxis: SCDs reduce the incidence of thromboembolic complications. Pharmaceutical prophylaxis: No clearcut recommendations due to significant risk of post-operative bleeding and hematoma When to restart patients home medication blood thinners? Just ask the North American Spine Society

13 Slide 37 Summary of the RECORD Trials The oral direct factor Xa inhibitor, rivaroxaban, was approved by the FDA for preventing DVT, which may be associated with PE, in patients undergoing THR or TKR surgery. This decision was based, in part, on the findings of four phase III trials known as the Regulation of Coagulation in Orthopedic Surgery to Prevent Deep Venous Thrombosis and Pulmonary Embolism (RECORD) trials: RECORD 1, RECORD 2, RECORD 3, and RECORD 4. They compared various regimens of rivaroxaban and enoxaparin in THR or TKR surgery. The primary efficacy outcome was composite DVT, nonfatal PE, or all-cause mortality. The primary safety outcome was major bleeding. Enoxaparin=Lovenox Rivaroxaban=Xarelto Slide 38 Summary of Outcomes From the RECORD Trials RECORD 1 and 2 trials (THR): There was reduced risk of the primary efficacy outcome with prolonged rivaroxaban (started 6 8 hours postoperatively, for 35 4 days) when compared with enoxaparin given as either prolonged (started evening before surgery, for 36 4 days) or standardduration (started evening before surgery, for 13 2 days) prophylaxis. RECORD 1: The primary efficacy outcome occurred in 1.1 percent of patients given rivaroxaban and 3.7 percent of patients given enoxaparin (ARR = 2.6%; 95% CI, 1.5 to 3.7; P < 0.001). RECORD 2: The primary efficacy outcome occurred in 2.0 percent of patients given rivaroxaban and 9.3 percent of patients given enoxaparin (ARR = 7.3%; 95% CI, 5.2 to 9.4; P < ). RECORD 3 and 4 trials (TKR): Rivaroxaban decreased the risk of the primary efficacy outcome when compared with enoxaparin. RECORD 3: The primary efficacy outcome occurred in 9.6 percent of patients given rivaroxaban and 18.9 percent of patients given enoxaparin (ARR = 9.2%; 95% CI, 5.9 to 12.4; P < 0.001). RECORD 4: The primary efficacy outcome occurred in 6.9 percent of patients given rivaroxaban and in 10.1 percent of patients given enoxaparin (ARR = 3.19%, 95% CI, 0.71 to 5.67; P = ). In all four trials, there were no significant differences in the risk for the primary safety outcome of major bleeding or for the risks of mortality or minor bleeding outcomes. Slide 39 Summary of Conclusions Estimated native (i.e., without pharmacological prophylaxis) incidence of DVT after THR and TKR surgery was 39 percent and 46 percent, respectively. Pharmacological prophylaxis decreases the risk of DVT with some increased risk of minor bleeding when compared with no pharmacological prophylaxis. LMWH may decrease the risk for DVT when compared with warfarin at the expense of increases in major and minor bleeding. LMWH provides greater protection against DVT and PE when compared with unfractionated heparin while reducing the risk of bleeding and heparin-induced thrombocytopenia. LMWH was not as effective in protecting against the risk of DVT when compared with an injectable factor Xa inhibitor (Arixtra/fondaparinux), although the odds of bleeding were reduced. Prolonged prophylaxis decreased the risk of thromboembolism at the risk of increased minor bleeding when compared with standard-duration prophylaxis.

14 Slide 40 Don t we use a lot of Aspirin?? In Europe, Aspirin for DVT prophylaxis has been found to be more effective than LMWH for knee surgery, but not hip surgeries. Data is lacking, but as our surgical techniques and length of convalescence improve, aspirin has become an extremely cost effective option Slide 41 Gaps in Knowledge Inadequate data did not permit conclusions about the comparative benefits and adverse effects associated with VTE prophylaxis in non joint replacement surgery. More information is needed on the following aspects of VTE prophylaxis in the setting of major orthopedic surgery: Clinically important outcomes including symptomatic venous thromboembolism, post-thrombotic syndrome, clinically relevant bleeding, prosthetic infection, reoperation, and mortality and whether intermediate outcomes predict health outcomes Surgical, postsurgical, or patient factors that predict outcomes The optimal followup period needed to determine longer term outcomes Optimal duration of thromboprophylaxis The role of combined pharmacological and mechanical prophylaxis Slide 42 What To Discuss With Your Patients General background information on the risk of thromboembolic disease That thromboembolic disease is a major risk after joint replacement surgery and why some form of prophylactic treatment is indicated Options for prophylaxis Bleeding as the major risk of pharmacological prophylaxis Signs of a DVT

15 Slide 43 Presentation and Physical Examination Calf pain or tenderness, or both Swelling with pitting edema Increased skin temperature and fever Superficial venous dilatation Cyanosis can occur with severe obstruction Slide 44 Diagnostic Studies Clinical examination alone is able to confirm only 20-30% of cases of DVT Blood Tests The D-dimer Imaging Studies Ultrasound Doppler of lower extremities Phlebography Slide 45 D-dimer Specific degradation product of cross-linked fibrin. Because concurrent production and breakdown of clot characterize thrombosis, patients with thromboembolic disease have elevated levels of D-dimer. False-positive D-dimers occur in patients with recent (within 10 days) surgery or trauma, recent myocardial infarction or stroke, acute infection, disseminated intravascular coagulation, pregnancy or recent delivery, active collagen vascular disease, or metastatic cancer

16 Slide 46 Treatment Anticoagulation Thrombolytic therapy for DVT Surgery for DVT Filters for DVT Compression stockings Slide 47 Resource for Patients Preventing Blood Clots After Hip or Knee Replacement Surgery or Surgery for a Broken Hip, A Review of the Research for Adults is a free resource for patients. It can help patients talk with their health care professionals about the many options for treatment. It provides information about: Pharmacological options for preventing venous thromboembolism (VTE) Nonpharmacological options for preventing VTE Current evidence of effectiveness and harms associated with VTEprevention methods Questions for patients to ask their doctor