Preventing Hospital-Associated Thrombosis (HAT)

Preventing Hospital-Associated Thrombosis (HAT) Recommendations for extending venous thromboembolism (VTE) prophylaxis* beyond the immediate hospital stay *VTE prophylaxis consists of pharmacological and mechanical measures to diminish the risk of deep vein thrombosis (DVT) and pulmonary embolism (PE) 1 Image courtesy of James Heilman, MD Full prescribing information for Clexane is available on slide 13 Adverse events should be reported; adverse event reporting information for Clexane is available on slide 13 1. Lau BD et al. BMJ Qual Saf 2014; 23:187 95. 1

Pathogenesis of deep vein thrombosis formation and embolisation A common initial site for thrombus formation in the deep venous system of the leg is in venous valve pockets adjacent to the cusps 1 When a thrombus propagates, it expands and grows by proximal addition 1 Venous thrombi can become dislodged from their sites of formation in venous valve pockets 1, and the weak force of venous luminal blood flow can be sufficient to break the contact and the thrombus can embolise 2 a pulmonary embolism (PE) Development of a DVT The sequelae of DVT include postthrombotic syndrome (PTS) 2 PE is a serious complication of thrombosis that occurs when the blood clot escapes into the circulation and becomes lodged in the lungs. The pulmonary-artery obstruction seen with PE can cause death and disability 3 Development of a PE Long-term complications of PE include chronic thromboembolic pulmonary hypertension (CTEPH) 4 DVT, deep vein thrombosis; PE, pulmonary embolism 1. Sevitt S. Br J Surgery 1974; 61:641 49. 2. Malone PC. Medical Hypotheses 2016; 86:60 6. 3. Goldhaber SZ. Lancet 2004; 363:1295 305. 4. Piazza G, Goldhaber SJ. N Engl J Med 2011; 364:351 60. 2

Epidemiology of venous thromboembolism (VTE) VTE is a collective term for deep vein thrombosis (DVT) and pulmonary embolism (PE) The incidence of VTE is estimated to be 1 2 cases per 1000 population per year 1 PE is an important cause of in-hospital death 2 It is estimated that 60% of VTE cases are associated with surgery or hospitalisation 3 The Million Women Study showed the risk of VTE was greater for women with hospital admissions for surgical procedures compared to admissions without, and the risk was greatest in the third post-operative week 4 Given the duration of VTE risk after surgery, 4 VTE deaths are expected to occur after discharge from hospital VTE occurring in-hospital or within 90 days of discharge is called hospital-associated thrombosis (HAT) 5 VTE prophylaxis with anticoagulants can reduce the risk of HAT 2 NICE CG92 recommends VTE prophylaxis for appropriate hospitalised patients based on assessment of VTE and bleeding risk 2 For certain patients, based on an assessment of VTE and bleeding risk, VTE prophylaxis is recommended beyond the immediate hospital stay 2 1. Oger E. Thromb Haemost 2000; 83:657 69. 2. NICE. Venous thromboembolism: reducing the risk for patients in hospital. Clinical guideline [CG92]. Last updated: June 2015. 3. Spencer FA et al. Arch Intern Med 2007; 167:1471 5. 4. Sweetland S et al. BMJ 2009; 339:b4583. 5. NHS England. Root cause analysis. https://www.england.nhs.uk/patientsafety/venous-thromb/rca/ Accessed May 2017. 3

The risk of VTE after surgery is substantially increased in the first 12 postoperative weeks in middle aged UK women (Million Women Study) 1 Relative risk of VTE by time since inpatient surgery and since day case surgery Adapted from Sweetland et al, 2009 Relative risk for time without surgery = 1 947,454 women were included; 239,614 women (25%) had an operation, 149,355 as a day case and 90,259 as an inpatient Main outcome measure was adjusted relative risks (surgery vs no surgery) and standardised incidence rates for hospital admission or death from VTE Compared with incidence rates without surgery Women were 40.3 times more likely to develop VTE during the week after an inpatient operation Relative risk 40.3 (95% CI 30.7 to 52.8) Absolute risk 0.064% per week Women were 112 times more likely to develop VTE during the third postoperative week Relative risk 112.5 (95% CI 95.3 to 132.8) Absolute risk 0.18% per week The highest relative risk was after inpatient surgery for hip or knee replacement (weeks 1 6) Relative risk 220.6 (95% CI 187.8 to 259.2) Absolute risk 0.35% The overall pattern of relative risk was similar for PE and DVT as separate outcomes DVT, deep vein thrombosis; PE, pulmonary embolism; VTE, venous thromboembolism; AR, absolute risk; RR, relative risk 1. Sweetland S et al. BMJ 2009; 339:b4583. 4

Clexane (enoxaparin sodium) for VTE prophylaxis Therapeutic indications and posology 1 Clexane is indicated for: Prophylaxis of venous thromboembolic disease in moderate and high risk surgical patients, in particular those undergoing orthopaedic or general surgery including cancer surgery Prophylaxis of venous thromboembolic disease in medical patients with an acute illness (such as acute heart failure, respiratory insufficiency, severe infections or rheumatic diseases) and reduced mobility at increased risk of VTE Dose and duration of Clexane: In surgical patients at moderate risk of VTE 2,000 IU (20 mg) OD SC; preoperative initiation (2 h before surgery) was proven effective in moderate risk surgery For a minimal period of 7 to 10 days, whatever the recovery status (e.g. mobility) and continued until the patient no longer has significantly reduced mobility In surgical patients at high risk of VTE 4,000 IU (40 mg) OD SC preferably started 12 h before surgery For major orthopaedic surgery, an extended thromboprophylaxis up to 5 weeks is recommended For abdominal or pelvic surgery for cancer, an extended thromboprophylaxis up to 4 weeks is recommended In medical patients at increased risk of VTE 4,000 IU (40 mg) OD SC For at least 6 14 days whatever the recovery status (e.g. mobility) The benefit is not established for treatment longer than 14 days OD, once daily; SC, subcutaneous; h, hours; VTE, venous thromboembolism 1. Clexane Summary of Product Characteristics, April 2017. 5

NICE Clinical Guideline 92 Recommendations for VTE prophylaxis duration and discharge planning VTE, venous thromboembolism Elective hip replacement or hip fracture Offer combined VTE prophylaxis with mechanical and pharmacological methods Continue pharmacological VTE prophylaxis for 28 35 days Elective knee replacement Offer combined VTE prophylaxis with mechanical and pharmacological Continue pharmacological VTE prophylaxis for 10 14 days Cancer surgery Offer VTE prophylaxis to patients undergoing gynaecological, thoracic or urological surgery who are assessed to be at increased risk of VTE Extend pharmacological VTE prophylaxis to 28 days postoperatively for patients who have had major cancer surgery in the abdomen or pelvis Patient information and planning for discharge Ensure that patients who are discharged with pharmacological and/or mechanical VTE prophylaxis are able to use it correctly, or have arrangements made for someone to be available who will be able to help them Notify the patient's GP if the patient has been discharged with pharmacological and/or mechanical VTE prophylaxis to be used at home 1. NICE. Venous thromboembolism: reducing the risk for patients in hospital. Clinical guideline [CG92]. Last updated: June 2015. 6

What is best practice? NICE Quality Standard [QS3] 1 VTE, venous thromboembolism 1. NICE. Venous thromboembolism in adults: reducing the risk in hospital. Quality standard QS3. June 2010. 7

Extended-duration Clexane prophylaxis significantly reduces the frequency of VTE after total hip replacement 1,2 Hip replacement surgery 1 10 11 days of in-hospital Clexane 4,000 IU (40 mg) OD followed by 18 19 days of Clexane or placebo post-discharge* Hip replacement surgery 2 13 15 days of in-hospital LMWH followed by 21 days of Clexane 4,000 IU (40 mg) OD or placebo post-discharge* Major bleeding occurred in two Clexane-treated patients and in four patients in the placebo group; haematomas at the injection site occurred in one placebo-treated patient and six patients in the Clexane group LMWH, low molecular weight heparin; DVT, deep vein thrombosis; OD, once daily; OR, odds ratio; VTE, venous thromboembolism No major bleeding occurred; three minor bleeding episodes occurred with Clexane and one in the placebo group, but none led to study withdrawal * Patients were randomised to Clexane or placebo after the initial period of prophylaxis; treatment was double-blind 1. Bergqvist D et al. N Engl J Med 1996; 335:696 700. 2. Planes A et al. Lancet 1996; 348: 224 28. 8

The frequency of VTE after 8 12 days of prophylaxis after abdominal or pelvic cancer surgery remains substantial ENOXACAN I 1 8 12 days of prophylaxis OR = 0.78 (95% CI 0.51 1.19) Double-blind, multinational randomised trial Inclusion criteria Plan to undergo curative open surgery for abdominal or pelvic malignancy Age 40 years Duration of surgery 45 mins and hospitalisation 6 days Life expectancy at least 6 months Clexane 40 mg OD was equivalent to UFH TID in preventing VTE 14.7% vs. 18.2%, respectively, OR = 0.78 (95% CI 0.51 1.19) Major bleeding occurred in 2.9% (16/560) of patients receiving UFH and in 4.1% (23/555) of Clexane-treated patients (p = NS) UFH, unfractionated heparin; OD, once daily; OR, odds ratio; TID, three-times daily; VTE, venous thromboembolism The frequency of VTE in this study (14.7 18.2%) despite prophylaxis identified the need to investigate extended duration prophylaxis in this cancer surgery group 2 1. ENOXACAN Study Group. Br J Surg 1997; 84:1099 103. 2. Bergqvist D, et al. N Engl J Med 2002; 346:975 80. 9

Extending Clexane prophylaxis after surgery for abdominal or pelvic cancer significantly reduces the frequency of VTE ENOXACAN II 1 6 10 days of Clexane 4,000 IU (40 mg) OD followed by an additional 21 days of Clexane or placebo Randomised, double-blind, placebo-controlled, parallel-group, multinational trial Inclusion criteria Plan to undergo curative open surgery for abdominal malignancy Age 40 years Duration of surgery 45 minutes Life expectancy at least 6 months The significant reduction in VTE at the end of the double-blind phase with Clexane persisted at 3 months 13.8% vs. 5.5%, p = 0.01 There was no increase in major or minor bleeding with extended prophylaxis with Clexane vs placebo 0.4% vs 0%, p > 0.99 (major) 4.7% vs 3.6%, p = 0.66 (minor) OD, once daily; VTE, venous thromboembolism 1. Bergqvist D, et al. N Engl J Med 2002; 346:975 80. 10

Clexane (enoxaparin sodium) adverse event profile 1 MedDRA system organ class Very common ( 1/10) Common ( 1/100 to < 1/10) Uncommon ( 1/1000 to < 1/100) Rare ( 1/10,000 to <1/1,000) Very rare < 1/10,000 Blood and the lymphatic system disorders Haemorrhage; haemorrhagic anaemia; thrombocytopenia; thrombocytosis Eosinophilia; cases of immunoallergic thrombocytopenia with thrombosis Immune system disorders Allergic reaction Anaphylactic / anaphylactoid reactions including shock Nervous system disorders Headache Vascular disorders Spinal haematoma Hepato-biliary disorders Hepatic enzymes increases (mainly transaminases > 3xULN Hepatocellular liver injury Cholestatic liver injury Skin and subcutaneous tissue disorders Urticaria, pruritus, erythema Bullous dermatitis Alopecia; cutaneous vasculitis; skin necrosis; injection site nodules Musculoskeletal, connective tissue and bone disorders Osteoporosis following long term therapy (> 3 months) General disorders and administration site conditions Injection site haematoma; injection site pain; other injection site reaction Local irritation; skin necrosis at injection site Investigations Hyperkalaemia 1. Clexane Summary of Product Characteristics, April 2017. 11

Summary It is estimated that 60% of VTE cases are associated with surgery or hospitalisation 1 VTE that occurs in-hospital or within 90 days of discharge is called hospital-associated thrombosis (HAT) 2 VTE prophylaxis with anticoagulants can reduce the risk of HAT 3 NICE CG92 recommends VTE prophylaxis for hospitalised patients based on assessment of VTE and bleeding risk 3 For certain patients, based on an assessment of VTE and bleeding risk, VTE prophylaxis is recommended beyond the hospital stay Total hip replacement 3 Extending Clexane prophylaxis significantly reduces the incidence of VTE 4 NICE recommends continuing pharmacological VTE prophylaxis for 28 35 days Abdominal or pelvic cancer 3 Extending Clexane prophylaxis significantly reduces the incidence of VTE 5 NICE recommends extending pharmacological VTE prophylaxis to 28 days postoperatively VTE, venous thromboembolism 1. Spencer FA et al. Arch Intern Med 2007; 167:1471 5. 2. NHS England. Root cause analysis. https://www.england.nhs.uk/patientsafety/venous-thromb/rca/ Accessed May 2017. 3. NICE. Venous thromboembolism: reducing the risk for patients in hospital. Clinical guideline [CG92]. Last updated: June 2015. 4. Bergqvist D et al. N Engl J Med 1996; 335:696 700. 5. Bergqvist D, et al. N Engl J Med 2002; 346:975 80. 12

Clexane Syringes, Clexane Forte Syringes, and Clexane Multidose vial prescribing information Presentations. Clexane Syringes: single dose pre-filled syringes containing either: 2,000 IU (20 mg) enoxaparin sodium in 0.2 ml, 4,000 IU (40 mg) enoxaparin sodium in 0.4 ml, 6,000 IU (60 mg) enoxaparin sodium in 0.6 ml, 8,000 IU (80 mg) enoxaparin sodium in 0.8 ml or 10,000 IU (100 mg) enoxaparin sodium in 1ml. Clexane Forte Syringes: single dose pre-filled syringes containing either: 12,000IU (120 mg) enoxaparin sodium in 0.8 ml or 15,000 IU (150 mg) enoxaparin sodium in 1 ml. Clexane Multidose vial: Vial containing 30,000 IU (300 mg) enoxaparin sodium in 3.0 ml solution for injection for single patient use. Indications. In adults for: prophylaxis of venous thromboembolic disease in moderate and high risk surgical patients, in particular those undergoing orthopaedic or general surgery including cancer surgery; prophylaxis of venous thromboembolic disease in medical patients with an acute illness and reduced mobility at increased risk of venous thromboembolism (VTE); treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), excluding PE likely to require thrombolytic therapy or surgery; prevention of thrombus formation in extra corporeal circulation during haemodialysis; in adults for the following acute coronary syndromes: treatment of unstable angina and non ST-segment elevation myocardial infarction (NSTEMI), in combination with oral acetylsalicylic acid; treatment of acute ST-segment elevation myocardial infarction (STEMI) including patients to be managed medically or with subsequent percutaneous coronary intervention (PCI). Dosage & Administration. Prophylaxis in Surgical Patients: With moderate risk of thromboembolism, recommended dose of enoxaparin sodium is 2,000 IU (20 mg) once daily by subcutaneous (SC) injection. Initiation 2 hours before surgery was proven effective and safe in moderate risk surgery. Treatment should be maintained for at least 7-10 days and until the patient no longer has significantly reduced mobility. In patients at high risk of thromboembolism, the recommended dose of enoxaparin sodium is 4,000 IU (40 mg) once daily by SC injection preferably started 12 hours before surgery. If there is a need for earlier than 12 hours enoxaparin sodium preoperative prophylactic initiation (e.g. high risk patient waiting for a deferred orthopaedic surgery), the last injection should be administered no later than 12 hours prior to surgery and resumed 12 hours after surgery. For patients undergoing major orthopaedic surgery an extended thromboprophylaxis up to 5 weeks is recommended. For patients with high risk of VTE undergoing abdominal or pelvic surgery for cancer, extended thromboprophylaxis up to 4 weeks is recommended. Prophylaxis in Medical Patients: Recommended dose of enoxaparin sodium is 4,000 IU (40 mg) once daily by SC injection. Treatment with enoxaparin sodium is prescribed for at least 6 to 14 days. Benefit is not established for treatment longer than 14 days. Treatment of VTE: 50 IU/kg (1.5 mg/kg) administered SC once-daily should be used in uncomplicated patients with low risk of VTE recurrence. 100 IU/kg (1 mg/kg) twicedaily should be used in all other patients such as those with obesity, symptomatic PE, cancer, recurrent VTE or proximal (vena iliaca) thrombosis. The regimen should be selected based on individual assessment including evaluation of the thromboembolic risk and risk of bleeding. Enoxaparin sodium treatment is prescribed for an average period of 10 days. Oral anticoagulant therapy should be initiated when appropriate. Treatment of Acute Coronary Syndromes: For treatment of unstable angina and NSTEMI, the recommended dose of enoxaparin sodium is 100 IU/kg (1 mg/kg) every 12 hours by SC injection administered in combination with antiplatelet therapy. Treatment should be for a minimum of 2 days and until clinical stabilization (usual duration 2 to 8 days). Acetylsalicylic acid recommended for all patients without contraindications at an initial oral loading dose of 150 300 mg (in acetylsalicylic acid-naive patients) and a maintenance dose of 75 325 mg/day long-term. For treatment of acute STEMI, recommended dose of enoxaparin sodium is a single intravenous (IV) bolus of 3,000 IU (30 mg) plus a 100 IU/kg (1 mg/kg) SC dose followed by 100 IU/kg (1 mg/kg) administered SC every 12 hours (maximum 10,000 IU (100 mg) for each of the first two SC doses). Appropriate antiplatelet therapy such as oral acetylsalicylic acid (75 mg to 325 mg once daily) should be administered concomitantly unless contraindicated. Recommended duration of treatment is 8 days or until hospital discharge. When administered in conjunction with a thrombolytic (fibrin specific or nonfibrin specific), enoxaparin sodium should be given between 15 minutes before and 30 minutes after the start of fibrinolytic therapy. For patients managed with PCI, if the last dose of enoxaparin sodium SC was given less than 8 hours before balloon inflation, no additional dosing needed. If the last SC administration was given more than 8 hours before balloon inflation, an IV bolus of 30 IU/kg (0.3 mg/kg) enoxaparin sodium should be administered. During haemodialysis: 1 mg/kg (100 IU/kg) Clexane introduced into arterial line of the circuit at beginning of dialysis. This dose is usually sufficient for a 4 hour session. If fibrin rings are found, e.g. after a longer session, a further 0.5 to 1mg/kg (50 to 100 IU/kg) may be given. In patients with high risk of haemorrhage reduce the dose to 0.5mg/kg (50 IU/kg) (double vascular access) or 0.75 mg/kg (75 IU/kg) (single vascular access). Elderly: For treatment of acute STEMI in elderly patients 75 years of age, an initial IV bolus must not be used. Initiate dosing with 75 IU/kg (0.75 mg/kg) SC every 12 hours (maximum 7,500 IU (75 mg) for each of the first two SC doses only, followed by 75 IU/kg (0.75 mg/kg) SC dosing for the remaining doses). Children: Safety and efficacy not established. Renal impairment: Not recommended for patients with end stage renal disease Dosage adjustment required for patients with severe renal impairment. Hepatic Impairment: Limited data in this population therefore caution should be used. Contraindications. Hypersensitivity to enoxaparin sodium, heparin or its derivatives, including low molecular weight heparins (LMWH) or any of the excipients. Recent (<100 days) history of immune mediated heparin-induced thrombocytopenia (HIT) or in the presence of circulating antibodies. Active clinically significant bleeding and conditions with a high risk of haemorrhage, including recent haemorrhagic stroke, gastrointestinal ulcer, presence of malignant neoplasm at high risk of bleeding, recent brain, spinal or ophthalmic surgery, known or suspected oesophageal varices, arteriovenous malformations, vascular aneurysms or major intraspinal or intracerebral vascular abnormalities. Multiple dose vials containing benzyl alcohol: Hypersensitivity to benzyl alcohol. Newborns or premature neonates. Warnings and Precautions. Do not use interchangeably (unit for unit) with other LMWHs. Use with extreme caution in patients with a history (>100 days) of HIT without circulating antibodies, only after careful benefitrisk assessment and after non-heparin alternative treatments are considered; platelet counts should be measured before and regularly thereafter during the treatment and patients should be warned of symptoms. Use with caution in conditions with increased potential for bleeding (e.g. impaired haemostasis, history of peptic ulcer, recent ischemic stroke, severe arterial hypertension, recent diabetic retinopathy, neuro- or ophthalmologic surgery). Increases in activated partial thromboplastin time (aptt), and activated clotting time (ACT) may occur at higher doses but not linearly correlated with dose. Spinal/epidural anaesthesia or lumbar puncture must not be performed within 24 hours of administration of therapeutic doses of enoxaparin sodium; placement or removal of an epidural catheter or lumbar puncture is best performed when the anticoagulant effect of enoxaparin sodium is low. Skin necrosis and cutaneous vasculitis have been reported with LMWHs and should lead to prompt treatment discontinuation. Following vascular instrumentation during the treatment of unstable angina, NSTEMI and acute STEMI: adhere precisely to the recommended dosing intervals; in case a closure device is used, the sheath can be removed immediately; If a manual compression method is used, sheath should be removed 6 hours after the last IV/SC enoxaparin sodium injection; The site should be observed for signs of bleeding or hematoma. Use of heparin is usually not recommended in patients with acute infective endocarditis. Enoxaparin sodium has not been adequately studied for thromboprophylaxis in patients (including in pregnancy) with mechanical prosthetic heart valves. Elderly patients may be at increased risk of bleeding at treatment doses. Low body weight patients are at increased risk of bleeding at prophylactic and treatment dose ranges. Obese patients are at higher risk for thromboembolism however there is no consensus for dose adjustment; these patients should be observed carefully. Heparins can suppress adrenal secretion of aldosterone leading to hyperkalaemia, particularly in patients such as those with diabetes mellitus, chronic renal failure, pre-existing metabolic acidosis, taking medicinal products known to increase potassium; plasma potassium should be monitored regularly especially in patients at risk. Pregnancy. Enoxaparin sodium should be used during pregnancy only if the physician has established a clear need. As benzyl alcohol may cross the placenta, it is recommended to use a formulation that does not contain benzyl alcohol. Interactions. Not Recommended: Systemic salicylates, acetylsalicylic acid at anti-inflammatory doses, and NSAIDs including ketorolac. Other thrombolytics (e.g. alteplase, reteplase, streptokinase, tenecteplase, urokinase) and anticoagulants. Caution: Platelet aggregation inhibitors including acetylsalicylic acid used at anti-aggregant dose (cardioprotection), clopidogrel, ticlopidine, and glycoprotein IIb/IIIa antagonists indicated in acute coronary syndrome due to the risk of bleeding. Dextran 40. Systemic glucocorticoids. Medicinal products increasing potassium levels. Adverse Reactions. Very Common: Hepatic enzyme increases (mainly transaminases > 3 times the upper limit of normality), haemorrhage, thrombocytosis (platelet increase >400 G/L). Common: haemorrhagic anaemia, thrombocytopenia, allergic reaction, headache, urticarial, pruritus, erythema, injection site haematoma / pain / other reaction (such as oedema, haemorrhage, hypersensitivity, inflammation, mass, pain, or reaction). Uncommon: hepatocellular liver injury, skin necrosis at injection site, intracranial haemorrhage. Rare: Retroperitoneal haemorrhage, eosinophilia, cases of immuno-allergic thrombocytopenia with thrombosis (in some cases thrombosis was complicated by organ infarction or limb ischaemia), anaphylactic/anaphylactoid reactions including shock, spinal/neuraxial haematoma resulting in varying degrees of neurologic injuries including long-term or permanent paralysis, cholestatic liver injury, Osteoporosis following therapy > 3 months, hyperkalaemia. For a full list of undesirable effects please refer to the Summaries of Product Characteristics. Pharmaceutical Precautions. Do not mix with other products. Do not store above 25 C. Do not refrigerate or freeze. The contents of the multidose vial should be used within 28 days of opening. Legal Category. POM; PL 04425/0187: Clexane Syringes; PL04425/0185: Clexane Forte Syringes; PL 04425/0186: Clexane Multidose Vials Basic NHS cost for 10 pre-filled syringes. 2,000 IU - 20.86, 4,000 IU - 30.27, 6,000 IU - 39.26, 8,000 IU - 55.13, 10,000 IU - 72.30, 12,000 IU - 87.93, 15,000 IU - 99.91, Basic NHS cost for one Multidose Vial - 21.33. Date of Revision. May 2017 denotes a Registered Trade Mark. Further information is available on request from Sanofi, One Onslow St, Guildford, Surrey, GU1 4SY 0845 372 7101. Adverse events should be reported. Reporting forms and information can be found at www.mhra.gov.uk/yellowcard Adverse events should also be reported to the Sanofi Drug Safety Department on 0800 0902314. 13