Diagnosis and Management of Venous Thromboembolism

Transcription

1 Diagnosis and Management of Venous Thromboembolism Muhammad Sajid Pervaiz Consultant Haematologist Chairman VTE committee Pennine Acute Hospitals NHS trust

2 TOPICS 1-Introduction (Seriousness of problem) 2- VTE diagnosis, treatment and guidelines overview 3-Case Studies 4- Navigating the evidence in VTE including NOAC clinical trials

3 Introduction to venous thromboembolism (Seriousness of problem)

4 VTE is a serious medical problem DVT is a common disease, often asymptomatic, presenting in about 1.6 per 1,000 people/year 1 VTE causes an estimated 60,000 deaths each year in the UK 2 Incidence rises with 3 : Age incidence ~ 1/100 in patients >80 years Obesity 2 3 fold in BMI>30 kg/m 3 Hospitalisation 10-fold Complications include PE 3 PE often results from asymptomatic DVT and may present with clinical complications, even death 3 Fatal PE is under diagnosed because of non specificity of symptoms 3 About 10% of hospital deaths were attributed to PE in the UK 3,4 Non-fatal PE may delay discharge or require readmission to hospital 3 It is estimated that a similar proportion of VTE events occur in hospital and in the community 5 60,000 40,000 20,000 0 Estimated number of deaths in the UK per year (2010) ,167 VTE 2, Traffic accidents MRSA HIV 1. Khan et al. Dinajpur Med Col J 2014 Jan; 7 (1):52 59; 2. Report of the Independent Group on the Prevention of VTE in Hospitalised Patients. Department of Health 2007; 3.SIGN Guideline 122 Prevention and management of venous thromboembolism; 4. Sandler et al. J R Soc Med 1989; 82:203 5; 5.Select committee on health PP-ELI-GBR-0032 Date of preparation: May 2016 /cm200405/cmselect/cmhealth/99/99we07.htm. Last accessed March 2016; 6. Eurostat 7. Office for National Statistics Last accessed March 2016; 8. Cohen et al. Thromb Haemost 2007;98:756 64; 9. Office for National Statistics Last accessed March 2016.

5 Risk factors for VTE 1 Active cancer or cancer treatment Critical care admission Risk factors for VTE include: Age over 60 years Dehydration Known thrombophilias Obesity (BMI over 30 kg/m 2 ) One or more significant medical comorbidities (e.g. heart disease; metabolic, endocrine or respiratory pathologies; acute infectious diseases; inflammatory conditions) Use of hormone replacement therapy Varicose veins with phlebitis A surgical procedure with a total anaesthetic and surgical time of more than 90 minutes, or 60 minutes if the surgery involves the pelvis or lower limb Personal history or first-degree relative with a history of VTE Use of oestrogen-containing contraceptive therapy Pregnancy Acute surgical admission with inflammatory or intra-abdominal condition BMI, body mass index PP-ELI-GBR-0032 Date of preparation: May NICE clinical guideline (CG92). Venous thromboembolism: reducing the risk for patients in hospital. January 2010.

6 Provoked vs unprovoked VTE Provoked VTE With an antecedent (within 3 months) and transient major clinical risk factor for VTE for example, surgery, trauma, significant immobility (being bedbound, unable to walk unaided or likely to spend a substantial proportion of the day in bed or in a chair), pregnancy or puerperium, or Undergoing hormonal therapy (oral contraceptive or hormone replacement therapy) Unprovoked VTE With no antecedent major clinical risk factor for VTE, who is not having hormonal therapy (oral contraceptive or hormone replacement therapy) or With no active cancer PP-ELI-GBR-0032 Date of preparation: May NICE clinical guideline (CG144). Venous thromboembolic diseases: diagnosis, management and thrombophilia testing. July 2012.

7 VTE is associated with significant morbidity and mortality Morbidity Without extended treatment after unprovoked VTE, a recurrence may occur in: 1 11% of patients after 1 year 29.1% of patients after 5 years VTE is associated with longterm, clinically significant complications, including post-thrombotic syndrome and chronic thromboembolic pulmonary hypertension 2 Mortality Nearly 550,000 annual deaths due to VTE across the EU 3 PE may be responsible for 1 in ~10 hospital deaths 4 Mortality Pre-Hospital is still around 25% PP-ELI-GBR-0032 Date of preparation: May Prandoni et al. Haematologica 2007;92: ; 2. Palareti. Scientifica 2012;2012:1 17; 3. Cohen et al. Thromb Haemost 2007;98: ; 4. Geerts et al. Chest 2004;126(3 Suppl):338S 400S.

8 VTE risk increases with age 800 Overall incidence rate of first VTE: [95% CI ( )] per 100,000 person-years 58.1 % are unprovoked VTE IR of first VTE per 100,000 (years) Male Female IR, incidence rate; CI, confidence interval 0 < >89 Age (years) Adapted from Martinez et al Population-based cohort study of 35,373 patients with a first VTE event in the UK between 2001 and 2011 (26.9 million person-years of observation) PP-ELI-GBR-0032 Date of preparation: May Martinez et al. Thromb Haem 2014;112:

9 Secondary complications of VTE Post-thrombotic syndrome (PTS) 1 Can occur within 1 2 years after DVT in 20% to 50% of all patients Severe PTS occurs in 25 33% of patients with PTS Can lead to deep vein insufficiency and leg ulcers Chronic thromboembolic pulmonary hypertension (CTPH) Can occur after PE and is associated with significant morbidity and mortality 2 Incidence of CTPH after an acute episode of PE 3 1.0% at 6 months 3.1% at 1 year 3.8% at 2 years PP-ELI-GBR-0032 Date of preparation: May Kahn SR, Ginsberg JS. Arch Intern Med 2004;164:17 26; 2. McNeil K, Dunning J. Heart 2007;93:1152 8; 3. Pengo V et al. N Engl J Med 2004;350(22):

10 The risk of recurrent VTE is high Risk factors associated with VTE recurrence Adapted from Martinez et al Idiopathic presentation 2,3 Thrombophilia 2 Presentation of primary DVT 2 Cancer 3 Residual thrombus mass 4 Proximal DVT 3,5 Increasing age 2,5 Male gender 5 D-dimer 5 These were patients without active cancer 1 PP-ELI-GBR-0032 Date of preparation: May Martinez et al. Thromb Haem 2014;112: ; 2. Prandoni et al. Haematologica 2007;92: ; 3. Hansson et al. Arch Intern Med 2000;160: ; 4. Prandoni et al. Ann Intern Med 2002;137: ; 5. Eichinger et al. Circulation 2010;121:

11 Higher recurrence rates in unprovoked VTE Cumulative incidence of recurrent VTE (%) % 20.5% p< Provoked VTE Unprovoked VTE Years after first VTE Data from patients with non-active cancer Adapted from Martinez et al PP-ELI-GBR-0032 Date of preparation: May Martinez et al. Thromb Haem 2014;112:

12 key learning points VTE is a significant public health burden it causes an estimated 60,000 deaths per year in the UK 1 Risk of VTE increases with age and is higher in women 2 Risk of recurrent VTE remains elevated for up to 4 years following the first event, and is higher in unprovoked VTE 2 Implementation of appropriate VTE prophylaxis is a high priority given the high mortality rate associated with VTE in the EU PP-ELI-GBR-0032 Date of preparation: May Report of the Independent Group on the Prevention of VTE in Hospitalised Patients. Department of Health 2007; Martinez et al. Thromb Haem 2014;112:

13 VTE diagnosis, treatment and guidelines overview

14 Approaches to Diagnosis of DVT Patient History Clinical Symptoms and Signs Clinical Probability Score Laboratory Testing Imaging Testing PP-ELI-GBR-0032 Date of preparation: May 2016

15 Clinical Signs and Symptoms of DVT Leg pain (90%) Tenderness (85%) Ankle oedema (76%) Calf swelling (42%) Dilated veins (33%) Homan s sign (33%) (sharp pain in the calf on dorsiflexion of the foot) PP-ELI-GBR-0032 Date of preparation: May 2016

16 Clinical Signs and Symptoms of DVT (cont d) DVT cannot be reliably diagnosed on the basis of history and physical exam, even in high-risk patients. Patients with lower extremity DVT often do not exhibit erythema, warmth, swelling, or tenderness Symptoms in surgical patients are often masked by common post operative pain and limb swelling When present, these findings merit further evaluation despite lack of specificity PP-ELI-GBR-0032 Date of preparation: May 2016

17 Diagnostic Algorithms Clinical diagnosis of DVT is non-specific because none of the signs in isolation are particular to the disease In symptomatic patients, clinical pre-test models can be used to determine probability of DVT or PE PP-ELI-GBR-0032 Date of preparation: May 2016

18 VTE diagnosis Deep vein thrombosis (DVT) 1,2 Pulmonary embolism (PE) 2,3 D-dimer measurements Two-level DVT Wells score Venous ultrasonography Contrast venography D-dimer has a high falsepositive rate Sensitive but nonspecific also increased in other conditions: cancer, inflammation, postoperatively, Image by Hellerhoff (Own work) [CC-BY-SA-3.0 ( or GFDL ( via Wikimedia Commons injury, pregnancy. Geneva Score/PERC PESI Score (OP) ECG Chest radiograph CT angiogram Ventilation-perfusion (V/Q) scan 4 Pulmonary angiogram Bates SM et al. Chest 2012;141(2 Suppl):e351S e418s; 2. NICE clinical guideline (CG144) 2. Venous thromboembolic diseases: the management of venous thromboembolic diseases and the role of thrombophilia testing. June 2012; 3. Tapson VF. N Engl J Med 2008;358: ; 4. Schümichen C. Respiration 2003;70(4):

19 Venous system in lower limbs PROXIMAL VEINS DISTAL VEINS

20 DVT PATHWAY PP-ELI-GBR-0032 Date of preparation: May 2016

21 Geneva score and PERC rule

22 Four Goals of VTE Treatment 1.Prevent fatal PE 2.Reduce morbidity associated with acute leg or lung thrombus 3.Prevent recurrent VTE 4.Prevent long-term sequelae PP-ELI-GBR-0032 Date of preparation: May 2016

23 DVT Confirmed 1.Full medical assessment to consider underlying pathology including breast examination in women over 30yrs of age and rectal examination if indicated by symptoms. 2. If PV examination is necessary this will be highlighted in the discharge letter as the DVT clinic is not a suitable environment for this to occur. 3. Full blood screen including : FBC, Ferritin, U+E/ egfr, LFT, Baseline Coag and INR, Bone profile, Urine dipstick (and Pregnancy test in women of child bearing age) CXR in unprovoked DVT PSA if required (following PR examination/if prostatic symptoms) Tumour markers if abdominal symptoms/signs.

24 Malignancy 10% Unprovoked DVT / PE present with cancer within 1 year A Presenting sign in: Pancreatic cancer Prostate cancer Late sign in: Breast cancer Lung cancer Uterine cancer Brain cancer

25 Investigations for cancer Offer all patients diagnosed with unprovoked DVT or PE who are not already known to have cancer the following investigations for cancer: a physical examination (guided by the patient's full history) and a chest X-ray and blood tests (full blood count, serum calcium and liver function tests) and urinalysis. Consider Further investigations for cancer with an abdomino-pelvic CT scan (and a mammogram for women) in all patients aged over 40 years with a first unprovoked DVT or PE who do not have signs or symptoms of cancer based on initial investigation (see 'Investigations for cancer' above).

26 Phases of anticoagulation treatment for DVT and PE Initial 1 (0 to ~7 days) Long-term (~7 days to ~3 6 months) Extended (~3 6 months to indefinite) Parenteral* VKA or other agent Risk of recurrent VTE Start of treatment and secondary prevention 2 Treatment Secondary prevention Time since starting treatment Completion of active treatment LMWH, low molecular weight heparin; NOACs, non-vka oral anticoagulants. * Heparin, LMWH, fondaparinux. Where approved, initial therapy may be with oral rivaroxaban or apixaban Includes LMWH and NOACs Created from Kearon et al ,2 PP-ELI-GBR-0033 Date of preparation: May Kearon et al. Chest 2012;141(2 Suppl):e419s e494s; 2. Kearon. J Thromb Haemost 2012;10:

27 1 st Provoked DVT Surgery past 12 weeks Lower limb fracture Lower limb in plaster Pregnant Post partum up to 12 weeks (Travel / COCP / HRT) 1 st Unprovoked DVT Recurrent DVT Distal DVT (below knee) Proximal DVT (above knee) Distal DVT (below knee) Proximal DVT (above knee) Anticoagulate 3 months Anticoagulate 3 months If no family history DVT / PE Discharge at end of treatment If family history DVT / PE Thrombosis Clinic Follow up at 3 months

28 Traditional approaches of Anticoagulation Heparin Minimum of 5 days Until INR > 2 on at least 2 occasions Warfarin PE Idiopathic proximal DVT Idiopathic distal DVT Provoked distal DVT Recurrent DVT / PE minimum 3 months minimum 3 months 3 months 3 months long term

29 New approaches to anticoagulation Vitamin K antagonists (VKAs) and ODIs Initiation VKA X TF VIIa VII IX VKA Propagation Xa IXa II VKA Inactive factor Active factor Transformation Catalysis RIVAROXABAN APIXABAN EDOXABAN IIa DABIGATRAN Clot formation Fibrinogen Fibrin

30 Current clinical challenges of VTE treatment 1,2 Advantages Disadvantages VKA Mainstay of long-term therapy since Can be used in patients with severe renal impairment 2 Anticoagulation can be reversed 2 Slow onset/offset requires bridging 1 Numerous interactions with other drugs and food 1 Narrow therapeutic window 1 Inter-individual variability in dose response 1 Need for INR monitoring 1,2 NOACs Predictable pharmacological profiles 1 Absence of major interactions with food or other drugs 1 Do not require routine INR monitoring 1 May shift practice to longer treatment duration 1 No readily available monitoring for special circumstances (e.g. major bleeding, urgent procedure) No long term data PP-ELI-GBR-0033 Date of preparation: May Van Es J et al. J Thromb Haemost 2011;9:265 74; 2. Warfarin SmPC. Available at

31 Safety analysis of pooled NOAC data vs VKA in VTE treatment 1 Intracranial, major gastrointestinal, fatal and clinically relevant non-major bleeding Pooled NOAC (n/n) Pooled VKA (n/n) Risk ratio (95% CI) P value ARR (95% CI) Intracranial bleeding 15/13477 (0.1%) 43/13481 (0.3%) 0.37 ( ) % (-0.30% to -0.03%) Fatal bleeding 7/13477 (0.1%) 22/13481 (0.2%) 0.35 ( ) % (-0.16% to -0.01%) Major GI bleeding 63/13477 (0.5%) 76/13481 (0.6%) 0.78 ( ) % (-0.37% to 0.13%) CRNM bleeding 854/13477 (6.3%) 1103/13481 (8.0%) 0.73 ( ) % (-3.24% to -0.52%) 0.1 Favours NOAC 1 Favours VKA 10 Adapted from Van Es et al There are no head-to-head studies between these agents. There are limitations such as differing patient populations, designs and outcomes, and caution should therefore be exercised when interpreting these findings. No conclusions about the relative efficacy or safety of any of these agents should be drawn from these data. Please refer to individual product SmPCs for further information ARR: absolute risk reduction; CRNM: clinically relevant nonmajor; GI: gastrointestinal; NOAC: non-vka oral anticoagulant; RR: relative risk; VKA: vitamin K antagonist. PP-ELI-GBR-0032 Date of preparation: May Van Es et al. Blood. 2014:

32 NICE technology appraisal guidance on NOACs in VTE Apixaban Recommended as an option for treating and for preventing recurrent deep vein thrombosis and pulmonary embolism in adults 1 Recommended as an option for the prevention of venous thromboembolism in adults after elective hip or knee replacement surgery 2 Rivaroxaban Recommended as an option for treating deep vein thrombosis and preventing recurrent deep vein thrombosis and pulmonary embolism after a diagnosis of acute deep vein thrombosis in adults 3 Recommended as an option for treating pulmonary embolism and preventing recurrent deep vein thrombosis and pulmonary embolism in adults 4 Recommended as an option for the prevention of venous thromboembolism in adults having elective total hip replacement surgery or elective total knee replacement surgery 5 Dabigatran Recommended as an option for the primary prevention of venous thromboembolic events in adults who have undergone elective total hip replacement surgery or elective total knee replacement surgery 6 Recommended as an option for treating and for preventing recurrent deep vein thrombosis and pulmonary embolism in adults 7 Edoxaban Recommended as an option for treating and for preventing recurrent deep vein thrombosis and pulmonary embolism in adults 8 PP-ELI-GBR-0033 Date of preparation: May NICE technology appraisal guidance (TA341). Apixaban for the treatment and secondary prevention of deep vein thrombosis and/or pulmonary embolism. June 2015; 2. NICE technology appraisal guidance (TA245). Apixaban for the prevention of venous thromboembolismafter total hip or knee replacement in adults. January 2012; 3. NICE technology appraisal guidance (TA261). Rivaroxaban for the treatment of deep vein thrombosis and prevention of recurrent deep vein thrombosis and pulmonary embolism. July 2012; 4. NICE technology appraisal guidance (TA287). Rivaroxaban for treating pulmonary embolism and preventing recurrent venous thromboembolism. June 2013; 5. NICE technology appraisal guidance (TA170). Rivaroxaban for the prevention of venous thromboembolism after total hip or total knee replacement in adults. April 2009; 6. NICE technology appraisal guidance (TA157). Dabigatran etexilate for the prevention of venous thromboembolism after hip or knee replacement surgery in adults. September 2008; 7. NICE technology appraisal guidance (TA327). Dabigatran etexilate for the treatment and secondary prevention of deep vein thrombosis and/or pulmonary embolism. December 2014; 8. NICE technology appraisal guidance (TA354). Edoxaban for treating and for preventing deep vein thrombosis and pulmonary embolism. August 2015.

33 Patients with VTE who should be treated for 3 months and who should be treated indefinitely. Clive Kearon, and Elie A. Akl Blood 2014;123: by American Society of Hematology

34 key learning points The mainstay of VTE treatment is oral anticoagulation 1 Tailored treatment strategies for anticoagulant treatments for VTE consider aetiology, risk, benefit, cost, and patient preference 1 Anticoagulant therapy for VTE has an 'active treatment' phase of approximately 3 months 2 Once the initial thrombosis has been adequately treated, further anticoagulation serves as 'secondary prevention' of recurrent VTE 2 NICE and SIGN guidelines provide a framework to support the treatment of VTE and prevention of recurrent VTE 3,4 1. Wells et al. JAMA. 2014;311:717 28; 2. Kearon C. J Thromb Haemost. 2012;10:507 11; PP-ELI-GBR-0033 Date of preparation: 2. May 3. NICE 2016 guidelines (CG144). Venous thromboembolic diseases: the management of venous thromboembolic diseases and the role of thrombophilia testing. June 2012; 4. SIGN Guideline (122). Prevention and management of venous thromboembolism. December 2010.

35 Navigating the evidence in VTE: NOAC clinical trials

36 Overview of NOAC trials in VTE 1 8 Initial Long-term Extended Parenteral VKA Parenteral therapy Parenteral therapy Dabigatran (RE-COVER & RE-COVER II) 1,2 Dabigatran (RE-SONATE & RE-MEDY) 3 Edoxaban (Hokusai-VTE) 4* Rivaroxaban (EINSTEIN-DVT & EINSTEIN-PE) 5,6 Rivaroxaban (EINSTEIN-Extension) 5 Apixaban (AMPLIFY) 7 Apixaban (AMPLIFY-EXT) 8 All four NOACS are licensed for the treatment of DVT and PE, and prevention of recurrent DVT and PE in adults. Please refer to individual SmPCs for further information. PP-ELI-GBR-0032 Date of preparation: May Schulman et al. N Engl J Med 2009;361: ; 2. Schulman et al. Circulation 2014;129(7):764 72; 3. Schulman et al. N Engl J Med 2013;368(8):709 18; 4. The Hokusai-VTE Investigators. N Engl J Med 2013;369: ; 5. The EINSTEIN Investigators. N Engl J Med 2010;363: ; 6. The EINSTEIN-PE Investigators. N Engl J Med 2012;366: ; 7. Agnelli et al. N Engl J Med 2013;369: ; 8. Agnelli et al. N Engl J Med 2013;368(8):

37 NOAC trial designs in acute VTE treatment NOAC Trial Number of patients Design Parenteral required before NOAC? NOAC dosing Comparator Treatment length (months) Follow-up period Key inclusion criteria Apixaban AMPLIFY 1 DVT: 3,532 5,395 PE: 1,836 Double-blind No Apixaban 10 mg twice daily for 7d, then 5 mg twice daily Enoxaparin bridge to warfarin 6 30 days after study completion DVT/PE requiring treatment for 6 months Dabigatran RE-COVER 2 2,539 DVT:1,749 PE: 786 RE-COVER II 3 2,568 DVT: 1,750 PE: 816 Double-blind Required for at least 5 days Dabigatran 150 mg twice daily Enoxaparin bridge to warfarin 6 30 days after study completion DVT of the legs/pe requiring treatment for 6 months Rivaroxaban EINSTEIN-DVT 4 DVT: 3,449 Rivaroxaban DVT without PE 15 mg twice Enoxaparin 3, 6, For duration Open-label No daily for 21d, bridge to then 20 mg VKA or 12* of treatment EINSTEIN-PE 5 PE: 4,832 PE with or without DVT once daily Edoxaban Hokusai-VTE 6 DVT: 4,921 8,240 PE: 3,319 Double-blind Enoxaparin or UFH 5 days Edoxaban 60 mg once daily Enoxaparin bridge to warfarin 3 12 For duration of treatment DVT without PE PE with or without DVT There are no head-to-head studies between these agents. There are limitations such as differing patient populations, designs and outcomes, and caution should therefore be exercised when interpreting these findings. No conclusions about the relative efficacy or safety of any of these agents should be drawn from these data. Please refer to individual product SmPCs for further information *Duration of treatment was determined by the treating physician before randomisation. Most patients received 6 or 12 months of therapy. Paents with body weight 60 kg or a creatinine clearance of mll/min, and patients receiving concomitant treatment with potent P-glycoprotein inhibitors were treated with edoxaban 30 mg once daily. DVT, deep-vein thrombosis; NOAC, non-vka oral anticoagulant; PE, pulmonary embolism; VKA, vitamin K antagonist. PP-ELI-GBR-0032 Date of preparation: May Agnelli et al. N Engl J Med. 2013;369: ; 2. Schulman et al. N Engl J Med. 2009;361: ; 3. Schulman et al. Circulation. 2014;129: ; 4. The EINSTEIN Investigators. N Engl J Med. 2010;363: ; 5. The EINSTEIN-PE Investigators. N Engl J Med. 2012;366: ; 6. Büller et al. N Engl J Med. 2013;369:

38 NOAC dosing regimens across each stage of VTE treatment Initial VTE treatment Ongoing VTE Treatment Prevention of Recurrent VTE Apixaban 1 Rivaroxaban 2 Dabigatran 3 Edoxaban 4 10 mg BD Day mg BD with food Day 1 21 Parenteral anticoagulant For at least 5 days (not to be taken concomitantly with dabigatran) Parenteral anticoagulant For at least 5 days (not to be taken concomitantly with edoxaban) 5 mg BD Day 8 onwards for at least 3 months* 20 mg OD with food Day 22 onwards for at least 3 months * 2.5 mg BD Following completion of 6 months of treatment with apixaban 5 mg BD or another oral anticoagulant 150 mg BD For at least 3 months* (Dose adjustments to 110 mg BD in patients 80 years, patients on concomitant verapamil, and those at high risk of bleeding) 60 mg OD For at least 3 months* (Dose adjustment required to 30 mg OD in patients with CrCl ml/min or body weight 60 kg or with concomitant use of the following P-gp inhibitors: ciclosporin, dronedarone, erythromycin or ketoconazole. Refer to edoxaban SmPC for further information) The duration of overall therapy should be individualised after careful assessment of the treatment benefit against the risk of bleeding *Short duration of treatment (at least 3 months) should be based on transient risk factors (e.g. Recent surgery, trauma, immobilisation) Longer duraons should be based on permanent risk factors of idiopathic DVT or PE. Apixaban: Use with caution in severe renal impairment (CrCl ml/min). Not recommended in CrCl <15 ml/min or in patients undergoing dialysis. Rivaroxaban: Consider reduction from 20 mg OD to 15 mg OD (after the initial 15 mg BD for 3 weeks) in patients with moderate (CrCl ml/min) or severe (CrCl ml/min) renal impairment if patient s assessed bleeding risk outweighs risk for recurrent DVT and PE. Use with caution in severe renal impairment. Not recommended in CrCl < 15 ml/min. Dabigatran: Contraindicated in CrCl < 30 ml/min. Edoxaban: In patients with moderate or severe renal impairment (CrCl ml/min) the recommended dose is 30 mg OD. Not recommended in CrCl <15 ml/min or in patients undergoing dialysis. CrCl, creatinine clearance; OD, once daily; BD, twice daily. PP-ELI-GBR-0032 Date of preparation: May Apixaban SmPC. Available at 2. Rivaroxaban SmPC. Available at 3. Dabigatran SmPC. Available at 4. Edoxaban SmPC. Available at

39 key learning points All NOACs (apixaban, rivaroxaban, edoxaban and dabigatran) are licensed for the treatment of VTE, and the prevention of recurrent VTE in adults Treatment of VTE The NOACs were comparable to enoxaparin/warfarin in reducing recurrent VTE or VTE-related deaths 1-7 The NOACs were comparable to or superior in reducing the risk of major bleeding compared to enoxaparin/warfarin 1-7 Apixaban and rivaroxaban can be initiated for VTE treatment without the need for initial parenteral administration unlike dabigatran and edoxaban 5,6 Prevention of recurrent VTE Apixaban, rivaroxaban and dabigatran were evaluated against placebo and significantly reduced the risk of recurrent VTE or VTE-related death for the prevention of recurrent VTE 4,8,9 Apixaban demonstrated comparable major bleeding rates vs placebo for the prevention of recurrent VTE 8 PP-ELI-GBR-0032 Date of preparation: May Agnelli et al. N Engl J Med. 2013;369: ; 2. Schulman et al. N Engl J Med. 2009;361: ; 3. Schulman et al. Circulation. 2014;129: ; 4. The EINSTEIN Investigators. N Engl J Med. 2010;363: ; 5. The EINSTEIN-PE Investigators. N Engl J Med. 2012;366: ; 6. Apixaban SmPC. January 2016; 7. Büller et al. N Engl J Med. 2013;369: ; 8. Agnelli et al. N Engl J Med. 2013;368: ; 9. Schulman et al. N Engl J Med. 2013;368: