Prevention and treatment of venous thromboembolic disease

REVIEW Prevention and treatment of venous thromboembolic disease SUSAN McNEILL AND CATHERINE BAGOT Awareness of the risk factors for venous thromboembolic (VTE) disease and timely administration of thromboprophylaxis can prevent many VTE events. This article examines these risk factors and the recommended strategies to prevent VTE, as well as discussing the diagnosis and treatment of an event that has already occurred. SPL Deep vein thrombosis (DVT) and pulmonary embolism (PE) are both manifestations of venous thromboembolic (VTE) disease and together have an annual incidence of 1 2 per 1000 population. 1 Both can cause significant morbidity, and in the case of PE an early fatality rate of approximately 5%. While up to half of VTE events appear unprovoked, many are associated with known risk factors including surgery or acute medical admission to hospital. 2 Thus, careful application of thromboprophylaxis strategies for those at high risk, and early diagnosis and treatment for those with acute VTE, are the cornerstones of reducing the burden of these largely preventable conditions. This article will focus on DVT (see Figure 1); however, it should be noted that prevention, diagnosis and treatment strategies are broadly similar for PE. Risk factors for VTE There are numerous risk factors for VTE, both congenital and acquired (see Table 1), with the presence of multiple factors often having a greater than additive effect. Increasing age is an inherent VTE risk, in particular when over the age of 60 years. 3 Women who use combined oral contraception or hormone-replacement therapy (HRT) have a two- to three-fold increased VTE risk secondary to exposure to exogenous estrogen. The level of risk is increased by a higher estrogen dose, the use of third-generation progestogens and with concurrent smoking or obesity. Non-oral administration of HRT is associated with the least risk. 4 Women should be discouraged from using such hormonal preparations if they have a family history of VTE, and they are contraindicated in women with a previous VTE. In women at high risk of VTE, progestogens can be used for contraception but there is a small increased VTE risk in women requiring higher doses for menstrual irregularities. Figure 1. Acute deep vein thrombosis of left leg Prescriber July 2018 15

REVIEW l Venous thromboembolism Congenital Approximate increased risk of first event (compared with general population) Acquired Approximate increased risk of first event (compared with general population) Antithrombin deficiency 40x Hospitalisation with an acute medical illness 8x Protein C deficiency 10x Surgery 70x Protein S deficiency 10x Malignancy 50x Factor V Leiden 2 3x Age >60 years 10x Prothrombin gene mutation G20210A 2 3x Combined oral contraceptive pill/hrt 2-3x Pregnancy/postpartum 10x Smoking 1.5x Obesity 1.5x Long-haul travel >4 hours 1.5x Relative risk (95% Cl) 140 120 100 80 60 40 20 0 Table 1. Congenital and acquired risk factors for venous thromboembolism (VTE) deep vein thrombosis (DVT) or pulmonary embolism (PE) Pregnancy is associated with a 10-fold increased risk of VTE. The risk is similar throughout all trimesters and is at its greatest during the six weeks postpartum. All pregnant women with a personal history of VTE or multiple risk factors for VTE should be referred to an obstetrician-led antenatal clinic at an early stage of pregnancy for specialist assessment and advice. 5 Admission to hospital is also a significant risk factor for VTE. Surgical procedures increase the risk, which persists for up to three months following discharge, with a similar but lesser effect following day surgery (see Figure 2). This Inpatient surgery Day case surgery Relative risk for time without surgery = 1 1 4 8 12 4 5 6 7 8 9 10 11 12 1+ prolonged risk is particularly prevalent in patients who have undergone lower-limb arthroplasty. Patients hospitalised with an acute medical illness are also at significantly increased risk of VTE, although it is unknown how long this risk persists postdischarge. 6 Malignancy imparts a very high risk of VTE, with the level of risk dependent on the type of malignancy, its stage and concurrent use of chemotherapy. However, there is no evidence that these patients should routinely receive formal thromboprophylaxis unless hospitalised. One exception to this is in ambulatory patients with myeloma receiving chemotherapy. Air travel is considered by the general public to present a significant risk for the development of VTE. However, the risk is very low and only applies to journeys over four hours, albeit using any mode of transport. Smoking and obesity also carry a small risk of VTE but this risk is multiplied when they occur concurrently or in association with other VTE risk factors. 6 Inherited thrombophilias are congenital coagulation factor abnormalities that increase VTE risk. These vary in frequency and in the level of associated risk, eg anti-thrombin deficiency carries the greatest VTE risk and is uncommon, factor V Leiden is present in 3 5% of the general population and is associated with the least risk. Antiphospholipid syndrome is an acquired thrombophilia that is associated with a very high risk of VTE recurrence. 3 Weeks Months Years Time since surgery Figure 2. Relative risk of venous thromboembolism by time since inpatient surgery or since day case surgery (from Sweetland S, et al., BMJ 2009;339:b4583) 2 Prevention of VTE Mechanical methods Above-knee anti-embolism stockings (AES) have a role in VTE prevention in many circumstances. Patients should always be measured accurately prior to use and Sigel-compliant stock- 16 Prescriber July 2018

Venous thromboembolism l REVIEW DVT (usually unilateral) Pain Swelling Pitting oedema Tenderness Increased temperature Prominent superficial veins ings prescribed. There is good evidence that these have a role alongside low-molecular-weight heparin (LMWH) in preventing VTE following all forms of surgery, particularly orthopaedic procedures. AES are also an effective alternative method of VTE prevention in those patients at increased bleeding risk who cannot safely receive heparin. There is less evidence for their use in hospitalised medical patients and AES are ineffective in VTE prevention for patients with recent stroke. AES are sometimes used in obstetric patients but the evidence for effectiveness is limited. AES are usually recommended during hospital admission but may be continued post-discharge if immobility persists. 7 Pharmacological methods LMWH has been demonstrated in both medical and surgical inpatients to be effective in the prevention of VTE, reducing the risk by approximately 60% compared with placebo. 8 LMWH also has a role in obstetric patients assessed to be at high VTE risk. 5 This therapy is as effective as unfractionated heparin but with fewer side-effects. However, it must be avoided in patients at increased risk of bleeding, including those with severe renal impairment. Post-operative patients remain at risk of VTE following discharge, and in some patients there is a benefit in continuing LMWH for up to six weeks. This particularly applies to those patients who have undergone lower-limb arthroplasty and those deemed to be at very high VTE risk, eg those undergoing major surgery for cancer. 6 For air travel, very few people require preventive LMWH and consideration should be given to discussing such cases with a haematologist if there is any doubt, as there is no reliable evidence base for LMWH in this setting. 9 Direct oral anticoagulants (DOACs) licensed for orthopaedic thromboprophylaxis include dabigatran etexilate (a direct thrombin inhibitor), rivaroxaban (a direct Factor Xa inhibitor) and apixaban (also a direct factor Xa inhibitor). Such agents require no monitoring to assess therapeutic levels and have minimal side-effects, although they still impart a bleeding risk similar to that of LMWH. These drugs PE Chest pain Collapse Hypotension Cyanosis/hypoxia Breathlessness/tachypnoea Tachycardia Focal chest signs (of infarction) Haemoptysis Table 2. Signs and symptoms of deep vein thrombosis (DVT) and pulmonary embolism (PE) are easier to administer for extended thromboprophylaxis as their oral formulation avoids a prolonged period of daily injections as an outpatient. These medications continue to undergo research for thromboprophylaxis in other clinical situations. 10 Finally, aspirin is known to provide a modest reduction in VTE rate in at-risk patients but there is far stronger evidence for the effectiveness of LMWH. For this reason, aspirin is no longer recommended as a sole pharmacological agent in the prevention of VTE by reputable guidelines, including NICE. 6 Signs and symptoms Signs and symptoms can be relatively non-specific. Therefore, DVT can often be included in the differential diagnosis of patients with otherwise unexplained leg symptoms. 11 Symptomatic DVT and PE are not commonly seen simultaneously most patients with acute PE will have no leg symptoms, presumably because the precipitating DVT has been nonocclusive or already embolised. Acute DVT is associated with asymptomatic PE in 30 50% of cases. 12 The presence of key signs or symptoms (see Table 2), either in the absence of an obvious cause or in the presence of known risk factors for VTE, should prompt systematic assessment for DVT and/or referral to secondary care. Diagnosis of DVT It is long accepted that a clinical diagnosis of DVT, or indeed PE, even as assessed by an expert, is an unreliable basis for committing a patient to a protracted period of anticoagulation. Thus, an objective diagnosis is required historically by leg vein venography but now more conveniently for patient and operator negative Possible DVT <2 Wells clinical score 2 positive DVT unlikely ( 1/200) Consider other diagnoses before discharge negative Treat as DVT until confirmed or excluded by ultrasound Figure 3. Diagnostic algorithm for deep vein thrombosis (DVT) positive Prescriber July 2018 17

REVIEW l Venous thromboembolism by Doppler ultrasound scan of leg veins. However only 10 15% of patients presenting to an Accident and Emergency department with possible DVT will have this diagnosis. 11 Therefore, in order to preserve resources, initial systematic assessment for DVT will normally include application of a clinical scoring system combined with a blood test to quantify fibrin levels (see Figure 3). Such algorithms, when applied to the appropriate population, have been shown to effectively categorise patients into two groups: Those in whom acute DVT is very unlikely ( 0.5% risk of presenting with acute VTE during the following three months) and therefore no anticoagulation or radiographic imaging is required Those in whom DVT cannot be excluded and who therefore require anticoagulation while awaiting Doppler ultrasound to confirm or exclude DVT. Similar diagnostic algorithms also exist for PE, while variations of the DVT algorithm have been tested in the community setting. 3 Treatment Once a diagnosis of DVT has been established, the patient will most often be commenced on a DOAC, unless there is a contraindication to its use, eg renal impairment with estimated glomerular filtration rate (egfr) <30ml/min, or severe liver disease. 3,8 Apixaban is a commonly used DOAC because of the low incidence of bleeding episodes in both clinical trial and real-world data. Apixaban is commenced at a dosage of 10mg twice daily for seven days then reduced to 5mg twice daily thereafter with no requirement for monitoring (see Table 3). For those patients in whom a DOAC is felt to be unsuit- Drug category (mechanism of action) Name Route of administration Standard dosing Half-life Monitoring Elimination route Heparin and related molecules (indirect Factor IIa and/or Xa inhibition) Unfractionated heparin sc (prophylaxis) 5000units 8 12 hourly ~2h Nil Partly renal iv (therapeutic) ~16 18units/kg/hour 45 60min APTT ratio LMWH (enoxaparin, dalteparin, tinzaparin) sc (prophylaxis) sc (therapeutic) Variable depending on product 3 4h Nil Fondaparinux sc (prophylaxis) 2.5mg daily 17 21h Mostly renal Danaparoid sc (prophylaxis) 750 units twice daily 17 28h Coumarins (vitamin K antagonists) Warfarin sodium oral 3 5mg daily 36 42h INR Mainly liver Acenocoumarol 3 4mg daily 9h Direct oral anticoagulant (direct thrombin inhibitor) Dabigatran etexilate oral (prophylaxis) oral (therapeutic) 110mg day 1, then 220mg daily 150mg twice daily (after 5 days LMWH) 7 9h Nil Mostly renal Direct oral anticoagulants (direct factor Xa inhibitors) Rivaroxaban Oral (prophylaxis) 10mg daily 3 9h Nil Partly renal Oral (therapeutic) 15mg twice daily days 1 21, then 20mg daily Apixaban Oral (prophylaxis) 2.5mg twice daily 12h Oral (therapeutic) 10mg twice daily days 1 7, then 5mg twice daily Edoxaban Oral (therapeutic) 60mg daily (after 5 days LMWH) 10 14h LMWH = low-molecular-weight heparin; APTT = activated partial thromboplastin time; INR = international normalised ratio Table 3. Pharmacological agents for prevention and treatment of venous thromboembolism 18 Prescriber July 2018

Venous thromboembolism l REVIEW able, the oral anticoagulant warfarin may be used with LMWH treatment initially given concurrently for five to seven days until the warfarin effect is fully established with an International Normalised Ratio (INR) between 2.0 and 3.0. INR levels below 2.0 are suboptimal and those above 3.0 are associated with a higher bleeding risk, and are unnecessary unless a patient has suffered a VTE event despite an INR in the 2 3 range. 3,8 Patients with underlying cancer should be offered treatment with LMWH throughout, rather than introducing warfarin, as this strategy has been shown to be superior in this patient category in terms of both lower recurrent VTE and bleeding rates. The use of DOACs in cancer-associated DVT is currently under investigation in clinical trials. 13,14 Outpatient diagnosis and treatment of patients with DVT has been shown to be safe and easily managed within rapid medical assessment units or dedicated VTE services. Duration of anticoagulation will be determined by the presence of risk factors at the time of the event, and whether these persist. Typically, patients with proximal DVT will require three months of anticoagulation. Patients with persisting major risk factors and those with unprovoked VTE events, particularly males for whom the recurrence risk is higher, may be considered for indefinite anticoagulation. Such patients should be assessed individually and the potential benefits of long-term anticoagulation weighed against the bleeding risk. 3 Use of risk scoring systems can provide an assessment of risk of recurrent DVT. 15,16 The DASH score is one such scoring system, in which a patient receives one point for each of the following: age <50 years and male sex; and two points for a positive off-anticoagulation (three to five weeks after cessation of therapy). The system deducts two points for hormone-associated thrombosis. A score 2 suggests an above-average risk of VTE recurrence and a likely overall benefit from long-term anticoagulation. 15 The HERDOO2 clinical decision rule can be applied without stopping anticoagulation before measurement of. The HERDOO2 rule identifies women with one or fewer of the following four criteria as being at low risk of recurrence: hyperpigmentation, oedema or redness in either leg; level 250µg/L during treatment with anticoagulants; obesity with body mass index 30; and age >65 years. 16 Following DVT, there is a long-term risk of post-thrombotic syndrome, including pain, swelling, skin discoloration and itch, venous insufficiency, varicosities and, in extreme cases, ulceration. The use of graduated elastic compression stockings can alleviate symptoms for many patients and should be used for as long as they are felt to be effective. 7 Conclusion VTE is a common event that can lead to significant morbidity and mortality. There are well-recognised risk factors for VTE and an awareness of these risk factors can lead to the timely administration of thromboprophylaxis and prevention of many VTE events. When a patient does present with symptoms or signs suggestive of VTE, they should be promptly assessed using a clinical decision algorithm leading to an objectively confirmed diagnosis and treatment in an effort to prevent serious long-term sequelae. References 1. Silverstein M, et al. Trends in the incidence of deep vein thrombosis and pulmonary embolism: a 25-year population-based study. Arch Intern Med 1998;158(6):585 93. 2. Sweetland S, et al. Duration and magnitute of the postoperative risk of venous thromboemolism in middle aged women: prospective cohort study. BMJ 2009;339:b4583. 3. National Institute for Health and Care Excellence. Venous thromboembolic diseases: diagnosis, management and thrombophilia testing. CG144. June 2012 (updated November 2015). Available from: www. nice.org.uk/guidance/cg144 4. Canonico M, et al. Hormone replacement therapy and risk of venous thromboembolism in postmenopaual women: systematic review and meta-analysis. BMJ 2008;336:1227 31. 5. Royal College of Obstetricians and Gynaecologists. Reducing the risk of venous thromboembolism during pregnancy and the puerperium. Green-top Guideline no. 37a. April 2015. Available from: www.rcog.org. uk/globalassets/documents/guidelines/gtg-37a.pdf 6. National Institute for Health and Care Excellence. Venous thromboembolism: reducing the risk for patients in hospital. CG 92. January 2010 (updated June 2015). Available from www.nice.org.uk/ guidance/cg92 7. Khan SR, et al. Compression stockings to prevent post-thrombotic syndrome: a randomised placebo-controlled trial. Lancet 2014;383:880 8. 8. Kearon C, et al. Antithrombotic therapy for VTE disease: CHEST guideline and expert panel report. Chest 2016;149(2):315 52. 9. Watson HG, Baglin TP. Guidelines on travel-related venous thrombosis. Br J Haematol 2011;152:31 4. 10. Ufer M. Comparative efficacy and safety of the novel oral anticoagulants dabigatran, rivaroxaban and apixaban in preclinical and clinical development. Thromb Haemost 2010;103:572 85. 11. Lowe G, Tait C. Limb pain and swelling. Medicine 2009;37:96 9. 12. White R. The epidemiology of venous thromboembolism. Circulation 2003;107(23, Suppl. 1):14 8. 13. Meyer G, et al. Comparison of low-molecular-weight heparin and warfarin for the secondary prevention of venous thromboembolism in patients with cancer. Arch Int Med 2002;162:1729 35. 14. Lee AY, et al. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med 2003;349:146 53. 15. Tosetto A, et al. Predicting disease recurrence in patients with previous unprovoked venous thromboembolism: a proposed prediction score (DASH). J Thromb Haemost 2012;10(6):1019 25. 16. Rodger MA, et al. Validating the HERDOO2 rule to guide treatment duration for women with unprovoked venous thrombosis: multinational prospective cohort management study. BMJ 2017; 356:j1065. Declaration of interests None to declare. Dr McNeill is a Haematology Registrar in Greater Glasgow and Clyde, and Dr Bagot is a Consultant Haematologist in the Department of Haematology, Royal Infirmary, Glasgow Prescriber July 2018 19