06RC2-Llau. Prophylaxis, diagnosis and treatment of venous thromboembolism. Juan V. Llau. Introduction. Rationale for thromboprophylaxis [1,5] - 1 -

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1 06RC2-Llau Prophylaxis, diagnosis and treatment of venous thromboembolism Juan V. Llau Department of Anaesthesiology and Critical Care Hospital Clínico València, Spain Introduction Pulmonary embolism (PE) and deep vein thrombosis (DVT) are two clinical presentations of venous thromboembolism (VTE) which share the same predisposing factors. In most cases PE is a consequence of DVT. Among patients with proximal DVT, about 50% have an associated, but often clinically asymptomatic PE identifi ed by a lung scan. Conversely, evidence of DVT can be found in the lower limbs if an appropriate diagnostic method is used, in about 70% of those diagnosed with a PE []. Currently, VTE isregarded as the result of the interaction between patient-related and setting-related risk factors. Patient-related predisposing factors are usually permanent, whereas setting-related predisposing factors are more often temporary. Patient-related predisposing factors include age, history of previous VTE, active cancer, neurological disease with extremity paresis, medical disorders causing prolonged bed rest (such as heart or acute respiratory failure) and congenital or acquired thrombophilia, hormone replacement therapy and oral contraceptive therapy [2,3]. The incidence of VTE varies widely between countries. For example, in the USA this ranges from cases/00,000 inhabitants per year, whereas in Europe the incidence is between per 00,000 [4]. In any case, the incidence increases exponentially with age, therefore it is necessary to consider age as an independent risk factor. Rationale for thromboprophylaxis [,5] The rationale for the use of thromboprophylaxis in patients admitted to hospital is based on solid principles and scientifi c evidence, including: High prevalence of VTE among hospitalized patients: almost all of them will have one or more risk factors for VTE. If no prophylaxis is given, the risk of developing VTE is dependent on the medical/surgical condition of the patient (table ) [,6,7]. Adverse consequences of symptomatic DVT or PE, fatal PE and post-thrombotic syndrome in the absence of VTE prophylaxis Cost-effectiveness of both pharmacological and mechanical methods of thromboprophylaxis The recommendation, therefore, is that all patients are assessed with regard to their thrombotic risk (balanced against their bleeding risk) to determine the optimum form of thromboprophylaxis required - -

2 . CATEGORY VTE PREVALENCE (%) MEDICAL PATIENT Fully mobile Bed rest GENERAL SURGERY (total) Distal DVT Proximal DVT Symptomatic PE and/or DVT ,5-4 ORTHOPAEDIC SURGERY THA/TKA/HF (total) THA/TKA/HP (proximal DVT) Ambulatory arthroscopy (total) Neurosurgery Major gynaecological surgery Major trauma Spinal cord injury Table. Approximate risk of Venous Thromboembolism (VTE) in hospitalized patients (personal adaptation from references, 6, 7). Thromboprophylaxis measures General measures include mobilisation and leg exercises. Adequate hydration should be ensured in immobilised patients. Mechanical methods increase mean fl ow velocity in leg veins and reduce venous stasis. They include graduated compression stockings (GCS), intermittent pneumatic compression (IPC) devices and pneumatic foot pumps (PFP). Although they are included in most guidelines, the effi cacy of GCS for medical patients has been recently challenged [8]. Pharmacological methods are necessary when the thrombotic risk is moderate to high. They include low molecular weight heparins (LMWH) which are the most widely used drugs employed for thromboprophylaxis. Other drugs are fondaparinux, unfractionated heparin (UFH), anti vitamin K agents (VKAs) (warfarin/acenocumarol) and new oral anticoagulants with a direct action against factor Xa (apixaban and rivaroxaban) or against factor IIa (dabigatran). The new oral anticoagulants appear to be very effective in most cases, however they may increase the bleeding risk in some sensitive patients. Table 2 shows the recommended doses of each drug for thromboprophylaxis

3 Prophylaxic dose per day Treatment dose per day Unfractionated heparin Low-molecular-weight-heparins Fondaparinux Dabigatran Rivaroxaban Apixaban Vitamin k antagonists 3 x 5000 UI (sc) > 3500 UI (*) 2.5 mg 220 mg (fi rst dose 0 mg) 50 mg in elderly (fi rst dose 75 mg) 0 mg 2 x 2.5 mg Adjusted to an INR target 2.5 Initial iv bolus of 5000 UI + continuous infusion at adjusted dose for an aptt ratio of x UI/kg (*) 7.5 mg (body weight kg) 2 x 50 mg 2 x 5 mg (3 weeks) afterwards, 20 mg 2 x 0 mg ( week) afterwards, 2 x 5 mg Adjusted dose for INR Table 2. Suggested doses for thromboprophylaxis in high risk patients and for venous thromboembolism treatment. (*) Dose depending on the LMWH considered We all agree that the risk/benefi t ratio of VTE prophylaxis is indisputable in surgery. However, in some procedures such as bariatric surgery, arthroscopy and others, the optimal dose, timing and duration of the treatment remains undetermined [8]. In table 3 we have collated the most important recommendations for thromboprophylaxis based on VTE risk stratifi cation [,5,7,9,0]. LEVEL OF RISK PROCEDURE MAIN RECOMMENDATION LOW RISK - Minor surgery in mobile and no risk patients - Medical patients who are fully mobile - Early mobilisation - General methods MOERATE RISK - Major surgery lasting < 60 min - Benign disease - Transurethral surgery - Laparoscopic surgery without personal risk factors - LMWH (< 3500 UI/24h) - Mechanical methods (preferred is bleeding risk) HIGH RISK - Most major surgery : orthopaedic, general, abdominal, thoracic, gynaecologic, bariatric, urologic - Oncologic surgery - Critical patients - Major trauma - Medical patients: bed rest, cancer patients - Neurosurgery, spine surgery (assess bleeding risk) - LMWH (> 3500 UI/24h) - Fondaparinux (2,5 mg/24h) - VKA (INR target 2,5) - New oral anticoagulants when indicated - Mechanical methods tp complement pharmacological methods or when there is a high bleeding risk. Table 3. Basic guidelines for thromboprophylaxis based on VTE risk stratifi cation

4 It is not always clear when to initiate thromboprophylaxis with LMWH to derive the optimal effect. There appears to be no difference reported in the literature in terms of effi cacy and safety between pre- or postoperative administration of the fi rst dose of LMWH, and the guidelines leave this open to individual clinical preference [0,]. Nevertheless the current tendency is to commence thromboprophylaxis in the postoperative period (most drugs are only given after surgery), and if a LMWH is selected for once daily administration, the consensus is to start between 6 and 2 hours after completion of surgery. Figure represents a compilation of the timing of commencement of the drugs used for VTE prophylaxis in the perioperative period. Figure. Compilation of the moment of administration of the fi rst dose of anticoagulant drugs in the perioperative period when indicated for thromboprophylaxis. Thromboprophylaxis in the perioperative period: implications for the anaesthesiologist The utilization of regional anaesthesia, particularly neuraxial blocks, appears to be safe in patients receiving anticoagulant drugs for thromboprophylaxis provided there is an appropriate time interval between the proposed type of anaesthetic-analgesic technique and the drug s administration. This decision will be based on the characteristics of the individual drug [2]. Nevertheless, the fi nal decision to perform regional anaesthesia in patients receiving drugs that affect haemostasis has to be made after careful assessment of the likely risks and benefi ts, especially in patients receiving a combination of VTE and antiplatelet therapy for a separate medical indication []. The principal recommendations for the provision of neuraxial anaesthesia and deep peripheral nerve blocks in the presence of anticoagulant therapy are contained in guidelines issued by the European Society of Anaesthesiology and are shown in table 4 []. Time before puncture/catheter manipulation or removal Time after puncture/catheter manipulation or removal Unfractionated heparin Low-molecular-weight-heparins Fondaparinux Dabigatran Rivaroxaban Apixaban Vitamin K antagonists 4-6 h 2 h h Contraindicated (*) h 26-30h INR <.4 h 4 h 6-2 h 6 h 4-6 h 4-6 h After catheter removal Table 4. Main recommendations for the performance of neuraxial and deep peripheral nerve blocks in patients receiving anticoagulant drugs for thromboprophylaxis in the perioperative period []. (*) According with the manufacturer - 4 -

5 Diagnosis of acute venous thromboembolism The fi rst step in the diagnosis of VTE is the clinical assessment. Acute venous thromboembolism should be suspected in patients with a combination of symptoms and/or signs suggestive of VTE. Most patients with a confi rmed PE do not have clinically evident DVT and around 30% of patients with symptomatic DVT have an asymptomatic PE. Suggestive symptoms and signs include [5]: DVT: unilateral leg pain, swelling, tenderness, increased temperature, pitting oedema, prominent superfi cial veins PE: breathlessness, chest pain, haemoptysis, collapse, tachycardia, hypotension, tachypnoea, raised jugular venous pressure, focal signs in chest, hypoxia/cyanosis. Several diagnostic algorithms can be used to assess the clinical probability of having a DVT and/or PE [5,3]. The most commonly used scales are the Wells score for DVT and the revised Geneva score for PE (table 5). WELLS SCORE REVISED GENEVA SCORE Parameter Score Parameter Score Active cancer within last 6 months or palliative Age 65 or over Recently bedridden >3 days, or major surgery Previous DVT/PE 3 requiring regional or general anaesthetic in past Surgery or fracture (< month) 2 four weeks Active malignant condition 2 Calf swelling >3 cm compared to other calf Unilateral lower limb pain 3 Collateral superfi cial veins (non-varicose) Haemoptysis 2 Pitting oedema (confi ned to symptomatic leg) Heart rate: Swelling of entire leg 75 to 94 rpm 3 Localized pain along distribution of deep venous > 95 rpm 5 system Pain or deep palpation of lower limb or unilateral Paralysis, paresis, or recent cast immobilization oedema 4 of lower extremities Previously documented DVT Alternative diagnosis at least as likely -2 PROBABILITY OF DVT PROBABILITY OF PE Low 0- Low (8%) 0-3 Intermediate 2-6 Intermediate (28%) 4-0 High 7 High (74%) Table 5. Probability scores for the assessment of suspected VTE With regard to diagnostic tests, it is useful to discuss the role of D-dimer: This is a degradation product of cross-linked fi brin. D-dimer concentrations are elevated in the plasma and signal the formation of an acute clot. Hence, a normal D-dimer infers a PE or DVT is unlikely since the negative predictive value of D-dimer is high. On the other hand, although D-dimer is a very specifi c marker for fi brin deposition, the specifi city of fi brin as an indicator for VTE is relatively poor because fi brin is produced in a wide variety of situations including the postoperative period. Therefore the positive predictive value of D-dimer is low [4]. Hence, D-dimer is not useful as a confi rmatory test for VTE

6 In order to confi rm a clinically suspected VTE we need an imaging test [5,4]. Confi rmation of a suspected DVT: Venous ultrasound is the imaging investigation of choice for patients with suspected DVT. Patients who have a negative or inadequate initial scan but who have a persisting clinical suspicion of DVT or whose symptoms do not settle, should have a repeat ultrasound scan at 5-7 days. The same recommendation is made for patients with a moderate suspicion with a positive D-dimer result or those in whom, on clinical reassessment, the suspicion of DVT remains high. Confi rmation of a suspected PE: Computed tomography pulmonary angiography (CTPA) should be the fi rst line investigation of pulmonary embolism, assessing the right ventricular/left ventricular diameter ratio (RV/LV) as an indicator of severity (prognostic signifi cance of RV dysfunction when RV/LV>). Isotope lung scintigraphy should be considered if CTPA is unavailable and the patient is clinically stable. In order to diagnose a silent DVT around the time of discharge from hospital, it has been suggested that all patients at high risk of VTE are screened before discharge using doppler ultrasound of the legs. At present this practice is not recommended routinely for all patients. Currently this investigation is only regarded as cost-effective in those patients who actually exhibit clinical signs suggestive of DVT [5]. Management of venous thromboembolism It is quite diffi cult to summarize the comprehensive management of VTE in a few words. Therefore the main recommendations, adapted mainly from those found in the latest ACCP recommendations are summarized below [6]: For patients with confi rmed DVT or PE: Commencement of anticoagulant therapy with subcutaneous LMWH, intravenous or subcutaneous UFH (with aptt monitoring) or SC fondaparinux (all Grade A) for at least 5 days rather than a shorter period (Grade C) is recommended. After this period, the treatment should be augmented with a transition to VKAs which should be monitored using the international normalized ratio (INR) of >2.0 for at least 24 h (Grade A) For patients in whom there is a high clinical suspicion of DVT or PE: Anticoagulant treatment should be commenced while awaiting the outcome of diagnostic tests (Grade C). For patients with confi rmed PE: An early evaluation of the risks and benefi ts of thrombolytic therapy should be made (Grade C); for those with hemodynamic compromise, thrombolytic therapy should be initiated (Grade B), but for those with a small PE or stable haemodynamic criteria, thrombolytic therapy is not recommended (Grade B). For patients with DVT or PE secondary to a transient risk factor: Treatment with a VKA should last 3 months (Grade A). For patients who experience an unprovoked DVT or PE, treatment with a VKA should last at least 3 months (Grade A), thereafter patients should be assessed with regard to the risks to benefi ts of indefi nite therapy (Grade C). Selected patients with lower-extremity (Grade 2B) and upper-extremity (Grade 2C) DVT may be considered for treatment involving thrombus removal, generally by employing catheter-based thrombolytic techniques. Long term anticoagulation and secondary prophylaxis [4] Long-term anticoagulant treatment of patients with VTE is intended to prevent recurrent thrombotic events. By convention the duration of treatment ranges between 3-6 months, although specifi c cases may be treated for longer (2 months or more) after assessing the risk on an individual patient basis. In the vast majority of patients the recommended drugs are VKAs at doses adjusted to maintain a target INR of 2.5 (range ). LMWH may be an effective and safe alternative to VKAs, mainly in cancer patients. The implications for treatment of a proximal DVT or PE are very similar, the main difference being that recurrent episodes of PE are more likely to occur after an initial PE than after an initial DVT

7 New treatments New oral anticoagulants have been used in trials to assess the effi cacy, effectiveness and safety in the treatment of acute VTE and to decrease of the recurrence of thrombotic events. Encouraging results associated with dabigatran, rivaroxaban and apixaban may signal their inclusion in future guidelines for fi rst line treatment of VTE, or, more likely for prolonged treatment on the basis that some of them have clear advantages over the current treatment offerred by VKAs. Key learning points Assessment of the need for thromboprophylaxis in all patients admitted to hospital is a major recommendation because the high prevalence of VTE among hospitalised patients, the adverse consequences of VTE due to an absence of prophylaxis and the effi cacy and safety of methods for thromboprophylaxis. Most surgical patients should receive pharmacological thromboprophylaxis due to the high thrombotic risk associated with surgery which should also include individual factors specifi c to the patient. The implications for the anaesthesiologist are important and there is a requirement to assess the risk of complications if regional anaesthesia (mainly neuraxial) is selected. In such circumstances it is important to observe the relavant window of opportunity that governs administration of regional anaesthetics in the presence of anticoagulant therapy. The diagnosis of VTE is commonly based on clinical suspicion, supported by the results of diagnostic algorithms and confi rmed by appropriate imaging tests (venous ultrasound in DVT and computed tomography pulmonary angiography in PE). Anticoagulant therapy is the cornerstone of the treatment of VTE. If a patient has a PE which results in haemodynamic unstability, specifi c thrombolytic therapy should be considered. 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