Core Topics in General & Emergency Surgery: Companion to Specialist Surgical Practice (71 page)
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Authors: Simon Paterson-Brown MBBS MPhil MS FRCS
Patients presenting with symptoms suggestive of PE should have a clinical assessment and pretest probability determined. Those at low risk with D-dimers below the laboratory ‘cut-off’ for the exclusion of VTE do not usually need further investigation. For those with suspected PE in whom the diagnosis is ‘PE likely’ or ‘PE unlikely but with positive D-dimers’, CTPA should be performed; a negative multislice scan can safely exclude the presence of a PE. Hospital inpatients with symptoms/signs of PE should have imaging investigations performed. Pregnant women should have duplex ultrasound of the leg veins performed as the initial investigation.
Aims of treatment
The primary aims of the treatment of VTE are to relieve symptoms and to prevent thrombus extension and recurrent thrombotic events, thereby reducing the risks of the long-term complications of VTE (the post-thrombotic syndrome and chronic thromboembolic pulmonary hypertension). Anticoagulation is the mainstay of treatment of VTE for both DVT and PE.
Before starting anticoagulation, assessment should be undertaken to determine whether any disorders predisposing to VTE are present (i.e. malignancy or pregnancy), to assess the safety of proposed anticoagulant therapy and to determine whether appropriate monitoring of anticoagulant therapy is achievable. Thorough clinical history taking and examination will identify factors contributing to the development of VTE and risks for anticoagulant therapy. Baseline blood tests should be undertaken (full blood count, renal function and coagulation screen) to allow safe prescribing of anticoagulant therapy. Heparins are renally excreted, vitamin K antagonists and unfractionated heparin require coagulation test monitoring, and care should be taken with anticoagulant therapy in anaemia and thrombocytopenia.
Anticoagulation should be started as soon as an objective diagnosis of VTE has been made, of if there are any delays in investigation of patients at high risk of VTE.
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For most patients, this will mean immediate anticoagulation with an injectable anticoagulant (UFH, LMWH or fondaparinux), followed by oral anticoagulation with a vitamin K antagonist. Rivaroxaban, an oral direct Xa antagonist, is now licensed for the treatment of DVT. Some patients (such as those with PE with haemodynamic compromise or DVT associated with phlegmasia caerulea dolens) may benefit from thrombolytic therapy or even surgical intervention.
Haemodynamically compromised patients with PE should be managed in an appropriate clinical setting – usually a coronary care or high-dependency unit. Haemodyanamic support (inotropes) and oxygen should be administered if required. Intravenous UFH will achieve therapeutic levels faster than LMWH, and the dose can be adjusted if thrombolytic therapy is required; therefore, it should be used in preference to subcutaneous LMWH in shocked patients.
Thrombolysis achieves clot lysis more rapidly than anticoagulation alone, accelerating the reduction in pulmonary vascular obstruction, potentially increasing pulmonary perfusion and gas exchange, and should be considered in patients with haemodynamic instability.
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UFH
UFH is renally excreted, has an unpredictable dose response and a narrow therapeutic window; it therefore needs monitoring. It is an injectable anticoagulant and has a short half-life of 60–90 minutes. It is usually administered by a continuous intravenous infusion after an initial loading dose (loading dose 80 U/kg followed by an infusion of 18 U/kg per hour) with subsequent dose adjustments made to maintain an activated partial thromboplastin time (APTT) ratio of 1.5–2.5. Randomised clinical trials have shown that treatment with intravenous (i.v.) UFH for 5–7 days followed by more prolonged treatment with an oral anticoagulant is as efficacious as longer treatment with i.v. UFH.
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Haemorrhage occurs in up to 5% of individuals receiving UFH infusions, the risk being greater in the elderly and those receiving antiplatelet therapies. Care should be taken to monitor for HIT (see earlier). Oral anticoagulation (see below) should be started concurrently with UFH, and the UFH stopped when the INR is therapeutic on two consecutive days.
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Use of UFH has now largely been superseded by LMWH other than in patients with renal failure, or those at high risk of bleeding.
LMWHs are made by chemical or enzymatic depolymerisation of UFH. Their predominant mode of action is to inhibit anti-Xa activity, although all have variable anti-IIa activity. In comparison to UFH, they have more reliable pharmacokinetics and a greater bioavailability and can be given by once or twice daily weight-adjusted subcutaneous administration. A Cochrane review that compared fixed-dose LMWH with UFH for acute PE treatment found an odds ratio of 0.88 (95% confidence interval 0.48–1.63) for risk of recurrent PE in favour of LMWH.
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LMWH does not, routinely, require monitoring. In certain circumstances, however (e.g. in renal impairment or elderly patients with low body weight), monitoring may be of benefit. Peak anti-Xa levels should be measured 3–4 hours after LMWH injection, the therapeutic range being 1.0–2.0 IU/mL with once-daily injection and 0.5–1.0 IU/mL with twice-daily injections. The risk of bleeding is less with LMWH compared with UFH, as is the risk of HIT.
Studies have shown that, for the treatment of DVT, outpatient LMWH administration at therapeutic licensed dosages is as safe and efficacious as UFH infusion.
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LMWHs have been shown to be as safe and effective as UFH in treating non-massive haemodynamically stable PE, but the optimal dosing schedule (once or twice daily) remains controversial. Prognostic prediction models (such as Pulmonary Embolism Severity Index) are being used to categorise risk of mortality, and patients at low risk are suitable for outpatient management or early discharge.
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LMWHs are the treatment of choice for VTE in pregnancy, as warfarin is teratogenic. As the half-life of LMWH in pregnancy is shorter, twice-daily regimens should be utilised for pregnant patients. Furthermore, these patients should be managed in consultation with an obstetrician and a haematologist with an interest in obstetric haematology.
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Studies in cancer patients comparing LMWH to standard warfarin anticoagulation in patients with acute VTE and malignancy demonstrated a significant reduction in the occurrence of recurrent VTE without an increase in bleeding in those receiving LMWH.
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Although there was no reduction in mortality, LMWH was well tolerated and avoided the necessity of frequent INR checks; it therefore should be offered to patients with malignancy and VTE, especially whilst undergoing chemotherapy, which can cause unstable INRs.
Fondaparinux is a pentasaccharide that exerts a selective anti-Xa anticoagulant effect via antithrombin. Once-daily, subcutaneous, fixed-dose fondaparinux (7.5 mg subcutaneously once daily for patients 50–100 kg in weight) has been shown to be as effective and safe as UFH and LMWH for the management of acute symptomatic DVT and PE, and has a licence for these indications. Whilst it is more expensive than UFH and LMWH, it does not need monitoring, nor has it been associated with the development of HIT.
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Warfarin remains the treatment of choice for the majority of patients with VTE. It has a narrow therapeutic window, there is considerable variability in dose response between subjects, it has numerous drug and food interactions, and requires regular monitoring. All too frequently there are dosing problems due to patient non-adherence or miscommunication between patient and health professional. Warfarin inhibits the metabolism of vitamin K, which is required for the essential post-translational modification (carboxylation) of the vitamin K-dependent coagulation factors (factors II, VII, IX and X). The rate of inhibition of these coagulation factors is dependent on their rate of synthesis; factor VII (with a half-life of 6 h) is rapidly inhibited, whereas it takes considerably longer for the activity of factor II (with a half-life of 72 h) to fall. It usually takes 4–7 days for the activities of these vitamin K-dependent coagulation factors to fall to a level at which the patient is therapeutically anticoagulated.
Warfarin is monitored by the INR (derived from the prothrombin time). ‘Bridging’ anticoagulation with UFH, LMWH or fondaparinux should be continued for a minimum of 5 days and until the INR is > 2. The target INR for a patient with DVT or PE (unless the thrombosis occurred on warfarin) is 2.5. Not surprisingly, the most serious adverse complication of oral anticoagulation is bleeding. The risk is directly related to the intensity of anticoagulation and the length of therapy, and is greatest in the elderly, those with unstable anticoagulation and those with significant concomitant illnesses (including past history of gastrointestinal bleeding, renal or liver failure, anaemia, uncontrolled hypertension). The risk of major bleeding with warfarin anticoagulation is reported to be 0.5–6.5% per year and fatal bleeding 0.1–1.0% per year.
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For patients newly starting warfarin anticoagulation it is not (yet) possible to predict their dose, and induction algorithms (such as the modified Fennerty algorithm) should be used to guide dosing.
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Rivaroxaban, a once-daily, oral, direct Xa inhibitor has now been licensed in the UK and approved by NICE and the Scottish Medicines Consortium for the treatment of DVT and the secondary prevention of VTE. In the management of acute DVT, rivaroxaban was non-inferior when compared to traditional anticoagulation (LMWH and warfarin) in the prevention of symptomatic, recurrent VTE, without an increase in bleeding.
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Similar findings were seen in the more recently published study in patients presenting with PE,
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but as yet rivaroxaban is not licensed in the acute management of PE.
There are clear advantages to the use of rivaroxaban in the treatment of patients with DVT; it is an oral medication with a reliable pharmacokinetic profile and therefore does not need monitoring. One disadvantage is that there is no direct antidote, although there is some evidence for the use of prothrombin complex concentrates and novoseven in the management of patients bleeding while taking rivaroxaban.
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It is expected that as clinical experience with these new anticoagulants grows, they will, in time, largely replace the use of warfarin.
Thrombolysis has been used for the treatment of DVT, initially given systemically and more recently by local catheter. Thrombolysis has been demonstrated to produce more rapid early clot lysis and reduced incidence of the post-thrombotic syndrome (PTS), but is associated with a significant risk of bleeding. Patients at low risk of bleeding (predominantly young patients), with extensive iliofemoral DVT, may significantly benefit from this treatment.
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Local administration of thrombolytic agents, or the use of combined catheter-directed thrombolysis with mechanical thrombectomy, reduces that bleeding risk.
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Thrombolytic therapy should be considered for patients with recent-onset (within 7–10 days) massive iliofemoral DVT or those with limb-threatening thrombosis.
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There is no evidence to support the routine use of IVC filters where a patient can be anticoaguated. There is only one randomised trial of the use of vena caval filters in the management of VTE in patients who were anticoagulated; this demonstrated a reduction in symptomatic PE, but a higher risk of recurrent DVT without a reduction in mortality in patients with IVC filters.
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The remainder of the evidence for IVC filter use comes predominantly from descriptive case series and therefore there is little robust evidence to guide the clinician on their use. Both permanent and retrievable filters are available (some may be retrieved up to a few months after insertion). It is recommended that insertion of an IVC filter be considered to prevent PE in patients with VTE and a contraindication to anticoagulation; this includes patients with recent (within 2 months) VTE who require cessation of anticoagulation for surgery. Anticoagulation should be commenced when the contraindication to its use resolves, and should be considered for all patients with IVC filters in situ (dependent on perceived risks of thrombosis from disease and bleeding associated with anticoagulant therapy). It is also reasonable to consider IVC filter insertion in patients who have PE despite therapeutic anticoagulation. If the indication for the filter is temporary, retrievable filters should be used (and then removed) where possible.