Evidence-based Cardiology – part 10 docx

Evidence-based Cardiology 868 with size and number, and the presence of a normal ventilation scan (“mismatched” defect). 42,45 A lung scan with mismatched segmental or larger perfusion defects is termed “high probability”. 45 A single mismatched defect is associated with a prevalence of PE of about 80%. 46 Three or more mismatched defects are associated with a prevalence of PE of Ն90%. 46 Lung scan findings are highly age dependent with a relatively high proportion of normal scans and a low proportion of non-diagnostic scans in younger patients. 33 Lung scanning and clinical assessment Clinical assessment of PE is complementary to ventilation– perfusion lung scanning; a moderate or high clinical suspicion in a patient with a high probability lung scan is diagnostic (prevalence of PE of Ն90%); however, a low clinical suspicion with a high probability defect requires further investigation because the prevalence of PE with these findings is only about 50%. 42,45 The prevalence of PE with subsegmental, matched, perfusion defects (“low probability” scan) and a low clinical suspicion is expected to be less than 10% (see below). 27,30,42 Helical (spiral) computerized tomography (CT) Helical CT following intravenous injection of radiographic contrast can be used to visualize the pulmonary arteries. Although widely used to diagnose PE, the technique has yet to be definitively evaluated for this purpose. 47,48 Grade B Grade A Current evidence suggests that helical CT can be interpreted as follows: ● Intraluminal filling defects in lobar or main pulmonary arteries are likely to be associated with a probability of PE of at least 85%, similar to a high-probability ventilation– perfusion scan. 48 ● Intraluminal defects confined to segmental or subsegmental pulmonary arteries are non-diagnostic, and patients with such findings require further testing. 48 ● A normal helical CT substantially reduces the probability of PE but does not exclude the diagnosis (that is, similar to a “low probability” ventilation–perfusion scan). 47,48 Although this statement is largely based on extrapolation from experience with patients who have non-diagnostic lung scans, patients with helical CT scans that are not diagnostic for PE can be managed as outlined in Box 61.4. Grade C Table 61.3 Model for determining a clinical suspicion of pulmonary embolism (Wells et al 123 ) Variables Points Clinical signs and symptoms of deep vein 3·0 thrombosis (minimum leg swelling and pain with palpation of the deep veins) An alternative diagnosis is less likely than 3·0 pulmonary embolism Heart rate Ͼ100 beats/min 1·5 Immobilization or surgery in the 1·5 previous 4 weeks Previous deep vein thrombosis/pulmonary 1·5 embolism Hemoptysis 1·0 Malignancy (treatment ongoing or within 1·0 previous 6 months or palliative) Total points Pretest probability calculated as follows: High Ͼ6 Moderate 2–6 Low Ͻ2 Box 61.4 Test results which effectively confirm or exclude pulmonary embolism (PE) ● Diagnostic for PE ● Pulmonary angiography: intraluminal filling defect ● Helical CT: intraluminal filling defect in a lobar or main pulmonary artery 47,48 ● Ventilation–perfusion scan: high probability scan and moderate/high clinical suspicion 42,43 ● Diagnostic for DVT: with non-diagnostic ventilation– perfusion scan or helical CT 124 ● Excludes PE ● Pulmonary angiogram: normal 39 ● Perfusion scan: normal 41 ● D-dimer: normal test, which has a very high sensitivity (Ն98%) and at least a moderate specificity (Ն40%) 27 ● Non-diagnostic ventilation–perfusion scan, or normal helical CT, and normal proximal VUI and (a) low clinical suspicion for PE 30,50 a (b) normal D-dimer test, which has at least a moderately high sensitivity (Ն85%) and specificity (Ն70%) 30,32 a ● Low clinical suspicion for PE and normal D-dimer, which has at least a moderately high sensitivity (Ն85%) and specificity (Ն70%) 30,32 a If serial VUI (venous ultrasound imaging) is performed it is expected to become abnormal in 1–2% of these patients and reduce the frequency of symptomatic VTE (venous thromboembolism) during 3 months of follow up from ϳ1.5% to ϳ0.5%. (Adapted from Kearon 40 ) D-dimer testing As previously discussed when considering diagnosis of DVT, a normal D-dimer result, alone 27 or in combination with another negative test, 30,32 can be used to exclude PE (Box 61.4). Grade A evolving proximal DVT, the forerunner of recurrent PE. If serial VUI for DVT (two additional tests a week apart) is negative, the subsequent risk of recurrent VTE during the next 3 months is less than 1%, 30,44,51 which is similar to that after a normal pulmonary angiogram. 39 As an additional precau- tion, patients who have had PE and/or DVT excluded should routinely be asked to return for re-evaluation if symptoms of PE and/or DVT persist or recur. Diagnosis of PE in pregnancy Pregnant patients with suspected PE can be managed similarly to non-pregnant patients, with the following modifications: ● VUI can be performed first and lung scanning performed if there is no DVT; patients with unequivocal evidence of DVT can be presumed to have PE. ● The amount of radioisotope used for the perfusion scan can be reduced and the duration of scanning extended. ● If pulmonary angiography is performed, the brachial approach with abdominal screening is preferable. ● In the absence of safety data relating to helical CT in pregnancy, this is discouraged (if it is necessary, abdominal screening should be used). Consistent with other young patients who are suspected of having PE, a high proportion of pregnant patients have normal scans and a small proportion have high probability scans. 33,52 These recommendations are based on a belief that the risk of inaccurate diagnosis of suspected PE during pregnancy is greater than the risk of radioactivity to the fetus. 52,53 Algorithms for the diagnosis of PE Local availability of methods of testing and differences among patient presentations influence the diagnostic approach to PE. A number of prospectively validated algorithms have been published, which emphasize the use of different initial non-invasive tests in conjunction with ventilation–perfusion lung scanning including: ● structured clinical assessment and serial VUI; 44 ● sensitive D-dimer assay, empiric clinical assessment, and single bilateral VUI; 27 ● clinical assessment, moderately sensitive D-dimer assay and serial VUI. 30 Prevention of VTE (Box 61.6) In a non-randomized trial, oral anticoagulation was shown to prevent PE in patients with fractured hips, without caus- ing an unacceptable increase in bleeding. 54 Subsequently, low-dose unfractionated heparin was shown to reduce postoperative DVT and fatal PE by two thirds. 55,56 Further studies have demonstrated that the efficacy of Grade A Grade B Venous thromboembolic disease 869 Tests for DVT in patients with suspected PE Testing for DVT is an indirect way to diagnose PE (see Box 61.4). 49 VUI of the proximal veins is the usual method, although bilateral ascending venography, or CT or MRI of the legs at the same time as examination of the pulmonary veins, can also be used. Negative tests for DVT do not rule out PE but they reduce the probability, and suggest that the short-term risk of recurrent PE is low. 49 Because the prevalence of PE is expected to be less than 5% in patients with a non-diagnostic lung scan, a low clinical suspicion of PE, and a normal VUI of the proximal veins, it is reasonable to exclude PE with these findings. 27,30,44,50 Management of patients with non-diagnostic combinations of non-invasive tests for PE (Box 61.5) Patients with non-diagnostic test results for PE at presentation have, on average, a prevalence of PE of 20%. 42,49 Two management approaches are reasonable in such patients. The first is the performance of pulmonary angiography, which is usually definitive. The second is the withholding of anticoagulants and performance of serial VUI to detect Grade B Box 61.5 Management of patients with non-diagnostic non-invasive tests for PE ● Serial VUI of the proximal veins after 1 and 2 weeks Suitable for most such patients, 30,44 although pulmonary angiography is preferred for the subgroups outlined below. This approach can be supplemented with bilateral venography (for patients that might otherwise be considered for pulmonary angiography). 116 ● Pulmonary angiography preferred option if: ● segmental intraluminal filling defect on helical CT a,b ● subsegmental intraluminal filling defect and high clinical suspicion ● high probability ventilation–perfusion scan and low clinical suspicion b ● symptoms are severe, post-test probability is high but non-diagnostic, and PE needs to be excluded from the differential diagnosis ● serial testing is not feasible (for example, scheduled for surgery, geographic inaccessibility) a A segmental intraluminal filling defect with a high clinical suspicion is likely to have a positive predictive value of Ն85% and could be considered diagnostic for PE. b Ventilation–perfusion scanning can be performed after these findings have been obtained with helical CT; or helical CT may be performed after these findings have been obtained with ventilation–perfusion scanning; 47,48 If the second test is also non-diagnostic for PE, serial ultrasounds may be reconsidered. Abbreviations: DVT, deep vein thrombosis; LMWH, low molecular weight heparin; PE, pulmonary embolism; VTE, venous thromboembolism; VUI, venous ultrasound imaging, (Adapted from Kearon 40 ) reduction in VTE), aspirin alone is not recommended during the initial postoperative period. 62 It may be a reasonable alternative to LMWH or warfarin for the weeks following hospital discharge, particularly if patients do not have additional risk factors for VTE. Recently, hirudin 66 (a direct thrombin inhibitor) and fondaparinux 67,67a,67b (the pentasaccharide of heparin that binds antithrombin) have been shown to be more effective than LMWH following major orthopaedic surgery; fondaparinux may cause marginally more bleeding. The evidence that short-term prophylaxis (for example, low-dose unfractionated heparin) prevents clinically important VTE in immobilized medical patients is less convincing, partly because it has been less extensively studied in this population, and because there is concern that medical patients remain at high risk of VTE after prophylaxis is stopped. 62,68 In addition to augmenting the efficacy of pharmacologic methods of prophylaxis, mechanical methods are effective on their own. Graduated compression stockings prevent postoperative VTE in moderate-risk patients (risk reduction of 68%), 62,69 and intermittent pneumatic compression devices prevent postoperative VTE in high-risk orthopedic patients. 62,70,71 The relative efficacy of graduated compression stockings and intermittent pneumatic compression devices is uncertain. No difference in efficacy was evident in neurosurgical patients; 72 however, pneumatic compression devices are expected to be superior to graduated compression stockings in high-risk patients. 62 Mechanical methods of prophylaxis should be used in patients who have a moderate or high risk of VTE if anticoagulants are contraindi- cated (for example, neurosurgical patients). 62 Because postoperative fatal PE is rarely preceded by symptomatic DVT, 55 prophylaxis is the best way to prevent it. Use of primary prophylaxis is strongly supported by cost effectiveness analyses, which indicate that it reduces overall costs in addition to reducing morbidity. 73 Treatment of VTE Heparin therapy In 1960, Barritt and Jordan established that heparin (1·5 days) and oral anticoagulants (2 weeks) reduced the risk of recurrent PE and associated death. 74 Based on expert opin- ion, 10–14 days of heparin therapy, and 3 months of oral anticoagulation became widely adopted in clinical practice. It was subsequently shown that 4 or 5 days of intravenous heparin is as effective as 10 days of therapy for the initial treatment of VTE. 75,76 Comparatively recently, the need for an initial course of heparin therapy was verified. 77 Many trials have established that weight-adjusted LMWH (without laboratory monitoring) is as safe and effective as adjusted-dose unfractionated heparin for the treatment of acute VTE; 78 it can be used to treat patients without hospital admission 79 and need only be Grade A Grade A Grade B Evidence-based Cardiology 870 low-dose unfractionated heparin can be improved either by increasing the dose so as to minimally prolong the activated partial thromboplastin time (APTT), 57 or by combining its use with graduated compression stockings 58 or intermittent pneumatic compression devices. 59 Meta-analyses support that, at doses that are associated with equivalent efficacy (odds ratio 1·03) following general surgery, low molecular weight heparins (LMWH) are associated with less bleeding (odds ratio 0·68) than low-dose unfractionated heparin. 60 Used at higher dose than for general surgery, LMWH is more effective (odds ratio 0·83) that unfractionated heparin following orthopedic surgery and is associated with a similar frequency of bleeding. 60 An additional 3 or 4 weeks of LMWH after hospital discharge further reduces the frequency of symptomatic VTE after orthopedic surgery (from 3·3% to 1·3% 61 ). Warfarin (target INR 2–3 for about 7 to 10 days) is less effective that LMWH at preventing DVT detected by venography soon after orthopedic surgery, 62 but appears to be similarly effective at preventing symptomatic VTE over a 3 month period. 62,63 There is evidence that aspirin reduces the risk of postoperative VTE by one third. 64 A study of over 17000 patients, mostly following hip fracture repair, confirmed these findings, including a reduction in fatal PE (0·27% v 0·65%) during the month following surgery. 65 However, as warfarin and LMWH are expected to be more effective (at least a two thirds Grade A Grade A Grade A Box 61.6 Prevention and treatment of venous thromboembolism ● Primary prophylaxis with anticoagulants and/or mechanical methods should be used in hospitalized patients who have a moderate or high risk of VTE. ● Acute VTE (DVT and/or PE) should be anticoagulated with: ● Heparin (unfractionated or LMWH) for a minimum of 4–5 days. If unfractionated heparin is used, a dose of at least (a) 30 000 U/ day or 18 U/kg/h by intravenous infusion; or (b) 33 000U/day, by twice daily, subcutaneous, injection, should be administered. Dose of unfractionated heparin should be adjusted to achieve “therapeutic” APTT results. ● Oral anticoagulation for 3–6 months, with a dose adjusted to achieve an INR of 2.0–3.0. Prolonged unfractionated heparin or LMWH at therapeutic, or near therapeutic, doses is a satisfactory alternative. Anticoagulation should be continued for longer than 3 months in patients with a first episode of idiopathic VTE, and when VTE is associated with a risk factor, for as long as such factors are active. See Box 61.5 for abbreviations Grade C Grade B Grade A Grade A Grade A Grade C Grade A Grade A Grade A injected subcutaneously once daily. 80 Danaparoid, hirudin, and argatroban can be used to treat heparin induced thrombocytopenia, with or without associated thrombosis. 81,82 Oral anticoagulant therapy A randomized trial of patients with DVT, comparing 3 months of warfarin (International Normalization Ratio (INR) ϳ3·0–4·0) with low-dose heparin after initial treatment with full-dose intravenous heparin, established the necessity for prolonged oral anticoagulation after initial heparin therapy. 83 Prolonged high-dose subcutaneous heparin 84 and, subsequently, LMWH (50–75% of acute treatment dose) was subsequently shown to be equally effective. 85 In the 1970s it was recognized that, because of differences in the responsiveness of thromboplastins to oral anticoagulants, a prothrombin time ratio of 2·0 reflected a much more intense level of anticoagulation in North America than in Europe. This prompted a comparison of two intensities of warfarin therapy (corresponding to mean INRs of ϳ2·1 and ϳ3·2) for the treatment of DVT. 86 This study found that the lower intensity of oral anticoagulation was as effective as the higher intensity but caused less bleeding. The trials showing that heparin therapy could be reduced to 5 days also showed that warfarin could be started at the same time as heparin. 75,76 A recent series of small studies support starting warfarin with the expected daily dose rather than a loading dose (for example, 5mg v 10mg), 87,88 and managing over-anticoagulation without bleeding (for example, INRsՆ6) with small oral rather than subcutaneous doses of vitamin K (for example, 1mg). 89 During the last decade, a series of well-designed studies have helped to define the optimal duration of anticoagulation. Their findings can be summarized as follows: ● Shortening the duration of anticoagulation from 3 90,91 or 6 92 months to 4 90,91 or 6 92 weeks results in a dou- bling of the frequency of recurrent VTE during 1 90,91 to 2 92 years of follow up. ● Patients with VTE provoked by a transient risk factor have a lower (about one third) risk of recurrence than those with an unprovoked VTE or a persistent risk factor. 90–94 ● Three months of anticoagulation is adequate treatment for VTE provoked by a transient risk factor; subsequent risk of recurrence is Յ3% per patient-year. 90,91,94–96 ● Three months of anticoagulation may not be adequate treatment for an unprovoked (“idiopathic”) episode of VTE; subsequent early risk of recurrence has varied from 5% to 25% per patient-year. 92,95,97,98 ● After 6 months of anticoagulation, recurrent DVT is at least as likely to affect the contralateral leg; this suggests that “systemic” rather than “local” (including inadequate treatment) factors are responsible for recur- rences after 6 months of treatment. 99 Grade A Grade A Grade A Grade A ● There is a persistently elevated risk of recurrent VTE after a first episode; this appears to be 5–12% per year after 6 or more months of treatment for an unprovoked episode. 92,95,98 ● Oral anticoagulants targeted at an INR of ϳ2·5 are very effective (risk reduction Ն90%) at preventing recurrent unprovoked VTE after the first 3 months of treatment. 97,100 ● Indefinite anticoagulation is an option for patients with a first unprovoked VTE who have a low risk of bleeding. ● A second episode of VTE does not necessarily indicate a high risk of recurrence or the need for indefinite anticoagulation. 97 ● Risk of bleeding on anticoagulants differs markedly among patients depending on the prevalence of risk factors (for example, advanced age; previous bleeding or stroke; renal failure; anemia; antiplatelet therapy; malignancy; poor anticoagulant control). 101 ● Risk of recurrence is lower (about half) following an isolated calf (distal) DVT; this favors a shorter duration of treatment. 92,95 ● Risk of recurrence is higher with antiphospholipid antibodies (anticardiolipin antibodies and/or lupus anticoagulants), 97,102 homozygous factor V Leiden 103 cancer 93 and, probably, antithrombin deficiency; these favor a longer duration of treatment. ● Heterozygous factor V Leiden and the G20210A prothrombin gene mutations do not appear to be clinically important risk factors for recurrence. 103 ● Other abnormalities, such as elevated levels of clotting factors VIII, IX, XI, and homocysteine, and deficiencies of protein C and protein S, may be risk factors for recurrence; they have uncertain implications for duration of treatment. Thrombolytic therapy Systemic thrombolytic therapy accelerates the rate of reso- lution of DVT and PE at the cost of around a fourfold increase in frequency of major bleeding, and about a 10-fold increase in intracranial bleeding. 104–107 This can be life-saving for PE with hemodynamic compromise. 106,108 Thrombolytic therapy may reduce the risk of the prothrom- botic syndrome following DVT but this does not appear to justify its associated risks 104,105 Catheter-based treatments (that is, thrombolytic therapy or removal of thrombus) require further evaluation before they can be recommended. Inferior vena caval filters A recent randomized trial demonstrated that a filter, as an adjunct to anticoagulation, reduced the rate of PE (asymptomatic and symptomatic) from 4·5% to 1·0% during the Grade A Grade B Grade B Grade B Grade B Grade A Venous thromboembolic disease 871 in the prevention of deep vein thrombosis in thrombotic stoke. 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Evidence-based Cardiology 872 12 days following insertion, with a suggestion of fewer fatal episodes (0% v 2%). 109 However, after 2 years, patients with a filter had a significantly higher rate of recurrent DVT (21% v 12%) and a non-statistically significant reduction in the frequency of PE (3% v 6%). This study supports the use of vena caval filters to prevent PE in patients with acute DVT and/or PE who cannot be anticoagulated (that is, they are bleeding), but does not support more liberal use of filters. Patients should receive a course of anticoagulation if this subsequently becomes safe. Treatment of VTE during pregnancy Unfractionated heparin and LMWH do not cross the placenta and are safe for the fetus, whereas oral anticoagulants cross the placenta and can cause fetal bleeding and malformations. 110,111 Therefore, pregnant women with VTE should be treated with therapeutic doses of subcutaneous heparin (unfractionated heparin or, increasingly, LMWH) throughout pregnancy. Care should be taken to avoid delivery while the mother is therapeutically anticoagulated; one management approach involves stopping subcutaneous heparin 24 hours prior to induction of labor and switching to intravenous heparin if there is a high risk of embolism. After delivery, warfarin, which is safe for infants of nursing mothers, should be given (with initial heparin overlap) for 6 weeks and until a minimum of 3 months of treatment has been completed. The future There are many questions relating to currently available antithrombotic agents and diagnostic techniques that need answering, and many new antithrombotic agents under development that will require clinical evaluation. In addition, future studies are expected to focus on clinical and genetic subgroups that may benefit from tailored management, such as different intensities or durations of prophylaxis or treatment. 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