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The European guidelines1 and American guidelines2 highlight that, in the diagnosis and management of acute pulmonary embolism (PE), the functional consequences determined by right ventricular (RV) dysfunction and elevation of cardiac biomarkers are more relevant for risk stratification than assessment of the anatomical burden and distribution of the pulmonary artery thrombus. The mortality rate associated with massive PE may reach 30%, while that associated with so-called submassive PE (defined as the presence of RV dysfunction without systemic hypotension) is between 5% and 10% and that associated with non-massive PE is <5%.1 While there is consensus that thrombolytic therapy, catheter embolectomy or surgery are indicated in patients with right heart failure and haemodynamic instability, the appropriate treatment of patients with submassive PE remains controversial. In this subset of patients, the ‘tricks of the trade’3 should be identified and clinical-laboratory aspects evaluated to judge the level of severity. RV echocardiographic parameters, cardiac troponins and peripheral ultrasound data are described as poor prognostic factors in the currently available literature.
Each of these tests has its own advantages and limitations. A number of studies have shown that RV dysfunction and dilation is a robust prognostic factor in acute PE. Still, some questions arise. First, the different pathophysiology of acute versus chronic pulmonary hypertension has recently been outlined.4 Similarities between PE (acute occlusive pulmonary hypertension) and chronic pulmonary hypertension include the fact that pulmonary circulatory resistance increases, RV function may decline and mortality and morbidity are correlated with the extent of RV dysfunction in both cases. Nevertheless, the mechanisms of cardiopulmonary changes are very different and result in different modes of RV injury that require unique therapeutic targets. Second, no uniform criteria have been used in different studies to assess the presence of RV dysfunction.5 6 In the majority of studies, RV dysfunction was defined as RV hypokinesis as assessed by qualitative evaluation of RV wall motion. The quantitative assessment has included RV dilation (end-diastolic diameter >30 mm in parasternal view, RV–LV end-diastolic diameter ratio >1 in four-chamber view, RV–LV end-diastolic diameter ratio >0.6 in parasternal or subcostal views, RV end-diastolic area >20 cm2 in apical, subcostal or transoesophageal four-chamber views), RV wall hypertrophy (free wall thickness >5 mm in parasternal or subcostal views), dilation of the right pulmonary artery (>12 mm/m2), loss of inspiratory collapse of the inferior vena cava and pulmonary hypertension (defined as Doppler pulmonary acceleration time <90 ms or the presence of a right ventricular–atrial gradient >30 mm Hg). Lastly, new echocardiographic parameters of RV dysfunction are being studied7 and, with recent advances in Doppler and tissue Doppler echocardiography, new methods for measuring regional and global RV function or contractility have been suggested.8 Thus, a uniformly accepted definition of the criteria for echocardiographically-detected RV dysfunction would be desirable to give a conclusive answer on the prognostic significance of echocardiographic RV dysfunction in haemodynamically stable patients with PE.
Several studies have attempted to identify laboratory data which have prognostic power in patients with acute PE. Many of these have focused on cardiac biomarkers including the troponins and natriuretic peptides which correlate with RV dysfunction on echocardiography. Comprehensive meta-analyses of the prognostic value of troponins in acute PE have been reported.9 10 Their prognostic value was consistent among the studies, regardless of the specific assay and the relative cut-off point. The results were consistent for both troponin I and T. However, it is unclear whether thrombolysis has a role in the management of haemodynamically stable patients on the basis of troponin elevation and, if it has, which patients should be selected for this treatment.
The prognosis in the presence of lower limb deep vein thrombosis (DVT) evaluated with compression ultrasound (CUS) in patients with symptomatic PE has been investigated.11 12 Multivariate analysis showed that active cancer, inadequate anticoagulation, leg symptoms, male gender, presence of DVT, presence of proximal DVT and previous DVT were independent risk factors for an adverse outcome. Whole leg CUS, which captures images from the iliac to the calf veins, may improve initial detection of distal DVT. Bilateral examination is justified especially in patients with a history of an active malignancy because of the high incidence of asymptomatic contralateral thrombosis. However, there is still much debate about the importance of DVT as a significant risk factor for the onset of PE. While several investigators have reported the important role of lower extremity CUS in the follow-up of PE, others found no significant difference in the risk of recurrent thromboembolic events or death among patients with PE with and without DVT.13 Each patient might have different risks for thrombosis or bleeding and potentially adverse consequences despite prophylaxis. What is best epidemiologically for the group is not necessarily what is best clinically for the individual patient.
Jiménez et al assessed the ability of three diagnostic tests (cardiac troponin I, echocardiography and lower extremity CUS) obtained soon after diagnosis of PE to prognosticate the primary study outcome—PE-related death—during 30 days of follow-up after PE diagnosis.14 Multivariate logistic regression confirmed these tests as significant predictors of death from PE. Use of any two-test strategy had a higher specificity and positive predictive value than either test alone. They concluded that, in haemodynamically stable patients with PE, a combination of echocardiography (or troponin testing if echocardiography is not readily available) and CUS improved prognostication compared with the use of each test alone for identification of those at high risk for PE-related death.
Previous studies have been published in this area15–18 but have provided equivocal findings regarding performance of test combinations for prognosticating PE-related adverse events. Whereas in some reports the addition of echocardiographic data to the blood test data did not improve the test characteristics,15 in others the combination of troponin I and echocardiography improved the prognostic value compared with each test alone.16–18 The paper by Jiménez and colleagues adds to the existing literature by providing a valuable contribution to this important debate and by showing that, among the two-test strategies, the combination of echocardiography and venous ultrasound had the best test characteristics of positive predictive value and positive likelihood ratio in all study patients and in the high-risk subgroup. This study supplies useful insights into risk stratification in normotensive patients presenting with acute PE, since there is a growing interest in the early discharge and outpatient management of subjects presenting with acute PE who are haemodynamically stable. Owing to the high rate of hospital mortality in this group, it is important that every attempt is made to identify those at the highest risk who could not be treated in an outpatient setting and could require close monitoring or even more aggressive therapy.
Some cautions should be noted in evaluating the conclusions drawn from this study. The particular approach may depend on available hospital resources, especially whether echocardiography can be readily obtained on holidays. Echocardiographic images are useful only if the RV free wall can be clearly defined. In any case, assessment of RV function can also be challenging with good acoustic windows and even with other alternative techniques such as CT scanning.19 In the presence of persistent elevation of troponins and the absence of coronary angiography data, a significant occlusion of coronary vessels cannot be excluded, especially in patients with ST segment elevation. Besides troponins, increased B-type natriuretic peptides were also found to be an independent prognostic marker of morbidity and mortality in acute PE.10 16 Patients with increased levels of both natriuretic peptides and troponins are at a particularly high risk of adverse outcomes, and natriuretic peptides appear to be especially helpful in identifying low-risk patients, given their very low positive rate among those with a poor outcome. The relative contribution of troponins and natriuretic peptides for risk stratification in clinical practice remains to be defined.
However, undoubtedly the use of echocardiography (including transoesophageal echocardiography), laboratory findings and venous ultrasonography should be encouraged in patients with suspected high-risk PE. Management decisions should be taken based on all collected data on a case by case basis. Each test comes to the rescue of the others. ‘One for all and all for one’.
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