Cardiac Troponins in Low-Risk Pulmonary Embolism Patients: A Systematic Review and Meta-Analysis

Outcomes of Studies with Corresponding Troponin+ and Troponin –

Seven studies used positive or negative troponin status as endpoint to assess low-risk participants (Table 2). However, only 5 studies were included in the final meta-analysis because some data were missing in the Sanchez¹⁴ study and the Oszu⁸ study’s mortality endpoint was more than 30 days. The risk of bias within the studies was evaluated, and for most studies, the quality was of moderate degree (Supplementary Table 1). Table 2 shows the results for the overall pooled data stratified by study. In the pooled data, 463 (67%) patients tested negative for troponin and 228 (33%) tested positive. The overall mortality (from sensitivity analysis) including in-hospital, 30-day, and 90-day mortalities was 1.2%. The NPVs for all individual studies and the overall NPV are 1 or approximately 1. The overall PPVs and by study were low, ranging from 0 to 0.60. The PLRs and NLRs were not estimated for an outcome within an individual study if none of the patients experienced the outcome. When outcomes were only observed among troponin-negative patients, such as in the study of Moores (2009)²² who used 30-day all-cause mortality, the PLR had a value of zero. When outcomes were only observed among troponin-positive patients, as for 30-day all-cause mortality in the Hakemi(2015)⁹, Lauque (2014)¹⁰, and Lankeit(2011)¹⁶ studies, the NLR had a value of zero. For zero cells, a continuity correction of 0.5 was applied. The pooled likelihood ratios (LRs) for all-cause mortality were positive LR 2.04 (95% CI, 1.53 to 2.72) and negative LR 0.72 (95% CI, 0.37 to 1.40). The OR for all-cause mortality was 4.79 (95% CI 1.11 to 20.68, P = .0357).

A forest plot was created to visualize the PLR from each study included in the main analysis (Figure 2).

A sensitivity analysis among troponin-positive patients was conducted using 90-day all-cause mortality outcome from the study of Ozsu⁸ (2015) and the 2 all-cause mortality outcomes from the study of Sanchez¹⁴ (2013). The pooled estimates from the 30-day all-cause mortality differed slightly from those previously reported. The PLR increased to 3.40 (95% CI 1.81 to 6.37), and the NLR decreased to 0.59 (95% CI 0.33 to 1.08).

In this meta-analysis of 5 studies, which included 691 patients with low-risk PESI or sPESI scores, those tested positive for troponin had nearly a fivefold increased risk of 30-day all-cause mortality compared with patients who tested negative. However, the clinical significance of this association is unclear given that the CI is quite wide and mortality could be associated with PE versus other causes. Similar results were reported by other meta-analyses that consisted of patients with normotensive PE.^23-25 To our knowledge, the present meta-analysis is the first to report outcomes in patients with low-risk PE stratified by the presence of cardiac troponin.

A published paper on simplifying the clinical interpretation of LRs state that a positive LR of greater than 5 and a negative LR of less than 0.20 provide dependable evidence regarding reasonable prognostic performance.⁶ In our analysis, the positive LR was less than 5 and the negative LR’s CI included one. These results suggest a small statistical probability that a patient with a low PESI/sPESI score and a positive troponin status would benefit from inpatient monitoring; simultaneously, a negative troponin does not necessarily translate to safe outpatient therapy, based on our statistical analysis. Previous studies also reported nonextreme positive LRs.^23,24 We therefore conclude that low-risk PE patients with positive troponins may be eligible for safe ambulatory treatment or early discharge. However, the number of outcomes of interest (mortality) occurred in only 6 patients among the 228 patients who had positive troponin status. The majority of deaths were reported by Hakemi et al.⁹ in their retrospective cohort study; as such, drawing conclusions is difficult. Furthermore, the low 30-day all-cause mortality rate of 2.6% in the positive troponin group may have been affected by close monitoring of the patients, who commonly received hemodynamic and oxygen support. Based on these factors, our conclusion is relatively weak, and we cannot recommend a change in practice compared to existing guidelines. In general, additional prospective research is needed to determine whether patients with low-risk PE tested positive for troponin can receive care safely outside the hospital or, rather, require hospitalization similar to patients with intermediate-high risk PE.

We identified a number of other limitations in our analysis. First, aside from the relatively small number of pertinent studies in the literature, most of the studies are of low-moderate quality. Second, the troponin classification in various studies was not conducted using the same assay, and the cut-off value determining positive versus negative results in each case may have differed. These differences may have created some ambiguity or misclassification when the data were pooled together. Third, although the mixed effects logistic regression model controls for some of the variations among patients enrolled in different studies, significant differences exist in terms of patient characteristics or the protocol for follow-up care. This aspect was unaccounted for in this analysis. Lastly, pooled outcome events could not be retrieved from all of the included studies, which would have resulted in a misrepresentation of the true outcomes.

The ESC guidelines suggest avoiding cardiac biomarker testing in patients with low-risk PE because this practice does not have therapeutic implications. Moreover, ESC and ACCP guidelines both state that a positive cardiac biomarker should discourage treatment out of the hospital. The ACCP guidelines further encourage testing of cardiac biomarkers and/or evaluating right ventricular function via echocardiography when uncertainty exists regarding whether patients may require close in-hospital monitoring or not. Although no resounding evidence suggests that troponins have therapeutic implications in patients with low-risk PE, the current guidelines and our meta-analysis cannot offer an overwhelmingly convincing recommendation about whether or not patients with low-risk PE and positive cardiac biomarkers are best treated in the ambulatory or inpatient setting. Such patients may benefit from monitoring in an observation unit (eg, less than 24 or 48 hours), rather than requiring a full admission to the hospital. Nevertheless, our analysis shows that making this determination will require prospective studies that will utilize cardiac troponin status in predicting PE-related events, such as arrhythmia, acute respiratory failure, and hemodynamic decompensation, rather than all-cause mortality.

Until further studies, hospitalists should integrate the use of cardiac troponin and other clinical data, including those available from patient history, physical exam, and other laboratory testing, in determining whether or not to admit, observe, or discharge patients with low-risk PE. As the current guidelines recommend, we support consideration of right ventricular function assessment, via echocardiogram or computed tomography, in patients with positive cardiac troponins even when their PESI/sPESI score is low.