Cardiac Troponins in Low-Risk Pulmonary Embolism Patients: A Systematic Review and Meta-Analysis
BACKGROUND: Patients with low-risk pulmonary embolism (PE) should be considered as per current scoring systems for ambulatory treatment. However, there is uncertainty whether patients with low scores and positive troponins should require hospitalization.
METHODS: We searched MEDLINE, SCOPUS, and Cochrane Library databases from inception to December 2016 and collected longitudinal studies that evaluated the prognostic value of troponins in patients with low-risk PE. The primary outcome measure was 30-day all-cause mortality. We calculated odds ratio (OR), likelihood ratios (LRs), and 95% confidence intervals (CI) by using random-effects models.
RESULTS: The literature search identified 117 candidate articles, of which 16 met the criteria for review. Based on pulmonary embolism severity index (PESI) or simplified PESI score, 1.2% was the all-cause mortality rate across 2,662 participants identified as low-risk. A positive troponin status in patients with low-risk PE was associated with an increased risk of 30-day all-cause mortality (odds ratio [OR]: 4.79; 95% confidence interval [CI]: 1.11 to 20.68). 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).
CONCLUSION: The use of positive troponin status as a predictor of increased mortality in low-risk PE patients exhibited relatively poor performance given the crossed negative LR CI (1.0) and modest positive LR. Larger prospective trials must be conducted to elucidate if patients with low-risk PE and positive troponin status can avoid hospitalization.
© 2018 Society of Hospital Medicine
Statistical Analysis
Data were summarized by using 30-day all-cause mortality only because it is the most consistent endpoint reported by all of the included studies. For each study, 30-day all-cause mortality was analyzed across the 2 troponin groups, and the results were summarized in terms of positive predictive value (PPV), negative predictive value (NPV), positive likelihood ratio (PLR), negative likelihood ratio (NLR), and odds ratio (OR). To quantify the uncertainty in the LRs and ORs, we calculated 95% confidence intervals (CI).
Overall measures of PPV, NPV, PLR, and NLR were calculated on the pooled collection of data from the studies. LRs are one of the best measures of diagnostic accuracy; therefore, we defined the degree of probability of disease based on simple estimations that were reported by McGee.6 These estimations are independent of pretest probability and include the following: PLR 5.0 increases the probability of the outcome by about 30%, whereas NLR 0.20 decreases the probability of the outcome by 30%. To identify reasonable performance, we defined a PLR > 5 as an increase in moderate to high probability and a NLR < 0.20 as a decrease in moderate to high probability.6
The overall association between 30-day all-cause mortality and troponin classification among patients with low-risk PE was assessed using a mixed effects logistic regression model. The model included a random intercept to account for the correlation among the measurements for patients within a study. The exponentiated regression coefficient for troponin classification is the OR for 30-day all-cause mortality, comparing troponin-positive patients to troponin-negative patients. OR is reported with a 95% CI and a P value. A continuity correction (correction = 0.5) was applied to zero cells. Heterogeneity was measured using Cochran Q statistic and Higgins I2 statistic.
RESULTS
Search Results
Figure 1 represents the PRISMA flow diagram for literature search and selection process to identify eligible studies for inclusion.
Study Characteristics
The abstracts of 117 articles were initially identified using the search strategy described above. Of these, 18 articles were deemed appropriate for review based on the criteria outlined in “Study Selection.” The full-text articles of the selected studies were obtained. Upon further evaluation, we identified 16 articles (Figure 1) eligible for the systematic review. Two studies were excluded because they did not provide the number of study participants that met the primary endpoints. The included studies were published from 2009–2016 (Table 1). For patients with low-risk PE, the number of patients with right ventricle dysfunction was either difficult to determine or not reported in all the studies.
Regarding study design, 11 studies were described as prospective cohorts and the remaining 5 studies were identified as retrospective (Table 1). Seven studies stratified participants’ risk of mortality by using sPESI, and 8 studies employed the PESI score. A total of 6952 participants diagnosed with PE were obtained, and 2662 (38%) were recognized as being low-risk based on either the PESI or sPESI. The sample sizes of the individual studies ranged from 121 to 1,291. The studies used either hs-cTnT, hs-cTnI, cTnT, cTnI, or a combination of hs-cTnT and cTnI or cTnT for troponin assay. Most studies used a pre-defined cut-off value to determine positive or negative troponin status.
Thirteen studies reported 30-day event rate as one of the primary endpoints. The 3 other studies included 90-day all-cause mortality, and 2 of them included in-hospital events. Secondary event rates were only reported in 4 studies and consisted of nonfatal PE, nonfatal major bleeding, and PE-related mortality.
Our systematic review revealed that 5 of the 16 studies used either hemodynamic decompensation, cardiopulmonary resuscitation, mechanical ventilation, or a combination of any of these parameters as part of their primary or secondary endpoint. However, none of the studies specified the number of patients that reached any of these endpoints. Furthermore, 10 of the 16 studies did not specify 30-day PE-related mortality outcomes. The most common endpoint was 30-day all-cause mortality, and only 7 studies reported outcomes with positive or negative troponin status.
Outcome Data of All Studies
A total of 2662 participants were categorized as being low risk based on the PESI or sPESI risk score. The pooled rate of PE-related mortality (specified and inferred) was 5 (0.46%) from 6 studies (1,093 patients), in which only 2 studies specified PE-related mortality as the primary endpoint (Vanni [2011]19 and Jimenez [2011]20). The pooled rate of 30-day all-cause mortality was 24 (1.3%) from 12 studies (1882 patients). In 14 studies (2163 patients), the rates of recurrence of PE and major bleeding were 3 (0.14%) and 6 (0.28%), respectively.
