Prognosis of stable patients with acute pulmonary embolism (PE) has been assessed with cardiac troponin I (cTnI) and right ventricular (RV) function or size. Whether creatine kinase-MB isoenzyme (CK-MB) would add to the prognostic assessment is uncertain. We retrospectively assessed in-hospital mortality from PE in 392 stable patients to test the hypothesis that CK-MB would be of greater prognostic value than cTnI or RV size and we assessed whether combinations would increase prognostic value. CK-MB was high in 29 patients (7.4%); cTnI was high in 76 patients (19%) and intermediate in 78 patients (20%). The right ventricle was dilated in 128 patients (33%). Trends showed highest in-hospital mortality from PE in 4 of 29 (14%) with high CK-MB compared to 6 of 76 (7.9%) with high cTnI and 8 of 128 (6.3%) with RV dilatation (differences NS). High CK-MB and high cTnI provided added prognostic information only in patients with RV dilatation. Mortality with high CK-MB plus RV dilatation (4 of 19, 21%) tended to exceed mortality with high cTnI plus RV dilatation (5 of 39, 13%, NS). When CK-MB and cTnI were high and the right ventricle was dilated, PE mortality tended to be highest (4 of 14, 29%, NS). In conclusion, cardiac biomarkers contributed to prognosis only in patients with RV dilatation. CK-MB was the strongest predictor of death from PE but its prevalence was low, thus limiting its value as a single prognostic indicator. The combination of high CK-MB, high cTnI, and RV dilatation tended to indicate the highest mortality.
Cardiac troponin I (cTnI) has been used for risk stratification of stable patients with acute pulmonary embolism (PE) and has been particularly useful in combination with an echocardiographic assessment of right ventricular (RV) function or size. There are sparse data on creatine kinase-MB isoenzyme (CK-MB) for assessment of prognosis. High levels of CK-MB have been observed in patients with acute PE. CK-MB has been shown to be an independent predictor of mortality. It seemed to be more specific with regard to prognosis but overall incidence of a high CK-MB was low, limiting its sensitivity. We are not aware of investigations in stable patients with PE in which prognosis was assessed from CK-MB in combination with cTnI or RV size. We assessed in-hospital mortality from acute PE in stable patients to test the hypothesis that CK-MB would be of greater prognostic value than cTnI or RV size and whether combinations with CK-MB would increase its prognostic value.
Methods
This was a retrospective study of stable patients hospitalized with acute PE who had measurements of cTnI, CK-MB, and estimates of RV size. Patients were studied from March 2007 through May 2010 at St. Joseph Mercy Oakland Hospital, Pontiac Michigan and from January 2004 through June 2008 at William Beaumont Hospital, Royal Oak, Michigan. The investigation was approved by the institutional review boards of the 2 hospitals. Diagnosis of PE was made with computed tomographic pulmonary angiography in 378 of 392 patients (96%) and a high probability interpretation of ventilation/perfusion lung scan in 14 of 392 patients (4%).
Exclusions included 573 patients with PE who did not have assessments of each marker (cTnI, CK-MB, and RV size). Patients were also excluded if they were hypotensive (systolic blood pressure <90 mm Hg) or on ventilatory support. Additional exclusions were for possible causes of cTnI increase other than PE such as heart failure (which we defined as an ejection fraction <40%), chronic obstructive pulmonary disease, pneumonia, hemodialysis, coronary artery bypass graft surgery within 1 week, or myocardial infarction or ischemia within 1 week. Exclusions for other known causes of high CK or CK-MB included rhabdomyolysis, severe muscle trauma, and liposuction.
Cardiac biomarkers (CK-MB and cTnI) were measured within 48 hours before or after diagnosis of PE. CK-MB at William Beaumont Hospital was assayed in 382 patients with a 2-site sandwich immunoassay (ADVIA Centaur CK-MB, Deerfield, Illinois). Levels >5.0 ng/ml were defined as high. CK-MB at St. Joseph Mercy Oakland Hospital was assayed in 10 patients with a modified 2-site immunoenzymatic (sandwich) assay (Access Immunoassay System, Beckman Coulter, Fullerton, California). Levels >6.3 ng/mL were defined as high.
Cardiac TnI before October 2006 at William Beaumont Hospital was measured in 73 patients by a Bayer Diagnostics TnI 2-site sandwich immunoassay (Siemens ADVIA Centaur TnL-Ultra, Deerfield, Illinois). A normal level was <0.3 ng/ml, an intermediate or indeterminate level was 0.4 to 1.4 ng/mL, and highly suggestive of myocardial infarction (high) or critical was a level >1.5 ng/ml. Cardiac TnI after October 2006 at William Beaumont Hospital was measured in 309 patients by a Bayer Diagnostics TnI UltraTM troponin 3-site sandwich immunoassay (Siemens ADVIA Centaur TnL-Ultra). A normal level was ≤0.05 ng/ml, an intermediate or indeterminate level was 0.06 to 0.19 ng/ml, and highly suggestive of myocardial infarction (high) or critical was a level ≥0.20 ng/ml. Cardiac TnI at St. Joseph Mercy Oakland Hospital was measured in 10 patients by a 2-site immunoenzymatic (sandwich) assay (Access Immunoassay System, Beckman Coulter, Brea, California). A normal level was <0.05 ng/mL, an intermediate or indeterminate level was 0.05 to 0.49 ng/mL, and highly suggestive of myocardial infarction (high) or critical was a level ≥0.50 ng/ml.
RV dilatation by echocardiography was determined by qualitative impression of reports in 325 of 392 (83%). RV/left ventricular ratios were measured in 67 of 392 (17%). An RV/left ventricular ratio >1 was defined as RV dilatation.
Data were analyzed using SPSS 11.5 for Windows (SPSS, Inc., Chicago, Illinois). Significant tests of equality of 2 proportions were carried out using 2-tailed Fisher’s exact test ( http://www.graphpad.com/quickcalcs/contingency2.cfm ). Although multiple comparisons were made, we did not use Bonferroni correction and considered a p value ≤0.05 as statistically significant. Odds ratios and 95% confidence intervals were calculated using online software ( http://www.hutchon.net/ConfidOR.htm ). Multiple logistic regression analysis was carried out using SAS 9.2 (SAS Institute, Cary, North Carolina).
Results
The mean age of 392 stable patients with acute PE was 68 ± 16 years (mean ± SD); 172 patients (44%) were men. CK-MB was high in 29 patients (7.4%), cTnI was high in 76 patients (19%) and intermediate in 78 patients (20%), and the right ventricle was dilated in 128 patients (33%).
Death from PE in patients with high CK-MB, high cTnI, or RV dilatation was higher than in patients with normal values, but mortality with intermediate cTnI was not higher ( Table 1 ). Mortality with these markers did not significantly differ from each other due to the small sample.
| Mortality Value Normal | Mortality Value Abnormal | p Value (normal vs abnormal) | |
|---|---|---|---|
| Creatine kinase-MB isoenzyme | 8/363 (2.2%) | 4/29 (14%) | 0.008 |
| Cardiac troponin I | 4/238 (1.7%) | ||
| High | 6/76 (7.9%) | 0.02 | |
| Intermediate | 2/78 (2.6%) | NS | |
| Right ventricular size | 4/264 (1.5%) | 8/128 (6.3%) | 0.02 |
Mortality with high CK-MB plus RV dilatation (21%) tended to exceed mortality with high cTnI plus RV dilatation (13%, NS; Table 2 ). Mortality tended to be highest with all 3 markers in combination (high CK-MB, high cTnI, and RV dilatation, 29%; Table 2 ). Cardiac biomarkers provided added prognostic information only in patients with RV dilatation. As with individual markers, combinations did not differ significantly from each other due to the small sample.
| Variable | CK-MB High | cTnI High | CK-MB High and cTnI High | cTnI Intermediate or High | CK-MB High and cTnI Intermediate or High | CK-MB Normal | cTnI Normal | CK-MB Normal and cTnI Normal |
|---|---|---|---|---|---|---|---|---|
| Right ventricle dilated | 4/19 (21%) ⁎ | 5/39 (13%) | 4/14 (29%) | 6/71 (8.5%) | 4/18 (22%) | 4/109 (3.7%) | 2/57 (3.5%) | 2/56 (3.6%) |
| Right ventricle not dilated | 0/10 (0%) | 1/37 (2.7%) | 0/5 (0%) | 2/83 (2.4%) | 0/7 (0%) | 4/254 (1.6%) | 2/181 (1.1%) | 2/178 (1.1%) |
| Total | 4/29 (14%) † | 6/76 (7.9%) | 4/19 (21%) # | 8/154 (5.2%) | 4/25 (16%) ‡ | 8/363 (2.2%) | 4/238 (1.7%) | 4/234 (1.7%) |
⁎ p = 0.02, creatine kinase-MB isoenzyme high and dilated right ventricle versus creatine kinase-MB isoenzyme normal and dilated right ventricle.
† p = 0.008, creatine kinase-MB isoenzyme high versus normal.
‡ p = 0.004, creatine kinase-MB isoenzyme high and cardiac troponin I intermediate or high versus creatine kinase-MB isoenzyme normal and cardiac troponin I normal.
# p = 0.03, creatine kinase-MB isoenzyme high and cardiac troponin I high verses cardiac troponin I intermediate or high. p = 0.002, creatine kinase-MB isoenzyme high and cardiac troponin I high verses creatine kinase-MB isoenzyme normal. p = 0.001, creatine kinase-MB isoenzyme high and cardiac troponin I high verses cardiac troponin I normal. p = 0.001, creatine kinase-MB isoenzyme high and cardiac troponin I high verses creatine kinase-MB isoenzyme normal and cardiac troponin I normal.
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