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Background: Early diagnosis is the cornerstone for management of Acute Myocardial Infarction (AMI). This study compared the diagnostic accuracy of high sensitive troponin T assay (hs cTnT) with Myeloperoxidase (MPO) and Pregnancy Associated Plasma Protein-A (PAPP-A) in patients with recent onset chest pain for early diagnosis of AMI.
Methods: We determined the levels of hs cTnT, MPO and PAPP-A in sixty one consecutive patients with suspected AMI and sixty healthy controls at the time of admission, at 6-9 hours and 12 hours after admission. Receiver Operating Curve was constructed and the Area under the Curve (AUC), 95% confidence intervals (CI), were calculated.
Results: For samples obtained on admission diagnostic accuracy of MPO was equivalent to that for the hs cTnT assay (AUC 0.94; 95% CI 0.891-0.980; vs 0.92; 95% CI 0.858-0.962) .The diagnostic accuracy of PAPP-A was slightly lower (AUC 0.85; 95% CI 0.771-0.907). hs cTnT and MPO diagnosed a greater number of patients at admission as compared to PAPP-A ( 53 (87%) for hs cTnT, 54 (88%) for MPO and 39 (69%) for PAPP-A .
Conclusion: The diagnostic accuracy of MPO is equivalent to that of hs cTnT for the early diagnosis of AMI in patients with recent onset of chest pain.
AMI is associated with considerable mortality and morbidity worldwide. Cardiac Troponins used in conjunction with clinical assessment and ECG are currently the preferred biomarkers of myocardial necrosis for patients presenting with chest pain (Thygesen et al, 2007). However, ECG has low sensitivity for the diagnosis of AMI at the time of patient's presentation in the emergency department of hospitals (Menown, 2000). A delay in the diagnosis of AMI increases the risk of complications and delays the treatment (Bassand, 2007). Therefore early and specific diagnosis is the cornerstone for management of these patients in the coronary care unit and to avoid unnecessary admissions of non-cardiac patients. Standard Troponin assays have low sensitivity and specificity within the first few hours after the onset of chest pain. Recently developed hs cTnT assays have a lower limit of detection as compared to the traditional assays and facilitate earlier diagnosis of AMI in the patients presenting with recent onset chest pain (Reichlin, 2010).
MPO is an enzyme, released from neutrophils in response to acute inflammatory changes in the atherosclerotic plaque. It is being investigated for its role in the early diagnosis of AMI (Eggers, 2010; Gururajan et al; 2009). Patients of AMI presenting less than 2 hours after the onset of chest pain who are initially negative for troponin T have been reported to have significantly higher levels of MPO than healthy controls. It has therefore been suggested that measurement of MPO may be useful for triage in the emergency department (Brennan et al; 2003).
Pregnancy associated plasma protein-A (PAPA-A), a member of the metzincin metalloproteinase superfamily, was first reported to be elevated in the patients of AMI (Bayes-Genis et al; 2001). Since then numerous reports have highlighted its significance in predicting the rupture of unstable atherosclerotic plaque in the patients of coronary artery disease (Lund et al; 2003; Cosin-Sales et al; 2005). However, studies investigating its role in diagnosis of AMI are contradictory. Dominguez-Rodriguez reported that PAPP-A was not a valid early marker for AMI (Dominguez-Rodriguez, 2005). A recent report on the other hand showed PAPP-A to be a more sensitive marker for the diagnosis of AMI than Troponin T and CK-MB (Iversen et al; 2008). Multiple cardiac biomarker approach has previously been studied in the emergency department setting for the early diagnosis of AMI by using standard Troponin assays with MPO and PAPP-A assays along with other biomarkers, however MPO and PAPP-A were found to have low sensitivity and specificity for patients presenting within four hours of symptom onset as compared to the standard Troponin assay (McCann, 2009).
The diagnostic performance of multiple biomarker approach including hs cTnT, MPO and PAPP-A for early detection of patients of AMI needs to be investigated. Objective of this study was to determine the diagnostic accuracy of newly developed hs cTnT as compared with MPO and PAPP-A for the early diagnosis of AMI in patients presenting to the emergency department with recent onset of chest pain.
Materials and Methods
This diagnostic accuracy case-control study was carried out between May-December 2009 at the Chemical Pathology Department, Army Medical College in collaboration with National Institute of Heart Disease Rawalpindi (NIHD)/AFIC, Rawalpindi, Pakistan. Research protocol was approved by institutional ethical committee of AM College, National University of science and technology, Rawalpindi, Pakistan and complies with the Declaration of Helsinki.
Total 69 patients aged 35 to 80 years of either sex, presented to the Emergency Department of AFIC/NIHD within 6 hours of the onset of chest pain and other symptoms suggestive of AMI were consecutively enrolled in this study. Eight patients were excluded because 3 patients were unwilling to participate in the study, 4 patients had chronic renal failure and 1 died in the emergency department. Equal number (n= 60) of age and sex matched controls were recruited from the angiography negative subjects and staff from AFIC after screening through relevant investigation including Exercise Tolerance Test. Informed consent was obtained from all study participants.
All patients underwent an initial clinical assessment by a cardiologist that included a clinical history taking, physical examination, 12 lead ECG, continuous monitoring and serial cardiac troponine were measured. Diagnosis of AMI was based on European society of cardiology/ American college cardiology guideline as detection of rise and/or fall of cardiac troponine with at least one value above the 99th percentile of the upper reference limit together with development of pathological Q waves on ECG (Thygesen et al., 2007). At admission, patients were asked to provide information about history of CAD and associated risk factors. Data were collected prospectively using structured proforma and reviewed by cardiologist for final diagnosis of AMI. Blood samples were collected in K EDTA and plain tubes (5ml) from the patients at the time of presentation to the Emergency Department, before the administration of heparin, and again at 6 and 12 hours after admission. Blood samples were transported immediately to the laboratory where the plasma and serum were separated by centrifugation at 1500 x g for 15 minutes. The samples were stored at -80 C till analysis.
Biochemical analysis was carried out by qualified laboratory technologist according to validated standard procedures in the Pathology Laboratory of Army Medical College, Rawalpindi, Pakistan. Total cholesterol, plasma glucose, and serum creatinine were measured on Vita Lab Selectra ââ‚¬" E Chemistry Analyzer (Netherland) using kits provided by Pioneer Diagnostics (USA). Analysis of hs cTnT was done by using electrochemiluminescence based kit on Elecsys 2010 (Roche Diagnostic, Germany). The kit has a measuring range of 3-10,000 ng/l and a coefficient of variation (CV) was 5.8%. Plasma MPO was analyzed on Architect Analyzer by using the kits of same manufacture (Abbott Diagnostic, USA) which has a measuring range of 20-10,000 pmol/l and CV 4.7%. Serum PAPP-A was measured by ultrasensitive ELISA kit provided by IBL, Germany and cv was 8.1%.
The statistical analysis was performed using SPSS 16 (SPSS Inc, Chicago) and MedCalc software version 184.108.40.206. Continuous normally distributed variables were summarized as mean Â± SD, while other data was expressed as median (first and third quartiles range) for variables with a skewed distribution, or percentage for categorical variables. The distribution of serum hs cTnT, PAPP-A and MPO were non parametric so Mann-Whitney was applied. The area under receiver operator curves (AUROC) of serum hs cTnT, PAPP-A and MPO were calculated for diagnosing AMI. Receiver operator characteristic curves were used to evaluate the diagnostic values and compared by Hanley and McNeil test (Hanley, 1996). The diagnostic accuracy of hs cTnT, PAPP-A and MPO were assessed by sensitivity (SN), specificity (SP), likelihood ratio (LR) and diagnostic odds ratio of the tests. We set the cut-off value at which the discrimination between the cases with positive and negative diagnosis is optimal. Sensitivity, specificity, positive and negative likelihood ratios were calculated, and were used to derive the diagnostic odds ratio. A p-value of p<0.05 was considered significant.
A total of 61 patients of AMI and 60 healthy controls were included in the study from May-June 2009. Their baseline characteristics are given in the table-1. Mean time from the onset of symptom to presentation was 3.4 hours. Retrosternal chest pain (98%) and sweating (61%) were the commonest presenting symptoms, followed by nausea (39%), vomiting (36%), anxiety (13%) and shortness of breath (8%). 6 (9%) patients went into cardiac arrest at the time of presentation to the ER. Baseline serum hs cTnT levels were higher in patients of AMI median IQR 10 (7-10) vs 169 (39-714) ng/L) in controls (p=0.000). Novel biomarkers MPO and PAPP-A were also significantly elevated in patients of AMI at the time of admission Median, IQR for MPO 224.5 (108.12-373) pmol/l vs 906 (564.8-1631.1) (p=0.000), for PAPP-A 1.87 (0.75-3.27) vs 5.78 (2.67-13.48) (p=0.000) (Figure 1).
The diagnostic accuracy for AMI as quantified by the AUC for patients presenting with 3 hours of chest pain onset was the highest for MPO, followed by hscTn T, and PAPP-A (AUC for MPO 0.94; 95% confidence interval [CI], 0.891-0.980; for hs TnT 0.92; 95% CI 0.858-0.962; and for PAPP-A 0.85; 95% CI 0.771-0.907) (Figure 2). AUC for hs cTnT and MPO was significantly greater than the AUC for PAPP-A (p=0.082 for comparison of hs cTnT and PAPP-A, p=0.007 for comparison of MPO and PAPP-A). However, no difference was observed between AUC for MPO and hs cTnT (p=0.387).
The sensitivity and specificity of hs cTnT, MPO and PAPP-A at different cutoff levels were determined (Table 2). The best cutoff value of hs cTnT was 14 ng/L with a sensitivity and specificity of 82.81% and 98.33% respectively for diagnosing AMI. The accuracy of hs cTnT at this cutoff had a positive likelihood ratio of 47.2 and negative likelihood ratio of 0.17 and diagnostic oddââ‚¬â„¢s ratio of 278. The best cut off for MPO and PAPP-A was at 567 pmol/l and 4.7 mIU/l respectively, with sensitivity and specificity of 79.7 % and 98.25% for MPO and 60.94% and 98.25 % for PAPP-A. This cutoff for MPO had a positive likelihood ratio of 45.42 and negative likelihood ratio of 0.21, for PAPP-A positive and negative likelihood ratios were 34.73 and 0.40 respectively whereas the diagnostic odds ratios were 216 and 87 respectively.
Hs cTnT concentrations >14 ng/L were seen in 53 (87%) of 61 patients with STEMI on presentation, in 7 (11%) of 61 patients within 6-9 hrs, and in all patients within 12 h. Estimation of MPO and PAPP-A was performed on the same samples.MPO levels >543 pmol/l derived from healthy controls was present in 54 (88%) of AMI patients at the time of presentation to the ER and in all patients at 6-9 hours. The estimation of MPO therefore diagnosed the same number of patients at the time of initial sampling as hs cTnT. However, PAPP-A > 4.7 mIU/l was present in only 39 (64%) of AMI patients at presentation, in 20 (33%) patients at 6-9 hours and in 2 (3%) at 12 hours (Table 3).
We investigated the diagnostic accuracy of MPO and PAPP-A as compared to hs cTnT in an attempt to identify novel and diagnostically useful biomarkers that could either be used alone or in combination with cardiac Troponins for the early detection of AMI and more importantly for timely patient triage, therapeutic management, and discharge. We found significantly elevated levels of hs cTnT, MPO and PAPP-A in our AMI patients with recent onset chest pain. The levels of MPO observed in our study were similar to the levels observed in previous studies which investigated MPO as a marker of unstable atherosclerotic plaque. Biasucci at al demonstrated reduced intracellular neutrophil MPO content and therefore elevated levels in the circulation of patients with AMI and unstable angina as compared to chronic stable angina and controls (Biasucci et al, 1996). Ndrepapa et al also found the highest circulating levels of MPO in patients of AMI as compared to unstable angina, stable angina and healthy controls (Ndrepapa et al, 2008). Elevated levels of PAPP-A as seen in our patients of AMI were previously observed by Bayes-Genis et al. They reported the highest levels of PAPP-A in patients with AMI as compared to controls (Bayes-Genis et al, 2001).
Based on the AUC we found that MPO, like the hs Trop T assay has excellent diagnostic ability particularly for patients with onset of chest pain within three hours. The diagnostic ability of MPO was first highlighted by Brennan et al, who demonstrated highest AUC for MPO for the diagnosis of ACS in patients who were consistently negative for Trop (Brennan et al, 2001). In a cross-sectional study by Esporcatte et al., an MPO concentration higher than 100 pmol/L had a diagnostic sensitivity of 92% and specificity of 40% as a marker for identifying patients with an acute myocardial infarction (AMI) presenting with acute chest pain and nonââ‚¬"ST elevation electrocardiogram findings (Esporcatte et al;2005). Recently, Gururajan et al; tested MPO levels in patients presenting within 4-6 hours of symptoms of ACS and found an AUC of 0.956 with 95% CI (0.934 to 0.973) (p<0.0001) (Gururajan et al; 2009). The diagnostic ability of MPO in our study was superior to that of PAPP-A as previously suggested by Loria (Loria, 2007). The reasons for this are likely diverse but the most important one is the early rise of MPO and the excellent performance of hs Trop T assay and MPO. The results of our study regarding the accuracy of hs Trop T assay are in complete agreement with two recently conducted studies which compared the new more sensitive assay with the standard fourth generation Trop T assay. In our study the AUC for hs Trop T was 0.92, whereas in the study by Reichlin et al, the AUC of hs Trop T for patients who presented within three hours of onset of chest pain to the emergency department was 0.92; CI, 0.87-0.97. The sensitivity and specificity of the baseline samples at the 99th percentile was 95% and 80% respectively. They thus concluded that the diagnostic performance of sensitive cardiac troponin assays was excellent for the early diagnosis of patients with recent onset chest pain (Reichlin, 2009). Similarly, Gianitsis in his study also demonstrated that use of the 99th percentile cutoff for hs Trop T assay allows earlier diagnosis of NSTEMI. Sensitivity and specificity of samples obtained from patients with signs and symptoms suggestive of ACS at presentation was 61.54% and 77.42% respectively (Gianitsis et al, 2010). Our study demonstrated a sensitivity of 87% and specificity of 98%. This difference in the sensitivity and specificity can be attributed to the difference in the percentage of patients in these studies who presented within three hours of symptom onset, as compared to our study population which was composed exclusively of patients with recent onset of chest pain.
Elevated hs cTnT and MPO levels were already present in 87% and 88% of the patients with AMI respectively and increased gradually to 100% in the serial measurements. Compared to MPO and hs cTnT, PAPP-A on initial measurement identified a relatively smaller percentage of patients (64%), thus allowing us to demonstrate the superior diagnostic ability of MPO in a multiple biomarker strategy.
Our findings are unique in that instead of accepting the non peer reviewed cutoff concentrations provided by assay manufacturers, we independently determined or confirmed biomarker reference limits in our healthy population to establish the cutoffs of novel biomarkers studied for early diagnosis of AMI. We also acknowledge potential limitations of our study, the first one undoubtedly being its small size. Secondly, our study population was comprised of a select group of patients presenting to the emergency department of a cardiology unit. Our results therefore may not be generalized to other settings of patients with more diverse presentations. Moreover, since ours was a cross sectional, observational study we could not evaluate the therapeutic benefit achieved from the early diagnosis. Future studies carried out on larger patient population prospectively evaluating the clinical benefit achieved from the early diagnosis of AMI by MPO are therefore needed. Nevertheless we recommend that the diagnostic performance of MPO is excellent and equivalent to that of hs Trop T assay. It can find potential use in the emergency department for the early diagnosis of AMI either alone or complementary to the hs cTnT.