Sylvie R. Stacy, MD, MPH (1); Catalina Suarez-Cuervo, MD (1); Zackary Berger, MD, PhD; Lisa M. Wilson, ScM; Hsin-Chieh Yeh, PhD; Eric B. Bass, MD, MPH; Erin D. Michos, MD, MHS
* Drs. Stacy and Suarez-Cuervo contributed equally to this work.
This article was published online first at www.annals.org on 12 August 2014.
Disclaimer: The authors of this article are responsible for its contents, including any clinical or treatment recommendations. No statement in this article should be construed as an official position of AHRQ or the U.S. Department of Health and Human Services.
Acknowledgment: The authors thank Elisabeth Nannes, Brijesh Patel, Sunil Agrawal, Allen Zhang, Sylvia Wang, and Oluwaseun Shogbesan for their help in reviewing articles and abstracting data.
Financial Support: This article is based on research conducted by the Johns Hopkins University Evidence-based Practice Center under contract with AHRQ (contract 290-2012-00007-I).
Disclosures: Dr. Stacy reports that she worked under a contract from AHRQ during the conduct of the study. Ms. Wilson reports that she worked under a contract from AHRQ during the conduct of the study. Dr. Bass reports receiving a contract from AHRQ for the conduct of the study. Dr. Michos worked under a contract from AHRQ during the conduct of the study and a grant from the National Institutes of Health outside of the submitted work. Authors not named here have disclosed no conflicts of interest. Disclosures can also be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M14-0746.
Requests for Single Reprints: Erin D. Michos, MD, MHS, Associate Professor of Medicine, Division of Cardiology, Johns Hopkins University School of Medicine, 600 North Wolfe Street, Carnegie 568, Baltimore, MD 21287; e-mail, email@example.com.
Current Author Addresses: Dr. Stacy: Johns Hopkins Bloomberg School of Public Health, 615 North Wolfe Street, Room WB602, Baltimore, MD 21205.
Dr. Suarez-Cuervo and Ms. Wilson: Johns Hopkins University, Evidence-based Practice Center, 624 North Broadway, Suite 680, Baltimore, MD 21205.
Dr. Berger: Johns Hopkins Outpatient Center, 601 North Caroline Street, Suite 7143, Baltimore, MD 21287.
Dr. Yeh: Johns Hopkins University, 2024 East Monument Street, Suite 2-500, Baltimore, MD 21287.
Dr. Bass: Johns Hopkins University School of Medicine, 624 North Broadway, Room 680A, Baltimore, MD 21205.
Dr. Michos: Johns Hopkins University School of Medicine, 600 North Wolfe Street, Carnegie 568, Baltimore, MD 21287.
Author Contributions: Conception and design: C. Suarez-Cuervo, Z. Berger, L.M. Wilson, H.C. Yeh, E.B. Bass, E.D. Michos.
Analysis and interpretation of the data: S.R. Stacy, C. Suarez-Cuervo, Z. Berger, L.M. Wilson, H.C. Yeh, E.B. Bass, E.D. Michos.
Drafting of the article: S.R. Stacy, C. Suarez-Cuervo, Z. Berger, E.D. Michos.
Critical revision of the article for important intellectual content: C. Suarez-Cuervo, Z. Berger, L.M. Wilson, H.C. Yeh, E.B. Bass, E.D. Michos.
Final approval of the article: S.R. Stacy, C. Suarez-Cuervo, Z. Berger, L.M. Wilson, E.B. Bass, E.D. Michos.
Provision of study materials or patients: L.M. Wilson, E.B. Bass.
Statistical expertise: H.C. Yeh.
Obtaining of funding: E.B. Bass.
Administrative, technical, or logistic support: L.M. Wilson, E.B. Bass, E.D. Michos.
Collection and assembly of data: S.R. Stacy, C. Suarez-Cuervo, Z. Berger, L.M. Wilson, E.D. Michos.
Stacy SR, Suarez-Cuervo C, Berger Z, Wilson LM, Yeh H, Bass EB, et al. Role of Troponin in Patients With Chronic Kidney Disease and Suspected Acute Coronary Syndrome: A Systematic Review. Ann Intern Med. 2014;161:502-512. doi: 10.7326/M14-0746
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Published: Ann Intern Med. 2014;161(7):502-512.
Patients with chronic kidney disease (CKD) have high prevalence of elevated serum troponin levels, which makes diagnosis of acute coronary syndrome (ACS) challenging.
To evaluate the utility of troponin in ACS diagnosis, treatment, and prognosis among patients with CKD.
MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials through May 2014.
Studies examining elevated versus normal troponin levels in terms of their diagnostic performance in detection of ACS, effect on ACS management strategies, and prognostic value for mortality or cardiovascular events after ACS among patients with CKD.
Paired reviewers selected articles for inclusion, extracted data, and graded strength of evidence (SOE).
Twenty-three studies met inclusion criteria. The sensitivity of troponin T for ACS diagnosis ranged from 71% to 100%, and specificity ranged from 31% to 86% (6 studies; low SOE). The sensitivity and specificity of troponin I ranged from 43% to 94% and from 48% to 100%, respectively (8 studies; low SOE). No studies examined how troponin levels affect management strategies. Twelve studies analyzed prognostic value. Elevated levels of troponin I or troponin T were associated with higher risk for short-term death and cardiac events (low SOE). A similar trend was observed for long-term mortality with troponin I (low SOE), but less evidence was found for long-term cardiac events for troponin I and long-term outcomes for troponin T (insufficient SOE). Patients with advanced CKD tended to have worse prognoses with elevated troponin I levels than those without them (moderate SOE).
Studies were heterogeneous in design and in ACS definitions and adjudication methods.
In patients with CKD and suspected ACS, troponin levels can aid in identifying those with a poor prognosis, but the diagnostic utility is limited by varying estimates of sensitivity and specificity.
Agency for Healthcare Research and Quality.
Diagnosis of acute coronary syndrome (ACS) is generally based on clinical symptoms, electrocardiographic (ECG) changes, and cardiac enzyme assays (1). Troponin is a protein complex released from cardiac muscle in proportion to the degree of muscle injury. Guidelines define a clinically relevant increase in troponin level as one that exceeds the 99th percentile of a normal reference population. Clinicians use this information to stratify patients according to risk and to choose treatment (2).
The diagnosis of ACS—including acute myocardial infarction (AMI) and unstable angina—is outlined by the Global MI Task Force's Third Universal Definition of Myocardial Infarction (3), which requires increasing or decreasing troponin levels plus additional evidence of myocardial ischemia. The diagnosis can be particularly challenging in patients with advanced chronic kidney disease (CKD). High prevalence of persistently elevated troponin levels in these patients may reduce the specificity of troponin for diagnosing AMI. Elevated troponin levels in patients with CKD may be explained by cardiac injury associated with chronic structural heart disease (such as coronary artery disease or heart failure) rather than acute ischemia, especially when levels do not change rapidly over time (4). Reduced renal clearance is probably not the primary mechanism of persistently elevated troponin levels in patients with CKD, although this issue is controversial (5).
Thus, diagnosing ACS in patients with CKD and elevated troponin levels presents a dilemma to the clinician and often requires extended evaluation for an accurate diagnosis. A change in troponin level greater than 20% within 9 hours (with ≥1 value exceeding the 99th percentile) is recommended for AMI diagnosis among patients with end-stage renal disease and suspected ACS (6). No consensus exists on whether the criteria for AMI diagnosis with the use of a troponin assay should differ for patients with and without CKD or whether baseline elevated troponin levels reduce the ability to diagnose AMI in patients with end-stage renal disease but not in those with earlier stages of CKD (5). Whether troponin levels in patients with CKD (vs. those without it) and suspected ACS are associated with differences in the comparative effectiveness of interventions or treatment strategies is also unknown.
In addition to their use in diagnosing and managing ACS, troponin assays have been investigated as independent predictors of morbidity and mortality after an acute ischemic event. Previous reviews have examined the prognostic performance of troponin testing in patients with CKD but excluded studies of those with ACS (7, 8). Therefore, the prognostic significance of elevated troponin levels with regard to short- and long-term major adverse cardiovascular events (MACEs) for patients with CKD and ACS is uncertain. Given that the prevalence of CKD in the United States reached 15% in 2008, interpretation of troponin levels in this population is an important issue (9, 10).
We aimed to systematically review the evidence for the diagnostic performance of elevated troponin levels for the detection of ACS in patients with CKD, the extent to which elevated troponin level modifies the comparative effectiveness of interventions or management strategies for ACS in this population, and the prognostic value of elevated troponin levels in estimating short- and long-term outcomes in patients with CKD and suspected ACS.
A protocol was developed and posted online, and guidelines for systematic review were followed (11). Additional details are provided in the comprehensive evidence report (12).
We searched MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials from January 1990 through September 2013. The MEDLINE search was updated through May 2014 (Appendix Table 1). We also searched ClinicalTrials.gov and requested relevant published or unpublished trials from manufacturers of troponin assays.
Appendix Table 1. Detailed Search Strategies
We included original, peer-reviewed studies that evaluated troponin T and/or troponin I in patients with CKD who had clinically suspected ACS or met ACS criteria (as defined by the study authors). Studies evaluating management and prognosis must have directly compared patients with elevated versus normal troponin levels. We included randomized, controlled trials and observational studies with a comparison group.
Two reviewers independently evaluated titles, abstracts, and full-text articles to identify studies evaluating troponin assays for the determination of diagnosis, treatment, or prognosis in patients with CKD and suspected ACS. We included studies regardless of sample size, language, length of follow-up, or setting.
We extracted details of study, patient, and troponin assay characteristics; definitions of ACS and CKD; outcome measures and results; and data on any subgroups analyzed. Outcomes of interest included the sensitivity, specificity, positive predictive value, and negative predictive value of troponin assays for a final clinical diagnosis of ACS (vs. a non-ACS event). We also looked for differences in ACS management strategies, interventions, or treatments by troponin thresholds and differences in subsequent all-cause mortality, cardiovascular mortality, and MACEs between groups based on troponin level. Although MACE was defined differently across studies, it was generally a composite of AMI, cardiovascular death, and/or revascularization. We separately analyzed studies with short- and long-term follow-up after the index hospitalization for suspected ACS to determine whether the association between troponin level and prognostication differed by length of follow-up. We hypothesized that elevated troponin levels would be more strongly associated with short-term outcomes after an index event.
We used standardized forms to extract information on study characteristics, troponin assays, and outcome measures. For studies reporting hazard ratios (HRs), we abstracted the most adjusted HR. Two reviewers independently assessed study quality by using the Downs and Black checklist (13), supplemented with recommendations from the Methods Guide for Effectiveness and Comparative Effectiveness Reviews (14). We assessed quality as “good,” “fair,” or “poor” on the basis of risk of bias. A third-party adjudicator resolved differences between reviewers.
We assessed study limitations and graded overall strength of evidence (SOE) for each set of studies. The grade incorporated risk-of-bias assessments, consistency of direction of the effect across studies for a given comparison and outcome, relevance to the question of interest, and precision based on the width of the CIs. We classified SOE as “high,” “moderate,” “low,” or “insufficient” to reflect the likelihood that additional research would affect conclusions about the intervention.
This research was funded by the Agency for Healthcare Research and Quality (AHRQ) under a contract to support the work of the Johns Hopkins University Evidence-based Practice Center. The AHRQ reviewed the key questions, methods, and draft of the evidence report but had no role in study selection, quality ratings, or interpretation and synthesis of the evidence.
The literature search identified 23 relevant studies (in 25 publications) (Figure 1). Sample sizes ranged from 31 to 31 586 patients, with the largest including a group of patients without CKD. Details on study quality and SOE grading are shown in Table 1.
Summary of evidence search and selection.
ACS = acute coronary syndrome; CKD = chronic kidney disease.
* Articles could be excluded for >1 reason.
Table 1. SOE for Diagnostic Accuracy and Prognostic Value of Elevated Troponin Level in Patients With CKD and Suspected ACS
Among patients with CKD presenting with ACS symptoms, 14 studies reported operating characteristics (sensitivity, specificity, positive predictive value, and/or negative predictive value) for the use of elevated troponin levels for a final clinical diagnosis of ACS (15–27) (Table 2). There was low-strength evidence for the diagnostic accuracy of troponin T and troponin I, due largely to incomplete information on adjudication of ACS and lack of blinding.
Table 2. Operating Characteristics of Elevated Troponin Level in Diagnosis of ACS Among Patients With CKD
Five studies based ACS diagnosis on the European Society of Cardiology standards (28) (1 also used the American College of Cardiology standards ), and 5 did not report the diagnostic criteria used. Troponin assay manufacturers varied among studies. Additional study characteristics are shown in Appendix Table 2.
Appendix Table 2. Characteristics of Studies Analyzing Operating Characteristics of Elevated Troponin Level in Diagnosis of ACS Among Patients With CKD
Six studies of troponin T (17, 21, 25–27, 29) and 8 studies of troponin I (15–20, 26, 27) examined sensitivity and specificity for ACS diagnosis (Figures 2 and 3 ). Three of these assessed more than 1 assay cutoff value. The sensitivity for ACS diagnosis ranged from 71% to 100% for troponin T and from 43% to 94% for troponin I. Specificity ranged from 31% to 86% for troponin T and from 48% to 100% for troponin I. Given heterogeneity of troponin cutoffs and assay manufacturers in these studies, we could not identify a trend relating assay cutoff value to these characteristics.
Sensitivity and specificity of elevated troponin T level in the diagnosis of ACS among patients with CKD.
Solid symbols represent studies that adjudicated ACS, and open symbols represent studies that did not adjudicate or did not report adjudicating ACS. Diamonds indicate studies that used a troponin T cutoff <0.1 µg/L. Circles indicate studies that used a troponin T cutoff ≥0.1 µg/L. ACS = acute coronary syndrome; CKD = chronic kidney disease; hsTnT = high-sensitivity troponin T.
* Did not specify whether patients were receiving dialysis.
† Included patients receiving dialysis.
Sensitivity and specificity of elevated troponin I level in the diagnosis of ACS among patients with CKD.
Solid symbols represent studies that adjudicated ACS, and open symbols represent studies that did not adjudicate or did not report adjudicating ACS. Diamonds indicate studies that used a troponin I cutoff <0.1 µg/L. Circles indicate studies that used a troponin I cutoff of 0.1 to <0.5 µg/L. Squares indicate studies that used a troponin I cutoff of 0.5 to <1.0 µg/L. Triangles indicate studies that used a troponin I cutoff ≥1.0 µg/L. ACS = acute coronary syndrome; CKD = chronic kidney disease.
* Included both patients who were and were not receiving dialysis.
‡ Did not specify whether patients were receiving dialysis.
§ Included patients not receiving dialysis.
We found insufficient evidence from 1 study (21) for the diagnostic accuracy of a change in troponin level. The magnitude of change in troponin T level in the first 24 hours after hospitalization did not differ between the control and ACS groups (n = 46). Similarly, the rates of change from 0 to 6 and from 6 to 12 hours after hospitalization did not differ between groups.
Subgroups based on age (24) and creatinine level (22) were used to report on the sensitivity and specificity of elevated troponin T levels in diagnosis of ACS. We could not directly compare the findings but noted that the operating characteristics varied for both variables (insufficient SOE). For troponin I, one study reported areas under the curve for ACS diagnosis across groups of patients with CKD classified by creatinine clearance (23). Although the results suggested similar diagnostic performance in all subgroups, the evidence was insufficient to support a definitive conclusion (23). We did not find evidence on troponin T or troponin I for other relevant subgroups, such as those based on dialysis status, history of coronary artery disease, presence of ischemic symptoms, ECG changes, diabetes mellitus, other comorbid conditions, or race or ethnicity.
One study directly compared troponin T with troponin I (17). The troponin T Elecsys assay (Roche Diagnostics), with a cutoff of 0.1 µg/L, was associated with sensitivity of 100% and specificity of 42% for diagnosis of ACS. In contrast, the troponin I Immulite assay (DPC), with a 1.0-µg/L cutoff, had sensitivity and specificity of 45% and 100%, respectively.
One study compared troponin testing for ACS diagnosis in patients with and without CKD and found a higher sensitivity for troponin T in patients with moderate to severe renal failure than in those with normal function. However, it also found lower specificity, positive predictive value, and negative predictive value, as well as an area under the curve of 0.54 for patients with CKD. This study was limited by a heterogeneous population, relaxed criteria for assessment of renal function, and lack of long-term outcomes (29).
No study addressed harms associated with a false-positive diagnosis.
No studies evaluated benefits and harms of treating patients with CKD and suspected ACS on the basis of troponin levels.
Twelve studies assessed troponin T or troponin I for establishing short- or long-term prognosis for patients with CKD presenting with symptoms suggestive of ACS. The studies had heterogeneity of methods for ACS diagnosis, comparators, and outcomes, which precluded pooled analyses (Appendix Table 3). Although several studies required the presence of symptoms and ECG and enzymatic changes for ACS diagnosis (16, 30–33), 1 classified its patients only by the presence of clinical symptoms (34); 2 categorized patients as being at low, moderate, or high risk for ACS (35, 36); 1 based diagnosis on medical records (37); and 3 did not specify diagnostic criteria (38–40). Only 3 studies reported how the diagnosis was adjudicated (30, 33, 36), and only 1 reported whether a cardiologist was involved (30).
Appendix Table 3. Characteristics of Studies Evaluating Short- or Long-Term Prognosis of Patients With CKD After Presentation With ACS
Definitions of CKD also varied, with 5 studies using creatinine clearance (16, 31, 34–36), 4 using serum creatinine level (32, 33, 37, 39), and 3 using unspecified definitions (30, 38, 40). Three studies used the Cockcroft–Gault equation to calculate glomerular filtration rate (35, 36, 39), 3 used the Modification of Diet in Renal Disease equation (16, 31, 34), and 6 did not specify the method (30, 32, 33, 37, 38, 40). Stages of CKD differed, with 1 study excluding patients receiving dialysis (39) and 2 including only those receiving it (38, 40).
Six studies analyzed the role of elevated troponin T levels in predicting adverse outcomes after a suspected ACS event (30–32, 34, 37, 38) (Appendix Table 4).
Appendix Table 4. Association of Elevated Troponin T Level With Adverse Outcomes Among Patients With CKD Presenting With ACS Symptoms
Of the 3 studies evaluating the association of troponin T level with all-cause mortality, 1 did not specify the length of follow-up (30). We found low-strength evidence that patients with elevated troponin T levels had increased short-term mortality (30, 31) but insufficient evidence on long-term mortality because of a high risk of bias (38).
Studies with short-term follow-up showed that risk for other outcomes (cardiac mortality, AMI, cardiac ischemia, revascularization, dysrhythmia, congestive heart failure, and composites of these end points) increased with elevated troponin T levels (32, 34, 37). Assay cutoffs ranged from 0.01 to 0.1 µg/L. Strength of evidence for the prognostic value of an elevated troponin T level was low; 1 study found higher rates of a composite outcome with elevated levels (32), whereas another found no difference between groups (34). In a comparison of patients with and without events, a 0.11-µg/L increase in troponin T level from baseline had sensitivity of 27% and specificity of 96% for MACE (positive likelihood ratio, 7.2) (37).
Evidence from 2 analyses of outcomes by severity of CKD was insufficient because of differences in definitions of CKD stages, follow-up, and outcomes assessed. One found no difference in in-hospital mortality between patients with elevated and normal troponin T levels (based on the hospital's upper-limit cut point for any renal function subgroup) (31), whereas the other found a greater risk for MACE within 30 days in patients with elevated troponin levels who had more severe CKD (32). In addition, outcomes did not differ when patients receiving dialysis were analyzed separately from those with severe CKD (31).
Seven studies (in 9 publications) investigated the prognostic value of elevated troponin I levels (16, 31, 34, 35, 38–42) (Appendix Table 5).
Appendix Table 5. Association of Elevated Troponin I Level With Adverse Outcomes Among Patients With CKD Presenting With ACS Symptoms
We found low-strength evidence for elevated troponin I level as a predictor of long-term mortality in patients with CKD and ACS. Cut points ranged from 0.15 to 1 µg/L, with 2 studies not reporting a threshold. Two studies found higher mortality with elevated troponin I levels after adjustment for age (35) and multiple clinical factors (39); however, a third study that did not adjust for covariates found no difference (38).
Short-term mortality as an independent outcome was limited to a single investigation with low SOE. After adjustment for clinical factors, the only association between in-hospital mortality and elevated troponin I level was in patients with an estimated glomerular filtration rate of 30 to 60 mL/min/1.73 m2 (31).
Studies of troponin I that reported MACEs used cut points ranging from 0.0001 to 1 µg/L. We found insufficient evidence with a medium risk of bias for long-term prognostic value, with 1 study reporting more cardiac deaths within 1 year (35) and a second reporting no differences between groups for AMI, revascularization, or composite MACE (39). In comparisons of assays, the rate of death or AMI was higher in patients with elevated levels for 3 types of troponin I assay (34).
Results from an analysis of AMI as the primary diagnosis on discharge (16) and an analysis of a composite end point comprising cardiac death, AMI, revascularization, or congestive heart failure (40) suggested that elevated troponin I levels in patients with CKD can predict short-term MACE (low SOE).
In patients with ACS receiving dialysis, elevated troponin I level was associated with a higher risk for short-term adverse cardiac outcomes (31, 38, 40).
A large, good-quality study (n = 2179) evaluated troponin T and troponin I but did not distinguish between them in its analysis (36). When patients with elevated and normal troponin levels were compared, differences in composite death or AMI remained significant after adjustment for baseline clinical characteristics, ECG changes, and laboratory findings at 30 days (HR, 2.1 [95% CI, 1.5 to 2.8]) and 1 year (HR, 1.7 [CI, 1.4 to 2.2]). Elevated troponin levels were associated with increased risk for cardiovascular outcomes in patients with moderate CKD (creatinine clearance of 30 to 60 mL/min) but not in those with advanced CKD (creatinine clearance <30 mL/min), although the sample size limited the power to detect differences across troponin groups (36).
A troponin T assay with a cut point of 0.1 µg/L predicted MACE with sensitivity and specificity of 43% and 46%, respectively, during hospitalization (33); 45% and 72%, respectively, within 6 months (33); and 57% and 88%, respectively, within 2 years (38). A troponin I assay with a 0.6-µg/L cutoff predicted MACE with sensitivity of 28% and specificity of 80% during hospitalization and sensitivity of 27% and specificity of 83% within 6 months (33). Sensitivity and specificity were 57% and 67%, respectively, with a 0.4-µg/L cutoff and 2-year follow-up (38).
Although elevated troponin level is a specific marker of myocardial damage, troponin levels are frequently elevated in patients with CKD, which makes it challenging to distinguish ACS from non-ACS conditions. Moreover, the value of troponin testing in managing and assessing prognosis in ACS is unclear for this population. In a systematic review of the evidence, we found low-quality or insufficient evidence for the utility of troponin T and troponin I assays for diagnosis and management of ACS and for the prognostic value of elevated troponin levels for ACS in patients with CKD, except in certain patient subgroups.
Troponin levels were associated with a range of sensitivities and specificities for ACS diagnosis. Studies addressing these operating characteristics had marked heterogeneity of settings, populations, and completeness of reporting of definition and adjudication of ACS. In addition, studies were heterogeneous regarding assay manufacturers and cut points used for ACS diagnosis. We found limited evidence from studies directly comparing the use of troponin T and troponin I assays to diagnose ACS in comparable populations of patients with CKD and studies examining the operating characteristics among relevant subgroups.
The National Academy of Clinical Biochemistry recommends a dynamic change in troponin level greater than 20% within 9 hours (with ≥1 value exceeding the 99th percentile) for diagnosis of AMI among patients with end-stage renal disease and suspected ACS (6), although we did not find studies that tested this criterion. Overall, we were struck by the paucity of evidence and could not establish a clear cut point that maximized sensitivity and specificity.
The sensitivities and specificities for diagnosing AMI among patients with CKD may seem problematically low or too variable to draw conclusions. However, one must keep in mind that using troponin levels to diagnose ACS can be challenging even in a general patient population. A study in an emergency care setting found that most patients (66%) with a troponin I level greater than 0.04 µg/L did not meet criteria for AMI (43). In another study, clinicians ultimately diagnosed only 55% of patients with AMI (44). Furthermore, an evaluation of 4 new point-of-care assays for troponin I among patients with suspected ACS found that assays that used the 99th percentile criterion (according to the Global MI Task Force's guidelines) had sensitivities that varied from 26% to 68% and specificities that ranged from 81% to 93% for diagnosing AMI (45).
Our findings must be put in context with the concept that the utility of any diagnostic test depends on the pretest probability of disease (5). Even with laboratory evidence suggesting myocardial necrosis, the posttest probability of ACS associated with an elevated troponin level is low if the pretest probability is low. Conversely, low troponin levels do not rule out ACS if the pretest probability is high. Therefore, it is difficult to interpret the results of studies that do not specifically state the pretest probability of ACS in the sample. Although we found only 1 study that compared the use of troponin for diagnosing ACS in patients with and without CKD in the same sample, our findings suggest that troponin level is equally effective in diagnosing ACS in patients with CKD and those with normal renal function.
A key difficulty with the use of troponin assays, as with any laboratory test, is the possibility of inappropriate testing or an inaccurate interpretation of results. Clinicians should aim to test only when it is clinically indicated and, when possible, to rely on serial test values instead of a single value.
Clinicians use troponin levels to further stratify patients presenting with suspected ACS by risk. Glycoprotein IIb/IIIa inhibitors, low-molecular-weight heparin, and an early invasive strategy may be more effective for patients with elevated troponin levels than for those with normal levels (2). Patients with CKD presenting with ACS also have a worse prognosis than patients without CKD (46). However, many randomized clinical trials that tested therapeutic agents for ACS management excluded patients with advanced CKD. Because no studies directly addressed the question of whether troponin levels can affect management strategies in patients with CKD and ACS symptoms, we recommend further study in this area, such as post hoc analyses of clinical trials comparing gradations of elevated troponin levels across treatment groups, with a focus on patients with CKD.
Overall, evidence of the prognostic significance of elevated troponin levels with regard to short- and long-term outcomes for patients with CKD and ACS is limited. Our findings suggest that elevated troponin levels seem to identify patients with CKD who are at higher risk for subsequent MACE after presentation with suspected ACS; however, few studies rigorously adjusted for clinical factors. Patients with elevated troponin levels are more likely to have underlying comorbid conditions, such as coronary artery disease, that place them at higher risk for death. Although an elevated troponin level can identify a patient with CKD as being at higher risk, available evidence does not indicate how to subsequently decrease a patient's risk beyond usual guideline-directed therapy.
Findings specific to certain stages of CKD cannot necessarily be extrapolated to other stages. The heterogeneity of assays and results also limits interpretation, and comparison of results from study to study and from population to population will be problematic until troponin assays are harmonized and standardized (as other laboratory tests have been).
We recognize that the variability in ACS definitions and protocols for adjudication of ACS diagnosis limits our analysis of identified data. Variability in length of follow-up across studies was also a limitation in our review and posed a challenge in defining short- and long-term outcome periods.
In conclusion, successful interpretation of troponin levels for ACS diagnosis in patients with CKD largely depends on pretest probability based on symptoms, ECG changes, and other factors. Elevated cardiac troponin levels may provide incremental prognostic value over carefully assessed clinical risk factors but must be considered in the context of a larger clinical picture. Our findings do not refute the utility of troponin testing in patients with CKD and ACS but call attention to insufficient data on optimal cut points and the lack of comparisons with patients without CKD.
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Neelesh Gupta, Nayan Gupta
Kastuba Hospital,Bhopal,India ; Mu Sigma Business Solutions Pvt.Ltd.,Bengaluru,India
November 4, 2014
True Significance of Elevated Troponin
We read with interest the systematic review and meta-analysis by Erin D Michos et al. published recently in Annals of Internal Medicine.(1) Despite US Food and Drug Administration approval for the measurement of Troponin T ( and not Troponin I) levels for prediction of mortality in patients receiving dialysis.(2) The application of this in the day-to-day clinical practice is not homogeneous and wide.One of the reasons could be , practicing physicians and nephrologists are not fully convinced about the data and results of various studies showing the calculations of hazard or odds ratios or relative risk ( as done in this meta-analysis as well (1)).May be, it would have been more informative and convincing for a practicing clinician if C-statistics would have been calculated( we know the limitation of such precision in the meta-analysis).Calculating increases in the area under the curve and may be new statistical metrics of discrimination and reclassification. For example, AppleFS et al. showed an increased hazard ratios for cTnI above and below the 99th percentile cutoff while C-statistics showed an area under the curve of 0.53 to predict mortality at two years, exhibiting poor performance.Now , as in many countries like India( still not in USA ) high sensitivity cardiac troponin T( hs cTnT) assays are routinely used in many centers .This makes the true significance of the elevated troponin even more challenging, as most patients on hemodialysis have elevated levels of hs cTn T.Conflict of Interest: NoneReferences:1.Michos Erin D, Wilson Lisa M, Yeh Hsin-chieh et al.:Prognostic value of cardiac troponin in patients with chronic kidney disease without suspected acute coronary syndrome: A systematic review and meta-analysis: Ann Intern Med.2014;161(7):502-512.doi:10.7326/M14-07462.Roche. FDA clears new intended uses for Roche Diagnostics Troponin T test.Trade News.24 May 2004.3.Apple FS,Murakami MM, Pearce LA,Herzog CA. Predictive value of cardiac Troponin I and T for subsequent death in end-stage renal disease.Circulation.2002; 106:2941-5Neelesh Gupta,Medical student (Intern), Kastuba Hospital,Bhopal,IndiaNayan Gupta,B.Tech, Data analyst,Mu Sigma Business Solutions Pvt.Ltd.,Bangaluru,India
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