A Study of Biochemical Markers of Reperfusion Early After Thrombolysis for Acute Myocardial Infarction
Background In acute myocardial infarction (AMI), early noninvasive identification of patients with occluded infarct-related arteries (IRAs) after thrombolysis has important prognostic and therapeutic implications. The aims of this study were to evaluate biochemical methods for the early diagnosis of patency after thrombolysis prospectively and to establish the optimal diagnostic criteria retrospectively.
Methods and Results In 97 patients with AMI treated with thrombolytic agents ≤6 hours after the onset of symptoms, myoglobin, troponin T, creatine kinase, the MB isoenzyme and MM isoforms of creatine kinase were measured just before thrombolysis began and 90 minutes later. IRA patency was assessed by means of 90-minute coronary angiography. For each marker, compared with the expected sensitivity and specificity based on published thresholds for the diagnosis of patency, the observed values were consistently lower but were markedly improved in a subset of patients treated >3 hours after the onset of symptoms. With receiver-operator characteristic curve analysis of the slopes of increase and relative increases in each marker over 90 minutes, the best diagnostic performance was achieved by use of the relative increase in myoglobin, troponin T, and MM3/MM1 creatine kinase isoforms in patients treated >3 hours after onset (areas under the curve of 0.84, 0.83, and 0.85, respectively).
Conclusions Effective early noninvasive diagnosis of patency after thrombolysis is possible in patients treated >3 hours after symptom onset by use of criteria derived from the relative increase over 90 minutes in plasma markers, particularly myoglobin, troponin T, and MM3/MM1 creatine kinase isoforms. The diagnostic performance of the relative increase in myoglobin appears to be less susceptible to small changes in the diagnostic threshold value.
During AMI, failure of thrombolysis to unblock the infarct-related vessel is associated with poor outcome.1 Both randomized and nonrandomized studies have supported the concept of emergency rescue angioplasty, which appears to have excellent short- and long-term results, notably preventing death and severe congestive heart failure.2 3 4 5 However, widespread application of rescue angioplasty requires rapid identification of patients with a persistently occluded IRA, ideally within 90 minutes of the start of thrombolytic treatment.
Clinical criteria and simple ECG parameters have limited value for the noninvasive diagnosis of myocardial reperfusion,6 although some authors have suggested that their combination may result in enhanced diagnostic performance.7 Other methods, such as continuous ST-segment monitoring and kinetic analysis of biochemical markers, may also be of value in early identification of IRA patency. The plasma kinetics of myoglobin,8 9 10 11 12 tropomyosin-binding component troponin T,11 total CK activity, CK-MB,11 and isoforms of the CK-MM isoenzyme (MM1, MM2, and MM3)8 9 13 14 appear to be the most promising biochemical markers. However, their diagnostic performance has usually been evaluated in retrospective analyses of patients undergoing coronary angiography, often performed after AMI. In addition, the thresholds suggested for the diagnosis of reperfusion were generally derived from “time-to-peak” values. This rules out early diagnosis because peak CK plasma values are reached, on average, 9±6 hours after thrombolysis; peak troponin T values, after 12±9 hours.11
This study was based on a cohort of patients who underwent 90-minute coronary angiography. The aim was to evaluate prospectively biochemical markers for the diagnosis of coronary patency early after intravenous thrombolysis for AMI. In addition, this patient cohort was used to establish optimal biochemical criteria retrospectively.
Ninety-seven patients referred to seven cardiology departments within 6 hours of MI were enrolled. All gave informed consent to participate in the study, which was approved by the ethics committee of the Hôpital Saint-Louis, Paris, France. Eligibility criteria were AMI occurring <6 hours previously and in-hospital treatment with intravenous thrombolytic agents. Eligibility for thrombolytic therapy was based on the following conventional criterion: prolonged chest pain (>30 minutes) resistant to nitrates that was associated with ST-segment elevation ≥0.1 mV in two limb leads or ≥0.2 mV in two contiguous precordial leads. The thrombolytic agent was RTPA in 56 patients, streptokinase in 34 patients, RTPA and streptokinase in 6 patients, and RTPA and urokinase in 1 patient. None of the patients had severe renal failure or musculoskeletal disease that could interfere with biochemical results. One patient received an electric countershock before initiation of thrombolytic therapy. All patients underwent coronary angiography 90 minutes after the start of the treatment to ascertain the patency status of the IRA, which was graded according to the TIMI score and determined on the first contrast injection.15 Patency was defined as TIMI grade 3 flow in the IRA (group A).16 17 Patients with TIMI grade flow ≤2 were considered to have occluded arteries (group B). All angiograms were recorded on 35-mm cinefilm or super VHS videotapes. Analysis was performed in a core laboratory by two independent experienced angiographers blinded to all biochemical information.
Blood samples were obtained just before thrombolysis began and 90 minutes later. Venous blood (10 mL) was collected in two Vacutainer tubes: one containing 150 U lithium heparinate for measurement of myoglobin, troponin T, and CK-MB; the other, EDTA for measurement of CK-MM isoforms. EDTA avoids carboxypeptidase hydrolysis of C-terminal lysine residues in vitro, which converts CK-MM3 to CK-MM2 and CK-MM1.18 19 The tubes were immediately centrifuged for 5 minutes at 1900g, and plasma was divided into aliquots and immediately stored at −20°C pending further analysis.
Myoglobin was determined by use of an automated latex-enhanced immunonephelometric technique (Behring nephelometer analyzer BNA, N-Latex Myoglobin). The measurement range of myoglobin was 24 to 396 μg/L, and samples >396 μg/L were automatically diluted. The upper limit of normal was 90 μg/L. The analyzer processed a single specimen in <15 minutes.
Plasma CK activity was measured at 37°C on a multiparametric analyzer (Hitachi 737, Boehringer Mannheim Corp) with CK-NAC reagents (Enzyline, BioMerieux). Results were obtained in 10 minutes. The normal range was 20 to 195 IU/L.
CK-MB mass was measured with a microparticle enzyme immunoassay (Opus CK-MB test module for use with the Opus automated analyzer, Behring). The upper limit of normal was 6 μg/L, and the time required to process a single specimen was 20 minutes.
CK-MM3, CK-MM2, and CK-MM1 in plasma samples were separated and revealed by use of rapid, high-voltage electrophoresis on an automated analyzer (Rep, Helena Laboratories). The individual isoforms of CK-MM were expressed as percentages of the total area under the absorbent profile contributed by each isoform. The MM3-to-MM1 ratio was also computed. The assay took 30 minutes.
Troponin T was measured with an ELISA (Boehringer Mannheim Corp). The upper limit of normal was 0.2 μg/L; the measurement range was 0.2 to 15 μg/L. The assay was completed semiautomatically within 90 minutes.
For all these biochemical markers, within- and between-day coefficients of variation ranged from 1.9% to 5.9% and from 2.7% to 7.6%, respectively.
For each marker, the slope of increase 90 minutes after thrombolysis was calculated as follows: slope=T90−T0/90 (international units, micrograms, or percent per liter per minute, as appropriate; T90 is the value at 90 minutes and T0 is the value before thrombolysis) and the relative increase was calculated as relative increase=T90−T0/T0.
All continuous variables are expressed as mean±SD. Groups were compared by means of χ2 analysis for categorical variables and by the Mann-Whitney test for numerical variables.
For each biochemical marker, the sensitivity and specificity of each threshold for the diagnosis of patency at 90 minutes were determined by use of published thresholds.9 10 11 12 20 Because the diagnosis had to be obtained within 90 minutes of the start of thrombolysis, criteria involving the time to peak value of a biochemical marker and rates of rise over periods >90 minutes were not used. For all comparisons, values of P≤.05 were considered significant.
For each marker studied, ROC curves were constructed by plotting sensitivity against (1−specificity) for both the slope and the relative increase in the plasma value.21 The best compromise between sensitivity and specificity was determined graphically.
We enrolled 97 patients (82 men, 15 women) in this study. Mean age was 59±12 years. Mean time from the onset of symptoms to thrombolytic therapy was 212±97 minutes (range, 25 to 360 minutes). Forty-nine patients were treated >3 hours after the onset of symptoms. Angiography at 90 minutes showed that IRA was patent in 45 patients (group A), while TIMI flow grade was ≤2 in 52 patients (group B) (TIMI flow grade 0 to 1 in 35 patients; grade 2 in 17 patients). Table 1⇓ summarizes the clinical characteristics of these patients. There were no significant differences between the groups in terms of sex, age, location of MI, or thrombolytic regimen. Likewise, the IRA distribution was similar in the two groups. However, there was a nonsignificant trend toward a longer delay before treatment in patients with occluded arteries (P=.07). This was associated with statistically higher baseline myoglobin values in these patients (Table 2⇓).
Slopes of increase at 90 minutes did not differ between the groups, regardless of the marker studied. Relative increases at 90 minutes were consistently higher in group A than in group B, a difference that reached statistical significance for myoglobin, troponin T, and CK-MM3/CK-MM1 isoforms.
Prospective Validation of Published Thresholds for the Diagnosis of IRA
Table 3⇓ summarizes the observed sensitivity and specificity of several published thresholds for the diagnosis of IRA patency 90 minutes after the start of thrombolysis.9 10 11 12 20 For each biochemical marker, the observed values in this study were consistently lower than those reported in retrospective analyses. Switching patients with TIMI grade 2 IRA flow from group B to group A resulted in consistently increased specificity but inconsistent changes in sensitivity (Table 3⇓).
Stratification According to Time to Treatment
The diagnostic performance of all the markers was markedly improved when patients were stratified according to the time until treatment and when the analysis was restricted to those patients treated >3 hours after the onset of symptoms (Table 4⇓).
Retrospective Analysis of Biochemical Markers
For each biochemical marker, we performed ROC curve analyses of the slope of increase and the relative increase at 90 minutes. These curves were constructed for the whole cohort and for the subset of patients treated >3 hours after the onset of symptoms (Fig 1⇓). Areas under the curves ranged from 0.56 to 0.85; the largest were those of the relative increases in myoglobin, troponin T, and CK-MM3/CK-MM1 isoforms in patients treated >3 hours after onset, which were high and very similar (0.83, 0.84, and 0.85, respectively). Criteria based on CK or CK-MB isoforms had lower sensitivity and specificity. For each marker, a cutoff value above which patency of the infarct vessel is likely was determined from the ROC curves through an attempt to identify the best compromise between sensitivity and specificity (Table 5⇓). For each marker except CK-MM3 isoforms, the relative rates of increase in plasma values consistently yielded better results than slopes of increase.
Fig 2⇓ shows the sensitivity and specificity of the relative increase in each biochemical marker for the prediction of patency, according to the threshold value used for patients treated >3 hours after onset. The diagnostic performance of myoglobin was less susceptible than that of troponin T to changes in the threshold value: an elevation from 6.8 to 9 (a 1.3-fold increase) of the threshold value of the relative increase in troponin T resulted in a loss of sensitivity of 17 points (89% to 72%) and no gain in specificity (83%). When the myoglobin threshold value was increased 1.3-fold (from 3 to 4), sensitivity and specificity did not change; however, when the threshold value increased from 3 to 6 (2-fold) there was a loss of sensitivity of 11 points (79% to 68%) but an increase in specificity (82% to 84%). Finally, although the relative increase in CK-MM3/CK-MM1 appeared to have good diagnostic performance, it was extremely susceptible to changes in the threshold value: a 1.3-fold increase (from 2 to 2.6) resulted in an increase in specificity (87% to 96%) but a loss of sensitivity (68% to 62%).
Rationale of the Study
This study was aimed at prospectively validating noninvasive criteria of coronary artery patency on the basis of biochemical markers. IRA patency early after thrombolysis has a strong beneficial impact on short- and long-term outcome that does not appear to be entirely related to improved left ventricular function.1 22 Early identification of patients with persistent occlusion after thrombolysis during AMI also is important because it can pave the way for rescue interventions such as rescue percutaneous transluminal coronary angioplasty4 5 or repeated thrombolysis.23 24 25 Finally, it may be used as a surrogate end point for angiographic demonstration of patency in future clinical studies of reperfusion therapy. Coronary angiography has several limitations as a gold standard method for assessing reperfusion that are related primarily to the frequent fluctuations in coronary patency early after thrombolysis,26 absence of assessment of patency between 0 and 90 minutes, protective role of collateral circulation (which cannot be routinely quantified by angiography27 28 ), and no-reflow phenomenon. Therefore, angiography is an appropriate method for studying coronary patency rather than reperfusion. However, considering the fact that angiographic patency has been demonstrated to have an important prognostic impact1 29 30 and because there currently is no validated substitute for angiographic patency as a gold standard, we relied on coronary angiography for validation of our biochemical results. We thus focused on early biochemical indexes, obtained within 90 minutes, and not criteria based on the time required to reach the peak plasma value of biochemical markers (several hours generally are required before a diagnosis can be established).
The first part of this study showed that, when studied prospectively, the diagnostic performance (sensitivity and specificity) of biochemical criteria for patency did not match that in previous studies. This discrepancy between the value of a diagnostic threshold defined by retrospective examination of a patient cohort and its prospective validation is not surprising, especially when the small number of patients with persistent occlusion in some studies is considered.9 10 12 20 In addition, the diagnostic value of some methods may be particularly sensitive to changes in the threshold value.11 All previous studies defined patency as TIMI grade 2 and 3 flow in the IRA. It has recently been shown that patients with TIMI grade 2 flow in the IRA at the end of thrombolysis have a worse prognosis than patients with TIMI grade 3 flow; as a result, only the latter is currently considered to define successful thrombolysis in terms of artery patency.16 17 However, this difference in the definition of infarct-vessel patency relative to previous studies does not appear to influence the results because switching patients with TIMI grade 2 flow from the occlusion to the patency group led to only a mild increase in specificity and inconsistent changes in sensitivity. Finally, although the biochemical methods we used are standard and widely used, there were subtle differences in the methods for CK-MM isoforms and CK-MB isoenzyme determination between our study and previous work (related mainly to the use of mass rather than activity measurements for CK-MB isoenzymes20 ). However, this probably will not have a substantial impact on the results and does not explain any of the differences observed for other markers.
Diagnostic performance improved when the analysis was restricted to patients treated >3 hours after the onset of symptoms but failed to reach reported sensitivity and specificity values, regardless of the criteria used to define patency (including or excluding patients with TIMI grade 2 flow in the IRA). It must be pointed out that the better results for patients treated relatively late cannot account for the better diagnostic performance reported in the literature because in most reports10 11 the time until treatment approximated that in our study.
Using the same patient cohort, we evaluated the diagnostic performance of each biochemical marker by means of ROC curve analysis. In the overall cohort, the diagnostic performance of most markers was acceptable; the areas under the curve ranged from 0.56 to 0.72 (values >0.5 are not due to chance). However, as in the prospective analysis, the diagnostic performance of all the markers was markedly better in patients treated >3 hours after onset, with areas under the curve ranging from 0.63 to 0.85. This probably resulted because plasma values of the markers studied start to rise about 3 hours after symptom onset (1 to 4 hours for myoglobin, 3 to 12 hours for troponin T and CK-MB isoenzymes, and 1 to 6 hours for CK-MM isoforms31 ). These methods are nonetheless useful in clinical practice because the mean time until admission or treatment initiation in recent studies of thrombolytic therapy was close to 3 hours32 33 and because the proven value of late (up to 12 hours) thrombolytic therapy34 will probably lead to increased use of this approach between 6 and 12 hours after onset. Early biochemical diagnosis of IRA patency after thrombolysis is thus possible in patients treated >3 hours after onset. On the basis of the area under ROC curves, the best makers were myoglobin, troponin T, and CK-MM3/CK-MM1 isoforms, which had very similar diagnostic performance (area under the curves of the relative increase were 0.84, 0.83, and 0.85, respectively).
Determination of Diagnostic Thresholds
For each marker, a cutoff value above which patency of the infarct vessel is likely was determined from the ROC curves (Table 5⇑). When noninvasive diagnosis of patency is used to triage patients with suspected failure of thrombolysis to angiography and angioplasty, high specificity is important to avoid overlooking patients who require rescue angioplasty. However, this must be combined with good sensitivity to avoid a large number of unnecessary coronary angiographies in patients with patent IRAs. The compromise chosen may vary with the clinical situation (patient’s age or extent of the infarct) and availability of emergency coronary angiography, which may differ from center to center.
Most previous studies have focused on slopes of increase; in this study, particularly with myoglobin, troponin T, and CK-MM3/CK-MM1 isoforms, threshold values had better diagnostic performance when established from relative increases. The fact that relative increases take into account the basal value of the marker may explain in part their superiority over slopes of increase.
The diagnostic performance achieved by the relative increases in troponin T at 90 minutes (threshold of 6.8: sensitivity, 89%; specificity, 83%), myoglobin (threshold of 4: sensitivity, 79%; specificity, 82%), and CK-MM3/CK-MM1 isoforms (threshold of 2: sensitivity, 68%; specificity, 87%) appears high enough to allow clinicians to comfortably rely on biochemical diagnosis in deciding whether to undertake emergency and rescue angioplasties. However, the sensitivity and specificity of the myoglobin threshold were less susceptible to changes in the cutoff value: with troponin T and CK-MM3/CK-MM1 isoforms, a 1.3-fold increase in the threshold value led to a large loss of sensitivity (Fig 2⇑). Therefore, myoglobin may be the marker of choice for noninvasive diagnosis of patency after thrombolysis. It must be emphasized, however, that these retrospectively defined criteria now require prospective validation.
The time necessary to obtain the results of each test is important in clinical practice.35 However, rapid methods are already available36 37 or will become available within months38 for most criteria for clinical use.
This study shows that early noninvasive identification of patients with failed thrombolysis is possible with biochemical criteria. In this prospective study, the actual diagnostic performance of most markers did not match the results obtained in retrospective analyses of previously published cohorts. However, diagnostic performance was markedly improved when analysis was restricted to patients receiving thrombolysis >3 hours after symptom onset and when criteria derived from the relative increase in plasma values over the first 90 minutes were used. In this patient subset, the diagnostic performance of myoglobin, troponin T, and CK-MM3/CK-MM1 isoforms was good and very similar (areas under ROC curves, 0.84, 0.83, and 0.85, respectively). However, the diagnostic performance of the relative increase in plasma myoglobin appears to be less susceptible to changes in the threshold value used.
Selected Abbreviations and Acronyms
|AMI||=||acute myocardial infarction|
|CK-MB||=||MB isoenzyme of CK|
|CK-MM1, CK-MM2, CK-MM3||=||isoforms of CK|
|RTPA||=||recombinant tissue-type plasminogen activator|
|TIMI||=||Thrombolysis in Myocardial Infarction|
The following made up the PERM Study Group.
Principal investigators: Thierry Laperche, MD, Hôpital Beaujon, Clichy, and P. Gabriel Steg, MD, Hôpital Bichat, Paris.
Biochemistry core laboratory: Joëlle Benessiano, PhD, Monique Dehoux, PhD, and Fouzi Mestari, PhD, Hôpital Bichat, Paris.
Angiography core laboratory: Pierre Aubry, MD, Dominique Himbert, MD, and Jean-Michel Juliard, MD, Hôpital Bichat, Paris; Damien Coisne, MD, Hôpital la Milétrie, Poitiers; and Serge Makowski, MD, Hôpital Broussais, Paris.
Statistical consultant: Jean-Louis Golmard, Département de Biomathématiques et Unité INSERM U 436, Hôpital de la Pitié Salpétrière, Paris.
Scientific Analysis Committee: Marie-Claude Aumont, MD, Hôpital Bichat, Paris; René Gourgon, MD, Hôpital Beaujon, Clichy; Gilles Grollier, MD, Hôpital de la Côte de Nacre, Caen; Jean-Pierre Monassier, MD, Hôpital de Mulhouse, Mulhouse; and Paul-Etienne Valère, MD, Hôpital Bichat, Paris.
Groupe Hospitalier Bichat-Beaujon, Paris: P. Gabriel Steg, MD (principal investigator); and Pierre Aubry, MD; Hakim Benamer, MD; Alain Cohen-Solal, MD; Dominique Himbert, MD; and Jean-Michel Juliard, MD (coinvestigators).
Hôpital de la Côte de Nacre, Caen: Gilles Grollier, MD (principal investigator), and Sabine Fradin, PhD, and Benoı̂t Valette, MD (coinvestigators).
Hôpital Central, Nancy: Etienne Aliot, MD (principal investigator); and Christian de Chillou, MD, and Gérard Ethévenot, MD (coinvestigators).
Hôpital de Hautepierre, Strasbourg: Jean-Marie Mossard, MD (principal investigator), and André Sacrez, MD (coinvestigator).
Hôpital la Milétrie, Poitiers: Damien Coisne, MD (principal investigator), and José Allal, MD (coinvestigator).
Clinique Saint Joseph, Colmar: Michel Hanssen, MD (principal investigator), and Jean-Marc Boulenc, MD, and Olivier Katz, MD (coinvestigators).
Hôpital Broussais, Paris: Marie-Christine Iliou, MD (principal investigator).
This work was supported by the Délégation à la Recherche Clinique, Assistance Publique-Hôpitaux de Paris. We thank Véronique Benard for her excellent secretarial assistance.
A complete list of investigators participating in the Prospective Evaluation of Reperfusion Markers (PERM) Study Group is given in the “Appendix.”
Presented in part at the 67th Scientific Sessions of the American Heart Association, Dallas, Tex, November 14-17, 1994.
- Received March 14, 1995.
- Revision received May 8, 1995.
- Accepted May 13, 1995.
- Copyright © 1995 by American Heart Association
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