Applicability of Cardiac Troponin T and I for Early Risk Stratification in Unstable Coronary Artery Disease
Background Studies have demonstrated that troponin T is a strong independent indicator of a poor prognosis in patients with unstable coronary artery disease. Up to the present, no study has compared the prognostic value of troponin T with that of troponin I in the same cohort of patients.
Methods and Results Patients (n=516) suspected of having unstable coronary artery disease were investigated. Follow-up was done after 30 days, and the occurrences of cardiac death, acute myocardial infarction, refractory angina pectoris, and recurrent angina pectoris were registered. Elevated levels of troponin T (≥0.10 μg/L) were associated with an increased risk of cardiac death at 30 days compared with patients with normal levels, 3.2% versus 0.4% (P=.014). Troponin I values above the chosen cutoff (2.0 μg/L) were similarly found to be an indicator of increased risk of cardiac death, 3.2% versus 0.7% (P=.026). With regard to the composite end point of cardiac death/acute myocardial infarction, the troponins were strong independent indicators of adverse outcome.
Conclusions In patients suspected of having unstable coronary artery disease, both troponin T and troponin I provide independent prognostic information with regard to cardiac death and acute myocardial infarction.
Unstable coronary artery disease is still associated with high mortality and morbidity, despite advances in treatment.1 2 3 4 5 6 7 8 The pathological basis of the clinical manifestations of UCAD consists of a variable degree of myocardial injury, ranging from mild reversible myocardial ischemia with a good long-term prognosis to life-threatening cardiac necrosis. Changes in the ECG are valuable for the detection of ischemia in the myocardium, and in addition, can be used for identification of patients at increased risk of subsequent cardiac events.9 10 However, ECG changes are equivocal in a large proportion of patients with UCAD,11 and further indicators of an increased cardiac risk would be advantageous to commence appropriate intervention, ie, medical treatment and/or invasive procedures. New sensitive biochemical markers of ischemic myocardial damage, ie, cTnT and mass concentrations of CK-MB, have exhibited promising features in this respect. cTnT has been the subject of special attention because of its high sensitivity and specificity for injury of the myocardium.12 13 14 15 16 17 18 Several studies have demonstrated that cTnT is a powerful predictor of poor prognosis in patients with UCAD.3 4 6 15 19 cTnI has recently also been found to be a useful marker in the detection of myocardial damage.20 21 22 23 Reports have indicated that cTnI, like cTnT, can predict poor outcome in patients with UCAD.7 8 24 Up to the present, however, no prospective study has compared the prognostic values of cTnT and cTnI in the same cohort of patients. Therefore, the objective of the present study was to determine whether cTnT and cTnI have comparable prognostic properties in patients with UCAD.
The present investigation was carried out as a component of the TRIM study (ThRombin Inhibition in Myocardial ischemia), which was a double-blind, randomized, multicenter trial.25 The purpose of the main study was to investigate the efficacy of a new specific thrombin inhibitor (Inogatran) for the treatment of UCAD. A total of 1209 patients from 60 centers in Denmark, Finland, Norway, and Sweden were included in the main protocol of the TRIM study. For the present substudy, 516 patients from 22 centers had blood samples drawn according to a predefined time schedule. Patients suspected of having UCAD were eligible. The inclusion criteria were (1) age between 25 and 80 years; (2) the latest episode of chest pain within the last 24 hours; and (3) new episodes of chest pain within the last 4 weeks or an aggravation of a previously stable AP or the development of rest angina and one of the following: (a) ECG changes compatible with ischemia (ST-segment depression, T-wave inversion) or (b) coronary artery disease documented by previous myocardial infarction, coronary angiography, myocardial scintigraphy, or exercise testing. The main exclusion criteria were body weight <50 kg, indication for thrombolytic treatment, heart failure, ongoing cardiac arrhythmias, increased risk of hemorrhage, reduced kidney function (serum-creatinine >150 μg/L), anemia (hemoglobin <6.2 mmol/L), known liver disease, drug or alcohol abuse, or previous inclusion in the investigation.
The study population of 516 patients, as a part of the main TRIM protocol, was retrospectively categorized as either unstable AP (n=309), non–Q-wave AMI (n=190), or other diseases (n=17). The diagnoses were based on the clinical course, ECG changes, and plasma levels of cardiac markers available at each participating center (total CK, CK-MB mass, or CK-MB catalytic activity, obtained within 6 hours after inclusion).
Definition of End Points
All patients were subjected to a follow-up examination 30 days after enrollment. AMI, cardiac death, refractory AP, and recurrent AP were considered cardiac events. All cases of cardiac events were evaluated by an independent End Point Committee. The End Point Committee had no knowledge of the cTnT and cTnI values. AMI was considered present when at least two of the following criteria were complied with: (1) typical prolonged chest pain; (2) recently occurring pathological Q waves or loss of R waves, or ST-segment elevation followed by T-wave inversion in at least two leads in two consecutive ECG recordings; and (3) an increase in cardiac enzymes exceeding the upper reference level. Special attention was paid by the End Point Committee to separate the inclusion event (unstable AP/non–Q-wave AMI) from AMI occurring in the follow-up period. Cardiac death was defined as fatal AMI and death caused by arrhythmias or heart failure occurring in the period from inclusion up to 30 days after inclusion. Refractory AP was defined as recurrence of chest pain lasting ≥5 minutes despite optimal medication, including intravenous nitroglycerin and β-blockers or calcium antagonists, associated with transient ECG changes indicative of myocardial ischemia and leading to coronary angiography. Recurrent AP was defined as recurrent chest pain of ≥5 minutes duration, typical of myocardial ischemia and responding to sublingual nitroglycerin but not fulfilling the criteria for refractory AP. After hospital discharge, recurrent AP was defined as readmission because of anginal chest pain. Refractory AP and recurrent AP occurring during the period from inclusion up to 30 days were used in the statistical analyses.
If more than one event of the same type occurred, only the first was considered.
The patients of the TRIM study were randomized to a regimen of either low-dose, medium-dose, or high-dose Inogatran or heparin (active control group). All received low-dose aspirin daily, provided that no contraindications were present. Nitrates, β-blockers, calcium channel blockers, antiarrhythmic drugs, and analgesics were given according to the routine of each participating center. The medication the patients received just before inclusion is listed in Table 1⇓. The need for coronary angiography, CABG, and PTCA was determined by the treating physician. All clinical decisions were made without knowledge of cTnT and cTnI values.
Venous whole blood was drawn into tubes containing heparin at the following times: at inclusion and 6, 12, 24, 36, 48, 72, and 96 hours later. The blood samples were immediately centrifuged at 2000g for a period of 20 minutes. The plasma was kept at −80°C and sent for analysis to the core laboratory at Aarhus University Hospital, Denmark. The main study was designed to investigate the occurrence of AMI taking place from 6 hours up to 30 days after enrollment and cardiac death, refractory AP, and recurrent AP from inclusion up to 30 days. Therefore, the patients were considered positive for cTnT and cTnI if the highest value on inclusion or 6 hours after enrollment exceeded the chosen discriminator values.
Measurements of cTnT [ELISA Troponin(e) T] were carried out with an ES 300 analyzer (Boehringer Mannheim GmbH). The method is based on a single-step sandwich principle with streptavidin-coated tubes as the solid phase and two monoclonal anti-human cTnT antibodies. The method is described in detail elsewhere.18 In our laboratory, the range and median of cTnT values in 95 healthy blood donors were 0.00 to 0.02 μg/L and 0.00 μg/L, respectively. We used 0.10 μg/L as the cutoff value for cTnT, which is the discriminator recommended by the manufacturer. In addition, we evaluated the prognostic value of cTnT at alternative cutoff values of 0.05, 0.15, and 0.20 μg/L. cTnI was measured with an Opus Magnum device (Behring Diagnostics Inc). The method for the detection of cTnI is based on the principle of two-site immunoassay using polyclonal antibodies to recognize epitopes unique to cTnI. A discriminator value of 2.0 μg/L was used for cTnI, as recommended by the manufacturer. In accordance with this recommendation, we found a 97.5 percentile of 2.0 μg/L in 95 healthy blood donors (median, 0.0 μg/L; range, 0.0 to 8.4 μg/L). We also evaluated the applicability of 1.0, 1.5, and 2.5 μg/L as cutoff values for cTnI.
The discriminator values were used to separate patients with significant myocardial damage and increased risk of cardiac events from patients without myocardial damage and at low cardiac risk.
Statistical assessment of the prognostic value of cTnT and cTnI was carried out by the log-rank test. In patients in whom more than one cardiac event occurred, the most serious event was used in the calculations. These were weighted as follows: cardiac death >AMI >refractory AP >recurrent AP. The prognostic importance of the troponins and other parameters available at inclusion with regard to the composite end point of cardiac death/AMI was evaluated with a univariate regression analysis (parameters listed in Table 2⇓). To determine the independent prognostic value of the troponins at different cutoff values in comparison with the other parameters, forward “stepwise” multivariate logistic regression analyses were used. A multivariate analysis was performed for each cutoff value of cTnT or cTnI. Accordingly, eight separate models were built to evaluate the independent prognostic significance of each cutoff value with regard to clinical outcome in comparison with the variables used in the univariate analysis. In the multivariate models, parameters with a value of P<.20 were used as criteria for selection. ORs and 95% CIs were calculated. A value of P<.05 was considered significant.
The baseline characteristics and clinical features of the study population are shown in Table 1⇑. Three hundred forty-six patients (67%) had a history of AP, and 252 (49%) had suffered an AMI previously. Thirty-three percent and 61% had ST-segment depression and T-wave inversion, respectively, on the inclusion ECG. Neither ST-segment depression nor T-wave inversion was present in 25%. The four treatment groups, low-dose, middle-dose, and high-dose Inogatran and heparin, were equally represented. The median time from onset of chest pain to the start of blood sampling (inclusion) was 12 hours. The number of patients with onset of chest pain occurring in selected time intervals is shown in Table 1⇑. Among patients with cTnT <0.10 μg/L, 79% had a history of AP and 56% had previous AMI, compared with 46% and 41% in patients with levels ≥0.10 μg/L. A similar pattern was seen in patients with cTnI <2.0 μg/L, of whom 76% had a history of AP and 55% had suffered an AMI previously compared with 52% and 40%, respectively, in the group of patients with cTnI ≥2.0 μg/L.
In the 30-day follow-up period, 8 patients died (1.7%), 34 patients developed AMI (6.6%), refractory AP was reported in 21 patients (4.0%), and 242 patients had recurrent AP (46.8%). CABG or PTCA was performed on 102 patients (19.5%).
Appearance of cTnT and cTnI in Plasma
The median of cTnT values obtained within the initial 6 hours after inclusion was 0.07 μg/L; it ranged from 0.00 to 13.63 μg/L. Two hundred forty-nine patients (48%) had a highest value exceeding the cutoff value for cTnT (0.10 μg/L). For cTnI, the median of values obtained within 6 hours was 0.4 μg/L; range, 0.0 to 155.1 μg/L. Two hundred fourteen patients (41%) had a highest value of cTnI ≥2.0 μg/L. In 213 patients, both markers were above the chosen cutoff values; in 36 patients, only cTnT was elevated; and in 1 patient, only cTnI was elevated. There was a strong positive relationship between values of cTnT and cTnI within 6 hours after inclusion (Spearman’s coefficient, ρ=.93; P<.0001). The time courses of the cumulative proportions of patients with elevated values of cTnT and cTnI, respectively, are shown in Fig 1⇓.
Prognostic Value of cTnT and cTnI in Plasma
The occurrences of cardiac events in patients with normal and elevated levels of cTnT and cTnI are listed in Table 3⇓. Patients with cTnT ≥0.10 μg/L had a significantly higher incidence of cardiac death than patients with a highest value of cTnT <0.10 μg/L (P=.014). Furthermore, AMI occurred significantly more frequently in patients with cTnT ≥0.10 μg/L (P=.045). When cardiac death and AMI were combined, the difference was highly significant (P=.006). Kaplan-Meier curves of the occurrence of cardiac death and AMI in patients with and without elevated levels of the cardiac troponins are shown in Fig 2⇓. However, cTnT contained no prognostic information with regard to the combined end points of cardiac death/AMI/refractory AP/recurrent AP (P=.41).
As for cTnI, we found that patients with elevated levels within 6 hours after inclusion had a significantly higher risk of cardiac death than patients with normal levels (P=.026). In contrast to the result obtained for cTnT, patients with cTnI ≥2.0 μg/L did not have an increased risk of AMI (P=.15). However, when the composite end points of cardiac death and AMI were considered, patients with cTnI ≥2.0 μg/L had a significantly poorer prognosis than patients with cTnI <2.0 μg/L (P=.02). cTnI did not possess prognostic information when the combined end points cardiac death/AMI/refractory AP/recurrent AP were taken in consideration (P=.32).
Logistic Regression Analyses of Biochemical and Clinical Parameters Predictive of Outcome
To investigate the applicability of cutoff values other than those recommended by the manufacturers, we also included 0.05, 0.15, and 0.20 μg/L as cutoff values for cTnT and 1.0, 1.5, and 2.5 μg/L for cTnI in the logistic regression analyses. ORs, 95% CIs, and probability values for the evaluated parameters are shown in Table 2⇑. Age, cTnT above cutoff within 6 hours (0.05, 0.10, 0.15, and 0.20 μg/L), cTnI above cutoff within 6 hours (1.5, 2.0, and 2.5 μg/L), and ST-segment depression on the enrollment ECG were found to be significant with regard to a poor prognosis in the univariate regression analysis. We performed a multivariate logistic regression analysis for each of the cutoff values for cTnT and cTnI in comparison with the clinical parameters tested in the univariate analysis (see Table 4⇓). Only age, cTnT, and cTnI level and ACE inhibitor treatment persisted in the final models. Age was found to be an independent predictor of poor outcome in all eight multivariate models (OR, 1.07; 95% CI, 1.02 to 1.11; P<.002). cTnT was also found to contain independent prognostic value at all the cutoff values evaluated. As for cTnI, only cutoff values of 1.5, 2.0, and 2.5 μg/L contained independent prognostic information. None of the other parameters evaluated in the multivariate analyses provided any extra prognostic information. The ORs, 95% CIs, and probability values are listed in Table 4⇓.
Prognostic Value of cTnT and cTnI in Patients With Unstable AP
In the subset of patients who were retrospectively categorized as unstable AP (n=309), both cTnT and cTnI contained prognostic information regarding the occurrence of cardiac death/AMI (Table 5⇓).
Clinical Outcome in Patients Receiving Study Drug Versus Heparin
In the group of patients with cTnT ≥0.10 μg/L, 5 of 67 patients (8.0%) in the heparin group suffered a cardiac event (cardiac death/AMI), compared with 22 of 182 patients (12.1%) receiving Inogatran (P=.3). No statistically significant difference was found in the cTnI-positive group; the event rate was 7.2% in the patients who where treated with heparin and 11.9% in the Inogatran group (P=.3). In patients with normal levels of the troponins receiving heparin or Inogatran, no statistically significant differences in the event rates were found.
The present study was designed to compare the prognostic value of cTnT and cTnI in the same cohort of patients suspected of having UCAD. In accordance with a recent large study of this category of patients,26 we found overall incidences of cardiac death and AMI of 1.7% and 6.6%, respectively. Elevated levels of both cardiac troponins within the first 6 hours after inclusion were significantly associated with increased mortality rates at 30 days. Furthermore, the markers identify patients with an increased risk of the composite end point of cardiac death/AMI. Multivariate analysis demonstrated that the cardiac troponins were strong independent prognostic factors with regard to cardiac death/AMI. The inclusion of ECG changes did not provide any extra information about the clinical outcome. A close correlation of cTnT and cTnI values was found (Spearman’s ρ=.93, P<.0001), which further supports the theory that elevation of these markers reflects the same pathological process in the myocardium.
Because of the relatively high incidence of refractory AP and recurrent AP in the group of patients with cardiac troponins below the cutoff values, neither cTnT nor cTnI levels were predictive of the combined end points of cardiac death/AMI/refractory AP/recurrent AP. The high occurrence of refractory AP and recurrent AP in the group of patients with normal levels of the cardiac troponins is probably caused by the higher prevalence of AP and AMI at baseline compared with patients with elevated levels of the markers. Thus, patients with normal values of the troponins would also be prone to episodes of AP during the follow-up period. The frequent reports of recurrent AP and refractory AP in the patients with normal levels of the troponins probably explains why there was no association between cTnT levels and the performance of PTCA and CABG, inasmuch as invasive procedures are directed primarily by the presence of recurrent chest pain.
Prognostic Value of cTnT in Unstable AP
As in previous reports, we found that cTnT identifies a subgroup of patients diagnosed as having unstable AP with elevated cTnT, who have a poorer prognosis than patients with normal levels.4 27 28 However, the proportion with an event (11.8%) in the patients with elevated cTnT levels was somewhat lower than reported in other studies.27 28 These differences might be due to different designs and study populations. The prognostic capacity of cTnI seems to be comparable to that of cTnT in the subset of patients suffering from unstable AP.
Choice of Cutoff Values for the Present Study
In the evaluation of the prognostic value of cTnT and cTnI, we applied the cutoff values for myocardial damage recommended by the manufacturers of the assays. As for cTnT, several studies have confirmed the applicability of 0.10 μg/L as the cutoff value for risk stratification in patients with acute ischemic heart disease.3 19 27 A value of 0.20 μg/L was used as the discriminator limit in the early studies of the prognostic value of cTnT.16 28 29 However, as the cTnT assay has improved, the detection limit has been successively lowered. We found that cTnT also provides independent prognostic information with 0.05, 0.15, and 0.20 μg/L used as cutoff values. The multivariate analysis indicates that use of 0.20 μg/L as the cutoff value provides the best separation between high-risk and low-risk patients. Thus, the optimal cutoff values extracted from different study populations might vary because different inclusion criteria and blood sampling protocols are used, rather than being unequivocal and constant. It seems that a cutoff value as low as 0.05 μg/L can be used for risk stratification in patients with UCAD.
In the multivariate logistic regression analysis, cTnI provided independent prognostic information at 1.5, 2.0, and 2.5 μg/L. Assessed by the ORs, it seems that 2.5 μg/L is the best cutoff value for cTnI for early risk stratification in patients with UCAD. However, increased levels of cTnI were found in 3 of the 95 blood donors. This may have been due to unspecific binding of the cTnI antibodies to other plasma components of the blood donors.
Comparison With Other cTnI Assays
Several other immunoassays for the detection of cTnI exist that use miscellaneous methods and antibodies.7 20 21 22 24 The cTnI assays use different discriminator limits, ranging from 0.10 to 3.1 μg/L. This underlines the substantial differences in methodology and emphasizes difficulties in comparing studies that use different cTnI assays. Consequently, the prognostic capacity must be documented for each assay, and a standardization of cTnI assays is needed. A conversion factor for each cTnI assay could be calculated from standard reference samples containing predetermined concentrations of purified cTnI. cTnI concentrations determined by different assays would thereby be comparable.
Optimal Timing of Blood Sampling for Risk Stratification
Two large studies have shown that the samples of cTnT and cTnI taken on enrollment provide important prognostic information regarding cardiac death.3 7 In our study, we used the highest value within the first 6 hours after inclusion. When only the admission sample is used for risk stratification, a considerable number of patients who are suffering from significant myocardial damage is overlooked; this is probably due to the delay in the release of the cardiac troponins from injured myocardial cells. During the 96 hours in which blood samples were collected, a total number of 270 patients had cTnT values exceeding the cutoff value of 0.10 μg/L. We found that at 12 hours after enrollment, the cumulative number of patients with cTnT ≥0.10 μg/L was 256 (95%); at 24 hours, it was found that 259 patients (96%) had cTnT ≥0.10 μg/L, and only 81% of patients had an elevated value on admission. In 77% of the patients with an elevated value of cTnI in the 96-hour sampling period, cTnI exceeded the cutoff value on admission, whereas 97% were elevated at 12 hours. On the basis of these data, it seems that an in-hospital observation period of at least 12 hours gives an accurate identification of the majority of patients suffering from myocardial damage.
At present, much effort is put into developing new treatment modalities for patients suffering from UCAD. Studies that investigated the utility of low-molecular-weight heparin have shown promising results.1 2 The applicability of the cardiac troponins as indicators of high risk in patients with UCAD might provide a useful tool for the choice of optimal treatment. A large study has recently shown that elevation of cTnT identifies a subgroup of patients in whom prolonged antithrombotic treatment with a low-molecular-weight heparin (Dalteparin) can improve the prognosis.19 However, additional prospective studies are needed to document whether antithrombotic treatment and/or invasive procedures can improve the prognosis of patients with elevated levels of the cardiac troponins.
Comparison With Previous Studies
In a retrospective study of 1404 patients with unstable AP/non–Q-wave AMI, Antman et al7 found elevated levels of cTnI to be a strong indicator of cardiac death. Among the 573 patients with elevated cTnI levels, 3.7% died during the 42-day follow-up period, which is comparable to the 3.2% mortality rate we found in the cTnI-positive group. The event rate in patients with normal levels of cTnI was also concordant with our results: 1.0% in the study by Antman et al versus 0.7% in our study.
A recent large prospective study by Ohman et al3 reported that elevated levels of cTnT were strongly associated with a poor prognosis. The mortality rate at 30 days in patients with cTnT ≥0.10 μg/L on admission was 11.8% versus 3.9% among patients with normal levels. The higher mortality rate found by Ohman et al compared with our results is probably due to differences in study populations: we investigated patients suspected of unstable AP/non–Q-wave AMI, whereas Ohman et al included patients with Q-wave AMI, non–Q-wave AMI, and unstable AP. Only 36% had elevated levels of cTnT on admission, but a relatively short period from onset of symptoms to blood sampling (median time, 3 hours) was reported by Ohman et al, which might have caused false-negative cTnT values on admission in some patients with myocardial damage.
The present investigation was performed as a substudy in a multicenter trial in which several exclusion criteria were applied. This may have resulted in the exclusion of patients with concomitant diseases such as severe heart failure, renal failure, liver disease, and diseases with increased risk of bleeding. The exclusion of these patients might favor the troponins, because false-positives could occur when concomitant diseases are present. Furthermore, the interpretation of ECG findings was done by the treating physician at each participating center. A central evaluation by uniform criteria might have increased the prognostic value of the ECG changes.
In patients suspected of having UCAD, both cTnT and cTnI convey independent prognostic information with regard to cardiac death/AMI. The addition of ECG changes did not add any extra information with regard to the clinical outcome. The predictabilities of the markers vary at different cutoff values and are already significant at 0.05 μg/L for cTnT and 1.5 μg/L for cTnI. Prospective trials may indicate whether cTnT and cTnI can identify patients who will benefit from antithrombotic treatment and/or invasive procedures.
Selected Abbreviations and Acronyms
|AMI||=||acute myocardial infarction|
|CABG||=||coronary artery bypass grafting|
|cTnI||=||cardiac troponin I|
|cTnT||=||cardiac troponin T|
|PTCA||=||percutaneous transluminal coronary angioplasty|
|UCAD||=||unstable coronary artery disease|
Participating Centers and Investigators in the TRIM Substudy Concerning Biochemical Markers of Myocardial Damage
Denmark: Aarhus Amtssygehus, Aarhus: Kristian Thygesen, Bjarne Linde Nørgaard, Michael S. Lüscher, Jan Ravkilde. Rigshospitalet, Copenhagen: Peer Grande. Esbjerg Centralsygehus, Esbjerg: Tonny Nielsen. Sønderborg Sygehus, Sønderborg: Jan Pedersen. Bispebjerg Hospital, Copenhagen: Jørgen Videbæk, Kim Klarlund, Jørn Dalsgaard Nielsen. Norway: Regionsykehuset, Tromsø: Kurt Hofsøy. Flekkefjord Sykehus, Flekkefjord: Tor Omlan. õstfold Sentralsykehus, Fredrikstad: Thor Edvardsen.
Sweden: Höglandssjukhuset, Eksjö: Steen Ekdahl, Krister Kihlström, Jan-Olof Magnusson. Östra Sjukhuset, Göteborg: Karl Swedberg, Mikael Dellborg, Karl Andersen. Karolinska Sjukhuset, Stockholm: Lars Grip, Rikard Linder. Borås Lasarett, Borås: Erland Hall, Christer Wettervik, Sven-Åke Forsberg, Hans Thygesen. Länssjukhuset Ryhov, Jönköping: Jan-Erik Karlsson, Olof Svensson. Länssjukhuset, Kalmar: Finn Landgren, Bengt Holmgren, Stefan Ryden. Universitetssjukhuset, Lund: Hans Öhlin, Ole Hansen, Erik Tingberg. Universitetssjukhuset, Linköping: Eva Swahn, Magnus Janzon. Akademiska Sjukhuset, Uppsala: Lars Wallentin, Bertil Lindahl. Lasarettet, Falun: Helge Saetre, Gösta, Greger Ahlberg, Björn Linde, Lars Hageström. Söndersjukhuset, Stockholm: Johan Hulting, Jonas Höijer. Bollnäs Sjukhus, Bollnäs: Eskil Hammarström, Lennart Åström. Skellefteå Lasarett, Skellefteå: Kurt Boman, Jan Remmets. Sundsvalls Sjukhus, Sundsvall: Bengt Hj. Möller, Mona Lycksell.
This study was supported by a grant from the Danish Heart Foundation. We wish to thank Astra Hässle Sweden AB for making this study possible by financial and practical support, and we would also like to thank Lars Frison for his assistance with the statistical analyses. We appreciate the skillful assistance of the staff of each participating center.
↵1 The TRIM Study Group investigators and their institutions are listed in the “Appendix.”
- Received February 27, 1997.
- Revision received May 20, 1997.
- Accepted May 28, 1997.
- Copyright © 1997 by American Heart Association
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