European Heart Journal Advance Access published online on September 29, 2008
European Heart Journal, doi:10.1093/eurheartj/ehn438
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Diverging associations of an intended early invasive strategy compared with actual revascularization, and outcome in patients with non-ST-segment elevation acute coronary syndrome: the problem of treatment selection bias
1 Department of Cardiology, B2-137, Academic Medical Center, Meibergdreef 9, PO Box 22660, 1100 DD Amsterdam, The Netherlands
2 Department of Cardiology, Canisius Wilhelmina Hospital, Nijmegen, The Netherlands
3 Department of Cardiology, Erasmus Medical Center, Rotterdam, The Netherlands
4 Department of Cardiology, Medical Center Alkmaar, Alkmaar, The Netherlands
5 Department of Cardiology, University Medical Center St Radboud, Nijmegen, The Netherlands
Received 4 May 2008; revised 24 August 2008; accepted 12 September 2008.
* Corresponding author. Tel: +31 20 5669111, Fax: +31 20 6962609, Email: r.j.dewinter{at}amc.uva.nl
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Abstract |
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Aims: In several observational studies, revascularization is associated with substantial reduction in mortality in patients with non-ST-segment elevation acute coronary syndrome (nSTE-ACS). This has strengthened the belief that routine early angiography would lead to a reduction in mortality. We investigated the association between actual in-hospital revascularization and long-term outcome in patients with nSTE-ACS included in the ICTUS trial.
Methods and results: The study population of the present analysis consists of ICTUS participants who were discharged alive after initial hospitalization. The ICTUS trial was a randomized, controlled trial in which 1200 patients were randomized to an early invasive or selective invasive strategy. The endpoints were death from hospital discharge until 4 year follow-up and death or spontaneous myocardial infarction (MI) until 3 years. Among 1189 patients discharged alive, 691 (58%) underwent revascularization during initial hospitalization. In multivariable Cox regression analyses, in-hospital revascularization was independently associated with a reduction in 4 year mortality and 3 year event rate of death or spontaneous MI: hazard ratio (HR) 0.59 [95% confidence interval (CI) 0.37–0.96] and 0.46 (95% CI 0.31–0.68). However, when intention-to-treat analysis was performed, no differences in cumulative event rates were observed between the early invasive and selective invasive strategies: HR 1.10 (95% CI 0.70–1.74) for death and 1.27 (95% CI 0.88–1.85) for death or spontaneous MI.
Conclusion: The ICTUS trial did not show that an early invasive strategy resulted in a better outcome than a selective invasive strategy in patients with nSTE-ACS. However, similar to retrospective analyses from observational studies, actual revascularization was associated with lower mortality and fewer MI. Whether an early invasive strategy leads to a better outcome than a selective invasive strategy cannot be inferred from the observation that revascularized patients have a better prognosis in non-randomized studies.
Key Words: Unstable angina • Treatment strategy • Revascularization • Prognosis
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Introduction |
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Data from several large observational studies have demonstrated that revascularization in patients with non-ST-segment elevation acute coronary syndrome (nSTE-ACS) is associated with a substantial reduction in mortality compared with medical treatment.1–7 In these studies, patients who underwent revascularization within a certain time frame after admission (i.e. within 14 days) were compared with patients who underwent revascularization at a later time point or not at all. These observations were consistent across a wide range of subgroups and persisted after conventional risk adjustment, such as logistic regression analysis or propensity scores. For example, a substudy of the GUSTO-IV trial showed a 47% reduction in mortality at 1 year associated with revascularization within 30 days after adjustment for known patient and hospital characteristics.3 For many clinicians, these results have strengthened the belief that routine early angiography and subsequent revascularization would reduce mortality.8 In contrast, results from recent randomized studies have questioned whether early, invasive management reduces mortality. When long-term results from the three most recent trials (FRISC-II, RITA 3, ICTUS) are combined, there is only a non-significant trend towards fewer deaths with early invasive management [relative risk (RR) 0.90, 95% confidence interval (CI) 0.77–1.06; P = 0.20].9–11
These apparently contradictory findings may have several explanations. In the randomized studies, patients assigned to an early invasive approach undergo early diagnostic angiography but may subsequently be managed medically because revascularization is considered not indicated [no or non-significant coronary artery disease (CAD)], considered of little benefit (small side branch occlusion), or associated with high risk (unfavourable coronary anatomy or significant co-morbidities). In addition, a high proportion of patients assigned to the selective invasive approach may be revascularized depending on the criteria for ‘cross-over’. And even the proportion of patients revascularized in each strategy arm differed substantially between the randomized trials.12,13
At 4 years, the ICTUS trial did not show a benefit of an early invasive strategy compared with a selective invasive strategy in 1200 patients with nSTE-ACS and an elevated troponin T.9 The aim of the present analysis was to investigate the association between actual in-hospital revascularization and long-term outcome in the entire study population and to compare these results with the outcomes of the randomized treatment strategies. In addition, we further characterized the patients who were triaged to medical management despite an intended invasive strategy.
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Methods |
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Patients and study procedures
Design, methods, and results up to 4 year follow-up of the ICTUS trial have previously been described.9,12 In short, the trial was a prospective, randomized multicentre trial in which 1200 patients with nSTE-ACS were randomized to an early invasive or a selective invasive treatment strategy. Patients were eligible for inclusion if they had symptoms of ischaemia that were increasing or occurring at rest, with the last episode occurring no longer than 24 h prior to randomization, and if they had an elevated serum cardiac troponin T (
0.03 µg/L). Furthermore, they had either ischaemic changes on the electrocardiogram or a documented history of CAD. Under early invasive treatment strategy, angiography was to be performed within 24–48 h after randomization, followed by percutaneous revascularization when appropriate based on the coronary anatomy. Cardiac surgery was recommended in the event of extensive three-vessel disease or severe left main stem disease and was to be performed as soon as possible. In the case report form, for patients randomized to the early invasive management strategy who underwent angiography but who did not undergo revascularization, the investigator had to specify the clinical consideration for this: either A, no significant CAD, or B, other reasons, with a text field in order to capture additional information concerning co-morbidities, peri-operative risk, etc. Patients randomized to the selective invasive treatment strategy were initially managed medically with angiography and subsequent revascularization in the event of refractory angina under maximal medical treatment, haemodynamical or rhythmical instability, or significant ischaemia on the pre-discharge exercise test. Angiography and revascularization after hospitalization were performed if severe anginal symptoms were present despite optimal anti-anginal medication or when documented ischaemia on an ischaemia detection test was present.
The protocol specified that patients would receive daily aspirin, enoxaparin for at least 48 h, and abciximab during all percutaneous coronary intervention (PCI) procedures. Intensive lipid-lowering therapy was recommended per protocol, started as soon as possible after randomization.
Follow-up data were obtained on clinical events up to 3 years after randomization and on vital status up to 4 years. The clinical outcome events were evaluated by outpatient visits after 1, 6, and 12 months and by telephone contact between 2 and 4 years. All potential outcome events were recorded, and in the event of a repeat hospital admission, follow-up information was obtained from hospital records. Information for vital status and cause of death when applicable was also obtained by identifying the patients in the national population registry (Dutch Central Bureau of Statistics).
The main endpoints for the current analysis were death or spontaneous myocardial infarction (MI). MIs related to percutaneous or surgical revascularization were not counted for in this analysis. Spontaneous MI was defined as documented myocardial necrosis following the recommendations of the Consensus Committee for the definition of MI.14 The decision levels for cardiac enzymes of myocardial necrosis have been described in detail previously, and all events were adjudicated by a blinded events adjudication committee.9
All patients gave written informed consent before randomization and the collection of long-term follow-up information was approved by the authorized Ethics Committee. The study has been assigned the International Standard Randomised Control Trial Number ISRCTN82153174 [controlled-trials.com] .
Statistical analysis
In the present analysis, we compared the difference in event rates between patients who had been revascularized and those who had not, with the treatment effect observed between the arms of the prospectively randomized treatment strategies. In other words, we analysed the data from the ICTUS trial as if the data had been obtained by means of an observational study.
All patients who were alive at discharge were included in the present analysis. Patients who underwent revascularization during initial hospitalization were compared with those who did not. In addition, patients randomized to the early invasive strategy were compared with the selective invasive strategy. The outcomes events for the current analysis were the composite of death or spontaneous MI within 3 years after discharge and death within 4 years. Patients who had a non-fatal event during initial hospitalization were again at risk for a spontaneous MI between hospital discharge and end of follow-up.
Cumulative event rates were calculated according to the Kaplan–Meier method, and the timing of the events illustrated by Kaplan–Meier plots. Log-rank tests were applied to evaluate the differences between survival functions. Hazard ratios (HRs) with 95% CIs were obtained with Cox proportional hazards models. Follow-up for the composite endpoint was censored at the actual date of the last contact or at 3 years, whichever came first. Follow-up for mortality was censored at the date the national population registry verified vital status (1 May 2006), or at 4 years. Data on patients who were lost to follow-up were censored at the time of the last contact.
Randomized treatment strategies were compared without adjustments for covariates, and analysis was by intention-to-treat. In the analyses for actual revascularization, we used the method of stratified analysis involving estimated baseline risk to adjust for possible imbalance in risk between revascularized and non-revascularized patients.15 First, multivariable Cox proportional hazards models were developed for the endpoint ‘death’ and for the composite endpoint ‘death or spontaneous MI’, respectively. We included in the models the variable in-hospital revascularization and factors known to have an influence on the endpoint death or MI in patients with nSTE-ACS (Table 1).16,17 Then, for each patient, we calculated a risk score for death and a risk score for death or spontaneous MI, from the coefficients in the final models. The covariate in-hospital revascularization was set to ‘zero’. Patients were ranked accordingly and subsequently divided into three strata of low, medium, and high risk. The boundaries were chosen so that each stratum contained an equal number of patients in whom the endpoint had occurred. Finally, we performed stratified analyses to adjust for differences in baseline risk. Proportional hazards assumptions were verified by graphical examination of the partial residuals for all covariates and by testing the significance of the interaction between each covariate and time. For continuous variables, the linearity of the log HR was verified.
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In additional analyses, revascularized patients were compared with non-revascularized patients within each randomized treatment strategy. Furthermore, non-revascularized patients randomized to the early invasive strategy were subdivided into two categories: (i) patients who did not have a coronary artery stenosis of
70% (50% for left main) (group A: no revascularization, no CAD) and (ii) all remaining patients who were not revascularized during hospitalization because of other clinical decisions stated by the local investigators (i.e. angiography not succeeded, revascularization deemed to carry unacceptable risk, revascularization impossible, no treatable culprit lesion, or patient refusal) (group B: no revascularization, other). Sensitivity analyses were performed with all patients, including those who died before discharge, and with a different classification of revascularized and non-revascularized patients (revascularization within 30 days after randomization instead of during initial hospitalization).
Continuous variables were reported as medians with 25th and 75th percentiles, and categorical variables were reported as frequencies with percentages. The Mann–Whitney U test was used to compare continuous variables, and the 
2 test to compare categorical variables. All statistical tests were two-tailed, and a P-value <0.05 was deemed significant. Statistical analysis was done with the Statistical Package for Social Sciences software (SPSS 12.0 for Windows).
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Results |
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Main results of the ICTUS trial up to 4 year follow-up have been described previously.9,12 In short, 604 of the 1200 patients were randomly assigned to an early invasive strategy, and 596 to selective invasive strategy. The median age of the study population was 62 years; 73% were men; 14% had diabetes; 38% used aspirin before admission; and 23% were known to have a clinical history of MI. In both strategy groups, the median follow-up from randomization was 2.7 years for the combined endpoint death or spontaneous MI, and 3.4 years for vital status.
Use of invasive procedures during initial hospitalization
Among the 1189 patients discharged alive, coronary angiography was performed during initial hospitalization in 587 (98%) patients in the early invasive strategy and in 312 (53%) patients in the selective invasive strategy. A total of 691 (58%) patients underwent in-hospital revascularization: 454 (76%) patients in the early invasive strategy and 237 (40%) in the selective invasive strategy. Of these patients, coronary artery bypass grafting (CABG) was the first revascularization procedure in 21 and 29%, respectively. Descriptive analyses indicated that patients undergoing revascularization during hospitalization were more often men, more often used nitrates prior to admission, and had a lower C-reactive protein concentration and a higher creatinine clearance at admission. The median length of initial hospitalization was 6 days in the early invasive group compared with 7 days in the selective invasive group.
Actual revascularization vs. randomized treatment strategies
Figure 1 shows the Kaplan–Meier estimates from hospital discharge to the end of follow-up for death and the combined endpoint death or spontaneous MI stratified by both actual in-hospital revascularization and randomized treatment strategy. Of the patients discharged alive, 74 died during follow-up. The Kaplan–Meier estimates for death at 4 years were 4.8% (31/691) in patients who were revascularized during hospitalization compared with 10.0% (43/498) in patients not revascularized (HR 0.51; 95% CI 0.32–0.81). Similarly, the Kaplan–Meier estimates for death or spontaneous MI at 3 year were significantly lower in revascularized patients: 7.7% (43/691) vs. 15.1% (69/498), HR 0.43; 95% CI 0.29–0.62.
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However, when randomized treatment strategies were compared, the Kaplan–Meier estimate for death at 4 years was the same in patients randomized to the early invasive strategy and in those randomized to the selective invasive strategy: 7.0% (39/598) and 6.9% (35/591), respectively, HR 1.10; 95% CI 0.70–1.74. In patients randomized to the early invasive strategy, the estimated cumulative event rate for death or spontaneous MI at 3 years was 12.6% (63/598) compared with 8.9% (49/591) in patients in the selective invasive strategy (HR 1.27; 95% CI 0.88–1.85).
Adjustment for baseline incomparability and subgroup analysis
After adjustment for other known risk factors in multivariable Cox regression analyses, in-hospital revascularization remained significantly associated with a reduction in 4 year mortality and 3 year event rate of death or spontaneous MI (adjusted HR 0.59; 95% CI 0.37–0.96 and 0.46; 95% CI 0.31–0.68, Table 1).
We used a stratified analysis to show the outcome in patients with the same baseline risk. From the coefficients in the two models described in Table 1, a risk score was calculated for death and for death or spontaneous MI. Patients were then divided into a low, medium, and high-risk group. The stratum-specific HRs for death and for death or spontaneous MI between revascularized and non-revascularized patients did not differ substantially between the strata and thereby no effect modification is apparently present (Table 2). The overall risk group adjusted HR was 0.56 (95% CI 0.35–0.89) for death and 0.45 (95% CI 0.31–0.66) for death or spontaneous MI.
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The association between actual in-hospital revascularization, randomized treatment strategy, and 4 year mortality in several subgroups is depicted in Figure 2. The reduced risk of death in patients who were revascularized during hospitalization was consistent in all subgroups. When randomized treatment strategies were compared, there was no survival benefit of the early invasive strategy in any subgroup.
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Actual revascularization by randomized treatment strategy
The Kaplan–Meier event rates in revascularized and non-revascularized patients stratified by randomized treatment strategy are described in Table 3. The association of in-hospital revascularization and outcome was present in both the early invasive and the selective invasive treatment strategy. The 144 patients who were not revascularized during hospital admission but randomized to the early invasive treatment strategy had the highest event rate after discharge.
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In 53 of the 144 non-revascularized patients randomized to the early invasive treatment strategy, revascularization was not considered indicated because there was no significant CAD present on the angiogram (group A). The remaining 91 patients were managed medically because of other clinical reasons such as unfavourable coronary anatomy, no treatable culprit lesion, angiography not succeeded, or patient refusal (group B). The baseline characteristics of these subgroups are shown in Table 4. Compared with revascularized patients in the early invasive treatment group, patients in group B were older, were more likely to have diabetes mellitus, more likely to have a history of MI and CABG, had higher levels of NT-proBNP, a lower creatinine clearance, and had more severe CAD. The timing of the events of these different subgroups of the early invasive strategy is illustrated in Figure 3. Non-revascularized patients in group B had a clear increased risk of death and death or spontaneous MI compared with revascularized patients and patients in group A (P < 0.0001).
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Sensitivity analysis
Sensitivity analyses were performed with all patients, including those who died before discharge. In multivariable analysis including the same covariates as described in Table 1, the adjusted HRs for in-hospital revascularization vs. no revascularization were 0.60 (95% CI 0.38–0.94) for death within 4 years and 0.59 (95% CI 0.42–0.84) for the endpoint death or spontaneous MI within 3 years.
We also repeated the analysis with another classification of revascularized and non-revascularized patients. Patients who underwent revascularization within 30 days after randomization were compared with patients who underwent no revascularization. At 30 days, 1189 of the 1200 patients were alive and 710 (60%) of these patients were revascularized within 30 days. The association between revascularization and outcome remained similar with an adjusted HR for death at 4 years of 0.59 (95% CI 0.37–0.95) and for death or spontaneous MI at 3 years of 0.53 (95% CI 0.36–0.78).
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Discussion |
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In the present ICTUS substudy, we showed that in-hospital revascularization was associated with a 40% relative reduction in mortality within 4 years and a nearly 50% reduction in death or spontaneous MI within 3 years. After adjustment for baseline patient characteristics and stratified analysis involving estimated baseline risk, the association between revascularization and outcome remained present across a wide range of subgroups without heterogeneity. The relation between revascularization and outcome was present in both the early invasive and selective invasive treatment strategies. In particular, the event rates were highest in patients who were randomized to the early invasive strategy group and who did not undergo revascularization. We found that this specific group consisted of a heterogeneous population: (i) patients with a low-risk profile and good prognosis who were managed medically because no significant CAD was present and (ii) patients with significant CAD but nevertheless triaged to medical management who had a high-risk profile and worse prognosis. Importantly, when intention-to-treat analysis was performed and randomized treatment strategies were compared, no difference in event rates was observed between the early invasive and selective invasive treatment strategies.
The association between actual revascularization and outcome in our trial was comparable with the results from several observation studies.1–7 For example, retrospective analysis of data from patients included in the GUSTO-IV trial showed an almost 50% reduction in 1 year mortality among patients who had undergone revascularization within 30 days after admission compared with non-revascularized patients (adjusted RR 0.53; 95% CI 0.37–0.77).3 A similar reduction in mortality was found in other registries, including a large Swedish registry with more than 20 000 patients.1 In the absence of sufficient data from randomized trials, findings from observational studies are also used to support a strategy of early revascularization for certain subgroups of patients with nSTE-ACS, for example patients with a history of CABG.6
In the new guidelines for the diagnosis and treatment of nSTE-ACS from the European Society of Cardiology, a linear relationship is suggested between the relative mortality benefit of a routine invasive strategy compared with a selective invasive strategy and the ‘gradient’ (actual difference) in revascularization rates between the two treatment arms: the greater the difference in the rate of revascularization, the greater the benefit on mortality.16 This linear relationship is in part dependent on the GUSTO-IV analysis. These data are considered derived from a trial with a 100% difference in the revascularization rate with a 50% relative reduction in mortality and it is suggested that this observed mortality reduction reflects the true benefit of revascularization.8,16
However, in the randomized nSTE-ACS strategy trials that evaluated the role of an early invasive treatment strategy, patients were not assigned to revascularization or medical therapy, but prospectively randomized to two different diagnostic strategies. An early invasive treatment strategy consists of routine cardiac catheterization only followed by early percutaneous or surgical revascularization when considered indicated and after clinical evaluation of potential procedural risks. The selective invasive approach reserves coronary angiography for patients with recurrent angina or stress-induced ischaemia despite optimal medical therapy. We have shown in the present analysis that the estimated association of revascularization with mortality in observational data sets will not answer the question whether to routinely refer patients with nSTE-ACS for invasive procedures, or whether to treat such patients aggressively with pharmacological interventions followed by selective referral of those with refractory or inducible ischaemia.
To understand our observations further, we stratified the patients according to randomized treatment strategy and investigated the reason for medical management in patients randomized to the early invasive treatment group. Non-revascularized patients in the early invasive strategy group almost all underwent catheterization during hospitalization and therefore we could divide these patients according to the presence or absence of significant CAD. Some patients will be treated medically because no treatable culprit lesion is present and others because revascularization carries unacceptable risk or is unlikely to be successful. We showed that these two groups differed substantially in both baseline characteristics and prognosis. Patients managed medically without significant CAD had an excellent prognosis, whereas one-third of the patients with significant CAD managed medically experienced a spontaneous MI or died within 3 years after discharge. In the selective invasive group, as in many observational studies, a large part did not undergo catheterization and thereby no information on CAD is available. A limitation of our study is that the number of patients and events was not sufficient enough to further divide the patients according to the specific reasons why revascularization was not attempted. Furthermore, more detailed information about the anatomical form of the coronary arteries and stenoses is difficult to quantify and was not available.
Data from large ‘real world’ registries regarding invasive or non-invasive practice patterns in nSTE-ACS are conflicting.1,4,6,18–22 An analysis from a large Medicare database has shown that a high ‘area level of invasive treatment intensity’ did not provide a clinical benefit over lower invasive treatment intensity when beta-blocker treatment intensity in appropriate patients was high.20 However, in a large Swedish registry, early revascularization was associated with a substantial reduction in mortality irrespective of the use of beta-blockers.1 The different results from observational studies may in part be explained by the different analytic methods used. First, as discussed before, in strategy trials, patients are assigned to a treatment strategy before coronary catheterization and consequently an invasive strategy will not always result in revascularization. Therefore, it would be more appropriate to use catheterization as a measure of invasive strategy instead of revascularization. Secondly, factors that contribute to the decision making to perform catheterization and subsequent revascularization in clinical practice are complex and often immeasurable. In a recent article from Stukel et al.,23 the authors showed that the observational association of invasive practice and outcome in acute MI is highly sensitive to the analytic method used. Standard risk adjustment techniques, such as logistic regression or propensity scores, that are commonly used in analysing observation data can only account for measured confounders and thereby inevitably suffers from residual confounding. There are other alternative approaches, like instrumental variable analysis, that are designed to control for hidden bias as well. An instrumental variable is an observable factor that is associated with a specific treatment pattern but is otherwise unrelated to patient characteristics and does not directly affect the outcome of interest.24 With regard to acute coronary syndromes and outcome, variability in the intensity of invasive diagnostic and therapeutic treatment across regions or hospitals is often used in observational studies.20–22 In a way, these differences can be compared with strategies in randomized trials. Compared with standard modelling, instrumental variable analysis may produce less biased estimates of treatment effects.23
Instead of comparing an invasive strategy to a non-invasive strategy, the ICTUS trial compared routine, early revascularization to less aggressive, delayed intervention. The high percentage of patients who were revascularized in the selective invasive group compared with the other randomized trials is one of the reasons that could explain the discrepancy between the outcomes of the trials. The in-hospital revascularization rate in the different randomized trials varied 10–40% in the selective invasive arm, and 44–78% in the early invasive arm.12,13 In other trials that included high-risk nSTE-ACS patients with an intended early invasive strategy, the revascularization rate was comparable. For example, in the SYNERGY and ACUITY trials, the in-hospital revascularization rates were 66 and 68%, respectively.25,26 In view of the long-term results from the FRISC-II, RITA 3, and the ICTUS study, an early invasive treatment may not be necessary for all nSTE-ACS patients.
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Conclusions |
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The long-term follow-up of the ICTUS trial did not show that an early invasive strategy resulted in a better outcome than a more selective invasive strategy in patients with nSTE-ACS and a positive troponin. However, similar to retrospective analyses from observational studies, actual revascularization during hospital admission was associated with lower mortality and fewer MIs, even after the use of appropriate risk adjustment techniques. This apparent discrepancy is primarily driven by the poor prognosis in patients who underwent angiography but were not revascularized because of co-morbidities and anticipated high procedure-related risks. Therefore, we conclude that the observation that revascularization is associated with improved prognosis cannot be used as evidence to support that an early invasive treatment strategy leads to a better outcome compared with a selective invasive treatment strategy.
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The ICTUS study was supported by the Interuniversitary Cardiology Institute of the Netherlands (ICIN), the Working group on Cardiovascular Research of The Netherlands (WCN), and educational grants from Eli Lilly, Sanofi/Synthelabo, Aventis, Pfizer, and Medtronic. Roche Diagnostics, The Netherlands, kindly provided the reagents for Core Laboratory cardiac troponin T measurements.
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Acknowledgements |
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We thank all the investigators and coordinators of the ICTUS trial and all the medical and nursing staff in the recruitment and intervention centres who made the trial possible. The complete list of investigators has been published previously.12 Most of all, we would like to thank all the patients who participated in the trial.
Conflict of interest: None of the authors have any financial interest to disclose with respect to the ICTUS trial. F.W.A.V. has received educational and research grants from Bayer AG, Roche, Eli Lilly, and Boehringer Ingelheim, and received honoraria for consultancies from Pharmacia Upjohn, Eli Lilly, Merck, and Bayer (The Netherlands).
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References |
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