Author + information
- Received January 19, 2017
- Accepted February 4, 2017
- Published online April 10, 2017.
- Niels P.G. Hoedemaker, MD,
- Peter Damman, MD, PhD,
- Pier Woudstra, MD,
- Alexander Hirsch, MD, PhD,
- Fons Windhausen, MD, PhD,
- Jan G.P. Tijssen, PhD,
- Robbert J. de Winter, MD, PhD∗ (, )
- ICTUS Investigators
- Department of Cardiology, Heart Center, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands
- ↵∗Address for correspondence:
Prof. Robbert J. de Winter, Department of Cardiology, B2-137, Academic Medical Center, Meibergdreef 9, 1105 Amsterdam, the Netherlands.
Background The ICTUS (Invasive Versus Conservative Treatment in Unstable Coronary Syndromes) trial compared early invasive strategy with a selective invasive strategy in patients with non–ST-segment elevation acute coronary syndrome (NSTE-ACS) and an elevated cardiac troponin T. No long-term benefit of an early invasive strategy was found at 1 and 5 years.
Objectives The aim of this study was to determine the 10-year clinical outcomes of an early invasive strategy versus a selective invasive strategy in patients with NSTE-ACS and an elevated cardiac troponin T.
Methods The ICTUS trial was a multicenter, randomized controlled clinical trial that included 1,200 patients with NSTE-ACS and an elevated cardiac troponin T. Enrollment was from July 2001 to August 2003. We collected 10-year follow-up of death, myocardial infarction (MI), and revascularization through the Dutch population registry, patient phone calls, general practitioners, and hospital records. The primary outcome was the 10-year composite of death or spontaneous MI. Additional outcomes included the composite of death or MI, death, MI (spontaneous and procedure-related), and revascularization.
Results Ten-year death or spontaneous MI was not statistically different between the 2 groups (33.8% vs. 29.0%, hazard ratio [HR]: 1.12; 95% confidence interval [CI]: 0.97 to 1.46; p = 0.11). Revascularization occurred in 82.6% of the early invasive group and 60.5% in the selective invasive group. There were no differences in additional outcomes, except for a higher rate of death or MI in the early invasive group compared with the rates for the selective invasive group (37.6% vs. 30.5%; HR: 1.30; 95% CI: 1.07 to 1.58; p = 0.009), driven by a higher rate of procedure-related MI in the early invasive group (6.5% vs. 2.4%; HR: 2.82; 95% CI: 1.53 to 5.20; p = 0.001).
Conclusions In patients with NSTE-ACS and elevated cardiac troponin T levels, an early invasive strategy has no benefit over a selective invasive strategy in reducing the 10-year composite outcome of death or spontaneous MI, and a selective invasive strategy may be a viable option in selected patients.
Different treatment strategies are available for patients presenting with non–ST-segment elevation acute coronary syndromes (NSTE-ACS). In the ICTUS (Invasive Versus Conservative Treatment in Unstable Coronary Syndromes) trial, an early invasive treatment strategy (also called routine invasive strategy) consisted of intensive antianginal and antithrombotic medical treatment aimed at stabilization and coronary angiography within 24 to 72 h, and angiography-guided subsequent appropriate treatment, either by revascularization or continued optimized pharmacological therapy. A selective invasive strategy (or ischemia-driven strategy) also consisted of antianginal and antithrombotic medical treatment, but with coronary angiography only in cases of refractory angina or inducible ischemia by pre-discharge noninvasive stress testing. The definitions used in the ICTUS trial predate the definitions that are currently used in the European and American guidelines. Current guidelines recommend an early invasive strategy (<24 h) for high-risk patients, whereas a delayed strategy (<25 to 72 h) is recommended for intermediate-risk patients. For low-risk patients either a delayed strategy or an ischemia-driven strategy can be used (1,2). Importantly, NSTE-ACS patients with an elevated cardiac troponin T are considered high risk.
Those recommendations are largely based on multiple randomized clinical trials that have been included in several meta-analyses (3–6). A patient-pooled meta-analysis of the FRISC II (Fragmin and Fast Revascularisation During Instability in Coronary Artery Disease), ICTUS, and RITA-3 (Third Randomised Intervention Treatment of Angina) trials (FIR) showed a reduction of long-term rates of cardiovascular death or myocardial infarction (MI) at 5 years, for patients who underwent an early invasive strategy (7). In the analysis, the largest risk reduction was observed in patients with the highest baseline risk. This reduction in clinical outcomes was mainly driven by a reduction in nonfatal MI, whereas a nonsignificant trend was observed in cardiovascular death.
Long-term follow-up is important to appreciate the full clinical impact of such treatment strategies in NSTE-ACS patients. The ICTUS trial assigned 1,200 NSTE-ACS patients with an elevated cardiac troponin to either an early invasive or a selective invasive strategy. After 1 year of follow-up, an early invasive strategy was not associated with a benefit in death, MI, or rehospitalization for anginal symptoms despite an increase in early procedure-related myocardial infarction (8). At 5-year follow-up, there was no significant benefit of an early invasive strategy regardless of the patient baseline risk profile (9,10).
Recently, the RITA-3 study showed no difference between an early invasive or a noninvasive strategy for all-cause and cardiovascular mortality after 10 years of follow-up, in contrast to the 5-year outcome that showed a mortality benefit of an early invasive strategy (3,11). In addition, the 15-year follow-up of the FRISC-II study was recently published, showing a significant 18-month postponement of the occurrence of death or next MI and 37 months postponement of rehospitalization for ischemic heart disease, but similar mortality with either strategy (12). In this report we describe the 10-year clinical outcomes of the ICTUS trial. We report all-cause mortality, cardiovascular mortality, MI (spontaneous and procedure-related), and revascularization, and we assess the impact of baseline risk.
The original design and methods of the ICTUS study have been published previously (8). Between July 2001 and August 2003, we enrolled 1,200 NSTE-ACS patients with an elevated cardiac troponin T in 42 Dutch hospitals (Online Appendix). Within 24 h after onset of symptoms, the patients were randomized to either an early invasive strategy or a selective invasive strategy.
Patients ages 18 to 80 years were eligible if they had all 3 of the following: ongoing chest pain (>20 min); an elevated cardiac troponin T level (≥0.03 g/l); and either ischemic changes as assessed by electrocardiography (defined as ST-segment depression or transient ST-segment elevation exceeding 0.05 mV or T-wave inversion of ≥0.2 mV in 2 contiguous leads) or a documented history of coronary artery disease (clinical history of MI, percutaneous coronary intervention [PCI], and/or coronary artery bypass graft [CABG]). Patients were excluded in case of: an ST-segment elevation MI <48 h before randomization, an indication for reperfusion therapy, hemodynamic instability or overt congestive heart failure, and an increased bleeding risk.
Patients randomized to an early invasive strategy underwent coronary angiography within 24 to 48 h after randomization and the requirement for revascularization by PCI or CABG was guided by the findings of the angiography. Patients assigned to a selective invasive strategy received optimal (antianginal) medical treatment. Coronary angiography was performed in cases of refractory angina or inducible signs of ischemia during a mandatory pre-discharge ischemia detection test.
Optimized medical therapy
All patients received optimal pharmacological treatment including aspirin, clopidogrel, enoxaparin, intravenous nitrates, beta-blockers, and intensive lipid-lowering therapy. The protocol recommended all PCI be performed with the use of abciximab, given as bolus of 0.25 mg/kg, followed by an infusion of 0.125 μg/kg/min for 12 h, and started 10 to 60 min before the first balloon inflation.
We collected the patients’ vital status from the Dutch national population registry at least 10 years after randomization. We contacted all patients known to be alive at 10 years by telephone to collect information on rehospitalization for cardiac reasons. If patients were rehospitalized, we obtained the discharge letters from the hospitals the patients were admitted to. If necessary, hospitalization information was obtained from their general practitioners. For deceased patients, we collected clinical event information and cause of death from their general practitioners or from hospital records. Patients were considered lost to follow-up if no contact could be made with either the patient or the general practitioner. The Medical Ethics Committee of the Academic Medical Center–University of Amsterdam approved the long-term follow-up.
The main outcome of this study was the composite of all-cause death and spontaneous MI. Additional outcomes were the composite of all-cause death and MI, all-cause death, cardiovascular death, noncardiovascular death, MI, spontaneous MI, procedure-related MI, and revascularization by PCI or CABG. All deaths were considered cardiovascular unless an unequivocal noncardiovascular cause could be established. MI was defined as documented myocardial necrosis either in the setting of myocardial ischemia (spontaneous MI) or in the setting of PCI or CABG (procedure-related MI) following the recommendations of the Consensus Committee for the definition of MI (13). All events were adjudicated, those within the first 5 years by a blinded adjudication committee and later ones by 2 co-authors (N.P.G.H. and P.D.).
The analyses were by intention to treat. We calculated the nonparametric estimator of the cause-specific cumulative incidence of revascularization to account for competing risk of death. We performed a landmark analysis for revascularization with a landmark at 1 year. For all other outcomes, we used the Kaplan-Meier method to estimate cumulative incidence, and Cox proportional hazards model to obtain hazard ratios (HRs) with 95% confidence intervals (CIs). Follow-up was censored at 3,655 days or at the last date of known clinical outcome status for patients with incomplete follow-up. For endpoints not including all-cause death, cardiovascular death, or noncardiovascular death, follow-up was censored at the time of death if not preceded by the outcome. We performed a stratified analysis according to baseline risk using the FIR risk score (7). The FIR score is a sum of the following factors: age (<60 years [+0], 60 to 64 years [+1], 65 to 69 years [+2], 70 to 74 years [+3], ≥75 years [+5]); diabetes mellitus (+4); previous MI (+3); ST-segment depression (+2); hypertension (+1); and body mass index (<25 [+1], 25 to <35 [+0], ≥35 [+2]). A multivariate predictive model for death or spontaneous MI was developed with a Cox proportional hazards model. The model was developed by backward stepwise elimination from a larger predefined set of baseline variables including the following: age ≥65 years; sex; body mass index; diabetes mellitus; current smoker at time of enrollment; hypertension; hypercholesterolemia; family history of coronary artery disease; history of MI; history of PCI; history of CABG; aspirin use at admission; C-reactive protein ≥10 mg/l; ST-segment depression; ST-segment elevation; ST-segment deviation; creatinine clearance ≤60 ml/min/1.73 m2. We used the Wald test with a p value of 0.1 for exclusion from the model. All statistical analyses were performed with SPSS version 23.0 (SPSS Inc., IBM, Armonk, New York), except for the calculation of nonparametric estimator of the cause-specific cumulative incidence of revascularization and the landmark analysis, for which we used R version 3.3.0 (R Foundation, Vienna, Austria).
Of 1,200 patients, 604 patients were assigned to an early invasive strategy and 596 patients were assigned to a selective invasive strategy (Figure 1). The 2 groups showed well-matched baseline characteristics (Table 1).
The median age was 62 years; approximately 75% of the patients were male; and 14% had diabetes. Ischemic electrocardiographic changes were present in 50% of patients. All patients had elevated cardiac troponin T levels. The median troponin T level at admission was 0.29 μg/l. Cardiac catheterization was performed during the initial hospitalization in 98% of patients in the early invasive group and 53% in the selective invasive group. Within 1 year, 79% of the patients in the early invasive group had undergone revascularization compared with 54% in the selective invasive group. When we accounted for competing risk of death, the 10-year revascularization rate was 83% in the early invasive group and 61% in the selective invasive group (Figure 2A). There was no difference in revascularization from 1 year to 10 years of follow-up (p = 0.61) (Figure 2B).
Vital status at 10 years was known for 1,152 patients (96.0%) and was equally distributed between both groups (Figure 1). Clinical outcome status (MI and revascularization) at 10 years was known for 1,171 patients (97.6%), 594 patients (98.3%) in the early invasive group and 577 patients (96.8%) in the selective invasive group. Table 2 displays the 10-year cumulative event rates and HR of the main composite and individual outcomes. The 10-year composite outcome of death or spontaneous MI was 33.8% for the early invasive group and 29.0% for the selective invasive group (Central Illustration) (HR: 1.12; 95% CI: 0.97 to 1.46; p = 0.11) and 37.6% versus 30.4% (HR: 1.30; 95% CI: 1.07 to 1.58; p = 0.009) for death or MI, respectively.
Figure 3 shows the Kaplan-Meier curves for the other additional outcomes. There was no difference in all-cause death for early invasive strategy (26.6%) versus selective invasive strategy (23.7%) (HR: 1.14; 95% CI: 0.91 to 1.44; p = 0.25) (Table 2, Figure 3A) or for cardiovascular death (17.6% vs. 15.2%, respectively; HR: 1.15; 95% CI: 0.86 to 1.54; p = 0.34) (Table 2, Figure 3C). Additionally, MI in the early invasive group was 18.9% versus 14.9% in the selective invasive group (HR: 1.30; 95% CI: 0.98 to 1.73; p = 0.07) (Table 2, Figure 3B). This nonsignificant difference in MI was mainly driven by a higher rate of procedure-related MI: 6.5% versus 2.4% for early invasive and selective invasive strategies, respectively (HR: 2.82; 95% CI: 1.53 to 5.20; p = 0.001), as the 10-year rate of spontaneous MI was similar in both groups (13.8% vs. 12.9% respectively; HR: 1.04; 95% CI: 0.75 to 1.43; p = 0.82).
Figure 4 displays the Kaplan-Meier estimate curves for death or spontaneous MI stratified by FIR score. There was no benefit for an early invasive strategy regardless of the baseline risk: 1) for low risk, HR = 0.95 (95% CI: 0.67 to 1.34; p = 0.76); 2) for intermediate risk, HR = 1.40 (95% CI: 0.99 to 1.97; p = 0.054); and 3) for high risk, HR = 1.07 (95% CI: 0.69 to 1.67; p = 0.76). Looking at both risk score (FIR) and treatment strategy, we could not demonstrate an interaction of sex with outcomes.
Table 3 shows baseline characteristics independently associated with 10-year death or spontaneous MI. In the multivariate model, there was no difference between the early invasive and selective invasive strategy with regard to the 10-year risk of death or spontaneous MI (HR: 1.20; 95% CI: 0.97 to 1.48; p = 0.096).
In this study, we report the 10-year clinical outcomes of the ICTUS study. Our results show that, in patients with NSTE-ACS with elevated cardiac troponin T levels, there was no benefit associated with an early invasive strategy in reducing death or spontaneous MI after 10 years of follow-up. In addition, we did not observe differences in rates of death or spontaneous MI after risk stratification with the FIR score. No late effects were observed, with comparable increments for death or MI in both treatment groups up to 10-year follow-up. Although more procedure-related MI occurred in the early invasive group, there was no significant difference in mortality at 10 years. The current result confirms and extends the results of previous studies, with one-third of patients enduring death or spontaneous MI within 10 years despite treatment. These findings are in contrast to the results of the long-term outcome of the FRISC-II and RITA-3 studies, where a benefit of an early invasive strategy was shown.
Context and interpretation of the current results
There may be many reasons for the differences observed in the ICTUS trials when compared with the FRISC-II and RITA-3 studies. The trials enrolled patients in different time periods, and there were differences in clinical practice. Compared with the RITA-3 and FRISC-II trials, the ICTUS trial was the most contemporary and included the use of stents, glycoprotein IIb/IIIa inhibitors during PCI, long-term (dual) antiplatelet agents, and high-dose statin treatment.
Perhaps the most important difference among the 3 trials was the timing and intensity of revascularization (Figure 5). In the ICTUS trial, in the early invasive strategy as per protocol, 97% of patients underwent coronary angiography within 48 h and 98% during hospitalization (8). Coronary angiography during hospitalization was 96% in both early invasive groups of RITA-3 and FRISC-II, and by design, was to be performed <72 h from randomization and <7 days from admission for the index event, respectively (14,15). More importantly, coronary angiography during hospitalization in the noninvasive groups of FRISC-II and RITA-3 was only 7% and 16%, respectively, compared with 53% of patients in the selective invasive group in ICTUS, which better reflects contemporary practice (8,14,15). All patients in ICTUS were troponin positive, making the presence of an ACS more likely. Furthermore, after diagnostic coronary angiography, subsequent revascularization was more frequent in the ICTUS trial. Revascularization during hospitalization was 76% in the early invasive group and 40% in selective invasive group compared with 76% in the early invasive group versus 14% in the noninvasive group of FRISC-II and 44% versus 10% in RITA-3 (8,14,15).
Meta-analyses have shown a mortality benefit with an early invasive strategy at 2 years when combining data from randomized trials (5,16). In ICTUS, an absolute 22% difference in revascularization between the early invasive and the selective invasive group was sustained until 10 years, with mortality showing no difference at 1-, 5-, and 10-year follow-up. In FRISC-II, a significant difference in mortality was observed at 2 years, which dissipated at 5-year and 15-year follow-ups (4,12). In the RITA-3 study, there was no difference in mortality at 2-year follow-up. A significant difference in mortality was observed at 5 years, which no longer existed at 10-year follow-up (3,11). We are unaware of a plausible pathophysiological mechanism or change in clinical practice over time that may explain these observations. Therefore, considering the long-term observations of all 3 strategy trials, one may assume that any observed difference in mortality is the result of a play of chance. In summary, although the 3 individual trials may not be statistically powered to detect a difference in mortality, the long-term (≥10 years) results found in the 3 studies suggest that, compared with a selective invasive strategy, an early invasive strategy is not associated with a long-term mortality benefit, even in NSTE-ACS patients with an elevated cardiac troponin.
Concerning the incidence of MI, the long-term results varied among the 3 strategy trials. Our current results show there is no benefit associated with an early invasive strategy in reducing death or MI at 10 years, and our results are consistent with the earlier results from the ICTUS study (8–10). At 1 and 5 years, an early invasive strategy was not associated with a reduction in the composite of death or MI. Nor was there is difference in the 2 individual endpoints. In contrast to our results, the 5-year composite of death or MI in RITA-3 was higher in the noninvasive group (20.0%) compared with the early invasive group (16.6%; p = 0.044) (3). Yet, MI as an individual endpoint did not differ between the 2 groups at 5 years (early invasive: 6.8% vs. 8.3%; p = 0.22). In FRISC-II, death or MI at 5 years was significantly higher in the noninvasive group (24.5% vs. 19.9%; p = 0.009) and was mainly driven by a higher number of MI in the noninvasive group (17.7%) compared with the early invasive group (12.9%; p = 0.002) (4). Looking at all events, not just the first event, this result persisted at 15 years of follow-up in FRISC-II. In this study, an early invasive strategy was associated with a postponement of death or new MI by 18 months and death or next readmission for ischemic heart disease by 37 months. This was mainly driven by a higher rate of MI or readmission in the noninvasive group during the first 3 to 4 years of the study, with the event curves running parallel thereafter (12). Again, the difference in early revascularization between the early invasive and the noninvasive treatment arm in FRISC-II was profound, with unplanned revascularization occurring 30% more often in the noninvasive group during the first 3 to 4 years. Thus, the more frequent occurrence of spontaneous MI in the noninvasive group in the first 3 years in FRISC-II over time, parallels a low percentage of early revascularization followed by more frequent unplanned revascularization at a later time when compared with the early invasive group. Current European and American NSTE-ACS guidelines recommend an early invasive strategy for troponin-positive patients, with coronary angiography being done preferably within 24 h (1,2). Yet, in the long-term results of FIR there was no mortality benefit associated with an early invasive strategy. Moreover, we could not show a reduction in MI at 10-year follow-up, provided there was a revascularization rate of 61% in the selective invasive group at 10 years (with an absolute difference in revascularization of 22%). Taken together, when balancing the risks and benefits of angiography and revascularization, we conclude that a selective invasive strategy may be a viable option in selected patients.
We acknowledge several important developments in diagnostic and therapeutic armamentarium for NSTE-ACS patients over the past years. First, the high-sensitivity troponin assay (hs-cTn) is now widely available. The introduction of hs-cTn has improved the rule-out process in NSTE-ACS patients with a normal hs-cTn (17). Since its introduction, hs-cTn also has markedly changed the troponin-positive NSTE-ACS population; a recent study demonstrated an increase of troponin-positive NSTE-ACS (or non–ST-segment elevation MI) and a decrease in unstable angina diagnoses at discharge (18). Subsequently, a rise or fall in cardiac troponin has been indicated as a high-risk feature, mandating an invasive strategy by the most recent treatment guidelines. Therefore, more patients who were previously diagnosed with unstable angina now have an indication for early coronary angiography. Patients with minor elevations measured with hs-cTn, who are at the lower end of the risk spectrum, have not been included in any the strategy trials.
Second, pharmacological and invasive treatment options, used at the time of enrollment of the study, have been developed further. For example, several trials with novel P2Y12 inhibitors have shown benefit over clopidogrel in reducing death, MI, and stroke, including patients with an intended noninvasive management (19–21). The use of radial approach is more prevalent and has been shown to reduce major bleeding in NSTE-ACS patients, and stent technology has improved with the introduction of latest generation drug-eluting stents (22,23).
Finally, we emphasize the importance of secondary prevention by means of optimized medical treatment, lifestyle changes, and smoking cessation, as recommended by international guidelines (1,2). As all these new developments affect both an early invasive approach and a more selective invasive approach, a future study is warranted.
First, we collected our follow-up information through patient phone calls, general practitioners, hospital records, and the national population registry. Unreported hospital admissions or patients who were lost-to-follow-up may lead to an underestimation of event rates. Second, routine serial measurement of cardiac biomarkers after PCI was not part of clinical practice during long-term follow-up and some procedure-related MI without clinical symptoms may have been missed. Third, the results of this study reflect clinical practice in the Dutch health care system. The Netherlands is a small, densely populated country with many heart centers, adequate capacity for PCI or CABG, and well-organized primary care. Fourth, mean age of the patients in our study was 62 years with relatively few patients older than 80 years, making a comparison with the recently published After Eighty study difficult (24). Finally, although the quality of secondary prevention including medical treatment was likely to be high, this was not prospectively recorded during the 10-year follow-up.
Our results show that, in patients with NSTE-ACS with elevated cardiac troponin T levels, an early invasive strategy has no benefit in reducing the 10-year composite and individual outcomes of death or spontaneous MI. Additionally, rates of the composite of death or spontaneous MI did not differ after risk stratification for baseline risk with the FIR score. When balancing the risks and benefits of angiography and revascularization, we believe that a selective invasive strategy may be a viable option in selected patients. Future randomized controlled trials reflecting present-day clinical practice for NSTE-ACS patients, are warranted.
COMPETENCY IN MEDICAL KNOWLEDGE: In patients with NSTE-ACS with elevated cardiac troponin-T levels, an early invasive strategy does not reduce the 10-year composite outcome of death or spontaneous MI compared to a selective invasive strategy.
TRANSLATIONAL OUTLOOK: Further research is needed to determine the optimum basis on which to decide between early and selective invasive strategies for NSTE-ACS patients in the era of hs-cTn, novel P2Y12 inhibitors, radial arterial access, and drug-eluting stents.
The authors thank the investigators of the ICTUS trial and the medical and nursing staff in the participating centers (Online Appendix). The authors also thank all the patients who participated in this trial.
For the investigators and research coordinators that participated in the ICTUS trial, please see the online version of this article.
This work was supported by the Interuniversity Cardiology Institute of the Netherlands, the Working Group on Cardiovascular Research of the Netherlands, and educational grants from Eli Lilly, Sanofi/Synthelabo, Sanofi, Pfizer, and Medtronic. Roche Diagnostics, the Netherlands, provided the reagents for core laboratory cardiac troponin T measurements. Dr. Damman has received a research grant from AstraZeneca. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Anthony A. Bavry, MD, served as Guest Editor for this paper.
- Abbreviations and Acronyms
- coronary artery bypass graft
- confidence interval
- FRISC II, ICTUS, and RITA-3 trials
- hazard ratio
- high-sensitivity troponin assay
- myocardial infarction
- non–ST-segment elevation acute coronary syndrome
- percutaneous coronary intervention
- Received January 19, 2017.
- Accepted February 4, 2017.
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