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The ICTUS trial was a study that compared an early invasive with a selective invasive treatment strategy in patients with non-ST-elevation acute coronary syndrome (nSTE-ACS). The study reported no difference between the strategies for frequency of death, myocardial infarction, or rehospitalisation after 1 year. We did a follow-up study to assess the effects of these treatment strategies after 4 years. 1200 patients with nSTE-ACS and an elevated cardiac troponin were enrolled from 42 hospitals in the Netherlands. Patients were randomly assigned either to an early invasive strategy, including early routine catheterisation and revascularisation where appropriate, or to a more selective invasive strategy, where catheterisation was done if the patient had refractory angina or recurrent ischaemia. The main endpoints for the current follow-up study were death, recurrent myocardial infarction, or rehospitalisation for anginal symptoms within 3 years after randomisation, and cardiovascular mortality and all-cause mortality within 4 years. Analysis was by intention-to-treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN82153174. The in-hospital revascularisation rate was 76% in the early invasive group and 40% in the selective invasive group. After 3 years, the cumulative rate for the combined endpoint was 30·0% in the early invasive group compared with 26·0% in the selective invasive group (hazard ratio 1·21; 95% CI 0·97–1·50; p=0·09). Myocardial infarction was more frequent in the early invasive strategy group (106 [18·3%] vs 69 [12·3%]; HR 1·61; 1·19–2·18; p=0·002). Rates of death or spontaneous myocardial infarction were not different (76 [14·3%] patients in the early invasive and 63 [11·2%] patients in the selective invasive strategy [HR 1·19; 0·86–1·67; p=0·30]). No difference in all-cause mortality (7·9%vs 7·7%; p=0·62) or cardiovascular mortality (4·5%vs 5·0%; p=0·97) was seen within 4 years. Long-term follow-up of the ICTUS trial suggests that an early invasive strategy might not be better than a more selective invasive strategy in patients with nSTE-ACS and an elevated cardiac troponin, and implementation of either strategy might be acceptable in these patients.

New evidence has emerged that the assessment of multiple biomarkers such as cardiac troponin T (cTnT) and N-terminal pro–brain natriuretic peptide (NT-proBNP) in patients with non–ST-elevation acute coronary syndrome (nSTE-ACS) provides unique prognostic information. The purpose of this study was to assess the association between baseline NT-proBNP levels and outcome in patients who have nSTE-ACS with an elevated cTnT and to determine whether patients with elevated NT-proBNP levels benefit from an early invasive treatment strategy. Baseline samples for NT-proBNP measurements were available in 1141 patients who have nSTE-ACS with an elevated cTnT randomized to an early or a selective invasive strategy. Patients were followed-up for the occurrence of death, myocardial infarction (MI), and rehospitalization for angina. We showed that increased levels of NT-proBNP were associated with several indicators of risk and severe coronary artery disease. Mortality by 1 year was 7.3% in the highest quartile (≥1170 ng/L for men, ≥2150 ng/L for women) compared with 1.1% of patients in the lower 3 quartiles ( P < .0001). N-terminal pro–brain natriuretic peptide (highest quartile vs lower 3 quartiles) was a strong independent predictor of mortality (hazard ratio 5.0, 95% CI 2.1-11.6, P = .0002). However, NT-proBNP levels were not associated with the incidence of recurrent MI by 1 year. Furthermore, we could not demonstrate a benefit of an early invasive strategy compared with a selective invasive strategy in patients with an elevated NT-proBNP level. We confirmed that NT-proBNP is a strong independent predictor of mortality by 1 year but not of recurrent MI in patients who have nSTE-ACS with an elevated cTnT. We could not demonstrate a benefit of an early invasive strategy compared with a selective invasive strategy.

ObjectiveTo perform a patient-pooled analysis of a routine invasive versus a selective invasive strategy in elderly patients with non-ST segment elevation acute coronary syndrome.MethodsA meta-analysis was performed of patient-pooled data from the FRISC II–ICTUS–RITA-3 (FIR) studies. (Un)adjusted HRs were calculated by Cox regression, with adjustments for variables associated with age and outcomes. The main outcome was 5-year cardiovascular death or myocardial infarction (MI) following routine invasive versus selective invasive management.ResultsRegarding the 5-year composite of cardiovascular death or MI, the routine invasive strategy was associated with a lower hazard in patients aged 65–74 years (HR 0.72, 95% CI 0.58 to 0.90) and those aged ≥75 years (HR 0.71, 95% CI 0.55 to 0.91), but not in those aged <65 years (HR 1.11, 95% CI 0.90 to 1.38), p=0.001 for interaction between treatment strategy and age. The interaction was driven by an excess of early MIs in patients <65 years of age; there was no heterogeneity between age groups concerning cardiovascular death. The benefits were smaller for women than for men (p=0.009 for interaction). After adjustment for other clinical risk factors the HRs remained similar.ConclusionThe current analysis of the FIR dataset shows that the long-term benefit of the routine invasive strategy over the selective invasive strategy is attenuated in younger patients aged <65 years and in women by the increased risk of early events which seem to have no consequences for long-term cardiovascular mortality. No other clinical risk factors were able to identify patients with differential responses to a routine invasive strategy.Trial registrationhttp://www.controlled-trials.com/ISRCTN82153174 (ICTUS), http://www.controlled-trials.com/ISRCTN07752711 (RITA-3).

In acute coronary syndromes without ST-segment elevation, an early invasive strategy (early angiography followed by revascularization if appropriate) is recommended over a conservative strategy (angiography only if medical therapy fails) for high-risk patients. In this trial, such patients did not benefit from early invasive treatment. In this trial, high-risk patients did not benefit from early invasive treatment. Patients with acute coronary syndromes without ST-segment elevation are at risk for adverse cardiac events. 1 Optimal treatment consists of intensive medical therapy followed by diagnostic coronary angiography and revascularization in some patients. In five large, randomized trials (Veterans Affairs Non–Q-Wave Infarction Strategies in Hospital [VANQWISH], Fragmin and Fast Revascularization during Instability in Coronary Artery Disease [FRISC] II, Treat Angina with Aggrastat and Determine Cost of Therapy with an Invasive or Conservative Strategy–Thrombolysis in Myocardial Infarction 18 [TACTICS–TIMI 18], TIMI IIIB, and the Third Randomized Intervention Treatment of Angina [RITA-3]), a routine, early invasive strategy (early angiography followed by revascularization, depending . . .

We assessed the prognostic significance of the presence of cumulative ( ∑) ST-segment deviation on the admission electrocardiogram (ECG) in patients with non–ST-elevation acute coronary syndrome and an elevated troponin T randomized to a selective invasive (SI) or an early invasive treatment strategy. A 12-lead ECG obtained at admission was available for analysis from 1163 patients. The presence and magnitude of ST-segment deviation was measured in each lead, and absolute ST-segment deviation was summed. The effect of treatment strategy was assessed for patients with or without ∑ ST-segment deviation of at least 1 mm. The incidence of death or myocardial infarction (MI) by 1 year in patients with ∑ ST-segment deviation of at least 1 mm was 18.0% compared with 11.1% in patients with ∑ ST-segment deviation of less than 1 mm ( P = .001). Among patients with ∑ ST-segment deviation of at least 1 mm, the incidence of death or MI was 21.9% in the early invasive group compared with 14.2% in SI group ( P < .01). However, we observed a significantly higher rate of MI after hospital discharge among patients with ∑ ST-segment deviation of at least 1 mm randomized to SI who did not undergo angiography compared with patients who underwent angiography before discharge (10.9% vs 2.4%, P = .003). In a forward logistic regression analysis, the presence of ST-segment deviation was an independent predictor for failure of medical therapy (coronary angiography within 30 days after randomization in the SI group) (odds ratio, 1.56; 95% confidence interval, 1.12-2.18; P = .009). Patients with non–ST-elevation acute coronary syndrome and an elevated troponin T and ∑ ST-segment deviation of at least 1 mm are at increased risk of death or MI, more often fail on medical therapy, and more often experience a spontaneous MI after discharge when angiography was not performed during initial hospitalization.

Background: We assessed the value of cystatin C for improvement of risk stratification in patients with non–ST elevation acute coronary syndrome (nSTE-ACS) and increased cardiac troponin T (cTnT), and we compared the long-term effects of an early invasive treatment strategy (EIS) with a selective invasive treatment strategy (SIS) with regard to renal function. Methods: Patients (n = 1128) randomized to an EIS or an SIS in the ICTUS trial were stratified according to the tertiles of the cystatin C concentration at baseline. The end points were death within 4 years and spontaneous myocardial infarction (MI) within 3 years. Results: Mortality was 3.4%, 6.2%, and 13.5% in the first, second, and third tertiles, respectively, of cystatin C concentration (log-rank P < 0.001), and the respective rates of spontaneous MI were 5.5%, 7.5%, and 9.8% (log-rank P = 0.03). In a multivariate Cox regression analysis, the cystatin C concentration in the third quartile remained independently predictive of mortality [hazard ratio (HR), 2.04; 95% CI, 1.02–4.10; P = 0.04] and spontaneous MI (HR, 1.95; 95% CI, 1.05–3.63; P = 0.04). The mortality rate in the second tertile was lower with the EIS than with the SIS (3.8% vs 8.7%). In the third tertile, the mortality rates with the EIS and the SIS were, respectively, 15.0% and 12.2% (P for interaction = 0.04). Rates of spontaneous MI were similar for the EIS and the SIS within cystatin C tertiles (P for interaction = 0.22). Conclusions: In patients with nSTE-ACS and an increased cTnT concentration, mild to moderate renal dysfunction is associated with a higher risk of death and spontaneous MI. Use of cystatin C as a serum marker of renal function may improve risk stratification.

We assessed the prognostic significance of the presence of cumulative (Sigma) ST-segment deviation on the admission electrocardiogram (ECG) in patients with non-ST-elevation acute coronary syndrome and an elevated troponin T randomized to a selective invasive (SI) or an early invasive treatment strategy. A 12-lead ECG obtained at admission was available for analysis from 1163 patients. The presence and magnitude of ST-segment deviation was measured in each lead, and absolute ST-segment deviation was summed. The effect of treatment strategy was assessed for patients with or without SigmaST-segment deviation of at least 1 mm. The incidence of death or myocardial infarction (MI) by 1 year in patients with SigmaST-segment deviation of at least 1 mm was 18.0% compared with 11.1% in patients with SigmaST-segment deviation of less than 1 mm (P = .001). Among patients with SigmaST-segment deviation of at least 1 mm, the incidence of death or MI was 21.9% in the early invasive group compared with 14.2% in SI group (P < .01). However, we observed a significantly higher rate of MI after hospital discharge among patients with SigmaST-segment deviation of at least 1 mm randomized to SI who did not undergo angiography compared with patients who underwent angiography before discharge (10.9% vs 2.4%, P = .003). In a forward logistic regression analysis, the presence of ST-segment deviation was an independent predictor for failure of medical therapy (coronary angiography within 30 days after randomization in the SI group) (odds ratio, 1.56; 95% confidence interval, 1.12-2.18; P = .009). Patients with non-ST-elevation acute coronary syndrome and an elevated troponin T and SigmaST-segment deviation of at least 1 mm are at increased risk of death or MI, more often fail on medical therapy, and more often experience a spontaneous MI after discharge when angiography was not performed during initial hospitalization.

To the Editor: The Invasive versus Conservative Treatment in Unstable Coronary Syndromes (ICTUS) trial reported by de Winter et al. (Sept. 15 issue) 1 shows that an early invasive strategy was not superior to a conservative strategy in patients who had acute coronary syndromes without ST-segment elevation and with an elevated cardiac troponin T level. However, we disagree with the authors' statement that they “studied a high-risk population,” because such a conclusion is not supported by the data that they present (i.e., <50 percent of the patients were older than 65 years of age, <15 percent had diabetes, and <50 percent . . .