Review of the ICTUS trial

Early Invasive versus Selectively Invasive Management for Acute Coronary Syndromes

N Engl J Med 2005;353:1095-1104

Background: Prior trials on revascularization in patients with acute coronary syndromes without ST-segment elevation have yielded mixed results. While FRISC II and TACTICS-TIMI 18 demonstrated a significant reduction in myocardial infarction, this benefit was not observed in RITA 3. None of these trials showed a significant reduction in mortality. Further research is needed to guide treatment strategies in this population, particularly after the introduction of early use of clopidogrel and intensive lipid-lowering therapy.

The Invasive versus Conservative Treatment in Unstable Coronary Syndromes (ICTUS) trial sough to test the hypothesis that an early invasive strategy is superior to selective invasive strategy for patients with non-ST elevation myocardial infarction (NSTEMI).

Patients: Eligible patients had to have all of the following: Worsening symptoms of ischemia or symptoms at rest with the last episode being 24 hours before randomization, elevated cardiac troponin T level (≥0.03 μg per liter); and either ischemic EKG changes (defined as ST-segment depression or transient ST-segment elevation exceeding 0.05 mV, or T-wave inversion of ≥0.2 mV in two contiguous leads) or a documented history of coronary artery disease.

Patients were excluded if they were older than 80 years, had an indication for primary percutaneous coronary intervention or fibrinolytic therapy, hemodynamic instability or overt congestive heart failure, oral anticoagulant drugs use in the past 7 days, fibrinolytic treatment within the past 96 hours, percutaneous coronary intervention within the past 14 days, elevated bleeding risk, plus others.

Baseline characteristics: The trial randomized 1,200 patients from 42 Dutch hospitals – 604 randomized to early invasive strategy and 596 randomized to selective invasive strategy.

The average age of patients was 62 years and 74% were men. Approximately 39% had hypertension, 14% had diabetes, 35% had hyperlipidemia, 23% had prior myocardial infarction and 41% were current smokers.

Approximately 48% of the patients had ST deviation equal to or greater than 0.1 mV.

Procedures: Patients were randomly assigned in a 1:1 ratio to undergo early invasive vs selective invasive strategy.

Patients received 300 mg of aspirin at the time of randomization, followed by at least 75 mg daily indefinitely, and enoxaparin (1 mg/kg for a maximum of 80 mg) subcutaneously twice daily for at least 48 hours. The early use of clopidogrel (300 mg immediately, followed by 75 mg daily) in addition to aspirin was recommended to the investigators after the drug was approved for acute coronary syndrome in 2002. Intensive lipid-lowering therapy, preferably atorvastatin 80 mg daily or the equivalent was recommended as soon as possible after randomization. All interventional procedures during the index admission were performed with the use of abciximab.

Patients assigned to the early invasive strategy were scheduled to undergo angiography within 24 - 48 hours after randomization. Patients assigned to the selective invasive strategy underwent coronary angiography if they had refractory angina despite optimal medical therapy, hemodynamic or rhythm instability, or significant ischemia on pre-discharge exercise test.

In both groups, percutaneous coronary intervention (PCI) was performed when appropriate, without providing more details in the manuscript.

The level of creatine kinase MB was measured at 6-hour intervals during the first day, after each new clinical episode of ischemia, and after each percutaneous revascularization procedure.

Endpoints: The primary endpoint was a composite of all-cause death, myocardial infarction, or rehospitalization for angina at 1-year.

The estimated sample size to provide 80% power to detect 25% relative risk difference between the two treatment groups at 5% alpha was 1,200 patients. This assumed that 21% of the patients in the early invasive arm would experience the primary outcome.

Results: During the index admission, 98% of the patients in the early invasive strategy arm underwent coronary angiogram compared to 53% in the selective invasive arm. At 1-year, 79% of the patients in the early invasive strategy arm underwent revascularization compared to 54% in the selective invasive arm.

The primary outcome was not significantly different between both treatment groups (22.7% with early invasive vs 21.2% with selective invasive, RR: 1.07; 95% CI: 0.87 - 1.33; p= 0.33). All-cause death was the same in both groups (2.5%). Myocardial infarction was significantly higher with the early invasive strategy (15.0% vs. 10.0%, RR: 1.50, 95% CI: 1.10 – 2.04; p= 0.005), while rehospitalization for angina was lower with early invasive (7.4% vs. 10.9%, RR: 0.68, 95% CI: 0.47 – 0.98; p= 0.04). Most myocardial infarctions were revascularization related and these were significantly more frequent with early invasive (11.3% vs 5.4%). Spontaneous myocardial infarctions were 3.7% with early invasive and 4.6% with selective invasive and this was not statistically significant.

Major bleeding, not related CABG, during the index admission was more frequent with the early invasive strategy (3.1% vs 1.7%).

There were no significant subgroup interactions for the primary outcome, including based on ST deviation and troponin levels.

Conclusion: In patients with NSTEMI, an early invasive strategy was not superior to selective invasive strategy in reducing the composite endpoint of all-cause death, myocardial infarction, or rehospitalization for angina at 1-year. An early invasive strategy was associated with more myocardial infarctions with a number needed to harm of 20 patients, which was secondary to revascularization related myocardial infarction. An early invasive strategy reduced rehospitalization for angina with a number needed to treat of approximately 29 patients.

The ICTUS trial showed that revascularization can cause harm and highlighted how counting procedural myocardial infarctions can influence outcome estimates. While there is ongoing debate about the significance of periprocedural myocardial infarctions, evidence indicates an association with increased mortality. Whether periprocedural myocardial infarctions are 'less severe' than spontaneous myocardial infarctions remains controversial, as their impact varies based on infarct size and patient characteristics. This underscores the importance of including all-cause mortality or advanced systolic heart failure as endpoints in trials of revascularization.

Patients in ICTUS received better background medical therapy compared to prior trials in this area. While this could be responsible for the divergent results compared to other prior trials. It also highlights the heterogeneity of NSTEMI patients and that an invasive strategy is not appropriate for all.