Timing of Intervention in Patients With Acute Coronary Syndromes - TIMACS

Description:

Although patients with non–ST-elevation acute coronary syndromes (NSTE-ACS) have been shown to benefit with an early invasive therapy as compared with medical management, especially in high-risk patients, the optimal timing of an invasive strategy is still unknown. The TIMACS trial sought to study the efficacy of an early invasive strategy (within 24 hours of presentation) compared with a delayed invasive strategy (any time >36 hours following presentation).

Hypothesis:

An early invasive strategy would be associated with an improvement in cardiovascular outcomes in patients presenting with NSTE-ACS.

Study Design

Patients Enrolled: 3,031
Mean Follow Up: 6 months
Mean Patient Age: 65.4 years
Female: 35

Patient Populations:

  • Unstable angina or NSTEMI with two of the following three criteria: age >60 years, ischemic ECG changes, increased biomarkers
  • Anatomy suitable for revascularization

Exclusions:

  • Age <21 years
  • Life expectancy <6 months
  • Contraindication for low molecular weight heparin
  • High risk for bleeding
  • Not a suitable candidate for revascularization

The initial 1,633 patients were subject to the following additional exclusion criteria:
  • Contraindication to LMWH
  • Creatinine >3 mg/dl
  • Hemorrhagic stroke within the past 12 months
  • Anticoagulation for reasons other than ACS

Primary Endpoints:

  • Composite of death, new MI, or stroke at 6 months

Secondary Endpoints:

  • First occurrence of death, new MI, or refractory ischemia
  • Composite of death, new MI, stroke, refractory ischemia, or repeat revascularization at 6 months
  • Stroke

Drug/Procedures Used:

Patients were randomized in a 1:1, 1:2, or 2:1 fashion to either an early invasive strategy (coronary angiography as soon as possible, followed by percutaneous coronary intervention [PCI] or coronary artery bypass grafting [CABG] within 24 hours) or a delayed strategy (coronary angiography any time >36 hours followed by PCI or CABG).

Concomitant Medications:

Aspirin (98%), thienopyridine (87%), glycoprotein IIb/IIIa inhibitor (23%), fondaparinux (41.5%), low molecular weight heparin (64.2%), unfractionated heparin (24.6%), bivalirudin (0.5%), beta-blockers (86.9%), and statins (85%)

Principal Findings:

A total of 3,031 patients were randomized, 1,593 to an early invasive strategy, and 1,438 to a delayed invasive strategy. Baseline characteristics were fairly similar between the two groups. About 27% of the patients had diabetes, and 20% had a history of prior myocardial infarction (MI). Ischemic ECG changes were noted in about 80% of the patients, and about 77% of the patients had elevated biomarkers (NSTEMI).

Crossover from early to delayed invasive strategy occurred in 9.9% of the patients, and in the opposite direction in 20.5% of the patients (secondary to refractory ischemia, new MI, or hemodynamic instability). The median times to coronary angiography in the early and delayed arms were 14 and 50 hours, respectively. PCI was conducted more often in the early invasive group (59.6% vs. 55.2%).

There was no difference in the incidence of the primary outcome of death, MI, and stroke between the early invasive and delayed invasive arms at 6 months (9.6% vs. 11.3%, hazard ratio [HR] 0.85, 95% confidence interval [CI] 0.68-1.06, p = 0.15). However, the secondary endpoint of death, MI, or refractory ischemia at 6 months was significantly lower in the early invasive arm (9.5% vs. 12.9%, HR 0.72, 95% CI 0.58-0.89, p = 0.003), mainly due to a significant reduction in refractory ischemia (1.0% vs. 3.3%, p < 0.001).

Other outcomes at 6 months such as death (4.8% vs. 5.9%, p = 0.19), MI (4.8% vs. 5.7%, p = 0.25), stroke (1.3% vs. 1.4%, p = 0.74), and repeat revascularization (8.7% vs. 8.5%, p = 0.73) were similar between the two arms, respectively. When patients at high risk for adverse events, as determined by a GRACE score of >140, were separately evaluated, there was a significant reduction in the incidence of the primary endpoint in the early invasive arm compared with the delayed invasive arm (13.9% vs. 21.0%, HR 0.65, 95% CI 0.48-0.89, p = 0.006).

Major bleeding during hospitalization was similar between the two arms (3.1% vs. 3.5%, p = 0.55), including retroperitoneal (0.1% vs. 0.2%) and ≥3 g/dl drop in hemoglobin (2.3% vs. 2.6%).

Interpretation:

The results of the TIMACS trial indicate that an early invasive strategy is not superior to a delayed invasive strategy in patients presenting with NSTE-ACS in reducing the composite endpoint of death, MI, or stroke, except in high-risk patients with a GRACE score of >140. However, there was a significant reduction in the incidence of refractory ischemia, without any difference in the incidence of bleeding.

This is a very interesting trial, and is the largest trial on this topic. It refutes the “cooling off” strategy that had been suggested by earlier trials, similar to ISAR-COOL.

Although the primary endpoint was not significant, there was definitely no harm with an early invasive strategy, and it was beneficial in reducing refractory ischemia, as well as in high-risk patients. Low- and moderate-risk patients could thus be managed equally well with either strategy, although cost-effectiveness analyses are as yet unavailable. There was a high drop-in rate into the early invasive arm (20.5%), which may have diluted the investigators’ ability to identify a difference in an intention-to-treat analysis.

References:

Mehta SR, Granger CB, Boden WE, et al. Early versus delayed invasive intervention in acute coronary syndromes. N Engl J Med 2009;360:2165-75.

Presented by Dr. Shamir Mehta at the American Heart Association Annual Scientific Sessions, New Orleans, November 2008.

Clinical Topics: Acute Coronary Syndromes, Cardiac Surgery, Invasive Cardiovascular Angiography and Intervention, Noninvasive Imaging, ACS and Cardiac Biomarkers, Aortic Surgery, Interventions and ACS, Interventions and Imaging, Angiography, Nuclear Imaging

Keywords: Stroke, Acute Coronary Syndrome, Myocardial Infarction, Electrocardiography, Hemodynamics, Percutaneous Coronary Intervention, Hemoglobins, Coronary Angiography, Biological Markers, Confidence Intervals, Coronary Artery Bypass, Diabetes Mellitus


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