TIMACS

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Mehta SR, et al. "Early versus Delayed Invasive Intervention in Acute Coronary Syndromes". The New England Journal of Medicine. 2009. 360:2165-2175.
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Clinical Question

Among patients presenting with unstable angina or NSTEMI, does early intervention with coronary angiography (≤24 h after randomization) improve outcomes compared to delayed intervention (≥36 h)?

Bottom Line

Among patients with unstable angina or NSTEMI, early intervention (≤24 h) does not result in a decrease in the composite of death, MI, or stroke at 6 months compared to delayed intervention (≥36 h) except in patients at high-risk (GRACE score >140).

Major Points

Numerous randomized controlled trials including FRISC-II, RITA-3, and TACTICS-TIMI 18 have demonstrated the benefit of early invasive intervention with angiography in high-risk patients with unstable angina (UA) and NSTEMI. While these trials have shown the life-saving benefit of early intervention in UA and NSTEMI, the exact timing of intervention had not been clearly established — what constitutes "early"? Prior to this trial, observational studies had suggested lower rates of complications in patients undergoing PCI ≥48 h of medical therapy with the hypothesis that this "cooling-off" strategy allows for plaque stabilization and better interventional outcomes.

Published in 2009, the The Timing of Intervention in Acute Coronary Syndromes (TIMACS) trial randomized 3,031 patients with unstable angina or NSTEMI to either early-intervention (as early as possible and within 24 hours) or delayed-intervention (minimum delay of 36 hours after randomization). At 6 months, the primary outcome (composite of death, new MI, or stroke) occurred in 9.6% of patients in the early-intervention group compared to 11.3% in the delayed-intervention group (HR 0.95; 95% CI 0.68 to 1.06; P=0.15). There was a significant difference in the secondary outcome of death, MI, or refractory ischemia at 6 months in the early-intervention group (9.5%) versus delayed-intervention patients (12.9%) which was largely driven by a reduction in refractory ischemia (HR 0.72, CI 0.58 to 0.89, p=0.003). Interestingly, a prespecified subgroup analysis showed the highest risk patients (classified as having a GRACE risk score >140) undergoing early intervention had a significantly lower rate of the primary outcome compared to those in the delayed intervention arm (13.9% vs. 21.0% HR 0.65, CI 0.48 to 0.89, p=0.006). When this same subgroup analysis was applied to low- to moderate-risk patients, there was no significant difference in the primary outcome between early or delayed intervention.

The overall findings from this trial suggest that in patients with UA/NSTEMI, an early intervention strategy is not superior to delayed intervention except in those patients at highest risk determined by the GRACE risk score tool. Early intervention was associated with a significant decrease in refractory ischemia suggesting that in patient’s presenting to a PCI-capable institution, early intervention may be more favorable but not critical. A 2013 meta-analysis evaluating 7 RCTs and 4 observational studies of early vs delayed intervention treatment in UA/NSTEMI found no survival benefit with early intervention.[1] Based on the results of this trial 2014 AHA/ACC guidelines on NSTEMI suggest that it may be reasonable to choose an early invasive strategy over a delayed one in patients with high-risk UA/NSTEMI.

Guidelines

ACC/AHA NSTE-ACS (2014, adapted)[2]

  • An urgent/immediate invasive strategy is indicated in patients with NSTE-ACS who have refractory angina or hemodynamic or electrical instability (without serious comorbidities or contraindications to such procedures) (class I, Level of Evidence: A)
  • An early invasive strategy is indicated in initially stabilized patients with NSTE-ACS (without serious comorbidities or contraindications to such procedures) who have an elevated risk for clinical events (class I, Level of Evidence: B)
  • It is reasonable to choose an early invasive strategy (within 24 hours of admission) over a delayed invasive strategy (within 25 to 72 hours) for initially stabilized high-risk patients with NSTE-ACS. For those not at high/intermediate risk, a delayed invasive approach is reasonable (class IIa, Level of Evidence: B)
  • An early invasive strategy (i.e., diagnostic angiography with intent to perform revascularization) is not recommended in patients with:
    • Extensive comorbidities in whom the risks of revascularization and comorbid conditions are likely to outweigh the benefits (Class III, Level of Evidence: C)
    • Acute chest pain and a low likelihood of ACS who are troponin-negative (Class III, Level of Evidence: C), especially women (Class III, Level of Evidence: B)

Design

  • Multicenter, blinded, parallel-group, randomized, controlled trial
  • N=3,031 patients with UA/NSTEMI
    • Early intervention (n=1,593)
    • Delated intervention (n=1,438)
  • Setting: 152 sites in 19 countries
  • Enrollment: 2003-2008
  • Mean follow-up: 6 months
  • Analysis: Modified Intention-to-treat
  • Primary outcome: Composite of death, myocardial infarction, or stroke

Population

Inclusion Criteria

  • Admission to the hospital with NSTE-ACS (unstable angina or NSTEMI)
  • Able to be randomized within 24 hours of onset of symptoms
  • Two out of the three following criteria:
    • Age >60 years
    • Troponin T or I or CK-MB above the upper limit of normal for the local institution
    • ECG changes compatible with ischemia (ST depression at least 1mm in 2 contiguous leads or T wave inversion > 3mm or any dynamic ST changes)

Exclusion Criteria

  • Age <21 years
  • Not a suitable candidate for revascularization
  • Comorbid condition with life expectancy <6 months

Baseline Characteristics

Comparisons are early intervention vs. delayed intervention

  • Age: 65 vs. 66 years
  • Female Sex: 34.8% vs. 34.6%
  • Medical History:
    • Diabetes: 26.5% vs. 27.4%
    • Previous MI: 19.7% vs. 20.9%
    • Previous Stroke: 7.2% vs. 7.5%
    • Ischemic changes on ECG: 80.5% vs. 79.9%
    • Elevated cardiac biomarker: 77.2% vs. 76.9%
  • Previous coronary procedure
    • PCI: 13.9% vs. 14.2%
    • CABG: 7.0% vs. 7.3%
  • In-hospital medication
    • Aspirin: 98% vs. 98.1%
    • Thienopyridine: 87.2% vs. 86.7%
    • Glycoprotein IIb/IIIa inhibitor: 23.2% vs. 22.4%
    • Anticoagulant: 97% vs. 97%
    • Beta-blocker: 86.8% vs. 86.9%
    • Statin: 85.1% vs. 84.3%
    • ACEi: 74.2% vs. 73.6%
  • Extent of coronary disease
    • Left main: 10% vs. 9.5%
    • 1vs: 31.6% vs. 31.1%
    • 2vs: 24.5 vs. 23.4%
    • 3vs: 17.1% vs. 15.8%
  • Interventions after randomization
    • Coronary angiography: 97.6% vs. 95.7%
    • PCI: 59.6% vs. 55.1%
    • CABG: 14.8% vs. 13.6%

Interventions

Patients randomized to:

  • Early intervention: To have coronary angiography within 24 hours of randomization
  • Delayed intervention: To have coronary angiography any time after 36 hours after randomization (including post-discharge from initial hospitalization)

Outcomes

Comparisons are early intervention vs. delayed intervention

Primary Outcomes

Composite of death, myocardial infarction, or stroke
9.6% vs. 11.3% (HR 0.85; 95% CI 0.68-1.06; P=0.15)

Secondary Outcomes

Composite of death, myocardial infarction, stroke, or refractory ischemia
9.5% vs. 12.9% (HR 0.72; 95% CI 0.58-0.89; P=0.003)

Adverse Events

In-hospital major bleeding
3.1% vs. 3.5% (HR 0.89; 95% CI 0.60-1.31; P=0.55)
Primary safety outcome.

Subgroup Analysis

Primary outcome in patients with GRACE score >140
13.9% vs. 21.0% (HR 0.65; 95% CI 0.48-0.89; P=0.006)
Primary outcome in patients with GRACE score <140
7.6% vs. 6.7% (HR 1.12; 95% CI 0.81-1.56; P=0.48; P=0.01 for heterogeneity)

Criticisms

  • Finding of benefit with early intervention in high-risk patients came out of subgroup analysis.
  • Trial was relatively underpowered to detect differences in the primary end point
  • High crossover rate into the early intervention arm
  • Anticoagulant used was heparin rather than low-molecular weight heparin, the latter associated with improvements in outcomes among patients with ACS[3]

Funding

This study was funded by the Population Health Research Institute.

Further Reading

  1. Navarese EP et al. Optimal timing of coronary invasive strategy in non-ST-segment elevation acute coronary syndromes: a systematic review and meta-analysis. Ann. Intern. Med. 2013. 158:261-70.
  2. Amsterdam EA, et al. "2014 AHA/ACC guideline for the management of patients with non-ST-elevation acute coronary syndromes: Executive summary." JACC. 64(24):2645-87.
  3. Damman P et al. Acute coronary syndromes. N. Engl. J. Med. 2009. 361:925; author reply 926-7.