TACTICS-TIMI 18

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Cannon CP, et al. "Comparison of early invasive and conservative strategies in patients with unstable coronary syndromes treated with the glycoprotein IIb/IIIa inhibitor tirofiban". New England Journal of Medicine. 2001. 344(25):1879-1887.
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Clinical Question

In patients with unstable angina or non-ST segment elevation MI, does an early invasive PCI strategy reduce major cardiovascular events versus a more conservative, selectively invasive PCI strategy?

Bottom Line

In patients with unstable angina or non-ST segment elevation MI, an early invasive strategy (in combination with glycoprotein IIb/IIIa inhibition with tirofiban) significantly reduced major cardiovascular events versus a selectively invasive strategy. This benefit was largely limited to higher risk patients with TIMI score > 2.

Major Points

Unlike patients presenting with STEMI in which there is a clear mortality benefit to emergent coronary angiography and PCI, it is less clear whether patients with non-STEMI ACS (unstable angina or non-ST segment elevation MI) also benefit from routine early angiography and intervention.

The 2001 Treat Angina with Aggrastat and Determine Cost of Therapy with an Invasive or Conservative Strategy - Thrombolysis in Myocardial Infarction 18 (TACTICS-TIMI 18) trial randomized 2220 patients to either a protocolized early invasive strategy versus a delayed selectively invasive strategy with each arm receiving the IIb/IIIa inhibitor tirofiban. In the early invasive strategy arm, 97% of patients underwent coronary angiography a median of 22 hours (all within 48 hours) after presentation with PCI or CABG to culprit lesions. In the conservative strategy, patients underwent coronary angiography only if noninvasive stress testing was positive or there was failure of medical therapy (prolonged angina at rest, hemodynamic instability, recurrent angina or MI). Overall, 60% of patients in the early invasive arm underwent revascularization versus 36% in the conservative arm. TACTICS-TIMI 18 demonstrated a clear reduction in major adverse cardiovascular events with an early invasive approach, driven primarily by a reduction in nonfatal MI and recurrent ischemia. This benefit was most apparent in patients presenting with ST segment changes, troponin elevation at presentation, and patients with intermediate or high TIMI risk scores (3 or greater). Notably there was no mortality benefit with an early invasive approach, and this strategy was associated with a 2% absolute increase in protocol-defined bleeding. Importantly, patients with TIMI score 0-2 and patients with undetectable troponins (25% of the study population) did not appear to benefit from routine angiography and PCI, suggesting that it is reasonable to pursue stress testing in these low-risk patients with intervention reserved for patients with significant ischemia on functional testing.

Overall the results of TACTICS-TIMI 18 provide practical guidance for the selection of patients who are most likely to benefit from early coronary angiography and intervention in non-STEMI ACS. It is important to note that although both the biomarker and TIMI risk stratification findings (i.e., patients with negative troponins or patients with TIMI risk score 0-2 do not benefit from an early invasive strategy) are often incorporated into routine clinical practice, the interaction between the primary outcome and these individual subgroups did not reach statistical significance; however, given stark numerical differences and apparent risk-response pattern within the TIMI score group (i.e., as TIMI risk increased, benefit with early angiography increased), lack of statistical interaction likely reflects underpowered subgroups in this case rather than a spurious finding. In addition, TACTICS-TIMI 18 was also a trial of the IIb/IIIa inhibitor tirofiban, which continues to have a limited role in NSTE-ACS, primarily as bailout therapy in patients undergoing PCI of high-risk lesions.

Guidelines

Adapted from 2014 ACCF/AHA Guideline for the Management of Patients with Non-ST-Elevation Acute Coronary Syndromes[1]

  • An urgent/immediate invasive strategy (diagnostic angiography with intent to perform revascularization if appropriate based on coronary anatomy) 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 (diagnostic angiography with intent to perform revascularization if appropriate based on coronary anatomy) 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 24 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)
  • In initially stabilized patients, an ischemia-guided strategy may be considered for patients with NSTE-ACS (without serious comorbidities or contraindications to this approach) who have an elevated risk for clinical events (Class IIb, Level of Evidence B)
  • The decision to implement an ischemia-guided strategy in initially stabilized patients (without serious comorbidities or contraindications to this approach) may be reasonable after considering clinician and patient preference (Class IIb, Level of Evidence C)

Design

  • Multicenter, open-label, nested randomized, controlled trial
  • N=2220
    • Invasive Strategy (n=1114)
    • Conservative Strategy (n=1106)
  • Setting: Multicenter international
  • Period: 12/18/1997 - 12/22/1999
  • Mean follow-up:
  • Analysis: Intention-to-treat
  • Primary Outcome: Combined incidence of death, nonfatal MI, and rehospitalization for ACS at 6 months

Population

Inclusion Criteria

  • Angina within past 24 hours
    • Accelerating pattern or prolonged (> 20 minutes)
  • ST segment change
    • ST segment depression of at least 0.05mV
    • Transient ST segment elevation of at least 0.1mV
    • T-wave inversion of at least 0.3mV in at least two leads
  • Elevated levels of cardiac markers
  • Coronary disease
    • History of catheterization, revascularization, or myocardial infarction

Exclusion Criteria

  • Contraindication to coronary angiography
  • Persistent ST segment elevation
  • Secondary angina
  • History of PCI or CABG in preceding 6 months
  • Factors associated with increased risk of bleeding
  • LBBB or paced rhythm
  • Severe CHF or cardiogenic shock
  • Serious systemic disease
  • Creatinine > 2.5mg/dL
  • Current participation in another study of an investigational drug or device
  • On warfarin or received ticlopidine or clopidogrel for more than 3 days before enrollment

Baseline Characteristics

From the invasive strategy group.

  • Demographics: Age 62 years, female 35%, white 77%
  • Comorbidities: Prior MI 39%, diabetes 28%
  • Medications: Prior aspirin use 68%
  • ACS features at presentation: ST segment changes 39%, ST segment or T wave changes 48%, MI without ST segment elevation 37%, TnT > 0.01 ng/mL 56%, mean TnT 0.38 ng/mL

Interventions

  • All patients received medical therapy with 325MG aspirin, IV UFH for 48 hours, and tirofiban for 48 hours or until revascularization
  • Recommended medical therapy with beta blockers, nitrates, and lipid-lowering agents
  • Patients randomized to an early invasive strategy or a conservative strategy
    • Patients assigned to an early invasive strategy underwent coronary angiography between 4 and 48 hours after randomization and revascularization when appropriate on the basis of coronary anatomical findings
    • Patients assigned to an early conservative strategy were treated medically and, if their condition was stable, underwent an exercise-tolerance test before being discharged
      • These patients received coronary angiography and revascularization as appropriate only if they had one of the following
        • Prolonged or recurrent angina at rest with ECG changes consistent with ischemia or changes in cardiac enzyme levels
        • Hemodynamic instability
        • Documented ischemia before the end of Bruce stage 2 or any time during pharmacological stress test
        • Unstable angina requiring rehospitalization
        • CCS III or IV angina with an abnormal exercise-tolerance test
        • New MI
  • Follow up was conducted by telephone at 30 days and 6 months
  • Medical records were examined to verify all end points

Outcomes

Comparisons are invasive vs. conservative strategy

Primary Outcomes

Death, nonfatal MI, or rehospitalization for ACS (30 days)
7.4% vs. 10.5%; RR 0.67 95% CI [0.50-0.91]; p=0.009
Death, nonfatal MI, or rehospitalization for ACS (6 months)
15.9% vs. 19.4%; RR 0.78 95% CI [0.62-0.97]; p=0.025

Secondary Outcomes

Death or nonfatal MI (30 days)
4.7% vs. 7.0%; RR 0.65 95% CI [0.45-0.93]; p=0.02
Death or nonfatal MI (6 months)
7.3% vs. 9.5%; RR 0.74 95% CI [0.54-1.00]; p<0.05
Death (30 days)
2.2% vs. 1.6%; RR 1.40 95% CI [0.76-2.59]; p=0.29
Death (6 months)
3.3% vs. 3.5%; RR 0.93 95% CI [0.58-1.47]; p=0.74
Fatal or nonfatal MI (30 days)
3.1% vs. 5.8%; RR 0.51 95% CI [0.33-0.77]; p=0.002
Fatal or nonfatal MI (6 months)
4.8% vs. 6.9%; RR 0.67 95% CI [0.46-0.96]; p=0.029
Rehospitalization for ACS (30 days)
3.4% vs. 5.5%; RR 0.61 95% CI [0.40-0.92]; p=0.018
Rehospitalization for ACS (6 months)
11.0% vs. 13.7%; RR 0.78 95% CI [0.60-1.00]; p=0.054

Subgroup Analyses

Endpoint for all subgroup analyses is primary outcome

Prior ASA use (interaction p=0.02)
12.2% vs. 21.0% (ASA)
17.7% vs. 18.6% (no ASA)
ST segment change (interaction p=0.006)
16.4% vs. 26.3% (ST segment change present)
12.2% vs. 21.0% (ST segment change absent)
TIMI Risk Score (interaction p=0.15)
12.8% vs. 11.8% (Low [0-2])
16.1% vs. 20.3% (Intermediate [3-4])
19.5% vs. 30.6% (High [5-7])

Adverse Events

Protocol-defined bleeding
5.5% vs. 3.3% (p < 0.01)
TIMI major bleeding
1.9% vs. 1.3% (p=0.24)

Criticisms

  • Nearly all patients received upstream tirofiban, which is now utilized primarily as bailout therapy in patients with NSTE-ACS, bringing into question generalizability of these findings to the current era of widespread upstream P2Y12 inhibitor use.
  • Sizable proportion (25%) of patients in the study were in the low-risk TIMI score group and about half of the study population had no ECG changes or troponin elevation. This, along with an overall low rate of death or MI (5%), may have limited the ability to detect a mortality benefit with an early invasive strategy.
  • Although both the biomarker and TIMI risk stratification findings (i.e., patients with negative troponins or patients with TIMI risk score 0-2 do not benefit from an early invasive strategy) are often incorporated into routine clinical practice, the interaction between the primary outcome and these individual subgroups did not reach statistical significance. However, given stark numerical differences and apparent risk-response pattern within the TIMI score group (i.e., as TIMI risk increased, benefit with early angiography increased), lack of statistical interaction likely reflects underpowered subgroups in this case rather than a spurious finding.

Funding

  • Study supported by Merck (several authors employed by Merck)

Further Reading

  1. 2014 ACCF/AHA Guideline for the Management of Patients with Non-ST-Elevation Acute Coronary Syndromes. J Am Coll Cardiol 2014; 64(24): 2647-87