Implications of Upstream Glycoprotein IIb/IIIa Inhibition and Coronary Artery Stenting in the Invasive Management of Unstable Angina/Non–ST-Elevation Myocardial Infarction
A Comparison of the Thrombolysis In Myocardial Infarction (TIMI) IIIB Trial and the Treat angina with Aggrastat and determine Cost of Therapy with Invasive or Conservative Strategy (TACTICS)-TIMI 18 Trial
Background— TIMI IIIB and TACTICS-TIMI 18 were 2 trials of an early invasive strategy in unstable angina (UA)/non–ST-elevation myocardial infarction (NSTEMI) that were conducted nearly a decade apart but with virtually identical enrollment criteria and designs, except that upstream glycoprotein IIb/IIIa inhibition was mandated and coronary artery stenting was routinely used in TACTICS-TIMI 18. We sought to examine the effect of these advances on clinical outcomes and the benefits of an early invasive strategy in UA/NSTEMI.
Methods and Results— Patients were stratified on the basis of their TIMI risk score into low-, intermediate-, and high-risk categories. Within each risk category, the rates of clinical outcomes and the benefit of an early invasive strategy were compared. Compared with patients in TIMI IIIB and adjusting for baseline risk, patients in TACTICS-TIMI 18 had lower rates of death, MI, or rehospitalization for acute coronary syndromes (OR, 0.62; P<0.0001). Across both trials, the benefit of an early invasive strategy was significantly greater with increasing baseline risk: OR, 1.39 in low-risk, 0.80 in intermediate-risk, and 0.57 in high-risk patients (P≤0.004 for interactions). After adjustment for baseline risk, an early invasive strategy tended toward a more favorable result in TACTICS-TIMI 18 than in TIMI IIIB (OR, 0.79; 95% CI, 0.56 to 1.11).
Conclusions— Advances in the care of patients with UA/NSTEMI, including glycoprotein IIb/IIIa inhibition and stenting, were associated with lower rates of death, MI, and rehospitalization for acute coronary syndromes and a trend toward a greater benefit of an early invasive strategy.
Received June 17, 2003; de novo received August 28, 2003; revision received November 20, 2003; accepted November 21, 2003.
The TIMI IIIB and TACTICS-TIMI 18 trials were conducted nearly a decade apart but had virtually identical enrollment criteria and designs.1,2 Both trials examined the role of an early invasive strategy in unstable angina/non–ST-elevation myocardial infarction (UA/NSTEMI). The major differences were that in TACTICS-TIMI 18, all patients received upstream glycoprotein (GP) IIb/IIIa inhibition with tirofiban, and most patients who underwent percutaneous coronary revascularization (PCI) received intracoronary stents. The similarity of the 2 trials created the unique opportunity to estimate the impact of the aforementioned differences on overall event rates and the benefits of an early invasive strategy.
Of concern, however, was the need to account for potential differences in baseline risk between the 2 trial populations, despite the nearly identical enrollment criteria. To address this issue, we used the TIMI risk score for UA/NSTEMI to perform analyses stratified by baseline risk. The score is an integrated risk assessment tool that was developed by Antman and colleagues in TIMI 11B3 and has subsequently been validated in multiple clinical trials.2–5 The TIMI risk score has a c statistic of 0.65 and a Hosmer-Lemeshow statistic of 3.56df8 (P=0.89), consistent with moderate discrimination and excellent calibration.
Using the TIMI risk score, we stratified patients into low-, intermediate-, and high-risk categories. Our objective was to use integrated risk stratification in the setting of 2 similar clinical trials to gain insight into the effects of GP IIb/IIIa inhibition and coronary artery stenting on clinical outcomes and the potential benefits of an early invasive strategy in UA/NSTEMI.
The study designs and main results of TIMI IIIB and TACTICS-TIMI 18 have been reported.1,2 In brief, TIMI IIIB enrolled 1473 patients (from 1989 to 1992) and TACTICS-TIMI 18 enrolled 2220 patients (from 1997 to 1999) with UA/NSTEMI. For both trials, patients were required to have ischemic discomfort within the previous 24 hours that was accompanied by objective evidence of ischemic heart disease. The latter consisted of ECG changes, elevated cardiac biomarkers of necrosis, or a documented history of coronary artery disease.
In both trials, patients were randomized to either an early invasive arm (angiography within 48 hours) or a conservative arm (angiography only if the patient experienced spontaneous or significant stress-test–induced ischemia). All patients received aspirin and unfractionated heparin. In TACTICS-TIMI 18 but not in TIMI IIIB, all patients also received upstream GP IIb/IIIa inhibition with tirofiban. For these analyses, the prespecified primary end point for TACTICS-TIMI 18 was used, which was the composite of death, (re)infarction, or rehospitalization for acute coronary syndromes (ACS) through 6 months.
Patients were stratified on the basis of their TIMI risk score for UA/NSTEMI.3 In brief, patients are risk-stratified on the basis of 7 baseline characteristics: age ≥65 years, ≥3 risk factors for coronary artery disease, known coronary artery disease, use of aspirin in the last 7 days, ≥2 episodes of angina in the previous 24 hours, ST deviation ≥0.5 mm, and elevated cardiac biomarkers of necrosis. Patients are assigned 1 point for each risk factor that is present. On the basis of their TIMI risk score, patients were categorized as low risk (0 to 2 points), intermediate risk (3 or 4 points), or high risk (5 to 7 points).
The TIMI risk score distribution in the 2 trials was compared by use of the χ2 test for trend. Within each risk stratification category, the proportions of patients experiencing an end point in TIMI IIIB and TACTICS-TIMI 18 were compared by the χ2 test. Heterogeneity of the effect of trial (TIMI IIIB versus TACTICS-TIMI 18) among different subgroups of patients was assessed by the Breslow-Day test. If there was no significant heterogeneity, a stratified Mantel-Haenszel odds ratio (OR) with 95% confidence intervals (CIs) was computed. A multivariable logistic regression model was constructed to assess the independent effect of trial on the composite end point after adjustment for baseline TIMI risk score, treatment strategy, index hospitalization procedures, and cardiac medication use. Stratified analyses were performed to calculate the ORs and 95% CIs for the effect of an early invasive strategy on the composite end point within each risk category and trial. Interaction terms were introduced into a regression model to estimate the effects of TIMI risk score category and of trial on the efficacy of an early invasive strategy.
Baseline Differences Between TIMI IIIB and TACTICS-TIMI 18
The baseline characteristics of the 2 trial populations are shown in Table 1 and index hospitalization procedures and medications in Table 2. The distributions of risk scores (the risk profile) of the 2 trials are shown in Figure 1. Despite nearly identical eligibility criteria, patients enrolled in TACTICS-TIMI 18 had a markedly higher risk profile than those in TIMI IIIB (P<0.0001 by χ2 for trend).
Differences in Rates of Clinical End Points in TIMI IIIB Versus TACTICS-TIMI 18
The rates of the composite end point in the 2 trials among patients matched for similar degrees of baseline risk are shown in Figure 2. Compared with patients in TIMI IIIB, patients in TACTICS-TIMI 18 had lower rates of death, MI, or rehospitalization for ACS through 6 months in the low (OR, 0.50; P<0.0001), intermediate (OR, 0.72; P=0.005), and high (OR, 0.50; P=0.003) risk groups. There was no evidence for heterogeneity among the 3 different risk groups in terms of the effect of trial on outcome (Breslow-Day test P=0.11), and the Mantel-Haenszel adjusted OR for the risk of the composite end point in TACTICS-TIMI 18 versus TIMI IIIB was 0.62 (95% CI, 0.52 to 0.73; P<0.0001).
Directional consistency was seen with each of the individual components of the composite end point (Figure 3), with the exception of death in the low-risk group, which was an infrequent event and hence associated with wide CIs. For each of the individual components of the composite end point, there was no evidence of heterogeneity among the different risk groups (Breslow-Day tests nonsignificant), and the Mantel-Haenszel adjusted ORs and 95% CIs were as follows: death, 0.87 (0.60 to 1.27); MI, 0.56 (0.43 to 0.74); death/MI, 0.67 (0.53 to 0.85); and rehospitalization for ACS, 0.72 (0.59 to 0.88). Cumulative incidence curves are shown in Figure 4 and suggest that the greatest difference between the 2 trials in the occurrence of the composite end point was in the first 30 days.
Subgroup analyses (Table 3) revealed that the pattern of lower rates of adverse cardiac events seen in TACTICS-TIMI 18 compared with TIMI IIIB in risk-matched patients was observed both in patients randomized to an early invasive strategy and in patients randomized to a conservative strategy. Similar consistency was seen when patients were stratified by actual revascularization status.
Although our analyses were stratified for baseline risk by use of the TIMI risk score, it remained possible that other baseline differences or nonrandomized treatments influenced outcomes. Therefore, we first constructed a multivariable logistic regression model that adjusted for baseline TIMI risk score and treatment strategy. In this model, the OR for the composite end point in patients in TACTICS-TIMI 18 compared with patients in TIMI IIIB was 0.62 (95% CI, 0.52 to 0.73; P<0.0001). We then adjusted for additional factors, including previous PCI and previous CABG; in-hospital revascularization; and use of aspirin, β-blockers, ACE inhibitors, and statins. Patients in TACTICS-TIMI 18 still had lower event rates, with an unchanged OR of 0.62 (95% CI, 0.49 to 0.79; P<0.0001).
Differences in Efficacy of an Early Invasive Strategy
In the overall trial cohorts, the OR for the benefit of an invasive strategy on death, MI, or rehospitalization for ACS was 1.08 (95% CI, 0.85 to 1.38; P=0.53) in TIMI IIIB and 0.78 (95% CI, 0.63 to 0.97; P=0.028) in TACTICS-TIMI 18. In Table 4, the ORs and 95% CI for the association between an invasive strategy and the primary end point are listed for patients grouped by baseline TIMI risk score and stratified by trial. Two important trends are apparent.
First, across both trials combined, the benefit of an early invasive strategy was greater with increasing baseline risk. The OR for the composite end point at 6 months with an early invasive versus a conservative strategy was 1.39 (95% CI, 1.02 to 1.88; P=0.03) in low-risk patients, 0.80 (95% CI, 0.64 to 0.99; P=0.04) in intermediate-risk patients, and 0.57 (95% CI, 0.38 to 0.87; P=0.0083) in high-risk patients. In a multivariable logistic regression model, these differences in the efficacy of an invasive strategy based on risk group were highly statistically significant (low versus intermediate, P=0.004 for interaction; low versus high, P=0.001).
Second, within each risk stratum, an early invasive strategy tended toward a more favorable result in TACTICS-TIMI 18 than in TIMI IIIB. In low-risk patients, the OR for the composite end point at 6 months for patients randomized to an early invasive strategy versus a conservative strategy was 1.55 (95% CI, 1.06 to 2.27) in TIMI IIIB and 1.10 (95% CI, 0.66 to 1.03) in TACTICS-TIMI 18. In intermediate-risk patients, the ORs were 0.87 (95% CI, 0.61 to 1.24) and 0.75 (95% CI, 0.57 to 0.99) in the 2 trials. In high-risk patients, the ORs were 0.71 (95% CI, 0.32 to 1.54) and 0.55 (95% CI, 0.33 to 0.91) in the 2 trials. Overall, by use of a multivariable logistic regression model that included terms for TIMI risk score group, trial, treatment strategy, and their interactions, there was a trend for an early invasive strategy to be more beneficial in TACTICS-TIMI 18 than in TIMI IIIB (OR, 0.79; 95% CI, 0.56 to 1.11). Qualitatively and quantitatively similar results were obtained when the individual components of the composite end point were examined.
The first major, multicenter randomized trial of an early invasive strategy versus a conservative strategy was TIMI IIIB, which started enrollment in October 1989.1 The results from that trial suggested that the 2 strategies yielded similar outcomes. Two subsequent studies (Veterans Affairs Non–Q-Wave Infarction Strategies in Hospital [VANQWISH] and Medicine versus Angiography in Thrombolytic Exclusion [MATE]) also failed to show a clear benefit to an early invasive strategy.6,7 However, since that time, new therapeutic modalities were introduced that had the potential to shift the balance between invasive and conservative treatment strategies. In particular, intracoronary stents and GP IIb/IIIa inhibitors rapidly gained clinical acceptance8,9 and were used to varying degrees in Fragmin and fast Revascularisation during InStability in Coronary artery disease (FRISC) II,10 TACTICS-TIMI 18,2 Randomized Intervention Treatment of Angina (RITA)-3,11 and Intracoronary Stenting and Antithrombotic Regimen COOLing-off (ISAR-COOL),11a all of which showed an advantage to an early invasive strategy. Although individual trials have demonstrated the efficacy of these treatments, formal 2×2 factorial design trials have not been performed to specifically assess the interaction between these advances and an early invasive versus conservative treatment strategy. Moreover, such trials are unlikely to be conducted, given current practice patterns. Thus, we sought to take advantage of the similarities in trial design between TIMI IIIB and TACTICS-TIMI 18 to gain insight into the impact of these advances on treatment strategy.
Using the TIMI risk score for UA/NSTEMI, we found that despite the similar eligibility criteria, patients enrolled in TACTICS-TIMI 18 had a more severe risk profile than did patients in TIMI IIIB. Even with 2 trials with nearly identical enrollment criteria conducted by the same clinical trials study group, significant differences in patient populations occurred. Our approach illustrates how, in the appropriate setting, a simple integrated risk tool such as the TIMI risk score can be used to profile the risk distribution in a given cohort and thereby facilitate more quantitative comparisons across trials.5
After adjustment for differences in baseline risk, patients in TACTICS-TIMI 18 were significantly less likely to experience the composite end point of death, MI, or rehospitalization for ACS by 6 months. Directional consistency was seen for the individual components of the composite end point, with the magnitude of effect appearing to be greatest for MI and somewhat less for rehospitalization for ACS and death. The advantage in TACTICS-TIMI 18 was robust and was observed regardless of randomized treatment strategy or revascularization status and persisted even after adjustment for differences in index hospitalization procedures and use of cardiac medications. The explanations for this difference are most likely multifactorial, and we speculate as to the contributions below.
In TACTICS-TIMI 18, 85% of patients who underwent PCI received an intracoronary stent, whereas no patient in TIMI IIIB received a stent. Multiple interventional studies have confirmed that stenting prevents restenosis and hence the need for target vessel revascularization.12,13 Thus, the use of stents might partially explain the lower rate of rehospitalization for ACS through 6 months, although restenosis typically does not present as an ACS. However, stenting has not been shown to decrease the rate of death or MI, and thus, our observation of lower rates of these adverse events in patients in TACTICS-TIMI 18 compared with patients in TIMI IIIB is unlikely to be attributable to stenting. Of note, patients in TACTICS-TIMI 18 who underwent stenting very likely also received a thienopyridine for 2 to 4 weeks. Although data show that thienopyridines reduce ischemic complications in the setting of UA/NSTEMI,14 this cannot be the sole explanation, because lower rates of death and ischemic complications in TACTICS-TIMI 18 compared with TIMI IIIB were seen even in the subset of patients who did not undergo PCI and hence did not receive a thienopyridine.
The use of GP IIb/IIIa inhibitors in UA/NSTEMI has been shown to reduce the rate of death or MI. In the Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms (PRISM-PLUS) trial, treatment with tirofiban was associated with a 20% reduction in the rate of death or MI through 6 months.15 Moreover, this benefit was seen as early as 48 hours. These observations are in keeping with our findings of an early and sustained difference between the event rates in TACTICS-TIMI 18 and TIMI IIIB.
Using event rates stratified by the TIMI risk score, we were able to dissect out the complex interrelationships between baseline risk, clinical trial, and the benefits of an early invasive strategy. We found that the efficacy of an early invasive strategy was strongly related to a patient’s baseline risk, with increasing benefits with higher levels of baseline risk. This relationship was apparent in both TIMI IIIB and TACTICS-TIMI 18. This observation underscores the importance of adjusting for baseline differences when attempting to synthesize data across multiple trials. Such differences can be particularly important if, as in this case, they interact with the treatment being tested in the trials. For example, a meta-analysis of the results of TIMI IIIB and TACTICS-TIMI 18 would yield a statistically nonsignificant OR for the effect of an early invasive strategy on the composite end point of 0.90 (95% CI, 0.77 to 1.06; P=0.23). However, by performing stratified analyses, we revealed a more complex picture and demonstrated statistically significant and clinically important heterogeneity with an early invasive strategy offering no benefit in low-risk patients but ≈20% and ≈40% reductions in death and ischemic complications in intermediate- and high-risk patients, respectively. Moreover, after adjustment for baseline risk, there was a trend toward an interaction between an early invasive therapy and trial, with an early invasive strategy being ≈20% more effective in TACTICS-TIMI 18 than in TIMI IIIB. These data support the notion that an early invasive approach may be even more efficacious in reducing adverse cardiac events when used in the setting of upstream GP IIb/IIIa inhibition and intracoronary stenting.
Although we attempted to adjust for differences in baseline risk between the 2 trial populations, any intertrial comparison must be viewed with caution, and because multiple comparisons were made in these post hoc analyses, even those with statistical significance must be viewed as exploratory. Unknown and therefore uncontrolled-for confounding factors may have led to the introduction of bias. It should also be noted that although use of the TIMI risk score then permitted stratified analyses, the score may not have fully captured a patient’s risk. Although GP IIb/IIIa inhibition and stenting are probably the predominant causes of the lower event rate and greater benefit of an early invasive strategy in TACTICS-TIMI 18, such attribution remains speculative, and other interventions may have been responsible for the improved outcome in TACTICS-TIMI 18. Nonetheless, using careful multivariable analysis, we have attempted to estimate the potential beneficial effects of GP IIb/IIIa inhibitors and stenting in the absence of an opportunity for future randomized trials.
An integrated risk tool such as the TIMI risk score can be used to allow stratified comparisons between patients of similar risk in different trials. Using such an approach in TIMI IIIB and TACTICS-TIMI 18, we found that among patients matched for similar degrees of baseline risk, patients in TACTICS-TIMI 18 had lower rates of death, MI, or rehospitalization for ACS through 6 months. We also found that the benefits of an early invasive strategy were significantly greater with increasing baseline risk and that, within each risk stratum, there was a trend toward the benefit of an early invasive strategy being greater in TACTICS-TIMI 18 than in TIMI IIIB. Although the contribution of many factors is possible, these differences most likely reflect the use of GP IIb/IIIa inhibitors and coronary stents in TACTICS-TIMI 18 and thus support the most recent American College of Cardiology/American Heart Association guidelines,16 which call for GP IIb/IIIa inhibition and an early invasive approach in patients with high-risk UA/NSTEMI.
Dr Sabatine was supported in part by National Heart, Lung, and Blood Institute grant F32-HL68455-01. TACTICS-TIMI 18 was supported by Merck & Co. The TIMI Study Group and Dr Weintraub have received research grant support from Merck & Co.
Drs Demopoulos and DiBattiste are Merck & Co, Inc, employees and potentially own stock and/or hold stock options in the company.
The TIMI IIIB Investigators. Effects of tissue plasminogen activator and a comparison of early invasive and conservative strategies in unstable angina and non–Q-wave myocardial infarction: results of the TIMI IIIB trial. Circulation. 1994; 89: 1545–1556.
Morrow DA, Antman EM, Snapinn SM, et al. An integrated clinical approach to predicting the benefit of tirofiban in non–ST elevation acute coronary syndromes: application of the TIMI risk score for UA/NSTEMI in PRISM-PLUS. Eur Heart J. 2002; 23: 223–229.
McCullough PA, O’Neill WW, Graham M, et al. A prospective randomized trial of triage angiography in acute coronary syndromes ineligible for thrombolytic therapy: results of the Medicine versus Angiography in Thrombolytic Exclusion (MATE) trial. J Am Coll Cardiol. 1998; 32: 596–605.
The Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms (PRISM-PLUS) Study Investigators. Inhibition of the platelet glycoprotein IIb/IIIa receptor with tirofiban in unstable angina and non–Q-wave myocardial infarction. N Engl J Med. 1998; 338: 1488–1497.
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