Small molecule glycoprotein IIb/IIIa receptor inhibitors as upstream therapy in acute coronary syndromes
Insights from the TACTICS TIMI-18 trial
Christopher P. Cannon, MD*,*
* TIMI Study Group, Cardiovascular Division, Brigham and Women’s Hospital, Boston, Massachusetts, USA
Manuscript received May 7, 2002;
accepted December 18, 2002.
*
Reprint requests and correspondence: Dr. Christopher P. Cannon, TIMI Study Group, Cardiovascular Division, Brigham and Women’s Hospital, 75 Francis Street, Boston, Massachusetts 02115, USA.
cpcannon{at}partners.org
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Abstract
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Glycoprotein (GP) IIb/IIIa inhibitors are beneficial in unstable angina/non–ST-segment elevation myocardial infarction (UA/NSTEMI). In large trials, the GP IIb/IIIa inhibitors tirofiban and eptifibatide were each found to reduce the risk of death or myocardial infarction (MI) in these patients at 30 days. These agents appear to be of greatest benefit in patients with a positive troponin at baseline, diabetes or ST-segment depression, recurrent angina, prior aspirin use, or a Thrombolysis In Myocardial Infarction (TIMI) risk score  4. The Treat angina with Aggrastat and determine Cost of Therapy with an Invasive or Conservative Strategy (TACTICS) TIMI-18 trial was designed to compare the benefits of an early invasive versus a conservative strategy in high-risk UA/NSTEMI patients treated with GP IIb/IIIa inhibition. Patients were treated with tirofiban (for 48 h) plus aspirin and heparin and randomized to either invasive therapy (coronary angiography and revascularization when feasible) or conservative treatment (angiography only for patients with recurrent ischemia at rest or a positive stress test). A significant reduction in death or MI was demonstrated at 30 days (p = 0.02) and at 6 months (p = 0.0498). Death, MI, or rehospitalization for an acute coronary syndrome was also reduced with the invasive therapy at six months (p = 0.025). These results provide evidence to physicians that early GP IIb/IIIa inhibition in combination with a prompt invasive approach should be used more widely in UA/NSTEMI patients, particularly those at high risk.
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Abbreviations and Acronyms
| | CABG | = coronary artery bypass graft | | GP | = glycoprotein | | MI | = myocardial infarction | | NSTE | = non–ST-segment elevation | | PCI | = percutaneous coronary intervention | | UA | = unstable angina |
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With the elucidation of the role of platelets in the pathophysiology of unstable angina (UA) and non–ST-segment elevation myocardial infarction (NSTEMI), glycoprotein (GP) IIb/IIIa receptor inhibitors have been identified and developed as a promising new therapy for the reduction of coronary thrombus and the improvement of outcomes. Currently, the Food and Drug Administration in the U.S. has approved three GP IIb/IIIa inhibitors for use as antiplatelet agents: tirofiban, eptifibatide, and abciximab. The influence of these novel agents on the management of NSTEMI patients has recently been explored in several large, randomized studies. In particular, insights into the role of upstream GP IIb/IIIa inhibition in early invasive versus early conservative strategies have recently been gained from the Treat angina with Aggrastat and determine Cost of Therapy with an Invasive or Conservative Strategy (TACTICS) Thrombolysis In Myocardial Infarction (TIMI)-18 trial.
In atherosclerotic disease, platelet aggregation occurs as part of an interconnected pattern of plaque disruption, lipid accumulation, mural thrombus formation, and lesion progression. When plaque rupture occurs, the subendothelial protein matrix is disrupted, allowing platelet adhesion molecules such as von Willebrand factor and collagen to interact with circulating platelets. Platelet activation and degranulation result. The GP IIb/IIIa receptors on the platelet surfaces are upregulated and bind to circulating fibrinogen and von Willebrand factor, causing cross-linking and aggregation of the platelets. Antagonists of the GP IIb/IIIa receptors can prevent binding of fibrinogen and von Willebrand factor, reducing platelet aggregation and inhibiting platelet function.
Several large trials have shown GP IIb/IIIa inhibition to be beneficial in UA/NSTEMI, either in patients treated predominantly with medical management (1), early interventional management (2), or both (3–6). In the Platelet Receptor inhibition for Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms trial (PRISM-PLUS), tirofiban plus heparin and aspirin significantly reduced the rate of death, myocardial infarction (MI), or refractory ischemia at seven days compared with heparin plus aspirin (3). Death or MI at 30 days was also reduced significantly by 30%, from 11.9% to 8.7%, with the reduction consistent across all management strategies (i.e., medical therapy, 25% reduction; percutaneous transluminal coronary angioplasty, 35% reduction; and coronary artery bypass graft [CABG] surgery, 30% reduction) (Fig. 1) (7). In the Platelet glycoprotein IIb/IIIa in Unstable angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) trial, involving 10,948 patients, eptifibatide also significantly reduced the rate of death or MI at 30 days (4). In this trial, a greater benefit with eptifibatide was observed in patients undergoing early angioplasty than with other treatment strategies (4). A meta-analysis involving over 30,000 patients found that treatment with a GP IIb/IIIa inhibitor led to a 21% reduction in death or MI at 30 days (5,6).
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Figure 1 PRISM-PLUS: 30-day death/MI by strategy. Benefit of upstream tirofiban stratified by the ultimate treatment strategy employed. CI = confidence interval; CABG = coronary artery bypass graft; MI = myocardial infarction; PRISM-PLUS = the Platelet Receptor inhibition for ISchemic Management in Patients Limited to very Unstable Signs and Symptoms; PTCA = percutaneous transluminal coronary angioplasty; Rx = treatment. Data from Barr E, Thornton AR, Sax FL, Snapinn SM, Theroux P. Benefit of tirofiban + heparin therapy in unstable angina/non–Q-wave myocardial infarction patients is observed regardless of interventional treatment. Circulation 1998;98 Suppl I:I504. Reprinted with permission from Lippincott, Williams and Wilkins.
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Recently, an analysis of pooled data from PRISM-PLUS, PURSUIT, and the Chimeric c7E3 AntiPlatelet Therapy in Unstable REfractory angina (CAPTURE) trials, involving 12,296 patients, was carried out. A 34% relative reduction in death or MI during 24 to 48 h of medical-management-only (3.8% vs. 2.5%; p = 0.001) was found among patients who received a GP IIb/IIIa inhibitor (8). These findings support the use of GP IIb/IIIa inhibition in the medical management of patients with UA/NSTEMI for the prevention of early events.
Of note, the Global Use of Strategies To Open Occluded coronary arteries IV in Acute Coronary Syndromes (GUSTO IV-ACS) trial found no benefit with abciximab treatment in patients managed conservatively (9). Although no clear explanation is apparent, one hypothesis is that the dose of the infusion of abciximab may have been too low, which led to sub-optimal levels of platelet inhibition. After a 12-h infusion, the mean level of platelet inhibition was found to be only 80% (indicating that half the patients had levels <80%) (Fig. 2) (10). After 24 to 48 h, the levels might have fallen to even lower concentrations. By contrast, the small-molecule GP IIb/IIIa inhibitors have documented high, steady levels of platelet inhibition during the 48 to 72 h infusion periods (11). Accordingly, based on the clinical trial data, the 2002 American College of Cardiology/American Heart Association UA/NSTEMI Guidelines recommend only tirofiban and eptifibatide for upstream use in UA/NSTEMI (12).
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Figure 2 Level of platelet inhibition achieved after a 12-h bolus and infusion of abciximab. RPFA = rapid platelet function assay. Reprinted with permission from Lippincott, Williams and Wilkins. Steinhubl SR, Kottke-Marchant K, Moliterno DJ, et al. Attainment and maintenance of platelet inhibition by standard dosing of abciximab in diabetic and nondiabetic patients undergoing percutaneous coronary intervention. Circulation 1999;100:1977–82.
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Targeting high-risk patients
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The benefit of GP IIb/IIIa inhibition appears to be greatest in patients at higher risk, as evidenced by those who have a positive troponin value at baseline (Fig. 3) (13–16), diabetes (17,18), ST-segment changes (3), recurrent angina (3,19), prior aspirin use (20), or a TIMI risk score 4 (21). In patients who are troponin-positive, the benefit is an approximately 70% reduction in death or MI (Fig. 3). No other intervention, not even aspirin, can achieve such a marked benefit. Nonetheless, GP IIb/IIIa inhibition appears to be very underused in current practice, representing a missed opportunity for improving outcomes in this high-risk population.
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Figure 3 Benefit of glycoprotein IIb/IIIa inhibition in UA/NSTEMI based on positive or negative troponin levels. CAPTURE = c7E3 AntiPlatelet Therapy in Unstable REfractory angina to standard treatment; PRISM = Platelet Receptor inhibition for ISchemic Management; TnI = troponin I; TnT = troponin T. Data from Hamm CW, Heeschen C, Goldmann B, et al. Benefit of abciximab in patients with refractory unstable angina in relation to serum troponin T levels. N Engl J Med 1999;340:1623–9. Data from Heeschen C, Hamm CW, Goldmann B, et al. Troponin concentrations for stratification of patients with acute coronary syndromes in relation to therapeutic efficacy of tirofiban. Lancet 1999;354:1757–62. Reprinted with permission from Elsevier Science.
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The mechanism for this benefit has emerged from recent angiographic studies, including new data from the TACTICS TIMI-18 trial. Patients with a positive troponin were found to have more coronary thrombus, worse coronary flow, and impaired myocardial perfusion (22,23). Furthermore, angiographic analyses have shown that the use of GP IIb/IIIa inhibitors, and longer infusion times for these agents, can resolve thrombus and improve coronary flow and myocardial perfusion more rapidly and completely than aspirin and heparin alone (Fig. 4) (24–26).
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Figure 4 Preliminary results from the Percutaneous Coronary Intervention-Treat Angina with Aggrastat and determine Cost of Therapy with an Invasive or Conservative Strategy (PCI-TACTICS) substudy. Longer duration of tirofiban was associated with improvements in myocardial perfusion grade coronary flow and coronary thrombus grade. MV = multivariate; TIMI = Thrombolysis In Myocardial Infarction; TnT = troponin T. Reprinted with permission from Lippincott, Williams and Wilkins. Data from Gibson M, Murphy SA, Weisberg S, et al. Early initiation of tirofiban therapy before percutaneous coronary intervention is associated with improved flow and tissue level perfusion: a TACTICS TIMI-18 substudy. Circulation 2001;104 Suppl II:II548–9.
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TACTICS TIMI-18.
Further validation of the benefit of GP IIb/IIIa inhibition in the overall management of UA/NSTEMI comes from the TACTICS TIMI-18 trial. This trial was designed to re-examine the question of which treatment strategy is optimal in the management of UA/NSTEMI. In the TIMI IIIB trial, no difference was seen between patients treated with an early invasive versus a conservative strategy (27). An invasive strategy involved routine coronary angiography 18 to 48 h after randomization with revascularization (percutaneous coronary intervention [PCI] or CABG) when feasible, based on anatomy. The conservative strategy reserved angiography only for patients with recurrent ischemia at rest or a positive stress test.
Since the time of that trial, however, there have been two major advances in cardiology that possibly affect the overall efficacy and safety of an invasive approach: the advent of coronary stenting and GP IIb/IIIa inhibition. The primary hypothesis of the TACTICS TIMI-18 trial was that, with the benefit of GP IIb/IIIa inhibition and coronary stenting, an early invasive strategy would be superior to a conservative approach.
The TACTICS TIMI-18 trial enrolled patients (n = 2,220) with a typical history of UA/NSTEMI, with either electrocardiographic changes, positive cardiac markers, or a history of coronary disease. All were treated with aspirin, heparin, and the GP IIb/IIIa inhibitor tirofiban for 48 h, including 12 h after PCI. The primary hypothesis was demonstrated. In patients treated with a GP IIb/IIIa inhibitor, the early invasive strategy led to a significant reduction in the primary end point, death, MI, or rehospitalization for an acute coronary syndrome at six months: 15.9% in the early invasive group versus 19.4% in the conservatively treated group (odds ratio, 0.78; p = 0.025) (28). Death or MI was also significantly reduced at 30 days (invasive group, 4.7%; conservative, 7.0%; p = 0.02) and at 6 months (p = 0.0498).
When these data are compared with those from the four previous randomized trials of invasive versus conservative strategies (27,29–33), an interesting difference emerges. In the trials without GP IIb/IIIa inhibition, the rate of MI tends to be higher in the invasive group over the first two weeks; this is consistent with an early hazard associated with coronary interventions (34). By contrast, in TACTICS TIMI-18, there was a significantly lower rate of MI over the first weeks, an effect that probably results from the well-documented protection afforded by GP IIb/IIIa inhibition (6).
A direct comparison of TIMI IIIB versus TACTICS TIMI-18 shows a consistently superior outcome with the latter trial, as had been hypothesized (Fig. 5) (35). In low-risk patients enrolled in TIMI IIIB, the incidence of death, MI or rehospitalization after six months was significantly worse among patients randomized to the invasive strategy arm, whereas in TACTICS TIMI-18, event rates among low-risk patients were approximately equivalent for both treatment strategies. For intermediate-risk patients, the outcomes for invasive versus conservative approaches were roughly equal in TIMI IIIB, whereas in TACTICS TIMI-18, outcomes were significantly better with the invasive approach. Finally, while there was a trend for improved outcomes among high-risk patients treated invasively in the TIMI IIIB trial, in TACTICS TIMI-18, a dramatic 10% absolute reduction in events was found with the invasive approach.
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Figure 5 Comparison of event rates in the Thrombolysis In Myocardial Infarction (TIMI) IIIB versus Treat Angina with Aggrastat and determine Cost of Therapy with an Invasive or Conservative Strategy (TACTICS)-TIMI 18 trials stratified by TIMI risk score (TRS). ACS = acute coronary syndromes; CONS = conservative; Intermed = intermediate; INV = invasive; MI = myocardial infarction; Rehosp = rehospitalization. Reprinted with permission from Lippincott, Williams and Wilkins. Data from Sabatine MS, Cannon CP, Murphy SA, DiBattiste PM, Demopoulos LA, Braunwald E. Implications of upstream GP IIb/IIIa inhibition and stenting in the invasive management of UA/NSTEMI: a comparison of TIMI IIIB and TACTICS TIMI-18. Circulation 2001;104 Suppl II:II549.
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Risk stratification
As was observed with GP IIb/IIIa inhibition, a significantly greater benefit was seen in patients with positive troponin values compared with patients with negative values (Fig. 3) (28). In patients with a troponin T <0.01 ng/ml (54% of the population) or in those with troponin I <0.1 ng/ml (60% of the population), there was a relative 39% risk reduction in the primary end point with the invasive versus conservative strategy (p < 0.001 in each). Patients with a negative troponin had similar outcomes with either strategy (36). The outcomes of death or non-fatal MI followed the same pattern, with a significant reduction in the invasive strategy group in patients with positive troponin compared with no benefit in those with a negative troponin. The same pattern of benefit was also seen in patients with ST-segment changes on the baseline electrocardiogram, a group that comprised 38% of the population. A TIMI risk score 3 was also associated with increased benefit when the invasive approach was used.
This study demonstrated that among patients with UA/NSTEMI treated with the GP IIb/IIIa inhibitor, tirofiban, an early invasive strategy was superior to a conservative strategy in reducing major cardiac events at 30 days and 6 months. In addition, the absolute rate of death or MI at 30 days in the invasive group, 4.7%, was the lowest observed rate in any UA/NSTEMI trial to date (3,4,6,37). Thus, this strategy of upstream GP IIb/IIIa inhibition with tirofiban combined with an early invasive strategy leads to excellent outcomes and could be considered the treatment of choice for the majority of patients with UA/NSTEMI.
Summary
According to the current evidence from TACTICS TIMI-18 and now, several other trials in UA/NSTEMI (33,38–44), an early invasive strategy reduces the risk of major cardiac events in patients with UA/NSTEMI more effectively than a conservative approach (38). This benefit was observed in most patients studied, particularly those at intermediate- or high-risk and notably in those with positive troponin or ST-segment changes. By contrast, lower-risk patients had similar outcomes with either strategy, suggesting that either a conservative or invasive strategy is appropriate for low-risk patients. The contribution of GP IIb/IIIa inhibition is evidenced by the placebo-controlled trials, in which upstream GP IIb/IIIa inhibition was initiated upon admission. In these trials, reductions in death or MI were demonstrated, particularly in troponin-positive patients or those with TIMI risk score >3, regardless of whether or not they ultimately underwent PCI. These results provide encouragement to physicians for the wider employment of early GP IIb/IIIa inhibition in combination with an early invasive approach in intermediate- or high-risk patients.
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Footnotes
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Please refer to the Trial Appendix at the back of this supplement for the complete list of clinical trials.
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References
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Abstract
Targeting high-risk patients