Managing Unstable Angina in High-Risk Patients (Part II)

Continued from previous page PURSUIT. The PURSUIT trial was designed to evaluate eptifibatide as an adjunct to a broad spectrum of management strategies used to prevent death and MI in the 30 days following an urgent episode of UA or NQWMI. The 10,948 patients enrolled in PURSUIT experienced chest pain at rest (lasting >= 10 minutes) within the previous 24 hours and had one or more ECG or cardiac enzyme (CK-MB) test results confirming a diagnosis of UA or NQWMI.⁵⁸ Patients were randomized to receive eptifibatide 180 µg/kg bolus plus 1.3 µg/kg/min infusion, eptifibatide 180 µg/kg bolus plus 2.0 µg/kg/min infusion, or placebo bolus plus infusion. The primary endpoint was death from any cause and nonfatal MI over the 30 days following initiation of drug therapy. Prospectively defined secondary endpoints included death or MI at 96 hours and 7 days; all-cause mortality within 30 days; first or recurrent MI within 30 days; and safety and efficacy in the subset of patients undergoing PTCA. Safety endpoints included bleeding complications, incidence of stroke and incidence of thrombocytopenia.⁵⁸ Treatment with eptifibatide was associated with a statistically significant decrease in the composite primary endpoint at 30 days (15.7% placebo versus 14.2% eptifibatide; p = 0.04), and this benefit also was seen in the composite rates of death or MI at 96 hours (9.1% placebo versus 7.6% eptifibatide; p = 0.01) and 7 days (11.6% placebo versus 10.1% eptifibatide; p = 0.02).⁵⁸ Major bleeding occurred in 10.6% and 9.1% of eptifibatide and placebo patients, respectively (p = 0.02), and approximately 80% of the major bleeding complications occurred in patients undergoing coronary artery bypass surgery. Minor bleeding occurred more frequently in eptifibatide versus placebo patients (12.9% versus 7.4%, respectively), but in most cases bleeding was mild and occurred at the femoral access site. Strokes occurred with similar frequency in the two study groups (0.7% eptifibatide versus 0.8% placebo), as did the incidence of thrombocytopenia (6.8% versus 6.7%, respectively). Intracranial bleeding was rare, occurring in less than 0.1% of patients in both study groups.⁵⁸ In a sub-analysis of the 1,228 patients undergoing PCI within 72 hours of randomization in the PURSUIT trial, eptifibatide was associated with a 31% RR reduction in 30-day death or MI (11.6% eptifibatide versus 16.7% placebo; p = 0.01). Among patients undergoing PCI after 72 hours and before 30 days, a marginal difference in the 30-day rate of death or MI was observed (14.6% eptifibatide versus 15.6% placebo; p = 0.23). These data support the concept that benefit with glycoprotein IIb/IIIa inhibitors is of greater magnitude when associated with an early invasive approach.⁶⁴PRISM. The Platelet Receptor Inhibition in Ischemic Syndrome Management (PRISM) trial examined whether inhibition of platelet aggregation with tirofiban would improve clinical outcome in patients with unstable angina. This double-blind study randomly assigned 3,232 patients who were already receiving aspirin (300–325 mg/day) to additional treatment with either intravenous tirofiban (0.6 µg/kg body weight/minute for 30 minutes followed by 0.15 µg/kg/min) or heparin (5,000 U intravenous bolus followed by 1,000 U/hour infusion) for 48 hours. The primary endpoint was a composite of death, MI or refractory ischemia at 48 hours.⁶⁵ At 48 hours, the incidence of the composite endpoint was decreased by 32% in the group that received tirofiban (3.8% tirofiban versus 5.6% heparin; p = 0.01). At 30 days, the frequency of the composite endpoint (including patients readmitted for UA) was similar in the two groups (15.9% tirofiban versus 17.1% heparin; p = 0.34). A trend toward a reduction in the rate of death or MI was observed in the tirofiban group (5.8% tirofiban versus 7.1% heparin; p = 0.11). Patients in the tirofiban group also had a lower mortality rate (2.3% tirofiban versus 3.6% heparin; p = 0.02). Major bleeding occurred in 0.4% of the patients in both groups, but reversible thrombocytopenia occurred more frequently with tirofiban than with heparin (1.1% versus 0.4%; p = 0.04).⁶⁵ Tirofiban was generally well tolerated and, compared with heparin, reduced ischemic events during the 48-hour infusion period, during which revascularization procedures were not performed. The incidence of refractory ischemia and MI was not significantly reduced at 30 days, but mortality was lower among the patients given tirofiban.⁶⁵PRISM-PLUS. PRISM-PLUS was a double-blind study that randomized 1,915 patients with UA or NQWMI to receive tirofiban alone, heparin alone, or tirofiban plus heparin.59 Study drugs were infused for a mean (± standard deviation) of 71.3 ± 20 hours, during which coronary angiography and angioplasty were performed, when indicated, after 48 hours. The primary endpoint was the composite of death, MI or refractory ischemia within 7 days following randomization.⁵⁹ The group receiving tirofiban alone was stopped prematurely because of excess mortality at 7 days (4.6% tirofiban alone versus 1.1% heparin alone). The frequency of the composite primary endpoint at 7 days was lower among patients who received tirofiban plus heparin than among those who received heparin alone (12.9% tirofiban-heparin versus 17.9% heparin; p = 0.004).⁵⁹ The frequency of the composite endpoint in the tirofiban-plus-heparin group was also lower than the heparin-only group at 30 days (18.5% versus 22.3% respectively; p = 0.03) and at 6 months (27.7% versus 32.1%, respectively; p = 0.02). At 7 days, the frequency of death or MI was 4.9% in the tirofiban-plus-heparin group versus 8.3% in the heparin-only group (p = 0.006). At 30 days, the frequency of death or myocardial infarction was 8.7% and 11.9%, respectively (p = 0.03), and at 6 months was 12.3% and 15.3%, respectively (p = 0.06).⁵⁹ The therapeutic benefit was consistent in the various subgroups of patients (males and females, younger and older patients, those taking aspirin and those not taking aspirin, and those taking heparin and those not taking heparin) and in those treated medically as well as those treated with angioplasty. Major bleeding occurred in 3.0% of the patients receiving heparin alone and 4.0% of those receiving tirofiban plus heparin (p = 0.34). No patient experienced intracerebral hemorrhage or died from a bleeding complication related to a study drug.⁵⁹PARAGON-B. Platelet IIb/IIIa Antagonism for the Reduction of Acute Coronary Syndrome Events in a Global Organization Network (PARAGON-B) was a randomized, double-blind study designed to assess the efficacy of lamifiban in improving patient outcomes when dosed according to creatinine clearance (target, 20–40 ng/ml). The 5,228 patients with non-ST elevation ACS enrolled in this multinational trial were randomized to receive either lamifiban (500 µg intravenous bolus and infusion of 1.0, 1.5 or 2.0 µg/min) for 72 hours or placebo bolus plus infusion. The primary endpoint of this study was the 30-day composite of death, MI and severe recurrent ischemia requiring urgent revascularization. Secondary endpoints included the composite and its components at 7, 30 and 180 days; death at 1 year; and the incidence of major and minor bleeding.⁶⁶ Preliminary results failed to demonstrate any statistically significant reduction in the composite primary endpoint or in any of its individual components in the patients treated with lamifiban compared to those who receive placebo. The published results are expected to be available this year.⁶⁷ As shown in a recent report on the PARAGON-B troponin-T substudy of 1,160 patients in the PARAGON-B trial, investigators obtained troponin T levels before treatment began and 24 and 72 hours later. At baseline, 40.2% of patients were troponin-T positive (>= 0.1 ng/mL). Patients who were positive at baseline had a significantly higher rate of the primary endpoint at 30 days than those who were troponin-negative (odds ratio, 1.5; 95% confidence interval, 1.1–2.1). Patients who were troponin-T positive and treated with lamifiban had a significant reduction in the primary endpoint (19.4% placebo versus 11.0 lamifiban; p = 0.01). However, this treatment benefit did not extend to patients who were troponin-T negative (11.2% placebo versus 10.8% lamifiban; p = 0.86). This pattern was similar for the secondary endpoints of death alone or death or MI at 30 days. These findings suggest that the presence of elevated troponin T predicts poor short-term outcomes in non-ST segment elevation ACS.⁶⁸ Similar observations have been made in the PRISM⁶⁵ and CAPTURE⁵⁷ studies. GUSTO-IV-ACS. This trial was designed to evaluate the effect of abciximab on reducing the composite endpoint of death or MI by 30 days in patients with non-ST segment elevation ACS who were not undergoing early revascularization. The inclusion criteria for the trial were angina at rest >= 5 minutes within the preceding 24 hours, ST-segment depression >= 0.5 mm, and/or troponin I or T positivity. All patients received aspirin and unfractionated heparin (UFH) or dalteparin, a low-molecular-weight heparin (LMWH), and were randomized to placebo or standard-dose abciximab for either 24 or 48 hours. Of the 7,800 patients in this trial, 2,598 received placebo, 2,590 received abciximab for 24 hours, and 2,612 received abciximab for 48 hours.⁶⁹ No significant differences were found in reductions of death or AMI at 30 days among the three patient groups (placebo, 8.0%; abciximab 24 hours, 8.2%; abciximab 48 hours, 9.1%). However, rates of adverse effects (stroke, intracerebral hemorrhage, bleeding, transfusion or low platelets) were low and comparable in the three treatment groups.⁶⁹ The investigators concluded that in patients with ST-segment depression or troponin-positive ACS, treatment with abciximab for 24 or 48 hours with adjunctive aspirin and UFH or LMWH, and without early intervention, did not reduce death or MI. There are several possible explanations for these results. First, the trial may have been underpowered; although GUSTO-IV-ACS was 80% powered to show an anticipated 20% reduction in clinical event rates, the overall event rate of 8% was lower than the expected 11% rate, yielding only 58% power, not enough to show a 20% reduction. Second, it is possible that prolonged (24- or 48-hour) platelet inhibition with a GP IIb/IIIa agent may have adverse clinical effects not observed prior to this trial.⁶⁹TACTICS-TIMI 18. Treat Angina with Aggrastat and Determine Cost with Invasive or Conservative Strategy (TACTICS-TIMI 18) was an international, multicenter, randomized trial to evaluate an early invasive strategy (catheterization between 4 and 48 hours with revascularization for suitable coronary anatomy) versus an early conservative or “selective invasive” strategy (catheterization for refractory angina, hemodynamic instability, marked exercise test abnormality, new MI or rehospitalization for UA, and clinical class III or IV angina with positive exercise test findings) in patients with non-ST segment elevation ACS. The 2,220 patients enrolled in TACTICS-TIMI 18 were initially administered aspirin, heparin and tirofiban “upstream” prior to coronary angiography. The primary endpoint was the composite of death, nonfatal MI and rehospitalization for ACS at 6 months following enrollment.⁷⁰ At 6 months, the primary endpoint was observed significantly less frequently (15.9%) in patients allocated to the early invasive strategy versus those patients randomized to conservative treatment (19.4%; p = 0.025). The rate of death or nonfatal MI at 6 months was similarly reduced (7.3% early invasive versus 9.5% conservative; p p = 0.029).70 The greatest reduction in adverse clinical events following treatment with tirofiban in conjunction with early angiography and revascularization was in those patients with elevated serum troponin levels and those with ST-segment changes on presentation. This study lends further credence to the recommendation that patients who present with non-ST segment elevation ACS and who have elevated troponin or high-risk clinical predictors should receive therapy with a platelet GP IIb/IIIa inhibitor and should undergo early invasive evaluation and treatment.⁷¹ Table 2 describes phase-III trials supporting the use of GP IIb/IIIa inhibitors in the management of unstable angina.^{57–59,61–63,65,66,69,70,72–79} Clinical Trials of Early Invasive Strategies in UA/NQWMI Recently, two studies have provided important evidence supporting a routine invasive strategy compared to ischemia-driven invasive management among patients presenting with non-ST segment elevation acute coronary syndromes. First, the FRISC II study evaluated the low-molecular-weight heparin, dalteparin, and early invasive therapy among 2,267 patients in a 2 x 2 factorial design. Among the patients receiving at least 5 days of open-labeled dalteparin twice daily and then randomized to dalteparin twice daily for 3 months, a reduction in 30-day death or MI was observed (3.1% dalteparin versus 5.9% placebo; p = 0.002). This reduction was not significant at 3 months (6.7% versus 8.0%; p = 0.17).⁸⁰ In addition, contrasting previous studies of early invasive treatment among similar patient populations, a total of 2,457 patients were randomly assigned to an early invasive or noninvasive treatment strategy. Patients in the invasive group experienced lower rates of death or MI, a benefit that remained evident at 6 months (9.4% invasive versus 12.1% ischemia-driven; p = 0.031). Angiography was performed at a median of 4 days in the early invasive arm of this study.⁸¹ Likewise, in the TACTICS-TIMI 18 study invasive investigation was required within 48 hours in the invasive arm (median, 22 hours). As discussed earlier, outcomes were improved with the early invasive approach at 6 months. A substantial proportion of the benefit was seen as a reduction in repeat MI (6.9% versus 4.8%; p = 0.029). Within this study, patients presenting with elevated troponin levels appeared to derive a greater reduction in the primary endpoint (24.2% versus 14.8%; p 70 Thus, considered collectively, these studies support the notion that within the context of modern antithrombotic therapy, routine invasive management provides superior long-term outcomes in patients with ACS. Clinical Trials of Clopidogrel and LMWH in UA/NQWMI Further evidence of support for antiplatelet therapy and the use of LMWH in patients presenting with ACS has been collected in several additional studies. CURE. The Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial randomized 12,562 patients to clopidogrel 300 mg initially and then 75 mg daily or placebo for 3–12 months. All patients received aspirin therapy. By 12 months, the composite endpoint of death, nonfatal myocardial infarction and stroke occurred in 9.3% of the clopidogrel group and 11.4% of the placebo group (p p = 0.001).40 Further, a substudy of the CURE trial examined the benefit of clopidogrel pre-treatment among those patients undergoing percutaneous coronary revascularization. Among the 2,658 patients studied, clopidogrel provided a 30% reduction in death, myocardial infarction or urgent revascularization at 30 days (4.5% versus 6.4%; p = 0.03). Interestingly, GP IIb/IIIa inhibition was required less often in the clopidogrel-treated group (20.9% versus 26.6%; p = 0.001). Furthermore, bleeding events up to 30 days were not increased in the clopidogrel group.⁸²ESSENCE. The Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q wave Coronary Events (ESSENCE) trial randomized 3,171 patients with UA/NQWMI to treatment with enoxaparin (a LMWH) 1 mg/kg subcutaneously twice daily, or to continuous intravenous unfractionated heparin for a minimum of 48 hours to a maximum of 8 days.⁴⁹ The primary composite endpoint of death, MI or recurrent angina at 14 days was 16.6% for the enoxaparin patients compared to 19.8% for the heparin patients (p = 0.019). The benefit of enoxaparin was sustained at 30 days, with a similar reduction in the composite endpoint (19.8% versus 23.3%; p = 0.016). Patients who received enoxaparin also experienced a significantly lower rate of revascularization procedures by 30 days (27.1% versus 32.2%; p = 0.001). The lower recurrent ischemic event rate observed in the enoxaparin arm of this study was achieved without an increase in major bleeding, but minor bleeding complications (mainly injection-site ecchymosis) were associated with this LMWH.⁴⁹TIMI-11A and TIMI-11B. The TIMI-11A trial was a phase-II, dose-ranging study to determine the safety and tolerability of enoxaparin in patients with UA and NQWMI.⁸³ TIMI-11B then assessed the benefits of uninterrupted treatment with enoxaparin during the in-hospital and outpatient phases of treatment. The 3,910 patients were randomized to receive intravenous UFH for >= 3 days followed by subcutaneous placebo injections or enoxaparin during both the acute phase (initial intravenous 30 mg bolus followed by injections of 1.0 mg/kg every 12 hours) and outpatient phase (40 mg injections every 12 hours for patients = 65 kg weight). Within 8 days of initiating treatment, the primary composite endpoint of death, MI or need for urgent revascularization occurred in 14.5% of patients treated with UFH compared to 12.4% of those who received enoxaparin (p = 0.048). Within 43 days, the composite endpoint occurred in 19.7% of the UFH/placebo arm and 17.3% of the enoxaparin arm (p = 0.048). No differences in the rate of major hemorrhage were observed between treatment groups during hospitalization, but during the outpatient phase major hemorrhage occurred in 1.5% of the placebo group and 2.9% of the enoxaparin group (p = 0.021).⁴⁸ A prospectively planned meta-analysis of the ESSENCE and TIMI-11B trials revealed a 20% reduction in death and serious cardiac ischemic events that appeared within the first few days of treatment with enoxaparin, and this benefit was sustained through 43 days. Although treatment with enoxaparin was not associated with an increase in major hemorrhage during the acute phase of therapy, it did cause an increase in the rate of minor hemorrhage. The evidence accumulated in these trials suggests that enoxaparin should be considered as an antithrombin to replace UFH in the acute management of patients with high-risk, unstable UA or NQWMI.⁸⁴ Summary Patients with ACS should be risk-stratified based on clinical symptom complex, age, electrocardiographic ST-segment depression, and serum biochemical markers (troponin). Those who are at “high risk” should be triaged to early angiography with definition of the coronary anatomy and revascularization as indicated and feasible. Adjunctive platelet GP IIb/IIIa inhibitor therapy may be initiated “upstream” prior to coronary angiography in this patient population, particularly if symptoms are refractory to conventional therapy or in the context of an elevated serum troponin level. Substitution of enoxaparin for unfractionated heparin should be considered in these patients, based upon the growing body of data demonstrating improved outcomes with this low-molecular-weight heparin. However, its role in the context of invasive management awaits clarification. Clopidogrel may also be used early in these patients, although if this irreversible platelet inhibitor is administered prior to defining coronary anatomy, surgical revascularization may be delayed to allow a 3–5 day wash-out period. However, with the evolving evidence for LMWH and clopidogrel, the therapeutic options and combinations continue to expand, and the optimal pharmacological management across this diverse spectrum of patients will need to be individualized. Acknowledgments. The authors wish to thank Eileen L. Sullivan, PharmD and Gordon Beck, RPh for their assistance in preparing this manuscript.