Applied Radiology

Lee MacDonald, MD is a Cardiology Fellow at Northwestern University Medical School, Chicago, IL. He received his MD from the University of Colorado Medical School, Denver, CO, in 1996. He completed his Internal Medicine Residency at Northwestern University Medical School, Chicago, IL, in 1999.

Updated guidelines regarding acute coronary syndromes (ACS) were released recently by the American College of Cardiology/American Heart Association. These guidelines help establish national standards regarding medication and strategies used in coronary care units. These incorporate new trial results that help create significant changes in the use of glycoprotein IIb/IIIa inhibitors, thienopyridines, and an early aggressive approach to ACS.

In 2002, an estimated 1.1 million people will go to hospitals presenting with acute coronary syndromes (ACS). Approximately 650,000 of these will be first presentations and 450,000 will be recurrent attacks. ¹ Recently, the American College of Cardiology (ACC) and the American Heart Association (AHA) released updated guidelines for the management of patients with unstable angina and non­ST-segment elevation myocardial infarction. ² This update reflects the results of multicenter randomized trials that were reported since the previous guidelines were written. ³ The most significant changes were in the recommendations for an aggressive approach to high-risk patients with ACS and the recommended uses of glycoprotein (GP) IIb/IIIa inhibitors and the thienopyridine, clopidogrel. Application of these guidelines should identify patients likely to benefit from these therapies.

Three intravenous glycoprotein IIb/IIIa inhibitors are approved for use in the United States: abciximab, eptifibatide, and tirofiban. Although each of these inhibitors is approved for use in patients with ACS, the data support their use only in certain patient subsets, with different indications for each agent.

Abciximab

The use of abciximab during percutaneous coronary intervention (PCI) was evaluated initially in the Evaluation of Platelet IIb/IIIa Inhibition for Prevention of Ischemic Complications (EPIC) trial. This trial included 2099 patients who underwent balloon angioplasty or directional atherectomy and had a recent or evolving myocardial infarction (MI), unstable angina, or high-risk angiographic or clinical characteristics. At 3 years, the primary endpoints of death, MI, or revascularization were 41.1% in the abciximab-bolus-plus-infusion arm compared with 47.2% in the placebo arm ( P = 0.009). There was no difference in mortality rate (6.8% versus 8.6%, P = NS); however, there was a reduction in patients with subsequent MIs (10.7% versus 13.6%, P = 0.08). ⁴

The Evaluation in PTCA to Improve Long-Term Outcome With Abciximab GP IIb/IIIa Blockade trial was able to broaden the patient population to patients at lower risk, including those who underwent elective or urgent percutaneous coronary revascularization. It showed that the benefits of abciximab were present at 1 year. ^5,6 The Evaluation of Platelet GP IIb/IIIa Inhibitor for Stenting Trial (EPISTENT) showed a reduction in the primary endpoints of 30-day mortality, MI, or severe myocardial ischemia requiring repeat revascularization in the stent-abciximab group compared with the stent-placebo group (5.3% versus 10.8%, P <0.001). Death or large periprocedural MI was also significantly reduced (3.0% versus 7.8%, P <0.001). There was no significant difference in mortality rates. The balloon angioplasty-plus-abciximab group had favorable results compared with stenting alone, which may indicate that this therapy was important if intracoronary stents were placed. ⁷ At 6 months, there was a reduction in death or MI with the combination of stent plus abciximab compared with stent plus placebo (5.6% versus 11.4%, P <0.001). The stent-plus-placebo group again had higher event rates than the balloon angioplasty-plus-abciximab group (11.4% versus 7.8%, P = 0.01). ⁸ The EPISTENT Diabetic Substudy also reported a marked risk reduction in the combination of stent plus abciximab compared with the other groups without one of these therapies. At 1 year, the mortality rates were 4.1% for patients with diabetes in the stent-placebo group versus 1.2% for patients with diabetes in the stent-abciximab group ( P = 0.11). ⁹

The c7E3 Fab Antiplatelet Therapy in Unstable Refractory Angina (CAPTURE) trial enrolled 1265 patients with angina refractory to heparin and nitrates and randomized them to abciximab plus angioplasty versus angioplasty alone. This study excluded patients with evidence of recent MI or patients with symptoms that necessitated immediate intervention. Angioplasty was more successful in the abciximab arm versus the placebo arm (94.0% versus 88.8%, P = 0.001). At 30 days, there were reductions in the rates of death and MI in the abciximab-treated group (4.8% versus 9.0%, P = 0.003). However, 6-month outcomes were similar (9.0% versus 10.9%, P = 0.19). ¹⁰ In patients who were troponin T positive, there was a reduction in death or nonfatal MI at 6 months in the abciximab-treated arm versus placebo (relative risk of 0.32; 95% confidence interval [CI], 0.14 to 0.62; P = 0.002). In patients without elevated troponin T levels, there was no benefit of treatment with abciximab with respect to death or MI. ¹¹

The Global Utilization of Strategies to Open Occluded Coronary Arteries-IV-Acute Coronary Syndromes (GUSTO IV-ACS) trial evaluated abciximab in patients presenting with ACS. ¹² The enrollment criteria for high risk included patients with >5 minutes of chest pain and either ST-segment depression and/or elevated troponin T or troponin I levels. In addition to aspirin and either unfractionated heparin or low-molecular-weight heparin, patients received either a placebo, a bolus and 24-hour infusion of abciximab, or a bolus and 48-hour infusion of abciximab. Revascularization was not pursued aggressively and was actually discouraged during the trial. At 30 days, there were no significant differences among the placebo group versus the 24-hour­abciximab group versus the 48-hour­abciximab group with respect to death and MI (8.0% versus 8.2% versus 9.1%, P = NS). A possible detrimental effect of abciximab was noted with increased early mortality rates. ¹² The reasons for this lack of effect may be explained by variable platelet inhibition at later time intervals during abciximab infusion.

Updated guidelines

Given these findings, the ACC/AHA guidelines now state, with a Class I indication (useful or effective), that a GP IIb/IIIa antagonist (including abciximab) should be administered in addition to aspirin and heparin in patients in whom catheterization and PCI are planned. The GP IIb/IIIa antagonist may also be administered just before PCI. Based on the findings of the GUSTO IV-ACS trial, abciximab administration in patients in whom PCI is not planned is now classified as Class III (not useful or potentially harmful) ^2,12 (Table 1).

Eptifibatide

The small-molecule GP IIb/IIIa inhibitors have also been studied in ACS. Many of these trials have included patients with ACS and patients undergoing elective PCI, which clouds the analysis of their benefit in specific subgroups. The Integrilin to Minimize Platelet Aggregation and Coronary Thrombosis II (IMPACT-II) trial included patients undergoing elective, urgent, or emergent interventions. The varying doses of eptifibatide bolus and infusion did not significantly reduce death or MI rates in the treated groups. ¹³ Using an altered infusion regimen, the Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) trial enrolled 10,948 patients with ischemic chest pain within the previous 24 hours who had either electrocardiographic changes (excluding ST elevation) or increased creatine kinase MB isoenzymes. Then patients were randomized to receive a bolus and 72- to 96-hour infusion of eptifibatide or placebo. In the eptifibatide-treated arm, there was a reduction in the primary endpoints of death or nonfatal MI at 30 days (14.2% versus 15.7%, P = 0.04). ¹⁴ A substudy analysis of the PURSUIT trial showed a greater event reduction (11.6% versus 16.7%, P = 0.01) in the 1228 patients who received PCIs with eptifibatide versus placebo, compared with the 8233 managed conservatively (14.6% versus 15.6%, P = 0.23). ¹⁵ The differences between IMPACT-II and PURSUIT highlight the importance of following studied dosage regimens and lengths of infusions, as subtle differences in these regimens may lead to differing platelet inhibition, and eventually differing event rates. The recent Enhanced Suppression of the Platelet IIb/IIIa Receptor With Integrilin Therapy trial supported eptifibatide use in PCI, but did not assess patients with ACS. ^16,17

Tirofiban

The Randomized Efficacy Study of Tirofiban for Outcomes and Restenosis trial evaluated tirofiban versus placebo and failed to show a significant reduction of the primary endpoints of death, MI, coronary bypass surgery required due to angioplasty failure or recurrent ischemia, need for repeat angioplasty, or stent insertion due to actual or threatened closure at 30 days. An analysis that limited the endpoints to death, MI, urgent or emergent target vessel revascularization, or coronary bypass surgery showed a reduction in the treated group (8.0% versus 10.5%, P = 0.052). ¹⁸

The Platelet Receptor Inhibition in Ischemic Syndrome Management (PRISM) study showed a reduction in the composite endpoints of death, MI, or refractory ischemia at 48 hours when patients presenting with unstable angina were treated with tirofiban compared with placebo (3.8% versus 5.6%, P = 0.01). At 30 days, there was a reduction in the mortality rate (2.3% versus 3.6%, P = 0.02), and a trend toward reduction in death or MI with tirofiban (5.8% versus 7.1%, P = 0.11). ¹⁹ These patients were not routinely referred for coronary angiography or intervention. The Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms (PRISM-PLUS) study assessed patients with ACS and randomized patients to heparin, tirofiban, or tirofiban plus heparin. ²⁰ Coronary angiography and angioplasty were performed, as necessary, after 48 hours of infusion. The study was stopped prematurely due to the excessively high mortality rate in the group that received tirofiban alone. However, when compared with the patients who received heparin alone, the patients who received tirofiban plus heparin had a reduction in the primary endpoint of death, MI, or refractory ischemia within 7 days after randomization (12.9% versus 17.9%, P = 0.004). This early risk reduction persisted at 6 months (27.7% versus 32.1%, P = 0.02). The frequency of death or MI was also reduced at 30 days (8.7% versus 11.9%, P = 0.03) and at 6 months (12.3% versus 15.3%, P = 0.06). However, in the 1069 patients not referred for early PCI, no statistically significant reduction in death, MI, or refractory ischemia was noted. ²⁰

The Thrombolysis in Myocardial Infarction (TIMI) risk score was defined recently to help risk stratify patients presenting with ACS and identify subsets that may derive benefit from various therapies. ²¹ This score incorporates 7 variables and assigns a score of 0 or 1 to each one: age >65 years, at least 3 risk factors for coronary artery disease, prior coronary stenosis of >= 50%, ST-segment deviation on electrocardiogram at presentation, more than 2 anginal events in the previous 24 hours, use of aspirin in the previous 7 days, and elevated serum cardiac markers. This summed score has been validated to help risk stratify patients with ACS. ^22,23 In a subset analysis of PRISM-PLUS, patients with elevated TIMI risk scores (sum >= 4) derived benefit from tirofiban with or without PCI. Patients with low TIMI risk scores (sum <4) did not derive benefit with tirofiban treatment. ²⁴ Another subset analysis of the PRISM-PLUS trial in patients with diabetes mellitus showed significant benefit from tirofiban treatment. ²⁵

Updated guidelines

The PURSUIT and PRISM-PLUS trials helped establish Class I indications for the small molecule GP IIb/IIIa antagonists, tirofiban and eptifibatide, in ACS for patients in whom catheterization and PCI are planned. Tirofiban and eptifibatide use in patients with continuing ischemia, an elevated troponin level, or other high-risk features in whom an invasive strategy is not planned has been downgraded to a Class IIa indication (conflicting evidence with weight of evidence in favor of usefulness or efficacy). Furthermore, in patients in whom a catheterization and PCI are planned and are already receiving aspirin, heparin, and clopidogrel, the use of a GP IIb/IIIa inhibitor is also a Class IIa indication. Finally, eptifibatide or tirofiban use in low-risk patients without continuing ischemia or other high-risk features and for whom no PCI is planned is a Class IIb indication (conflicting evidence with weight of evidence less well established) ² (Table 1).

In combining all major trials of GP IIb/IIIa inhibitors with ACS, death or MI occurred in 1252 of 10,508 patients (11.9%) treated with placebo compared with 1362 of 13,028 patients (10.5%) treated with a GP IIb/IIIa antagonist, for a relative risk reduction of 0.88 (95% CI, 0.82 to 0.94; P <0.001) ² (Figure 1). Including all patients who have had PCI with GP IIb/IIIa inhibitors, there was a risk reduction of 0.83 (95% CI, 0.78 to 0.88; P <0.001) ² (Figure 2). A meta-analysis of all patients with diabetes in the PURSUIT, PRISM, PRISM-PLUS, GUSTO IV-ACS, Platelet IIb/IIa Antagonism for the Reduction of Acute Coronary Syndrome Events in a Global Organization Network (PARAGON), and PARAGON B trials showed a significant reduction in mortality rates in patients treated with GP IIb/IIIa antagonists at 30 days (4.6% versus 6.2%, P = 0.007). This improved mortality rate was magnified in patients with diabetes undergoing PCI (1.2% versus 4.0%, P = 0.002). ²⁶

Early invasive approach

Although not specifically an evaluation of GP IIb/IIIa inhibitor use, the Treat Angina With Aggrastat and Determine Cost of Therapy With an Invasive or Conservative Strategy study (TACTICS ­ TIMI 18) did show reductions in death, MI, or rehospitalization rates at 6 months when an early invasive approach was taken compared with an early conservative approach (15.9% versus 19.4%, P = 0.025). ²³ A subset analysis again defined several recurring high-risk characteristics that suggest benefit from an early aggressive approach. Patients with dynamic ST changes or with diabetes mellitus derived significant benefit from this approach. In addition, in the 54% of patients with positive troponin T markers, there was a reduction in the composite endpoints of death, MI, and rehospitalization at 6 months (14.3% versus 24.2%, P <0.001). The subset with negative cardiac markers had similar 6-month event rates when either approach was used (14.5% versus 16.9%, P = NS). Again, it is important to note that this trial did not evaluate the use of GP IIb/IIIa inhibitor use during ACS, but rather helped establish evidence to support an early aggressive management approach including tirofiban use in these patients. ²³

Subsequent analysis of three critical trials with ACS, CAPTURE, ¹⁰ PRISM-PLUS, ²⁰ and PURSUIT, ¹⁴ identified a significant reduction in precardiac catheterization myocardial reinfarction rates with each agent (Table 2). These myocardial reinfarctions that occurred in patients admitted with ACS before PCI are critical determinants of prognosis. In the PURSUIT trial alone, the mortality rate was 15.2% in those who had precardiac catheterization myocardial reinfarctions, compared with 3.5% in those who did not. This represents a 77% relative risk reduction in mortality rate, P = 0.0127 (Figure 3).

Updated guidelines

The updated guidelines expand the list of patients with Class I recommendations for an early invasive approach ² (Table 3).

Clopidogrel

The recent Clopidogrel in Unstable Angina to Prevent Recurrent Ischemic Events (CURE) trial assessed patients with unstable angina or non-ST elevation MIs. Patients were randomized to clopidogrel or placebo, with no routine plans for early PCI. There was a reduction in the primary endpoints of cardiovascular death, MI, or stroke in the patients treated with clopidogrel (9.3% versus 11.5%, P <0.001). There was an increased risk of major bleeding with clopidogrel versus placebo (3.7% versus 2.7%, P = 0.001). There was no significant increase in bleeding episodes after coronary artery bypass grafting (CABG); however, the medication was discontinued for 5 days before surgery in most patients. Only a small number of the patients received GP IIb/IIIa inhibitors in addition to clopidogrel. ²⁸

The Percutaneous Coronary Intervention--Clopidogrel in Unstable Angina to Prevent Recurrent Ischemic Events (PCI-CURE) trial assessed the 2658 patients in the CURE trial who underwent PCI. Patients underwent PCI after a pretreatment period with placebo or clopidogrel. Patients then received a 4-week, open-label treatment with clopidogrel or ticlopidine after PCI. The medication or placebo was then continued for an additional mean of 8 months. Patients treated with clopidogrel compared with those who received placebo had a reduction in the primary endpoints of death, MI, or urgent target vessel revascularization at 30 days (4.5% versus 6.4%, P = 0.03). Cardiovascular deaths or MIs that occurred from PCI until the end of the follow-up period were reduced with clopidogrel (6.0% versus 8.0%, P = 0.047). Cardiovascular deaths or MIs were also reduced overall during the entire treatment period (both before and after PCI) (8.8% versus 12.6%, P = 0.002). ²⁹

Updated guidelines

Class I indications for clopidogrel therapy have expanded from those who have contraindications to aspirin, to include those in whom an early noninvasive approach or PCI is planned, excluding those at high risk for bleeding. The length of therapy should be at least 1 month and perhaps up to 9 months for all patients. In patients referred for elective CABG, clopidogrel should be withheld for 5 to 7 days before surgery. Treatment with a loading dose of 300 mg to 600 mg is also acceptable in patients who undergo diagnostic catheterization immediately followed by PCI. ²

ST elevation MIs and GP IIb/IIIa antagonists

As an adjunct to ST elevation MIs, only abciximab has been studied. The ReoPro and Primary PTCA Organization and Randomized Trial (RAPPORT) assessed 483 patients with acute MIs and showed no difference in the primary endpoints of death, nonfatal MI, or target vessel revascularization at 6 months (28.2% versus 28.1%, P = NS). ³⁰ Death, nonfatal MI, or urgent target vessel revascularization were significantly reduced with abciximab use at both 30 days and 6 months. More recently, stent use and abciximab use has been evaluated in the Abciximab Before Direct Angioplasty and Stent in Myocardial Infarction Regarding Acute and Long-Term Follow-Up (ADMIRAL) trial and the Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications (CADILLAC) trial. ^31,32

In the ADMIRAL trial, the use of stents and abciximab reduced event rates compared with the use of stents alone at 30 days (7.4% versus 14.6%, P = 0.04). Additionally, there was an improvement in TIMI-3 flow rates at the end of the procedure in patients treated with stents and abciximab compared with those treated with stents alone (95.1% versus 86.7%, P = 0.03). ³¹ Contradicting this evidence are the CADILLAC trial results that used a 2-by-2 factorial design to test stents versus balloons and abciximab versus placebo in combination in patients presenting with acute MIs. At 6 months and 1 year, the primary endpoints of death, reinfarction, disabling stroke, and ischemia-driven revascularization of the target vessel were reduced in both stent groups compared with those without stents. No statistically significant additional incremental benefit was noted with the use of abciximab if stents were used. However, in those receiving balloon angioplasty, there was a significant benefit with abciximab compared with placebo. ^32,33

Conclusion

A uniform policy of GP IIb/IIIa use for all patients presenting with ACS cannot be advocated at this time. Clearly there are differential pharmacologic effects for small molecules and monoclonal antibodies, which may explain the differing clinical trial results. Proper risk stratification is essential before electing to use a GP IIb/IIIa inhibitor. Important subsets of patients with ACS have been identified that derive particular benefit from GP IIb/IIIa inhibitors including high-risk patients with dynamic ST changes, elevated troponin markers, elevated TIMI risk scores, and patients with diabetes mellitus. Those receiving an aggressive approach with early PCIs are more likely to derive benefit. In combination with GP IIb/IIIa inhibitors, patients at high risk benefit from an early interventional approach. In patients who present with ACS, clopidogrel therapy for 1 to 9 months is beneficial regardless of whether a PCI is performed or an early conservative approach is used. The updated ACC/AHA guidelines on ACS incorporate the important recent trial results on GP IIb/IIIa inhibitors, clopidogrel, and an early invasive strategy. In ST elevation MIs, GP IIb/IIIa inhibitors are of unclear significance when used in combination with stents.