Antiplatelet Therapy in Patients with Unstable Angina and Non-ST-Segment-Elevation Myocardial Infarction: Findings from the CRUSADE National Quality Improvement Initiative

Michael B. Bottorff, Pharm.D.; Edith A. Nutescu, Pharm.D.; Sarah Spinler, Pharm.D.

Disclosures

Pharmacotherapy. 2007;27(8):1145-1152. 

In This Article

Findings From the CRUSADE Initiative: Underuse of Antiplatelet Agents

Analysis of the CRUSADE data provides a profile of early intervention and discharge evidence-based drug use that clearly illustrates underutilization of guideline-recommended antiplatelet therapies (Figure 1).[30,41] Although almost all patients without contraindications are treated with aspirin within the first 24 hours of presentation, the proportion of eligible patients who receive GP IIb-IIIa inhibitors and clopidogrel is much lower (45% and 60%, respectively). This is despite the guideline recommendations that GP IIb-IIIa inhibitors should be used as early treatment with aspirin in high-risk patients in whom early intervention is planned, and that clopidogrel should be used with aspirin in all patients other than those in whom emergency coronary artery bypass graft (CABG) surgery is indicated. Almost all patients are discharged receiving aspirin therapy, but only three quarters of patients are discharged receiving clopidogrel, despite the ACC-AHA guideline recommendation that clopidogrel plus aspirin be used in all patients with unstable angina or NSTEMI at discharge for up to 9 months. This provides the pharmacist with an opportunity to enhance the translation of evidence-based guidelines to direct patient care.

Figure 1.

Early and discharge antiplatelet therapy use in distinct populations of patients with unstable angina or NSTEMI has been evaluated in several analyses of the CRUSADE data ( Table 3 ).[30,42–49] Specifically, the factors that are likely to reduce the chances of receiving any antiplatelet drug in either the early intervention or discharge setting are age older than 75 years, being female, presence of renal insufficiency, or presence of heart failure.[30,42,45,46] The proportions of patients with unstable angina or NSTEMI experiencing cardiogenic shock who receive antiplatelet therapies are also low.[48] Racial factors may influence prescribing practices that result in disparities in care; African-Americans are less likely to be treated with clopidogrel and/or GP IIb-IIIa inhibitors.[49] Similarly, patients of Hispanic origin are less likely to receive antiplatelet agents than those of non-Hispanic origin.[44] The insurance status of patients also significantly affects whether or not antiplatelet therapy is administered.[43] Reasons for the lower antiplatelet utilization in these patient groups are likely to be complex and multifactorial. Possible factors include disparities in the type of hospital in which these patient groups tend to receive treatment, underrepresentation of certain patient groups (e.g., elderly patients, African-American patients) in clinical trials, lack of knowledge on the part of the treating physician regarding the utility and safety of newer antiplatelet therapies in high-risk subgroups, and physician attitudes and commu-nication with patients in minority groups.

Clopidogrel

Analysis of the CRUSADE data indicates that the patients who are overlooked with respect to clopidogrel prescription at discharge are those who do not undergo PCI during hospitalization.[50] A total of 61,052 patients admitted to 461 hospitals participating in the CRUSADE initiative between January 2002 and December 2003 were grouped by in-hospital management strategies, and 73.6% of patients proceeded to catheterization. Of the patients who underwent catheterization, 7.6% who received clopidogrel at discharge and 21.4% of those who were not prescribed clopidogrel had a diagnosis of insignificant CAD; 41.6% were referred for PCI and 13.8% were referred for CABG surgery. Of the patients who were treated with PCI, almost all (≥ 90%) received clopidogrel at discharge between the first quarter of 2002 and fourth quarter of 2003 (Figure 2).[50] However, less than 50% of eligible patients in the non-PCI groups were prescribed clopidogrel at discharge; this was lowest among patients who underwent CABG surgery, with only 23.5% of this subgroup being prescribed clopidogrel at discharge in the latter half of 2003 (Figure 2). Thus, most patients with unstable angina or NSTEMI who are treated medically or with CABG surgery do not receive clopidogrel as recommended in the ACC-AHA guidelines.

Figure 2.

These findings are consistent with another study of CRUSADE data collected between March 2000 and September 2002 (17,926 patients), which also determined that early invasive care is associated with increased use of antiplatelet therapies.[41] Patients were more likely to be prescribed aspirin (93.8% vs 87.7%, p<0.001), clopidogrel (51.3% vs 26.1%, p<0.001), and GP IIb-IIIa inhibitors (50.9% vs 14.2%, p<0.001) within 24 hours of admission when an early invasive strategy rather than medical manage-ment was planned. A similar profile of antiplatelet therapy was apparent at discharge: of those patients offered early invasive care, 92.6% and 63.4% were discharged receiving aspirin and clopidogrel, respectively, compared with 85.2% and 38.9% of those who were medically managed (p<0.001 for both comparisons of early invasive care vs medical management).

A third CRUSADE analysis that evaluated discharge care for 33,316 patients who underwent PCI or CABG surgery demonstrated that discharge care for patients undergoing PCI is more aggressive and consistent with guideline recommendations than for those receiving CABG.[51] Of interest, patients undergoing PCI were more commonly in the care of a cardiologist than were patients undergoing CABG surgery (74.3% vs 65.9%), again illustrating the lack of use of a risk-based clinical strategy to inform early treatment decisions.

Compared with aspirin alone, treatment with clopidogrel plus aspirin, starting within 24 hours of symptom onset, has been shown to provide comparable benefits with respect to both in-hospital and 9-month outcomes for patients with non−ST-segment-elevation ACS managed either medically or by interventional means, as demonstrated in the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial.[39] In the CURE study, clopidogrel, compared with placebo, was associated with a significant reduction in the risk of death from cardiovascular causes, nonfatal myocardial infarction, or stroke (relative risk [RR] 0.80, 95% CI 0.72−0.90).[52] Overall, 16.5% of patients in the CURE study underwent CABG surgery and 21.2% underwent PCI, whereas the remainder of patients were treated medically and did not undergo revascularization. Although the study was not specifically powered to detect a treatment difference among the subgroup of patients who proceeded to CABG surgery, the benefit of clopidogrel on reducing the risk of death from cardiovascular causes, nonfatal myocardial infarction, or stroke in these patients (RR 0.89, 95% CI 0.71−1.11) was consistent with the treatment effect observed in the study population as a whole and in the subgroups of patients who underwent PCI (RR 0.72, 95% CI 0.57−0.90) or medical therapy (RR 0.80, 95% CI 0.69−0.92).

Glycoprotein IIb-IIIa Inhibitors

Glycoprotein IIb-IIIa inhibitors have been shown to reduce the risk of death and myocardial infarction in patients with ACS, including those who are not scheduled for early revascular-ization, and their use is recommended by the ACC-AHA guidelines.[4,53,54] However, there is evidence to indicate that early (< 24 hrs after presentation) GP IIb-IIIa inhibitor therapy is underutilized in patients with ACS.[4,47,53,54] In an analysis of registry data from 60,770 patients with non−ST-segment-elevation ACS who were treated at 1189 hospitals in the United States between July 2000 and July 2001, only 25% of those eligible for early GP IIb-IIIa inhibitor therapy were given such treatment.[54] Another analysis of the early use of GP IIb-IIIa inhibitors in 65,424 patients with non−ST-segment-elevation ACS from 443 hospitals between January 2001 and June 2003 revealed that only 35% of eligible patients received GP IIb-IIIa inhibitors within 24 hours after hospital admission.[47] This study showed that in practice GP IIb-IIIa inhibitors are underused in patients at high risk because of older age, being female, or having preexisting heart failure. The most significant factor associated with early GP IIb-IIIa inhibitor use was admission to the care of a cardiologist, suggesting a lack of risk-based clinical decision making in the emergency department.

Although routine initial treatment with GP IIb-IIIa inhibitors with the assumption that PCI will follow shortly is advocated by the guidelines, the optimal time for starting therapy is unclear. Early administration of GP IIb-IIIa inhibitors in patients with non−ST-segment-elevation ACS may be associated with reduced myocardial damage compared with administration just before PCI,[55] although conflicting results have been reported[56] and the optimal timing of GP IIb-IIIa inhibition in patients with non−ST-segment-elevation ACS who are to undergo a planned PCI remains under investigation.[57] In the above-mentioned study reported in 2005,[47] approximately one third of the CRUSADE patients who received GP IIb-IIIa inhibitors received them in the emergency department, another one third in the coronary care unit, and the remaining one third in the catheterization laboratory. Seventy-five percent of emergency physicians surveyed in CRUSADE deferred the decision to administer a GP IIb-IIIa inhibitor until the time of consultation with a cardiologist. Hesitation about initiation of GP IIb-IIIa inhibitor therapy also appeared to influence the use of other ACC-AHA guideline-recommended therapies, and patients who did not receive early GP IIb-IIIa inhibitor therapy were less likely to receive other antiplatelet agents ( Table 3 ).

Most of the clinical trials with GP IIb-IIIa inhibitors preceded the availability of clopidogrel. Part of the reluctance to use GP IIb-IIIa inhibitors may be the result of uncertainty over their relative benefit in patients who are also eligible to receive clopidogrel. Results from the Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment Trial (ISAR-REACT)-2 indicated that abciximab reduces the risk of death, myocardial infarction, or urgent target-vessel revascularization in patients with non−ST-segment-elevation ACS who are to undergo PCI with pretreatment with clopidogrel 600 mg.[58] The benefits were confined to patients with an elevated troponin level, a high-risk feature for death or myocardial infarction.

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