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.


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

In This Article

Barriers to Guideline Adherence

The factors that are likely to contribute to the underuse of clopidogrel and GP IIb-IIIa inhibitors by physicians of all specialties are unfamiliarity with the guidelines, the relative novelty of these agents, concerns about their benefit:risk ratio, and concerns about their cost.[8] Although aspirin is relatively inexpensive and its benefit:risk ratio is better documented, potential barriers to the appropriate use of aspirin include uncertainties in risk assessment relating to gastrointestinal toxicity and the potential for aspirin resistance. In addition, lower priority may be assigned to aspirin compared with other drugs available for reduction of specific cardiovascular risk factors.[71]

Unfamiliarity with Guidelines

Although there appears to be wide acknowledgment concerning the existence of the ACC-AHA unstable angina−NSTEMI guidelines, some health care providers may not be familiar with the details of the guidelines and/or the levels of evidence contained within the guidelines, or with ACC-AHA performance measures for the treatment of unstable angina and NSTEMI. This educational deficit may contribute to lack of guideline adherence.[8,72] This deficit represents an opportunity for the pharmacist to interact with physicians and other health care providers and provide education concerning guideline-recommended therapies.

Novelty of Therapy

Clinical practice guidelines are developed to help physicians offer evidence-based treatment to their patients. However, in practice the publication of guidelines has only a limited effect on the adoption of evidence-based treatment. A systematic study of barriers to guideline adherence has shown nonadherence to be complex and multilayered.[8] Aspects of physician behavior that contribute to nonadherence include lack of awareness (inability to keep up to date with volume of information, problems with accessibility of guidelines), lack of agreement (differences in interpretation of evidence, belief that benefits are not worth patient risk), lack of outcome expectancy (physician believes that performance of the guideline recommendation will not lead to the desired outcome), and inertia of previous practice (entrenchment of established habits and routines). These factors may be particularly pertinent to novel and relatively recent-to-market agents such as clopidogrel and GP IIb-IIIa inhibitors and should be at least in part addressed by the CRUSADE quality improvement initiative. External barriers that may be related to the guidelines, the patient, or the prescribing environment may also contribute to nonadherence.

Risk of Bleeding

A third reason for the underuse of GP IIb-IIIa inhibitors and clopidogrel in the early interven-tion setting may be related to concern about the potential risk of excess bleeding associated with these drugs. A meta-analysis of randomized trials of GP IIb-IIIa inhibitors in patients with unstable angina or NSTEMI not scheduled to undergo early coronary revascularization established that major bleeding complications were more common in patients treated with GP IIb-IIIa inhibitor therapy than in those who received placebo or control therapy.[53] In this study, treatment with GP IIb-IIIa inhibitors was associated with an increased risk of major bleeding (OR 1.62, 95% CI 1.36−1.94), compared with placebo, although the risk of intracranial hemorrhage was not significantly increased (OR 1.11, 95% CI 0.84−1.45). The benefit of GP IIb-IIIa inhibitor therapy has been established in patients who undergo early intervention, since the benefits outweigh the bleeding risk.[4] The benefit of GP IIb-IIIa inhibitor therapy using abciximab in patients with non−ST-segment-elevation ACS who received pretreatment with a clopidogrel loading dose of 600 mg in addition to aspirin 500 mg appeared to be confined to those with an elevated troponin level at presentation.[58]

Similarly, for optimal clopidogrel use, the emergency physician must balance the need to achieve the benefits of early clopidogrel treatment, as demonstrated in the CURE study[39] and PCI-CURE substudy,[73] against the potential risk of excess bleeding during surgery, if emergency CABG surgery should be required. The ACC-AHA guidelines recommend that clopidogrel be withdrawn at least 5 days before surgery in patients scheduled for elective CABG surgery.[4] However, during the 12 months preceding June 30, 2006, CABG surgery was required in only 12% of patients in the CRUSADE initiative,[30] and it might be expected that unscheduled emergency CABG surgery would be required in a considerably lower proportion of patients. Thus, the perception of the numbers of patients at risk of perioperative bleeding related to clopidogrel may be overstated.

Regarding the discontinuation of other antiplatelet therapies in patients undergoing CABG surgery, the ACC-AHA STEMI guidelines recommend that aspirin should not be withheld before elective or nonelective CABG surgery; timing of CABG surgery should also take into account the fact that platelet function returns toward normal within 4 hours after stopping GP IIb-IIIa inhibitor treatment with tirofiban or eptifibatide and more than 48 hours after stopping abciximab.[74]

Cost of Therapy

The underuse of GP IIb-IIIa inhibitors and clopidogrel may be linked to the perception that these therapies are expensive. Economic evaluation of these agents should go beyond looking at pure acquisition costs and should include overall cost analyses accounting for clinical and mortality benefit.

Most of the economic studies of GP IIb-IIIa inhibitors have indicated that the high acquisition costs of these drugs are offset by cost savings made by the reduction of further complications in high-risk patients and those undergoing PCI, where risk-stratification is used.[75] Analyses of data from the Platelet Glycoprotein IIb-IIIa Inhibitor in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) trial and a U.S. substudy of PURSUIT gave cost-effectiveness ratios of $33,619/life-year gained and $16,491/life-year gained, respectively, for eptifibatide in patients with unstable angina or NSTEMI.[75,76] In patients with ACS who underwent PCI, abciximab had estimated cost-effectiveness ratios of $8750/life-year gained and $4400/life-year gained, respectively, in the Evaluation of c7E3 for the Prevention of Ischemic Complication (EPIC) and Evaluation in PTCA to Improve Long-Term Outcome by c7E3 GP IIb-IIIa Receptor Blockade (EPILOG) studies.[77]

The long-term (12-mo) cost-effectiveness of clopidogrel treatment in conjunction with standard therapy in patients with unstable angina or NSTEMI was established in an analysis of clinical data from the CURE trial, which showed that the probability of clopidogrel remaining cost-effective within an accepted quality-adjusted life-year (QALY) was greater than 80%.[78] The clopidogrel incremental cost-effectiveness ratio (ICER)/QALY gained was shown to be within the $50,000 threshold in the CURE trial.[79] On the basis of the Saskatchewan Health database, the ICER of clopidogrel in the CURE study was $6475/QALY. In high-risk patients in the CURE study, adding clopidogrel to aspirin for 1 year, followed by lifelong aspirin therapy, was cost-effective from a societal perspective compared with lifelong aspirin therapy.[80] This analysis used a Markov model to calculate an ICER of $15,400/QALY for 1 year of clopidogrel plus aspirin versus aspirin monotherapy.

An analysis of data from the Clopidogrel for the Reduction of Events During Observation (CREDO) trial showed that continuing clopidogrel therapy for 1 year was also cost-effective in patients who underwent PCI, compared with discontinuing clopidogrel after 1 month.[81] An ICER of $15,696/life-year gained was calculated for extending clopidogrel treatment to 1 year after PCI. However, broad application of clopidogrel plus aspirin for secondary prevention in all patients with coronary heart disease who are eligible for aspirin therapy is not considered to be cost-effective, with one analysis showing an ICER of more than $130,000 for each QALY gained over a 25-year period.[82]


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