Real-World Safety and Efficacy of Glycoprotein IIb/IIIa Inhibitors
during Percutaneous Coronary Intervention

Percutaneous coronary intervention (PCI) is commonly employed in the management of patients with coronary artery disease (CAD), but the optimal adjunctive pharmacologic strategy for patients undergoing PCI is a frequently debated issue, without an identified consensus of expert opinion.
Anticoagulant and antiplatelet regimens have a significant impact on the benefits, risks, complications and costs of PCI. Appropriate antiplatelet therapy during the periprocedural phase of PCI reduces the incidence of myocardial infarction (MI), urgent target vessel revascularization (TVR) and death.¹ However, such therapy may be associated with an increased risk of bleeding complications, including life-threatening events, such as retroperitoneal or intracranial hemorrhage.² Major bleeding complications may result in increased length of hospital stay, increased cost of hospitalization, and, most importantly, increased mortality.³
A wide variety of anticoagulant and antiplatelet regimens are currently available, creating uncertainty over the ideal adjunctive drug regimen for PCI patients. In extensive clinical investigations, glycoprotein (GP) IIb/IIIa inhibitors, namely abciximab, eptifibatide and tirofiban, have demonstrated the ability to significantly reduce ischemic complications following PCI.^4–8 However, the clinical benefits of these drugs have been offset somewhat by an increased risk of bleeding complications. Although the occurrence of bleeding complications can be minimized by the use of low-dose, weight-based heparin, reduction of the GP IIb/IIIa inhibitor dose in the setting of impaired renal function, and early vascular access sheath removal following PCI,^9–11 there has been disagreement about whether GP IIb/IIIa inhibition during PCI is necessary in various clinical scenarios. It is also unclear which of the three currently available GP IIb/IIIa inhibitors is preferable with regard to efficacy and safety.
Because of the positive results of numerous randomized clinical trials, GP IIb/IIIa antagonists were frequently used (69–94% of PCI cases) during the years 2000 through 2004 in patients undergoing PCI at our institution (LDS Hospital). Institutional guidelines were developed and followed regarding weight-based heparin dosing, adjustment of the dose of GP IIb/IIIa drugs in patients with renal impairment and vascular access sheath management. We hypothesized that with such guidelines, bleeding complications could be significantly lower than those reported by other investigators who have evaluated the real-world outcomes of GP IIb/IIIa inhibitors in PCI.^11,12 Using information obtained prospectively from the dedicated, detailed and extensive computerized catheterization laboratory database at our institution, we performed a retrospective analysis of the safety and efficacy of GP IIb/IIIa inhibition during PCI in a full range of patients who are reflective of those seen in clinical practice.

Methods
Patients undergoing PCI at LDS Hospital during the years 2000 to 2004 were eligible for inclusion in the primary analysis if they had received any single GP IIb/IIIa inhibitor. Of note, patients with significant comorbidities and high-risk predictors of adverse outcomes such as advanced age, renal insufficiency, diabetes mellitus, acute MI and cardiogenic shock were included in our analysis. For comparison purposes in the assessment of safety outcomes, we performed a separate analysis of the outcomes of PCI patients who were treated in the same time frame as this study, but did not receive a GP IIb/IIIa antagonist.
Baseline patient data collection included gender, age and cardiovascular risk factors such as the presence of hypertension (systolic blood pressure 3 140 mmHg, diastolic blood pressure 3 90 mmHg, or antihypertensive medication use), diabetes mellitus (fasting blood glucose level > 125 mg/dL, clinical diagnosis of diabetes mellitus, or antidiabetic medication use), hyperlipidemia (total cholesterol level 3 200 mg/dL, low-density lipoprotein level 3 130 mg/dL, or cholesterol-lowering medication use), cigarette smoking (active smokers or those with a > 10- pack/year history), and family history of premature CAD (firstdegree male relative with CAD at < 55 years of age or first-degree female relative with documented CAD at < 65 years of age). The patient’s clinical presentation was characterized as acute coronary syndrome (ACS) (unstable angina [UA], non-ST-elevation myocardial infarction [NSTEMI], ST-elevation myocardial infarction [STEMI]), or stable CAD. When available from the cardiac catheterization laboratory database at our institution, lesion types were categorized using the ACC/AHA classification system.¹³ Mean and peak activated clotting times (ACT) during PCI were assessed when available. Patients received GP IIb/IIIa inhibitors per product labeling, including recommended dosing adjustments in the presence of impaired renal function.
The primary endpoint of the study was the incidence of thrombolysis in myocardial infarction (TIMI) major bleeding¹⁴ or requirement of blood product transfusion (packed red blood cells or platelets) during the index hospitalization in which PCI was performed. Secondary outcomes included 1-year all-cause mortality and a 1-year composite endpoint of death, MI (as defined by the ICD-9 discharge diagnosis code), and urgent TVR (defined as either urgent percutaneous revascularization or bypass surgery involving a vessel that had been treated during the index procedure). The incidence of TIMI minor bleeding¹⁴ or thrombocytopenia (defined as a GP IIb/IIIa inhibitor-related platelet count < 50,000) during the index hospitalization, necessity for surgical repair of access vessels and descriptive data on the overall prevalence and distribution of GP IIb/IIIa inhibitor use were also analyzed.
Chi-square and analysis of variance (ANOVA) tests were used to describe the study population and to examine univariate associations of categorical and continuous variables among the different GP IIb/IIIa inhibitors. To confirm the associations determined by univariate analysis, multivariate logistic regression analysis (SPSS software, version 13.0, SPSS, Inc., Chicago, Illinois) was performed to determine odds ratios (ORs) corrected for confounding factors. Models entered variables using forward stepwise regression and forced variable entry; final models entered significant and confounding covariables, which included age, gender, hypertension, diabetes mellitus, family history of CAD, cigarette smoking and clinical presentation (stable angina, UA or MI). Two-tailed p-values are presented, with 0.05 designated as nominally significant.

Results

During the study period, 5,055 patients underwent PCI at LDS Hospital. Of these, 4,321 (85%) received a single GP IIb/IIIa inhibitor, 89 (2%) received 2 GP IIb/IIIa inhibitors, and 645 (13%) did not receive a GP IIb/IIIa inhibitor. The average patient age was 64.3 ± 11.8 years; the majority were male (72.2%) and had hypertension (67%) and hyperlipidemia (69.5%). A substantial portion of subjects had a family history of premature CAD (53.5%); diabetes was present in 25% of patients, and a history of smoking in 20% (Table 1). Each GP IIb/IIIa inhibitor was received by approximately one-third of the study population; although differences were noted, there was fair distribution among clinical presentations of stable CAD versus acute coronary syndrome (Table 2). Femoral artery access was utilized in 99.2% (4,288) of the patient population, with 0.8% (33 patients) undergoing brachial or radial artery access. Vascular sheath size varied from 6–9 Fr, with the majority of patients (3,972 [92%]) receiving 7 or 8 Fr sheaths. Vascular access closure techniques included manual compression, collagen vascular closure device with anchor (Angio-Seal^™, St. Jude Medical, Inc., St. Paul, Minnesota), and suture-mediated closure (Perclose^™, Abbott Vascular, Abbott Park, Illinois).

Evaluation of the primary endpoint showed no significant difference in outcomes among the three patient groups, with very low rates of major bleeding complications. TIMI major bleeding rates were 1.9% with eptifibatide, 2.0% with abciximab and 3.1% with tirofiban, with a trend toward a higher incidence in patients receiving tirofiban that did not achieve statistical significance. Similarly, blood product transfusion rates did not vary significantly among groups and were quite low: eptifibatide, 0.8%; tirofiban, 2.0%; abciximab, 2.1% (Figure 1). The incidence of TIMI minor bleeding was also not significantly different among the three treatment groups (abciximab, 9.1%; eptifibatide, 10.8%; tirofiban, 12.5%). Mean ACT (238 ± 116 seconds) did not vary significantly by drug (p = 0.44), although data were available for only 884 of our study patients. Peak ACT level was not associated with major (p = 0.75) or minor (p = 0.17) bleeding by independent t-test assessment. Efficacy analysis revealed that the 1-year mortality and composite endpoint rates were not significantly different among the three treatment groups (Figure 2).
During the study period, 645 patients undergoing PCI did not receive a GP IIb/IIIa antagonist. The clinical presentation of this small subset of patients was more stable than our index population: 125 (19%) with MI, 276 (43%) with UA, and 244 (38%) with stable CAD. Data on lesion types treated were limited, but showed a fairly consistent distribution of lesion types between patients receiving GP IIb/IIIa inhibitor therapy versus those who were not treated (Table 2). The incidence of TIMI major bleeding complications in patients who did not receive a GP IIb/IIIa inhibitor vs those who did was 27/645 (4.2%) versus 102/4,321 (2.4%), respectively (p = 0.007) (Figure 3). The 30-day mortality rate was 1.7% with GP IIb/IIIa inhibitor therapy versus 2.5% without treatment (OR, 0.58; p = 0.06), and the 1-year mortality incidence was 4.2% versus 8.2%, respectively (OR, 0.47; p < 0.0001).

Discussion
Our study represents the largest available data set to date evaluating safety and efficacy outcomes of patients treated with GP IIb/IIIa antagonists during PCI. Remarkably, the incidence of TIMI major bleeding in our patient population was exceedingly low (1.9–3.1%), and transfusion rates were even lower (0.8–2.1%), with no significant differences identified among treatment groups. Furthermore, these findings occurred in a clinical environment of frequent GP IIb/IIIa antagonist use (average, 87% of all PCI procedures) during the study period. Our study evaluated the outcomes of GP IIb/IIIa antagonist use across a broad range of patient types typically seen in clinical practice and provides a valuable assessment of the risk-benefit ratio of these agents in a realworld setting. Our institution is a large tertiary care hospital that frequently treats high-acuity patients, many of whom are transferred from other hospitals. The data presented here do not reflect a single or a small group of physicians but, rather, the aggregate outcomes of 15 interventional cardiologists practicing within a single institution. Therefore, these outcomes may presumably be achieved in other tertiary care cardiac facilities.
We attribute our low bleeding rates to careful attention paid to risk reduction measures that have been proven to lower the incidence of bleeding with use of GP IIb/IIIa antagonists.^9,15,16 Specifically, the use of low-dose weight-based heparin (target ACT, 200–250 seconds) during PCI, dosage adjustment of GP IIb/IIIa antagonists in the setting of renal impairment, discontinuation of intravenous heparin after PCI, and early sheath removal after PCI have helped to reduce the incidence of vascular access site bleeding in our institution. The benefits of this approach have been previously demonstrated in randomized clinical trials that led to the approval of GP IIb/IIIa antagonists.^6,10 Interestingly, we observed a trend toward a higher incidence of major and minor bleeding complications in patients treated with tirofiban. During the time frame of our study, tirofiban was the most commonly used agent in patients transferred to our facility from other institutions. We theorize that the duration of drug infusion in these patients may have been longer, thus accounting for the increased bleeding trend observed in these patients.
Another interesting finding was that bleeding complications occurred more frequently in patients who did not receive a GP IIb/IIIa antagonist than in those who did. This may reflect an intrinsically higher risk of bleeding in the former population, which may have been the rationale for not treating these patients with a glycoprotein IIb/IIIa antagonist initially. Further speculation about the cause of this finding is ill advised given the nonrandomized, observational nature of our study.
Despite extensive evidence supporting the clinical benefit of GP IIb/IIIa inhibition during PCI, these agents are not used widely or consistently, primarily due to concerns about the potential risk of bleeding complications. In early trials of abciximab, major bleeding rates as high as 14% were observed.⁴ Subsequent studies demonstrated that lower-dose, weight-adjusted heparin in conjunction with GP IIb/IIIa antagonist therapy results in a much lower, more acceptable incidence of bleeding complications.^6,10 More recently, data from the Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes With Early Implementation of the American College of Cardiology/American Heart Association Guidelines (CRUSADE) National Quality Improvement Initiative Registry indicate that among non-ST-segment elevation ACS (NSTE ACS) patients, excessive dosing of GP IIb/IIIa inhibitors occurs more frequently in the elderly, women and patients with renal insufficiency, low body weight, diabetes mellitus or congestive heart failure.¹⁷ Excessive dosing of GP IIb/IIIa inhibitors was associated with a significant increase in the risk of bleeding complications. Appropriate dosing of GP IIb/IIIa inhibitors is of paramount importance to optimize outcomes while minimizing bleeding complications.
Use of a pre-PCI loading dose of clopidogrel plus heparin or the direct thrombin inhibitor bivalirudin has been advocated as an alternative to low-dose heparin and a GP IIb/IIIa antagonist. In the Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events (REPLACE)-2¹⁸ and the Intracoronary Stenting and Antithrombotic Regimen-Rapid Early Action for Coronary Treatment (ISAR-REACT)¹⁹ trials, the combination of clopidogrel plus bivalirudin or clopidogrel plus heparin, respectively, demonstrated similar efficacy to GP IIb/IIIa antagonist plus heparin comparators. These studies primarily evaluated patients with stable CAD. However, the recently completed Acute Catheterization and Urgent Intervention Triage strategY (ACUITY)²⁰ and ISAR-REACT-2 studies8 address the same questions in an ACS population. The ACUITY trial demonstrated noninferiority of bivalirudin alone versus bivalirudin plus GP IIb/IIIa or heparin plus GP IIb/IIIa, as well as a reduced incidence of bleeding complications in patients receiving bivalirudin monotherapy. In contrast, the ISAR-REACT-2 trial concluded that the combination of frontloaded clopidogrel, heparin and abciximab was superior to clopidogrel plus heparin without abciximab in ACS patients undergoing PCI.
Optimal adjunctive pharmacotherapy in ACS patients continues to evolve at a rapid pace. The outcomes of recent trials such as ISAR-REACT and ACUITY have resulted in reduced utilization of GP IIb/IIIa inhibitors plus low-dose heparin, in favor of alternative regimens such as clopidogrel plus heparin or clopidogrel plus bivalirudin. In fact, GP IIb/IIIa inhibitor use decreased to 69% of PCI cases in the final year of our study compared with prior utilization rates as high as 94%. However, aspirin and clopidogrel resistance, thrombus-laden culprit coronary lesions, and high-risk ACS clinical scenarios are situations in which GP IIb/IIIa inhibitors will likely continue to be used frequently. Thus, it is encouraging that our study confirms that the appropriate dosing of GP IIb/IIIa antagonists with low-dose heparin is associated with a low incidence of major bleeding complications and necessity for blood product transfusion.
Efficacy outcomes among patients receiving abciximab, eptifibatide, or tirofiban showed no identifiable differences in the 1-year incidence of death or the composite of death, MI, and urgent target vessel revascularization, and the event rates in our study are similar to those observed in clinical trials evaluating the GP IIb/IIIa antagonist class. It is notable that our results are in contrast to the randomized Do Tirofiban and ReoPro Give Similar Efficacy (TARGET) trial, which demonstrated superiority of abciximab compared with tirofiban in PCI.²¹ However, the observational, nonrandomized nature of our study does not permit further conclusions about the comparative efficacy of the three agents in the prevention of adverse clinical events.
Study Limitations. The retrospective design of our study has limitations in that without prospective randomization, relevant patient differences may not be recognized. The high-frequency use of GP IIb/IIIa antagonist therapy in our study also constitutes a limitation, in that a comparable group of untreated patients was not available for evaluation. However, our analysis group comprised a broad range of patients with varying clinical presentations, with approximately two thirds of the study population presenting with ACS; thus, our study population is reflective of patients routinely encountered in clinical practice.

Conclusions
Our study confirms the premise that a broad range of patients undergoing PCI can be safely treated with a GP IIb/IIIa antagonist, with a minimal risk of significant bleeding complications.

References

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