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Journal of Clinical Pharmacology, 2004; 44:1328-1332
© 2004 the American College of Clinical Pharmacology

ADVERSE EFFECTS

Glycoprotein IIb/IIIa Receptor Antagonists and Risk of Bleeding: A Single-Center Experience in 1020 Patients

Arshad Ali, MBBS, MRCP (UK), FACC, Mustafa Hashem, MD, Howard S. Rosman, MD, FACC, Lynette Moser, PharmD, Arshad Rehan, MD, Thomas Davis, MD, Michael Romanelli, MD, Thomas LaLonde, MD, Hiroshi Yamasaki, MD, FACC, Brian Barbish, MD, FACC, Julia Michael, BS, Shamsa A. Ali, MD, Theodore L. Schreiber, MD, FACC and Julius M. Gardin, MD, FACC

From St. John Hospital & Medical Center, Detroit, Michigan.

Address for reprints: Arshad Ali, Director Interventional Cardiology, Guthrie Clinic, One Guthrie Square, Sayre, PA 18840.


   ABSTRACT
TOP
 ABSTRACT
METHODS
 STATISTICAL ANALYSIS
 RESULTS
 DISCUSSION
 LIMITATIONS
 CONCLUSIONS
 REFERENCES
 
The safety of glycoprotein (GP) IIb/IIIa inhibitors has been well documented in clinical trials. Although these trials have included a broad patient population, the strict enrollment criteria may have resulted in exclusion of patients at a higher risk of bleeding complications. The authors conducted a retrospective chart review of 1020 consecutive patients who received GP IIb/IIIa inhibitors and underwent percutaneous coronary intervention in a large community hospital. They used Thrombolysis in Myocardial Infarction (TIMI) criteria to define major or minor bleeding complications. Bleeding complications developed in 214 (21%) patients, with major bleeding in 89 (9%). Univariate predictors of bleeding were older age, lower body weight, elevated serum creatinine, higher activated partial thromboplastin time (aPTT) level, history of diabetes mellitus (DM), peripheral vascular disease (PVD), congestive heart failure (CHF), and emergency procedure for acute myocardial infarction (AMI). Multivariate predictors of major bleeding were PVD (20% in bleeding group vs 11% in nonbleeders, odds ratio [OR] = 1.8, 95% confidence interval [CI] = 1.2-2.6, P < .004), age (68 ± 2 years, 95% CI = 66-70 in bleeding group vs 63 ± 13 years, 95% CI = 61.2-63 in nonbleeders, P < .001), and higher aPTT level (66 ± 27 seconds, 95% CI = 63-70 in bleeding group vs 53 ± 28 seconds, 95% CI = 51-56 in nonbleeders, P < .001). The risk of bleeding in the large community hospital setting may be higher than in randomized clinical trials. This increased risk is associated with higher hospitalization costs. Recognition of predictors of bleeding should further enhance the safety of these antiplatelet agents.

Key Words: Abciximab • eptifibatide • tirofiban • percutaneous coronary intervention (PCI)

Growing evidence of the pivotal role of platelets in the pathogenesis of abrupt vessel closure and acute ischemic complications after percutaneous transluminal coronary revascularization has led to the development of agents for more effective prophylaxis for these complications. The platelet glycoprotein (GP) IIb/IIIa receptor inhibitors, which block the final pathway of platelet aggregation, have occupied the central stage among such agents. The Food and Drug Administration (FDA) has approved 3 GP IIb/IIIa inhibitors for clinical use. The safety and efficacy of these agents have been documented by a series of randomized clinical trials.1-5 Although these trials have included a broad patient population, they are characterized by strict inclusion and exclusion criteria. These criteria may have resulted in the exclusion of patients at a particularly higher risk of bleeding complications. Accordingly, the purpose of our uncontrolled, retrospective study was to define the frequency of hemorrhagic complications and identify clinical variables associated with a high risk of bleeding complications among patients undergoing percutaneous coronary intervention (PCI) at a community hospital.


   METHODS
TOP
 ABSTRACT
 METHODS
STATISTICAL ANALYSIS
 RESULTS
 DISCUSSION
 LIMITATIONS
 CONCLUSIONS
 REFERENCES
 
This study was conducted using a retrospective chart review. Clinical records of 1100 consecutive patients, who received GP IIb/IIIa inhibitors and underwent PCI between August 1997 and December 1999, were reviewed. Data were collected for the type of GP IIb/IIIa antagonist used, indication for the procedure, demographic and clinical variables, timing of arterial sheath removal following PCI, concomitant use of other antiplatelet antithrombotic and fibrinolytic agents, and incidence of bleeding complications. Hospital billing records were collected to estimate cost of hospitalization for each patient. Patients undergoing coronary artery bypass grafting (CABG) during the same hospitalization were excluded (n = 53), as were the patients who did not receive ticlopidine or clopidogrel (n = 24) or aspirin (n = 3). The study population consisted of 1020 patients.

Bleeding complications were categorized as major or minor according to the Thrombolysis in Myocardial Infarction (TIMI) study group criteria.6 Specifically, a major bleeding complication was defined as intracranial hemorrhage, recorded as a new neurological deficit with computerized axial tomographic or magnetic resonance imaging evidence of blood density; a decrease in hemoglobin of >5 g/dL from baseline; or bleeding associated with any hemodynamic compromise.

A minor bleeding complication was defined as (1) spontaneous and observed hematuria or hematemesis, (2) observed blood loss associated with a decrease in hemoglobin of >3 g/dL, or (3) a decrease in hemoglobin of ≥4 g/dL in the absence of clinical bleeding.


   STATISTICAL ANALYSIS
TOP
 ABSTRACT
 METHODS
 STATISTICAL ANALYSIS
RESULTS
 DISCUSSION
 LIMITATIONS
 CONCLUSIONS
 REFERENCES
 
Data were analyzed using SPSS Version 10.0 statistical software (SPSS Inc, Chicago). Categorical variables were compared by the chi-square test. Continuous variables were compared using the Student t test. Discriminant analysis was used for multivariate analysis. Hospital lengths of stay and gross cost were calculated for each patient and compared between patients who did and did not develop a bleeding complication. All statistical tests were 2-sided. A P value < .05 was considered significant.


   RESULTS
TOP
 ABSTRACT
 METHODS
 STATISTICAL ANALYSIS
 RESULTS
DISCUSSION
 LIMITATIONS
 CONCLUSIONS
 REFERENCES
 
Patient demographics, cardiovascular risk factors, and indications for PCI are shown in Table I. Abciximab was used in 39% of the patients, at a dosage of 0.25 mg/kg bolus followed by a 10-µg/min infusion, for a mean duration of 12 hours (range, 1-16 hours). Eptifibatide was used in 40% of the patients, at a dosage of 180 µg/kg bolus, followed by a 2-µg/kg/min infusion for 18 hours (range, 1-36 hours). Tirofiban was used in 21% of the patients at a dosage of 0.4 µg/kg/min for 30 minutes, followed by a 0.1-µg/kg/min infusion for 20 hours (range, 1-30 hours). All patients received heparin boluses during PCI, as determined by individual operators. Postprocedure heparin use was at the operator's discretion and was used in 95% of patients who received eptifibatide or tirofiban and in 65% of the patients who received abciximab. Low molecular weight heparin was not used in any patient. Preprocedure aspirin was used in 100% of patients. Ticlopidine and clopidogrel were used in 12% and 88% of patients, respectively. Procedural success was achieved in 98% of cases. Access site sheaths were removed as soon as the activated clotting time (ACT) dropped under 180 seconds after discontinuation of heparin. In the abciximab group, the mean time to sheath removal postprocedure was 15 hours (range, 2-21 hours); in the eptifibatide group, the mean was 17 hours (range, 1-40 hours); and in the tirofiban group, the mean was 16 hours (range, 1-36 hours).


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  		Table I Patient Demographic Characteristics, Cardiovascular Risk Factors, and Indications for Percutaneous Coronary Intervention

 

Bleeding complications developed in 214 (21%) patients, with major bleeding in 89 (9%). All-cause mortality during the index hospitalization was 3.2% (33 points). There were 9 (0.9%) deaths attributable to bleeding complications: 4 in the abciximab group, 4 in the eptifibatide group, and 1 in the tirofiban group. Bleeding type and number of bleeding-related deaths are shown in Table II. Groin hematoma was the most common (18%), with all other types being 1% or less. The cine-angiograms of the 3 patients with pericardial tamponade were reviewed retrospectively, and there was no evidence of coronary perforation. None of these 3 patients had right heart catheterization prior to development of tamponade. One patient had presented with transmural myocardial infarction, but there was no echocardiographic evidence of myocardial rupture.


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  		Table II Mortality and Types of Bleeding

 

Tables III, IV, and V show univariate and multivariate predictors of bleeding complications, respectively. Univariate predictors of bleeding complications were older age; lower body weight; elevated baseline creatinine; higher activated partial thromboplastin time (aPTT); history of diabetes mellitus (DM), congestive heart failure (CHF), and PVD; and acute myocardial infarction as mode of presentation. On multivariate analysis, the only predictors of bleeding were age, history of PVD, and higher aPTT.


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  		Table III Clinical Variables and Major Bleeding

 

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  		Table IV Predictors of Bleeding (Multivariate Analysis)

 

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  		Table V Predictors of Bleeding (Multivariate Analysis)

 

Overall, bleeding complications were significantly higher in the abciximab and tirofiban groups versus the eptifibatide group (Table VI). There was also a significantly higher incidence of major bleeding complications in patients who received abciximab and tirofiban than those who received eptifibatide (Table VI).


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  		Table VI Differences Among 3 Glycoprotein (GP) IIb/IIIa Inhibitors in Incidence of Total Bleeding

 

Length of stay was 8 days in patients who developed bleeding complications versus 4 days in patients without bleeding (P < .0001). The cost of hospitalization was 50% higher in patients with bleeding complications ($52,994 ± $41,072 vs $29,758 ± $20,491, P < .0001).


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 STATISTICAL ANALYSIS
 RESULTS
 DISCUSSION
LIMITATIONS
 CONCLUSIONS
 REFERENCES
 
There is no doubt that platelet GP IIb/IIIa inhibitors are a powerful addition to the therapeutic armamentarium. However, the use of these powerful therapeutic agents is not free of risk. Defining the bleeding risk in the general patient population is clinically important because the usefulness of newer antiplatelet agents ultimately depends on the demonstration of clinical benefit that outweighs any significant increase in risk.

In our study, the overall incidence of bleeding was higher than in published randomized trials. However, most hemorrhagic events were transient and clinically well tolerated. The vascular access site was the most common source of bleeding events overall, accounting for 87.6% of patients with bleeding complications. Access site sheath removal was delayed in the majority of our patients. In EPIC, sheaths were removed 6 hours after abciximab infusion ended—usually 16 hours after the intervention—resulting in higher access site bleeding complications.1 In EPILOG, sheaths were removed much earlier, usually 4 to 6 hours after intervention, with a resultant decrease in access site bleeding complications.4 Spontaneous major organ bleeding was uncommon (31 patients, 3% of total study group). Spontaneous hematemesis, gross hematuria, and spontaneous pulmonary hemorrhage accounted for the majority of spontaneous major organ hemorrhagic events (2.2% for the 3 complications; Table II). Spontaneous pulmonary hemorrhage is a rare but potentially devastating complication that may be associated with high mortality.7,8

Older age, acute myocardial infarction, and lower body weight were independently associated with an increased risk of total and major bleeding in the EPIC trial.9 All these clinical variables were predictors of increased bleeding risk in our group on univariate analysis. However, on multivariate analysis, lower body weight and mode of presentation did not achieve statistical significance. The importance of older age and lower body weight as predictors of increased bleeding risk has been well described. Aguirre et al,9 usingaregression model, predicted a 6% probability of a major bleeding event with c7E3 Fab therapy in a 50-year-old patient weighing 90 kg. In contrast, a 70-year-old patient weighing 70 kg was predicted to have an 18% chance of major bleeding with c7E3 Fab.

In the EPIC trial, the rate of non-CABG-related major bleeding complications was 10.6% in the bolus-plus-infusion group,9 which is very similar to our group of patients (11%) who received abciximab. In our patients, heparin use was at the discretion of the individual operator, with 65% of patients receiving heparin infusion after PCI. Similarly, the incidence of major bleeding in the eptifibatide group, which also received postprocedural heparin, was 6%. This compares favorably with a 10.6% incidence of major bleeding with eptifibatide in the PURSUIT trial.3 The incidence of major bleeding of 10.3% in our patients who received tirofiban, along with the liberal use of heparin, is much higher than the 4% incidence of major bleeding in the PRISM-PLUS trial with tirofiban. In PRISM-PLUS, the heparin regimen was mandated, with specified monitoring guidelines, resulting in less liberal use of heparin.5

Postprocedure, heparin was used in a significant proportion of our patients—in 95% of patients who received tirofiban or eptifibatide and 65% of those who received abciximab. This compares to no postprocedure heparin use in the EPILOG and ESPIRIT trials. Heparin was used in 90% of patients who received eptifibatide in the PURSUIT trial. In the PRISM-PLUS trial, investigators were required to use heparin and tirofiban for 48 hours before performing coronary angiography, and postprocedure heparin was discontinued at least 2 hours prior to sheath removal.4,5,10,11 Although the timing of sheath removal in our patients was not regulated, the use of postprocedure heparin in a significant majority contributed to delayed sheath removal, which probably was a contributing factor in the development of access site bleeding complications. Not surprisingly, in our study, a higher aPTT was predictive of bleeding risk. Use of weight-adjusted heparin and avoidance of postprocedural heparin were associated with a lower risk of bleeding with abciximab in the EPILOG trial, without any loss of clinical efficacy.4 Despite this, postprocedure heparin was still used in a significant number of our patients who received abciximab. Previous studies have shown disappointing adherence to the results of well-published randomized studies and therapies recommended in published guidelines.12,13 In the PURSUIT trial, the benefit of eptifibatide was only evident in the group that received concomitant heparin.10 Dosing of eptifibatide in our patients was based on the PURSUIT trial, with the liberal use of heparin. Nonetheless, the risk of major bleeding with eptifibatide in our patient population was lower than in the PURSUIT trial. In the ESPRIT trial, a double-bolus regimen of eptifibatide was used along with a lower heparin dosage, with a significant decrease in bleeding complications.11

Recently, bivalirudin has shown a lower bleeding risk when compared with unfractionated heparin, a benefit that was offset by concomitant use of GP IIb/IIIa inhibitors.14 Despite these encouraging results, more studies are needed to further define the role of bivalirudin alone, as compared to heparin and GP IIb/IIIa inhibitors in this patient population. A meta-analysis of 19 randomized trials of intravenous GP IIb/IIIa inhibitors showed a significant and sustained mortality benefit with these agents. Again, the risk of excess major bleeding was associated with postprocedural heparin use. More important, major bleeding did not offset the overall survival benefit in this meta-analysis.15


   LIMITATIONS
TOP
 ABSTRACT
 METHODS
 STATISTICAL ANALYSIS
 RESULTS
 DISCUSSION
 LIMITATIONS
CONCLUSIONS
 REFERENCES
 
Our study is a retrospective analysis of a large group of patients undergoing PCI for a variety of indications, with all the inherent limitations of this study design. Despite these limitations, our study population represents a broad spectrum of patients presenting to a tertiary care community hospital and being cared for by a diverse group of clinical cardiologists.


   CONCLUSIONS
TOP
 ABSTRACT
 METHODS
 STATISTICAL ANALYSIS
 RESULTS
 DISCUSSION
 LIMITATIONS
 CONCLUSIONS
REFERENCES
 
The risk of bleeding complications with platelet GP IIb/IIIa inhibitors is higher in our patient population than in randomized clinical trials. Liberal use of postprocedure heparin, along with delayed access site sheath removal, probably contributed to this higher risk of bleeding complications. In our series, the risk of bleeding was significantly lower with eptifibatide than with tirofiban or abciximab. Although most bleeding complications were transient and well tolerated, they resulted in prolonged hospital stays, with a 50% increase in hospital cost, and were fatal in nearly 1% of patients treated. Careful patient selection—based on clinical risk factors for bleeding complications, reduced heparin dosing, avoidance of postprocedure heparin, and careful access site management—should further reduce the risk of these complications.


   FOOTNOTES
 
DOI: 10.1177/0091270004269559

Submitted for publication January 15, 2004; Revised version accepted July 26, 2004.


   REFERENCES
TOP
 ABSTRACT
 METHODS
 STATISTICAL ANALYSIS
 RESULTS
 DISCUSSION
 LIMITATIONS
 CONCLUSIONS
 REFERENCES
 

1. EPIC Investigators. Use of a monoclonal antibody directed against the platelet glycoprotein IIb/IIIa receptor in high-risk coronary angioplasty. N Engl J Med. 1994;330: 956-961.[Abstract/Free Full Text]

2. The CAPTURE Investigators. Randomized placebo-controlled trial of abciximab before and during coronary intervention in refractory unstable angina: the CAPTURE study. Lancet. 1997;349: 1429-1435.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

3. The PURSUIT Trial Investigators. Inhibition of the platelet glycoprotein IIb/IIIa with epitifibatide in patients with acute coronary syndromes. N Engl J Med. 1998;339: 436-443.[Abstract/Free Full Text]

4. The EPILOG Investigators. Platelet glycoprotein IIb/IIIa receptor blockade and low dose heparin during percutaneous coronary revascularization. N Engl J Med. 1997;336: 1689-1696.[Abstract/Free Full Text]

5. The PRISM-PLUS Investigators. Inhibition of the platelet glycoprotein IIb/IIIa receptor with tirofiban in unstable angina and non-Q wave myocardial infarction. N Engl J Med. 1998;338: 1488-1497.[Abstract/Free Full Text]

6. Bovill EG, Terrin ML, Stump DC, et al, for the TIMI Investigators. Hemorrhagic events during therapy with recombinant tissue-type plasminogen activator, heparin, and aspirin for acute myocardial infarction. Ann Intern Med. 1991;115: 256-265.

7. Khanlou H, Tsiodras S, Eiger G, et al. Fatal alveolar hemorrhage and abciximab therapy for acute myocardial infarction. Cathet Cardiovasc Diag. 1998;44: 313-316.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

8. Ali A, Patil S, Grady KJ, Schreiber TL. Diffuse alveolar hemorrhage following administration of tirofiban or abciximab: a nemesis of platelet glycoprotein IIb/IIIa inhibitors. Cathet Cardiovasc Intervent. 2000;49: 181-184.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

9. Aguirre F, Topol EJ, Ferguson JJ, et al. Bleeding complications with the chimeric antibody to platelet glycoprotein IIb/IIIa integrin in patients undergoing percutaneous coronary intervention. Circulation. 1995;91: 2882-2890.[Abstract/Free Full Text]

10. Peterson JG, Lauer MA, Sapp SK, Topol EJ. Heparin use is required for clinical benefit of GIIb/IIIa inhibitor eptifibatide in acute coronary syndromes: insights from the PURSUIT Trial. Circulation. 1998;98(suppl I): I-360.

11. The ESPRIT Investigators. Novel dosing regimen of eptifibatide in planned coronary stent implantation (ESPRIT): a randomized, placebo-controlled trial. Lancet. 2000;356: 2037-2044.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

12. Gurwitz JH, Goldberg RJ, Chen Z, Gore JM. Beta-blocker therapy in acute myocardial infarction: evidence for underutilization in the elderly. Am J Med. 1992;93: 605-610.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

13. McLaughlin TJ, Soumerai SB, Willison DJ, et al. Adherence to national guidelines for drug treatment of suspected acute myocardial infarction. Arch Intern Med. 1996;156: 799-805.[Abstract/Free Full Text]

14. The REPLACE 2 Investigators. AHA Scientific Session 2002.

15. Karvouni E, Katritsis DG, Ioannidis JP. Intravenous glycoprotein IIb/IIIa receptor antagonists reduce mortality after percutaneous coronary interventions. J Am Coll Cardiol. 2003;41: 26-32.[Abstract/Free Full Text]
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