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J Am Coll Cardiol, 2006; 47:2374-2379, doi:10.1016/j.jacc.2005.09.080 (Published online 25 May 2006).
© 2006 by the American College of Cardiology Foundation
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CLINICAL RESEARCH: CLINICAL TRIAL

Correlates of Bleeding Events Among Moderate- to High-Risk Patients Undergoing Percutaneous Coronary Intervention and Treated With Eptifibatide

Observations From the PROTECT–TIMI-30 Trial

Ajay J. Kirtane, MD, SM*, Gregory Piazza, MD*, Sabina A. Murphy, MPH{dagger}, Daniela Budiu, MD{dagger}, David A. Morrow, MD, MPH, FACC{dagger}, David J. Cohen, MD, MSc*,1, Eric Peterson, MD, MPH, FACC{ddagger},2, Nasser Lakkis, MD, FACC§, Howard C. Herrmann, MD, FACC||,3, Theresa M. Palabrica, MD,4, C. Michael Gibson, MS, MD, FACC*,{dagger},5,* for the TIMI Study Group

* Cardiovascular Division, Department of Medicine, Beth Israel Deaconess Medical Center
{dagger} Cardiovascular Division, Department of Medicine, Brigham & Women’s Hospital, Harvard Medical School, Boston, Massachusetts
{ddagger} Duke Clinical Research Institute, Durham, North Carolina
§ Ben Taub General Hospital, Houston, Texas
|| University of Pennsylvania Medical Center, Philadelphia, Pennsylvania
Millennium Pharmaceuticals, Cambridge, Massachusetts

Manuscript received May 29, 2005; revised manuscript received September 1, 2005, accepted September 8, 2005.

* Reprint requests and correspondence: Dr. C. Michael Gibson, 350 Longwood Avenue, First Floor, Boston, Massachusetts 02115. (Email: mgibson{at}timi.org).


   Abstract
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 Abstract
Methods
 Results
 Discussion
 References
 
OBJECTIVES: We aimed to identify correlates of Thrombolysis In Mycocardial Infarction (TIMI) major/minor bleeding among eptifibatide-treated patients undergoing percutaneous coronary intervention (PCI).

BACKGROUND: Evaluation of bleeding predictors among patients treated with glycoprotein IIb/IIIa receptor inhibition might aid in the identification of targets to reduce bleeding risk.

METHODS: Data were analyzed from 567 moderate- to high-risk PCI patients with non–ST-segment elevation acute coronary syndrome (NSTEACS) treated with eptifibatide/reduced-dose unfractionated heparin or eptifibatide/reduced-dose enoxaparin enrolled in the Randomized Trial to Evaluate the Relative Protection Against Post-PCI Microvascular Dysfunction and Post-PCI Ischemia Among Anti-Platelet and Anti-Thrombotic Agents–Thrombolysis In Myocardial Infarction-30 (PROTECT–TIMI-30).

RESULTS: The incidence of significant bleeding was 3.2% with a median time to event of 7.0 h after the first eptifibatide bolus. Increased age was the only independent correlate of bleeding events. Among patients with reduced creatinine clearance (CrCl), lack of adjustment of the maintenance infusion for CrCl ≤50 ml/min occurred frequently (15 of 33 patients, or 45%) and was associated with a high rate of bleeding (20%). The association of CrCl with bleeding appeared to be largely mediated by the incorporation of age in the estimation of CrCl. Patient gender, Cr, weight, and the peak activated clotting time were not associated with bleeding.

CONCLUSIONS: Among NSTEACS PCI patients treated with eptifibatide, increased age was a significant correlate of bleeding events and appeared to explain the association between low CrCl and bleeding. The more widespread use of CrCl or other estimates of renal function over Cr may lead to more appropriate dose adjustments of eptifibatide.

Abbreviations and Acronyms
  ACS = acute coronary syndrome
  ACT = activated clotting time
  Cr = creatinine
  CrCl = creatinine clearance
  GFR = glomerular filtration rate
  GPIIb/IIIa = glycoprotein IIb/IIIa receptor
  NSTEACS = non–ST-segment elevation acute coronary syndrome
  PCI = percutaneous coronary intervention
  UFH = unfractionated heparin

The adjunctive use of platelet glycoprotein IIb/IIIa receptor (GPIIb/IIIa) inhibitors during percutaneous coronary intervention (PCI) has been associated with improved clinical outcomes (1–4), primarily through a reduction in periprocedural ischemic events. Although GPIIb/IIIa inhibitors have been demonstrated to be beneficial in improving both short- and long-term outcomes, combined antithrombin and GPIIb/IIIa regimens have also been associated with a higher risk of bleeding (5,6).

Bleeding complications in PCI patients are associated with patient discomfort, prolonged hospital stays, increased cost, and adverse outcomes (7,8). Given the demonstrated efficacy of GPIIb/IIIa inhibitors in the prevention of ischemic events, particularly in higher risk patients with acute coronary syndrome (ACS), further efforts to limit bleeding complications are critical to ensure the maximal benefit from this drug class. To identify potential targets to reduce bleeding, we evaluated the correlates of bleeding complications among eptifibatide-treated patients enrolled in the Randomized Trial to Evaluate the Relative Protection Against Post-PCI Microvascular Dysfunction and Post-PCI Ischemia Among Anti-Platelet and Anti-Thrombotic Agents–Thrombolysis In Myocardial Infarction-30 (PROTECT–TIMI-30) of PCI in moderate- to high-risk non–ST-segment elevation acute coronary syndromes (NSTEACS).


   Methods
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 Abstract
 Methods
Results
 Discussion
 References
 
PROTECT–TIMI-30 was a randomized multicenter trial to evaluate the efficacy of eptifibatide in combination with low-dose heparin (unfractionated heparin [UFH] or enoxaparin) compared with bivalirudin monotherapy in high-risk NSTEACS patients undergoing PCI (9). Patients treated with a GPIIb/IIIa inhibitor or those with active abnormal bleeding within 30 days of enrollment were excluded from the trial.

Patients in the eptifibatide/UFH arm were treated with a standard double bolus/infusion of eptifibatide (2) for 18 to 24 h plus a low-dose bolus of UFH (50 U/kg) with additional protocol-specified boluses to achieve a target activated clotting time (ACT) of 200 to 250 s. Patients in the eptifibatide/enoxaparin arm were treated with the same regimen of eptifibatide plus 0.5 mg/kg intravenous enoxaparin. For both arms, the protocol specified that the dose of the eptifibatide infusion was to be reduced to 1 µg/kg/min for patients with estimated creatinine clearance (CrCl) of ≤50 ml/min. For patients who were being treated with UFH at screening, the UFH infusion was discontinued for 2 h before anticipated randomization unless the activated partial thrombaplastin time was known to be <40 s or the ACT was <150 s. Study medications were administered following diagnostic coronary angiography and before PCI. All patients received aspirin before PCI and a thienopyridine (clopidogrel or ticlopidine) if stenting was performed.

Bleeding end points were assessed by Thombolysis In Myocardial Infarction (TIMI) criteria. For the purpose of this analysis, we considered two end points: 1) the occurrence of any significant bleeding (the composite of TIMI major or TIMI minor bleeding); and 2) the occurrence of a blood transfusion within 48 h of randomization. All bleeding events were adjudicated by a blinded Clinical Events Committee.

For this analysis, CrCl was estimated using the Cockroft-Gault formula, and glomerular filtration rate (GFR) was estimated using the abbreviated Modification of Diet in Renal Disease formula. The primary analyses were performed in the as-treated patient population with data pooled from the UFH and enoxaparin groups; study results were no different in intent-to-treat analyses. Univariate analyses were performed using Fisher exact test and Wilcoxon rank sum test. Covariates associated with bleeding events with p < 0.2 were included in multivariable stepwise selection logistic regression models. When adjusting for renal function, the individual components of the Cockroft-Gault formula (age, weight, 1/Cr, gender) were entered into the model separately as covariates. First-order interaction terms of these separate variables in the formula were additionally tested.


   Results
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 Abstract
 Methods
 Results
Discussion
 References
 
The incidence of significant bleeding was 3.2%. Of the 18 adjudicated bleeding events, 4 were major bleeding events and 14 were minor. The primary locations of bleeding were as follows: five at access sites, three retroperitoneal, five gastrointestinal, and five coronary artery bypass graft-related. Age (Fig. 1), low CrCl (Fig. 2), low GFR, and lower baseline hemoglobin were associated with significant bleeding in univariate analyses (Table 1). Although CrCl and GFR both were correlates of bleeding, serum Cr was not.


Figure 1
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  		Figure 1 Relation of age and bleeding.

 

Figure 2
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  		Figure 2 Relation of creatinine clearance (CrCl) and bleeding. IQ = interquartile range.

 

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  		Table 1. Correlates of Major or Minor Bleeding
 
Although all major bleeding events occurred among patients treated with enoxaparin, the overall rate of significant bleeding was similar among patients treated with UFH versus enoxaparin (3.3% vs. 3.0%; p = NS). There were no significant differences in the rates of pretreatment with UFH or enoxaparin or in the rate of "cross-over" to a different study antithrombin between patients with and without bleeding events (Table 2).


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  		Table 2. Rates of Bleeding Events and Transfusions According to Prior Antithrombin
 
The majority of significant bleeding events occurred several hours after PCI, and half the bleeding events occurred >6 h after study drug administration (median 7.0 h [interquartile range 3.1 to 14.0 h] after the first eptifibatide bolus). The length of eptifibatide infusion was shorter among patients with bleeding events (median 5.3 h vs. 18.1 h among patients without bleeding; p < 0.001), suggesting that the infusion was terminated early in these patients (Fig. 3). There was no significant difference in the time from the administration of the first eptifibatide bolus to sheath removal among patients with bleeding events compared with those without bleeding events (1.6 h vs. 0.9 h; p = 0.60), and the median time from sheath removal to significant bleeding was 5.7 h.


Figure 3
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  		Figure 3 Cumulative distribution function of duration of eptifibatide infusion in patients (pts) with bleeding. IQ = interquartile range.

 
Association of eptifibatide dosing with bleeding events.   Among the 33 patients with CrCl ≤50 ml/min by the Cockroft-Gault formula who met criteria for a reduced-dose eptifibatide infusion, 15 (45%) instead received the full-dose infusion. Appropriate dose adjustment of eptifibatide for low CrCl occurred less frequently among women than among men (41% vs. 82%; p = 0.03). Among patients who met criteria for a reduced-dose infusion, those who received the full-dose eptifibatide infusion had a trend toward lower serum Cr (1.3 vs. 1.5; p = 0.08) but similar weight and age.

The incidence of bleeding events among patients with CrCl ≤50 ml/min was 9.1% (3 of 33), and all bleeding events in this reduced CrCl group occurred in patients treated with a full-dose eptifibatide infusion. There were no bleeding events among patients with reduced CrCl who received the reduced-dose infusion. In the overall study population, administration of a full-dose infusion to patients with reduced CrCl was associated with an over five-fold greater incidence of bleeding events compared with the incidence of bleeding events among patients with CrCl >50 ml/min (Fig. 4).


Figure 4
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  		Figure 4 Relation of dose adjustment of eptifibatide infusion to bleeding. CrCl = creatinine clearance.

 
Multivariable analysis.   In multivariable analyses, advanced age was the only covariate independently associated with the development of bleeding complications (odds ratio [OR] 2.6 [95% confidence interval (CI) 1.5 to 4.6] for each decade increase in age; p = 0.001). Age was the only component of CrCl that was independently associated with bleeding complications, whereas weight, 1/Cr, and gender were not. Even after adjustment for the appropriate dosing of eptifibatide based on renal function, age remained an independent correlate of bleeding (OR 2.1 [95% CI 1.2 to 3.5] for each decade increase of age; p = 0.007). In a sensitivity analysis excluding bleeding events in patients with CrCl <50 ml/min who did not receive a reduced-dose eptifibatide infusion, age again remained the only independent correlate of bleeding events (OR 2.3 [95% CI 1.3 to 4.2] for each decade increase in age; p = 0.004).

Correlates of blood transfusion.   A blood transfusion was administered to 25 patients (4.4%), of which 15 had an adjudicated bleeding event (60%). Among the 10 additional patients who received a transfusion but did not have a significant bleeding event, three patients did not have any bleeding, and seven patients had bleeding that was adjudicated as neither major nor minor. The baseline hemoglobin was significantly lower among the group of patients receiving transfusions who did not have significant bleeding events compared with patients receiving transfusions who had adjudicated bleeding events (11.0 vs. 12.6 g/dl; p = 0.002). All three patients with significant bleeding events who did not receive a transfusion had minor bleeding events.

Age, female gender, lower CrCl, and lower baseline hemoglobin were the baseline characteristics significantly associated with blood transfusion. The four patients with CrCl ≤50 ml/min who received a transfusion were all patients who were treated with a full-dose eptifibatide infusion rather than a reduced-dose infusion (Fig. 4). In multivariable analyses, advanced age (OR 1.6 [95% CI 1.0 to 2.6] for each decade of age; p = 0.04) and lower baseline hemoglobin (OR 0.5 [95% CI 0.4 to 0.7] for each g/dl increase in hemoglobin; p < 0.001) were the only covariates significantly associated with blood transfusion. After adjustment for the appropriate renal dosing of eptifibatide, age and lower baseline hemoglobin remained independent correlates of transfusion.


   Discussion
Top
 Abstract
 Methods
 Results
 Discussion
References
 
Evaluation of correlates of bleeding among patients treated with eptifibatide during and after PCI may allow better identification of patients at risk and may inform strategies to minimize bleeding risk. The strongest correlate of bleeding events in the present analysis was increased age. Although CrCl was also associated with bleeding, that appeared to be largely related to the incorporation of age in the estimate of CrCl. In addition, administration of a full-dose eptifibatide infusion to patients with reduced CrCl was not uncommon and resulted in a greater incidence of bleeding complications. Finally, more than half of all bleeding events occurred >6 h after the initiation of eptifibatide. Thus, adjustment of the eptifibatide infusion dose based upon a more complete estimate of renal function as well as adjustment of the duration of the eptifibatide infusion based upon patient risk factors may be two potential strategies to reduce bleeding.

Several risk factors for bleeding complications have been described previously concerning patients treated with GPIIb/IIIa inhibitors undergoing PCI. Patients with advanced age, renal insufficiency, female gender, peripheral vascular disease, lower body weight, history of diabetes mellitus, a greater dose of antithrombin, and an elevated peak ACT have been shown to be at increased risk for bleeding (10–13). Although the current analysis was a retrospective analysis of a randomized clinical trial and was not adequately powered to evaluate all of these correlates, our findings reemphasize the greater risk of bleeding complications among the elderly and those with impaired renal function.

Additionally, among patients with reduced CrCl, administration of a full-dose eptifibatide infusion was associated with a greater incidence of bleeding events. These findings parallel those observed in the Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes With Early Implementation of the ACC/AHA Guidelines (CRUSADE) registry, in which the risk of bleeding requiring transfusion was substantially increased among patients who were more likely to be administered excessive rather than appropriately reduced doses of GPIIb/IIIa inhibitors, including elderly patients and those with renal insufficiency (14).

The majority of bleeding events occurred >6 h after initiation of eptifibatide or during the eptifibatide infusion. Although a majority of ischemic events occur during or early after the PCI procedure (15), it nonetheless remains undetermined if early termination of the eptifibatide infusion would preserve or reduce the ischemia-related efficacy of the agent. Therefore, prospective randomized trials are needed to assess the relative efficacy and safety of a reduced duration of eptifibatide infusion.

Conclusions.   Among NSTEACS PCI patients treated with eptifibatide, increased age was the only constituent of CrCl that was associated with the occurrence of bleeding events. The use of serum Cr alone to adjust eptifibatide dosing may yield inadequate dose reductions, and use of CrCl or GFR may be preferable. Because half of the observed bleeding events occurred late, a reduced duration of eptifibatide infusion may be another target to reduce bleeding and awaits evaluation in future studies.


   Footnotes
 
Supported in part by a grant from Millennium Pharmaceuticals, Cambridge, Massachusetts, and Schering-Plough Research Institute, Kenilworth, New Jersey.

1 Dr. Cohen has received grant support from the Medicines Company, Millennium Pharmaceuticals, and Schering-Plough. Back

2 Dr. Peterson has received grant support from Schering-Plough and Millennium Pharmaceuticals. Back

3 Dr. Herrmann has received research funding from Millennium Pharmaceuticals and has served as a consultant for Millennium Pharmaceuticals. Back

4 Dr. Palabrica is an employee of Millennium Pharmaceuticals. Back

5 Dr. Gibson has received grant support and honoraria and has served as a consultant for the Medicines Company, Millennium Pharmaceuticals, and Schering-Plough. Back


   References
Top
 Abstract
 Methods
 Results
 Discussion
 References
 

  1. Topol EJ, Ferguson JJ, Weisman HF, et al. Evaluation of Platelet IIb/IIIa Inhibition for Prevention of Ischemic Complication (EPIC) Investigator Group Long-term protection from myocardial ischemic events in a randomized trial of brief integrin beta3 blockade with percutaneous coronary intervention JAMA 1997;278:479-484.[Abstract]
  2. The ESPRIT Investigators Novel dosing regimen of eptifibatide in planned coronary stent implantation (ESPRIT)a randomised, placebo-controlled trial. Lancet 2000;356:2037-2044.[CrossRef][ISI][Medline]
  3. 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]
  4. Kong DF, Hasselblad V, Harrington RA, et al. Meta-analysis of survival with platelet glycoprotein IIb/IIIa antagonists for percutaneous coronary interventions Am J Cardiol 2003;92:651-655.[CrossRef][ISI][Medline]
  5. Boersma E, Harrington RA, Moliterno DJ, et al. Platelet glycoprotein IIb/IIIa inhibitors in acute coronary syndromesa meta-analysis of all major randomised clinical trials. Lancet 2002;359:189-198.[CrossRef][ISI][Medline]
  6. Lincoff AM, Bittl JA, Harrington RA, et al. Bivalirudin and provisional glycoprotein IIb/IIIa blockade compared with heparin and planned glycoprotein IIb/IIIa blockade during percutaneous coronary interventionREPLACE-2 randomized trial. JAMA 2003;289:853-863.[Abstract/Free Full Text]
  7. Cohen DJ, Lincoff AM, Lavelle TA, et al. Economic evaluation of bivalirudin with provisional glycoprotein IIB/IIIA inhibition versus heparin with routine glycoprotein IIB/IIIA inhibition for percutaneous coronary interventionresults from the REPLACE-2 trial. J Am Coll Cardiol 2004;44:1792-1800.[Abstract/Free Full Text]
  8. Rao SV, Jollis JG, Harrington RA, et al. Relationship of blood transfusion and clinical outcomes in patients with acute coronary syndromes JAMA 2004;292:1555-1562.[Abstract/Free Full Text]
  9. Gibson CM. A randomized trial to evaluate the relative protection against post-PCI microvascular dysfunction and post-PCA ischemia among anti-platelet and anti-thrombotic agents. Presented at: Texas Heart Symposium; New Orleans, LA: November 2004..
  10. Popma JJ, Berger P, Ohman EM, et al. Antithrombotic therapy during percutaneous coronary interventionthe Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004;126:576S-599S.[Abstract/Free Full Text]
  11. Guagliumi G, Stone GW, Cox DA, et al. Outcome in elderly patients undergoing primary coronary intervention for acute myocardial infarctionresults from the Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications (CADILLAC) trial. Circulation 2004;110:1598-1604.[Abstract/Free Full Text]
  12. Freeman RV, Mehta RH, Al Badr W, et al. Influence of concurrent renal dysfunction on outcomes of patients with acute coronary syndromes and implications of the use of glycoprotein IIb/IIIa inhibitors J Am Coll Cardiol 2003;41:718-724.[Abstract/Free Full Text]
  13. Tolleson TR, O’Shea JC, Bittl JA, et al. Relationship between heparin anticoagulation and clinical outcomes in coronary stent interventionobservations from the ESPRIT trial. J Am Coll Cardiol 2003;41:386-393.[Abstract/Free Full Text]
  14. Alexander KP, Chen AY, Roe MT, et al. Excess dosing of antiplatelet and antithrombin agents in the treatment of non–ST-segment elevation acute coronary syndromes JAMA 2005;294:3108-3116.[Abstract/Free Full Text]
  15. Thel MC, Califf RM, Tardiff BE, et al. Timing of and risk factors for myocardial ischemic events after percutaneous coronary intervention (IMPACT-II) Am J Cardiol 2000;85:427-434.[CrossRef][ISI][Medline]

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