Ischemic and Bleeding Outcomes in Women Treated With Bivalirudin During Percutaneous Coronary Intervention: A Subgroup Analysis of the REPLACE-2 Trial
Matthews Chacko, MD; A. Michael Lincoff, MD; Katherine E. Wolski, MPH; David J. Cohen, MD; John A. Bittl, MD; Alexandra J. Lansky, MD; Yoshihiro Tsuchiya, MD; Amadeo Betriu, MD; Michael H. Yen, MD; Derek P. Chew, MBBS; Leslie Cho, MD; Eric J. Topol, MD 

Am Heart J.  2006;151(5):1032.e1-1032.e7.  ?2006 Mosby, Inc.
Posted 05/18/2006

Abstract and Introduction

Abstract

Background: Outcomes in women undergoing percutaneous coronary intervention (PCI) in the contemporary era are poorly defined. The REPLACE-2 trial demonstrated that bivalirudin with provisional glycoprotein IIb/IIIa (GpIIb-IIIa) blockade is noninferior to heparin with planned GpIIb-IIIa blockade during PCI, with regard to ischemic and bleeding end points. The aim of this study was to define sex-based clinical ischemic and bleeding outcomes from the REPLACE-2 trial.
Methods: A retrospective sex-based subgroup analysis of the REPLACE-2 trial comparing clinical ischemic and inhospital bleeding end points was conducted.
Results: Compared with men in REPLACE-2, women were older, had more diabetes, congestive heart failure and hypertension, and less prior revascularization and myocardial infarction. Female sex was a univariate predictor of death and bleeding complications. Among women treated with either bivalirudin or heparin, there was no significant difference in the individual or composite ischemic end points of death, myocardial infarction, or urgent revascularization at 30 days or 6 months. Protocol-defined major bleeding, minor bleeding, and access site bleeding were less frequent with bivalirudin compared with heparin. Multivariable modeling found no significant interactions between sexes, with the composite ischemic end point, major bleeding, or 1-year mortality.
Conclusions: Women remain at higher risk for poorer outcomes with contemporary PCI, likely because of comorbidities. Bivalirudin with provisional GpIIb-IIIa confers similar protection against ischemic end points compared with heparin and planned GpIIb-IIIa blockade and significantly reduces the inherent bleeding risk of women undergoing contemporary PCI.

Introduction

Although the impact of ischemic heart disease in men is widely acknowledged, the incidence in women is underappreciated and remains the leading cause of mortality.[1] Women have traditionally been thought to have poorer outcomes with percutaneous coronary intervention (PCI) compared with men. Evidence suggests that outcomes in women may be improving over time, although they remain poorly defined in the current antithrombotic and PCI era.[2-7] Direct thrombin inhibition has emerged as an effective alternative antithrombotic strategy during contemporary PCI. The REPLACE-2 trial demonstrated that the direct thrombin inhibitor bivalirudin with provisional glycoprotein IIb/IIIa (GpIIb-IIIa) blockade was noninferior compared with heparin and planned GpIIb-IIIa blockade with regard to suppression of acute ischemic end points and was associated with less bleeding among patients undergoing elective or urgent PCI.[8,9] This prospectively defined analysis was performed to determine if there are sex-based differences in the relative efficacy of these 2 antithrombotic regimens, as well as to assess whether women continue to have outcomes different from men in the contemporary PCI era.

Methods

The details of the design and outcomes of the REPLACE-2 trial have been previously published.[8,9] Briefly, this was a multicenter, randomized, double-blind, active controlled trial of 6010 patients (4465 men and 1537 women) undergoing urgent or elective PCI randomized to receive either bivalirudin (0.75mg/kg bolus and 1.75mg/kg per hour infusion) with provisional GpIIb-IIIa blockade versus heparin (65 U/kg bolus) and planned GpIIb-IIIa blockade. All patients were pretreated with aspirin (with clopidogrel pretreatment strongly encouraged) followed by aspirin and clopidogrel for at least 30 days after PCI. Provisional GpIIb-IIIa inhibition (with either abciximab or eptifibatide) could be administered during PCI at any time at the interventionalists discretion for procedural or angiographic complications. Outcomes measures included clinical ischemic end points (individual and composite end points of death, myocardial infarction [MI], revascularization at 30 days and 6 months, and death at 1 year) and inhospital bleeding end points (major and minor bleeding, access-site bleeding, retroperitoneal bleeding, and blood product transfusions). Major bleeding was defined as a hemoglobin drop >4 g/dL, overt bleeding with hemoglobin drop >3 g/dL; ≥2-U blood transfusion; or retroperitoneal, intraocular, or intracranial hemorrhage. Minor bleeding was defined as overt bleeding that did not meet criteria for major bleeding. Activated clotting times (ACT) were measured on the Hemochron device (ITC, Edison, NJ). Unless an approved closure device was used, vascular access sheaths were manually removed once the ACT was ≤175 s or the activated partial thromboplastin time 50 s or less. The study protocol was approved by the institutional review board at each participating center, and all patients provided written informed consent.

Statistical analyses were performed according to intention-to-treat principles. Univariate analyses included the log-rank test to compare the end points between groups, the χ2 statistic to compare qualitative variables and, the t test or appropriate nonparametric statistic to compare continuous variables. Proportional hazards models were used for the 30-day composite and the 1-year mortality end points, and a logistic model was used for the inhospital bleeding end point to examine the relationship of sex in the presence of other baseline factors associated with outcome. The following variables were entered into each model using a stepwise selection process: age, race, congestive heart failure (CHF), diabetes mellitus, hypertension, prior MI, prior revascularization, acute coronary syndrome, tobacco use, stroke, baseline creatinine, mean body mass index, baseline hemoglobin and leukocyte count, as well as concomitant medical therapy (ß-blockers, statins, clopidogrel, angiotensin-converting enzyme inhibitors, sulfonylureas, and insulin). Sex and geographic region were incorporated into each model. Statistical significance was defined as a P < .05. SAS version 8.0 (SAS Inc, Cary, NC) was used as statistical software.

Results

Baseline Characteristics

Compared with men in REPLACE-2, women were older, had more diabetes, CHF, hypertension, lower baseline hemoglobin values, and less frequent prior coronary artery bypass graft/PCI, MI, or tobacco use ( Table I ). Rates of prior clopidogrel use were not different between sexes. Procedural characteristics were more favorable for women compared with men in lesion complexity, duration of procedure, and rates of multivessel PCI. Among women, no significant differences existed between the randomized bivalirudin versus heparin groups ( Table I ).

Outcomes in Women versus Men

Although there were no significant differences in the frequencies of MI, revascularization, or composite ischemic end points between sexes at 30 days or 6 months, female sex was a univariate predictor of death at 30 days, 6 months, and 1 year ( Table II ). Female sex was not a significant predictor of the composite end point at 30 days or death at 1 year in multivariable modeling ( Table III ). Female sex was significantly associated with inhospital major bleeding, minor bleeding, access site bleeding, retroperitoneal bleeding, and blood product transfusion by univariate analysis ( Table II ). By multivariable modeling, however, there was no significant association between female sex and inhospital major bleeding, the prespecified primary bleeding end point ( Table III ) for the overall trial.

Outcome in Women Treated With Bivalirudin Versus Heparin Plus GpIIb-IIIa

Among women in the trial, rates of individual and composite ischemic end points (death, MI, and revascularization) at 30 days and 6 months as well as death at 1 year were similar among those randomized to either bivalirudin and provisional GpIIb-IIIa blockade versus heparin and planned GpIIb-IIIa blockade. Women in the bivalirudin arm had significantly lower rates of major bleeding, minor bleeding and access-site bleeding than those receiving heparin plus planned GpIIb-IIIa blockade ( Table IV ). Although there were no significant differences in the rates of retroperitoneal bleeding or blood product transfusions between women in the randomized groups, trends favored bivalirudin ( Table IV ). Although ACT was similar between sexes, they were significantly higher in those treated with bivalirudin compared with heparin and planned GpIIb-IIIa inhibition in the male and female subgroups (Figure 1, Table V ).

Figure 1. 

Peak intraprocedural ACT. Box and whisker plot of peak intraprocedural ACT values. The box spans the interquartile range (25th to 75th percentiles), whereas the line within the box denotes the median. The asterisk denotes the mean. Whiskers extend from the 10th to the 90th percentiles. Hep + IIb/IIIa, Heparin plus GpIIb-IIIa inhibitor; Bival, bivalirudin.

     

Discussion

The major findings of this analysis suggest that although ischemic and bleeding event rates were higher in women, this risk seems to be due primarily to comorbidities because multivariable modeling did not identify sex as an independent predictor of ischemic or bleeding complications.

Although trends in outcome of women undergoing PCI may be improving, women are still thought to have less favorable outcomes compared with men in the contemporary PCI era.[2,10,11] Data from the early PCI era demonstrate worse short-term bleeding and ischemic outcomes as well as long-term outcomes for women.[12-17] Although there is conflicting evidence regarding the short- and long-term outcomes of women undergoing contemporary PCI,[18] the totality of evidence suggests that sex-based differences in outcome may still persist. A recent retrospective analysis of >735000 patients undergoing PCI identified female sex as an independent predictor of inhospital mortality.[19] Recent data also suggest that female sex continues to be a risk factor for short-term bleeding complications with GpIIb-IIIa inhibitors in the contemporary PCI era.[20,21] Regarding long-term outcomes, an analysis of 18039 patients undergoing contemporary PCI suggests that 1-year mortality is no different between sexes but that there are significantly more postprocedural bleeding complications among women.[22] Another analysis from the FRISC-II trial found that female sex was an independent predictor of the long-term outcomes of death and MI in women with acute coronary syndrome and that outcomes were improved when a strategy of early PCI was undertaken.[23] The overall weight of evidence suggests that bleeding and to a lesser extent ischemic events appear to be higher in women in the contemporary PCI era. Whether female sex itself is an independent predictor of poor outcome in the contemporary PCI era or if other confounding issues such as referral bias, less aggressive treatment, or baseline factors (smaller body mass, smaller coronary lumen diameters, older presenting age, or other comorbidities) are responsible remains poorly defined.[4,24,25] In addition, changes in practice, adjunctive pharmacotherapy and improvements in equipment and technique may have partially neutralized any detectable sex-related effect. The true etiology of poorer outcomes in women is likely multifactorial. The early diagnosis of and screening for coronary artery disease in women remain elusive.[26] Traditional risk factor assessment in women is also challenging, exemplified by the paradigm shift in hormone replacement therapy with respect to cardiac protection.[27] Moreover, women may have more atypical presenting symptoms,[28] more subtle electrocardiographic changes of myocardial ischemia,[29] differential expression of cardiac biomarkers compared with men,[30] and may be subject to sex-biased access to cardiac care.[31,32]

The findings in our subgroup analysis of women parallel the major findings of the REPLACE-2 trial in that bivalirudin provided similar protection against short- and long-term ischemic events with less bleeding compared with heparin plus planned GpIIb-IIIa blockade.[8,9] Although controversy exists over female sex predicting poorer short and long-term outcome in contemporary PCI, our analysis supports baseline factors rather than female sex itself playing more of a role in determining outcome that is in keeping with other more current analyses of women undergoing PCI.[25] Our analysis also suggests that the inherent bleeding and vascular risks in women seen in the early PCI era still exists in the contemporary PCI era, although such risks may be attenuated to some degree by other factors such as smaller sheath sizes, improvements in equipment, closure devices, and better point-of-care anticoagulation monitoring.

Not only is there an independent bleeding and vascular complication risk among women undergoing PCI[20,33] but there may also be sex-specific responses to treatment with various antithrombotic agents. Furthermore, within the GpIIb-IIIa inhibitor class alone, there appears to be drug-specific variability in their relative efficacy in men and women.[34] These and other factors make selection of an appropriate adjunctive anticoagulation regimen both challenging and vital. Regarding specific antithrombotic regimens, a pooled analysis of outcome from several large trials of the GpIIb-IIIa inhibitor abciximab highlighted that although both sexes derive benefit during PCI in reduction in ischemic events, women have a higher bleeding risk independent of treatment.[35] Abciximab combined with stenting in 1 subgroup analysis of diabetic women in the EPISTENT trial was associated with a significant reduction in the long-term outcomes of death, MI, and target vessel revascularization at 1 year.[36] The GpIIb-IIIa inhibitor eptifibatide showed no benefit in women in the PURSUIT trial in 30-day ischemic end points[37] whereas, in another large trial of patients undergoing PCI, confirmed the inherent bleeding risk seen in women that had been noted with abciximab.[38] This bleeding risk in women was also noted with the GpIIb-IIIa inhibitor tirofiban in a subanalysis of patients with acute coronary syndrome from the PRISM-PLUS trial.[21] Our subgroup analysis of the REPLACE-2 trial reassuringly demonstrated that bivalirudin provided equal protection from ischemic events as well as a bleeding advantage in the female subgroup and in the overall trial.

Our analysis also revealed a significant increase in the mean peak intraprocedural ACT among men and women in the bivalirudin arm, compared with those in the heparin and planned GpIIb-IIIa blockade arm (men: 380 vs 347 s [P < .001], women: 363 vs 339 s [P < .03]) (Figure 1). These findings are congruent with a higher median ACT in the bivalirudin arms of the REPLACE-1[39] and REPLACE-2[8] trials, neither of which translated into higher bleeding rates. Ironically, despite a higher ACT values with bivalirudin compared with heparin plus GpIIb-IIIa blockade, bleeding rates were significantly lower among women in the bivalirudin arm of our analysis. The ACT does not appear to correlate with ischemic or bleeding complications in the contemporary PCI era with either unfractionated heparin or GpIIb-IIIa inhibitors.[40-42] There also appears to be a poor correlation between the ACT and blood concentration as well as anti-IIa activity of bivalirudin at therapeutic levels in patients undergoing PCI.[43,44] Although the optimal target ACT for bivalirudin has not been established, the higher ACT seen with its use does not seem to relate to adverse clinical outcomes.[45]

The limitations of this study are that statistical chance cannot totally be excluded because the results are based on a retrospective subgroup analysis of a trial designed to assess noninferiority of bivalirudin versus heparin in patients undergoing PCI. Although a large trial of >6000 patients with approximately one quarter being women, it is underpowered to detect a true independent association between sex and outcome related to contemporary PCI. In addition, ST-elevation MI patients, those requiring ongoing GpIIb-IIIa inhibitors, heparin, or warfarin therapy before randomization were excluded from the REPLACE-2 trial, and thus, it cannot directly be extrapolated whether our analysis applies to women in those populations. Although there were significant baseline differences between sexes in demographics, clinical variables, and procedural issues, these differences may not fully explain the differences in outcome in our analysis. Furthermore, these differences may represent the archetypal profile of women presenting with coronary artery disease.[46]

Conclusions

Women are at higher risk for poorer outcomes and bleeding in the contemporary PCI era not by virtue of sex but their propensity of having other comorbidities. We demonstrate that bivalirudin with provisional GpIIb-IIIa blockade during PCI confers similar protection against clinical ischemic events compared with heparin and planned GpIIb-IIIa blockade and significantly reduces the inherent bleeding risk of women undergoing contemporary PCI. Our analysis also serves to underscore the paucity of data regarding the outcome of women in the current antithrombotic era and that improving sensitivity toward women's cardiovascular health issues and outcomes requires greater knowledge of sex-related trends in PCI and cardiovascular medicine through the enrollment of more women in clinical trials.

Table I. Baseline Characteristics of REPLACE-2 by Sex and Treatment


Characteristics Women (n = 1537) Men (n = 4465) P Women (heparin + IIb/IIIa) (n = 779) Women (bivalirudin [?IIb/IIIa]) (n = 758) P
Age >75 y 20.6% 10.9% <.001 21.7% 19.5% .29
Mean BMI (kg/m2) 30.1 29.5 .002 30.1 30.3 .84
Diabetes 31.6% 25.6% <.001 31.1% 32.1% .65
Hypertension 76.0% 63.8% <.001 76.8% 75.3% .49
CHF 8.7% 6.4% .003 8.7% 8.6% .98
Smoking within 1 y 23.7% 27.6% .004 23.2% 24.3% .61
Prior PCI 31.8% 36.0% .003 32.0% 31.6% .86
Prior CABG 13.0% 20.2% <.001 13.8% 12.1% .35
Prior MI 29.5% 39.6% <.001 30.8% 28.2% .27
Prior clopidogrel 82.8% 84.7% .075 82.7% 83% .88
Baseline Hg (g/dL) 12.7 14.0 <.001 12.6 12.7 .33
Multivessel PCI 14.6% 16.6% .078 14.5% 14.7% .91
Worst lesion B2/C 50.6% 56.5% <.001 50.1% 51.1% .72
Procedure >1 h 5.7% 7.7% .010 6.4% 5.0% .26

BMI, Body mass index; CABG, coronary artery bypass graft; Hg, hemoglobin.

 

Table II. Sex-specific Outcomes from REPLACE-2


Outcome Time point Women (n = 1537) (%) Men (n = 4465) (%) P
Death 30 d 0.59 0.22 .03
MI 6.58 6.55 .95
Q-MI 0.46 0.41 .78
Non?Q-MI 6.13 6.16 .96
Urgent revascularization 1.11 1.35 .29
Composite* 7.10 7.40 .72
Death 6 m 2.02 0.92 <.001
MI 7.93 7.77 .79
Urgent revascularization 2.91 3.65 .22
Composite* 10.93 10.89 .90
Death 1 y 3.0 1.8 .007
Major bleeding Inhospital 4.8 2.7 <.001
Minor bleeding 22.2 18.6 .002
Access site bleeding 2.9 1.2 <.001
Retroperitoneal bleeding 0.8 0.2 .003
Blood transfusion 3.8 1.5 <.001

*Death, MI, and urgent revascularization.

 

Table III. Independent Effect of Female Sex on Outcome Using Proportional Hazard and Adjusted Logistic Models


Outcome OR 95% CI P*
Composite?,? (30 d) 0.943 (0.754-1.180) .608
Mortality? (1 y) 0.924 (0.610-1.398) .707
Major bleeding|| 1.340 (0.908-1.998) .139

?Death, MI, and urgent revascularization.
?Proportional hazard model adjusted for treatment, prior MI/PCI, body mass index, and geographic region.
?Proportional hazard model adjusted for treatment, age, CHF, diabetes, hypertension, renal function, body mass index, and geographic location.
||Adjusted logistic model adjusted for treatment, age, baseline hemoglobin/platelet count, procedure length, time to sheath pull, and geographic location.
*Overall P value based on model-2 log likelihood.

 

Table IV. Treatment-specific Outcomes Among Women From REPLACE-2


Outcome Time point Heparin + IIb/IIIa (n = 779) (%) Bivalirudin (?Ib/IIIa) (n = 758) (%) Hazard ratio (95% CI) P
Death 30 d 0.64 0.53 0.82 (0.22-3.06) .77
MI   7.07 6.09 0.86 (0.58-1.27) .43
Q-MI   0.39 0.53 1.37 (0.31-6.13) .68
Non?Q-MI   6.68 5.56 0.83 (0.55-1.24) .35
Urgent revascularization   0.77 1.46 1.89 (0.70-5.12) .20
Composite*   7.46 6.74 0.90 (0.62-1.31) .58
Death 6 m 2.32 1.72 0.74 (0.36-1.51) .41
MI   8.76 7.09 0.80 (0.55-1.14) .21
Urgent revascularization   2.47 3.35 1.36 (0.75-2.46) .31
Composite*   11.24 10.61 0.92 (0.68-1.25) .61
Death 1 y 3.5 2.5 0.72 (0.40-1.30) .27
Major bleeding Inhospital 5.9 3.7 0.61 (0.38-0.99) .04
Minor bleeding   28.2 16.0 0.48 (0.38-0.62) <.001
Access site bleeding   4.1 1.6 0.38 (0.19-0.74) .003
Retroperitoneal bleeding   1.0 0.5 0.51 (0.15-1.71) .27
Blood transfusion   4.6 3.0 0.65 (0.38-1.10) .11

*Death, MI and urgent revascularization.

 

Table V. Treatment Specific Outcomes Among Males From REPLACE-2


Outcome Time point Heparin + IIb/IIIa (n = 2229) (%) Bivalirudin (?IIb/IIIa) (n = 2236) (%) Hazard ratio (95% CI) P
Death 30 d 0.31 0.13 0.43 (0.11-1.65) .20
MI 5.86 7.24 1.25 (0.99-1.57) .06
Q-MI 0.45 0.36 0.80 (0.31-2.02) .63
Non?Q-MI 5.45 6.88 1.27 (1.00-1.61) .05
Urgent revascularization 1.62 1.08 0.66 (0.40-1.11) .12
Composite* 6.89 7.91 1.16 (0.93-1.44) .19
Death 6 m 1.04 0.81 0.78 (0.42-1.44) .43
MI 6.92 8.62 1.26 (1.02-1.56) .03
Urgent revascularization 3.75 3.56 0.93 (0.68-1.28) .67
Composite* 10.09 11.69 1.17 (0.98-1.40) .09
Death 1 y 2.02 1.65 0.82 (0.53-1.26) .37
Major bleeding Inhospital 3.5 1.9 0.54 (0.37-0.79) .001
Minor bleeding 24.7 12.5 0.43 (0.37-0.51) <.001
Access site bleeding 1.9 0.6 0.31 (0.16-0.57) <.001
Retroperitoneal bleeding 0.4 0.1 0.37 (0.10-1.41) .13
Blood transfusion 1.79 1.21 0.67 (0.41-1.09) .11

*Death, MI, and urgent revascularization.

 



References

  1. Anderson RN. Deaths: leading causes for 2000. In: National Vital Statistics Reports. In: Centers for Disease Control and Prevention. 50:2002;1-86.
  2. Jacobs AK, Johnston JM, Haviland A, et al.. Improved outcomes for women undergoing contemporary percutaneous coronary intervention: a report from the National Heart, Lung, and Blood Institute Dynamic registry. J Am Coll Cardiol. 2002;39:1608?1614.
  3. Ghali WA, Faris PD, Galbraith PD, et al.. Sex differences in access to coronary revascularization after cardiac catheterization: importance of detailed clinical data. Ann Intern Med. 2002;136:723?732.
  4. Peterson ED, Lansky AJ, Kramer J, et al.. Effect of gender on the outcomes of contemporary percutaneous coronary intervention. Am J Cardiol. 2001;88:359?364.
  5. Malenka DJ, Wennberg DE, Quinton HA, et al.. Gender-related changes in the practice and outcomes of percutaneous coronary interventions in Northern New England from 1994 to 1999. J Am Coll Cardiol. 2002;40:2092?2101.
  6. King KM, Ghali WA, Faris PD, et al.. Sex differences in outcomes after cardiac catheterization: effect modification by treatment strategy and time. JAMA. 2004;291:1220?1225.
  7. Holper EM, Faxon DP. Percutaneous coronary intervention in women. J Am Med Womens Assoc. 2003;58:264?271.
  8. Lincoff AM, Bittl JA, Harrington RA, et al.for the REPLACE-2 Investigators. Bivalirudin and provisional glycoprotein IIb/IIIa blockade compared with heparin and planned glycoprotein IIb/IIIa blockade during percutaneous coronary intervention. JAMA. 2003;289:853?863.
  9. Lincoff AM, Kleiman NS, Kereiakes DJ, et al.for the REPLACE-2 Investigators. Long-term efficacy of bivalirudin and provisional glycoprotein IIb/IIIa blockade vs heparin and planned glycoprotein IIb/IIIa blockade during percutaneous coronary revascularization. JAMA. 2004;292:696?703.
  10. Bennett SK, Redberg RF. Acute coronary syndromes in women: is treatment different? Should it be?. Curr Cardiol Rep. 2004;6:243?252.
  11. Nabel EG, Selker HP, Califf RM, et al.. Women's Ischemic Syndrome Evaluation: current status and future research directions: report of the National Heart, Lung and Blood Institute workshop: October 2-4, 2002: Section 3: diagnosis and treatment of acute cardiac ischemia: gender issues. Circulation. 2004;109:e50?e52.
  12. Azar RR, Waters DD, McKay RG, et al.. Short-and medium-term outcome differences in women and men after primary percutaneous transluminal mechanical revascularization for acute myocardial infarction. Am J Cardiol. 2000;85:675?679.
  13. Vakili BA, Kaplan RC, Brown DL. Sex-based differences in early mortality of patients undergoing primary angioplasty for first acute myocardial infarction. Circulation. 2001;104:3034?3038.
  14. Stack RS, Califf RM, Hinohara T, et al.. Survival and cardiac event rates in the first year after emergency coronary angioplasty for acute myocardial infarction. J Am Coll Cardiol. 1988;11:1141?1149.
  15. Gowda MS, Vacek JL, Hallas D. Gender-related risk factors and outcomes for non?Q wave myocardial infarction patients receiving in-hospital PTCA. J Invasive Cardiol. 1999;11:121?126.
  16. Welty FK, Lewis SM, Kowalker W, et al.. Reasons for higher in-hospital mortality >24 hours after percutaneous transluminal coronary angioplasty in women compared with men. Am J Cardiol. 2001;88:473?477.
  17. Watanabe CT, Maynard C, Ritchie JL. Comparison of short-term outcomes following coronary artery stenting in men versus women. Am J Cardiol. 2001;88:848?852.
  18. Mehilli J, Kastrati A, Dirschinger J, et al.. Sex-based analysis of outcome in patients with acute myocardial infarction treated predominantly with percutaneous coronary intervention. JAMA. 2002;287:210?215.
  19. Mukherjee D, Wainess RM, Dimick JB, et al.. Variation in outcomes after percutaneous coronary intervention in the United States and predictors of periprocedural mortality. Cardiology. 2005;103:143?147.
  20. Razakjr OA, Tan HC, Yip WL, et al.. Predictors of bleeding complications and thrombocytopenia with the use of abciximab during percutaneous coronary intervention. J Interv Cardiol. 2005;18:33?37.
  21. Huynh T, Piazza N, Dibattiste PM, et al.. Analysis of bleeding complications associated with glycoprotein IIb/IIIa receptors blockade in patients with high-risk acute coronary syndromes: insights from the PRISM-PLUS study. Int J Cardiol. 2005;100:73?78.
  22. Chiu JH, Bhatt DL, Ziada KM, et al.. Impact of female sex on outcome after percutaneous coronary intervention. Am Heart J. 2004;148:998?1002.
  23. Mueller C, Neumann FJ, Roskamm H, et al.. Women do have an improved long-term outcome after non ST-elevation acute coronary syndromes treated very early and predominantly with percutaneous coronary intervention: a prospective study in 1,450 consecutive patients. J Am Coll Cardiol. 2002;40:245?250.
  24. Cheng CI, Yeh KH, Chang HW, et al.. Comparison of baseline characteristics, clinical features, angiographic results, and early outcomes in men vs women with acute myocardial infarction undergoing primary coronary intervention. Chest. 2004;126:47?53.
  25. Carrabba N, Santoro GM, Balzi D, et al.for the AMI-Florence Working Group. In-hospital management and outcome in women with acute myocardial infarction (data from the AMI-Florence Registry). Am J Cardiol. 2004;94:1118?1123.
  26. Pope JH, Aufderheide TP, Ruthazer R, et al.. Missed diagnoses of acute cardiac ischemia in the emergency department. N Engl J Med. 2000;342:1163?1170.
  27. Manson JE, Hsia J, Johnson KC, et al.. Estrogen plus progestin and the risk of coronary heart disease. N Engl J Med. 2003;349:523?534.
  28. Milner KA, Funk M, Richards S, et al.. Gender differences in symptom presentation associated with coronary heart disease. Am J Cardiol. 1999;84:396?399.
  29. Dellborg M, Herlitz J, Emanuelsson H, et al.. ECG changes during myocardial ischemia. Differences between men and women. J Electrocardiol. 1994;27(Suppl):42?45.
  30. Wiviott SD, Cannon CP, Morrow DA, et al.. Differential expression of cardiac biomarkers by gender in patients with unstable angina/non?ST-elevation myocardial infarction: a TACTICS-TIMI 18 (Treat Angina with Aggrastat and determine Cost of Therapy with an Invasive or Conservative Strategy?Thrombolysis In Myocardial Infarction 18) substudy. Circulation. 2004;109:580?586.
  31. Maynard C, Beshansky JR, Griffith JL, et al.. Influence of sex on the use of cardiac procedures in patients presenting to the emergency department. A prospective multicenter study. Circulation. 1996;94(9 Suppl):II93?II98.
  32. Ayanian JZ, Epstein AM. Differences in the use of procedures between women and men hospitalized for coronary heart disease. N Engl J Med. 1991;325:221?225.
  33. Konstance R, Tcheng JE, Wightman MB, et al.. Incidence and predictors of major vascular complications after percutaneous coronary intervention in the glycoprotein IIb/IIIa platelet inhibitor era. J Interv Cardiol. 2004;17:65?70.
  34. Batchelor WB, Tolleson TR, Huang Y, et al.. Randomized Comparison of platelet inhibition with abciximab, tiRofiban and eptifibatide during percutaneous coronary intervention in acute coronary syndromes: the COMPARE trial. Comparison Of Measurements of Platelet aggregation with Aggrastat, Reopro, and Eptifibatide. Circulation. 2002;106:1470?1476.
  35. Cho L, Topol EJ, Balog C, et al.. Clinical benefit of glycoprotein IIb/IIIa blockade with Abciximab is independent of gender: pooled analysis from EPIC, EPILOG and EPISTENT trials. Evaluation of 7E3 for the Prevention of Ischemic Complications. Evaluation in Percutaneous Transluminal Coronary Angioplasty to Improve Long-Term Outcome with Abciximab GP IIb/IIIa blockade. Evaluation of Platelet IIb/IIIa Inhibitor for Stent. J Am Coll Cardiol. 2000;36:381?386.
  36. Cho L, Marso SP, Bhatt DL, et al.. Optimizing percutaneous coronary revascularization in diabetic women: analysis from the EPISTENT trial. J Womens Health Gend Based Med. 2000;9:741?746.
  37. The PURSUIT Investigators . Inhibition of platelet glycoprotein IIb/IIIa with eptifibatide in patients with acute coronary syndromes. The PURSUIT Trial Investigators. Platelet glycoprotein IIb/IIIa in unstable angina: receptor suppression using integrilin therapy. N Engl J Med. 1998;339:436?443.
  38. Fernandes LS, Tcheng JE, O'Shea JC, et al.. Is glycoprotein IIb/IIIa antagonism as effective in women as in men following percutaneous coronary intervention? Lessons from the ESPRIT study. J Am Coll Cardiol. 2002;40:1085?1091.
  39. Lincoff AM, Bittl JA, Kleiman NS, et al.. Comparison of bivalirudin versus heparin during percutaneous coronary intervention (the Randomized Evaluation of PCI Linking Angiomax to Reduced Clinical Events [REPLACE]?1 trial). Am J Cardiol. 2004;93:1092?1096.
  40. Brener SJ, Moliterno DJ, Lincoff AM, et al.. Relationship between activated clotting time and ischemic or hemorrhagic complications: analysis of 4 recent randomized clinical trials of percutaneous coronary intervention. Circulation. 2004;110:994?998.
  41. Brener SJ, Bhatt DL, Moliterno DJ, et al.. Revisiting optimal anticoagulation with unfractionated heparin during coronary stent implantation. Am J Cardiol. 2003;92:1468?1471.
  42. Casserly IP, Topol EJ, Jia G, et al.. Effect of abciximab versus tirofiban on activated clotting time during percutaneous intervention and its relation to clinical outcomes?observations from the TARGET trial. Am J Cardiol. 2003;92:125?129.
  43. Casserly IP, Kereiakes DJ, Gray WA, et al.. Point-of-care ecarin clotting time versus activated clotting time in correlation with bivalirudin concentration. Thromb Res. 2004;113:115?121.
  44. Cho L, Kottke-Marchant K, Lincoff AM, et al.. Correlation of point-of-care ecarin clotting time versus activated clotting time with bivalirudin concentrations. Am J Cardiol. 2003;91:1110?1113.
  45. Cheneau E, Canos D, Kuchulakanti PK, et al.. Value of monitoring activated clotting time when bivalirudin is used as the sole anticoagulation agent for percutaneous coronary intervention. Am J Cardiol. 2004;94:789?792.
  46. Coronado BE, Griffith JL, Beshansky JR, et al.. Hospital mortality in women and men with acute cardiac ischemia: a prospective multicenter study. J Am Coll Cardiol. 1997;29:1490?1496.
Funding Information

The REPLACE-2 trial was funded by a grant from The Medicines Company, Parsippany, NJ.

Reprint Address

A. Michael Lincoff, MD, Department of Cardiovascular Medicine, Cleveland Clinic Foundation, Desk F25, 9500 Euclid Avenue, Cleveland, OH 44195. Email: lincofa@ccf.org
Matthews Chacko, MD,a A. Michael Lincoff, MD,a Katherine E. Wolski, MPH,a David J. Cohen, MD,b John A. Bittl, MD,c Alexandra J. Lansky, MD,d Yoshihiro Tsuchiya, MD,d Amadeo Betriu, MD,e Michael H. Yen, MD,a Derek P. Chew, MBBS,f Leslie Cho, MD,a Eric J. Topol, MD,a

aCleveland Clinic Foundation, Cleveland, OH; bBeth Israel Deaconess Medical Center, Boston, MA; cOcala Heart Institute, Munroe Regional Medical Center, Ocala, FL; dColumbia University Medical Center, New York City, NY; eUniversity of Barcelona Hospital Clinic, Barcelona, Spain; fFlinders Medical Centre, Adelaide, Australia
Disclosure: Drs Chacko, Wolski, Betriu, Yoshihiro, Yen, Cho, Chew, and Topol?none; Drs Lincoff, Cohen, Bittl, and Lansky?research support from The Medicines Company, Parsippany, NJ.