Impact of Gender on In-Hospital Percutaneous Coronary Interventional Outcomes in African-Americans

Multiple studies have demonstrated that women are at increased risk for in-hospital mortality, stroke, vascular complications, repeat revascularization, and same-admission coronary artery bypass graft surgery (CABG) after percutaneous coronary intervention (PCI).^1,2 Poor outcomes post-PCI have been related to older age and a higher prevalence of risk factors in women compared to men.² This is considered one of the reasons for less frequent use of an invasive management strategy for acute coronary syndromes (ACS) in women.³ Women have been shown to be at higher risk for plaque dissection and adverse procedural events after percutaneous transluminal coronary angioplasty (PTCA),⁴ and glycoprotein IIb/IIIa inhibitors (GPI) have not been shown to be beneficial in women in a meta-analysis.⁵ Furthermore, angiographic restenosis of implanted stents has been shown to be more frequent in women compared to men.⁶ Major studies on conservative management versus early invasive management for ACS have yielded inconsistent results in women. The FRISC II (Fragmin and Revascularization during Instability in Coronary artery disease II)⁷ and RITA-3 (Randomized Intervention Trial of unstable Angina-3)⁸ randomized, controlled trials did not show any benefit of early invasive management in women while the TACTICS-TIMI-18 (Treat angina with Aggrastat and determine Cost of Therapy with an Invasive or Conservative Strategy–Thrombolysis In Myocardial Infarction-18) trial showed benefit in women with the use of early invasive management.⁹
The African-American population has been shown to have a higher prevalence of risk factors for coronary artery disease (CAD) and increased 1-year post-PCI mortality.¹⁰ However, gender differences on post-PCI outcomes in the African-American population are unknown. We sought to study the impact of gender on post-PCI outcomes in an African-American population. Of note, this population of patients was treated with a GPI bolus-only strategy, which is our center’s routine management approach.^11–13

Methods

Patient population. This is a retrospective study of 835 consecutive African-American patients (392 men and 443 women) who underwent PCI using a GPI bolus-only strategy at a single institution from January 2003 to August 2004. The hospital’s Institutional Review Board approved the study. Demographic, periprocedural, and laboratory data were collected by reviewing charts and hospital records. The in-hospital events and the length of stay were also recorded. Patients with ST-elevation myocardial infarction were excluded from the study.
Periprocedural medication. All patients were loaded with aspirin 325 mg and clopidogrel 300–600 mg just prior to PCI. All patients received an initial intravenous bolus of 40 units/kg unfractionated heparin (UFH) plus a GPI bolus at the beginning of the intervention. No infusion of GPI was administered following the bolus dose (routine management at SUNY Health Science Center). UFH was administered as supplemental boluses if required to achieve an activated clotting time (ACT) of at least 200 seconds. ACT was measured by using the Hemochron^® device (ITC Technidyne Corp, Edison, New Jersey).
Coronary intervention. Coronary interventional procedures were performed according to standard techniques, via a femoral approach. Balloon angioplasty, stents, and rotational atherectomy were used at the operator’s discretion. Femoral vascular closure devices (Angio-Seal, St. Jude Medical, Minnetonka, Minnesota) or Perclose (Perclose, Inc., Redwood City, California) were used unless contraindicated. Serial monitoring of cardiac biomarkers was performed every 8 hours for 24 hours after PCI, and hemoglobin levels were measured every 24 hours until the patient was discharged.
Definitions. Post-PCI myocardial infarction (MI) was defined according to the Thrombolysis in Myocardial Infarction (TIMI) criteria.¹⁴ A new MI was defined by biochemical, or electrocardiographic criteria: the MB isoform of creatine kinase (CK-MB) at least three times the upper limit of the normal range in at least one blood sample, or the finding of abnormal Q-waves in two or more contiguous leads. For patients with recent MI who had an elevated CK-MB level before the procedure, a value of more than three times the upper limit of normal and at least 50% above the baseline value was required to meet the definition.
Bleeding was defined according to the Randomized Evaluation in the PCI Linking Angiomax to Reduced Clinical Events (REPLACE-2) criteria.¹⁵ Major bleeding was defined as either any intracranial, intraocular, retroperitoneal, or clinically-overt bleeding with a drop of hemoglobin of 3 g/dl, or any drop of hemoglobin of 4 g/dl, or the transfusion of 2 or more units of packed red blood cells. Minor bleeding was defined as clinically-overt bleeding not meeting the above criteria. We chose to define and compare our bleeding complications using the REPLACE-2 trial definitions and outcomes, as this trial uses a sensitive definition of bleeding and has reported the lowest rates of bleeding in the context of modern PCI.
Thrombocytopenia was defined as a fall in the platelet count below 100,000/µl, or a decrease by 25% below baseline values, in the event the initial platelet count was less than 100,000/µl.
For the purpose of classification, all patients with stable angina or positive stress test or patients with new onset congestive heart failure undergoing PCI were included under “stable angina and others” (Table 1).
Statistical analysis. Continuous variables are presented as mean ± standard deviation (SD). Categorical variables are presented as percentages. The Chi-square test was used to compare the differences between categorical variables. The independent samples t-test was used to compare between continuous variables with normal distribution and the Mann-Whitney test was used to compare continuous variables without a normal distribution. Adjustment for baseline risk factors and angiographic characteristics was done using multivariate analysis with gender as an independent variable and in-hospital outcomes as dependent variables. Age, body mass index (BMI), family history of CAD, smoking, frequency of single-vessel disease, double-vessel disease and triple-vessel disease, and left ventricular (LV) dysfunction were the covariates used in the multivariate analysis as these risk factors were significantly different between the two groups. Multiple logistic regression analysis was performed to determine whether gender is an independent risk factor for in-hospital outcomes. A p-value <0.05 was considered significant. All statistical analyses are performed utilizing SPSS software, version 13.0 (SPSS, Inc., Chicago, Illinois).

Results

Baseline and procedural characteristics. The baseline characteristics and indication for the procedure are listed in Table 1 and procedural characteristics are presented in Table 2. The mean age of women was higher (63 vs. 61 years; p <0.01) and this group had a greater number of patients over the age of seventy years (20.8% vs. 13.5%; p <0.01). BMI of women was higher than men (31.5 vs. 29.5; p <0.001). The prevalence of hypertension and diabetes mellitus was similar in both groups. More women had a family history of CAD compared to men (32 vs. 24.5; p = 0.017). Men were more likely to smoke compared to women (46% vs. 21% respectively; p <0.001). The prevalence of congestive heart failure (CHF), end stage renal disease (ESRD), hyperlipidemia and renal insufficiency were similar in both the groups. Indication for the procedure was ACS in 56.3% and 53.3% in males and females respectively (p = NS). The ACC/AHA type B1 lesion was the most common lesion in both groups. Eptifibatide followed by abciximab was the most common GPI used in both the groups. Men had a significantly lower mean ejection fraction (EF) compared to women. Use of closure devices and procedural success was similar in both the groups. In-hospital outcomes. The in-hospital outcomes are presented in Table 3 and the breakdown of bleeding complications and other vascular complications are shown in Table 4. The mean length of stay was 1.6 days in men and 2.2 in women (p = NS). There were no deaths or in-hospital repeat revascularizations in both groups. After adjustment for baseline risk factors and procedural characteristics, there was no significant difference in the composite endpoint of in-hospital death, MI, and repeat revascularization between men and women (6.38% in men and 2.48% in women; p = 0.051). Men had a marginally higher incidence of post-PCI MI (6.38% vs. 2.48% in women; p = 0.051). These patients also had a higher incidence of LV dysfunction and after adjustment for risk factors (including LV dysfunction) there was no difference in the incidence of MI between the groups. Women had a significantly higher rate of major and minor bleeding complications (0.5 vs. 2.5; p = 0.019 and 0.5 vs. 2.3; p = 0.021, respectively). The mean hemoglobin values were significantly lower in women compared to men both prior to and post-PCI and the mean drop was significantly greater in women (p <0.01) (Table 6). In women the majority (64%) of the major bleeding was due to a drop in hemoglobin without an obvious source, requiring greater than 2 units of packed red blood cells for transfusion. Minor bleeding in women was predominantly (70%) due to bleeding or hematomas from the vascular puncture site. On multiple logistic regression analysis, female gender was an independent risk factor for bleeding post-PCI (adjusted odds ratio [OR]-5.6, 95% confidence intervals [CI]: 1.15–27.45). Other vascular complications like pseudoaneurysm, ischemic cerebrovascular accident (CVA)/transient ischemic attack (TIA), and thrombosis of the aorto-femoral bypass were similar in both the groups.

Discussion

This study demonstrates that although the in-hospital composite endpoint consisting of death, MI, and repeat revascularization is similar between African-American men and women, African-American women appear to be at increased risk for bleeding complications post-PCI. Previously there have been multiple studies on gender differences with respect to post-PCI outcomes, but the present study is unique in that we evaluated an exclusively African-American population. Furthermore, our study is unique in that all patients were administered a bolus-only GPI regimen during PCI, potentially lowering the rates of bleeding. However, in the context of even minimal GPI use, gender differences in bleeding rates were still detectable. The adoption of a bolus-only GPI strategy was based on the recently reported data on the efficacy and safety of this regimen during PCI.^11–13
Compared to previous studies on gender differences during PCI, women in the present study did not have a worse clinical profile compared to men.^16,17 Prior studies (which predominantly were comprised of a Caucasian population) have reported that women who underwent PTCA were older, more frequently had traditional risk factors for coronary artery disease (hypertension, diabetes, hyperlipidemia), and were more likely to have unstable angina, congestive heart failure and more severe concomitant noncardiac disease, and were more often deemed inoperable or high risk for surgery compared to men.¹⁶ In our study, the traditional risk factors of hypertension, diabetes mellitus, and hyperlipidemia (except smoking) were similar in both groups. Also, the indications for cardiac catheterization and intervention (ACS and stable angina) were similar between the groups. Similar to prior studies, women in our study were on average 2 years older than men and were more often above the age of 70 years compared to men. There was no difference in BMI between men and women in the prior studies, while the women in our group had significantly higher BMI compared to men.¹⁶ In the recent subanalysis of the TARGET (Do Tirofiban and ReoPro Give Similar Efficacy Outcomes?) trial on the effect of BMI on PCI, obese patients had lesser major bleeding complications.¹⁸ Women in our study with higher BMI still had higher major and minor bleeding complications compared to men.
Men have been reported to have a lower EF compared to women, perhaps secondary to men having a higher incidence of prior MI compared to women.^16,19 In our African-American population, although the history of CAD was similar in both groups, women on an average had 5% higher EF compared to men. Also, on logistic regression analysis, a history of CHF and low EF were independent predictors of post-PCI MI. Of the two National Heart, Lung, and Blood Institute's Coronary Angioplasty Registry reports on gender differences during PTCA, angiographic characteristics were similar in men and women in one report,¹⁶ and men had more frequent multivessel disease compared to women in another report.¹⁷ Also, the New Approaches to Coronary Intervention (NACI) registry had a greater number of men with triple-vessel disease compared to women.¹⁹ Similar to the prior studies, African-American men had more frequent triple-vessel disease compared to women. The rate of procedural success has been shown to be similar in both genders after angioplasty and stenting.^16,20 In our single-center experience, African-American men and women had similar success rates after PCI and the rate of multivessel interventions were similar in both groups. Women have been shown to have an increased in-hospital mortality after PTCA and stenting.¹ Women were considered to have increased mortality after PTCA because of small coronary vessel diameter, which may have been improved after increasing use of stents, but the post-PCI mortality remained twice compared to men after stent implantation.¹ In contrast, our study did not have any deaths or repeat revascularizations post-PCI and therefore no differences based on gender could be detected. This may reflect our relatively small sample size or improvements in technology (both pharmacological and mechanical) that have rendered PCI a safer procedure.
An additional distinction between our findings and the literature relates to gender-specific post-PCI MI rates. Previous reports have noted no difference in the rates of post-PCI MI in men versus women.^6,21 The post-PCI MI rates were marginally higher in men in our study, possibly secondary to a higher risk profile (higher smoking rates, triple-vessel disease and lower ejection fraction). On logistic regression analysis triple vessel disease and LV dysfunction were strong predictors of post-PCI MI, potentially explaining the higher rates of post-PCI MI in African-American men.
Women have been shown to have increased bleeding complications post PCI.²¹ In our study, African-American women had significantly higher major and minor bleeding complications compared to African-American men. On logistic regression analysis, increasing age, female gender, ESRD, and decreasing creatine clearance were independent risk factors for increased bleeding complications. The majority of the major bleeds were secondary to covert bleeds requiring greater than two units of blood transfusion and minor bleeds were predominantly due to complications at the vascular puncture site despite use of closure devices in more than one-third of the patients. In the REPLACE-2 trial, post-PCI bleeding was a stronger predictor of 1-year mortality (OR, 3.5; 95% CI, 1.9–6.5) than was creatine kinase-MB enzyme elevation (OR, 2.6; 95% CI; 1.5–4.5).²¹ Because African-American women appear to be at increased risk for bleeding complications, which strongly predicts increased 1-year mortality, interventionalists should take all reasonable measures to minimize bleeding in this population.
One of the strongest predictors for vascular complications in women was the use of GPI,²² but in our study all patients received only a standard bolus dose of GPI without prolonged infusions. Due to routine use of high-dose clopidogrel and stents at our institution, GPIs are given as a bolus-only regimen to reduce bleeding complications. Also, the percentage of the patients receiving abciximab, eptifibatide, and tirofiban was similar in men and women. The use of closure devices has been shown to reduce the incidence of vascular complications at the access site post-PCI, especially in patients who received GPI.²³ In our study the use of closure devices was slightly higher in males, which was not statistically significant.
Study limitations. This study is a retrospective analysis and has all the inherent limitations of a retrospective study. The sample size was not large and there were no deaths or repeat revascularizations to determine whether gender differences exist in African-Americans with respect to in-hospital mortality or repeat revascularization. The outcomes studied were only in-hospital, and there were no long-term follow-up data. However, the Integrilin to Minimize Platelet Aggregation and Coronary Thrombosis-II (IMPACT-II) investigators study on the time course of adverse events post-PCI showed that 66% of the total adverse events during the initial 30 days occur within the first 6 hours, the risk of events declined substantially between 6 hours and 9 hours, and the hazard function plot was flat after 9 hours.²⁴

Conclusion

Our study on the effect of gender on differences in post PCI outcomes in an African-American population showed that the in-hospital composite endpoint of death, MI, and repeat revascularization was similar in men and women, but African American women are at increased risk for bleeding complications, even in the context of a bolus-only GPI strategy.

References

1. 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.
2. Peterson ED, Lansky AJ, Kramer J, et al. National Cardiovascular Network Clinical Investigators. Effect of gender on the outcomes of contemporary percutaneous coronary intervention. Am J Cardiol 2001;88:359–364.
3. Maynard C, Litwin PE, Martin JS, et al. Gender differences in the treatment and outcome of acute MI: Results from the MITI Registry. Arch Intern Med 1992;152:972–976.
4. Carcagni A, Camellini M, Maiello L, et.al. Percutaneous transluminal coronary revascularization in women: Higher risk of dissection and need for stenting. Ital Heart J 2000;1:536–541.
5. Boersma E, Harrington RA, Moliterno DJ, et al. Platelet glycoprotein IIb/IIIa inhibitors in acute coronary syndromes: A meta-analysis of all major randomised clinical trials. Lancet 2002;359:189–198.
6. Trabattoni D, Bartorelli AL, Montorsi P, et al. Comparison of outcomes in women and men treated with coronary stent implantation. Catheter Cardiovasc Interv 2003;58:20–28.
7. Lagerqvist B, Safstrom K, Stahle E, et al. for the FRISC II Study Group Investigators. Is early invasive treatment of unstable coronary artery disease equally effective for both women and men? J Am Coll Cardiol 2001;38:41–48.
8. Fox KA, Poole-Wilson PA, Henderson RA, et al. Interventional versus conservative treatment for patients with unstable angina or non-ST-elevation myocardial infarction: The British Heart Foundation RITA 3 randomised trial. Lancet 2002;360:743–751.
9. Cannon CP, Weintraub WS, Demopoulos LA, et al. Comparison of early invasive and conservative strategies in patients with unstable coronary syndromes treated with the glycoprotein IIb/IIIa inhibitor tirofiban. N Engl J Med 2001;344:1879.
10. Leborgne L, Cheneau E, Wolfram R, et al. Comparison of baseline characteristics and one-year outcomes between African-Americans and Caucasians undergoing percutaneous coronary intervention. Am J Cardiol 2004;93:389–393.
11. Marmur JD, Mitre CA, Barnathan E, Cavusoglu E. Benefit of bolus-only platelet glycoprotein IIb/IIIa Inhibition during percutaneous coronary intervention: Insights from the very early outcomes in the EPIC Trial. Am Heart J 2006;152:876–881.
12. Fischell TA, Attia T, Rane S, Salman W. High-dose, single-bolus eptifibatide: A safe and cost-effective alternative to conventional glycoprotein IIb/IIIa Inhibitor use for elective coronary interventions. J Invasive Cardiol 2006;18:487–491.
13. Marmur JD, Poludasu S, Agarwal A, et al. Bolus-only platelet glycoprotein IIb-IIIa inhibition during percutaneous coronary intervention. J Invasive Cardiol 2006;18:521–526.
14. Bovill EG, Terrin ML, Stump DC, et al. Hemorrhagic events during therapy with recombinant tissue-type plasminogen activator, heparin, and aspirin for acute myocardial infarction. Results of the Thrombolysis in Myocardial Infarction (TIMI), Phase II Trial. Ann Intern Med 1991;115:256–265.
15. 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 intervention: REPLACE-2 randomized trial. JAMA 2003;289:853–863.
16. Kelsey SF, James M, Holubkov AL, et al. Results of PTCA in women: 1985–1986 NHLBI coronary angioplasty registry. Circulation 1993;87:720–727.
17. Cowley MJ, Mullin MM, Kelsey SF, et al. Sex differences in early and long-term results of coronary angioplasty in the NHLBI PTCA registry. Circulation 1985;71:90–97.
18. Martin JL, Jia G, Martin SS, et al. The relationship of obesity to ischemic outcomes following coronary stent placement in contemporary practice. Catheter Cardiovasc Interv 2006;67:563–570.
19. Robertson T, Kennard ED, Mehta S, et al. Influence of gender on in-hospital clinical and angiographic outcomes and on one-year follow-up in the New Approaches to Coronary Intervention (NACI) registry. Am J Cardiol 1997;80:26K–39K.
20. Schuhlen H, Kastrati A, Dirschinger J, et al. Intracoronary stenting and risk for major adverse cardiac events during the first month. Circulation 1998;98:104–111.
21. Thompson CA, Kaplan AV, Friedman BJ, et al. Gender-based differences of percutaneous coronary intervention in the drug-eluting stent era. Catheter Cardiovasc Interv 2006;67:25–31.
22. Feit F. Bivalirudin: Bleeding analysis of REPLACE-2 [TCTMD Webcast series]. New York, New York: Cardiovascular Research Foundation. Presented at: ACUITY Webcast Series; April 26, 2004. Available at: http://tctmd.com/descwebcasts/one.html?webcast_id=301.
23. Resnic FS, Blake GJ, Ohno-Machado L, et al. Vascular closure devices and the risk of vascular complications after percutaneous coronary intervention in patients receiving glycoprotein IIb-IIIa inhibitors. Am J Cardiol 2001;88:493–496.
24. Mark C.Thel, Robert M. Califf, Barbara E. Tardiff, et.al. Timing of and risk factors for myocardial ischemic events after percutaneous coronary intervention (IMPACT-II). Am J Cardiol 2000;85:427–434.