Sex and effect of abciximab in patients with acute coronary syndromes treated with percutaneous coronary interventions: Results from Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment 2 trial

doi:10.1016/j.ahj.2007.03.050

American Heart Journal

Volume 154, Issue 1, July 2007, Pages 158.e1-158.e7

https://doi.org/10.1016/j.ahj.2007.03.050 Get rights and content

Background

It is not known whether there exists a sex-dependent difference in the clinical benefit of abciximab in patients with acute coronary syndromes (ACS) undergoing a percutaneous coronary intervention (PCI).

Methods

We performed this retrospective analysis of 2022 patients (498 women) with ACS enrolled in the Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment 2 trial and randomized to receive abciximab or placebo during a PCI procedure. The incidence of major adverse cardiac events (MACE) during the 30 days after PCI was the primary end point of the study.

Results

Among men, the 30-day incidence of MACE was 8.6% in the abciximab group compared with 12.6% in the placebo group, relative risk (RR) 0.69 (95% confidence interval [CI] 0.50-0.94), P = .01. The 30-day incidence of MACE in women was 9.7% in the abciximab group compared with 9.9% in the placebo group, RR 0.98 (95% CI, 0.56-1.72), P = .97. After adjustment for baseline clinical and angiographic characteristics, there was no significant interaction between sex and abciximab (P = .71); adjusted RR was 0.70 (95% CI, 0.34-1.34) in women and 0.60 (95% CI, 0.40-0.90) in men. The incidence of major bleeding was significantly greater in women (3.6%) than in men (0.7%), RR 5.5 (95% CI, 2.54-11.9), P < .001, without any dependence on the form of therapy received.

Conclusions

In patients with non-ST elevation ACS undergoing a PCI, the benefit with abciximab is greater in men than in women. This is apparently the result of sex-based differences in risk profile.

Section snippets

Patients

A total of 2022 high-risk patients with NSTE-ACS (between March 2003 and December 2005) were included in ISAR-REACT 2. Detailed information about study design, and inclusion and exclusion criteria has been published previously.⁶ Briefly, patients presenting with angina within the preceding 48 hours and either troponin T level >0.03 μg/L or newly developed ST segment depression of at least 0.1 mV or transient (<20 minutes) ST segment elevation of at least 0.1 mV or new or presumed new bundle

Baseline characteristics

Baseline characteristics of women and men enrolled in the ISAR-REACT 2 trial independent of the treatment group showed significant differences. Women were older than men (70.5 ± 10.3 vs 64.9 ± 11.0 years; P < .001), more frequently had diabetes (33.9% vs 24.1%; P < .001) and arterial hypertension (75.1% vs 59.5%; P < .001), and had worse renal function (glomerular filtration rate, 71.4 ± 29.7 vs 92.4 ± 52.9 mL/min; P < .001) compared with men. On the other hand, a lower proportion of women were

Discussion

This study shows that women and men with NSTE-ACS differ in their response to abciximab therapy during PCI. Adjunct peri-interventional therapy with abciximab after loading with 600 mg clopidogrel is associated with 31% reduction of risk for death, myocardial infarction, or urgent target vessel revascularization in men presenting with NSTE-ACS. In contrast, women did not show any benefit after the use of abciximab. However, after adjustment for the risk profile and other baseline

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Cited by (16)

Cardiovascular Medications
2021, Sex Differences in Cardiac Diseases: Pathophysiology, Presentation, Diagnosis and Management
A 69-year-old Caucasian woman was admitted in the emergency department after 1 week with fever, shortness of breath, malaise, dry cough, and gastroenteritis with 4-day history of diarrhea. Past medical history was significant for hypertension, dyslipidemia, paroxysmal atrial fibrillation, and depression. Her home medications included furosemide (20 mg), valsartan (80 mg), simvastatin (40 mg), sotalol (80 mg twice daily), warfarin, escitalopram (20 mg), and omeprazole (20 mg). She had also recently initiated treatment with solifenacin (10 mg) due to urinary incontinence. On admission, she was febrile (102 °F) and tachycardic (90 bpm), with oxygen saturations of 95% on room air. Chest X-ray confirmed an interstitial pneumonia and the physician prescribed ceftriaxone (1 g i.v.) and azithromycin (500 mg once daily for 3 days). An initial electrocardiogram (ECG) revealed a prolonged QTc interval of 560 ms. Serum potassium was 3.5 mmol/L and serum magnesium was 1.4 mg/dL. Renal, hepatic, and thyroid functions were normal. The echocardiogram showed a left ventricular hypertrophy consistent with hypertension, a left ventricular ejection fraction of 55%, a mildly dilated left atrium, and no significant valvular disease. About 24 h after initiating the antibiotic therapy, she experienced intermittent dizziness of short duration. A marked QT prolongation (QTc 650 ms) was observed on the telemetry, with premature ventricular complexes with prolonged compensatory pauses and an episode of torsades de pointes (TdP) (Figure 1). Azithromycin, citalopram, sotalol, and solifenacin were withdrawn. Magnesium sulfate and lidocaine were administered slowly intravenously and electrolyte disturbances were corrected. During the next 2 days, the QTc interval gradually returned to normal and no further arrhythmias were observed. She was discharged to home from hospital by day 4. Two weeks later she presented to the outpatient clinic for a follow-up. ECG demonstrated a QTc interval of 435 ms.
Women and men exhibit significant differences in body composition and hormonal variations, and in drug pharmacokinetics and pharmacodynamics, such that they may respond differently to many cardiovascular drugs. However, the role of sex-related differences (SRDs) in clinical practice is not yet completely elucidated, probably because women are largely underrepresented in randomized clinical trials and sex-specific analysis usually is not included in the evaluation of clinical trials. Furthermore, women were prescribed more drugs, demonstrate less adherence to the prescribed medications, are less often treated with guideline-recommended drugs, and experienced more frequent and severe drug adverse reactions than men. But even when SRDs in cardiovascular pharmacology are well known, translation of these differences into clinical practice is slow. SRDs in drug efficacy and safety have to be considered at every step in the drug development to optimize medical therapy in both men and women. This chapter summarizes the most important SRDs in the pharmacokinetics, efficacy, and safety of the most frequently used cardiovascular drugs. A better understanding of SRDs in the efficacy and safety of cardiovascular drugs is the first step for developing a personalized drug therapy for the prevention and treatment of cardiovascular diseases, which represent the leading cause of morbidity and mortality among both men and women.
Sex-related effectiveness of bivalirudin versus abciximab and heparin in non-ST-segment elevation myocardial infarction
2013, American Heart Journal
Citation Excerpt :
Unlike those presenting with biomarker negative ACS, patients with NSTEMI-ACS benefit significantly from the use of the abciximab in addition to pretreatment with clopidogrel.14 However, the efficacy of abciximab appears to be sex dependent with greater benefit seen in men than in women.16 Sex-specific differences in pharmacologic response to antithrombotic drugs9,17 and differences in risk profile—older age, more frequent presentation with diabetes, or renal failure among women—are considered the most probable explanations for sex-related differences in performance of antithrombotic drugs.2,9,16,18-20
Female sex independently predicts bleeding risk after percutaneous coronary intervention (PCI). Bivalirudin is safer than abciximab plus heparin in patients with non–ST-segment elevation myocardial infarction (NSTEMI). Thus, a greater benefit of bivalirudin in women would be expected.
We performed a sex-based analysis of the patients with NSTEMI (n = 1,721, 399 women) enrolled in the ISAR-REACT 4 trial and randomized to receive bivalirudin or abciximab plus heparin. Main outcome was a 30-day composite of death, large recurrent myocardial infarction, urgent target vessel revascularization, or major bleeding. Secondary outcome was 1-year composite of death, myocardial infarction, or target vessel revascularization.
No difference in the main outcome was observed in groups with bivalirudin or abciximab plus heparin: 12.6% versus 15.5% (hazard ratio [HR] 0.81, 95% CI 0.48-1.37) among women and 10.6% versus 9.5% (HR 1.12, 95% CI 0.77-1.64) among men. Major bleeding occurred in 4.5% in the bivalirudin group versus 7.5% in the abciximab plus heparin group (HR 0.60, 95% CI 0.26-1.39) among women and 2.0% versus 3.8% (HR 0.52, 0.27-1.02) among men. At 1 year, the secondary outcome was observed in 24.1% in the bivalirudin group versus 28.7% in the abciximab plus heparin group among women, HR of 0.80 (95% CI 0.55-1.17), and in 20.6% and 19.0%, respectively, HR of 1.10 (95% CI 0.86-1.40) among men.
Despite a higher peri-PCI bleeding risk in women, bivalirudin is as effective as and safer than abciximab plus heparin in women and men with NSTEMI undergoing PCI.
Propensity score-matched analysis of effects of clinical characteristics and treatment on gender difference in outcomes after acute myocardial infarction
2011, American Journal of Cardiology
The greater mortality observed in women compared to men after acute myocardial infarction remains unexplained. Using an analysis of pairs, matched on a conditional probability of being male (propensity score), we assessed the effect of the baseline characteristics and management on 30-day mortality. Consecutive patients were included from January 2006 to December 2007. Two propensity scores (for being male) were calculated, 1 from the baseline characteristics and 1 from both the baseline characteristics and treatment. Two matched cohorts were composed using 1:1 matching and computed using the best 8 digits of the propensity score. Paired analyses were performed using conditional regression analysis. During the study period, 3,510 patients were included in the registry; 1,119 (32%) were women. Compared to the men, the women were 10 years older, had more co-morbidities, less often underwent angiography and reperfusion, and received less medical treatment. The 30-day mortality rate was 12.3% (130 of 1,060) for the women and 7.2% (167 of 2,324) for the men (p <0.001). The 2 matched populations represented 1,298 and 1,168 patients. After matching using the baseline characteristics, the only difference in treatment was a lower rate of angiography and reperfusion, with a trend toward greater 30-day mortality in women. After matching using both baseline characteristics and treatment, the 30-day mortality was similar for the men and women, suggesting that the increased use of invasive procedures in women could potentially be beneficial. In conclusion, compared to men, the 30-day mortality is greater in women and explained primarily by differences in baseline characteristics and to a lesser degree by differences in management. The difference in the use of invasive procedures persisted after matching by characteristics. In contrast, after matching using the baseline characteristics and treatment, the 30-day mortality was comparable across the genders.
Contemporary outcomes in women undergoing percutaneous coronary intervention for acute coronary syndromes
2011, International Journal of Cardiology
Citation Excerpt :
However, in the National Heart, Lung, and Blood Institute (NHLBI) registry the excess bleeding in women has persisted over time, as has the risk of vascular complications [24]. Similarly, a European study found that regardless of abciximab use, women with ACS undergoing PCI experience an increase in major bleeding requiring transfusion compared to men (3.6% vs. 0.7%, OR 5.5, 95% CI 2.54–11.92, p < 0.001), in line with our results [26]. A possible reason is that women have a smaller body surface area with smaller peripheral arteries [27,28].
Uncertainty remains as to whether females benefit as much as males from percutaneous coronary intervention (PCI) in the setting of an acute coronary syndrome (ACS).
We compared 802 women with 2151 men presenting with ACS, undergoing PCI from April 2004 to October 2006 from the Melbourne Interventional Group registry. Clinical characteristics, in-hospital, 30-day and 1-year outcomes were compared.
Women were older (69.6 ± 11.6 vs. 62.17 ± 12.3 years, p < 0.001), and had more diabetes (27.1% vs. 19.6%, p < 0.001) and hypertension (70.3% vs. 53.9%, p < 0.001) than men. Women were less likely to present with ST-elevation myocardial infarction (30.5% vs. 37.9%, p < 0.001). Bleeding (3.6% vs. 0.8%, p < 0.001) was higher among women. Thirty-day mortality (4.7 vs. 2.4%, p < 0.001) and MACE (10.1 vs. 6.4%, p < 0.001) were higher in women. Gender was an independent predictor of overall MACE at 30 days (OR 1.45, 95% CI 1.04–2.02, p = 0.03) but not death. At 12 months, there were no significant differences in mortality (6.4% vs. 4.8%, p = 0.09), myocardial infarction (5.5% vs. 5.0%, p = 0.64), target vessel revascularization (7.9% vs. 7.0%, p = 0.42) and MACE (16.3% vs. 14%, p = 0.13) between women and men.
There is an early hazard amongst women undergoing PCI for ACS, but not at 12 months. These data suggest that gender should not affect the decision to offer PCI but further gender specific studies are warranted.
Effect of Abciximab on Clinical and Angiographic Restenosis in Patients With Non-ST-Segment Elevation Acute Coronary Syndromes
2008, American Journal of Cardiology
Citation Excerpt :
Specifically, older patients, women, and those with small targeted vessels seemed to benefit most using abciximab in terms of decrease in need for target-lesion revascularization within the first year after stenting. Interestingly, some subsets that showed a greater decrease in restenosis with abciximab (elderly patients and women) were reported to have a smaller decrease in 30-day thrombotic complications using this drug.28,29 Although this finding comes from subset analysis, it may suggest the mechanistic independence of the 2 processes of thrombosis and restenosis.
The ISAR-REACT 2 trial was designed to assess the effect of abciximab in patients with acute coronary syndromes undergoing percutaneous coronary intervention after a 600-mg loading dose of clopidogrel. The aim of the present study was to investigate the impact of abciximab on clinical and angiographic restenosis after coronary stenting in patients with acute coronary syndromes. The angiographic substudy included 1,544 patients from the ISAR-REACT 2 trial randomly assigned to abciximab (771 patients) or placebo (773 patients). All patients were scheduled for routine angiographic follow-up at 6 to 8 months after intervention. The primary end point was incidence of angiographic in-segment binary restenosis. The secondary end point was 1-year incidence of target-lesion revascularization. Binary restenosis was observed in 21.9% of patients in the abciximab group and 24.5% of patients in the placebo group (p = 0.29). Percentages of in-stent (29 ± 22% vs 33 ± 24%; p = 0.02) and in-segment (35 ± 20% vs 38 ± 21%; p = 0.04) diameter stenoses were significantly lower in the abciximab group than the placebo group. There was a strong trend toward lower 1-year incidence of target-lesion revascularization in patients treated with abciximab than in patients treated with placebo (13.6% vs 16.8%; p = 0.08). In conclusion, in patients with non–ST-segment elevation acute coronary syndromes undergoing early percutaneous coronary intervention with stenting after a 600-mg loading dose of clopidogrel, abciximab therapy may have a slight positive impact on the prevention of restenosis.
Percutaneous Coronary Intervention in Women: In-Hospital Clinical Outcome. Experience from a Single Private Institution in Melbourne
2008, Heart Lung and Circulation
Differences in outcome between women and men treated with percutaneous coronary intervention (PCI) have decreased. This study was aimed at assessing the demographic, clinical, and angiographic features, procedural characteristics and in-hospital results of women undergoing PCI and comparing their results with those of a group of men undergoing PCI throughout the same period of time.
All consecutive PCI procedures performed at Epworth Hospital from November 2004 to January 2007 were analysed. Women and men were compared according to baseline clinical, angiographic and procedural characteristics, angiographic success rates and in-hospital outcomes.
A total of 1699 consecutive PCI procedures were performed; of these, 405 PCI (23.8%) were performed in women. Women were older (73.9 ± 10 years versus 66.1 ± 11.9 years, p < 0.0001), had a higher prevalence of hypertension (78% versus 63%, p < 0.0001), had lower prevalence of prior myocardial infarction (21% versus 27%, p = 0.026), and had less history of prior coronary artery by-pass surgery (13% versus 18%, p = 0.023) than men. A greater proportion of women presented with acute coronary syndromes (ACS) to PCI than men (63.7% versus 52.9%, p < 0.0001).
Women had more complex lesions B2/C (78% versus 74%, p = 0.049), a higher proportion of ostial lesions (10.5% versus 5.5%, p < 0.0001) and less multivessel disease (48% versus 54% p = 0.028) than men. Angiographic lesion success rates were similar in both groups.
Total unadjusted in-hospital mortality was higher in women than in men (1.97% versus 0.54%, respectively, p = 0.013). This difference in mortality was only at the expense of a higher unadjusted mortality in women presenting with ST segment elevation myocardial infarction (STEMI) than men (17.5% versus 1.87%, p = 0.002). No women with a stable coronary syndrome or non-ST-segment elevation acute coronary syndrome (NSTE-ACS) died in hospital. There were no differences in in-hospital myocardial infarction, new revascularisation or stroke between both groups.
PCI in women has good results but carries an increased unadjusted mortality than in men. This mortality difference between genders in our study, however, was solely at the expense of a higher unadjusted mortality in women than in men undergoing PCI for STEMI.

View all citing articles on Scopus

: Clinical Trial Registration Information: www.clinicaltrials.gov (Identifier: NCT00133003).

: This trial was supported in part by the grant Kommission für Klinische Forschung (KKF) 04-03 from Deutsches Herzzentrum, Munich, Germany.

: Disclosures: Dr Kastrati reports having received lecture fees from Bristol-Myers Squibb, Lilly, and Sanofi Aventis. Dr Berger reports having received lecture fees from Schering Plough and from CME companies supported by Bristol-Myers Squibb, Sanofi-Aventis. Dr Seyfarth reports having received lecture fees from Lilly, Bristol-Myers Squibb, and Sanofi-Aventis. The other authors report no potential conflicts of interest.

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Clinical InvestigationInterventional CardiologySex and effect of abciximab in patients with acute coronary syndromes treated with percutaneous coronary interventions: Results from Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment 2 trial

Background

Methods

Results

Conclusions

Section snippets

Patients

Baseline characteristics

Discussion

J Am Coll Cardiol

Am J Cardiol

J Am Coll Cardiol

Lancet

J Am Coll Cardiol

J Am Coll Cardiol

Am J Cardiol

Am J Cardiol

J Am Coll Cardiol

J Am Coll Cardiol

Am Heart J

J Am Coll Cardiol

Acute coronary syndrome: ST segment elevation myocardial infarction

BMJ

Evaluation of prolonged antithrombotic pretreatment (“cooling-off” strategy) before intervention in patients with unstable coronary syndromes: a randomized controlled trial

JAMA

Randomized clinical trial of abciximab in diabetic patients undergoing elective percutaneous coronary interventions after treatment with a high loading dose of clopidogrel

Circulation

Clinical Investigation
Interventional Cardiology
Sex and effect of abciximab in patients with acute coronary syndromes treated with percutaneous coronary interventions: Results from Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment 2 trial