doi: 10.1161/CIRCULATIONAHA.106.647883
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(Circulation. 2006;114:1344-1346.)
© 2006 American Heart Association, Inc.
Editorial |
Small-Molecule Glycoprotein IIb/IIIa Antagonists and Bleeding Risk in Women
Too Much of a Good Thing?
From the Cardiology Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass.
Correspondence to Jane A. Leopold, MD, Brigham and Women’s Hospital, 77 Ave Louis Pasteur, NRB 0630K, Boston, MA 02115. E-mail jleopold{at}partners.org
Key Words: Editorials • anticoagulants • hemorrhage • kidney • women
Initial treatment strategies for patients who present with non–ST-segment–elevation acute coronary syndromes (NSTE ACSs) recommend early administration of both antiplatelet and antithrombotic therapies. Clinical trials have borne out the efficacy of upstream use of small-molecule glycoprotein IIb/IIIa (GP IIb/IIIa) antagonists in high-risk patients identified by positive cardiac serum markers and ST-segment ECG changes. In troponin-positive patients, these agents were found to be equally efficacious in men and women.1 The magnitude of risk reduction is significant; a meta-analysis has demonstrated an 
9% relative reduction in the odds of death or myocardial infarction at 30 days in patients treated with GP IIb/IIIa antagonists.1
Article p 1380
Despite these clinical benefits, the decision to treat with a GP IIb/IIIa antagonist must consider, and adjust for, the increased risk of major bleeding inherent with the use of these agents. Meta-analyses have found a 32% increased risk of moderate to major bleeding in GP IIb/IIIa antagonist–treated patients, with an increased incidence of adverse hemorrhagic events in women compared with men (3.0% versus 2.2%).1,2 It is of particular interest that female gender has been identified consistently as a risk factor for hemorrhagic events.3 In women, the increased incidence of bleeding after GP IIb/IIIa antagonist administration has been attributed to advanced age at presentation, higher-risk clinical characteristics, and smaller body surface area (BSA) compared with their male counterparts, as well as altered platelet function and gender-specific differences in pharmacokinetic and pharmacodynamic effects.4–6 Although these risk factors were suggested by clinical trial results, "real-world" experience often differs significantly.7 Therefore, registry studies may provide valuable insight into the factors contributing to the increased risk of bleeding in women treated with small-molecule GP IIb/IIIa antagonists.
In this issue of Circulation, Alexander et al8 examine the influence of gender on bleeding complications in high-risk NSTE ACS patients treated with small-molecule GP IIb/IIIa inhibitors using the Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes With Early Implementation of the ACC/AHA Guidelines (CRUSADE) dataset. From January through December 2004, using data from this registry, the investigators identified 32 601 patients eligible for treatment with GP IIb/IIIa antagonists, yet only 18 436 patients (56.6%) received these agents; women were less likely to be treated than men (50% versus 60.4%). Among those patients treated with GP IIb/IIIa inhibitors, women had more high-risk clinical characteristics and worse renal function compared with men. Major bleeding, defined as intracranial hemorrhage, transfusion 
2 U red blood cells, or an absolute drop in hematocrit 12%, occurred more often in women than in men; in fact, the adjusted odds ratio for major bleeding after GP IIb/IIIa treatment (versus not treated) in women was 2.78 but only 1.98 in men.8
Interestingly, when the GP IIb/IIIa antagonist dosing regimen was examined, it was found that 26.9% of patients received an excess dose of drug. In this study, excess dosing was defined as full-dose tirofiban with a creatinine clearance <30 mL/min or full-dose eptifibatide with a creatinine clearance <50 mL/min. Notably, women were more likely than men (46.4% versus 17.2%) to receive the inappropriate dose, as were patients with a low creatinine clearance and serum creatinine <2.0 mg/dL. Administration of an excess GP IIb/IIIa antagonist dose was associated with a 72% increased odds of bleeding in women compared with only 27% in men, as well as a 25% increased bleeding risk attributable to excess dosing in women compared with only 4.4% in men.8
Utilizing this large-scale dataset, these investigators have identified an alternative explanation for the increased incidence of bleeding in women who present with NSTE ACS and are treated with small-molecule GP IIb/IIIa antagonists: Women more frequently receive an excess dose. Women had a 4-fold higher unadjusted likelihood of receiving an excess dose, which, in turn, resulted in a 5-fold increased risk of bleeding compared with men.8 Does excess dosing of GP IIb/IIIa antagonists occur frequently? This study suggests that 1 of every 4 treated patients (26.9%) received an excess dose. Similarly, another analysis from the CRUSADE study found that 42% of NSTE ACS patients received at least 1 initial dose of an antithrombotic agent outside the recommended range. In this trial, female gender, low body weight, and renal insufficiency were identified as risk factors associated with excess dosing.9
Why does excess dosing of GP IIb/IIIa antagonists occur? Observations from 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) suggest that it is due to failure to reduce the dose in the setting of renal insufficiency. Here, investigators demonstrated that failure to adjust for a creatinine clearance <50 mL/min occurred frequently, in 15 of 33 patients, and was associated with a 5-fold greater incidence of bleeding complications (20%).10
Although the CRUSADE and PROTECT-TIMI 30 substudy analyses8–10 highlight the influence of excess dosing on bleeding risk, they do not fully explain the higher rates of bleeding observed in women treated with the appropriate dose of GP IIb/IIIa antagonist. One potential explanation is that current methodologies used to estimate renal function may be inadequate in women, resulting in unrecognized and unintentional excess dosing. At present, dosing is based on creatinine clearance estimated by the Cockroft-Gault (CG) formula. This formula inputs the variables of age, body weight (in kilograms), and serum creatinine (in micromoles per liter) with a standard 15% downward adjustment for women owing to a theoretical lower muscle mass. Interestingly, this formula was originally derived from measurements taken from a group of 249 white men with creatinine levels in the steady state, and it has been suggested that the CG formula may not be as accurate in other racial or ethnic groups.11,12
In a study in healthy adults, the CG formula was compared with a direct measure of the glomerular filtration rate (GFR) and found to routinely overestimate GFR in people with normal kidney function.13 Another study found that the CG formula lacked precision to accurately predict GFR and, when applied in a population with a wide spectrum of renal function, resulted in only 67.6% of patients being classified appropriately according to Kidney Disease Outcomes Quality Initiative chronic kidney disease guidelines.14 The accuracy of the CG formula as an estimate of GFR also has been called into question in patients who are obese,15 those with congestive heart failure,16 diabetics,17 and patients with end-stage renal disease.18 To date, there has been no study of the accuracy of the CG formula to predict GFR in women that includes subjects from multiple racial and ethnic backgrounds.
It has been suggested that the Modification of Diet in Renal Disease (MDRD) formula may provide a more accurate estimate of GFR than the CG formula. The MDRD formula, derived in a population with a mean GFR of 40 mL/min per 1.73 m2 who were being screened for inclusion in a chronic kidney disease study,12 incorporates the same variables as the CG formula and is indexed for BSA and for race. In some studies, the MDRD formula has been shown to be more accurate than the CG formula for predicting GFR in healthy adults,13 diabetic patients,19 and patients with low GFR.14 When studied in a large population with a wide range of creatinine levels, the MDRD was found to provide more reliable estimates of renal function than the CG formula. Nevertheless, it should be noted that neither formula is perfect in all patient subgroups. In fact, it has been shown that the CG and MDRD formulas misclassified 29.2% and 32.4% of subjects, respectively, according to the Kidney Disease Outcomes Quality Initiative classification.14
In the CRUSADE study reported by Alexander et al,8 excess dosing was determined by using the CG formula to calculate creatinine clearance and correlating this finding with the dose of GP IIb/IIIa administered; however, the investigators did not simultaneously estimate GFR using the MDRD formula, which suggests that the true rate of excess dosing in this study remains unknown. Women in this study tended to be older and to have a greater incidence of diabetes and congestive heart failure at presentation than men. Although weight is reported to be less in women than men, the measurement is not indexed for BSA; therefore, the percentage of obese patients is unknown. Because all of these characteristics have been associated with decreased precision and accuracy of the CG formula, its utility as a true measure of renal function in this study requires further clarification.
This topic is also the subject of debate in other areas of medicine. For instance, in studies comparing CG with MDRD to assess kidney function to make dose adjustments for renally excreted antimicrobial drugs, significant differences in estimated GFR led to a different dosing recommendation in 21% to 37% of patients.20 Similarly, when CG was used as an estimate of renal function to determine appropriate dosing for renally excreted chemotherapeutic agents, it was found that indexing this result to BSA resulted in reclassification of patients from one GFR range to another.21
Taken together, studies such as these have led the National Kidney Disease Education Program and the Chronic Kidney Disease Epidemiology Collaboration to call for the development of new equations based on large datasets that include GFR, standardized serum creatinine levels, and cystatin C to assess renal function more accurately. These new equations will need to be validated further in independent populations including women and members of different racial and ethnic backgrounds to account for biological and measurement variability.22
Practically speaking, what can be learned from analysis of Alexander et al to limit the bleeding risk in women treated with GP IIb/IIIa antagonists? The first point is that small-molecule GP IIb/IIIa inhibitors not only are efficacious but also are recommended for upstream use in high-risk patients who present with NSTE ACS. In this registry, only 56.6% of eligible patients were treated with these agents, and women were less likely to receive a GP IIb/IIIa antagonist than men. This finding demonstrates the need for improved screening of NSTE ACS patients according to AHA/ACC guidelines and increased use of these agents in appropriate patients regardless of gender, race, or ethnic background. The second point is that the increased incidence of bleeding observed in women occurs, in large part, as a result of excess dosing. Package inserts for small-molecule GP IIb/IIIa antagonists, which are renally excreted, recommend calculating creatinine clearance as a measure of renal function; creatinine alone is not sufficient. Although the CG formula is commonly used for this purpose, it loses precision and accuracy in patients with obesity, diabetes, or congestive heart failure. In patients with these comorbidities, the MDRD formula is more accurate. It is therefore imperative that clinicians familiarize themselves with the limitations associated with currently available formulas to determine renal function in select patient subgroups and to maintain a heightened awareness of potential dosing errors, Only then can renally excreted drugs such as small-molecule GP IIb/IIIa antagonists be administered within a range that allows maximum therapeutic effect with minimal adverse consequences.
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Acknowledgments |
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The author thanks Dr Elliott Antman for critical appraisal of the manuscript.
Sources of Funding
This work was supported in part by grant HL-081110 from the National Institutes of Health and a Grant-in-Aid from the American Heart Association.
Disclosures
None.
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Footnotes |
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The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.
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