doi: 10.1161/CIRCULATIONAHA.107.705830
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
(Circulation. 2007;115:2796-2798.)
© 2007 American Heart Association, Inc.
Editorial |
Women, Acute Ischemic Heart Disease, and Antithrombotic Therapy
Challenges and Opportunities
From the Division of Cardiology, Department of Medicine, and the Duke Clinical Research Institute, Duke University Medical Center, Durham, NC.
Correspondence to Robert A. Harrington, MD, Duke Clinical Research Institute, 2400 Pratt St, Room 0311 Terrace Level, Durham NC 27705. E-mail robert.harrington{at}duke.edu
Key Words: Editorials • ischemia • heart diseases • women • myocardial infarction
There now exists an extensive and growing literature examining gender-based differences in the pathobiology, presentation, treatment patterns, and clinical outcomes of ischemic heart disease (IHD). IHD is a dominant mode of death for women,1 and, for >20 years, more women than men die annually from IHD.2 The first manifestation of IHD in women is frequently myocardial infarction or sudden cardiac death.2 A better understanding of the spectrum of issues—from pathophysiology through implementation of evidence-based care—among women with IHD is a public health imperative.
Article p 2822
Recently, many observations have converged around a common set of themes in the care of women with IHD, especially acute IHD. Lansky et al3 have pointed out that women with degrees of obstructive coronary artery disease comparable to those of men receive less revascularization. From the Can Rapid risk stratification of Unstable angina patients Suppress ADverse outcomes with Early implementation of the ACC/AHA Guidelines (CRUSADE) registry, we know that women presenting with high-risk non–ST-segment–elevation acute coronary syndromes (primarily myocardial infarction) are less likely than men to undergo an early invasive management strategy despite being at a higher baseline risk.4 Women with non–ST-segment–elevation acute coronary syndromes are less likely than men to receive recommended evidence-based medications and cardiac procedures, again despite being at higher baseline risk.5
However, there are also challenges in evaluating and deciding on treatments for women presenting with acute coronary syndromes. Roe and colleagues6 have shown that women presenting with non–ST-segment–elevation acute coronary syndromes have a greater likelihood of nonobstructive disease than do men, and the Women’s Ischemia Syndrome Evaluation (WISE) investigators have compiled a substantial body of work suggesting that the pathobiology of IHD differs in women compared with men.7 All of this makes it imperative that we perform enough research in women to properly ascribe both the benefits and potential risks to any therapy that might be used in a particular disease setting.
Because antithrombotic therapy is considered cornerstone therapy for all acute ischemic coronary syndromes (ST-segment elevation and non–ST-segment elevation),8,9 understanding these drugs, including measuring their benefits and risks, is critical. In the setting of non–ST-segment–elevation acute coronary syndromes, a systematic overview of glycoprotein IIb/IIIa inhibitors suggested heterogeneity of treatment effect in women compared with men, raising questions about the appropriateness of treating women with a potentially harmful group of drugs.10,11 However, additional analyses of men and women who were troponin positive as well as men and women undergoing percutaneous coronary intervention suggested that in patients with "proven" obstructive coronary artery disease as the cause of their acute syndrome, there was in fact a consistent treatment effect when women were compared with men.
In women, there is an added wrinkle to the story about quantifying harm. Alexander et al,12 in a series of studies from the CRUSADE registry, have pointed out that antithrombotic therapy is frequently overdosed; this issue is particularly problematic in women, directly translating into worse bleeding outcomes, including a need for transfusion. Because women are typically older, lighter, and have more associated comorbidities, including chronic kidney disease, that may contribute to bleeding risk, this is not surprising.13 Given the potential differences in pathobiology and presentation that may affect treatment choices and, subsequently, clinical outcomes, enrolling sizable numbers of women in research studies is critical to help clinicians to properly understand differential treatment effects.
Among patients presenting with ST-segment–elevation myocardial infarction who are to be treated initially with lytic therapy for reperfusion, adjunctive anticoagulation is a class I recommendation. Alternatives to unfractionated heparin have now been well investigated and include low-molecular-weight heparins,14,15 factor Xa inhibitors,16 and direct thrombin inhibitors.17,18 The Enoxaparin and Thrombolysis Reperfusion for Acute Myocardial Infarction Treatment–Thrombolysis in Myocardial Infarction (ExTRACT-TIMI) 25 trial demonstrated the superiority of enoxaparin, a low-molecular-weight heparin, over unfractionated heparin as adjunctive therapy for patients receiving fibrinolysis for ST-segment–elevation myocardial infarction. Overall, the primary end point of death or nonfatal recurrent myocardial infarction through 30 days was reduced by 17%. Bleeding was more common with enoxaparin than with unfractionated heparin, although there were similar rates of intracranial hemorrhage.15
In this issue of Circulation, Mega and colleagues report on the population of women enrolled in ExTRACT.19 As in other clinical trials of ST-segment–elevation myocardial infarction, the vast majority of patients enrolled in ExTRACT were men, but because of the overall large trial size there is information on >4000 women in this trial. Consistent with other reports, they were older, had more comorbidities, and received fewer evidence-based medications than men in the trial. The use of cardiac procedures in the trial was low overall, reflecting the practice patterns seen in a mostly non-US population, and was significantly lower in women than in men. Again, as has been previously and consistently noted, the risk of ischemic outcomes was worse in women, with a reported adjusted risk of mortality 25% higher than in men. This finding was consistent across age groups, with the greatest absolute risk for women relative to men being in the oldest age population.
The treatment effect with enoxaparin was similar in both sexes. Enoxaparin reduced the 30-day risk of the composite of death and recurrent myocardial infarction by 16% (relative risk, 0.84; 95% CI, 0.75 to 0.95) and of death by a nonsignificant 12% (relative risk, 0.88; 95% CI, 0.76 to 1.02).
The "cost" to this ischemic benefit was an increased risk of bleeding. Major bleeding, minor bleeding, and the composite of major or minor were all significantly increased among women treated with enoxaparin compared with women treated with unfractionated heparin. Intracranial hemorrhage was directionally, but not significantly, increased (relative risk, 1.43; 95% CI, 0.81 to 2.51). However, there was insufficient power to reliably detect a difference in this subgroup of women, again pointing to the need for large enough experience in key populations to be able to make meaningful treatment recommendations regarding novel therapies. It should be noted that the investigators report that bleeding was similar among men and women receiving enoxaparin.
A very important feature of ExTRACT was the attention given to the dosing of enoxaparin. The investigators were particularly careful in recommending the dosing of enoxaparin among the elderly, a critical feature given the diminished renal function of many elderly patients and the fact that enoxaparin is a renally excreted drug. In the group of patients aged 
75 years, no bolus dose of enoxaparin was given, and the maintenance dose was decreased by 25%. Major differences were noted in creatinine clearance in women compared with men in ExTRACT. Their median creatinine clearance of 66 mL/min (interquartile range, 51 to 84) suggests that almost one half of the women in the trial had stage III chronic kidney disease.20 Although Mega and colleagues do not provide data on compliance to this enoxaparin dosing strategy among their investigators or on the relationship between protocol compliance and bleeding, the fact that there was comparable major bleeding with enoxaparin in women and men despite this marked difference in renal function suggests that the investigators were successful with this dosing strategy; this reinforces the imperative to dose-adjust potent antithrombotics among patients with chronic kidney disease. Success with this protocol dosing is a major accomplishment of the ExTRACT investigators.
Several broader research issues are worth highlighting. Although there was no specification as to the number of women to be enrolled in the trial, the large sample size allowed recruitment of a large number of women, permitting reasonable insight into the risks and benefits of treating women with enoxaparin versus unfractionated heparin. Large trials are critical to advancing our understanding of new therapies because most future advances in acute care cardiovascular medicine are expected to be incremental. As trials become increasingly global, efforts need to be focused on including a spectrum of patients with characteristics such as advanced age and comorbidities such as chronic kidney disease, which are particularly problematic among women.21 Equally important is to make certain that the patterns of care, including angiography and its timing, are reflective of the areas of the world where the therapy will ultimately be used. ExTRACT had very little enrollment inside the US because of its focus on using fibrinolysis. Given the interplay among antithrombotic drugs, invasive cardiac procedures, and patient characteristics, understanding these relationships is critical.
ExTRACT should serve as an example of the benefits that can be realized with careful dosing of antithrombotic therapy both in practice and in clinical trials. High-risk patients typically have the most to gain from aggressive implementation of evidence-based prescribing because their baseline risk is higher, but, paradoxically, they are typically treated less aggressively.22 Efforts such as those described in the article in this issue of Circulation by Mega et al are invaluable in allowing confident estimates of both risks and benefits so that clinicians and patients can make quantitatively informed treatment decisions. Finally, although knowledge of evidence-based medicine has moved into the mainstream,23 the practice of evidence-based prescribing remains suboptimal. Despite an accumulating amount of data linking evidence-based performance to outcome,24 we continue to see lower use of evidence-based prescribing, particularly among subgroups such as women, as demonstrated by the current report. We know the challenges; now we have the opportunity to look at the data, understand the gaps, and make appropriate changes to our implementation of proven therapies.25
 |
Acknowledgments |
|---|
Disclosures
Dr Harrington reports having received research grants to the Duke Clinical Research Institute from Sanofi Aventis; payment from Sanofi Aventis for activities related to Data and Safety Monitoring Board work; and consulting monies from Sanofi Aventis related to clopidogrel. Since October 2006, all personal honoraria generated from industry-related activities have been donated to educational charities. A complete list of Dr Harrington’s industry relationships can be found at www.dcri.duke.edu/research/coi.jsp.
|
Footnotes |
|---|
The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.
|
References |
|---|
 Top References |
|---|
- Shaw LJ, Bairey Merz CN, Pepine CJ, Reis SE, Bittner V, Kelsey SF, Olson M, Johnson BD, Mankad S, Sharaf BL, Rogers WJ, Wessel TR, Arant CB, Pohost GM. Lerman A, Quyyumi AA, Sopko G; WISE Investigators. Insights from the NHLBI-sponsored Women’s Ischemia Syndrome Evaluation (WISE) Study, part I: gender differences in traditional and novel risk factors, symptom evaluation, and gender-optimized diagnostic strategies. J Am Coll Cardiol. 2006; 47 (suppl): S4–S20.
[Abstract/Free Full Text] - Bairey Merz CN, Shaw LJ Reis SE, Bittner V, Kelsey SF, Olson M, Johnson BD, Pepine CJ, Mankad S, Sharaf BL, Rogers WJ, Pohost GM, Lerman A. Quyyumi AA, Sopko G; WISE Investigators. Insights from the NHLBI-sponsored Women’s Ischemia Syndrome Evaluation (WISE) Study, part II: gender differences in presentation, diagnosis, and outcome with regard to gender-based pathophysiology of atherosclerosis and macrovascular and microvascular coronary disease. J Am Coll Cardiol. 2006; 47 (suppl): S21–S29.
[Abstract/Free Full Text] - Lansky AJ, Hochman JS, Ward PA, Mintz GS, Fabunmi R, Berger PB, New G, Grines CL, Pietras CG, Kern MJ, Ferrell M, Leon MB, Mehran R, White C, Mieres JH, Moses JW, Stone GW, Jacobs AK; American College of Cardiology Foundation, American Heart Association. Percutaneous coronary intervention and adjunctive pharmacotherapy in women: a statement for healthcare professionals from the American Heart Association. Circulation. 2005; 111: 940–953.
[Abstract/Free Full Text] - Bhatt DL, Roe MT, Peterson ED, Li Y, Chen AY, Harrington RA, Greenbaum AB, Berger PB, Cannon CP, Cohen DJ, Gibson CM, Saucedo JF, Kleiman NS, Hochman JS, Boden WE, Brindis RG, Peacock WF, Smith SC Jr, Pollack CV Jr, Gibler WB, Ohman EM; CRUSADE Investigators. Utilization of early invasive management strategies for high-risk patients with non-ST-segment elevation acute coronary syndromes: results from the CRUSADE Quality Improvement Initiative. JAMA. 2004; 292: 2096–2104.
[Abstract/Free Full Text] - Blomkalns AL, Chen AY, Hochman JS, Peterson ED, Trynosky K, Diercks DB, Brogan GX Jr, Boden WE, Roe MT, Ohman EM, Gibler WB, Newby LK; CRUSADE Investigators. Gender disparities in the diagnosis and treatment of non-ST-segment elevation acute coronary syndromes: large-scale observations from the CRUSADE (Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes With Early Implementation of the American College of Cardiology/American Heart Association Guidelines) National Quality Improvement Initiative. J Am Coll Cardiol. 2005; 45: 832–837.
[Abstract/Free Full Text] - Roe MT, Harrington RA, Prosper DM, Pieper KS, Bhatt DL, Lincoff AM, Simoons ML, Akkerhuis M, Ohman EM, Kitt MM, Vahanian A, Ruzyllo W, Karsch K, Califf RM, Topol EJ. Clinical and therapeutic profile of patients presenting with acute coronary syndromes who do not have significant coronary artery disease. Circulation. 2000; 102: 1101–1106.
[Abstract/Free Full Text] - Pepine CJ, Kerensky RA, Lambert CR, Smith KM, von Mering GO, Sopko G, Bairey Merz CN. Some thoughts on the vasculopathy of women with ischemic heart disease. J Am Coll Cardiol. 2006; 47 (suppl): S30–S35.
[Abstract/Free Full Text] - Braunwald E, Antman EM, Beasley JW, Califf RM, Cheitlin MD, Hochman JS, Jones RH, Kereiakes D, Kupersmith J, Levin TN, Pepine CJ, Schaeffer JW, Smith EE III, Steward DE, Theroux P, Gibbons RJ, Alpert JS, Faxon DP, Fuster V, Gregoratos G, Hiratzka LF, Jacobs AK, Smith SC Jr; American College of Cardiology, American Heart Association, Committee on the Management of Patients With Unstable Angina. ACC/AHA 2002 guideline update for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction: summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients With Unstable Angina). J Am Coll Cardiol. 2002; 40: 1366–1374.
[Free Full Text] - Antman EM, Anbe DT, Armstrong PW, Bates ER, Green LA, Hand M, Hochman JS, Krumholz HM, Kushner FG, Lamas GA, Mullany CJ, Ornato JP, Pearle DL, Sloan MA, Smith SC Jr; American College of Cardiology, American Heart Association, Canadian Cardiovascular Society. ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to revise the 1999 guidelines for the management of patients with acute myocardial infarction). J Am Coll Cardiol. 2004; 44: 671–719.
[Free Full Text] - Boersma E, Harrington RA, Moliterno DJ, White H, Theroux P, Van de Werf F, de Torbal A, Armstrong PW, Wallentin LC, Wilcox RG, Simes J, Califf RM, Topol EJ, Simoons ML. Platelet glycoprotein IIb/IIIa inhibitors in acute coronary syndromes: a meta-analysis of all major randomised clinical trials. Lancet. 2002; 359: 189–198.[CrossRef][Medline]
[Order article via Infotrieve]
- Redberg R. Citizen’s petition. Available at: www.fda.gov/ohrms/dockets/dockets/05p0107/05p-0107-ack0001-vol1.pdf. Accessed May 21, 2007.
- Alexander KP, Chen AY, Roe MT, Newby LK, Gibson CM, Allen-LaPointe NM, Pollack C, Gibler WB, Ohman EM, Peterson ED. 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] - Alexander KP, Chen AY, Newby LK, Schwartz JB, Redberg RF, Hochman JS, Roe MT, Gibler WB, Ohman EM, Peterson ED. Sex differences in major bleeding with glycoprotein IIb/IIIa inhibitors: results from the CRUSADE (Can Rapid risk stratification of Unstable angina patients Suppress ADverse outcomes with Early implementation of the ACC/AHA guidelines) initiative. Circulation. 2006; 114: 1380–1387.
[Abstract/Free Full Text] - The CREATE Trial Group Investigators. Effects of reviparin, a low-molecular-weight heparin, on mortality, reinfarction, and strokes in patients with acute myocardial infarction presenting with ST-segment elevation. JAMA. 2005; 293: 427–435.
[Abstract/Free Full Text] - Antman EM, Morrow DA, McCabe CH, Murphy SA, Ruda M, Sadowski Z, Budaj A, Lopez-Sendon JL, Guneri S, Jiang F, White HD, Fox KA, Braunwald E. Enoxaparin versus unfractionated heparin with fibrinolysis for ST-elevation myocardial infarction. N Engl J Med. 2006; 354: 1477–1488.
[Abstract/Free Full Text] - Yusuf S, Mehta SR, Chrolavicius S, Afzal R, Pogue J, Granger CB, Budaj A, Peters RJ, Bassand JP, Wallentin L, Joyner C, Fox KA. Effects of fondaparinux on mortality and reinfarction in patients with acute ST-segment elevation myocardial infarction: the OASIS-6 randomized trial. JAMA. 2006; 295: 1519–1530.[CrossRef][Medline]
[Order article via Infotrieve]
- The Direct Thrombin Inhibitor Trialists’ Collaborative Group. Direct thrombin inhibitors in acute coronary syndromes: principal results of a meta-analysis based on individual patients’ data. Lancet. 2002; 359: 294–302.[CrossRef][Medline]
[Order article via Infotrieve]
- The Hirulog and Early Reperfusion or Occlusion (HERO)-2 Trial Investigators. Thrombin-specific anticoagulation with bivalirudin versus heparin in patients receiving fibrinolytic therapy for acute myocardial infarction: the HERO-2 randomised trial. Lancet. 2001; 358: 1855–1863.[CrossRef][Medline]
[Order article via Infotrieve]
- Mega JL, Morrow DA, Östör E, Dorobantu M, Qin J, Antman EM, Braunwald E. Outcomes and optimal antithrombotic therapy in women undergoing fibrinolysis for ST-elevation myocardial infarction. Circulation. 2007; 115: 2822–2828.
[Abstract/Free Full Text] - Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D; Modification of Diet in Renal Disease Study Group. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Ann Intern Med. 1999; 130: 461–470.
[Abstract/Free Full Text] - Lee PY, Alexander KP, Hammill BG, Pasquali SK, Peterson ED. Representation of elderly persons and women in published randomized trials of acute coronary syndromes. JAMA. 2001; 286: 708–713.
[Abstract/Free Full Text] - Roe MT, Peterson ED, Newby LK, Chen AY, Pollack CV Jr, Brindis RG, Harrington RA, Christenson RH, Smith SC Jr, Califf RM, Braunwald E, Gibler WB, Ohman EM. The influence of risk status on guideline adherence for patients with non-ST-segment elevation acute coronary syndromes. Am Heart J. 2006; 151: 1205–1213.[CrossRef][Medline]
[Order article via Infotrieve]
- Gorman C. Are doctors just playing hunches? Time. February 15, 2007.
- Peterson ED, Roe MT, Mulgund J, DeLong ER, Lytle BL, Brindis RG, Smith SC Jr, Pollack CV Jr, Newby LK, Harrington RA, Gibler WB, Ohman EM. Association between hospital process performance and outcomes among patients with acute coronary syndromes. JAMA. 2006; 295: 1912–1920.
[Abstract/Free Full Text] - Califf RM, Peterson ED, Gibbons RJ, Garson A Jr, Brindis RG, Beller GA, Smith SC Jr; American College of Cardiology, American Heart Association. Integrating quality into the cycle of therapeutic development. J Am Coll Cardiol. 2002; 40: 1895–1901.
[Abstract/Free Full Text]
Related Article:
-
Issue Highlights
Circulation 2007 115: 2789.[Full Text]
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||