Thromb Haemost 2010; 104(03): 471-484
DOI: 10.1160/TH10-04-0232
Review Article
Schattauer GmbH

Impact of race and gender on antithrombotic therapy

Davide Capodanno
1   University of Florida College of Medicine-Jacksonville, Jacksonville, Florida, USA
,
Dominick J. Angiolillo
1   University of Florida College of Medicine-Jacksonville, Jacksonville, Florida, USA
› Author Affiliations
Further Information

Publication History

Received: 14 April 2010

Accepted after minor revision: 14 May 2010

Publication Date:
23 November 2017 (online)

Summary

Large randomised trials support the use of a variety of antithrombotic drugs for treatment of atherothrombotic disease processes leading to cardiovascular disease. The heterogeneous case-mix of patients enrolled in these trials, however, hamper the attempt to generalise their findings to subgroups which are not sufficiently represented in the study population, such as women and ethnic minorities. Sex- and race-specific disparities in the clinical presentation, management, and outcomes of coronary artery disease may relate to underlying differences in thrombotic profiles and response to antithrombotic therapies. The present manuscript provides an overview of the currently available data on the epidemiology of coronary artery disease based on gender and race as well as the biological considerations for their differences in thrombosis and haemostasis and effects of antithrombotic therapy.

 
  • References

  • 1 Kung HC. et al. Division of Vital Statistics. Deaths: final data for 2005. National vital statistics reports. April 2008. Available online at http://www.cdc.gov/nchs/data/nvsr/nvsr48/nvs48_11.pdf.
  • 2 Guyatt GH. et al. Grades of recommendation for antithrombotic agents: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008; 133 Suppl 123S-131S.
  • 3 Kim ESH, Menon V. Status of women in cardiovascular clinical trials. Arterioscler Thromb Biol 2009; 29: 279-283.
  • 4 Williams DR, Collins C. US Socioeconomic and racial difference in health: patterns and explanations. Annu Rev Sociol 1995; 21: 349.
  • 5 Rosamond W. et al. Heart disease and stroke statistics-2007 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation. 2007; 115: e69-e171.
  • 6 American Heart Association.. Women and cardiovascular disease: statistics. Dallas, Tex: American Heart Association; 2004. Available at: http://american-heart.org
  • 7 Chandra NC. et al. Observations of the treatment of women in the United States with myocardial infarction: a report from the National Registry of Myocardial Infarction-I. Arch Intern Med 1998; 158: 981-988.
  • 8 Blomkalns AL. et al. 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.
  • 9 US Census Bureau.. US Census Bureau Race Data. Available at: http://www.census.gov/population/www/socdemo/race.html. Accessed April 26, 2005.
  • 10 Mensah GA. et al. State of disparities in cardiovascular health in the United States. Circulation. 2005; 111: 1233-1241.
  • 11 Kurian AK, Cardarelli KM. Racial and ethnic differences in cardiovascular disease risk factors: a systematic review. Ethn Dis 2007; 17: 143-152.
  • 12 American Heart Association.. Heart Disease and Stroke Statistics—2005 Update. Available at: http://www.americanheart.org/presenter.jhtml?identifier=1928. Accessed March 2, 2005.
  • 13 Sabatine MS. et al. Influence of race on death and ischemic complications in patients with non-ST-elevation acute coronary syndromes despite modern, protocol-guided treatment. Circulation 2005; 111: 1217-1224.
  • 14 Sonel AF. et al. CRUSADE Investigators.. Racial variations in treatment and outcomes of black and White patients with high-risk non-ST-elevation acute coronary syndromes: insights from CRUSADE (Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes With Early Implementation of the ACC/AHA Guidelines?). Circulation 2005; Mar 15 111: 1225-1232.
  • 15 Cohen MG. et al. Clinical characteristics, process of care, and outcomes of Hispanic patients presenting with non-ST-segment elevation acute coronary syndromes: results from Can Rapid risk stratification of Unstable angina patients Suppress ADverse outcomes with Early implementation of the ACC/AHA Guidelines (CRUSADE). Am Heart J. 2006; 152: 110-117.
  • 16 Duncan BB. et al. Low-grade systemic inflammation and the development of type 2 diabetes: the atherosclerosis risk in communities study. Diabetes 2003; 52: 1799-1805.
  • 17 Lutsey PL. et al. Plasma hemostatic factors and endothelial markers in four racial/ ethnic groups: the MESA study. J Thromb Haemost 2006; 4: 2629-2635.
  • 18 LaMonte MJ. et al. Cardiorespiratory fitness and C-reactive protein among a tri-ethnic sample of women. Circulation 2002; 106: 403-406.
  • 19 Albert MA. Inflammatory biomarkers, race/ethnicity and cardiovascular disease. Nutr Rev 2007; 65: S234-S238.
  • 20 Wong ND. et al. Distribution of C-reactive protein and its relation to risk factors and coronary heart disease risk estimation in the National Health and Nutrition Examination Survey (NHANES) III. Prev Cardiol 2001; 4: 109-114.
  • 21 Liao Y. et al. Coronary angiographic findings in African-American and white patients from a single institution. J Natl Med Assoc 2001; 93: 465-474.
  • 22 Tang W. et al. Racial differences in coronary calcium prevalence among high-risk adults. Am J Cardiol 1995; 75: 1088-1091.
  • 23 Budoff MJ. et al. Ethnic differences in coronary atherosclerosis. J Am Coll Cardiol 2002; 39: 408-412.
  • 24 Bild DE. et al. Ethnic differences in coronary calcification: the Multi-Ethnic Study of Atherosclerosis (MESA). Circulation 2005; 111: 1313-1320.
  • 25 Folsom AR. et al. Risk factor correlates of platelet and leukocyte markers assessed by flow cytometry in a population-based sample. Atherosclerosis 2009; 205: 272-278.
  • 26 Gurbel PA. et al. Race and sex differences in thrombogenicity: risk of ischemic events following coronary stenting. Blood Coagul Fibrinolysis 2008; 19: 268-275.
  • 27 Schwertz DW, Penckofer S. Sex differences and the effects of sex hormones on hemostasis and vascular reactivity. Heart Lung 2001; 30: 401-426.
  • 28 Eshel-Green T. et al. Effect of sex difference on platelet adhesion, spreading and aggregate formation under flow. Thromb Haemost 2009; 102: 958-965.
  • 29 Johnson M. et al. Sex and age differences in human platelet aggregation. Nature 1975; 253: 355-357.
  • 30 Zwierzina WD. et al. Sex-related differences in platelet aggregation in native whole blood. Thromb Res 1987; 48: 161-171.
  • 31 Haque SF. et al. Sex difference in platelet aggregation detected by new aggregometry using light scattering. Endocr J 2001; 48: 33-41.
  • 32 Meade TW. et al. Epidemiological characteristics of platelet aggregability. Br Med J (Clin Res Ed) 1985; 290: 428-432.
  • 33 Faraday N. et al. Gender differences in platelet GPIIb-IIIa activation. Thromb Haemost 1997; 77: 748-754.
  • 34 Blais N. et al. Response to aspirin in healthy individuals. Cross-comparison of light transmission aggregometry, VerifyNow system, platelet count drop, thromboelastography (TEG) and urinary 11-dehydrothromboxane B(2). Thromb Haemost 2009; 102: 404-411.
  • 35 Grove EL. et al. A comparison of platelet function tests and thromboxane meta-bolites to evaluate aspirin response in healthy individuals and patients with coronary artery disease. Thromb Haemost 2010; 103: 1245-1253.
  • 36 Bailey AL. et al. Thrombosis and antithrombotic therapy in women. Arterioscler Thromb Vasc Biol 2009; 29: 284-288.
  • 37 Stevens RF, Alexander MK. A sex difference in the platelet count. Br J Haematol 1977; 37: 295-300.
  • 38 Leng XH. et al. Platelets of female mice are intrinsically more sensitive to agonists than are platelets of males. Arterioscler Thromb Vasc Biol 2004; 24: 376-381.
  • 39 Escolar G. et al. Sex-related differences in the effects of aspirin on the interaction of platelets with subendothelium. Thromb Res 1986; 44: 837-847.
  • 40 Gordon T. et al. Menopause and coronary heart disease. The Framingham Study. Ann Intern Med 1978; 89: 157-161.
  • 41 Rosenberg L. et al. Early menopause and the risk of myocardial infarction. Am J Obstet Gynecol 1981; 139: 47-51.
  • 42 Mikkola T. et al. 17 beta-estradiol stimulates prostacyclin, but not endothelin-1, production in human vascular endothelial cells. J Clin Endocrinol Metab 1995; 80: 1832-1836.
  • 43 Caulin-Glaser T. et al. 17 beta-estradiol regulation of human endothelial cell basal nitric oxide release, independent of cytosolic Ca2+ mobilization. Circ Res 1997; 81: 885-892.
  • 44 Herman SM. et al. Androgen deprivation is associated with enhanced endothelium-dependent dilatation in adult men. Arterioscler Thromb Vasc Biol 1997; 17: 2004-2009.
  • 45 Arora S. et al. Estrogen improves endothelial function. J Vasc Surg 1998; 27: 1141-1146.
  • 46 Lawrence JB. et al. Sex differences in platelet adherence to subendothelium: relationship to platelet function tests and hematologic variables. Am J Med Sci 1995; 309: 201-207.
  • 47 Pinto S. et al. Sex related differences in platelet TxA2 generation. Prostaglandins Leukot Essent Fatty Acids 1990; 40: 217-221.
  • 48 Ajayi AA. et al. Testosterone increases human platelet thromboxane A2 receptor density and aggregation responses. Circulation 1995; 91: 2742-2747.
  • 49 Rossouw JE. et al. Writing Group for the Women’s Health Initiative Investigators.. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women’s Health Initiative randomized controlled trial. J Am Med Assoc 2002; 288: 321-333.
  • 50 Grady D. et al. Postmenopausal hormone therapy increases risk for venous thromboembolic disease. The Heart and Estrogen/progestin Replacement Study. Ann Intern Med 2000; 132: 689-696.
  • 51 Langer RD. et al. Baseline associations between postmenopausal hormone therapy and inflammatory, haemostatic, and lipid biomarkers of coronary heart disease. The Women’s Health Initiative Observational Study. Thromb Haemost 2005; 93: 1108-1116.
  • 52 Manson JE. et al. Women’s Health Initiative Investigators.. Estrogen plus progestin and the risk of coronary heart disease. N Engl J Med 2003; 349: 523-534.
  • 53 Frederiksen H, Ravenholt RT. Thromboembolism, oral contraceptives, and cigarettes. Public Health Rep 1970; 85: 197-205.
  • 54 Mendelsohn ME, Karas RH. The protective effects of estrogen on the cardiovascular system. N Engl J Med 1999; 340: 1801-1811.
  • 55 Bonithon-Kopp C. et al. Relationship between sex hormones and haemostatic factors in healthy middle-aged men. Atherosclerosis 1988; 71: 71-76.
  • 56 Caron P. et al. Plasminogen activator inhibitor in plasma is related to testosterone in men. Metabolism 1989; 38: 1010-1015.
  • 57 Glueck CJ. et al. Endogenous testosterone, fibrinolysis, and coronary heart disease risk in hyperlipidemic men. J Lab Clin Med 1993; 122: 412-420.
  • 58 Anderson RA. et al. Haemostatic effects of supraphysiological levels of testosterone in normal men. Thromb Haemost 1995; 74: 693-697.
  • 59 O’Brien JR. The bleeding time in normal and abnormal subjects. J Clin Pathol 1951; 4: 272-285.
  • 60 Bain B, Forester T. A sex difference in the bleeding time. Thromb Haemost 1980; 3: 131-132.
  • 61 Buchanan MR. et al. The sex-related differences in aspirin pharmacokinetics in rabbits and man and its relationship to antiplatelet effects. Thromb Res 1983; 29: 125-139.
  • 62 Ho PC. et al. The effects of age and sex on the disposition of acetylsalicylic acid and its metabolites. Br J Clin Pharmacol 1985; 19: 675-684.
  • 63 Miners JO. et al. Influence of gender and oral contraceptive steroids on the metabolism of salicylic acid and acetylsalicylic acid. Br J Clin Pharmacol 1986; 22: 135-142.
  • 64 Eikelboom JW. et al. Adverse Impact of Bleeding on Prognosis in Patients With Acute Coronary Syndromes. Circulation 2006; 114: 774-782.
  • 65 Rao SV. et al. Bleeding and blood transfusion issues in patients with non–ST-segment elevation acute coronary syndromes. Eur Heart J 2007; 28: 1193-1204.
  • 66 Rao SV. et al. A comparison of the clinical impact of bleeding measured by two different classifications among patients with acute coronary syndromes. J Am Coll Cardiol 2006; 47: 809-816.
  • 67 Schulman S. et al. American College of Chest Physicians.. Hemorrhagic complications of anticoagulant and thrombolytic treatment: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008; 133: 257S-298S.
  • 68 Ferreiro JL. et al. Platelet function testing and risk of bleeding complications. Thromb Haemost 2010; 103: 1128-1135.
  • 69 Pengo V. et al. ISCOAT Study Group.(Italian Study on Complications of Oral Anticoagulant Therapy).. Oral anticoagulant therapy in patients with nonrheumatic atrial fibrillation and risk of bleeding. A Multicenter Inception Cohort Study. Thromb Haemost 2001; 85: 418-422.
  • 70 van der Meer FJ. et al. Bleeding complications in oral anticoagulant therapy. An analysis of risk factors. Arch Intern Med 1993; 153: 1557-1562.
  • 71 Jick H. et al. Efficacy and toxicity of heparin in relation to age and sex. N Engl J Med 1968; 279: 284-286.
  • 72 Shen AY. et al. Racial/ethnic differences in the risk of intracranial hemorrhage among patients with atrial fibrillation. J Am Coll Cardiol 2007; 50: 309-315.
  • 73 Broderick JP. et al. The risk of subarachnoid and intracerebral hemorrhages in blacks as compared with whites. N Engl J Med 1992; 326: 733-736.
  • 74 Sacco RL. et al. Stroke incidence among white, black, and Hispanic residents of an urban community: the Northern Manhattan Stroke Study. Am J Epidemiol 1998; 147: 259-268.
  • 75 Fang J. et al. Clinical characteristics of stroke among Chinese in New York City. Ethn Dis 2004; 14: 378-383.
  • 76 Tanaka H. et al. Risk factors for cerebral hemorrhage and cerebral infarction in a Japanese rural community. Stroke 1982; 13: 62-73.
  • 77 Ayala C. et al. Sex differences in US mortality rates for stroke and stroke subtypes by race/ethnicity and age, 1995–1998. Stroke 2002; 33: 1197-1201.
  • 78 Nakagawa Y. et al. Efficacy of abciximab for patients undergoing balloon angioplasty: data from Japanese evaluation of c7E3 Fab for elective and primary PCI organization in randomized trial (JEPPORT). Circ J 2009; 73: 145-151.
  • 79 Takahashi H. et al. Population differences in S-warfarin metabolism between CYP2C9 genotype-matched Caucasian and Japanese patients. Clin Pharmacol Ther 2003; 73: 253-263.
  • 80 Marín F. et al. Pharmacogenetics in cardiovascular antithrombotic therapy. J Am Coll Cardiol 2009; 54: 1041-1057.
  • 81 Quteineh L. et al. Vitamin K epoxide reductase (VKORC1) genetic polymorphism is associated to oral anticoagulant overdose. Thromb Haemost 2005; 94: 690-691.
  • 82 Rost S. et al. Mutations in VKORC1 cause warfarin resistance and multiple coagulation factor deficiency type 2. Nature 2004; 427: 537-541.
  • 83 Takahashi H. et al. Different contributions of polymorphisms in VKORC1 and CYP2C9 to intra- and inter-population differences in maintenance dose of warfarin in Japanese, Caucasians and African-Americans. Pharmacogenet Genomics 2006; 16: 101-110.
  • 84 Rieder MJ. et al. Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose. N Engl J Med 2005; 352: 2285-2293.
  • 85 Marsh S. et al. Population variation in VKORC1 haplotype structure. J Thromb Haemost 2006; 4: 473-474.
  • 86 Dang M-TN. et al. The influence of ethnicity on warfarin dosage requirement. Ann Pharmacother 2005; 39: 1008-1012.
  • 87 Yu HC. et al. Factors determining the maintenance dose of warfarin in Chinese patients. Q J Med 1996; 89: 127-135.
  • 88 Rettie AE. et al. Hydroxylation of warfarin by human cDNA-expressed cytoch-rome P-450: a role for P-4502C9 in the etiology of (S)-warfarin-drug interactions. Chem Res Toxicol 1992; 5: 54-59.
  • 89 Yasar U. et al. Validation of methods for CYP2C9 genotyping: frequencies of mutant alleles in a Swedish population. Biochem Biophys Res Commun 1999; 254: 628-631.
  • 90 Margaglione M. et al. Genetic modulation of oral anticoagulation with warfarin. Thromb Haemost 2000; 84: 775-778.
  • 91 Taube J. et al. Influence of cytochrome P-450 CYP2C9 polymorphisms on warfarin sensitivity and risk of over-anticoagulation in patients on long-term treatment. Blood 2000; 96: 1816-1819.
  • 92 Linder MW. et al. Warfarin dose adjustments based on CYP2C9 genetic polymorphisms. J Thromb Thrombolysis 2002; 14: 227-232.
  • 93 Brandt JT. et al. Common polymorphisms of CYP2C19 and CYP2C9 affect the pharmacokinetic and pharmacodynamic response to clopidogrel but not prasugrel. J Thromb Haemost 2007; 5: 2429-2436.
  • 94 Simon T. et al. French Registry of Acute ST-Elevation and Non-ST-Elevation Myocardial Infarction (FAST-MI) Investigators.. Genetic determinants of response to clopidogrel and cardiovascular events. N Engl J Med 2009; 360: 363-375.
  • 95 Kim KA. et al. The effect of CYP2C19 polymorphism on the pharmacokinetics and pharmacodynamics of clopidogrel: a possible mechanism for clopidogrel resistance. Clin Pharmacol Ther 2008; 84: 236-242.
  • 96 Umemura K. et al. The common gene variants of CYP2C19 affect pharmacokinetics and pharmacodynamics in an active metabolite of clopidogrel in healthy subjects. J Thromb Haemost 2008; 6: 1439-1441.
  • 97 Simon T. et al. French Registry of Acute ST-Elevation and Non-ST-Elevation Myocardial Infarction (FAST-MI) Investigators.. Genetic determinants of response to clopidogrel and cardiovascular events. N Engl J Med 2009; 360: 363-375.
  • 98 Mega JL. et al. Cytochrome p-450 polymorphisms and response to clopidogrel. N Engl J Med 2009; 360: 354-362.
  • 99 Sibbing D. et al. Cytochrome P450 2C19 loss-of-function polymorphism and stent thrombosis following percutaneous coronary intervention. Eur Heart J 2009; 30: 916-922.
  • 100 Trenk D. et al. Cytochrome P450 2C19 681G>A polymorphism and high onclopidogrel platelet reactivity associated with adverse 1-year clinical outcome of elective percutaneous coronary intervention with drug-eluting or bare-metal stents. J Am Coll Cardiol 2008; 51: 1925-1934.
  • 101 Collet JP. et al. Cytochrome P450 2C19 polymorphism in young patients treated with clopidogrel after myocardial infarction: a cohort study. Lancet 2009; 373: 309-317.
  • 102 Shuldiner AR. et al. Association of cytochrome P450 2C19 genotype with the antiplatelet effect and clinical efficacy of clopidogrel therapy. J Am Med Assoc 2009; 302: 849-857.
  • 103 Hoshino K. et al. Clopidogrel resistance in Japanese patients scheduled for percutaneous coronary intervention. Circ J 2009; 73: 336-342.
  • 104 Sibbing D. et al. Cytochrome 2C19*17 allelic variant, platelet aggregation, bleeding events and stent thrombosis in clopidogrel treated patients with coronary stent placement. Circulation 2010; 121: 512-518.
  • 105 Sim SC. et al. A common novel CYP2C19 gene variant causes ultrarapid drug metabolism relevant for the drug response to proton pump inhibitors and antidepressants. Clin Pharmacol Ther 2006; 79: 103-113.
  • 106 Kim ESH, Monon V. Status of Women in Cardiovascular Clinical Trials. Arterioscler Thromb Vasc Biol 2009; 29: 279-283.
  • 107 Chiaramonte GR, Friend R. Medical students’ and residents’ gender bias in the diagnosis, treatment, and interpretation of coronary heart disease symptoms. Health Psychol 2006; 25: 255-266.
  • 108 Van Spall HG. et al. Eligibility criteria of randomized controlled trials published in high-impact general medical journals: a systematic sampling review. J Am Med Assoc 2007; 297: 1233-1240.
  • 109 Gurwitz JH. et al. The exclusion of the elderly and women from clinical trials in acute myocardial infarction. J Am Med Assoc 1992; 268: 1417-1422.
  • 110 U.S. Congress Public Law No 103–43.. National Institutes of Health Revitalization Act of 1993. June 10, 1993.
  • 111 Ridker PM. et al. A randomized trial of low-dose aspirin in the primary prevention of cardiovascular disease in women. N Engl J Med 2005; 352: 1293-1304.
  • 112 Rossouw JE. et al. Writing Group for the Women’s Health Initiative Investigators.. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women’s Health Initiative randomized controlled trial. J Am Med Assoc 2002; 288: 321-333.
  • 113 Shavers VL. et al. Factors that influence African-Americans’ willingness to participate in medical research studies. Cancer 2001; 91 Suppl 233-236.
  • 114 Shavers VL. et al. Racial differences in factors that influence the willingness to participate in medical research studies. Ann Epidemiol 2002; 12: 248-256.
  • 115 Wendler D. et al. Are racial and ethnic minorities less willing to participate in health research?. PLoS Med 2006; 3: e19.
  • 116 Patrono C. et al. Low-dose aspirin for the prevention of atherothrombosis. N Engl J Med 2005; 353: 2373-2383.
  • 117 The RISC Group.. Risk of myocardial infarction and death during treatment with low dose aspirin and intravenous heparin in men with unstable coronary artery disease. Lancet 1990; 336: 827-830.
  • 118 ISIS-2 (Second International Study of Infarct Survival) Collaborative Group.. Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. Lancet 1988; 2: 349-360.
  • 119 Becker DM. et al. Sex differences in platelet reactivity and response to low-dose aspirin therapy. J Am Med Assoc 2006; 295: 1420-1427.
  • 120 Gum PA. et al. Profile and prevalence of aspirin resistance in patients with cardiovascular disease. Am J Cardiol 2001; 88: 230-235.
  • 121 Gum PA. et al. A prospective, blinded determination of the natural history of aspirin resistance among stable patients with cardiovascular disease. J Am Coll Cardiol 2003; 41: 961-965.
  • 122 Qayyum R. et al. Platelet inhibition by aspirin 81 and 325 mg/day in men versus women without clinically apparent cardiovascular disease. Am J Cardiol 2008; 101: 1359-1363.
  • 123 Eikelboom JW. et al. Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management and Avoidance (CHARISMA) Investigators.. Incomplete inhibition of thromboxane biosynthesis by acetylsalicylic acid: determinants and effect on cardiovascular risk. Circulation 2008; 118: 1705-1712.
  • 124 Eikelboom JW. et al. Aspirin-resistant thromboxane biosynthesis and the risk of myocardial infarction, stroke, or cardiovascular death in patients at high risk for cardiovascular events. Circulation 2002; 105: 1650-1655.
  • 125 Berger JS. et al. Aspirin for the primary prevention of cardiovascular events in women and men: a sex-specific meta-analysis of randomized controlled trials. J Am Med Assoc 2006; 295: 306-313.
  • 126 Antithrombotic Trialists’ (ATT) Collaboration. Baigent C, Blackwell L, Collins R. et al. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials. Lancet 2009; 373: 1849-1860.
  • 127 Yerman T. et al. The influence of gender on the effects of aspirin in preventing myocardial infarction. BMC Med 2007; 5: 29.
  • 128 Gum PA. et al. Profile and prevalence of aspirin resistance in patients with cardiovascular disease. Am J Cardiol 2001; 88: 230-235.
  • 129 Cohen HW. et al. Aspirin resistance associated with HbA1c and obesity in diabetic patients. J Diabetes Complications 2008; 22: 224-228.
  • 130 Brown DW. et al. Racial differences in the use of aspirin: an important tool for preventing heart disease and stroke. Ethn Dis 2005; 15: 620-626.
  • 131 Glasser SP. et al. Does differential prophylactic aspirin use contribute to racial and geographic disparities in stroke and coronary heart disease (CHD)?. Prev Med 2008; 47: 161-166.
  • 132 Bertrand ME. et al. CLASSICS Investigators.. Double-blind study of the safety of clopidogrel with and without a loading dose in combination with aspirin compared with ticlopidine in combination with aspirin after coronary stenting : the clopidogrel aspirin stent international cooperative study (CLASSICS). Circulation. 2000; 102: 624-629.
  • 133 Jochmann N. et al. Female-specific aspects in the pharmacotherapy of chronic cardiovascular diseases. Eur Heart J 2005; 26: 1585-1595.
  • 134 Serebruany VL. et al. Variability in platelet responsiveness to clopidogrel among 544 individuals. J Am Coll Cardiol 2005; 45: 246-251.
  • 135 Price MJ. Monitoring platelet function to reduce the risk of ischemic and bleeding complications. Am J Cardiol 2009; 103 Suppl 35A-39A.
  • 136 Ferreiro JL, Angiolillo DJ. Clopidogrel response variability: current status and future directions. Thromb Haemost 2009; 102: 7-14.
  • 137 Yusuf S. et al. Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators.. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 2001; 345: 494-502.
  • 138 Mehta SR. et al. Clopidogrel in Unstable angina to prevent Recurrent Events trial (CURE) Investigators.. Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study. Lancet 2001; 358: 527-533.
  • 139 Steinhubl SR. et al. CREDO Investigators.. Clopidogrel for the Reduction of Events During Observation. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. J Am Med Assoc 2002; 288: 2411-2420.
  • 140 Sabatine MS. et al. CLARITY-TIMI 28 Investigators.. Addition of clopidogrel to aspirin and fibrinolytic therapy for myocardial infarction with ST-segment elevation. N Engl J Med 2005; 352: 1179-1189.
  • 141 Chen ZM. et al. COMMIT (ClOpidogrel and Metoprolol in Myocardial Infarction Trial) collaborative group.. Addition of clopidogrel to aspirin in 45,852 patients with acute myocardial infarction: randomised placebo-controlled trial. Lancet 2005; 366: 1607-1621.
  • 142 Bhatt DL. et al. CHARISMA Investigators.. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med 2006; 354: 1706-1717.
  • 143 Berger JS. et al. The relative efficacy and safety of clopidogrel in women and men. J Am Coll Cardiol 2009; 54: 1935-1945.
  • 144 Mak KH. et al. Ethnic variation in adverse cardiovascular outcomes and bleeding complications in the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) study. Am Heart J 2009; 157: 658-665.
  • 145 Hoshino K. et al. Clopidogrel resistance in Japanese patients scheduled for percutaneous coronary intervention. Circ J 2009; 73: 336-342.
  • 146 Jinnai T. et al. Impact of CYP2C19 polymorphisms on the antiplatelet effect of clopidogrel in an actual clinical setting in Japan. Circ J 2009; 73: 1498-1503.
  • 147 Angiolillo DJ. et al. Prasugrel: a novel platelet ADP P2Y12 receptor antagonist. A review on its mechanism of action and clinical development. Expert Opin Pharmacother 2008; 9: 2893-2900.
  • 148 Wiviott SD. et al. TRITON-TIMI 38 Investigators. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007; 357: 2001-2015.
  • 149 Small DS. et al. The pharmacokinetics and pharmacodynamics of prasugrel in healthy Chinese, Japanese, and Korean subjects compared with healthy Caucasian subjects. Eur J Clin Pharmacol 2010; 66: 127-135.
  • 150 Mega JL. et al. Cytochrome P450 genetic polymorphisms and the response to prasugrel: relationship to pharmacokinetic, pharmacodynamic, and clinical outcomes. Circulation 2009; 119: 2553-2560.
  • 151 Wallentin L. et al. the PLATO Investigators. Ticagrelor versus Clopidogrel in Patients with Acute Coronary Syndromes. N Engl J Med 2009; 361: 1-13.
  • 152 Coller BS. et al. A murine monoclonal antibody that completely blocks the binding of fibrinogen to platelets produces a thrombasthenic-like state in normal platelets and binds to glycoproteins IIb and/or IIIa. J Clin Invest 1983; 72: 325-338.
  • 153 Tardiff BE. et al. PERIGEE Investigators.. Pharmacodynamics and pharmacokinetics of eptifibatide in patients with acute coronary syndromes: prospective analysis from PURSUIT. Circulation 2001; 104: 399-405.
  • 154 Cho L. 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.
  • 155 Fernandes LS. et al. ESPRIT investigators.. 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.
  • 156 Boersma E. 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.
  • 157 Hirsh J. et al. Heparin and low-molecular-weight heparin: mechanisms of action, pharmacokinetics, dosing considerations, monitoring, efficacy, and safety. Chest 1998; 114: 489S-510S.
  • 158 Hochman JS. et al. A new regimen for heparin use in acute coronary syndromes. Am Heart J 1999; 138: 313-318.
  • 159 Granger CB. et al. Activated partial thromboplastin time and outcome after thrombolytic therapy for acute myocardial infarction: results from the GUSTO-I trial. Circulation 1996; 93: 870-878.
  • 160 Thrombolysis In Myocardial Infarction 11A Investigators.. Dose-ranging trial of enoxaparin for unstable angina: results of TIMI 11A. J Am Coll Cardiol 1997; 29: 1474-1482.
  • 161 Becker RC. et al. TIMI 11A Investigators.. Influence of patient characteristics and renal function on factor Xa inhibition pharmacokinetics and pharmacodynamics after enoxaparin administration in non-ST-segment elevation acute coronary syndromes. Am Heart J 2002; 143: 753-759.
  • 162 Fragmin during Instability in Coronary Artery Disease (FRISC) Study Group.. Low-molecular-weight heparin during instability in coronary artery disease. Lancet 1996; 347: 561-568.
  • 163 Toss H. et al. Influences of sex and smoking habits on anticoagulant activity in low-molecular-weight heparin treatment of unstable coronary artery disease. Am Heart J 1999; 137: 72-78.
  • 164 Cohen M. et al. ESSENCE (Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-wave Coronary Events) and TIMI (Thrombolysis in Myocardial Infarction) 11B Investigators.. Enoxaparin in unstable angina/non-ST-segment elevation myocardial infarction: treatment benefits in prespecified subgroups. J Thromb Thrombolysis 2001; 12: 199-206.
  • 165 White HD. et al. Efficacy and safety of enoxaparin compared with unfractionated heparin in high-risk patients with non-ST-segment elevation acute coronary syndrome undergoing percutaneous coronary intervention in the Superior Yield of the New Strategy of Enoxaparin, Revascularization and Glycoprotein IIb/IIIa Inhibitors (SYNERGY) trial. Am Heart J 2006; 152: 1042-1050.
  • 166 Mega JL. et al. Outcomes and optimal antithrombotic therapy in women undergoing fibrinolysis for ST-elevation myocardial infarction. Circulation 2007; 115: 2822-2828.
  • 167 Lee CH. et al. Impact of different Asian ethnic groups on correlation between heparin dose, activated clotting time and complications in percutaneous coronary intervention. Int J Cardiol 2008; 130: 500-502.
  • 168 Anderson JL. et al. ACC/AHA 2007 guidelines for the management of patients with unstable angina/non-ST-Elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction) developed in collaboration with the American College of Emergency Physicians, the Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation and the Society for Academic Emergency Medicine. J Am Coll Cardiol 2007; 50: 1-157.
  • 169 Kushner FG. et al. 2009 focused updates: ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction (updating the 2004 guideline and 2007 focused update) and ACC/AHA/SCAI guidelines on percutaneous coronary intervention (updating the 2005 guideline and 2007 focused update) a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2009; 54: 2205-2241.
  • 170 Lincoff AM. et al. REPLACE-2 Investigators.. Bivalirudin and provisional glyco-protein IIb/IIIa blockade compared with heparin and planned glycoprotein IIb/ IIIa blockade during percutaneous coronary intervention: REPLACE-2 randomized trial. J Am Med Assoc 2003; 289: 853-863.
  • 171 Lincoff AM. et al. 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: REPLACE-2 randomized trial. J Am Med Assoc 2004; 292: 696-703.
  • 172 Chacko M. et al. Ischemic and bleeding outcomes in women treated with bivalirudin during percutaneous coronary intervention: a subgroup analysis of the Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events (REPLACE)-2 trial. Am Heart J 2006; 151: 1032.e1-7.
  • 173 Stone GW. et al., for the ACUITY Investigators. Bivalirudin for patients with acute coronary syndromes. N Engl J Med 2006; 355: 2203-2216.
  • 174 Stone GW. et al. Acute Catheterization and Urgent Intervention Triage strategy (ACUITY) trial investigators.. Bivalirudin in patients with acute coronary syndromes undergoing percutaneous coronary intervention: a subgroup analysis from the Acute Catheterization and Urgent Intervention Triage strategy (ACUITY) trial. Lancet 2007; 369: 907-919.
  • 175 Manoukian SV. et al. Impact of major bleeding on 30-day mortality and clinical outcomes in patients with acute coronary syndromes: an analysis from the ACUITY Trial. J Am Coll Cardiol 2007; 49: 1362-1368.
  • 176 Lansky AJ. et al. Impact of gender and antithrombin strategy on early and late clinical outcomes in patients with non-ST-elevation acute coronary syndromes (from the ACUITY trial). Am J Cardiol 2009; 103: 1196-1203.
  • 177 Stone GW. et al. HORIZONS-AMI Trial Investigators.. Bivalirudin during primary PCI in acute myocardial infarction. N Engl J Med 2008; 358: 2218-2230.
  • 178 Mehran R. et al. HORIZONS-AMI Trial Investigators.. Bivalirudin in patients undergoing primary angioplasty for acute myocardial infarction (HORIZONS-AMI): 1-year results of a randomised controlled trial. Lancet 2009; 374: 1149-1159.
  • 179 Grinfeld L. et al. Impact of gender on the safety and effectiveness of bivalirudin in patients with acute myocardial infarction undergoing primary angioplasty. Abstract presented at: Annual meeting of the American College of Cardiology, Chicago, March 29, 2008.
  • 180 Madsen JK. et al. Ischaemic events and bleeding in patients undergoing percutaneous coronary intervention with concomitant bivalirudin treatment. EuroIntervention 2008; 3: 610-616.
  • 181 Shammas NW. et al. APPROVE Investigators.. Predictors of in-hospital and 30-day complications of peripheral vascular interventions using bivalirudin as the primary anticoagulant: results from the APPROVE Registry. J Invasive Cardiol 2005; 17: 356-359.
  • 182 Roguin A. et al. Safety of bivalirudin during percutaneous coronary interventions in patients with abnormal renal function. Int J Cardiovasc Intervent 2005; 7: 88-92.
  • 183 van Ryn J. et al. Dabigatran etexilate – a novel, reversible, oral direct thrombin inhibitor: Interpretation of coagulation assays and reversal of anticoagulant activity. Thromb Haemost 2010; 103: 1116-1127.
  • 184 Connolly SJ. et al. the RE-LY Steering Committee and Investigators. Dabigatran versus Warfarin in Patients with Atrial Fibrillation. N Engl J Med 2009; 361: 1139-1151.
  • 185 Lewis BE. et al. Argatroban-915 Investigators.. Argatroban anticoagulation in patients with heparin-induced thrombocytopenia. Arch Intern Med 2003; 163: 1849-1856.
  • 186 Lewis BE. et al. ARG-911 Study Investigators.. Argatroban anticoagulant therapy in patients with heparin-induced thrombocytopenia. Circulation 2001; 103: 1838-1843.
  • 187 Swan SK, Hursting MJ. The pharmacokinetics and pharmacodynamics of argatroban: effects of age, gender, and hepatic or renal dysfunction. Pharmacotherapy 2000; 20: 318-329.
  • 188 Jang IK. et al. Argatroban therapy in women with heparin-induced thrombocytopenia. J Womens Health (Larchmt) 2007; 16: 895-901.
  • 189 Hursting MJ, Jang IK. Dosing patterns and outcomes in African American, Asian, and Hispanic patients with heparin-induced thrombocytopenia treated with argatroban. J Thromb Thrombolysis 2009; 28: 10-15.
  • 190 Blick SK. et al. Fondaparinux sodium: a review of its use in the management of acute coronary syndromes. Am J Cardiovasc Drugs 2008; 8: 113-125.
  • 191 Yusuf S. et al. Comparison of fondaparinux and enoxaparin in acute coronary syndromes. N Engl J Med 2006; 354: 1464-1476.
  • 192 Yusuf S. et al. OASIS-6 Trial Group.. Effects of fondaparinux on mortality and reinfarction in patients with acute ST-segment elevation myocardial infarction: the OASIS-6 randomized trial. J Am Med Assoc 2006; 295: 1519-1530.
  • 193 Oldgren J. et al. OASIS-6 Investigators.. Effects of fondaparinux in patients with ST-segment elevation acute myocardial infarction not receiving reperfusion treatment. Eur Heart J 2008; 29: 315-323.
  • 194 Fang MC. et al. Gender differences in the risk of ischemic stroke and peripheral embolism in atrial fibrillation: the AnTicoagulation and Risk factors In Atrial fibrillation (ATRIA) study. Circulation 2005; 112: 1687-1691.
  • 195 [No authors listed]. Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation. Analysis of pooled data from five randomized controlled trials. Arch Intern Med 1994; 154: 1449-1457.
  • 196 Gomberg-Maitland M. et al. Anticoagulation in women with non-valvular atrial fibrillation in the stroke prevention using an oral thrombin inhibitor (SPORTIF) trials. Eur Heart J 2006; 27: 1947-1953.
  • 197 Hart RG. et al. Factors associated with ischemic stroke during aspirin therapy in atrial fibrillation: analysis of 2012 participants in the SPAF I-III clinical trials. The Stroke Prevention in Atrial Fibrillation (SPAF) Investigators. Stroke 1999; 30: 1223-1229.
  • 198 Garcia D. et al. Warfarin maintenance dosing patterns in clinical practice. Chest 2005; 127: 2049-2056.
  • 199 Fibrinolytic Therapy Trialists’ (FTT) Collaborative Group.. Indications for fibrinolytic therapy in suspected acute myocardial infarction: collaborative overview of early mortality and major morbidity results from all randomised trials of more than 1000 patients. Lancet 1994; 343: 311-322.
  • 200 Woodfield SL. et al. Gender and acute myocardial infarction: is there a different response to thrombolysis?. J Am Coll Cardiol 1997; 29: 35-42.
  • 201 Gruppo Italiano per lo Studio Della Streptochinasi nell’Infarto Miocardico (GISSI).. Effectiveness of intravenous thrombolytic treatment in acute myocardial infarction. Lancet 1986; 1: 397-402.
  • 202 ISIS-2 (Second International Study of Infarct Survival) Collaborative Group.. Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17 187 cases of suspected acute myocardial infarction: ISIS-2. Lancet 1988; 2: 349-360.
  • 203 Wilcox RG. et al. Trial of tissue plasminogen activator for mortality reduction in acute myocardial infarction: Anglo-Scandinavian Study of Early Thrombolysis (ASSET). Lancet 1988; 2: 525-530.
  • 204 The GUSTO Investigators.. An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction. N Engl J Med 1993; 329: 673-682.
  • 205 Moen EK. et al, Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries. Long-term follow-up of gender-specific outcomes after thrombolytic therapy for acute myocardial infarction from the GUSTO-I trial. J Womens Health 1997; 6: 285-293.
  • 206 Lee KL. et al. Predictors of 30-day mortality in the era of reperfusion for acute myocardial infarction. Circulation 1995; 91: 1659-1668.
  • 207 White HD. et al. After correcting for worse baseline characteristics, women treated with thrombolytic therapy for acute myocardial infarction have the same mortality and morbidity as men except for a higher incidence of hemorrhagic stroke. The Investigators of the International Tissue Plasminogen Activator/ Streptokinase Mortality Study. Circulation 1993; 88: 2097-2103.
  • 208 Weaver WD. et al, GUSTO-I Investigators. Comparisons of characteristics and outcomes among women and men with acute myocardial infarction treated with thrombolytic therapy. J Am Med Assoc 1996; 275: 777-782.
  • 209 Woodfield SL. et al. Gender and acute myocardial infarction: is there a different response to thrombolysis?. J Am Coll Cardiol 1997; 29: 35-42.
  • 210 Nicolau JC. et al. The role of gender in the long-term prognosis of patients with myocardial infarction submitted to fibrinolytic treatment. Ann Epidemiol 2004; 14: 17-23.
  • 211 Van de Werf F. et al, ASSENT-2 Investigators. Incidence and predictors of bleeding events after fibrinolytic therapy with fibrin-specific agents: a comparison of TNK-tPA and rt-PA. Eur Heart J 2001; 22: 2253-2261.
  • 212 Berkowitz SD. et al., Global Utilization of Streptokinase and Tissue Plasminogen activator for Occluded coronary arteries (GUSTO) I Investigators. Incidence and predictors of bleeding after contemporary thrombolytic therapy for myocardial infarction. Circulation 1997; 95: 2508-2516.
  • 213 Topol EJ. Reperfusion therapy for acute myocardial infarction with fibrinolytic therapy or combination reduced fibrinolytic therapy and platelet glycoprotein IIb/IIIa inhibition: the GUSTO V randomised trial. Lancet 2001; 357: 1905-1914.
  • 214 Reynolds HR. et al. GUSTO V Investigators.. Impact of female sex on death and bleeding after fibrinolytic treatment of myocardial infarction in GUSTO V. Arch Intern Med 2007; 167: 2054-2060.
  • 215 Borzak S. et al. Lower thrombolytic use for African Americans with myocardial infarction: an influence of clinical presentation?. Am Heart J 1999; 137: 338-345.
  • 216 Taylor HA. et al. for the National Registry of Myocardial Infarction 2 Investigators.. Management and outcomes for black patients with acute myocardial infarction in the reperfusion era. Am J Cardiol 1998; 82: 1019-1023.
  • 217 Allison JJ. et al. Racial differences in the medical treatment of elderly Medicare patients with acute myocardial infarction. J Gen Intern Med 1996; 11: 736-743.
  • 218 Pashos CL. et al. Trends in the use of drug therapies in patients with acute myocardial infarction: 1988 to 1992. J Am Coll Cardiol 1994; 23: 1023-1030.
  • 219 Syed M. et al. Effect of delay on racial differences in thrombolysis for acute myocardial infarction. Am Heart J 2000; 140: 643-650.
  • 220 Taylor HA. et al. Race and prognosis after myocardial infarction. Results of the thrombolysis in myocardial infarction (TIMI) phase II trial. Circulation 1993; 88: 1484-1494.