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Percutaneous Coronary Revascularisation in Women
Thrombosis Research 103 (2001) S105 – S111
REGULAR ARTICLE
Percutaneous Coronary Revascularisation in Women
Marco L. Rossi1, Piera Angelica Merlini1 and Diego Ardissino2 1 Dipartimento Cardiologico A. De Gasperis, Ospedale Niguarda ‘‘Ca` Granda,’’ Milan, Italy and 2Divisione di Cardiologia, Ospedale Maggiore di Parma, Universita` degli Studi di Parma, Parma, Italy
Abstract Numerous studies of sex differences in morbidity and mortality after an episode of acute coronary disease shown unclear results. In particular is not clear if women undergoing coronary revascularization procedures have adverse in-hospital and long-term outcomes compared with men. Recent clinical trial have provided new insights into this problem. The influence on gender differences for the decision to undertake coronary angiography and percutaneous transluminal coronary angioplasty will be discussed. D 2001 Elsevier Science Ltd. All rights reserved. Key Words: Percutaneous transluminal coronary angioplasty; Coronary artery disease; Acute myocardial infarction; Women
O
ver recent years, increasing attention has been given to coronary artery disease (CAD) as a major cause of mortality and morbidity in women. A number of studies have examined gender differences in short- and long-term prognosis after an episode of CAD, and some have suggested that these may also play a role in diagnosis and patient management. We analyse here whether gender differences affect the decision to undertake arteriography in women and whether percutane-
Corresponding author: Dr. Diego Ardissino, Divisone di Cardiologia, Ospedale Maggiore, Universita` degli Studi di Parma, P.zza Gramsci 14, Parma 43100, Italy. Tel: +39 (2) 5275139.
ous transluminal coronary angioplasty (PTCA) results are different in women.
1. Are There Gender Differences in CAD? Table 1 summarises the main differences in CAD. 1.1. Onset and Progression of CAD in Women The clinical signs and symptoms of acute coronary disease typically develop an average of 8– 10 years later in women than in men, but when they appear, the probability of CAD is greater in women and they reach the same prevalence as men in a decade. In other words, CAD progresses more rapidly in women and this may have some pathophysiological implications in terms of the development of collateral vessels: from an angiographic point of view, women have fewer collateral vessels [1]. 1.2. Coronary Anatomy Both the arterial and luminal areas are smaller in women. Sheifer et al. [2] used intravascular ultrasound to investigate the left main (LM) and proximal left anterior descending (LAD) coronary artery segments in patients without atherosclerosis, and found that women had smaller LM and LAD arterial and luminal areas than men (Fig. 1); multivariate analysis confirmed that gender (regardless of body size) is an independent predictor of correct LA and LAD arterial areas. This intrinsic difference in coronary size suggests that it may play an important
0049-3848/01/$ – see front matter D 2001 Elsevier Science Ltd. All rights reserved. PII S0049-3848(01)00306-1
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M.L. Rossi et al./Thrombosis Research 103 (2001) S105–S111
Table 1. Main differences in CAD between men and women CAD: gender differences
of CAD Onset of CAD Progression Coronary anatomy Plaque composition Hypercoagulable state Environmental risk factors
role in the different outcomes of myocardial infarction and coronary revascularisation between men and women. Women with acute coronary syndromes undergoing angiography are more likely to have no significant CAD, and the extent of CAD is less in women than in men; however, they have a higher prevalence of systemic hypertension and diabetes mellitus [3]. Fewer women have suffered a previous acute myocardial infarction (AMI) or have a history of bypass surgery. The GUSTO IIb trial revealed gender-related differences in acute coronary syndrome profiles [4]; the proportion of women with AMI with ST elevation (i.e., a syndrome related to occlusive thrombus) was significantly lower, but the prevalence of unstable angina was significantly higher. These differences could be related to anatomical and pathophysiological differences between men and women because the reduced collateral blood flow in women [1] may lead to a higher rate of complications when AMI with total coronary occlusion occurs. The differences in thrombotic and fibrinolytic activity between the sexes may also explain the differences in coronary syndromes [5–9]. Another important gen-
Fig. 2. Prevalence of plaque erosion between men and women with AMI.
der-related difference is plaque composition: in a post-mortem study, Arbustini et al. [10,11] showed that about 25% of the plaques causing coronary thrombosis in AMI patients was not ruptured, but the plaque substrate for thrombosis was erosion. This finding was significantly more prevalent in women (Fig. 2), and confirmed previous observations of a higher incidence of plaque erosion in women than in men experiencing sudden death [12]. These data indicate morphological differences in the plaque, with women having a more thrombogenic substrate. Differences in plaque composition may also explain the higher coronary dissection rate during angioplasty in women [13].
2. Prothrombotic Genetic Risk Factors The major role of thrombogenicity in precipitating acute events is indirectly demonstrated by the fact that prothrombotic genetic risk factors, such as the factor V Leiden mutation and prothrombin gene mutation, increase the risk of developing myocardial infarction at a young age particularly in women, and closely interact with other prothrombotic risk factors such as smoking [8,9]. 2.1. Results of PTCA in Women
Fig. 1. Gender differences in coronary artery size performed by intravascular ultrasound.
In 1985, the National Heart, Lung and Blood Institute published its registry (NHLBI PTCA Registry) showing a higher number of postPTCA complications in women: although the men had a higher prevalence of multivessel disease and worse ventricular function, the women undergoing PTCA had a lower success rate and a
M.L. Rossi et al./Thrombosis Research 103 (2001) S105–S111
higher rate of complications and in-hospital deaths [13]. Women were more likely to experience coronary dissection, a six times higher rate of procedure-related deaths and a five times higher mortality rate with emergency bypass surgery; multivariate analysis showed that female gender was an independent predictor of a lower success rate and early mortality. However, if the angioplasty was not complicated, women had better late outcomes, with fewer infarctions, repeat angioplasties, bypass surgical interventions and deaths. These data were confirmed by the TIMI III Registry, which was used to evaluate the effect of gender on the management of unstable angina and non-Q-wave MI. This study found that women with various coronary syndromes are treated less aggressively and undergo coronary angiography less frequently than men [14]. In terms of gender-related outcomes, a number of studies have shown that women have a higher in-hospital event rate, including repeat angioplasty, myocardial re-infarction, and inhospital and short-term mortality [15–20]. The PAMI Registry showed that in-hospital mortality was 3.3 times greater in women than in men [20]. Gender-related differences have also been found in the outcomes of individual acute coronary syndromes: female gender is associated with an independent protective effect in unstable angina, whereas women with infarction and ST elevation have a higher short-term mortality rate. After adjusting for differences in body surface area, age, risk factors and treatment intervention, many studies [17–22] have
S107
excluded the possibility that sex is an independent predictor of mortality after AMI, but others have found the contrary [3,5,23–26]. It has been suggested [4] that this apparent contradiction reflects the different percentages of the individual acute coronary syndromes in population studies. The morphological differences in coronary plaques, the evidence of differences in the risk of death and nonfatal infarction in patients with unstable angina and AMI with ST elevation, and the similarity in outcomes despite the fact that women have less severe coronary disease suggest that the worse prognosis in women is probably due to unknown risk factors as well as pathophysiologically and anatomically different clinical profiles. The worse prognosis of women undergoing coronary angioplasty is also only partially explainable by their older age and worse clinical state (more severe angina and cardiac failure) [13,27]. These initial unfavourable experiences may account for the unwillingness of physicians to refer women for angiography and percutaneous revascularisation. The MITI Registry concentrated on ‘‘gender-related bias’’ in signs and symptoms when evaluating and treating of AMI: although the symptoms, hemodynamic and electrocardiographic findings in women were largely indistinguishable from those observed in men, women were less aggressively treated and less likely to undergo thrombolysis, acute catheterisation, angioplasty or coronary bypass surgery (Fig. 3), thus leading to a less favourable outcome [28].
Fig. 3. Different treatment of coronary artery disease according to sex in the MITI Registry.
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M.L. Rossi et al./Thrombosis Research 103 (2001) S105–S111
The prospective GUARANTEE Registry [3] has more recently evaluated gender differences in the management of unstable angina: once again, the women with a higher risk profile were less likely to undergo coronary arteriography, angioplasty and bypass surgery than men; however, when they used the Agency for Health Care Policy Research [29] and the TIMI IIIB criteria [14,30] for catheterisation and revascularisation, the authors found that a similar percentage of men and women was appropriately referred for angioplasty. On the contrary, fewer women with positive criteria underwent bypass surgery, which thus appears to be a gender bias against women (Fig. 4) as they have the same revascularisation outcome as men. The PAMI trial has recently demonstrated a significant proportional benefit of direct PTCA over t-PA in women with AMI [20], thus suggesting that PTCA rather than t-PA treatment is an age-independent predictor of improved outcome in women probably as a result of multifactorial events. Primary PTCA certainly reduces hemorrhagic complications, such as intracranial hemorrhage, which occur more frequently in women than men treated with t-PA (5.3% vs. 0.7%). Finally, in a recent trial of early revascularisation in patients with cardiogenic shock [31], the relative 30-day risk of death between the women assigned to revascularisation and those assigned to medical thrombolytic therapy was similar, and comparable with that observed in men. It has recently been shown that the use of GP IIb/IIIa in the catheter laboratory improves the survival of patients undergoing stenting [32] and leads to a decrease in acute complications in
Fig. 5. Differences in major and minor bleeding rate in men and women treated with abiciximab (Ref. [34], modified).
high-risk patients. Data from the EPIC trial [33] show that the risk reduction obtained when using these drugs in women is similar to that observed in men, and that women had a slightly increased risk of minor bleeding with abiciximab (Fig. 5). Women are generally at higher risk for major hemorrhages regardless of abiciximab treatment: it is known that the rate of moderate or severe bleeding is higher in women than men, and that female gender is a significant predictor of major bleeding [26]. Women are also at greater risk of bleeding during fibrinolytic therapy, although the benefit of fibrinolysis is similar in women and men [16,20–22,34]. Angioplasty is less frequently used in women than in men. This may stem from the fact that women even less frequently undergo coronary angiography, probably because physicians consider that there is a higher probability of finding nonsignificant CAD (Table 2). Furthermore, the rate of acute complications in the subset of patients who actually undergo the procedure is higher: GP IIb/IIIa inhibitors represent an imporTable 2. Possible reasons of underuse of revascularization procedures in women with CAD Differences on revascularization procedures: underuse in women, overuse in men or both?
of CAD Incidence Physician’s perception of sex-related differences in risk and efficacy Increased rates of hospital admission for women with ischemic symptoms in the absence of true coronary heart disease
Fig. 4. Differences in the interventional procedures in men and women with unstable angina (Ref. [3], modified).
bias in the delivery of medical care Sex Severity of coronary disease
M.L. Rossi et al./Thrombosis Research 103 (2001) S105–S111
tant tool for reducing acute complications in this subset of high-risk patients.
References 1. Johansson S, Bergstrand R, Schlossman D, Selin K, Vedin A, Wilhelmsson C. Sex differences in cardioangiographic findings after myocardial infarction. Eur Heart J 1984;5: 374–81. 2. Sheifer SE, Canos MR, Wienfurt KP, Arora UK, Mendelson FO, Gersh BJ, Weissman NJ. Sex differences in coronary artery size assessed by intravascular ultrasound. Am Heart J 2000;139:649–53. 3. Scirica BM, Moliterno DJ, Every NR, Anderson HV, Aguirre FV, Granger CB, Lambrew CT, Rabbani LE, Arnold A, Sapp SK, Booth JE, Ferguson JJ, Cannon CP. The GUARANTEE investigators. Differences between men and women in the management of unstable angina pectoris (the GUARANTEE Registry). Am J Cardiol 1999;84:1145–50. 4. Hochman JS, Tamis JE, Thompson TD, Douglas WW, White HD, Van de Werf F, Aylward P, Topol EJ, Califf RM. Sex, clinical presentation, and outcome in patients with acute coronary syndromes. N Engl J Med 1999;341:226–32. 5. Conlan MG, Folsom AR, Finch A, Davis CE, Marcucci G, Sorlie P, Wu KK. Associations of factor VIII and von Willerbrand factor with age, race, sex, and risk factors for the atherosclerosis: the Atherosclerosis Risk in Communities (ARIC) study. Thromb Haemostasis 1993;70:380–5. 6. Stegnar M, Pentek M. Fibrinolytic response to venous occlusion in healthy subjects: relationship to age, gender, body, weight, blood lipids and insulin. Thromb Res 1993;69:81–92 (published erratum appears in Thromb Res 1993;72:173). 7. Cucuianu M, Lanczek M, Roman S. Plasminogen activator inhibitor (PAI) in obese men and obese women. Rom J Intern Med 1993;31: 183–92. 8. Rosendaal FR, Siscovick DS, Schwartz SM,
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Beverly RK, Psaty BM, Longstreth WT, Raghunathan TE, Koepsell TD, Reitsma PH. Factor V Leiden (resistance to activated protein C) increases the risk of myocardial infarction in young women. Blood 1997;89: 2817–21. Rosendaal FR, Siscovick DS, Schwartz SM, Psaty BM, Raghunathan TE, Vos HL. A common prothrombin variant (20210 G to A) increases the risk of myocardial infarction in young women. Blood 1997;90:1747–50. Arbustini E, Dal Bello B, Morbini P, Burke AP, Bocciarelli M, Specchia G, Virmani R. Plaque erosion is a major substrate for coronary thrombosis in acute myocardial infarction. Heart 1999;82:269–72. Arbustini E, Morbini P, Dal Bello B, Prati F, Specchia G. From plaque biology to clinical setting. Am Heart J 1999;138:S55–60. Farb A, Burke AP, Tang AL, Mannan Poonam MS, Smialek J, Virmani R. Coronary plaque erosion without rupture into a lipid core. A frequent cause of coronary thrombosis in sudden coronary death. Circulation 1996;93: 1354–63. Cowley MJ, Mullin SM, Kelsey SF, Kent KM, Gruentzig AR, Detre KM, Passamani ER. Sex differences in early and long-term results of coronary angioplasty in the NHLBI PTCA Registry. Circulation 1985;71:90–7. Stone PH, Thompson B, Anderson HV, Kronenberg MW, Gibson RS, Roger WJ, Diver DJ, Theroux P, Warnica JW, Nasmith JB, Kells C, Kleiman N, McCabe CH, Schactman M, Knatterud GL, Braunwald E. Influence of race, sex, and age on management of unstable angina and non-Q-wave myocardial infarction: the TIMI III Registry. J Am Med Assoc 1996;275: 1104–12. Puletti M, Sunseri L, Curione M, Erba SM, Borgia C. Acute myocardial infarction: sexrelated differences in prognosis. Am Heart J 1984;108:63–6. Tofler GH, Stone PH, Muller JE, Millich SN, Davis VG, Poole WK, Strauss HW, Willerson JT, Jaffe AS, Robertson T. Effects of gender and race on prognosis after myocardial infarction: adverse prognosis for women,
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particularly black women. J Am Coll Cardiol 1987;9:473–82. Dittrich H, Gilpin E, Nicod P, Cali G, Henning H, Ross J. Acute myocardial infarction in women: influence of gender on mortality and prognostic variables. Am J Cardiol 1988; 62:1–7. Fiebach NH, Viscoli CM, Horwitz RI. Differences between women and men in survival after myocardial infarction: biology or methodology? J Am Med Assoc 1990;263:1092–6. Kostis JB, Wilson AC, O’Dowd K, Gregory P, Chelton S, Cosgrove N, Chirala A, Cui T. Sex differences in the management and long-term outcome of acute myocardial infarction: a statewide study. Circulation 1994; 90:1715–30. Stone GW, Grines CL, Browne KF, Marco J, Rothbaum D, O’Keefe J, Hartzler GO, Overlie P, Donohue B, Chelliah N, Vliestra R, Puchrowicz-Ochocki S, O’Neill WW. Comparison of in-hospital outcome in men versus women treated by either thrombolytic therapy or primary coronary angioplasty for acute myocardial infarction. Am J Cardiol 1995;75:987–92. Lincoff AM, Califf RM, Ellis SG, Sigmon KN, Lee KL, Leimberg JD, Topol EJ. Thrombolytic therapy for women with myocardial infarction: is there a gender gap? J Am Coll Cardiol 1993;22:1780–7. White HD, Barbash GI, Modan M, Simes J, Diaz R, Hampton JR, Heikkila J, Kristinsson A, Moulopoulos S. 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. Circulation 1993;88:2097–103. Greenland P, Reicher-Reiss H, Goldbourt U, Behar S. In-hospital and 1-year mortality in 1524 women after myocardial infarction: comparison with 4315 men. Circulation 1991;83:484–91. Weaver WD, White HD, Wilcox RG, Aylward PE, Morris D, Guearci A, Ohman EM, Barbash GI, Betriu A, Sadowski Z, Topol EJ,
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Califf RM. Comparisons of characteristics and outcomes among women and men with acute myocardial infarction treated with thrombolytic therapy. J Am Med Assoc 1996;275:777–82. Jacobs AK, Kelsey SF, Brooks MM, Faxon DP, Chaitman BR, Bittner V, Mock MB, Weiner BH, Dean L, Winston C, Drew L, Sopko G. Better outcome for women compared with men undergoing coronary revascularization. Circulation 1998;98:1279–85. Vaccarino V, Parsons L, Every NR, Barron HV, Krumholz HM. Sex-based differences in early mortality after myocardial infarction. N Engl J Med 1999;341:217–25. Bell MR, Grill DE, Garrat KN, Berger PB, Gersh BJ, Holmes DR. Long-term outcome of women compared with men after successful coronary angioplasty. Circulation 1995;91:2876–81. Kudenchuk PJ, Maynard C, Martin JS, Wirkus M, Weaver WD. Comparison of presentation, treatment, and outcome of acute myocardial infarction in men versus women (The Myocardial Infarction Triage and Intervention Registry). Am J Cardiol 1996;78:9–14. Braunwald E, Mark DB, Jones RH, Cheitlin MD, Fuster V, McCauley KM, Edwards C, Green LA, Mashlin AL, Swain JA. Unstable angina: diagnosis and management clinical practice guideline number 10. Rockville, MD: Agency for Health Care Policy and Research and the National Heart, Lung and Blood Institute, Public Health Service, US Department of Health and Human Services, 1994. p. 154. Hochman JS, McCabe CH, Stone PH, Becker RC, Cannon CP, DeFeo-Fraulini T, Thompson B, Steingart R, Knatterud G, Braunwald E. Outcome and profile of women and men presenting with acute coronary syndromes: a report from TIMI IIIB. TIMI investigators. Thrombolysis in Myocardial Infarction. J Am Coll Cardiol 1997; 30:141–8. Hochman JS, Sleeper LA, Webb JG, Sanborn TA, White HD, Talley JD, Buller CE, Jacobs AK, Slater JN, Col J, McKinlay SM,
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Lincoff AM. Early revascularization in acute myocardial infarction complicated by cardiogenic shock. N Engl J Med 1999; 341:625–34. 32. EPISTENT Investigators, Topol EJ, Mark DB, Lincoff AM, Cohen E, Burton J, Kleiman N, Talley D, Sapp S, Booth J, Cabot CF, Anderson KM, Califf RM. Outcomes at 1 year and economic implications of platelet glycoprotein IIb/IIIa blockade in patients undergoing coronary stenting: results from a multicentre randomised trial. Lancet 1999;354:2019–24.
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33. EPIC Investigators. Use of a monoclonal antibody directed against the platelet glycoprotein IIb/IIIa receptor in high-risk coronary angioplasty. N Engl J Med 1994;330: 956–61. 34. Cho L, Topol EJ, Balog C, Foody JM, Booth JE, Cabot C, Kleiman NS, Tcheng JE, Califf R, Lincoff AM. Clinical benefit of glycoprotein IIb/IIIa blockade with abiciximab is independent of gender. J Am Coll Cardiol 2000;36: 381–6.
REGULAR ARTICLE
Percutaneous Coronary Revascularisation in Women
Marco L. Rossi1, Piera Angelica Merlini1 and Diego Ardissino2 1 Dipartimento Cardiologico A. De Gasperis, Ospedale Niguarda ‘‘Ca` Granda,’’ Milan, Italy and 2Divisione di Cardiologia, Ospedale Maggiore di Parma, Universita` degli Studi di Parma, Parma, Italy
Abstract Numerous studies of sex differences in morbidity and mortality after an episode of acute coronary disease shown unclear results. In particular is not clear if women undergoing coronary revascularization procedures have adverse in-hospital and long-term outcomes compared with men. Recent clinical trial have provided new insights into this problem. The influence on gender differences for the decision to undertake coronary angiography and percutaneous transluminal coronary angioplasty will be discussed. D 2001 Elsevier Science Ltd. All rights reserved. Key Words: Percutaneous transluminal coronary angioplasty; Coronary artery disease; Acute myocardial infarction; Women
O
ver recent years, increasing attention has been given to coronary artery disease (CAD) as a major cause of mortality and morbidity in women. A number of studies have examined gender differences in short- and long-term prognosis after an episode of CAD, and some have suggested that these may also play a role in diagnosis and patient management. We analyse here whether gender differences affect the decision to undertake arteriography in women and whether percutane-
Corresponding author: Dr. Diego Ardissino, Divisone di Cardiologia, Ospedale Maggiore, Universita` degli Studi di Parma, P.zza Gramsci 14, Parma 43100, Italy. Tel: +39 (2) 5275139.
ous transluminal coronary angioplasty (PTCA) results are different in women.
1. Are There Gender Differences in CAD? Table 1 summarises the main differences in CAD. 1.1. Onset and Progression of CAD in Women The clinical signs and symptoms of acute coronary disease typically develop an average of 8– 10 years later in women than in men, but when they appear, the probability of CAD is greater in women and they reach the same prevalence as men in a decade. In other words, CAD progresses more rapidly in women and this may have some pathophysiological implications in terms of the development of collateral vessels: from an angiographic point of view, women have fewer collateral vessels [1]. 1.2. Coronary Anatomy Both the arterial and luminal areas are smaller in women. Sheifer et al. [2] used intravascular ultrasound to investigate the left main (LM) and proximal left anterior descending (LAD) coronary artery segments in patients without atherosclerosis, and found that women had smaller LM and LAD arterial and luminal areas than men (Fig. 1); multivariate analysis confirmed that gender (regardless of body size) is an independent predictor of correct LA and LAD arterial areas. This intrinsic difference in coronary size suggests that it may play an important
0049-3848/01/$ – see front matter D 2001 Elsevier Science Ltd. All rights reserved. PII S0049-3848(01)00306-1
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M.L. Rossi et al./Thrombosis Research 103 (2001) S105–S111
Table 1. Main differences in CAD between men and women CAD: gender differences
of CAD Onset of CAD Progression Coronary anatomy Plaque composition Hypercoagulable state Environmental risk factors
role in the different outcomes of myocardial infarction and coronary revascularisation between men and women. Women with acute coronary syndromes undergoing angiography are more likely to have no significant CAD, and the extent of CAD is less in women than in men; however, they have a higher prevalence of systemic hypertension and diabetes mellitus [3]. Fewer women have suffered a previous acute myocardial infarction (AMI) or have a history of bypass surgery. The GUSTO IIb trial revealed gender-related differences in acute coronary syndrome profiles [4]; the proportion of women with AMI with ST elevation (i.e., a syndrome related to occlusive thrombus) was significantly lower, but the prevalence of unstable angina was significantly higher. These differences could be related to anatomical and pathophysiological differences between men and women because the reduced collateral blood flow in women [1] may lead to a higher rate of complications when AMI with total coronary occlusion occurs. The differences in thrombotic and fibrinolytic activity between the sexes may also explain the differences in coronary syndromes [5–9]. Another important gen-
Fig. 2. Prevalence of plaque erosion between men and women with AMI.
der-related difference is plaque composition: in a post-mortem study, Arbustini et al. [10,11] showed that about 25% of the plaques causing coronary thrombosis in AMI patients was not ruptured, but the plaque substrate for thrombosis was erosion. This finding was significantly more prevalent in women (Fig. 2), and confirmed previous observations of a higher incidence of plaque erosion in women than in men experiencing sudden death [12]. These data indicate morphological differences in the plaque, with women having a more thrombogenic substrate. Differences in plaque composition may also explain the higher coronary dissection rate during angioplasty in women [13].
2. Prothrombotic Genetic Risk Factors The major role of thrombogenicity in precipitating acute events is indirectly demonstrated by the fact that prothrombotic genetic risk factors, such as the factor V Leiden mutation and prothrombin gene mutation, increase the risk of developing myocardial infarction at a young age particularly in women, and closely interact with other prothrombotic risk factors such as smoking [8,9]. 2.1. Results of PTCA in Women
Fig. 1. Gender differences in coronary artery size performed by intravascular ultrasound.
In 1985, the National Heart, Lung and Blood Institute published its registry (NHLBI PTCA Registry) showing a higher number of postPTCA complications in women: although the men had a higher prevalence of multivessel disease and worse ventricular function, the women undergoing PTCA had a lower success rate and a
M.L. Rossi et al./Thrombosis Research 103 (2001) S105–S111
higher rate of complications and in-hospital deaths [13]. Women were more likely to experience coronary dissection, a six times higher rate of procedure-related deaths and a five times higher mortality rate with emergency bypass surgery; multivariate analysis showed that female gender was an independent predictor of a lower success rate and early mortality. However, if the angioplasty was not complicated, women had better late outcomes, with fewer infarctions, repeat angioplasties, bypass surgical interventions and deaths. These data were confirmed by the TIMI III Registry, which was used to evaluate the effect of gender on the management of unstable angina and non-Q-wave MI. This study found that women with various coronary syndromes are treated less aggressively and undergo coronary angiography less frequently than men [14]. In terms of gender-related outcomes, a number of studies have shown that women have a higher in-hospital event rate, including repeat angioplasty, myocardial re-infarction, and inhospital and short-term mortality [15–20]. The PAMI Registry showed that in-hospital mortality was 3.3 times greater in women than in men [20]. Gender-related differences have also been found in the outcomes of individual acute coronary syndromes: female gender is associated with an independent protective effect in unstable angina, whereas women with infarction and ST elevation have a higher short-term mortality rate. After adjusting for differences in body surface area, age, risk factors and treatment intervention, many studies [17–22] have
S107
excluded the possibility that sex is an independent predictor of mortality after AMI, but others have found the contrary [3,5,23–26]. It has been suggested [4] that this apparent contradiction reflects the different percentages of the individual acute coronary syndromes in population studies. The morphological differences in coronary plaques, the evidence of differences in the risk of death and nonfatal infarction in patients with unstable angina and AMI with ST elevation, and the similarity in outcomes despite the fact that women have less severe coronary disease suggest that the worse prognosis in women is probably due to unknown risk factors as well as pathophysiologically and anatomically different clinical profiles. The worse prognosis of women undergoing coronary angioplasty is also only partially explainable by their older age and worse clinical state (more severe angina and cardiac failure) [13,27]. These initial unfavourable experiences may account for the unwillingness of physicians to refer women for angiography and percutaneous revascularisation. The MITI Registry concentrated on ‘‘gender-related bias’’ in signs and symptoms when evaluating and treating of AMI: although the symptoms, hemodynamic and electrocardiographic findings in women were largely indistinguishable from those observed in men, women were less aggressively treated and less likely to undergo thrombolysis, acute catheterisation, angioplasty or coronary bypass surgery (Fig. 3), thus leading to a less favourable outcome [28].
Fig. 3. Different treatment of coronary artery disease according to sex in the MITI Registry.
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M.L. Rossi et al./Thrombosis Research 103 (2001) S105–S111
The prospective GUARANTEE Registry [3] has more recently evaluated gender differences in the management of unstable angina: once again, the women with a higher risk profile were less likely to undergo coronary arteriography, angioplasty and bypass surgery than men; however, when they used the Agency for Health Care Policy Research [29] and the TIMI IIIB criteria [14,30] for catheterisation and revascularisation, the authors found that a similar percentage of men and women was appropriately referred for angioplasty. On the contrary, fewer women with positive criteria underwent bypass surgery, which thus appears to be a gender bias against women (Fig. 4) as they have the same revascularisation outcome as men. The PAMI trial has recently demonstrated a significant proportional benefit of direct PTCA over t-PA in women with AMI [20], thus suggesting that PTCA rather than t-PA treatment is an age-independent predictor of improved outcome in women probably as a result of multifactorial events. Primary PTCA certainly reduces hemorrhagic complications, such as intracranial hemorrhage, which occur more frequently in women than men treated with t-PA (5.3% vs. 0.7%). Finally, in a recent trial of early revascularisation in patients with cardiogenic shock [31], the relative 30-day risk of death between the women assigned to revascularisation and those assigned to medical thrombolytic therapy was similar, and comparable with that observed in men. It has recently been shown that the use of GP IIb/IIIa in the catheter laboratory improves the survival of patients undergoing stenting [32] and leads to a decrease in acute complications in
Fig. 5. Differences in major and minor bleeding rate in men and women treated with abiciximab (Ref. [34], modified).
high-risk patients. Data from the EPIC trial [33] show that the risk reduction obtained when using these drugs in women is similar to that observed in men, and that women had a slightly increased risk of minor bleeding with abiciximab (Fig. 5). Women are generally at higher risk for major hemorrhages regardless of abiciximab treatment: it is known that the rate of moderate or severe bleeding is higher in women than men, and that female gender is a significant predictor of major bleeding [26]. Women are also at greater risk of bleeding during fibrinolytic therapy, although the benefit of fibrinolysis is similar in women and men [16,20–22,34]. Angioplasty is less frequently used in women than in men. This may stem from the fact that women even less frequently undergo coronary angiography, probably because physicians consider that there is a higher probability of finding nonsignificant CAD (Table 2). Furthermore, the rate of acute complications in the subset of patients who actually undergo the procedure is higher: GP IIb/IIIa inhibitors represent an imporTable 2. Possible reasons of underuse of revascularization procedures in women with CAD Differences on revascularization procedures: underuse in women, overuse in men or both?
of CAD Incidence Physician’s perception of sex-related differences in risk and efficacy Increased rates of hospital admission for women with ischemic symptoms in the absence of true coronary heart disease
Fig. 4. Differences in the interventional procedures in men and women with unstable angina (Ref. [3], modified).
bias in the delivery of medical care Sex Severity of coronary disease
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tant tool for reducing acute complications in this subset of high-risk patients.
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