Comment
HE is Minister for International Development Cooperation, Sweden; PTK is Myanmar’s Minister of Health; AC-S is Senegal’s Minister of Health; RHP is Minister for Development Cooperation, Denmark; AA-B is Deputy DirectorGeneral of WHO; GM is Chair of the Partnership for Maternal, Newborn and Child Health and founder of the Graça Machel Trust; RS is Secretary General of the East African Community; JP is Executive Secretary of the African Leaders Malaria Alliance and Cochair of the independent Expert Review Group; AP-M is Assistant Administrator for Global Health at USAID; UM is Director General of the Federal Ministry for Economic Cooperation and Development, Germany; LG is the Dutch Special Ambassador for Sexual and Reproductive Health and Rights and HIV/ AIDS; JW is CEO of Save the Children International; LD is CEO of CHESTRAD and Convenor of Global Health South; RL is Vice President for Research and Policy for the Public Health Foundation India; JEL is Ambassador (Rt) and Senior Fellow for Global Health Diplomacy for the UN Foundation; and AN is Ambassador for Global Health, Sweden.
1 2
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The World Bank. World development report 1993: investing in health. Washington, DC: World Bank and Oxford University Press, 1993. Jamison DT, Summers LH, Alleyne G, et al. Global health 2035: a world converging within a generation. Lancet 2013; published online Dec 3. http://dx.doi.org/10.1016/S0140-6736(13)62105-4. Stenberg K, Axelson H, Sheehan P, on behalf of the Study Group for the Global Investment Framework for Women’s and Children’s Health. Advancing social and economic development by investing in women’s and children’s health: a new Global Investment Framework. Lancet 2013; published online Nov 19. http://dx.doi.org/10.1016/S01406736(13)62231-X. Commission on Information and Accountability for Women’s and Children’s Health. Keeping promises, measuring results. Geneva: World Health Organization, 2011.
Sex and percutaneous coronary intervention
Cavallini James/BSIP/Science Photo Library
See Articles page 1879
Blockage in coronary artery
1864
Ischaemic heart disease shows sex differences in terms of clinical characteristics and pathophysiological mechanisms. Women presenting with ischaemic heart disease are generally older, have more comorbidities,1 and have an increased risk of bleeding compared with men.2–4 Furthermore, they have a higher frequency of atypical causes of angina pectoris and acute coronary syndromes— microvascular disease, spasm, plaque erosion, and spontaneous coronary dissection—as opposed to the more frequent stenotic atherosclerotic plaque and plaque rupture.5,6 The feasibility, safety, and efficacy of percutaneous coronary interventions might therefore be different in women, and until now there have not been any precise data for women, mainly because of the small proportion of women in the reported randomised
trials. Sex differences in the invasive treatment and outcome of patients admitted with acute myocardial infarction have been reported in observational studies.7,8 In a Danish national observational cohort study, with data from nationwide registries, women with acute coronary syndromes were given much less invasive interventions and received less interventional treatment than did men, even after adjustment for differences in comorbidities and number of clinically significant stenoses.9 In The Lancet, Giulio Stefanini and colleagues10 investigated the safety and efficacy of drug-eluting stents in women during long-term follow-up. They pooled patient-level data for 11 557 female participants from 26 randomised trials of drug-eluting stents and analysed outcomes according to allocated stent type (bare-metal, early-generation drug-eluting, or newergeneration drug-eluting). 1108 (9·6%) women received bare-metal stents, 4171 (36·1%) early-generation drugeluting stents, and 6278 (54·3%) newer-generation drug-eluting stents. At 3 years, the overall rates of death or myocardial infarction (the primary endpoint) were 10·3%, target lesion revascularisation 8·0%, and definite or probable stent thrombosis 1·6%. The rates of death or myocardial infarction in women treated with bare-metal stents, early-generation drugeluting stents, and newer-generation drug-eluting stents were 12·8%, 10·9%, and 9·2%, respectively, and were significantly lower in women treated with newer-generation drug-eluting stents. This endpoint differs from the most often used primary endpoint of target lesion failure, and further it was attributed by Stefanini and colleagues to differences in myocardial www.thelancet.com Vol 382 December 7, 2013
Comment
infarction, because the reported rates of death did not differ significantly between the different stent types. However, all event rates reported by Stefanini and colleagues are similar to reported data for cohorts consisting of both men and women, and the same pattern was seen in women with a better safety profile and less very late stent thrombosis with the newergeneration drug-eluting stents. Rates of definite or probable stent thrombosis in women treated with baremetal stents, early-generation drug-eluting stents, and newer-generation drug-eluting stents were 1·3%, 2·1%, and 1·1%, respectively. The use of drug-eluting stents was associated with a significant reduction in rates of target-lesion revascularisation (bare-metal stents 18·6%, early-generation drug-eluting stents 7·8%, and newer-generation drug-eluting stents 6·3%). The findings of Stefanini and colleagues10 would have been stronger if data for men from the 26 randomised trials had been included in the report to confirm that there was no sex interaction. In the Scandinavian Organization for Randomized Trials With Clinical Outcome (SORT OUT) IV and V trials,11,12 no sex interaction was noted between women and men treated with a first-generation sirolimus-eluting stent or newer-generation everolimus-eluting stent or biolimus-eluting stent, respectively. Stefanini and colleagues conclude that use of drug-eluting stents in women was safe and effective compared with baremetal stents during long-term follow-up, with a further improved safety profile for newer-generation drug-eluting stents. However, two points have to be considered: the inclusion criteria, especially in the early trials in the pooled analysis, were more restrictive with less complex lesions; and the women in the pooled analysis do not represent those in daily clinical practice (ie, female patients of age >85 years, with low bodyweight, reduced kidney function, calcified lesions, long lesions, or atrial fibrillation requiring anticoagulation), and these factors affect the generalisability of the results. Moreover, prognosis for women in the trials might have improved over time with the inclusion of dual antiplatelet treatment for a longer period and improved secondary prevention. The lower
www.thelancet.com Vol 382 December 7, 2013
rate of the primary endpoint (death or myocardial infarction) in the newer-generation drug-eluting stent group, mainly attributable to the reduction in the rate of myocardial infarction, can thus partly be explained by improved medical treatment. Considering the available data together, we do not believe that female sex by itself contributes to worse outcomes after coronary intervention; rather, age, comorbidity, and the type and extent of coronary disease contribute to efficacy and safety. *Evald Høj Christiansen, Lisette Okkels Jensen Department of Cardiology, Aarhus University Hospital, Skejby Hospital, Aarhus DK-8200, Denmark (EHC); and Department of Cardiology, Odense University Hospital, Odense, Denmark (LOJ) [email protected] We declare that we have no conflicts of interest. 1
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Dey S, Flather MD, Devlin G, et al. Sex-related differences in the presentation, treatment and outcomes among patients with acute coronary syndromes: the Global Registry of Acute Coronary Events. Heart 2009; 95: 20–26. Moscucci M, Fox KA, Cannon CP, et al. Predictors of major bleeding in acute coronary syndromes: the Global Registry of Acute Coronary Events (GRACE). Eur Heart J 2003; 24: 1815–23. Ndrepepa G, Schulz S, Neumann FJ, et al. Bleeding after percutaneous coronary intervention in women and men matched for age, body mass index, and type of antithrombotic therapy. Am Heart J 2013; 166: 534–40. Ahmed B, Dauerman HL. Women, bleeding, and coronary intervention. Circulation 2013; 127: 641–49. Reynolds HR. Myocardial infarction without obstructive coronary artery disease. Curr Opin Cardiol 2012; 27: 655–60. Mortensen KH, Thuesen L, Kristensen IB, Christiansen EH. Spontaneous coronary artery dissection: a Western Denmark Heart Registry study. Catheter Cardiovasc Interv 2009; 74: 710–17. Doyle F, De La Harpe D, McGee H, Shelley E, Conroy R. Gender differences in the presentation and management of acute coronary syndromes: a national sample of 1365 admissions. Eur J Cardiovasc Prev Rehabil 2005; 12: 376–79. Wijnbergen I, Tijssen J, van’t Veer M, Michels R, Pijls NHJ. Gender differences in long-term outcome after primary percutaneous intervention for ST-segment elevation myocardial infarction. Catheter Cardiovasc Interv 2013; 82: 379–84. Hvelplund A, Galatius S, Madsen M, et al. Women with acute coronary syndrome are less invasively examined and subsequently less treated than men. Eur Heart J 2010; 31: 684–90. Stefanini GG, Baber U, Windecker S, et al. Safety and efficacy of drug-eluting stents in women: a patient-level pooled analysis of randomised trials. Lancet 2013; 382: 1879–88. Jensen LO, Thayssen P, Christiansen EH, et al. 2-year patient-related versus stent-related outcomes: the SORT OUT IV (Scandinavian Organization for Randomized Trials With Clinical Outcome IV) Trial. J Am Coll Cardiol 2012; 60: 1140–47. Christiansen EH, Jensen LO, Thayssen P, et al, for the Scandinavian Organization for Randomized Trials with Clinical Outcome (SORT OUT) V investigators. Biolimus-eluting biodegradable polymer-coated stent versus durable polymer-coated sirolimus-eluting stent in unselected patients receiving percutaneous coronary intervention (SORT OUT V): a randomised non-inferiority trial. Lancet 2013; 381: 661–69.
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HE is Minister for International Development Cooperation, Sweden; PTK is Myanmar’s Minister of Health; AC-S is Senegal’s Minister of Health; RHP is Minister for Development Cooperation, Denmark; AA-B is Deputy DirectorGeneral of WHO; GM is Chair of the Partnership for Maternal, Newborn and Child Health and founder of the Graça Machel Trust; RS is Secretary General of the East African Community; JP is Executive Secretary of the African Leaders Malaria Alliance and Cochair of the independent Expert Review Group; AP-M is Assistant Administrator for Global Health at USAID; UM is Director General of the Federal Ministry for Economic Cooperation and Development, Germany; LG is the Dutch Special Ambassador for Sexual and Reproductive Health and Rights and HIV/ AIDS; JW is CEO of Save the Children International; LD is CEO of CHESTRAD and Convenor of Global Health South; RL is Vice President for Research and Policy for the Public Health Foundation India; JEL is Ambassador (Rt) and Senior Fellow for Global Health Diplomacy for the UN Foundation; and AN is Ambassador for Global Health, Sweden.
1 2
3
4
The World Bank. World development report 1993: investing in health. Washington, DC: World Bank and Oxford University Press, 1993. Jamison DT, Summers LH, Alleyne G, et al. Global health 2035: a world converging within a generation. Lancet 2013; published online Dec 3. http://dx.doi.org/10.1016/S0140-6736(13)62105-4. Stenberg K, Axelson H, Sheehan P, on behalf of the Study Group for the Global Investment Framework for Women’s and Children’s Health. Advancing social and economic development by investing in women’s and children’s health: a new Global Investment Framework. Lancet 2013; published online Nov 19. http://dx.doi.org/10.1016/S01406736(13)62231-X. Commission on Information and Accountability for Women’s and Children’s Health. Keeping promises, measuring results. Geneva: World Health Organization, 2011.
Sex and percutaneous coronary intervention
Cavallini James/BSIP/Science Photo Library
See Articles page 1879
Blockage in coronary artery
1864
Ischaemic heart disease shows sex differences in terms of clinical characteristics and pathophysiological mechanisms. Women presenting with ischaemic heart disease are generally older, have more comorbidities,1 and have an increased risk of bleeding compared with men.2–4 Furthermore, they have a higher frequency of atypical causes of angina pectoris and acute coronary syndromes— microvascular disease, spasm, plaque erosion, and spontaneous coronary dissection—as opposed to the more frequent stenotic atherosclerotic plaque and plaque rupture.5,6 The feasibility, safety, and efficacy of percutaneous coronary interventions might therefore be different in women, and until now there have not been any precise data for women, mainly because of the small proportion of women in the reported randomised
trials. Sex differences in the invasive treatment and outcome of patients admitted with acute myocardial infarction have been reported in observational studies.7,8 In a Danish national observational cohort study, with data from nationwide registries, women with acute coronary syndromes were given much less invasive interventions and received less interventional treatment than did men, even after adjustment for differences in comorbidities and number of clinically significant stenoses.9 In The Lancet, Giulio Stefanini and colleagues10 investigated the safety and efficacy of drug-eluting stents in women during long-term follow-up. They pooled patient-level data for 11 557 female participants from 26 randomised trials of drug-eluting stents and analysed outcomes according to allocated stent type (bare-metal, early-generation drug-eluting, or newergeneration drug-eluting). 1108 (9·6%) women received bare-metal stents, 4171 (36·1%) early-generation drugeluting stents, and 6278 (54·3%) newer-generation drug-eluting stents. At 3 years, the overall rates of death or myocardial infarction (the primary endpoint) were 10·3%, target lesion revascularisation 8·0%, and definite or probable stent thrombosis 1·6%. The rates of death or myocardial infarction in women treated with bare-metal stents, early-generation drugeluting stents, and newer-generation drug-eluting stents were 12·8%, 10·9%, and 9·2%, respectively, and were significantly lower in women treated with newer-generation drug-eluting stents. This endpoint differs from the most often used primary endpoint of target lesion failure, and further it was attributed by Stefanini and colleagues to differences in myocardial www.thelancet.com Vol 382 December 7, 2013
Comment
infarction, because the reported rates of death did not differ significantly between the different stent types. However, all event rates reported by Stefanini and colleagues are similar to reported data for cohorts consisting of both men and women, and the same pattern was seen in women with a better safety profile and less very late stent thrombosis with the newergeneration drug-eluting stents. Rates of definite or probable stent thrombosis in women treated with baremetal stents, early-generation drug-eluting stents, and newer-generation drug-eluting stents were 1·3%, 2·1%, and 1·1%, respectively. The use of drug-eluting stents was associated with a significant reduction in rates of target-lesion revascularisation (bare-metal stents 18·6%, early-generation drug-eluting stents 7·8%, and newer-generation drug-eluting stents 6·3%). The findings of Stefanini and colleagues10 would have been stronger if data for men from the 26 randomised trials had been included in the report to confirm that there was no sex interaction. In the Scandinavian Organization for Randomized Trials With Clinical Outcome (SORT OUT) IV and V trials,11,12 no sex interaction was noted between women and men treated with a first-generation sirolimus-eluting stent or newer-generation everolimus-eluting stent or biolimus-eluting stent, respectively. Stefanini and colleagues conclude that use of drug-eluting stents in women was safe and effective compared with baremetal stents during long-term follow-up, with a further improved safety profile for newer-generation drug-eluting stents. However, two points have to be considered: the inclusion criteria, especially in the early trials in the pooled analysis, were more restrictive with less complex lesions; and the women in the pooled analysis do not represent those in daily clinical practice (ie, female patients of age >85 years, with low bodyweight, reduced kidney function, calcified lesions, long lesions, or atrial fibrillation requiring anticoagulation), and these factors affect the generalisability of the results. Moreover, prognosis for women in the trials might have improved over time with the inclusion of dual antiplatelet treatment for a longer period and improved secondary prevention. The lower
www.thelancet.com Vol 382 December 7, 2013
rate of the primary endpoint (death or myocardial infarction) in the newer-generation drug-eluting stent group, mainly attributable to the reduction in the rate of myocardial infarction, can thus partly be explained by improved medical treatment. Considering the available data together, we do not believe that female sex by itself contributes to worse outcomes after coronary intervention; rather, age, comorbidity, and the type and extent of coronary disease contribute to efficacy and safety. *Evald Høj Christiansen, Lisette Okkels Jensen Department of Cardiology, Aarhus University Hospital, Skejby Hospital, Aarhus DK-8200, Denmark (EHC); and Department of Cardiology, Odense University Hospital, Odense, Denmark (LOJ) [email protected] We declare that we have no conflicts of interest. 1
2
3
4 5 6
7
8
9
10
11
12
Dey S, Flather MD, Devlin G, et al. Sex-related differences in the presentation, treatment and outcomes among patients with acute coronary syndromes: the Global Registry of Acute Coronary Events. Heart 2009; 95: 20–26. Moscucci M, Fox KA, Cannon CP, et al. Predictors of major bleeding in acute coronary syndromes: the Global Registry of Acute Coronary Events (GRACE). Eur Heart J 2003; 24: 1815–23. Ndrepepa G, Schulz S, Neumann FJ, et al. Bleeding after percutaneous coronary intervention in women and men matched for age, body mass index, and type of antithrombotic therapy. Am Heart J 2013; 166: 534–40. Ahmed B, Dauerman HL. Women, bleeding, and coronary intervention. Circulation 2013; 127: 641–49. Reynolds HR. Myocardial infarction without obstructive coronary artery disease. Curr Opin Cardiol 2012; 27: 655–60. Mortensen KH, Thuesen L, Kristensen IB, Christiansen EH. Spontaneous coronary artery dissection: a Western Denmark Heart Registry study. Catheter Cardiovasc Interv 2009; 74: 710–17. Doyle F, De La Harpe D, McGee H, Shelley E, Conroy R. Gender differences in the presentation and management of acute coronary syndromes: a national sample of 1365 admissions. Eur J Cardiovasc Prev Rehabil 2005; 12: 376–79. Wijnbergen I, Tijssen J, van’t Veer M, Michels R, Pijls NHJ. Gender differences in long-term outcome after primary percutaneous intervention for ST-segment elevation myocardial infarction. Catheter Cardiovasc Interv 2013; 82: 379–84. Hvelplund A, Galatius S, Madsen M, et al. Women with acute coronary syndrome are less invasively examined and subsequently less treated than men. Eur Heart J 2010; 31: 684–90. Stefanini GG, Baber U, Windecker S, et al. Safety and efficacy of drug-eluting stents in women: a patient-level pooled analysis of randomised trials. Lancet 2013; 382: 1879–88. Jensen LO, Thayssen P, Christiansen EH, et al. 2-year patient-related versus stent-related outcomes: the SORT OUT IV (Scandinavian Organization for Randomized Trials With Clinical Outcome IV) Trial. J Am Coll Cardiol 2012; 60: 1140–47. Christiansen EH, Jensen LO, Thayssen P, et al, for the Scandinavian Organization for Randomized Trials with Clinical Outcome (SORT OUT) V investigators. Biolimus-eluting biodegradable polymer-coated stent versus durable polymer-coated sirolimus-eluting stent in unselected patients receiving percutaneous coronary intervention (SORT OUT V): a randomised non-inferiority trial. Lancet 2013; 381: 661–69.
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