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Canadian Journal of Cardiology

Outcomes in Premature Acute Coronary Syndrome: Has the Sex Gap Closed?

Published:September 25, 2016DOI:https://doi.org/10.1016/j.cjca.2016.06.005
      Premature acute coronary syndrome (ACS) remains a significant cause of morbidity and mortality worldwide. In 2012, ischemic heart disease was the cause of death in 1894 Canadians younger than 55 years. This represents 6% of all ischemic heart disease deaths and 9% of all deaths in individuals younger than 55 years in Canada annually.
      Statistics Canada
      Age standardized mortality rates by selected cause, by sex.
      Further, ACS remains a significant cause of lost work productivity, unemployment, and disability in this young age category.
      • Song X.
      • Quek R.G.W.
      • Gandra S.R.
      • et al.
      Productivity loss and indirect costs associated with cardiovascular event and related clinical procedures.
      Our current knowledge of short- and long-term clinical outcomes in younger adults after ACS is based mainly on studies focused on a subset of this population, namely, those with acute myocardial infarction (AMI). Previous studies of younger women and men have documented a survival disadvantage in women after AMI.
      • Vaccarino V.
      • Parsons L.
      • Peterson E.D.
      Sex differences in mortality after acute myocardial infarction: changes from 1994 to 2006.
      • Andrikopoulos G.K.
      • Tzeisa S.E.
      • Pipilis A.G.
      • et al.
      Younger age potentiates post myocardial infarction survival disadvantage of women.
      • Canto J.G.
      • Rogers W.J.
      • Goldberg R.J.
      • et al.
      Association of age and sex with myocardial infarction symptom presentation and in-hospital mortality.
      • Izadnegahdar M.
      • Singer J.
      • Lee M.K.
      • et al.
      Do younger women far worse? Sex differences in acute myocardial infarction hospitalization and early mortality rates over ten years.
      Using data from the National Registry of Myocardial Infarction in the United States, Vaccarino et al.
      • Vaccarino V.
      • Parsons L.
      • Peterson E.D.
      Sex differences in mortality after acute myocardial infarction: changes from 1994 to 2006.
      reported on short-term outcomes after AMI from 1994-2006. Although there was excess in-hospital mortality in women, this sex gap was less pronounced in 2004-2006 (odds ratio [OR], 1.32) compared with 1994-1995 (OR, 1.93). They found that changes in risk profiles and comorbidities accounted for most of this change. Based on a population-based study of 30-day mortality and time trends in outcomes after AMI, we also found in British Columbia that although mortality rates declined similarly in men and women, there was still an excess mortality risk in younger women, even in recent years (OR, 1.61 in 2008-2009).
      • Izadnegahdar M.
      • Singer J.
      • Lee M.K.
      • et al.
      Do younger women far worse? Sex differences in acute myocardial infarction hospitalization and early mortality rates over ten years.
      Assessing the sex differences in 30-day mortality in the broader ACS population, Berger et al.
      • Berger J.S.
      • Elliott L.
      • Gallup D.
      • et al.
      Sex differences in mortality following acute coronary syndromes.
      have highlighted that a significant interaction of sex by type of ACS exists. In this study, the adjusted risk for 30-day mortality was higher in women than in men only in the subgroup with ST-elevation myocardial infarction, whereas there were no significant sex differences among those with non-ST elevation myocardial infarction or unstable angina.
      • Berger J.S.
      • Elliott L.
      • Gallup D.
      • et al.
      Sex differences in mortality following acute coronary syndromes.
      The evidence for a sex gap in short-term, 30-day mortality among younger adults is compelling; however, the evidence remains inconsistent for the sex gap in long-term mortality after AMI. Although some studies have reported higher long-term mortality rates in women than in men,
      • Alter D.A.
      • Naylor C.D.
      • Austin P.C.
      • Tu J.V.
      Biology or bias: practice patterns and long-term outcomes for men and women with acute myocardial infarction.
      • Kostis J.B.
      • Wilson A.C.
      • Odowd K.
      • et al.
      Sex-differences in the management and long-term outcome of acute myocardial-infarction—a statewide study.
      • Vaccarino V.
      • Krumholz H.M.
      • Yarzebski J.
      • Gore J.M.
      • Goldberg R.J.
      Sex differences in 2-year mortality after hospital discharge for myocardial infarction.
      others have found that the mortality rates are similar between the sexes.
      • Johansson S.
      • Bergstrand R.
      • Ulvenstam G.
      • et al.
      Sex-differences in preinfarction characteristics and long-term survival among patients with myocardial infarction.
      • Robinson K.
      • Conroy R.M.
      • Mulcahy R.
      • Hickey N.
      The 15-year prognosis of a 1st acute coronary episode in women.
      In particular, studies focused on sex differences in long-term outcomes of younger patients are scarce, and the available findings remain inconclusive.
      The study by Pelletier et al.
      • Pelletier R.
      • Choi J.
      • Winters N.
      • et al.
      Sex differences in clinical outcomes after premature acute coronary syndrome.
      published in this issue of the Canadian Journal of Cardiology certainly contributes to narrowing this knowledge gap, and we commend them for their efforts given the challenges associated with prospectively enrolling this younger patient population with low ACS rates. The authors prospectively studied 1163 patients younger than 55 years from 26 centres across Canada, the United States, and Switzerland who were admitted to the hospital with an ACS diagnosis between 2009 and 2013. They examined sex differences in 12-month mortality, major adverse cardiac events (MACE), and causes of cardiac-related rehospitalization.
      • Pelletier R.
      • Choi J.
      • Winters N.
      • et al.
      Sex differences in clinical outcomes after premature acute coronary syndrome.
      Pelletier et al. found that the occurrence of MACE and mortality at 1 year was similar between men (1%) and women (1%); however, women had higher rates of first rehospitalization (13% compared with 9%; P = 0.006), although not for a cardiac cause. Sixty-nine percent of first rehospitalizations were cardiac related, 27% were attributed to chest pain or angina, and 27% were attributed to recurrent ACS.

      Has the Sex Gap in Outcomes After ACS in Patients Younger Than 55 Years Closed?

      As briefly described earlier, the answer to whether the sex gap has closed depends mainly on the population under study (ACS vs AMI only) and the length of follow-up (short- vs long-term). Certainly the results of this long-term study in an ACS population are reassuring in that no important differences were seen in mortality or MACE between men and women during the first 12 months. Women did have higher rates of first rehospitalization, although not for a cardiac cause.
      The authors do recognize that their study may be impacted by type 2 error given the low numbers of events seen. This low number of events may result not only from the nature of the prognosis in this younger patient population but also from the limitations in ascertaining adverse events during the first year after ACS, a challenge faced in any prospective study. In this study by Pelletier et al., the outcomes could not be ascertained for patients who were lost to follow-up at 12 months (could not be reached for the 12-month patient interview), as well as those who were admitted with an adverse event to a hospital other than their enrolling hospital (where the 12-month chart review took place). Therefore, the number of events, in particular death, may potentially be higher than reported in this study. This could result in attenuation of the sex difference in mortality estimates if differential loss to follow-up has occurred (ie, women were more likely than men to be lost to follow-up, and therefore fewer deaths were captured in women than expected). A similar study of 3501 patients with AMI younger than 55 years in the United States has reported a 12-month mortality rate of 2.3% in women,
      • Dreyer R.P.
      • Wang Y.
      • Strait K.M.
      • et al.
      Gender differences in the trajectory of recovery in health status among young patients with acute myocardial infarction:results from the variation in recovery: role of gender on outcomes of young AMI patients (VIRGO) study.
      a higher rate than that observed in the study by Pelletier et al. Although the higher rate could also be explained by the differences in the study population, the current findings should be interpreted with caution.
      The data presented by Pelletier et al. is contemporary and likely represents modern practice. There are numerous reasons why contemporary data might show the absence of a sex gap. First, procedure rates were high, with 98% of patients undergoing coronary angiography.
      • Pelletier R.
      • Choi J.
      • Winters N.
      • et al.
      Sex differences in clinical outcomes after premature acute coronary syndrome.
      This is a marked improvement compared with 2002 in which data from British Columbia found that only 49% of women and 66% of men with an ACS underwent coronary angiography.
      • Sedlak T.
      • Pu A.
      • Aymong E.
      • et al.
      Sex differences in coronary catheterization and revascularization following acute myocardial infarction: time trends from 1994 to 2003 in British Columbia.
      Second, medical management of ACS has improved significantly, with some recent studies showing no important clinically significant sex differences in prescribing rates.
      • Kragholm K.
      • Halim S.A.
      • Yang Q.
      • et al.
      Sex-stratified trends in enrollment, patient characteristics, treatment and outcomes among non-ST-segment elevation acute coronary syndrome patients.
      One study by Kragholm et al.
      • Kragholm K.
      • Halim S.A.
      • Yang Q.
      • et al.
      Sex-stratified trends in enrollment, patient characteristics, treatment and outcomes among non-ST-segment elevation acute coronary syndrome patients.
      reported significant increases in medication use after ACS from 1994-2010, with > 95% of patients receiving aspirin, > 85% receiving lipid-lowering drugs, > 80% receiving β-blockers and > 75% receiving thienopyridines in 2010.
      • Kragholm K.
      • Halim S.A.
      • Yang Q.
      • et al.
      Sex-stratified trends in enrollment, patient characteristics, treatment and outcomes among non-ST-segment elevation acute coronary syndrome patients.
      Third, it is well documented that women with an ACS are more likely to have no obstructive coronary artery disease (< 50% stenosis in any epicardial artery) on angiography than are men.
      • Saw J.
      • Aymong E.
      • Mancini J.
      • et al.
      Non-atherosclerotic coronary artery disease in young women.
      Causes of ACS in these cases include spontaneous coronary artery dissection (SCAD), coronary vasospasm, or microvascular coronary dysfunction. In the study by Pelletier et al., 11% of women and 1% of men had SCAD as the cause for their ACS. Increased recognition and enhanced treatment of these causes may account for some of the improvement in outcomes seen in women compared with previous studies.

      Why the High Rates of Rehospitalization?

      Sixty-nine percent of first rehospitalizations were cardiac related, 27% were attributed to chest pain or angina, and 27% were attributed to recurrent ACS.
      • Pelletier R.
      • Choi J.
      • Winters N.
      • et al.
      Sex differences in clinical outcomes after premature acute coronary syndrome.
      Interestingly only 3% of men and 0% of women underwent percutaneous coronary intervention (PCI), whereas only 1% of men and 0% of women underwent coronary artery bypass grafting (CABG) during the year after their initial ACS admission. This suggests that much of the recurrent chest pain and ACS hospitalizations were not caused by recurrent obstructive disease but instead might have resulted from microvascular angina, coronary vasospasm, or noncardiac causes such as gastrointestinal reflux disease or anxiety, or a combination of causes. The higher incidence of non–cardiac-related hospitalizations in women is not surprising. It is well known that women have higher levels of depression/anxiety after an ACS and also higher rates of bleeding,
      • Pelletier R.
      • Humphries K.H.
      • Shimony A.
      • et al.
      Sex-related differences in access to care among patients with premature acute coronary syndrome.
      • Mehta R.H.
      • Stebbins A.S.
      • Lopes R.D.
      • et al.
      Comparison of incidence of bleeding and mortality of men versus women with ST-elevation myocardial infarction treated with fibrinolysis.
      • Ahmed B.
      • Dauerman H.L.
      Women, bleeding, and coronary intervention.
      • Reynolds H.R.
      • Farkouh M.E.
      • Lincoff M.A.
      • et al.
      Impact of female sex on death and bleeding after fibrinolytic treatment of myocardial infarction in GUSTO V.
      which may account for some of the sex differences seen.

      What Are the Implications of This Study for Future Clinical Research and Practice?

      Despite the low MACE and mortality rates in this study, Pelletier et al. reported high rehospitalization rates at 12 months, which were primarily cardiac related although not necessarily amenable to PCI or CABG. Future study should focus on methods of improving this outcome. For example, cardiac rehabilitation (CR), which has many benefits including reduced morbidity and mortality, improved functional status, improved quality of life, and cost savings is grossly underused, particularly in women.
      • Anderson L.
      • Taylor R.S.
      Cardiac rehabilitation for people with heart disease: an overview of Cochrane systematic reviews.
      • Alter D.A.
      • Oh P.I.
      • Chong A.
      Relationship between cardiac rehabilitation and survival after acute cardiac hospitalization within a universal health care system.
      • Wong W.P.
      • Feng J.
      • Pwee K.H.
      • Lim J.
      A systematic review of economic evaluations of cardiac rehabilitation.
      • De Gruyter E.
      • Ford G.
      • Stavreski B.
      Economic and social impact of increasing uptake of cardiac rehabilitation services - a cost benefit analysis.
      • Samayoa L.
      • Grace S.L.
      • Gravely S.
      • et al.
      Sex differences in cardiac rehabilitation enrollment: a meta-analysis.
      • Colella T.J.F.
      • Gravely S.
      • Marzolini S.
      • et al.
      Sex bias in referral of women to outpatient cardiac rehabilitation? A meta-analysis.
      Methods of increasing enrollment and adherence, such as home-based CR or women-only programs may prove beneficial, and more study needs to be done.
      • Andraos C.
      • Arthur H.M.
      • Oh P.
      • et al.
      Women's preferences for cardiac rehabilitation program model: a randomized controlled trial.
      • Beckie T.M.
      • Beckstead J.W.
      The effects of a cardiac rehabilitation program tailored for women on their perceptions of health: a randomized clinical trial.
      Microvascular angina or coronary vasospasm, or both, may be responsible for some of the recurrent chest pain or recurrent ACS hospitalizations (or both) and are increasingly being recognized; however, treatment remains limited. Future studies should focus on therapies that reduce angina, improve quality of life, and reduce hospitalizations in these patients. Furthermore, the study by Pelletier et al. highlights the challenges in answering important questions related to prognosis in younger patients with ACS. Given the low rate of adverse events (in particular death) in this patient population, perhaps larger prospective studies with linkage to population-based vital statistics registries would provide better estimates of the sex difference. Linkage to vital statistics registries would ensure that the mortality outcomes could be ascertained even among patients who were lost to follow-up during the study period. Additionally, given the importance of recurrent hospitalization resulting from chest pain in this population, we need to find the most reliable and accurate way of capturing this information through a comprehensive process of chart reviews combined with linkages to administrative data or emergency department registries, or both, for future research.
      In conclusion, this comprehensive and well-written study by Pelletier et al. is encouraging for the future and provides valuable and much-needed insight into understanding and improving the prognosis of younger patients with ACS.

      Disclosures

      The authors have no conflicts of interest to disclose.

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