Persistent Sex Difference in Hospital Outcome following Percutaneous Coronary Intervention: Results from the New York State Repo
Although sex differences in percutaneous coronary intervention (PCI) outcomes have been observed in earlier reports,1–5 these differences were often attributed to the older age of the women.2,3,6 However, coronary disease is increasingly prevalent at a younger age and is associated with worse consequences in young women.7–10 Premenopausal women experience higher mortality both following acute myocardial infarction8 (AMI) and coronary artery bypass grafting (CABG).9,10 Recently, using the National Cardiovascular Database, Abramson et al reported that women younger than 50 years of age also experienced higher mortality following PCI than men of similar age.11 Since the prevalence of cardiovascular disease in women matches the prevalence in men by the fourth decade of life,7 confirmation of a sex difference in PCI outcome as early as in the fourth decade of life could have important clinical implications. It would not only underscore the need to accurately assess incremental benefit related to PCI, but also emphasize the need to identify the mechanism of risk in young women. However, to date, the existence of gender-related risk in young women has never been fully explored or described. Therefore, the purpose of this analysis was to examine the presence of a gender-based difference in early outcome among young patients undergoing an initial PCI procedure using the New York State PCI database.
We used the 1999–2002 New York state PCI reporting system (NYSPCIRS) from the Department of Health (DOH). This registry was developed in 1990 to track and record information on every patient undergoing PCI in New York State, the details of which are reported in prior publications.13 Between January 1, 1999 to December 31, 2002, 163,968 patients underwent percutaneous revascularization in 41 centers in New York State. We excluded 68,351 patients with prior PCI or prior open heart surgery from the analysis in order to explicitly define the risks of a first PCI procedure. Among the 95,617 patients with first-time revascularization procedures, 13,723 (14.3%) patients were 50 years of age or younger. AMI was determined based upon the presence of new (or presumably new) ST-segment elevation, pathologic Q-waves and enzymatic evidence of myocardial infarction based on local laboratory thresholds. Renal failure was defined as either serum creatine > 2.5 mg/dl, or renal failure requiring dialysis. Vessel disease was defined by the presence of at least 1 lesion with > 70% diameter stenosis within the 3 major coronary distributions. Angiographic success was defined as the successful dilatation of a lesion with the achievement of a final postprocedural stenosis < 50%. Procedural success was defined as total if all attempted lesions achieved angiographic success. Mortality during the hospitalization for an index PCI was recorded as in-hospital mortality, a vascular access site complication that required either surgical intervention or ultrasound-guided compression was defined as vascular damage.
Statistical analysis. Continuous variables were compared using the Student’s t-test and categorical variables using the chi-square test. Logistic regression models14 were used for crude as well as adjusted analyses of in-hospital mortality. In performing multivariable logistic regression, potential effect modifiers and confounding factors were assessed. The interaction between age and gender was analyzed initially in all patients undergoing PCI with age coded as either < 50 years or > 50 years. Later multivariable analyses were carried out in the population of interest (age < 50 years) alone. In assessing potential confounding, risk factors were considered sequentially in the multivariable model, and changes in the estimated regression coefficient of gender and its standard error monitored. Both potential risk factors that resulted in a 10% change in the estimated regression coefficient of gender or an improvement in precision of estimation and clinically important variables were retained in the model. Variables adjusted for included age, race, diabetes, hypertension, BMI, prior MI, prior stroke, congestive heart failure (CHF), renal failure, prior PCI, multivessel disease, left ventricular ejection fraction (LVEF) and initial presentation. The model of goodness-of-fit was assessed using the Hosmer-Lemeshow test and model fits considered adequate using predetermined thresholds (computed p > 0.05). Generalized estimating equations were used to account for clustering of observations within providers.15
Among 13,723 patients who formed the study population, only 18.7% were women. Although the average age of both young men and women undergoing PCI in New York State was similar, considerable differences in baseline and procedural characteristics were observed (Table 1). Young women undergoing PCI were more likely to be either black or Hispanic with a higher BMI. Comorbidities such as hypertension, diabetes, smoking, CHF, renal failure, COPD and vascular disease were observed more often in young women than in young men. Although the proportion of young women receiving PCI for AMI was smaller, they presented with similar frequency of cardiogenic shock and hemodynamic instability. Overall, the LVEF was significantly better in women, and women presented with single-vessel CAD more often compared to men. Although adjunct glycoprotein (GP) IIb/IIIa inhibitors and intracoronary stents were used less often in women, complete angiographic success was achieved equally in both.
Although complications following PCI occurred at a low frequency in this young population, overall in-hospital mortality was significantly higher in young women than in young men (0.70% vs. 0.22%; p < 0.0001) (Table 2). These differences were similar, regardless of whether PCI was performed for non-AMI indications (0.42% vs. 0.05%; p = 0.0007) or following AMI (1.07% vs. 0.37%; p = 0.002). Women also experienced higher relative mortality at all ages less than 50 years, although this difference was not statistically significant in the 45 women less than 30 years of age (2.2% vs. 0.82%; p = 0.4). In-hospital mortality was 0.65% in women between the ages of 30–40 years (n = 2,677; 464 women) compared to 0.14% in men; p = 0.03. Similarly, in those 40–50 years of age (n = 10,879; 2,052 women), in-hospital mortality was 0.68% in women compared to 0.23% in men; p = 0.001. Other clinical events such as stroke (0.20% vs. 0.13%; p = 0.39) or CABG (0.31% vs. 0.22%; p = 0.35) occurred equally in both men and women. However, women experienced significantly higher rates of serious vascular damage (0.82% vs. 0.24%; p < 0.0001) (Table 2). In univariate analysis, female sex was associated with a 3.2-fold higher risk of in-hospital mortality, 95% CI 1.8–6.1, and in multivariable models, it remained an independent predictor of mortality after adjustment for clinical and presentation characteristics, with an odds ratio of 4.0, and a 95% confidence interval of 1.9–8.1. In multivariable analyses, female sex was also an independent predictor of the composite outcome of death, stroke or CABG (OR 2.09; 95% CI: 1.2–3.4). In a multivariate model that included an age-sex interaction term, the interaction term was statistically significant when age was categorized either as < 50 vs. > 50 years (Wald chi square = 6.9; p = 0.009).
Sex-based difference in PCI outcomes has been an area of active investigation over the past two decades. Although initial studies postulated a gender bias in referral to cardiac catheterization as a possible explanation, currently, sex-related differences in outcomes is thought to result from the complex interplay of clinical factors.16,17 Although overall sex differences in outcomes following PCI have diminished considerably, several investigators have reported that subgroups such as premenopausal women with AMI and premenopausal women requiring CABG continue to demonstrate persistent differences.8,9,20 Although percutaneous revascularization is generally considered to be associated with lower risk and better recovery in young patients, we observed a difference in the relative risk of in-hospital mortality between young women and young men. In particular, PCI in young women was associated with 4.8 additional deaths/1,000 PCI procedures overall, ranging from 3.7/1,000 in non-AMI settings and 7/1,000 when PCI was performed following AMI. Although young women who underwent PCI had more comorbidities, they had less severe coronary disease and better left ventricular function. Female gender was an independent predictor of mortality following PCI, even after adjustment for these baseline differences. Possible explanations for the higher relative mortality rate among young women following PCI include the clustering of risk factors in young women with coronary disease,21 the higher prevalence of diabetes that may not only negate the protective effect of estrogen on vascular function,22 but also increase the risk of post-PCI complications.23 Premenopausal women with variant angina experience coronary ischemia during menstrual cycles due to low levels of endogenous estradiol.24 Similarly, premenopausal women with coronary disease also demonstrate early ischemic ST depressions during exercise testing when endogenous estradiol levels are low.25 Whether changes in endogenous estradiol levels during PCI could account for the higher risk in young women by modulating endothelial function is unknown and bears further investigation. However, due to the retrospective nature of this analysis, no causal inferences can be made regarding the higher risk observed in young women following PCI. Thus, our analysis suggests that the development of coronary disease needing PCI in young women is a marker for higher risk. Although we used multivariable analyses to account for comorbid illnesses, it is likely that the higher risk could result from unmeasured confounders. As a result, future studies are needed both to confirm our observations and to identify potential cause(s) for observed sex difference in outcomes. Nonetheless, since young women with coronary disease appear to face higher risk for death, both after surgical and percutaneous revascularization,17 our results underscore the need to enhance our efforts towards preventing cardiovascular disease in women.
Study limitations. The New York State PCI database was designed to track quality and outcomes, and potential confounders such as menopausal status of women undergoing PCI was not collected. Therefore, the effect of premature menopause on the reported outcomes cannot be determined. It is also well recognized that coronary disease is under-ascertained in women, and as a result, milder cases of CAD are diagnosed less often. As a result, young women who received PCI may have presented with advanced CAD and worse prognosis.
Following PCI, young women appear to experience higher risk for in-hospital mortality compared to young men. Further research to uncover the exact cause of this higher risk is warranted.
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- Jacobs AK, Johnston JM, Haviland A, et al. Improved outcomes for women undergoing contemporary percutaneous coronary intervention: A report from the National Heart, Lung, and Blood Institute Dynamic registry. J Am Coll Cardiol 2002;39:1608–1614.
- Ayanian JZ, Epstein AM. Differences in the use of procedures between women and men hospitalized for coronary heart disease. N Engl J Med 1991;325:221–225.
- Vakili BA, Kaplan RC, Brown DL. Sex-based differences in early mortality of patients undergoing primary angioplasty for first acute myocardial infarction. Circulation 2001;104:3034–3038.
- Jacobs AK. Gender differences in coronary revascularization: Does age make a difference? Rev Cardiovasc Med 2004;5:68–70.
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- Vaccarino V, Horwitz RI, Meehan TP, et al. Sex differences in mortality after myocardial infarction: Evidence for a sex-age interaction. Arch Intern Med 1998;158:2054–2062.
- Vaccarino V, Abramson JL, Veledar E, et al. Sex differences in hospital mortality after coronary artery bypass surgery: Evidence for a higher mortality in younger women. Circulation 2002;105:1176–1181.
- Vaccarino V, Lin ZQ, Kasl SV, et al. Gender differences in recovery after coronary artery bypass surgery. J Am Coll Cardiol 2003;41:307–314.
- Abramson JL, Veledar E, Weintraub WS, et al. Association between gender and in-hospital mortality after percutaneous coronary intervention according to age. Am J Cardiol 2003;91:968–971, A4.
- Hannan EL, Arani DT, Johnson LW, et al. Percutaneous transluminal coronary angioplasty in New York State. Risk factors and outcomes. JAMA 1992;268:3092–3097.
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- Lansky AJ, Hochman JS, Ward PA, et al. Percutaneous coronary intervention and adjunctive pharmacotherapy in women: A statement for healthcare professionals from the American Heart Association. Circulation 2005;111:940–953.
- King KM, Ghali WA, Faris PD, et al. Sex differences in outcomes after cardiac catheterization: Effect modification by treatment strategy and time. JAMA 2004;291:1220–1225.
- Vaccarino V, Parsons L, Every NR, et al. Sex-based differences in early mortality after myocardial infarction. National Registry of Myocardial Infarction 2 Participants. N Engl J Med 1999;341:217–225.
- Simon T, Mary-Krause M, Cambou JP, et al. Impact of age and gender on in-hospital and late mortality after acute myocardial infarction: increased early risk in younger women: Results from the French nation-wide USIC registries. Eur Heart J 2006;27:1282–1288.
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- Kok HS, van Asselt KM, van der Schouw YT, et al. Heart disease risk determines menopausal age rather than the reverse. J Am Coll Cardiol 2006;47:1976–1983.
- Steinberg HO, Paradisi G, Cronin J, et al. Type II diabetes abrogates sex differences in endothelial function in premenopausal women. Circulation 2000;101:2040–2046.
- Flaherty JD, Davidson CJ. Diabetes and coronary revascularization. JAMA 2005;293:1501–1508.
- Kawano H, Motoyama T, Ohgushi M, et al. Menstrual cyclic variation of myocardial ischemia in premenopausal women with variant angina. Ann Intern Med 2001;135:977–981.
- Lloyd GW, Patel NR, McGing E, et al. Does angina vary with the menstrual cycle in women with premenopausal coronary artery disease? Heart 2000;84:189–192.