Major Adverse Cardiovascular Events in Patients Treated With Anthracyclines for Breast Cancer or Lymphoma: 25-Year Follow-Up

Major Adverse Cardiovascular Events in Patients Treated With Anthracyclines for Breast Cancer or Lymphoma: 25-Year Follow-Up | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report Major Adverse Cardiovascular Events in Patients Treated With Anthracyclines for Breast Cancer or Lymphoma: 25-Year Follow-Up Eduardo Tellez-Garcia, Andres E. Daryanani Acevedo, Maria F. Gomez Ardila, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6778136/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Anthracyclines (ACs) are a risk factor for heart failure (HF), but their impact on broader composite outcomes such as major adverse cardiovascular events (MACE) remain less well characterized. From the Rochester Epidemiology Project, we identified patients with breast cancer or lymphoma to assess for association between AC use and MACE in these patients with > 25 years of follow-up. Methods We identified patients with cancer, with or without an AC as first-line treatment, and a control group of individuals without cancer, matched by age, sex, and cardiovascular comorbid conditions to the cancer patients. Outcomes of interest were 3-MACE (myocardial infarction, stroke, and cardiovascular death), and 4-MACE (3-MACE plus HF). Cox regression analysis was used to identify variables associated with MACE at 5, 10, and 25 years of follow-up. Results Of 812 patients with cancer, 675 had AC treatment (AC group) and 137 did not (no-AC group); the control group comprised 1,384 matched patients without cancer. The risk of 3-MACE was similar among the 3 groups at all time points. Older age, male sex, and hypertension were associated with 3-MACE. The risk of 4-MACE was similar between the control and no-AC groups; the risk was increased for the AC group vs controls at all time points. Older age, male sex, smoking history, type 2 diabetes, and hypertension were associated with 4-MACE. Conclusions Cardiovascular risk factors are the main drivers of 3-MACE and ACs increase the risk of 4-MACE given their association with HF. This underscores the importance of implementing lifestyle changes among these patients. anthracycline cardio-oncology MACE myocardial infarction stroke Figures Figure 1 Figure 2 Background Anthracyclines (ACs) are chemotherapeutic agents that are frequently used as part of the management of diverse solid and hematologic cancers, such as lymphomas and breast cancer (BC). However, their use is often associated with cardiac toxicity,( 1 , 2 ) heart failure (HF) being the most widely recognized complication( 3 – 5 ) with a reported incidence of up to 10.75% over 20 years.( 3 ) A 2013 meta-analysis reported that, after a median follow-up of 9 years, clinically overt cardiotoxicity developed in approximately 6% of patients treated with ACs, and 18% had subclinical toxic effects.( 6 ) The toxicity surveillance of ACs has primarily focused on HF and contractile dysfunction, but much less is known about their effects on other cardiovascular (CV) events. Cancer and CV diseases share common risk factors, such as obesity, type 2 diabetes (T2D), hypertension (HTN), and tobacco use, among others,( 7 , 8 ) and are often comorbid. One study showed that 17% of patients with BC and up to 33% with hematologic cancer have CV risk factors, such as coronary artery disease (CAD), carotid artery disease, peripheral vascular disease, HF, or cerebrovascular disease.( 9 ) Furthermore, patients with cancer have a higher risk of CV events compared with the general population. For instance, cancer patients have twice the likelihood of stroke compared with the general population( 10 ) and also have a higher incidence of myocardial infarction (MI).( 11 ) This suggests a milieu of concurring factors in oncology patients that increase the risk of CV events. The development of cardiotoxicity also has been associated with poorer survival outcomes.( 12 ) A study in patients older than 66 years with triple-negative BC treated with taxanes and ACs showed worse 3-year survival and cancer-specific survival for these patients compared with those treated only with taxanes.( 13 ) The authors propose that underlying cardiac disease may have developed in the patients receiving ACs, because those typically treated with ACs are younger and generally lack pre-existing CV comorbid conditions.( 13 ) One way to measure cardiotoxicity is to assess for the occurrence of major adverse cardiovascular events (MACE), the definition of which varies across studies but most commonly includes MI and stroke and occasionally also considers CV death, unstable angina, HF, and arrhythmia.( 14 ) To our knowledge, no population-based study has evaluated the impact of AC use on the occurrence of MACE. The aim of our study was to assess for an association between ACs and MACE in patients with BC, Hodgkin lymphoma (HL), or non-Hodgkin lymphoma (NHL), compared with a control population without cancer. Methods This was a retrospective, observational, population-based cohort study. The data for this study were obtained through the Rochester Epidemiology Project (REP), a collaboration among health care providers in Olmsted County, Minnesota (2022 population, 164,020), whose goal is to create a research infrastructure with complete data linkage of health records. It provides a unique opportunity for epidemiologic research because almost all medical care is provided by 2 providers. The Mayo Clinic Cancer Registry and the REP database were queried for the records of adult (age > 17 years) residents of Olmsted County who were newly diagnosed with and treated for BC, HL, or NHL between January 1, 1985, and December 31, 2010. This study was approved by the institutional review boards of Mayo Clinic and Olmsted Medical Center. Per Minnesota law, all participants agreed to the use of their data for research purposes,( 15 – 18 ) and those who did not consent were not included. Data were gathered through a combination of electronic extraction and manual record review. Information was collected from the REP regarding patients’ date of birth, sex, body mass index (BMI, calculated as weight in kg divided by height in m 2 ), the date they were last censored in Olmsted County, and, if applicable, the date and cause of death. A manual review of records was also conducted for all patients with cancer to gather details on cancer treatments, comorbid conditions, and CV outcomes. Baseline comorbid conditions and potential CV outcomes for the comparison cohort were initially obtained electronically, with manual record review for all comparison participants to ensure data quality and prevent misclassification. Among patients identified with BC or lymphoma, 2 groups were considered: those treated with chemotherapy (AC group) and those not treated with ACs (no-AC group). A third group included control patients with no history of cancer who were matched by age, sex, and baseline CV comorbid conditions at the index date to the patients with cancer. Participants in the control group were required to be followed up for at least as long as participants with cancer. The matching ratio was 1 case to 1.5 controls. Clinical characteristics abstracted for all patients included smoking history, T2D, HTN, dyslipidemia, body mass index greater than 30, and CAD (defined as coronary angiography showing stenosis > 50% of at least 1 artery, coronary revascularization, history of MI, presence of regional wall-motion abnormality on an imaging study, or a positive stress test). The primary outcome of interest was MACE, with 2 definitions: 3-point MACE including MI, stroke, and CV death (due to MI, HF exacerbation, or arrhythmia) ( 3-MACE ), and 4-point MACE that included MI, stroke, CV death, and HF ( 4-MACE ). New-onset HF as defined by the modified Framingham criteria, both in the inpatient and outpatient setting. Statistical Analysis The distribution of quantitative variables was analyzed with the Shapiro-Wilk test. Normally distributed continuous variables are expressed as mean (SD) and were statistically compared among groups with the Student t test. Nonnormally distributed continuous variables are expressed as median (IQR) and were compared with the Wilcoxon signed-rank test. Categorical variables are shown as frequencies (percentages) and were compared between groups with χ 2 tests. Two-sided P < .05 was used to define statistical significance. We performed univariable and multivariable Cox regression analysis to identify variables associated with 3-MACE and 4-MACE, reported as hazard ratio (HR) with 95% CI. Risk factors included in the multivariable analysis were those clinically relevant to the outcome. Additionally, separate analysis was performed for each component of MACE (MI, stroke, CV death, and HF). We analyzed the overall risk of 3-MACE and 4-MACE after > 25 years of follow-up and within 5 and 10 years of follow-up. Cumulative incidence of 3-MACE and 4-MACE was modeled accounting for the competing risk of non-CV death, at 5, 10, and 25 years of follow-up, and displayed graphically. BlueSky Statistics version 10.3.1. was used for statistical analysis. Results Table 1A. Baseline Characteristics Group a Characteristic Control (n=1,384) No-AC (n=137) AC (n=675) Age at matching, y 52.6 (14.6) 57.7 (15.4) b 51.6 (14.1) c Sex Male 303 (21.9) 45 (32.8) b 144 (21.3) c Female 1,081 (78.1) 92 (67.2) b 531 (78.7) c Smoking history 284 (20.5) 52 (38.0) b 295 (43.8) b Type 2 diabetes 93 (6.7) 14 (10.2) 50 (7.4) Hypertension 370 (26.7) 55 (40.1) b 191 (28.3) c Dyslipidemia 533 (38.5) 54 (39.4) 259 (38.4) BMI >30 432 (31.2) 42 (30.7) 205 (30.4) Coronary artery disease 25 (1.8) 11 (8.0) b 31 (4.6) b Abbreviations: AC, anthracycline; BMI, body mass index. a Values are mean (SD), median (IQR), or No. of patients (%). b P <.05 vs control group. c P <.05 vs no-AC group. Table 1B. Characteristics of Patients With Cancer and Treatment Regimens Group a Characteristic Breast cancer (n = 513) HL (n = 71) NHL (n = 228) First line chemotherapy regimen - AC 430 (84%) 68 (96%) 164 (72%) - Not-AC 70 (14%) 3 (4%) b 64 (28%) b,c - Trastuzumab 13 (3%) 0 0 Radiation - Right breast or chest wall radiation 173 (34%) 0 0 - Left breast or chest wall radiation 175 (34%) 1 (1%) b 0 - Mediastinal radiation 1 (<1%) 20 (28%) b 4 (2%) c Anthracycline dose, mg/m² - None 83 (16%) 3 (4%) b 64 (28%) c - 250 40 (8%) 38 (54%) b 99 (43%) b,c Treatment at cancer diagnosis - β-blocker 48 (9%) 3 (4%) 47 (21%) b,c - ACEI or ARBs 48 (9%) 6 (8%) 49 (22%) b,c - Statins 50 (10%) 4 (6%) 38 (17%) b,c Abbreviations: AC a Values are mean (SD), median (IQR), or No. of patients (%). b P <.05 vs breast cancer. c P <.05 vs HL Non-CV Death The cumulative incidence of non-CV death at 5, 10, and 25 years of follow-up was 0.1%, 4.1%, and 17%, respectively, in the control group; 32.4%, 45.8%, and 68.1% in the no-AC group; and 15.2%, 25%, and 44.4% in the AC group. Among the patients with cancer, 65 of 137 patients in the no-AC group and 148 of 675 patients in the AC group died of complications of cancer or cancer therapy. Analyzing the cumulative incidence of non-CV death with the competing risk of 3-MACE (Figure 1A) and 4-MACE (Figure 2A) showed that the no-AC group had the highest incidence of non-CV death and the control group had the lowest. The pairwise comparisons between all groups were significantly different (all P <.001). Cox regression analysis confirmed that even after adjusting for sex and age differences, the no-AC group (HR, 9.33; 95% CI, 6.90-12.60; P <.001) and AC group (HR, 5.87; 95% CI, 4.61-7.47; P <.001) were at significantly higher risk of non-CV death compared with the control group. Of note, these variations in incidence and risk between the groups should be considered when interpreting the results because a higher incidence of non-CV death reduces the number of patients at risk for MACE, particularly in the no-AC and AC groups. Analysis of 3-MACE The cumulative incidence of 3-MACE at 5, 10, and 25 years of follow-up was 3.6%, 7.4%, and 20.6%, respectively, in the control group; 3.8%, 6.6%, and 12.6% in the no-AC group; and 3.4%, 5.1%, and 12.9% in the AC group. The median (IQR) time to 3-MACE was 7.6 (4.3-12.0) years in the control group, 5.6 (3.9-10.3) years in the no-AC group, and 4.7 (2.4-11.0) years in the AC group. The cumulative incidence of 3-MACE was significantly greater for the control group than the AC group when adjusting for the competing risk of non-CV death ( P =.04) but was not different for the other pairwise comparisons (Figure 1B). On multivariable analysis, no group had an increased risk of 3-MACE compared with another after >25 years of follow-up (Table 2). Several demographic and clinical factors, however, were associated with a higher risk of 3-MACE for the entire cohort, including older age (HR per 5-y increase in age, 1.43; 95% CI, 1.34-1.52; P <.001), male sex (HR, 1.85; 95% CI, 1.37-2.51; P <.001), and HTN (HR, 1.56; 95% CI, 1.12-2.19; P =.008). Smoking history, T2D, CAD, dyslipidemia, and BMI greater than 30 did not significantly affect the risk of 3-MACE. In our subanalysis of 3-MACE within 5 and 10 years of follow-up, the 3 groups again had similar risk of 3-MACE at both time points (Table 2). In addition, at both time points, the increased risk persisted for older age, male sex, and HTN. Table 2. Risk Analysis of 3-MACE Overall (>25 years of follow up) Within 5 y of follow-up Within 10 y of follow-up Risk factor HR (95% CI) P value HR (95% CI) P value HR (95% CI) P value Univariable analysis Between-group comparisons - No-AC vs controls 1.14 (0.62-2.11) .66 1.37 (0.54-3.46) .49 1.26 (0.61-2.61) .52 - AC vs controls 0.85 (0.60-1.19) .35 1.17 (0.71-1.92) .52 0.80 (0.53-1.20) .29 - AC vs no-AC 0.75 (0.38-1.47) .41 0.85 (0.32-2.23) .74 0.65 (0.29-1.41) .28 Male sex 2.65 (2.00-3.51) <.001 1.08 (1.06-1.10) <.001 1.08 (1.07-1.10) <.001 Age (per 5-y increase) 1.52 (1.44-1.61) <.001 1.50 (1.34-1.63) <.001 1.29 (0.90-1.85) <.001 Smoking history 1.15 (0.85-1.56) .33 1.26 (0.78-2.04) .33 1.29 (0.90-1.85) .15 Type 2 diabetes 3.91 (2.70-5.68) <.001 3.56 (2.02-6.28) <.001 4.21 (2.77-6.39) <.001 Hypertension 4.83 (3.65-6.38) <.001 6.86 (4.18-11.27) <.001 7.07 (4.90-10.22) <.001 Coronary artery disease 3.83 (2.17-6.74) <.001 3.30 (1.43-7.62) .005 3.53 (1.85-6.72) <.001 Dyslipidemia 2.09 (1.59-2.77) <.001 2.65 (1.67-4.22) <.001 2.50 (1.77-3.53) 30 1.44 (1.08-1.90) .01 1.17 (0.72-1.88) .51 1.47 (1.04-2.07) .02 Multivariable analysis Between-group comparisons - No-AC vs controls 0.98 (0.53-1.82) .96 0.90 (0.35-2.28) .82 0.90 (0.43-1.86) .77 - AC vs controls 1.06 (0.74-1.52) .72 1.40 (0.83-2.35) .20 0.96 (0.63-1.47) .87 - AC vs no-AC 1.08 (0.55-2.11) .81 1.55 (0.58-4.14) .37 1.07 (0.48-2.35) .86 Age (per 5-y increase) 1.43 (1.34-1.52) <.001 1.36 (1.23-1.51) <.001 1.38 (1.28-1.49) <.001 Male sex 1.85 (1.37-2.51) <.001 1.64 (1.00-2.69) .04 1.78 (1.23-2.58) .002 Smoking history 1.25 (0.91-1.73) .16 1.14 (0.68-1.91) .60 1.26 (0.92-2.00) .11 Type 2 diabetes 1.37 (0.91-2.05) .12 1.09 (0.59-2.00) .77 1.23 (0.78-1.93) .36 Hypertension 1.56 (1.12-2.19) .008 2.44 (1.35-4.43) .003 2.42 (1.56-3.76) 30 1.01 (0.75-1.36) .93 0.71 (0.43-1.18) .19 0.91 (0.63-1.31) .61 We explored the risk of 3-MACE after >25 years of follow up by ACs cumulative dose, radiotherapy and cancer type, adjusting by age, sex and CV comorbidities. We found that when compared to a dose 250 mg/m2 (HR, 0.46; 95% CI, 0.18-1.16; P=0.10) were not associated with a higher risk. Chest radiotherapy was not associated with an increased risk of 3-MACE (HR, 0.59; 95% CI, 0.28-1.23; P=0.16). Subjects with HL (HR, 1.86; 95% CI, 0.20-16.90; P=0.58) and with NHL (HR, 1.67; 95% CI, 0.64-4.32; P=0.28) had a similar risk of 3-MACE when compared with those with breast cancer. Analysis of 4-MACE The cumulative incidence of 4-MACE at 5, 10, and 25 years of follow-up was 3.8%, 8.1%, and 23.9%, respectively, in the control group; 5.1%, 8.1%, and 17.5% in the no-AC group; and 5.8%, 9.0%, and 22.0% in the AC group. The median (IQR) time to 4-MACE was 7.8 (4.3-12.5) years in the control group, 5.6 (3.2-11.7) years in the no-AC group, and 4.9 (1.1-10.2) in the AC group. The cumulative incidence of 4-MACE was not significantly different between the groups when adjusting for the competing risk of non-CV death (Figure 2B). On multivariable analysis, the AC group had an increased risk of 4-MACE compared with the control group after >25 years of follow-up (HR, 1.61; 95% CI, 1.21-2.15; P =.001). However, there was no increased risk for the no-AC group vs controls or the AC group vs the no-AC group. Factors associated with a higher risk of 4-MACE for the entire cohort included older age (HR per 5-y increase in age, 1.44; 95% CI, 1.36-1.52; P <.001), male sex (HR, 1.55; 95% CI, 1.17-2.04; P =.001), smoking history (HR, 1.33; 95% CI, 1.04-1.76; P =.04), T2D (HR, 1.66; 95% CI, 1.18-2.34; P =.003), and HTN (HR, 1.42; 95% CI, 1.05-1.92; P =.02) (Table 3). CAD, dyslipidemia, and BMI greater than 30 did not significantly affect the risk of 4-MACE. In our subanalysis of 4-MACE within 5 and 10 years of follow-up, the increased risk of 4-MACE persisted for the AC group vs controls within both 5 and 10 years (Table 3). At 5 and 10 years, older age and HTN were associated with an increased risk of 4-MACE. In addition, male sex, smoking history, and T2D were associated with an increased risk of 4-MACE at 10 years (Table 3). Table 3 . Risk Analysis of 4-MACE Overall (>25 years of follow up) Within 5 y of follow-up Within 10 y of follow-up Risk factor HR (95% CI) P value HR (95% CI) P value HR (95% CI) P value Univariable analysis Between-group comparisons - No-AC vs controls 1.34 (0.79-2.27) .27 1.64 (0.74-3.61) .21 1.39 (0.72-2.66) .31 - AC vs controls 1.32 (1.01-1.74) .04 1.70 (1.13-2.57) .01 1.31 (0.94-1.81) .10 - AC vs no-AC 0.98 (0.55-1.71) .94 1.05 (0.47-2.36) .89 0.94 (0.48-1.84) .86 Age (per 5-y increase) 1.51 (1.44-1.58) <.001 1.50 (1.40-1.62) <.001 1.53 (1.45-1.62) <.001 Male sex 2.28 (1.77-2.94) <.001 2.47 (1.66-3.69) <.001 2.58 (1.90-3.50) <.001 Smoking history 1.39 (1.07-1.79) .01 1.42 (0.95-2.14) .08 1.57 (1.15-2.14) .004 Type 2 diabetes 4.61 (3.37-6.32) <.001 4.84 (3.08-7.61) <.001 5.08 (3.58-7.22) <.001 Hypertension 4.59 (3.59-5.87) <.001 6.66 (4.34-10.20) <.001 6.66 (4.83-9.19) <.001 Coronary artery disease 5.40 (3.48-8.40) <.001 5.87 (3.27-10.52) <.001 5.65 (3.50-9.12) <.001 Dyslipidemia 2.11 (1.65-2.70) <.001 2.61 (1.75-3.90) <.001 2.48 (1.83-3.36) 30 1.60 (1.25-2.05) <.001 1.41 (0.94-2.11) .08 1.66 (1.23- 2.25) <.001 Multivariable analysis Between-group comparisons - No-AC vs controls 1.14 (0.67-1.96) .60 1.08 (0.48-2.38) .84 0.98 (0.51-1.89) .96 - AC vs controls 1.61 (1.21-2.15) .001 2.06 (1.13-3.21) .001 1.53 (1.09-2.16) .01 - AC vs no-AC 1.40 (0.80-2.46) .23 1.42 (0.63-3.20) .39 1.56 (0.78-3.09) .20 Age (per 5-y increase) 1.44 (1.36-1.52) <.001 1.37 (1.26-1.50) <.001 1.40 (1.31-1.50) <.001 Male sex 1.55 (1.17-2.04) .001 1.40 (0.91-2.17) .12 1.49 (1.07-2.09) .01 Smoking history 1.33 (1.04-1.76) .04 1.08 (0.69-1.69) .71 1.43 (1.02-2.00) .03 Type 2 diabetes 1.66 (1.18-2.34) .003 1.51 (0.92-2.49) .09 1.51 (1.02-2.22) .03 Hypertension 1.42 (1.05-1.92) .02 2.14 (1.27-3.60) .004 2.11 (1.13-3.10) 30 1.11 (0.85-1.43) .42 0.80 (0.52-1.23) .32 0.99 (0.72-1.37) .98 We also analyzed the risk of 4-MACE after >25 years of follow up by ACs cumulative dose, radiotherapy and cancer type, considering age, sex and CV comorbidities. Our analysis yielded that compared to a dose 250 mg/m2 (HR, 0.70; 95% CI, 0.35-1.40; P=0.32) did not confer a higher risk. We also evaluated the impact of radiotherapy on 4-MACE and found that it was associated with a decreased risk of 4-MACE (HR, 0.49; 95% CI, 0.29-0.85; P<.001). Subjects with HL (HR, 2.21; 95% CI, 0.48-10.03; P=0.30) and with NHL (HR, 1.54; 95% CI, 0.76-3.12; P=0.22) had a similar risk of 4-MACE when compared with those with breast cancer. Analysis of Individual MACE Components The cumulative incidence of MI at 5, 10, and 25 years of follow-up was 0.7%, 1.9%, and 4.0%, respectively, in the control group; 0.9%, 5.5%, and 18.2% in the no-AC group; and 1.4%, 1.7%, and 4.4% in the AC group. The risk of MI was similar for the 3 groups (Table 4). Factors associated on multivariable analysis with a higher risk of MI included older age (HR per 5-y increase in age, 1.35; 95% CI, 1.20-1.53; P <.001) and male sex (HR, 4.21; 95% CI, 2.32-7.64; P <.001). The cumulative incidence of stroke at 5, 10, and 25 years of follow-up was 2.7%, 5.5%, and 13.6%, respectively, in the control group; 5.0%, 6.3%, and 9.1% in the no-AC group; and 2.0%, 3.3%, and 11.8% in the AC group. The risk of stroke on multivariable analysis was comparable across the 3 groups (Table 4). Higher risk of stroke was associated with older age (HR per 5-y increase in age, 1.33; 95% CI, 1.23-1.43; P <.001), HTN (HR, 1.72; 95% CI, 1.13-2.32; P =.01), and T2D (HR, 1.70; 95% CI, 1.03-2.80; P =.03). Table 4. Risk Analysis for Each Component of 4-MACE MI Stroke CV death HF Risk factor HR (95% CI) P value HR (95% CI) P value HR (95% CI) P value HR (95% CI) P value Univariable analysis Between-group comparisons - No-AC vs controls 2.41 (0.94-6.18) .06 1.07 (0.49-2.31) .85 1.04 (0.24-4.37) .95 2.30 (1.09-4.87) .02 - AC vs controls 1.13 (0.59-2.15) .70 0.70 (0.45-1.10) .12 0.98 (0.48-2.02) .97 2.80 (1.87-4.19) <.001 - AC vs no-AC 0.53 (0.18-1.53) .24 0.63 (0.27-1.48) .29 0.84 (0.18-3.86) .82 1.18 (0.54-2.56) .66 Age (per 5-y increase) 1.52 (1.37-1.69) <.001 1.41 (1.32-1.50) <.001 2.10 (1.80-2.46) <.001 1.55 (1.44-1.67) <.001 Male sex 5.77 (3.32-10.01) <.001 1.61 (1.10-2.36) .01 6.20 (3.39-11.32) <.001 2.54 (1.71-3.76) <.001 Smoking history 1.47 (0.83-2.61) .18 1.21 (0.83-1.75) .30 0.63 (0.29-1.35) .23 2.29 (1.56-3.37) <.001 Type 2 diabetes 5.72 (2.98-10.99) <.001 3.96 (2.52-6.24) <.001 5.33 (2.54-11.20) <.001 6.38 (4.04-10.08) <.001 Hypertension 5.62 (3.20-9.89) <.001 4.08 (2.88-5.77) <.001 8.25 (4.32-5.73) <.001 4.88 (3.30-7.21) <.001 Coronary artery disease 7.43 (3.14-17.56) <.001 1.59 (0.58-4.32) .35 5.86 (2.07-16.52) <.001 8.10 (4.50-14.58) <.001 Dyslipidemia 3.53 (1.99-6.26) <.001 1.82 (1.29-2.58) <.001 1.95 (1.07-3.57) .02 2.21 (1.50-3.27) 30 1.53 (0.88-2.67) .12 1.54 (1.08-2.18) .01 0.94 (0.49-1.80) .86 1.91 (1.30-2.80) <.001 Multivariable analysis Between-group comparisons - No-AC vs controls 1.86 (0.71-4.88) .20 0.91 (0.42-1.98) .81 1.01 (0.23-4.35) .98 1.83 (0.85-3.91) .11 - AC vs controls 1.50 (0.75-2.99) .24 0.78 (0.49-1.24) .30 2.15 (0.99-4.70) .06 3.20 (2.08-4.94) <.001 - AC vs no-AC 0.80 (0.27-2.33) .69 0.86 (0.37-2.01) .73 2.12 (0.45-9.96) .33 1.75 (0.81-3.77) .15 Age (per 5-y increase) 1.35 (1.20-1.53) <.001 1.33 (1.23-1.43) <.001 1.94 (1.63-2.31) <.001 1.48 (1.36-1.62) <.001 Male sex 4.21 (2.32-7.64) <.001 1.15 (0.77-1.73) .47 4.23 (2.17-8.25) <.001 1.64 (1.06-2.54) .02 Smoking history 1.21 (0.64-2.28) .54 1.45 (0.98-2.14) .06 0.67 (0.28-1.57) .35 1.77 (1.15-2.71) .009 Type 2 diabetes 1.84 (0.90-3.76) .09 1.70 (1.03-2.80) .03 1.80 (0.80-4.04) .14 2.43 (1.48-4.02) <.001 Hypertension 1.51 (0.77-2.98) .22 1.72 (1.13-2.32) .01 1.66 (0.81-3.39) .16 1.44 (0.89-2.35) .13 Coronary artery disease 0.96 (0.37-2.48) .94 0.41 (0.14-1.18) .10 0.92 (0.29-2.89) .29 1.24 (0.63-2.42) .52 Dyslipidemia 1.71 (0.90-3.22) .09 0.88 (0.60-1.30) .54 0.88 (0.45-1.77) .73 0.82 (0.52-1.28) .39 BMI >30 0.91 (0.50-1.66) .76 1.09 (0.75-1.56) .63 0.67 (0.33-1.33) .25 1.17 (0.78-1.76) .43 The cumulative incidence of CV death at 5, 10, and 25 years of follow-up was 0.3%, 1.0%, and 6.9%, respectively, in the control group; 0.9%, 2.2%, and 2.2% in the no-AC group; and 0.7%, 1.2%, and 2.6% in the AC group. The risk of CV death did not differ significantly among the 3 groups (Table 4). However, older age (HR per 5-y increase in age, 1.94; 95% CI, 1.63-2.31; P <.001) and male sex (HR, 4.23; 95% CI, 2.17-8.25; P <.001) were associated with an increased risk of CV death on multivariable analysis. The cumulative incidence of HF at 5, 10, and 25 years of follow-up was 0.9%, 2.1%, and 10.5%, respectively, in the control group; 1.9%, 6.3%, and 17.6% in the no-AC group; and 3.2%, 6.1%, and 20.2% in the AC group. The AC group had a higher risk of HF than the control group (HR, 3.20; 95% CI, 2.08-4.94; P <.001), but risk was not significantly different for other pairwise group comparisons (Table 4). Increased risk of HF was associated with older age (HR per 5-y increase in age, 1.48; 95% CI, 1.36-1.62; P <.001), male sex (HR, 1.64; 95% CI, 1.06-2.54; P =.02), smoking history (HR, 1.77; 95% CI, 1.15-2.71; P =.009), and T2D (HR, 2.43; 95% CI, 1.48-4.02; P <.001). Discussion To our knowledge, this is the first epidemiologic study to evaluate the impact of ACs on the incidence of MACE. We observed no association between AC use and an increase in the incidence of 3-MACE after 25 years of follow-up. Our results show that CV comorbid conditions are the main risk factors for the development of 3-MACE and 4-MACE in our cohort. Regarding 4-MACE, patients treated with ACs had an increased incidence compared with controls given the inclusion of HF in this definition. Our results showed that RT was associated with a decrease risk of 4-MACE, but not 3-MACE. Our findings may be influenced by the higher incidence of non-CV death in the no-AC and AC groups compared with the control group. In particular, the cumulative incidence of non-CV death was much lower in the control group than in the no-AC and AC groups at all time points. Even after adjusting for sex and age differences, the no-AC and AC groups were at significantly higher risk for non-CV death. It is possible that patients in the cancer groups may have died of non-CV causes before experiencing a stroke, MI, or CV death. It is also plausible that patients with cancer treated with ACs had closer monitoring than patients with CV risk factors but without cancer (control group), so that despite the lack of oncologic illness and cardiotoxic drugs, patients with CV risk factors in the control group were at high risk for MACE but had less surveillance in the community setting. Given the high incidence of non-CV death in the no-AC and AC groups, we analyzed the risk of MACE after 5 and 10 years of follow-up. The risk of 3-MACE was still similar among the 3 groups, but analysis of 4-MACE showed that the AC group had a greater risk than controls, possibly related to the contribution of HF. We previously showed the association of ACs with congestive HF(3) and observed similar findings in this study regarding HF (ie, 4-MACE). Our findings showed that CV comorbid conditions are associated with an increased risk of MACE after 5, 10, and >25 years of follow-up. Older age, male sex, and HTN were linked to 3-MACE at 5, 10, and >25 years of follow-up. Older age and HTN were risk factors for 4-MACE after 5, 10, and >25 years of follow-up, and male sex, smoking history, and T2D were associated with 4-MACE at 10 and >25 years of follow-up. A meta-analysis including 7,488 patients with BC, lymphoma, sarcomas, or gastrointestinal cancer receiving ACs reported that those with HTN, T2D, and obesity had an increased risk of AC-induced cardiotoxicity.(19) Given this, we believe that, in patients with cancer being treated with ACs, CV risk factors should be addressed to decrease the risk not only of MACE but also of AC cardiotoxicity. In our study, patients in the no-AC group did not have greater risk of 3-MACE or 4-MACE than controls, which suggests that cancer does not increase the risk of MACE, in contrast to other published findings.(10, 11) A possible reason for this difference is that our control group was not a group of healthy persons and were matched by age, sex, and CV comorbid conditions to patients with cancer. The similarity between no-AC patients and controls also may be attributed to a higher prevalence of male patients and HTN in the no-AC group, both of which were associated with an increased risk of MACE in our analysis. Interestingly, we found that the risk of 3-MACE and 4-MACE did not increase with higher anthracycline doses. Moreover, chest radiotherapy was associated with a decreased risk of 4-MACE, but not 3-MACE. This may be explained by the impact of radiotherapy on HF risk, which we investigated in a previous study (3). There, we found that the risk of congestive HF was not dose-dependent and was actually lower in patients who received chest radiotherapy. In our prospective cohort study of newly diagnosed lymphoma patients aged over 18 years with no prior history of CV disease, we examined the association of treatment with anthracyclines or radiotherapy and traditional CV risk factors. Our findings indicated that radiotherapy did not increase the overall risk of CV disease in this population (20). This is also consistent with the results of a large study with 308,861 women with localized or regional breast cancer, from SEER registries (1973–2001), followed until 2002. They found that radiotherapy regimens used in the 1970s and early 1980s were associated with a significantly increased long-term risk of death from heart disease when compared to treatment with chemotherapy alone. However, this excess risk disappeared by the 1990s, likely due to advances in radiotherapy techniques and the introduction of cardioprotective measures (21). Regarding cancer type, in a previous study we also observed that, in patients with HL and NHL, the risk of congestive HF was comparable to that seen in breast cancer (3). Similarly, in the present study, the risk of 3-MACE and 4-MACE did not differ significantly by cancer type. Our subanalysis for each component of 4-MACE (MI, stroke, CV death, HF) showed that the risk of each was similar among the 3 groups, except the risk of HF in the AC group compared with controls. Patients in the AC group were more than 3 times more likely to have HF, which is consistent with our previously published work (3) showing that this risk is irrespective of the cumulative dose of ACs. A recent SEER-Medicare study evaluated the incidence of MACE in a cohort of 2,215 older women with triple-negative BC treated with ACs and taxane vs taxane-only treatment.(22) The definition of MACE in that study included HF, fatal arrhythmias, MI, and stroke, but not CV death. Patients were followed up for a maximum of 36 months. Similar to our results, patients who received ACs with taxanes were not more likely to experience MACE when controlling for CV risk factors, which underscores the importance of CV comorbid conditions before chemotherapy. Additionally, the authors showed that diabetes increased the risk of MI and stroke. Interestingly, they reported that patients who received ACs with taxanes were less likely to have HF. The authors suggest that this may be influenced by current practices that assess patients for CV comorbid conditions before starting ACs and treating only those without substantial cardiac problems.(22) Our study followed patients up for a considerably longer period and is population-based; additionally, we included a control group without cancer. Our study has several limitations. Our population is primarily female, so results regarding men should be interpreted with caution. Additionally, the AC and no-AC groups are substantially smaller than the control group, which may affect the reliability of the results. Moreover, our analysis does not distinguish between different subtypes of BC, HL, or NHL or consider distinct cancer stages, treatment duration, or radiotherapy. Additionally, 13 patients in the AC group were treated with trastuzumab as first line chemotherapy agent; given the small sample size, no conclusions can be made regarding MACE and this medication. Strengths of our study include being population-based and facilitated by the REP, which benefits from large sample size, a uniform health care environment, and long-term follow-up. These features enhance the ability to assess the effects of health interventions in routine practice.(23) Such studies typically offer strong external validity, which makes our findings more generalizable to broader populations with similar demographics as Olmsted County.(23, 24) However, the internal validity of these studies may be limited by potential confounding factors.(23) Even though a population-based study can limit the racial and ethnic diversity of a cohort, our population is demographically similar to the Framingham Heart Study cohort.(25) We highlight the presence in our study of a control group without cancer, as well as the long follow-up period. It would be interesting to have longer follow-up for patients who did not die of non-CV causes and compare the incidence of MACE with controls or cancer patients not treated with ACs. Conclusion Our findings indicate that patients treated with ACs had a similar incidence of 3-MACE compared with controls and cancer patients not treated with ACs. These results may be influenced by the higher incidence of non-CV death in the cancer groups, which could limit the number of patients at risk for MACE. We also confirmed that ACs are a significant risk factor for the development of HF. Of additional high clinical relevance, CV risk factors were the main drivers of 3-MACE at 5, 10, and >25 years of follow. Our findings underscore the importance of promoting healthy habits and implementing lifestyle changes among patients with cancer. It is important, however, to interpret our results within the context of Olmsted County’s health care environment. Larger and, ideally, prospective studies are needed to establish causative relationships and fully understand the impact of ACs on MACE. We advocate for a broader approach in cardio-oncology that not only examines the association between ACs and HF but also explores other potential forms of cardiotoxicity. Abbreviations AC, anthracycline BC, breast cancer BMI, body mass index CAD, coronary artery disease CV, cardiovascular HF, heart failure HL, Hodgkin lymphoma HR, hazard ratio HTN, hypertension MACE, major adverse cardiovascular events MI, myocardial infarction NHL, non-Hodgkin lymphoma REP, Rochester Epidemiology Project T2D, type 2 diabetes Declarations Ethics approval and consent to participate This study was approved by the institutional review boards of Mayo Clinic and Olmsted Medical Center. Per Minnesota law, all participants agreed to the use of their data for research purposes, and those who did not consent were not included. Consent for publication Not applicable Availability of data and materials All relevant data supporting the findings of this study are reported within the article or are available from the corresponding author upon reasonable request. Competing interests The authors declare that they have no competing interests. Funding Not applicable Authors' contributions ETG performed the statistical analysis and was the main responsible for the writing of the manuscript. AEDA, MFGA, and CR contributed with writing and editing of the manuscript CML, JM, TCH and CAT supported data curation. JRC reviewed the statistical analysis and editing of the manuscript. HRV led the conceptualization, data curation, statistical analysis, methodology, project administration and editing of the manuscript. All authors read and approved the final manuscript Acknowledgements This study used the resources of the Rochester Epidemiology Project (REP) medical records linkage system, which is supported by the National Institute on Aging (NIA; AG 058738), by the Mayo Clinic Research Committee, and by fees paid annually by REP users. The content of this article is solely the responsibility of the authors and does not represent the official views of the National Institutes of Health (NIH) or Mayo Clinic. For this study we received statistical advice from the Mayo Clinic Center for Clinical and Translational Science (CCaTS). The Scientific Publications staff at Mayo Clinic provided editorial consultation, proofreading, and administrative and clerical support. References Bowles EJ, Wellman R, Feigelson HS, Onitilo AA, Freedman AN, Delate T, et al. Risk of heart failure in breast cancer patients after anthracycline and trastuzumab treatment: a retrospective cohort study. J Natl Cancer Inst. 2012;104(17):1293-305. Ho E, Brown A, Barrett P, Morgan RB, King G, Kennedy MJ, et al. Subclinical anthracycline- and trastuzumab-induced cardiotoxicity in the long-term follow-up of asymptomatic breast cancer survivors: a speckle tracking echocardiographic study. Heart. 2010;96(9):701-7. Larsen CM, Garcia Arango M, Dasari H, Arciniegas Calle M, Adjei E, Rico Mesa J, et al. Association of Anthracycline With Heart Failure in Patients Treated for Breast Cancer or Lymphoma, 1985-2010. JAMA Netw Open. 2023;6(2):e2254669. Swain SM, Whaley FS, Ewer MS. Congestive heart failure in patients treated with doxorubicin: a retrospective analysis of three trials. Cancer. 2003;97(11):2869-79. Pinder MC, Duan Z, Goodwin JS, Hortobagyi GN, Giordano SH. Congestive heart failure in older women treated with adjuvant anthracycline chemotherapy for breast cancer. J Clin Oncol. 2007;25(25):3808-15. Lotrionte M, Biondi-Zoccai G, Abbate A, Lanzetta G, D'Ascenzo F, Malavasi V, et al. Review and meta-analysis of incidence and clinical predictors of anthracycline cardiotoxicity. Am J Cardiol. 2013;112(12):1980-4. Koene RJ, Prizment AE, Blaes A, Konety SH. Shared Risk Factors in Cardiovascular Disease and Cancer. Circulation. 2016;133(11):1104-14. Wilcox NS, Amit U, Reibel JB, Berlin E, Howell K, Ky B. Cardiovascular disease and cancer: shared risk factors and mechanisms. Nat Rev Cardiol. 2024;21(9):617-31. Al-Kindi SG, Oliveira GH. Prevalence of Preexisting Cardiovascular Disease in Patients With Different Types of Cancer: The Unmet Need for Onco-Cardiology. Mayo Clin Proc. 2016;91(1):81-3. Zaorsky NG, Zhang Y, Tchelebi LT, Mackley HB, Chinchilli VM, Zacharia BE. Stroke among cancer patients. Nat Commun. 2019;10(1):5172. Bima P, Lopez-Ayala P, Koechlin L, Boeddinghaus J, Nestelberger T, Okamura B, et al. Chest Pain in Cancer Patients: Prevalence of Myocardial Infarction and Performance of High-Sensitivity Cardiac Troponins. JACC CardioOncol. 2023;5(5):591-609. Felker GM, Thompson RE, Hare JM, Hruban RH, Clemetson DE, Howard DL, et al. Underlying causes and long-term survival in patients with initially unexplained cardiomyopathy. N Engl J Med. 2000;342(15):1077-84. Schreiber AR, Kagihara J, Eguchi M, Kabos P, Fisher CM, Meyer E, et al. Evaluating anthracycline + taxane versus taxane-based chemotherapy in older women with node-negative triple-negative breast cancer: a SEER-Medicare study. Breast Cancer Res Treat. 2022;191(2):389-99. Bosco E, Hsueh L, McConeghy KW, Gravenstein S, Saade E. Major adverse cardiovascular event definitions used in observational analysis of administrative databases: a systematic review. BMC Med Res Methodol. 2021;21(1):241. Booth CM, Tannock IF. Randomised controlled trials and population-based observational research: partners in the evolution of medical evidence. Br J Cancer. 2014;110(3):551-5. Sorlie P, Wei GS. Population-based cohort studies: still relevant? J Am Coll Cardiol. 2011;58(19):2010-3. Rocca WA, Yawn BP, St Sauver JL, Grossardt BR, Melton LJ, 3rd. History of the Rochester Epidemiology Project: half a century of medical records linkage in a US population. Mayo Clin Proc. 2012;87(12):1202-13. Jacobsen SJ, Xia Z, Campion ME, Darby CH, Plevak MF, Seltman KD, et al. Potential effect of authorization bias on medical record research. Mayo Clin Proc. 1999;74(4):330-8. Yawn BP, Yawn RA, Geier GR, Xia Z, Jacobsen SJ. The impact of requiring patient authorization for use of data in medical records research. J Fam Pract. 1998;47(5):361-5. Boddicker NJ, Larson MC, Castellino A, Herrmann J, Inwards DJ, Thanarajasingam G, et al. Anthracycline treatment, cardiovascular risk factors and the cumulative incidence of cardiovascular disease in a cohort of newly diagnosed lymphoma patients from the modern treatment era. Am J Hematol. 2021;96(8):979-88. Darby SC, McGale P, Taylor CW, Peto R. Long-term mortality from heart disease and lung cancer after radiotherapy for early breast cancer: prospective cohort study of about 300,000 women in US SEER cancer registries. Lancet Oncol. 2005;6(8):557-65. St Sauver JL, Grossardt BR, Yawn BP, Melton LJ, 3rd, Rocca WA. Use of a medical records linkage system to enumerate a dynamic population over time: the Rochester epidemiology project. Am J Epidemiol. 2011;173(9):1059-68. Qiu S, Zhou T, Qiu B, Zhang Y, Zhou Y, Yu H, et al. Risk Factors for Anthracycline-Induced Cardiotoxicity. Front Cardiovasc Med. 2021;8:736854. Roy S, Lakritz S, Schreiber AR, Kuna EM, Bradley CJ, Kondapalli L, et al. Major cardiovascular adverse events in older adults with early-stage triple-negative breast cancer treated with adjuvant taxane + anthracycline versus taxane-based chemotherapy regimens: A SEER-medicare study. Eur J Cancer. 2024;196:113426. McKee PA, Castelli WP, McNamara PM, Kannel WB. The natural history of congestive heart failure: the Framingham study. N Engl J Med. 1971;285(26):1441-6. Additional Declarations No competing interests reported. Supplementary Files Graphicalabstractpart2V4.pptx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6778136","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":466395378,"identity":"ec44552b-f5fa-4a05-9d45-dbe02ad97a05","order_by":0,"name":"Eduardo Tellez-Garcia","email":"","orcid":"","institution":"Mayo Clinic","correspondingAuthor":false,"prefix":"","firstName":"Eduardo","middleName":"","lastName":"Tellez-Garcia","suffix":""},{"id":466395379,"identity":"1f556d25-db75-4052-a118-5f8ba289e1ca","order_by":1,"name":"Andres E. 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Thompson","email":"","orcid":"","institution":"Mayo Clinic","correspondingAuthor":false,"prefix":"","firstName":"Carrie","middleName":"A.","lastName":"Thompson","suffix":""},{"id":466395386,"identity":"00493603-e5a9-4e80-b253-22edb2d1f514","order_by":8,"name":"James R. Cerhan","email":"","orcid":"","institution":"Mayo Clinic","correspondingAuthor":false,"prefix":"","firstName":"James","middleName":"R.","lastName":"Cerhan","suffix":""},{"id":466395387,"identity":"7d9de74c-74cd-49ba-ab64-5557c685527e","order_by":9,"name":"Hector R. Villarraga","email":"data:image/png;base64,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","orcid":"","institution":"Mayo Clinic","correspondingAuthor":true,"prefix":"","firstName":"Hector","middleName":"R.","lastName":"Villarraga","suffix":""}],"badges":[],"createdAt":"2025-05-29 16:08:06","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6778136/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6778136/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":84323594,"identity":"495da78e-748e-4ff8-91ac-81505a8c0010","added_by":"auto","created_at":"2025-06-10 14:45:25","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":54865,"visible":true,"origin":"","legend":"\u003cp\u003eCumulative Incidence Curves for the Anthracycline (AC), No-AC, and Control Groups. A, Cumulative incidence of noncardiovascular (non-CV) death accounting for the competing risk of 3-MACE (myocardial infarction, stroke, and CV death). B, Cumulative incidence of 3-MACE.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-6778136/v1/ed77f283159c14d4a828d32b.png"},{"id":84324342,"identity":"a0a57bf9-32db-457f-a3f0-8f9b4618d28a","added_by":"auto","created_at":"2025-06-10 14:53:26","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":53035,"visible":true,"origin":"","legend":"\u003cp\u003eCumulative Incidence Curves for the Anthracycline (AC), No-AC, and Control Groups. A, Cumulative incidence of noncardiovascular (non-CV) death accounting for the competing risk of 4-MACE (myocardial infarction, stroke, CV death, and heart failure). B, Cumulative incidence of 4-MACE.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-6778136/v1/fffe5f71a590da5cb53d15cd.png"},{"id":86536635,"identity":"c2cb817a-b137-439b-9f5c-384faec9fec3","added_by":"auto","created_at":"2025-07-11 18:46:30","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1379658,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6778136/v1/ba02b18c-4fd1-4d2a-b46c-a9a11ffe9877.pdf"},{"id":84324349,"identity":"97b778c8-dc4f-4b64-af14-32304b128460","added_by":"auto","created_at":"2025-06-10 14:53:26","extension":"pptx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":545116,"visible":true,"origin":"","legend":"","description":"","filename":"Graphicalabstractpart2V4.pptx","url":"https://assets-eu.researchsquare.com/files/rs-6778136/v1/235e740a2b36c02bf46a01b9.pptx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Major Adverse Cardiovascular Events in Patients Treated With Anthracyclines for Breast Cancer or Lymphoma: 25-Year Follow-Up","fulltext":[{"header":"Background","content":"\u003cp\u003eAnthracyclines (ACs) are chemotherapeutic agents that are frequently used as part of the management of diverse solid and hematologic cancers, such as lymphomas and breast cancer (BC). However, their use is often associated with cardiac toxicity,(\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e) heart failure (HF) being the most widely recognized complication(\u003cspan additionalcitationids=\"CR4\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e) with a reported incidence of up to 10.75% over 20 years.(\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e) A 2013 meta-analysis reported that, after a median follow-up of 9 years, clinically overt cardiotoxicity developed in approximately 6% of patients treated with ACs, and 18% had subclinical toxic effects.(\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eThe toxicity surveillance of ACs has primarily focused on HF and contractile dysfunction, but much less is known about their effects on other cardiovascular (CV) events. Cancer and CV diseases share common risk factors, such as obesity, type 2 diabetes (T2D), hypertension (HTN), and tobacco use, among others,(\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e) and are often comorbid. One study showed that 17% of patients with BC and up to 33% with hematologic cancer have CV risk factors, such as coronary artery disease (CAD), carotid artery disease, peripheral vascular disease, HF, or cerebrovascular disease.(\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e) Furthermore, patients with cancer have a higher risk of CV events compared with the general population. For instance, cancer patients have twice the likelihood of stroke compared with the general population(\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e) and also have a higher incidence of myocardial infarction (MI).(\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e) This suggests a milieu of concurring factors in oncology patients that increase the risk of CV events.\u003c/p\u003e \u003cp\u003eThe development of cardiotoxicity also has been associated with poorer survival outcomes.(\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e) A study in patients older than 66 years with triple-negative BC treated with taxanes and ACs showed worse 3-year survival and cancer-specific survival for these patients compared with those treated only with taxanes.(\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e) The authors propose that underlying cardiac disease may have developed in the patients receiving ACs, because those typically treated with ACs are younger and generally lack pre-existing CV comorbid conditions.(\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eOne way to measure cardiotoxicity is to assess for the occurrence of major adverse cardiovascular events (MACE), the definition of which varies across studies but most commonly includes MI and stroke and occasionally also considers CV death, unstable angina, HF, and arrhythmia.(\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e) To our knowledge, no population-based study has evaluated the impact of AC use on the occurrence of MACE. The aim of our study was to assess for an association between ACs and MACE in patients with BC, Hodgkin lymphoma (HL), or non-Hodgkin lymphoma (NHL), compared with a control population without cancer.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eThis was a retrospective, observational, population-based cohort study. The data for this study were obtained through the Rochester Epidemiology Project (REP), a collaboration among health care providers in Olmsted County, Minnesota (2022 population, 164,020), whose goal is to create a research infrastructure with complete data linkage of health records. It provides a unique opportunity for epidemiologic research because almost all medical care is provided by 2 providers. The Mayo Clinic Cancer Registry and the REP database were queried for the records of adult (age\u0026thinsp;\u0026gt;\u0026thinsp;17 years) residents of Olmsted County who were newly diagnosed with and treated for BC, HL, or NHL between January 1, 1985, and December 31, 2010.\u003c/p\u003e \u003cp\u003e This study was approved by the institutional review boards of Mayo Clinic and Olmsted Medical Center. Per Minnesota law, all participants agreed to the use of their data for research purposes,(\u003cspan additionalcitationids=\"CR16 CR17\" citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e) and those who did not consent were not included. Data were gathered through a combination of electronic extraction and manual record review. Information was collected from the REP regarding patients\u0026rsquo; date of birth, sex, body mass index (BMI, calculated as weight in kg divided by height in m\u003csup\u003e2\u003c/sup\u003e), the date they were last censored in Olmsted County, and, if applicable, the date and cause of death. A manual review of records was also conducted for all patients with cancer to gather details on cancer treatments, comorbid conditions, and CV outcomes. Baseline comorbid conditions and potential CV outcomes for the comparison cohort were initially obtained electronically, with manual record review for all comparison participants to ensure data quality and prevent misclassification.\u003c/p\u003e \u003cp\u003eAmong patients identified with BC or lymphoma, 2 groups were considered: those treated with chemotherapy (AC group) and those not treated with ACs (no-AC group). A third group included control patients with no history of cancer who were matched by age, sex, and baseline CV comorbid conditions at the index date to the patients with cancer. Participants in the control group were required to be followed up for at least as long as participants with cancer. The matching ratio was 1 case to 1.5 controls.\u003c/p\u003e \u003cp\u003eClinical characteristics abstracted for all patients included smoking history, T2D, HTN, dyslipidemia, body mass index greater than 30, and CAD (defined as coronary angiography showing stenosis\u0026thinsp;\u0026gt;\u0026thinsp;50% of at least 1 artery, coronary revascularization, history of MI, presence of regional wall-motion abnormality on an imaging study, or a positive stress test). The primary outcome of interest was MACE, with 2 definitions: 3-point MACE including MI, stroke, and CV death (due to MI, HF exacerbation, or arrhythmia) (\u003cem\u003e3-MACE\u003c/em\u003e), and 4-point MACE that included MI, stroke, CV death, and HF (\u003cem\u003e4-MACE\u003c/em\u003e). New-onset HF as defined by the modified Framingham criteria, both in the inpatient and outpatient setting.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003eThe distribution of quantitative variables was analyzed with the Shapiro-Wilk test. Normally distributed continuous variables are expressed as mean (SD) and were statistically compared among groups with the Student \u003cem\u003et\u003c/em\u003e test. Nonnormally distributed continuous variables are expressed as median (IQR) and were compared with the Wilcoxon signed-rank test. Categorical variables are shown as frequencies (percentages) and were compared between groups with χ\u003csup\u003e2\u003c/sup\u003e tests. Two-sided \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;.05 was used to define statistical significance.\u003c/p\u003e \u003cp\u003eWe performed univariable and multivariable Cox regression analysis to identify variables associated with 3-MACE and 4-MACE, reported as hazard ratio (HR) with 95% CI. Risk factors included in the multivariable analysis were those clinically relevant to the outcome. Additionally, separate analysis was performed for each component of MACE (MI, stroke, CV death, and HF). We analyzed the overall risk of 3-MACE and 4-MACE after \u0026gt;\u0026thinsp;25 years of follow-up and within 5 and 10 years of follow-up. Cumulative incidence of 3-MACE and 4-MACE was modeled accounting for the competing risk of non-CV death, at 5, 10, and 25 years of follow-up, and displayed graphically. BlueSky Statistics version 10.3.1. was used for statistical analysis.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003eTable 1A.\u003c/strong\u003e Baseline Characteristics\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"498\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 169px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 329px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eGroup\u003c/strong\u003e\u003cstrong\u003e\u003csup\u003ea\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 169px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eCharacteristic\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 107px;\"\u003e\n \u003cp\u003eControl\u003c/p\u003e\n \u003cp\u003e(n=1,384)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 102px;\"\u003e\n \u003cp\u003eNo-AC\u003c/p\u003e\n \u003cp\u003e(n=137)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003eAC\u003c/p\u003e\n \u003cp\u003e(n=675)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 169px;\"\u003e\n \u003cp\u003eAge at matching, y\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 107px;\"\u003e\n \u003cp\u003e52.6 (14.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 102px;\"\u003e\n \u003cp\u003e57.7 (15.4)\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e51.6 (14.1)\u003csup\u003ec\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 169px;\"\u003e\n \u003cp\u003eSex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 107px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 102px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 169px;\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 107px;\"\u003e\n \u003cp\u003e303 (21.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 102px;\"\u003e\n \u003cp\u003e45 (32.8)\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e144 (21.3)\u003csup\u003ec\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 169px;\"\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 107px;\"\u003e\n \u003cp\u003e1,081 (78.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 102px;\"\u003e\n \u003cp\u003e92 (67.2)\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e531 (78.7)\u003csup\u003ec\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 169px;\"\u003e\n \u003cp\u003eSmoking history\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 107px;\"\u003e\n \u003cp\u003e284 (20.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 102px;\"\u003e\n \u003cp\u003e52 (38.0)\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e295 (43.8)\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 169px;\"\u003e\n \u003cp\u003eType 2 diabetes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 107px;\"\u003e\n \u003cp\u003e93 (6.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 102px;\"\u003e\n \u003cp\u003e14 (10.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e50 (7.4)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 169px;\"\u003e\n \u003cp\u003eHypertension\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 107px;\"\u003e\n \u003cp\u003e370 (26.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 102px;\"\u003e\n \u003cp\u003e55 (40.1)\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e191 (28.3)\u003csup\u003ec\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 169px;\"\u003e\n \u003cp\u003eDyslipidemia\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 107px;\"\u003e\n \u003cp\u003e533 (38.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 102px;\"\u003e\n \u003cp\u003e54 (39.4)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e259 (38.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 169px;\"\u003e\n \u003cp\u003eBMI \u0026gt;30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 107px;\"\u003e\n \u003cp\u003e432 (31.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 102px;\"\u003e\n \u003cp\u003e42 (30.7)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e205 (30.4)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 169px;\"\u003e\n \u003cp\u003eCoronary artery disease\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 107px;\"\u003e\n \u003cp\u003e25 (1.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 102px;\"\u003e\n \u003cp\u003e11 (8.0)\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e31 (4.6)\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eAbbreviations: AC, anthracycline; BMI, body mass index.\u003c/p\u003e\n\u003cp\u003e\u003csup\u003ea\u003c/sup\u003e Values are mean (SD), median (IQR), or No. of patients (%).\u003c/p\u003e\n\u003cp\u003e\u003csup\u003eb\u003c/sup\u003e \u003cem\u003eP\u003c/em\u003e\u0026lt;.05 vs control group.\u003c/p\u003e\n\u003cp\u003e\u003csup\u003ec\u003c/sup\u003e \u003cem\u003eP\u003c/em\u003e\u0026lt;.05 vs no-AC group.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 1B.\u003c/strong\u003e Characteristics of Patients With Cancer and Treatment Regimens\u003c/p\u003e\n\u003ctable border=\"0\" cellpadding=\"0\"\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 237px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 297px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eGroup\u003csup\u003ea\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 237px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eCharacteristic\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 94px;\"\u003e\n \u003cp\u003eBreast cancer\u003c/p\u003e\n \u003cp\u003e(n = 513)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 100px;\"\u003e\n \u003cp\u003eHL\u003c/p\u003e\n \u003cp\u003e(n = 71)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 99px;\"\u003e\n \u003cp\u003eNHL\u003c/p\u003e\n \u003cp\u003e(n = 228)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 237px;\"\u003e\n \u003cp\u003eFirst line chemotherapy regimen\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 99px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 237px;\"\u003e\n \u003cp\u003e- AC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e430 (84%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e68 (96%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 99px;\"\u003e\n \u003cp\u003e164 (72%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 237px;\"\u003e\n \u003cp\u003e- Not-AC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e70 (14%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e3 (4%) \u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 99px;\"\u003e\n \u003cp\u003e64 (28%) \u003csup\u003eb,c\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 237px;\"\u003e\n \u003cp\u003e- Trastuzumab\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e13 (3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 99px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 237px;\"\u003e\n \u003cp\u003eRadiation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 99px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 237px;\"\u003e\n \u003cp\u003e\u0026nbsp;- Right breast or chest wall radiation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e173 (34%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e0\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 99px;\"\u003e\n \u003cp\u003e0\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 237px;\"\u003e\n \u003cp\u003e- Left breast or chest wall radiation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e175 (34%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e1 (1%) \u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 99px;\"\u003e\n \u003cp\u003e0\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 237px;\"\u003e\n \u003cp\u003e- Mediastinal radiation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e1 (\u0026lt;1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e20 (28%) \u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 99px;\"\u003e\n \u003cp\u003e4 (2%) \u003csup\u003ec\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 237px;\"\u003e\n \u003cp\u003eAnthracycline dose, mg/m\u0026sup2;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 99px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 237px;\"\u003e\n \u003cp\u003e- None\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e83 (16%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e3 (4%) \u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 99px;\"\u003e\n \u003cp\u003e64 (28%) \u003csup\u003ec\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 237px;\"\u003e\n \u003cp\u003e- \u0026lt;180\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e20 (4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e10 (14%) \u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 99px;\"\u003e\n \u003cp\u003e43 (19%) \u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 237px;\"\u003e\n \u003cp\u003e- 180\u0026ndash;250\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e370 (72%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e20 (28%) \u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 99px;\"\u003e\n \u003cp\u003e22 (10%) \u003csup\u003eb,c\u003c/sup\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 237px;\"\u003e\n \u003cp\u003e- \u0026gt;250\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e40 (8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e38 (54%) \u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 99px;\"\u003e\n \u003cp\u003e99 (43%) \u003csup\u003eb,c\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 237px;\"\u003e\n \u003cp\u003eTreatment at cancer diagnosis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 99px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 237px;\"\u003e\n \u003cp\u003e- \u0026beta;-blocker\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e48 (9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e3 (4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 99px;\"\u003e\n \u003cp\u003e47 (21%) \u003csup\u003eb,c\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 237px;\"\u003e\n \u003cp\u003e- ACEI or ARBs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e48 (9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e6 (8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 99px;\"\u003e\n \u003cp\u003e49 (22%) \u003csup\u003eb,c\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 237px;\"\u003e\n \u003cp\u003e- Statins\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e50 (10%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e4 (6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 99px;\"\u003e\n \u003cp\u003e38 (17%) \u003csup\u003eb,c\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" style=\"width: 536px;\"\u003e\n \u003cp\u003eAbbreviations: AC\u003c/p\u003e\n \u003cp\u003e\u003csup\u003ea\u003c/sup\u003e Values are mean (SD), median (IQR), or No. of patients (%).\u003c/p\u003e\n \u003cp\u003e\u003csup\u003eb\u003c/sup\u003e \u003cem\u003eP\u003c/em\u003e\u0026lt;.05 vs breast cancer.\u003c/p\u003e\n \u003cp\u003e\u003csup\u003ec\u003c/sup\u003e \u003cem\u003eP\u003c/em\u003e\u0026lt;.05 vs HL\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eNon-CV Death\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe cumulative incidence of non-CV death at 5, 10, and 25 years of follow-up was 0.1%, 4.1%, and 17%, respectively, in the control group; 32.4%, 45.8%, and 68.1% in the no-AC group; and 15.2%, 25%, and 44.4% in the AC group. Among the patients with cancer, 65 of 137 patients in the no-AC group and 148 of 675 patients in the AC group died of complications of cancer or cancer therapy. Analyzing the cumulative incidence of non-CV death with the competing risk of 3-MACE (Figure 1A) and 4-MACE (Figure 2A) showed that the no-AC group had the highest incidence of non-CV death and the control group had the lowest. The pairwise comparisons between all groups were significantly different (all \u003cem\u003eP\u003c/em\u003e\u0026lt;.001). Cox regression analysis confirmed that even after adjusting for sex and age differences, the no-AC group (HR, 9.33; 95% CI, 6.90-12.60; \u003cem\u003eP\u003c/em\u003e\u0026lt;.001) and AC group (HR, 5.87; 95% CI, 4.61-7.47; \u003cem\u003eP\u003c/em\u003e\u0026lt;.001) were at significantly higher risk of non-CV death compared with the control group. Of note, these variations in incidence and risk between the groups should be considered when interpreting the results because a higher incidence of non-CV death reduces the number of patients at risk for MACE, particularly in the no-AC and AC groups.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eAnalysis of 3-MACE\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe cumulative incidence of 3-MACE at 5, 10, and 25 years of follow-up was 3.6%, 7.4%, and 20.6%, respectively, in the control group; 3.8%, 6.6%, and 12.6% in the no-AC group; and 3.4%, 5.1%, and 12.9% in the AC group. The median (IQR) time to 3-MACE was 7.6 (4.3-12.0) years in the control group, 5.6 (3.9-10.3) years in the no-AC group, and 4.7 (2.4-11.0) years in the AC group. The cumulative incidence of 3-MACE was significantly greater for the control group than the AC group when adjusting for the competing risk of non-CV death (\u003cem\u003eP\u003c/em\u003e=.04) but was not different for the other pairwise comparisons (Figure 1B).\u003c/p\u003e\n\u003cp\u003eOn multivariable analysis, no group had an increased risk of 3-MACE compared with another after \u0026gt;25 years of follow-up (Table 2). Several demographic and clinical factors, however, were associated with a higher risk of 3-MACE for the entire cohort, including older age (HR per 5-y increase in age, 1.43; 95% CI, 1.34-1.52; \u003cem\u003eP\u003c/em\u003e\u0026lt;.001), male sex (HR, 1.85; 95% CI, 1.37-2.51; \u003cem\u003eP\u003c/em\u003e\u0026lt;.001), and HTN (HR, 1.56; 95% CI, 1.12-2.19; \u003cem\u003eP\u003c/em\u003e=.008). Smoking history, T2D, CAD, dyslipidemia, and BMI greater than 30 did not significantly affect the risk of 3-MACE. In our subanalysis of 3-MACE within 5 and 10 years of follow-up, the 3 groups again had similar risk of 3-MACE at both time points (Table 2). In addition, at both time points, the increased risk persisted for older age, male sex, and HTN.\u0026nbsp;\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eTable 2.\u003c/strong\u003e Risk Analysis of 3-MACE\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"924\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 264px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eOverall (\u0026gt;25 years of follow up)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 252px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eWithin 5 y of follow-up\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 240px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eWithin 10 y of follow-up\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eRisk factor\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 186px;\"\u003e\n \u003cp\u003eHR (95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 168px;\"\u003e\n \u003cp\u003eHR (95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 162px;\"\u003e\n \u003cp\u003eHR (95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 216px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eUnivariable analysis\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 102px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 168px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 162px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003eBetween-group comparisons\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 186px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 168px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 162px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e- No-AC vs controls\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 186px;\"\u003e\n \u003cp\u003e1.14 (0.62-2.11)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003e.66\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 168px;\"\u003e\n \u003cp\u003e1.37 (0.54-3.46)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e.49\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 162px;\"\u003e\n \u003cp\u003e1.26 (0.61-2.61)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003e.52\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e- AC vs controls\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 186px;\"\u003e\n \u003cp\u003e0.85 (0.60-1.19)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003e.35\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 168px;\"\u003e\n \u003cp\u003e1.17 (0.71-1.92)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e.52\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 162px;\"\u003e\n \u003cp\u003e0.80 (0.53-1.20)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003e.29\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e- AC vs no-AC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 186px;\"\u003e\n \u003cp\u003e0.75 (0.38-1.47)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003e.41\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 168px;\"\u003e\n \u003cp\u003e0.85 (0.32-2.23)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e.74\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 162px;\"\u003e\n \u003cp\u003e0.65 (0.29-1.41)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003e.28\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003eMale sex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 186px;\"\u003e\n \u003cp\u003e2.65 (2.00-3.51)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003e\u0026lt;.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 168px;\"\u003e\n \u003cp\u003e1.08 (1.06-1.10)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e\u0026lt;.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 162px;\"\u003e\n \u003cp\u003e1.08 (1.07-1.10)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003e\u0026lt;.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003eAge (per 5-y increase)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 186px;\"\u003e\n \u003cp\u003e1.52 (1.44-1.61)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003e\u0026lt;.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 168px;\"\u003e\n \u003cp\u003e1.50 (1.34-1.63)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e\u0026lt;.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 162px;\"\u003e\n \u003cp\u003e1.29 (0.90-1.85)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003e\u0026lt;.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003eSmoking history\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 186px;\"\u003e\n \u003cp\u003e1.15 (0.85-1.56)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003e.33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 168px;\"\u003e\n \u003cp\u003e1.26 (0.78-2.04)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e.33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 162px;\"\u003e\n \u003cp\u003e1.29 (0.90-1.85)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003e.15\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003eType 2 diabetes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 186px;\"\u003e\n \u003cp\u003e3.91 (2.70-5.68)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003e\u0026lt;.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 168px;\"\u003e\n \u003cp\u003e3.56 (2.02-6.28)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e\u0026lt;.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 162px;\"\u003e\n \u003cp\u003e4.21 (2.77-6.39)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003e\u0026lt;.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003eHypertension\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 186px;\"\u003e\n \u003cp\u003e4.83 (3.65-6.38)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003e\u0026lt;.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 168px;\"\u003e\n \u003cp\u003e6.86 (4.18-11.27)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e\u0026lt;.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 162px;\"\u003e\n \u003cp\u003e7.07 (4.90-10.22)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003e\u0026lt;.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003eCoronary artery disease\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 186px;\"\u003e\n \u003cp\u003e3.83 (2.17-6.74)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003e\u0026lt;.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 168px;\"\u003e\n \u003cp\u003e3.30 (1.43-7.62)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e.005\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 162px;\"\u003e\n \u003cp\u003e3.53 (1.85-6.72)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003e\u0026lt;.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003eDyslipidemia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 186px;\"\u003e\n \u003cp\u003e2.09 (1.59-2.77)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003e\u0026lt;.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 168px;\"\u003e\n \u003cp\u003e2.65 (1.67-4.22)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e\u0026lt;.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 162px;\"\u003e\n \u003cp\u003e2.50 (1.77-3.53)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003e\u0026lt;.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003eBMI \u0026gt;30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 186px;\"\u003e\n \u003cp\u003e1.44 (1.08-1.90)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003e.01\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 168px;\"\u003e\n \u003cp\u003e1.17 (0.72-1.88)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e.51\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 162px;\"\u003e\n \u003cp\u003e1.47 (1.04-2.07)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003e.02\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" valign=\"top\" style=\"width: 396px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMultivariable analysis\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 252px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 240px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003eBetween-group comparisons\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 186px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 168px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 162px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e- No-AC vs controls\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 186px;\"\u003e\n \u003cp\u003e0.98 (0.53-1.82)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003e.96\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 168px;\"\u003e\n \u003cp\u003e0.90 (0.35-2.28)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e.82\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 162px;\"\u003e\n \u003cp\u003e0.90 (0.43-1.86)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003e.77\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e- AC vs controls\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 186px;\"\u003e\n \u003cp\u003e1.06 (0.74-1.52)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003e.72\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 168px;\"\u003e\n \u003cp\u003e1.40 (0.83-2.35)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e.20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 162px;\"\u003e\n \u003cp\u003e0.96 (0.63-1.47)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003e.87\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e- AC vs no-AC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 186px;\"\u003e\n \u003cp\u003e1.08 (0.55-2.11)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003e.81\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 168px;\"\u003e\n \u003cp\u003e1.55 (0.58-4.14)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e.37\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 162px;\"\u003e\n \u003cp\u003e1.07 (0.48-2.35)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003e.86\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003eAge (per 5-y increase)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 186px;\"\u003e\n \u003cp\u003e1.43 (1.34-1.52)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003e\u0026lt;.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 168px;\"\u003e\n \u003cp\u003e1.36 (1.23-1.51)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e\u0026lt;.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 162px;\"\u003e\n \u003cp\u003e1.38 (1.28-1.49)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003e\u0026lt;.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003eMale sex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 186px;\"\u003e\n \u003cp\u003e1.85 (1.37-2.51)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003e\u0026lt;.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 168px;\"\u003e\n \u003cp\u003e1.64 (1.00-2.69)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e.04\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 162px;\"\u003e\n \u003cp\u003e1.78 (1.23-2.58)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003e.002\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003eSmoking history\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 186px;\"\u003e\n \u003cp\u003e1.25 (0.91-1.73)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003e.16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 168px;\"\u003e\n \u003cp\u003e1.14 (0.68-1.91)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e.60\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 162px;\"\u003e\n \u003cp\u003e1.26 (0.92-2.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003e.11\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003eType 2 diabetes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 186px;\"\u003e\n \u003cp\u003e1.37 (0.91-2.05)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003e.12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 168px;\"\u003e\n \u003cp\u003e1.09 (0.59-2.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e.77\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 162px;\"\u003e\n \u003cp\u003e1.23 (0.78-1.93)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003e.36\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003eHypertension\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 186px;\"\u003e\n \u003cp\u003e1.56 (1.12-2.19)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003e.008\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 168px;\"\u003e\n \u003cp\u003e2.44 (1.35-4.43)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e.003\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 162px;\"\u003e\n \u003cp\u003e2.42 (1.56-3.76)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003e\u0026lt;.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003eCoronary artery disease\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 186px;\"\u003e\n \u003cp\u003e0.74 (0.40-1.36)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003e.33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 168px;\"\u003e\n \u003cp\u003e0.73 (0.29-1.80)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e.50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 162px;\"\u003e\n \u003cp\u003e0.66 (0.33-1.32)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003e.24\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003eDyslipidemia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 186px;\"\u003e\n \u003cp\u003e1.01 (0.74-1.37)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003e.92\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 168px;\"\u003e\n \u003cp\u003e1.15 (0.69-1.89)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e.57\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 162px;\"\u003e\n \u003cp\u003e1.04 (0.71-1.51)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003e.81\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003eBMI \u0026gt;30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 186px;\"\u003e\n \u003cp\u003e1.01 (0.75-1.36)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003e.93\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 168px;\"\u003e\n \u003cp\u003e0.71 (0.43-1.18)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e.19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 162px;\"\u003e\n \u003cp\u003e0.91 (0.63-1.31)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003e.61\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eWe explored the risk of 3-MACE after \u0026gt;25 years of follow up by ACs cumulative dose, radiotherapy and cancer type, adjusting by age, sex and CV comorbidities. We found that when compared to a dose \u0026lt;180 mg/m2 (reference group), a dose range from 180 to 250 mg/m2 (HR, 0.93; 95% CI, 0.31-2.79; P=0.90) and of \u0026nbsp;\u0026gt; 250 mg/m2 (HR, 0.46; 95% CI, 0.18-1.16; P=0.10) were not associated with a higher risk. Chest radiotherapy was not associated with an increased risk of 3-MACE (HR, 0.59; 95% CI, 0.28-1.23; P=0.16). Subjects with HL (HR, 1.86; 95% CI, 0.20-16.90; P=0.58) and with NHL (HR, 1.67; 95% CI, 0.64-4.32; P=0.28) had a similar risk of 3-MACE when compared with those with breast cancer.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eAnalysis of\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cem\u003e4-MACE\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe cumulative incidence of 4-MACE at 5, 10, and 25 years of follow-up was 3.8%, 8.1%, and 23.9%, respectively, in the control group; 5.1%, 8.1%, and 17.5% in the no-AC group; and 5.8%, 9.0%, and 22.0% in the AC group. The median (IQR) time to 4-MACE was 7.8 (4.3-12.5) years in the control group, 5.6 (3.2-11.7) years in the no-AC group, and 4.9 (1.1-10.2) in the AC group. The cumulative incidence of 4-MACE was not significantly different between the groups when adjusting for the competing risk of non-CV death (Figure 2B).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eOn multivariable analysis, the AC group had an increased risk of 4-MACE compared with the control group after \u0026gt;25 years of follow-up (HR, 1.61; 95% CI, 1.21-2.15; \u003cem\u003eP\u003c/em\u003e=.001). However, there was no increased risk for the no-AC group vs controls or the AC group vs the no-AC group. Factors associated with a higher risk of 4-MACE for the entire cohort included older age (HR per 5-y increase in age, 1.44; 95% CI, 1.36-1.52; \u003cem\u003eP\u003c/em\u003e\u0026lt;.001), male sex (HR, 1.55; 95% CI, 1.17-2.04; \u003cem\u003eP\u003c/em\u003e=.001), smoking history (HR, 1.33; 95% CI, 1.04-1.76; \u003cem\u003eP\u003c/em\u003e=.04), T2D (HR, 1.66; 95% CI, 1.18-2.34; \u003cem\u003eP\u003c/em\u003e=.003), and HTN (HR, 1.42; 95% CI, 1.05-1.92; \u003cem\u003eP\u003c/em\u003e=.02) (Table 3). CAD, dyslipidemia, and BMI greater than 30 did not significantly affect the risk of 4-MACE.\u0026nbsp;In our subanalysis of 4-MACE within 5 and 10 years of follow-up, the increased risk of 4-MACE persisted for the AC group vs controls within both 5 and 10 years (Table 3). At 5 and 10 years, older age and HTN were associated with an increased risk of 4-MACE. In addition, male sex, smoking history, and T2D were associated with an increased risk of 4-MACE at 10 years (Table 3).\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eTable 3\u003c/strong\u003e. Risk Analysis of 4-MACE\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"888\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 222px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eOverall (\u0026gt;25 years of follow up)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 204px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eWithin 5 y of follow-up\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 264px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eWithin 10 y of follow-up\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 156px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eRisk factor\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003eHR (95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003eP value\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003eHR (95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003eP value\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003eHR (95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003eP value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eUnivariable analysis\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003eBetween-group comparisons\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e- No-AC vs controls\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e1.34 (0.79-2.27)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e.27\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e1.64 (0.74-3.61)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e.21\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e1.39 (0.72-2.66)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e.31\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e- AC vs controls\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e1.32 (1.01-1.74)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e.04\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e1.70 (1.13-2.57)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e.01\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e1.31 (0.94-1.81)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e.10\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e- AC vs no-AC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e0.98 (0.55-1.71)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e.94\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e1.05 (0.47-2.36)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e.89\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e0.94 (0.48-1.84)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e.86\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003eAge (per 5-y increase)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e1.51 (1.44-1.58)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e\u0026lt;.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e1.50 (1.40-1.62)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e\u0026lt;.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e1.53 (1.45-1.62)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e\u0026lt;.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003eMale sex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e2.28 (1.77-2.94)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e\u0026lt;.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e2.47 (1.66-3.69)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e\u0026lt;.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e2.58 (1.90-3.50)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e\u0026lt;.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 156px;\"\u003e\n \u003cp\u003eSmoking history\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e1.39 (1.07-1.79)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e.01\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e1.42 (0.95-2.14)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e.08\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e1.57 (1.15-2.14)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e.004\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003eType 2 diabetes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e4.61 (3.37-6.32)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e\u0026lt;.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e4.84 (3.08-7.61)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e\u0026lt;.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e5.08 (3.58-7.22)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e\u0026lt;.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003eHypertension\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e4.59 (3.59-5.87)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e\u0026lt;.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e6.66 (4.34-10.20)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e\u0026lt;.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e6.66 (4.83-9.19)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e\u0026lt;.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003eCoronary artery disease\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e5.40 (3.48-8.40)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e\u0026lt;.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e5.87 (3.27-10.52)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e\u0026lt;.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e5.65 (3.50-9.12)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e\u0026lt;.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003eDyslipidemia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e2.11 (1.65-2.70)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e\u0026lt;.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e2.61 (1.75-3.90)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e\u0026lt;.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e2.48 (1.83-3.36)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e\u0026lt;.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003eBMI \u0026gt;30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e1.60 (1.25-2.05)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e\u0026lt;.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e1.41 (0.94-2.11)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e.08\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e1.66 (1.23- 2.25)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e\u0026lt;.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 378px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMultivariable analysis\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 204px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 264px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003eBetween-group comparisons\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e- No-AC vs controls\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e1.14 (0.67-1.96)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e.60\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e1.08 (0.48-2.38)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e.84\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e0.98 (0.51-1.89)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e.96\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e- AC vs controls\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e1.61 (1.21-2.15)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e2.06 (1.13-3.21)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e1.53 (1.09-2.16)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e.01\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e- AC vs no-AC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e1.40 (0.80-2.46)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e.23\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e1.42 (0.63-3.20)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e.39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e1.56 (0.78-3.09)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e.20\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003eAge (per 5-y increase)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e1.44 (1.36-1.52)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e\u0026lt;.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e1.37 (1.26-1.50)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e\u0026lt;.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e1.40 (1.31-1.50)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e\u0026lt;.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003eMale sex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e1.55 (1.17-2.04)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e1.40 (0.91-2.17)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e.12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e1.49 (1.07-2.09)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e.01\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003eSmoking history\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e1.33 (1.04-1.76)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e.04\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e1.08 (0.69-1.69)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e.71\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e1.43 (1.02-2.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e.03\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003eType 2 diabetes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e1.66 (1.18-2.34)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e.003\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e1.51 (0.92-2.49)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e.09\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e1.51 (1.02-2.22)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e.03\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003eHypertension\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e1.42 (1.05-1.92)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e.02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e2.14 (1.27-3.60)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e.004\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e2.11 (1.13-3.10)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e\u0026lt;.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003eCoronary artery disease\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e1.02 (0.63-1.67)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e.91\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e1.31 (0.68-2.52)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e.41\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e1.05 (0.61-1.78)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e.85\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003eDyslipidemia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e0.95 (0.72-1.23)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e.74\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e1.00 (0.64-1.56)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e.97\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e0.94 (0.67-1.32)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e.74\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003eBMI \u0026gt;30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e1.11 (0.85-1.43)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e.42\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e0.80 (0.52-1.23)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e.32\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e0.99 (0.72-1.37)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e.98\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eWe also analyzed the risk of 4-MACE after \u0026gt;25 years of follow up by ACs cumulative dose, radiotherapy and cancer type, considering age, sex and CV comorbidities. Our analysis yielded that compared to a dose \u0026lt;180 mg/m2 (reference group), a dose range from 180 to 250 mg/m2 (HR, 0.64; 95% CI, 0.28-1.43; P=0.28) and of \u0026gt; 250 mg/m2 (HR, 0.70; 95% CI, 0.35-1.40; P=0.32) did not confer a higher risk. We also evaluated the impact of radiotherapy on 4-MACE and found that it was associated with a decreased risk of 4-MACE (HR, 0.49; 95% CI, 0.29-0.85; P\u0026lt;.001). Subjects with HL (HR, 2.21; 95% CI, 0.48-10.03; P=0.30) and with NHL (HR, 1.54; 95% CI, 0.76-3.12; P=0.22) had a similar risk of 4-MACE when compared with those with breast cancer.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eAnalysis of Individual MACE Components\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe cumulative incidence of MI at 5, 10, and 25 years of follow-up was 0.7%, 1.9%, and 4.0%, respectively, in the control group; 0.9%, 5.5%, and 18.2% in the no-AC group; and 1.4%, 1.7%, and 4.4% in the AC group. The risk of MI was similar for the 3 groups (Table 4). Factors associated on multivariable analysis with a higher risk of MI included older age (HR per 5-y increase in age, 1.35; 95% CI, 1.20-1.53; \u003cem\u003eP\u003c/em\u003e\u0026lt;.001) and male sex (HR, 4.21; 95% CI, 2.32-7.64; \u003cem\u003eP\u003c/em\u003e\u0026lt;.001).\u003c/p\u003e\n\u003cp\u003eThe cumulative incidence of stroke at 5, 10, and 25 years of follow-up was 2.7%, 5.5%, and 13.6%, respectively, in the control group; 5.0%, 6.3%, and 9.1% in the no-AC group; and 2.0%, 3.3%, and 11.8% in the AC group. The risk of stroke on multivariable analysis was comparable across the 3 groups (Table 4). Higher risk of stroke was associated with older age (HR per 5-y increase in age, 1.33; 95% CI, 1.23-1.43; \u003cem\u003eP\u003c/em\u003e\u0026lt;.001), HTN (HR, 1.72; 95% CI, 1.13-2.32; \u003cem\u003eP\u003c/em\u003e=.01), and T2D (HR, 1.70; 95% CI, 1.03-2.80; \u003cem\u003eP\u003c/em\u003e=.03).\u003c/p\u003e\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" align=\"\" width=\"978\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"12\" valign=\"top\" style=\"width: 978px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTable 4.\u003c/strong\u003e Risk Analysis for Each Component of 4-MACE\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 162px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 174px;\"\u003e\n \u003cp\u003eMI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 186px;\"\u003e\n \u003cp\u003eStroke\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 186px;\"\u003e\n \u003cp\u003eCV death\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 216px;\"\u003e\n \u003cp\u003eHF\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 162px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eRisk factor\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003eHR (95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eP value\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003eHR (95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003eP value\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003eHR (95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003eP value\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003eHR (95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003eP value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 162px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eUnivariable analysis\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 162px;\"\u003e\n \u003cp\u003eBetween-group comparisons\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 162px;\"\u003e\n \u003cp\u003e- No-AC vs controls\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e2.41 (0.94-6.18)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e.06\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e1.07 (0.49-2.31)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e.85\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e1.04 (0.24-4.37)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e.95\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e2.30 (1.09-4.87)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e.02\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 162px;\"\u003e\n \u003cp\u003e- AC vs controls\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e1.13 (0.59-2.15)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e.70\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e0.70 (0.45-1.10)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e.12\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e0.98 (0.48-2.02)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e.97\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e2.80 (1.87-4.19)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e\u0026lt;.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 162px;\"\u003e\n \u003cp\u003e- AC vs no-AC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e0.53 (0.18-1.53)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e.24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e0.63 (0.27-1.48)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e.29\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e0.84 (0.18-3.86)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e.82\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e1.18 (0.54-2.56)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e.66\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 162px;\"\u003e\n \u003cp\u003eAge (per 5-y increase)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e1.52 (1.37-1.69)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e\u0026lt;.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e1.41 (1.32-1.50)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u0026lt;.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e2.10 (1.80-2.46)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u0026lt;.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e1.55 (1.44-1.67)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e\u0026lt;.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 162px;\"\u003e\n \u003cp\u003eMale sex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e5.77 (3.32-10.01)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e\u0026lt;.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e1.61 (1.10-2.36)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e.01\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e6.20 (3.39-11.32)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u0026lt;.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e2.54 (1.71-3.76)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e\u0026lt;.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 162px;\"\u003e\n \u003cp\u003eSmoking history\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e1.47 (0.83-2.61)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e.18\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e1.21 (0.83-1.75)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e.30\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e0.63 (0.29-1.35)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e.23\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e2.29 (1.56-3.37)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e\u0026lt;.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 162px;\"\u003e\n \u003cp\u003eType 2 diabetes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e5.72 (2.98-10.99)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e\u0026lt;.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e3.96 (2.52-6.24)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u0026lt;.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e5.33 (2.54-11.20)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u0026lt;.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e6.38 (4.04-10.08)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e\u0026lt;.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 162px;\"\u003e\n \u003cp\u003eHypertension\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e5.62 (3.20-9.89)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e\u0026lt;.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e4.08 (2.88-5.77)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u0026lt;.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e8.25 (4.32-5.73)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u0026lt;.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e4.88 (3.30-7.21)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e\u0026lt;.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 162px;\"\u003e\n \u003cp\u003eCoronary artery disease\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e7.43 (3.14-17.56)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e\u0026lt;.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e1.59 (0.58-4.32)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e.35\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e5.86 (2.07-16.52)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u0026lt;.001\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e8.10 (4.50-14.58)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e\u0026lt;.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 162px;\"\u003e\n \u003cp\u003eDyslipidemia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e3.53 (1.99-6.26)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e\u0026lt;.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e1.82 (1.29-2.58)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u0026lt;.001\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e1.95 (1.07-3.57)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e.02\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e2.21 (1.50-3.27)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e\u0026lt;.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 162px;\"\u003e\n \u003cp\u003eBMI \u0026gt;30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e1.53 (0.88-2.67)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e.12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e1.54 (1.08-2.18)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e.01\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e0.94 (0.49-1.80)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e.86\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e1.91 (1.30-2.80)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e\u0026lt;.001\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 336px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMultivariable analysis\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 186px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 186px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 216px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 162px;\"\u003e\n \u003cp\u003eBetween-group comparisons\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 162px;\"\u003e\n \u003cp\u003e- No-AC vs controls\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e1.86 (0.71-4.88)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e.20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e0.91 (0.42-1.98)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e.81\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e1.01 (0.23-4.35)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e.98\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e1.83 (0.85-3.91)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e.11\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 162px;\"\u003e\n \u003cp\u003e- AC vs controls\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e1.50 (0.75-2.99)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e.24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e0.78 (0.49-1.24)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e.30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e2.15 (0.99-4.70)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e.06\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e3.20 (2.08-4.94)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e\u0026lt;.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 162px;\"\u003e\n \u003cp\u003e- AC vs no-AC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e0.80 (0.27-2.33)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e.69\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e0.86 (0.37-2.01)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e.73\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e2.12 (0.45-9.96)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e.33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e1.75 (0.81-3.77)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e.15\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 162px;\"\u003e\n \u003cp\u003eAge (per 5-y increase)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e1.35 (1.20-1.53)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e\u0026lt;.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e1.33 (1.23-1.43)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u0026lt;.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e1.94 (1.63-2.31)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u0026lt;.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e1.48 (1.36-1.62)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e\u0026lt;.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 162px;\"\u003e\n \u003cp\u003eMale sex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e4.21 (2.32-7.64)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e\u0026lt;.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e1.15 (0.77-1.73)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e.47\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e4.23 (2.17-8.25)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u0026lt;.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e1.64 (1.06-2.54)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e.02\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 162px;\"\u003e\n \u003cp\u003eSmoking history\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e1.21 (0.64-2.28)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e.54\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e1.45 (0.98-2.14)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e.06\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e0.67 (0.28-1.57)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e.35\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e1.77 (1.15-2.71)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e.009\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 162px;\"\u003e\n \u003cp\u003eType 2 diabetes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e1.84 (0.90-3.76)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e.09\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e1.70 (1.03-2.80)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e.03\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e1.80 (0.80-4.04)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e.14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e2.43 (1.48-4.02)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e\u0026lt;.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 162px;\"\u003e\n \u003cp\u003eHypertension\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e1.51 (0.77-2.98)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e.22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e1.72 (1.13-2.32)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e.01\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e1.66 (0.81-3.39)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e.16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e1.44 (0.89-2.35)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e.13\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 162px;\"\u003e\n \u003cp\u003eCoronary artery disease\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e0.96 (0.37-2.48)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e.94\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e0.41 (0.14-1.18)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e.10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e0.92 (0.29-2.89)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e.29\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e1.24 (0.63-2.42)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e.52\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 162px;\"\u003e\n \u003cp\u003eDyslipidemia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e1.71 (0.90-3.22)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e.09\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e0.88 (0.60-1.30)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e.54\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e0.88 (0.45-1.77)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e.73\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e0.82 (0.52-1.28)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e.39\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 162px;\"\u003e\n \u003cp\u003eBMI \u0026gt;30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e0.91 (0.50-1.66)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e.76\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e1.09 (0.75-1.56)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e.63\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e0.67 (0.33-1.33)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e.25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e1.17 (0.78-1.76)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e.43\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eThe cumulative incidence of CV death at 5, 10, and 25 years of follow-up was 0.3%, 1.0%, and 6.9%, respectively, in the control group; 0.9%, 2.2%, and 2.2% in the no-AC group; and 0.7%, 1.2%, and 2.6% in the AC group. The risk of CV death did not differ significantly among the 3 groups (Table 4). However, older age (HR per 5-y increase in age, 1.94; 95% CI, 1.63-2.31; \u003cem\u003eP\u003c/em\u003e\u0026lt;.001) and male sex (HR, 4.23; 95% CI, 2.17-8.25; \u003cem\u003eP\u003c/em\u003e\u0026lt;.001) were associated with an increased risk of CV death\u0026nbsp;on multivariable analysis.\u003c/p\u003e\n\u003cp\u003eThe cumulative incidence of HF at 5, 10, and 25 years of follow-up was 0.9%, 2.1%, and 10.5%, respectively, in the control group; 1.9%, 6.3%, and 17.6% in the no-AC group; and 3.2%, 6.1%, and 20.2% in the AC group. The AC group had a higher risk of HF than the control group (HR, 3.20; 95% CI, 2.08-4.94; \u003cem\u003eP\u003c/em\u003e\u0026lt;.001), but risk was not significantly different for other pairwise group comparisons (Table 4). Increased risk of HF was associated with older age (HR per 5-y increase in age, 1.48; 95% CI, 1.36-1.62; \u003cem\u003eP\u003c/em\u003e\u0026lt;.001), male sex (HR, 1.64; 95% CI, 1.06-2.54; \u003cem\u003eP\u003c/em\u003e=.02), smoking history (HR, 1.77; 95% CI, 1.15-2.71; \u003cem\u003eP\u003c/em\u003e=.009), and T2D (HR, 2.43; 95% CI, 1.48-4.02; \u003cem\u003eP\u003c/em\u003e\u0026lt;.001).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eTo our knowledge, this is the first epidemiologic study to evaluate the impact of ACs on the incidence of MACE. We observed no association between AC use and an increase in the incidence of 3-MACE after 25 years of follow-up. Our results show that CV comorbid conditions are the main risk factors for the development of 3-MACE and 4-MACE in our cohort. Regarding 4-MACE, patients treated with ACs had an increased incidence compared with controls given the inclusion of HF in this definition. Our results showed that RT was associated with a decrease risk of 4-MACE, but not 3-MACE. \u003c/p\u003e\n\u003cp\u003eOur findings may be influenced by the higher incidence of non-CV death in the no-AC and AC groups compared with the control group. In particular, the cumulative incidence of non-CV death was much lower in the control group than in the no-AC and AC groups at all time points. Even after adjusting for sex and age differences, the no-AC and AC groups were at significantly higher risk for non-CV death. It is possible that patients in the cancer groups may have died of non-CV causes before experiencing a stroke, MI, or CV death. It is also plausible that patients with cancer treated with ACs had closer monitoring than patients with CV risk factors but without cancer (control group), so that despite the lack of oncologic illness and cardiotoxic drugs, patients with CV risk factors in the control group were at high risk for MACE but had less surveillance in the community setting.\u003c/p\u003e\n\u003cp\u003eGiven the high incidence of non-CV death in the no-AC and AC groups, we analyzed the risk of MACE after 5 and 10 years of follow-up. The risk of 3-MACE was still similar among the 3 groups, but analysis of 4-MACE showed that the AC group had a greater risk than controls, possibly related to the contribution of HF. We previously showed the association of ACs with congestive HF(3) and observed similar findings in this study regarding HF (ie, 4-MACE). \u003c/p\u003e\n\u003cp\u003eOur findings showed that CV comorbid conditions are associated with an increased risk of MACE after 5, 10, and \u0026gt;25 years of follow-up. Older age, male sex, and HTN were linked to 3-MACE at 5, 10, and \u0026gt;25 years of follow-up. Older age and HTN were risk factors for 4-MACE after 5, 10, and \u0026gt;25 years of follow-up, and male sex, smoking history, and T2D were associated with 4-MACE at 10 and \u0026gt;25 years of follow-up. A meta-analysis including 7,488 patients with BC, lymphoma, sarcomas, or gastrointestinal cancer receiving ACs reported that those with HTN, T2D, and obesity had an increased risk of AC-induced cardiotoxicity.(19) Given this, we believe that, in patients with cancer being treated with ACs, CV risk factors should be addressed to decrease the risk not only of MACE but also of AC cardiotoxicity.\u003c/p\u003e\n\u003cp\u003eIn our study, patients in the no-AC group did not have greater risk of 3-MACE or 4-MACE than controls, which suggests that cancer does not increase the risk of MACE, in contrast to other published findings.(10, 11) A possible reason for this difference is that our control group was not a group of healthy persons and were matched by age, sex, and CV comorbid conditions to patients with cancer. The similarity between no-AC patients and controls also may be attributed to a higher prevalence of male patients and HTN in the no-AC group, both of which were associated with an increased risk of MACE in our analysis. \u003c/p\u003e\n\u003cp\u003eInterestingly, we found that the risk of 3-MACE and 4-MACE did not increase with higher anthracycline doses. Moreover, chest radiotherapy was associated with a decreased risk of 4-MACE, but not 3-MACE. This may be explained by the impact of radiotherapy on HF risk, which we investigated in a previous study (3). There, we found that the risk of congestive HF was not dose-dependent and was actually lower in patients who received chest radiotherapy. In our prospective cohort study of newly diagnosed lymphoma patients aged over 18 years with no prior history of CV disease, we examined the association of treatment with anthracyclines or radiotherapy and traditional CV risk factors. Our findings indicated that radiotherapy did not increase the overall risk of CV disease in this population (20). This is also consistent with the results of a large study with 308,861 women with localized or regional breast cancer, from SEER registries (1973\u0026ndash;2001), followed until 2002. They found that radiotherapy regimens used in the 1970s and early 1980s were associated with a significantly increased long-term risk of death from heart disease when compared to treatment with chemotherapy alone. However, this excess risk disappeared by the 1990s, likely due to advances in radiotherapy techniques and the introduction of cardioprotective measures (21).\u003c/p\u003e\n\u003cp\u003eRegarding cancer type, in a previous study we also observed that, in patients with HL and NHL, the risk of congestive HF was comparable to that seen in breast cancer (3). Similarly, in the present study, the risk of 3-MACE and 4-MACE did not differ significantly by cancer type.\u003c/p\u003e\n\u003cp\u003eOur subanalysis for each component of 4-MACE (MI, stroke, CV death, HF) showed that the risk of each was similar among the 3 groups, except the risk of HF in the AC group compared with controls. Patients in the AC group were more than 3 times more likely to have HF, which is consistent with our previously published work (3) showing that this risk is irrespective of the cumulative dose of ACs. \u003c/p\u003e\n\u003cp\u003eA recent SEER-Medicare study evaluated the incidence of MACE in a cohort of 2,215 older women with triple-negative BC treated with ACs and taxane vs taxane-only treatment.(22) The definition of MACE in that study included HF, fatal arrhythmias, MI, and stroke, but not CV death. Patients were followed up for a maximum of 36 months. Similar to our results, patients who received ACs with taxanes were not more likely to experience MACE when controlling for CV risk factors, which underscores the importance of CV comorbid conditions before chemotherapy. Additionally, the authors showed that diabetes increased the risk of MI and stroke. Interestingly, they reported that patients who received ACs with taxanes were less likely to have HF. The authors suggest that this may be influenced by current practices that assess patients for CV comorbid conditions before starting ACs and treating only those without substantial cardiac problems.(22) Our study followed patients up for a considerably longer period and is population-based; additionally, we included a control group without cancer. \u003c/p\u003e\n\u003cp\u003eOur study has several limitations. Our population is primarily female, so results regarding men should be interpreted with caution. Additionally, the AC and no-AC groups are substantially smaller than the control group, which may affect the reliability of the results. Moreover, our analysis does not distinguish between different subtypes of BC, HL, or NHL or consider distinct cancer stages, treatment duration, or radiotherapy. Additionally, 13 patients in the AC group were treated with trastuzumab as first line chemotherapy agent; given the small sample size, no conclusions can be made regarding MACE and this medication. \u003c/p\u003e\n\u003cp\u003eStrengths of our study include being population-based and facilitated by the REP, which benefits from large sample size, a uniform health care environment, and long-term follow-up. These features enhance the ability to assess the effects of health interventions in routine practice.(23) Such studies typically offer strong external validity, which makes our findings more generalizable to broader populations with similar demographics as Olmsted County.(23, 24) However, the internal validity of these studies may be limited by potential confounding factors.(23) Even though a population-based study can limit the racial and ethnic diversity of a cohort, our population is demographically similar to the Framingham Heart Study cohort.(25) We highlight the presence in our study of a control group without cancer, as well as the long follow-up period. It would be interesting to have longer follow-up for patients who did not die of non-CV causes and compare the incidence of MACE with controls or cancer patients not treated with ACs.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eOur findings indicate that patients treated with ACs had a similar incidence of 3-MACE compared with controls and cancer patients not treated with ACs. These results may be influenced by the higher incidence of non-CV death in the cancer groups, which could limit the number of patients at risk for MACE. We also confirmed that ACs are a significant risk factor for the development of HF. Of additional high clinical relevance, CV risk factors were the main drivers of 3-MACE at 5, 10, and \u0026gt;25 years of follow. Our findings underscore the importance of promoting healthy habits and implementing lifestyle changes among patients with cancer. It is important, however, to interpret our results within the context of Olmsted County\u0026rsquo;s health care environment.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eLarger and, ideally, prospective studies are needed to establish causative relationships and fully understand the impact of ACs on MACE. We advocate for a broader approach in cardio-oncology that not only examines the association between ACs and HF but also explores other potential forms of cardiotoxicity.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eAC, anthracycline\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eBC, breast cancer\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eBMI, body mass index\u003c/p\u003e\n\u003cp\u003eCAD, coronary artery disease\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eCV, cardiovascular\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eHF, heart failure\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eHL, Hodgkin lymphoma\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eHR, hazard ratio\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eHTN, hypertension\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eMACE, major adverse cardiovascular events\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eMI, myocardial infarction\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eNHL, non-Hodgkin lymphoma\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eREP, Rochester Epidemiology Project\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eT2D, type 2 diabetes\u0026nbsp;\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003e\u003cem\u003eEthics approval and consent to participate\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was approved by the institutional review boards of Mayo Clinic and Olmsted Medical Center. Per Minnesota law, all participants agreed to the use of their data for research purposes, and those who did not consent were not included.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eConsent for publication\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eAvailability of data and materials\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll relevant data supporting the findings of this study are reported within the article or are available from the corresponding author upon reasonable request. \u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eCompeting interests\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003e \u003c/em\u003e\u003c/strong\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eFunding\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eAuthors\u0026apos; contributions\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eETG performed the statistical analysis and was the main responsible for the writing of the manuscript. AEDA, MFGA, and CR\u003csup\u003e \u003c/sup\u003econtributed with writing and editing of the manuscript\u003c/p\u003e\n\u003cp\u003eCML, JM, TCH and CAT supported data curation. JRC reviewed the statistical analysis and editing of the manuscript. HRV led the conceptualization, data curation, statistical analysis, methodology, project administration and editing of the manuscript. All authors read and approved the final manuscript\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eAcknowledgements\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study used the resources of the Rochester Epidemiology Project (REP) medical records linkage system, which is supported by the National Institute on Aging (NIA; AG 058738), by the Mayo Clinic Research Committee, and by fees paid annually by REP users. The content of this article is solely the responsibility of the authors and does not represent the official views of the National Institutes of Health (NIH) or Mayo Clinic.\u003c/p\u003e\n\u003cp\u003eFor this study we received statistical advice from the Mayo Clinic Center for Clinical and Translational Science (CCaTS). The Scientific Publications staff at Mayo Clinic provided editorial consultation, proofreading, and administrative and clerical support.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eBowles EJ, Wellman R, Feigelson HS, Onitilo AA, Freedman AN, Delate T, et al. Risk of heart failure in breast cancer patients after anthracycline and trastuzumab treatment: a retrospective cohort study. J Natl Cancer Inst. 2012;104(17):1293-305.\u003c/li\u003e\n\u003cli\u003eHo E, Brown A, Barrett P, Morgan RB, King G, Kennedy MJ, et al. Subclinical anthracycline- and trastuzumab-induced cardiotoxicity in the long-term follow-up of asymptomatic breast cancer survivors: a speckle tracking echocardiographic study. Heart. 2010;96(9):701-7.\u003c/li\u003e\n\u003cli\u003eLarsen CM, Garcia Arango M, Dasari H, Arciniegas Calle M, Adjei E, Rico Mesa J, et al. Association of Anthracycline With Heart Failure in Patients Treated for Breast Cancer or Lymphoma, 1985-2010. JAMA Netw Open. 2023;6(2):e2254669.\u003c/li\u003e\n\u003cli\u003eSwain SM, Whaley FS, Ewer MS. Congestive heart failure in patients treated with doxorubicin: a retrospective analysis of three trials. Cancer. 2003;97(11):2869-79.\u003c/li\u003e\n\u003cli\u003ePinder MC, Duan Z, Goodwin JS, Hortobagyi GN, Giordano SH. Congestive heart failure in older women treated with adjuvant anthracycline chemotherapy for breast cancer. J Clin Oncol. 2007;25(25):3808-15.\u003c/li\u003e\n\u003cli\u003eLotrionte M, Biondi-Zoccai G, Abbate A, Lanzetta G, D\u0026apos;Ascenzo F, Malavasi V, et al. Review and meta-analysis of incidence and clinical predictors of anthracycline cardiotoxicity. Am J Cardiol. 2013;112(12):1980-4.\u003c/li\u003e\n\u003cli\u003eKoene RJ, Prizment AE, Blaes A, Konety SH. Shared Risk Factors in Cardiovascular Disease and Cancer. Circulation. 2016;133(11):1104-14.\u003c/li\u003e\n\u003cli\u003eWilcox NS, Amit U, Reibel JB, Berlin E, Howell K, Ky B. Cardiovascular disease and cancer: shared risk factors and mechanisms. Nat Rev Cardiol. 2024;21(9):617-31.\u003c/li\u003e\n\u003cli\u003eAl-Kindi SG, Oliveira GH. Prevalence of Preexisting Cardiovascular Disease in Patients With Different Types of Cancer: The Unmet Need for Onco-Cardiology. Mayo Clin Proc. 2016;91(1):81-3.\u003c/li\u003e\n\u003cli\u003eZaorsky NG, Zhang Y, Tchelebi LT, Mackley HB, Chinchilli VM, Zacharia BE. Stroke among cancer patients. Nat Commun. 2019;10(1):5172.\u003c/li\u003e\n\u003cli\u003eBima P, Lopez-Ayala P, Koechlin L, Boeddinghaus J, Nestelberger T, Okamura B, et al. Chest Pain in Cancer Patients: Prevalence of Myocardial Infarction and Performance of High-Sensitivity Cardiac Troponins. JACC CardioOncol. 2023;5(5):591-609.\u003c/li\u003e\n\u003cli\u003eFelker GM, Thompson RE, Hare JM, Hruban RH, Clemetson DE, Howard DL, et al. Underlying causes and long-term survival in patients with initially unexplained cardiomyopathy. N Engl J Med. 2000;342(15):1077-84.\u003c/li\u003e\n\u003cli\u003eSchreiber AR, Kagihara J, Eguchi M, Kabos P, Fisher CM, Meyer E, et al. Evaluating anthracycline + taxane versus taxane-based chemotherapy in older women with node-negative triple-negative breast cancer: a SEER-Medicare study. Breast Cancer Res Treat. 2022;191(2):389-99.\u003c/li\u003e\n\u003cli\u003eBosco E, Hsueh L, McConeghy KW, Gravenstein S, Saade E. Major adverse cardiovascular event definitions used in observational analysis of administrative databases: a systematic review. BMC Med Res Methodol. 2021;21(1):241.\u003c/li\u003e\n\u003cli\u003eBooth CM, Tannock IF. Randomised controlled trials and population-based observational research: partners in the evolution of medical evidence. Br J Cancer. 2014;110(3):551-5.\u003c/li\u003e\n\u003cli\u003eSorlie P, Wei GS. Population-based cohort studies: still relevant? J Am Coll Cardiol. 2011;58(19):2010-3.\u003c/li\u003e\n\u003cli\u003eRocca WA, Yawn BP, St Sauver JL, Grossardt BR, Melton LJ, 3rd. History of the Rochester Epidemiology Project: half a century of medical records linkage in a US population. Mayo Clin Proc. 2012;87(12):1202-13.\u003c/li\u003e\n\u003cli\u003eJacobsen SJ, Xia Z, Campion ME, Darby CH, Plevak MF, Seltman KD, et al. Potential effect of authorization bias on medical record research. Mayo Clin Proc. 1999;74(4):330-8.\u003c/li\u003e\n\u003cli\u003eYawn BP, Yawn RA, Geier GR, Xia Z, Jacobsen SJ. The impact of requiring patient authorization for use of data in medical records research. J Fam Pract. 1998;47(5):361-5.\u003c/li\u003e\n\u003cli\u003eBoddicker NJ, Larson MC, Castellino A, Herrmann J, Inwards DJ, Thanarajasingam G, et al. Anthracycline treatment, cardiovascular risk factors and the cumulative incidence of cardiovascular disease in a cohort of newly diagnosed lymphoma patients from the modern treatment era. Am J Hematol. 2021;96(8):979-88.\u003c/li\u003e\n\u003cli\u003eDarby SC, McGale P, Taylor CW, Peto R. Long-term mortality from heart disease and lung cancer after radiotherapy for early breast cancer: prospective cohort study of about 300,000 women in US SEER cancer registries. Lancet Oncol. 2005;6(8):557-65.\u003c/li\u003e\n\u003cli\u003eSt Sauver JL, Grossardt BR, Yawn BP, Melton LJ, 3rd, Rocca WA. Use of a medical records linkage system to enumerate a dynamic population over time: the Rochester epidemiology project. Am J Epidemiol. 2011;173(9):1059-68.\u003c/li\u003e\n\u003cli\u003eQiu S, Zhou T, Qiu B, Zhang Y, Zhou Y, Yu H, et al. Risk Factors for Anthracycline-Induced Cardiotoxicity. Front Cardiovasc Med. 2021;8:736854.\u003c/li\u003e\n\u003cli\u003eRoy S, Lakritz S, Schreiber AR, Kuna EM, Bradley CJ, Kondapalli L, et al. Major cardiovascular adverse events in older adults with early-stage triple-negative breast cancer treated with adjuvant taxane + anthracycline versus taxane-based chemotherapy regimens: A SEER-medicare study. Eur J Cancer. 2024;196:113426.\u003c/li\u003e\n\u003cli\u003eMcKee PA, Castelli WP, McNamara PM, Kannel WB. The natural history of congestive heart failure: the Framingham study. N Engl J Med. 1971;285(26):1441-6.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"anthracycline, cardio-oncology, MACE, myocardial infarction, stroke","lastPublishedDoi":"10.21203/rs.3.rs-6778136/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6778136/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eAnthracyclines (ACs) are a risk factor for heart failure (HF), but their impact on broader composite outcomes such as major adverse cardiovascular events (MACE) remain less well characterized. From the Rochester Epidemiology Project, we identified patients with breast cancer or lymphoma to assess for association between AC use and MACE in these patients with \u0026gt;\u0026thinsp;25 years of follow-up.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eWe identified patients with cancer, with or without an AC as first-line treatment, and a control group of individuals without cancer, matched by age, sex, and cardiovascular comorbid conditions to the cancer patients. Outcomes of interest were \u003cem\u003e3-MACE\u003c/em\u003e (myocardial infarction, stroke, and cardiovascular death), and \u003cem\u003e4-MACE\u003c/em\u003e (3-MACE plus HF). Cox regression analysis was used to identify variables associated with MACE at 5, 10, and 25 years of follow-up.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eOf 812 patients with cancer, 675 had AC treatment (AC group) and 137 did not (no-AC group); the control group comprised 1,384 matched patients without cancer. The risk of 3-MACE was similar among the 3 groups at all time points. Older age, male sex, and hypertension were associated with 3-MACE. The risk of 4-MACE was similar between the control and no-AC groups; the risk was increased for the AC group vs controls at all time points. Older age, male sex, smoking history, type 2 diabetes, and hypertension were associated with 4-MACE.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eCardiovascular risk factors are the main drivers of 3-MACE and ACs increase the risk of 4-MACE given their association with HF. This underscores the importance of implementing lifestyle changes among these patients.\u003c/p\u003e","manuscriptTitle":"Major Adverse Cardiovascular Events in Patients Treated With Anthracyclines for Breast Cancer or Lymphoma: 25-Year Follow-Up","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-06-10 14:45:21","doi":"10.21203/rs.3.rs-6778136/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"91275285-ddf0-4bcc-8647-8143f694d8db","owner":[],"postedDate":"June 10th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-07-11T18:38:23+00:00","versionOfRecord":[],"versionCreatedAt":"2025-06-10 14:45:21","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6778136","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6778136","identity":"rs-6778136","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}