International Journal of Obesity (2014) 38, 432–437 & 2014 Macmillan Publishers Limited All rights reserved 0307-0565/14 www.nature.com/ijo

ORIGINAL ARTICLE Association of anemia with the risk of cardiovascular adverse events in overweight/obese patients

SA Winther1, N Finer2, AM Sharma3, C Torp-Pedersen4 and C Andersson1

OBJECTIVE: Anemia is associated with increased cardiovascular risks. Obesity may cause anemia in several ways, for example, by low-grade inflammation and relative deficit. The outcomes associated with anemia in overweight/obese patients at high cardiovascular risk are however not known. Therefore, we investigated the cardiovascular prognosis in overweight/obese subjects with anemia. METHODS: A total of 9 687 overweight/obese cardiovascular high-risk patients from the Sibutramine Cardiovascular OUTcomes trial were studied. Patients were stratified after baseline level and followed for the risks of primary event (comprising nonfatal , nonfatal , resuscitated cardiac arrest or cardiovascular death) and all-cause mortality. Risk estimates (hazard ratios (HR) with 95% confidence intervals (CI)) were calculated using Cox regression models. RESULTS: Anemia was unadjusted associated with increased risk for the primary event, HR 1.73 (CI 1.37–2.18) and HR 2.02 (CI 1.34–3.06) for patients with mild or moderate-to-severe anemia, respectively, compared with patients without anemia. Adjusted for several confounders, anemia remained of prognostic importance. Increased risk of the primary events appeared to be driven by risk of cardiovascular death, adjusted HR 1.82 (CI 1.33–2.51) for mild anemia and adjusted HR 1.65 (CI 0.90–3.04) for moderate-to-severe anemia, and all-cause mortality, adjusted HR 1.50 (CI 1.17–1.93) for mild and adjusted HR 1.61 (CI 1.04–2.51) for moderate-to-severe anemia. While adding serum to the models, the increased risk of mild anemia was still a significant predictor for mortality (cardiovascular and all-cause), whereas moderate-to-severe anemia was not. For the primary events, anemia was no longer of independent prognostic importance when including serum creatinine. CONCLUSION: Anemia is associated with an increased risk of long-term adverse cardiovascular events and deaths among overweight/obese cardiovascular high-risk patients. The increased risk appeared to be driven by the risk of cardiovascular death and all-cause mortality, and renal impairments seemed to have a role in the increased risk.

International Journal of Obesity (2014) 38, 432–437; doi:10.1038/ijo.2013.111 Keywords: anemia; cardiovascular disease; cardiovascular death; epidemiology

INTRODUCTION large population of overweight or obese, cardiovascular high-risk Anemia is a well-known independent predictor of a poor outcome patients. in patients with cardiovascular diseases as well in the general population. Among the elderly, anemia is common and has been associated with hospitalization and mortality;1–5 in the general population, anemia is an independent risk factor for METHODS cardiovascular disease6 and in patients with acute coronary Patients syndrome, failure or stroke, anemia is an independent risk The Sibutramine Cardiovascular OUTcomes (SCOUT) trial was a factor for mortality.7–9 prospective, randomized, double-blind, placebo-controlled clinical Overweight and obesity are also major health problems and are study of overweight and obese patients at increased risk of in the general population associated with a higher mortality rate.10 cardiovascular outcome conducted between January 2003 and Obesity-related inflammation, increased iron requirements and March 2009 in 16 countries worldwide. The purpose of the trial impaired iron absorption may increase the risk of anemia in was to investigate the cardiovascular consequences of weight overweight and obese individuals11–15 and may thereby management with and without the weight-lowering drug contribute to the adverse prognosis found for overweight and sibutramine in these overweight and obese patients with an obese patients.10,16 Despite this, the prevalence and importance of increased risk of adverse cardiovascular outcome. Details of the anemia in overweight and obese individuals with a high SCOUT trial have been published previously.17 Eligible subjects for cardiovascular risk profile is, to our knowledge, not known. the study included men and women, X55 years of age, with a Therefore, we investigated the association between anemia and body mass index (BMI) X27 and p45 kg m À 2. Subjects with a BMI the risk of developing cardiovascular adverse events or death in a X25 and p27 kg m À 2 in men and women, plus a waist

1Department of , Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark; 2Institute of Cardiovascular Science, University College London, London, UK; 3Royal Alexandra Hospital, University of Alberta, Edmonton, Alberta, Canada and 4Institute of Health, Science and Technology, Aalborg University, Aalborg, Denmark. Correspondence: Dr SA Winther, Department of Cardiology, Gentofte Hospital, University of Copenhagen, Post 635, Niels Andersens Vej 65, Hellerup, Copenhagen 2900, Denmark. E-mail: [email protected] Received 19 January 2013; revised 16 April 2013; accepted 2 June 2013; accepted article preview online 18 June 2013; advance online publication, 9 July 2013 Association of anemia with the risk of cardiovascular adverse events SA Winther et al 433 circumference of at least 88 cm in the case of women and 102 cm (that is, metformin), sulfonylureas and meglitinides. The category in the case of men were also eligible. of aspirin included drug classes of aspirin, any anticoagulant Subjects were required to have a history of cardiovascular agents and any antiplatelet drugs. Model assumptions, that is, disease (defined as , peripheral arterial proportional hazards, linearity of continuous variables and no two- occlusive disease or stroke) or a diagnosis of type 2 diabetes way interactions were tested and found valid, unless otherwise together with at least one other risk factor (hypertension, reported. All statistical analyses were performed with SAS software dyslipidemia, current smoker or diabetic nephropathy). A lower- versions 9.1 and 9.2 (SAS Institute, Cary, NC, USA). All tests were than-expected event rate forced a change in the inclusion criteria two-sided and P-values of less than 0.05 were required to reject of subjects with both cardiovascular disease and type 2 diabetes. the null hypothesis. Subjects with symptoms of greater than the New York Heart Association (NYHA) class II, uncontrolled hypertension Ethics (4160/100 mm Hg) or (4100 b.p.m.), recent history The study was performed in conformity with the Declaration of of cardiovascular events or symptoms ( 3 months), scheduled o Helsinki and was approved by all relevant ethical committees. cardiac , as well as those with a history of recent weight Written informed consent was obtained from all patients before loss (43 kg in the 3 months prior to screening) were excluded. participating. The SCOUT trial is registered at ClinicalTrials.gov Concomitant medical conditions such as hypertension and number NCT00234832. diabetes were to be treated in accordance with local guidelines. Prior to randomization, a medical history and physical examination including samples for biochemistry, urine RESULTS analyses and vital parameters were obtained for all patients. A total of 9 804 patients underwent randomization at baseline to Measurements of hemoglobin were obtained at randomization placebo or sibutramine. Baseline hemoglobin measurements were (baseline) and thereafter annually during the trial. Serum missing in 117 patients, leaving 9 687 patients for analysis. The creatinine was used as the measure of renal function, as eGFR is median follow-up time after randomization was 4.6 years shown to be a poor measurement of renal function in obese (interquartile range 3.7–5.0 years). A total of 1 036 patients individuals.18 experienced a primary outcome, including 444 with cardiovascular Subjects were followed until the final visit, which was between death, 353 with nonfatal myocardial infarction, 221 with nonfatal November 2008 and March 2009. stroke and 18 with resuscitated cardiac arrest. In addition, 810 The maximum follow-up time was 72 months. The primary patients (8.4%) died from any cause. outcome events were defined as the first occurrence of nonfatal The population consisted of 58% men, with median age of 62 myocardial infarction, nonfatal stroke, resuscitated cardiac arrest years (interquartile range 58–67 years). Median BMI was or cardiovascular death. Mortality of any cause was a secondary 34 kg cm À 2 (interquartile range 31–37 kg cm À 2), 84% had a outcome. history of type 2 diabetes, 88% had hypertension and 75% had a history of cardiovascular disease. Baseline characteristics of the Definition of anemia patients in relation to anemia severity are shown in Table 1. Hemoglobin (Hgb) was measured in mmol l À 1. For the present Anemia was associated with increasing age and in general analysis exploring the impact of anemia severity on prognosis, associated to several risk factors such as history of type 2 diabetes, subjects were stratified into one of the three groups according to hypertension, cardiovascular disease (primarily, peripheral arterial their baseline Hgb level. Anemia was defined according to the occlusive disease and stroke), CHF and use of glucose-lowering World Health Organization (WHO) as Hgbp120 g l À 1 in women agents and diuretics compared with patients without anemia. (7.32 mmol l À 1) andp130 g l À 1 in men (7.93 mmol l À 1). Severity Patients with anemia were more likely to have a lower diastolic was defined according to the subdivisions from WHO; due to very blood pressure, lower levels of low-density lipoprotein cholesterol, few cases of severe anemia, moderate and severe anemia groups high-density lipoprotein cholesterol and cholesterol, lower levels were merged to define: no anemia: Hgb X7.32 mmol l À 1 in of triglycerides, lower red count and higher serum women and Hgb X7.93 in men, mild anemia: 6.71pHgbo7.32 in creatinine. Patients with moderate-to-severe anemia had the women and 7.32pHgbo7.93 in men, and moderate-to-severe highest frequency of cardiovascular disease, history of type 2 anemia: Hgb o6.71 in women and Hgb o7.32 in men. diabetes and CHF, and use of insulin.

Statistics Anemia in relation to cardiovascular events Baseline characteristics between the anemia severity groups were In the univariate Cox proportional hazards model, both groups compared using either a Kruskal–Wallis test or a w2 test for with anemia (that is, the mild anemia and the moderate-to-severe continuous and discrete variables, respectively. Survival curves anemia groups) had increased risk of the primary outcome were presented using a Kaplan–Meier plot stratified by anemia compared with the group without anemia (Table 2). This severity, and a log-rank test was used to assess whether the association was also demonstrated in the Kaplan–Meier curves survival curves in the different anemia severity groups were showing the proportion of primary outcome event-free individuals statistically different. Cox proportional hazards models were used in each of the three anemia severity groups (Figure 1). Having to estimate the association between anemia severity and the anemia was associated with increased likelihood of having a primary outcome events, as well as its individual components. The cardiovascular event (log-rank test: P-value o0.0001), but there associations were estimated as hazard ratios (HR) with 95% seemed to be no substantial difference between the levels of confidence intervals (CI). Cox proportional hazards models were anemia (that is, mild vs moderate-to-severe anemia). The adjusted for the following demographic and baseline character- univariate Cox regression model showed the same trend; there istics: age, sex, BMI, waist–hip ratio, total cholesterol, high-density was no statistically significant difference between the levels of lipoprotein cholesterol, low-density lipoprotein cholesterol, trigly- anemia on the risk of a cardiovascular event; thus, the mild anemia cerides, serum creatinine, systolic blood pressure, diastolic blood group had a HR of 1.73 (CI 1.37–2.18) and the moderate-to-severe pressure, heart rate, history of hypertension, type 2 diabetes, anemia group had a HR of 2.02 (CI 1.34–3.06), compared with the cardiovascular disease and congestive heart failure (CHF), use of group without anemia. alcohol, smoking, use of diuretics, aspirin, insulin and oral glucose- In a multivariable Cox regression model controlling for age and lowering agents, which included thiazolidinediones, biguanides gender, there was also a similar and significantly increased risk in

& 2014 Macmillan Publishers Limited International Journal of Obesity (2014) 432 – 437 Association of anemia with the risk of cardiovascular adverse events SA Winther et al 434 Table 1. Baseline characteristics for the study cohort stratified by baseline anemia

No anemia Mild anemia Moderate-to-severe anemia P-value

n ¼ 9 103 (94%) n ¼ 463 (5%) n ¼ 121 (1%)

Age (years) 62 (58–67) 65 (60–70) 66 (62–71) o0.0001 Males 5 243 (58%) 268 (58%) 75 (62%) 0.622 BMI (kg m À 2) 33.8 (31.0–37.4) 33.8 (30.8–37.4) 33.5 (30.5–36.6) 0.591 Weight (kg) 95.0 (85.5–105.8) 93.2 (83.5–104.5) 93.1 (84.4–103.1) 0.028 Waist circumference men (cm) 113 (107–121) 113 (107–122) 114 (104–123) 0.868 Waist circumference women (cm) 109 (101–117) 110 (103–118) 109 (102–117) 0.440 Waist–hip ratio, men 1.02 (0.98–1.06) 1.02 (0.98–1.06) 1.02 (0.98–1.04) 0.504 Waist–hip ratio, women 0.91 (0.87–0.96) 0.92 (0.88–0.98) 0.93 (0.91–0.97) 0.016

Comorbidity Hypertension 7 995 (88%) 430 (93%) 112 (93%) 0.002 Diabetes mellitus type 2 7 557 (83%) 418 (90%) 115 (95%) o0.0001 Cardiovascular disease 6 805 (75%) 357 (77%) 102 (84%) 0.031 Coronary artery disease 5 887 (65%) 298 (64%) 82 (68%) 0.769 Previous stroke 806 (9%) 49 (11%) 19 (16 %) 0.016 Peripheral arterial occlusive disease 1 225 (13%) 87 (19%) 26 (21%) 0.0002 Congestive heart failure 754 ( 8%) 55 (12%) 23 (19%) o0.0001 Dyslipidemia 7 392 (81%) 369 (80%) 99 (82%) 0.708 Use of alcohol 5 623 (62%) 269 (58%) 71 (59%) 0.372 Smokers 5 309 (58%) 248 (54%) 77 (64%) 0.216

Pharmacological treatment Use of aspirin 7 140 (78%) 377 (81%) 104 (86%) 0.045 Use of diuretics 4 270 (47 %) 273 (59%) 72 (60%) o0.0001 Use of insulin 2 203 (24 %) 182 (39%) 56 (46%) o0.0001 Use of oral glucose-lowering agents 5 283 (58%) 313 (68%) 82 (68%) o0.0001 Use of sibutramine 4 547 (50%) 244 (53%) 60 (50%) 0.511 Blood pressure, systolic (mm Hg) 140 (130–148) 140 (129–148) 135 (128–150) 0.654 Blood pressure, diastolic (mm Hg) 80 (73–84.0) 75 (69–81) 72 (67–80.0) o0.0001 Heart rate (bpm) 71 (64–78) 71 (64–78) 71 (66–80) 0.463 Hgb (mmol l À 1) 8.88 (8.38–9.32) 7.45 (7.14–7.70) 6.71 (6.46–7.02) o0.0001 Creatinine (mmol l À 1) 88 (75–101) 100 (81–130) 114 (97–139) o0.0001 Triglycerides (mmol l À 1) 1.94 (1.45–2.66) 1.86 (1.34–2.62) 1.59 (1.22–2.34) 0.0002 LDL-C (mmol l À 1) 106.3 (85.1–133.4) 95.5 (75.4–119.9) 81.2 (67.7–106.7) o0.0001 HDL-C (mmol l À 1) 44.9 (38.7–52.6) 43.7 (36.7–51.0) 40.6 (34.4–50.3) o0.0001 Total cholesterol (mmol l À 1) 4.94 (4.27–5.72) 4.59 (3.95–5.40) 4.15(3.61–4.97) o0.0001 Abbreviations: DM, diabetes mellitus; the category of oral glucose-lowering agents includes thiazolidinediones, biguanides (that is, metformin), sulfonylureas and meglitinide. Hgb, hemoglobin; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol. Values are stated as median (interquartile range, IQR) and number (percent). The P-values are from Kruskal–Wallis test for continuous variables and by w2 test for categorical variables.

the two anemia groups, HR 1.57 (CI 1.24–1.97) and HR 1.78 (CI Overall, the relative risk of dying of any cause associated with 1.18–2.69), respectively. Further potential confounders (see anemia was less than the risk of dying a cardiovascular death. Table 2) were added to the model first separately and then The risk of nonfatal myocardial infarction was only increased for simultaneously, which attenuated the increased risk in the anemia the moderate-to-severe anemia group in Models 1 and 2 (Table 3). groups, HR 1.39 (CI 1.10–1.77) and 1.58 (CI 1.04–2.40), but did not Adjusting for further baseline characteristics made the association change the overall finding that anemia was a significant predictor nonsignificant. As regards nonfatal stroke alone, there was no of cardiovascular adverse events. When serum creatinine was significant difference between patients with anemia compared added as a covariate to the model, the increased risk associated with those without. Considering resuscitated cardiac arrest, there with anemia was no longer statistically significant. were only a few events with none in the moderate-to-severe Considering individual components of the primary outcome, anemia group (hence, no Cox regression models on this end point there were associations between anemia and nonfatal myocardial were performed). infarction, cardiovascular death and all-cause mortality (Table 3). In addition, there seemed to be no substantial difference in anemia severity for the increased risk of cardiovascular death and all-cause Other analyses mortality. The relation to cardiovascular death was overall stronger The same Cox proportional hazards models were applied using than that to the primary outcome and was significant in both hemoglobin levels measured after 1 year of follow-up stratified anemia groups and all models, with the exception of the according to the WHO anemia criteria. The prognostic importance moderate-to-severe anemia group when controlling for baseline of anemia was reflected in the fully adjusted model; HR 1.52 (CI characteristics (Table 3). The increased risk of all-cause mortality 1.20–1.92) for mild anemia and HR 1.42 (CI 1.01–2.01) for associated with anemia was significant for both the univariate and moderate-to-severe anemia. multivariate Cox regression models. In the fully adjusted model the Relations between hemoglobin levels and BMI were investi- relation persisted, showing a lower but still significantly increased gated and showed that there was only a weak relationship risk of death in the mild anemia group, HR 1.31 (CI 1.02–1.70). between hemoglobin levels and BMI, with a linear regression

International Journal of Obesity (2014) 432 – 437 & 2014 Macmillan Publishers Limited Association of anemia with the risk of cardiovascular adverse events SA Winther et al 435 Table 2. Association between anemia and the primary outcome event evaluated using Cox proportional hazards regression

Model Hazard P-value 95% CI ratio

Model 1: No anemia 1.0 (ref.) — — Mild anemia 1.73 o0.0001 1.37–2.18 Moderate-to-severe 2.02 0.0009 1.34–3.06 anemia

Model 2: No anemia 1.0 (ref.) — — Mild anemia 1.57 0.0002 1.24–1.97 Moderate-to-severe 1.78 0.0065 1.18–2.69 anemia

Model 3: No anemia 1.0 (ref.) — — Mild anemia 1.39 0.006 1.10–1.77 Moderate-to-severe 1.58 0.034 1.04–2.40 anemia

Model 4: Figure 1. Kaplan–Meier curves for primary outcome events. No anemia 1.0 (ref.) — — Mild anemia 1.26 0.064 0.99–1.60 Moderate-to-severe 1.23 0.354 0.80–1.89 which anemia was an independent predictor of mortality both in- anemia hospital and at 30 days even after adjusting for confounders in the 19 Primary outcome events ¼ Myocardial infarction, stroke, cardiovascular multivariable Cox regression model. Owing to the importance of death and resuscitated cardiac arrest. Cutoff points for groups of anemia: this finding, the authors suggested anemia to be part of a see main text. Ref ¼ reference. Model 1: Anemia. Model 2: As model 1 þ prognostic score (the GRACE risk score) for patients with ACS. age and sex. Model 3: As model 2 þ BMI, waist–hip ratio, total cholesterol, In patients with heart failure, anemia is common and also an HDL-C, LDL-C, triglycerides, systolic blood pressure, diastolic blood independent prognostic factor for death,21 even though the pressure, heart rate, history of hypertension, type 2 diabetes mellitus, increased risk seems to be the most important factor just after the cardiovascular disease, use of alcohol, smoking, use of diuretics, aspirin, diagnosis of heart failure and loses its influence on mortality over insulin and oral glucose-lowering agents (that is, thiazolidinediones, time.22 A poor outcome also has been shown in anemic patients biguanides (that is, metformin), sulfonylureas and meglitinide). Model 4: 9,23 As model 3 þ congestive heart failure and level of creatinine at baseline. developing an acute stroke. In a prospective cohort, patients hospitalized with acute stroke and having anemia had after 1-year an increased risk of disability, nursing facility care and death of all R-square value of 0.0002 for men and 0.0004 for women. cause after 1 year.23 Thus, studies investigating anemia as a risk Concerning waist circumference we saw the same weak relation- factor in cardiac patients have demonstrated a positive association ship with a R-square value of 0.0005 for men and 0.0000 for between anemia and adverse cardiovascular events and/or death. women. We found a prevalence of 6% anemia in our high-risk population, and these patients were found to have a substantially increased risk of cardiovascular morbidity and mortality, com- pared with those without anemia. To some extent, this was driven DISCUSSION by traditional risk factors, although after adjusting for a range of In this cohort of nearly 10 000 overweight/obese cardiovascular other cardiovascular risk factors in the Cox regression models high-risk patients, anemia was an independent prognostic factor (Table 2, Model 3) we still found an association between anemia for adverse cardiovascular outcomes. The increased risk of adverse and the cardiovascular adverse events. Nevertheless, the association cardiovascular events was driven primarily by a higher incidence in the final proportional regression model became nonsignificant of cardiovascular death in patients with anemia in whom all-cause after adjusting for serum creatinine, and only the Cox regression mortality was also increased. To our knowledge, the association models for cardiovascular death as end point were statistically between anemia and cardiovascular adverse outcomes among significant (Table 3). It remains unclear which mechanisms of overweight or obese cardiovascular high-risk patients has not anemia in obese high-risk patients worsen the cardiovascular previously been reported. adverse outcomes. In patients with ACS, a potential mechanism Previous studies have investigated the risk of anemia in patients for the adverse outcome is thought to involve a decrease in with different cardiovascular diseases. Among patients with acute delivery to the myocardium and a resulting increase in coronary syndrome (ACS), an increased risk of cardiovascular myocardial oxygen demand through a necessarily higher cardiac mortality and ischemic events was found in those with output to maintain adequate systemic oxygen delivery.20,24,25 It anemia.7,19,20 In a large cohort of almost 40 000 patients with has also been speculated that anemia in patients with stabile ACS, an independent association between low hemoglobin and pectoris could be a surrogate marker of a poor health adverse cardiovascular outcomes was demonstrated.20 This latter status, possibly due to more comorbidities or malnutrition.19,26 study showed a significantly increased 30-day cardiovascular The mechanisms behind the association of anemia with increased mortality, even after adjusting for baseline characteristics. The frequency of adverse cardiovascular outcome in the overweight hemoglobin thresholds below which the patients were at and obese are not known, but a combination of these factors increased risk differed between STEMI (8.5 mmol l À 1) and described above may in part explain the association found in the NSTEMI (6.5 mmol l À 1) patients. A similar result was shown in a present analysis. As in other studies, the patients with anemia in prospective French study among patients hospitalized with ACS in the present cohort were more likely to have one or more

& 2014 Macmillan Publishers Limited International Journal of Obesity (2014) 432 – 437 Association of anemia with the risk of cardiovascular adverse events SA Winther et al 436 Table 3. Components of the primary outcome event

Model Myocardial infarction Stroke CV death All-cause mortality

Model 1: No anemia 1 (ref) 1 (ref) 1 (ref) 1 (ref) Mild anemia 1.07 (0.66–1.74) 1.31 (0.75–2.29) 2.42 (1.78–3.30) 2.03 (1.59–2.60) Moderate-to-severe anemia 2.23 (1.15–4.33) 1.20 (0.38–3.74) 2.36 (1.29–4.29) 2.42 (1.57–3.74)

Model 2: No anemia 1 (ref) 1 (ref) 1 (ref) 1 (ref) Mild anemia 1.00 (0.61–1.63) 1.19 (0.68–2.08) 2.13 (1.56–2.90) 1.71 (1.34–2.19) Moderate-to-severe anemia 2.05 (1.05–3.98) 1.06 (0.34–3.31) 1.99 (1.09–3.63) 1.96 (1.27–3.03)

Model 3: No anemia 1 (ref) 1 (ref) 1 (ref) 1 (ref) Mild anemia 0.93 (0.57–1.52) 1.11 (0.63–1.97) 1.82 (1.33–2.51) 1.50 (1.17–1.93) Moderate-to-severe anemia 1.93 (0.99–3.79) 1.02 (0.32–3.21) 1.65 (0.90–3.04) 1.61 (1.04–2.51)

Model 4: No anemia 1 (ref) 1 (ref) 1 (ref) 1 (ref) Mild anemia 0.87 (0.53–1.44) 1.05 (0.59–1.88) 1.57 (1.14–2.17) 1.31 (1.02–1.70) Moderate-to-severe anemia 1.66 (0.83–3.34) 0.91(0.28–2.94) 1.16 (0.62–2.17) 1.17 (0.74–1.85)

Abbreviation: CV, cardiovascular. Cutoff points for groups of anemia: see main text. Ref ¼ reference. Models 1–4: see Table 2. Estimates shown in bold type are statistically significant.

comorbidities such as type 2 diabetes, hypertension, Anemia is usually considered as a binary variable when assessed cardiovascular disease and heart failure. Thus, the associations as a risk factor for cardiovascular events. In this study, we have between anemia and cardiovascular risk may partly be driven by considered two different levels of anemia and shown no other cardiovascular risk factors. However, although not substantial difference in the risk between the groups of anemia, investigated in the present analysis, it is well-established that that is, mild anemia or moderate-to-severe anemia. Both groups of obese individuals carry a state of chronic low-grade inflammation, anemia showed a similar risk of cardiovascular adverse events and which is linked to iron deficiency.12,13,27,28 The low-grade deaths, making anemia a qualitative predictor of cardiovascular inflammation seems to induce the peptide synthesized adverse events. These findings in part correspond to the result primarily by the liver and maybe also by adipose tissue. Hepcidin from another study looking at hemoglobin as a continuous inhibits intestinal iron absorption and sequestering of iron in variable in ACS patients.20 A threshold of hemoglobin was found macrophages, which predisposes for anemia,11,27,29–31 and this for NSTEMI patients suffering cardiovascular death, myocardial could, although speculative, potentially increase the risk of both infarction or recurrent , but this was not the case for anemia and cardiovascular disease. However, in this analysis we STEMI patients in whom there was a linear association with did not find that BMI or waist circumference increased with cardiovascular death and hemoglobin. The same trend was shown anemia. Adjusting for serum creatinine in the final model in this in patients with stroke, in whom the 1-year mortality risk increased study made the association between anemia and cardiovascular linearly with increasing anemia.23 adverse events nonsignificant, indicating that renal dysfunction Our findings support previous results found in other cardiovas- and anemia in our study are closely related and it is possible, cular high-risk populations with anemia, but add to this discussion therefore, that (most likely due to diabetes by substantiating the risk in middle-aged and elderly patients with mellitus) was driving both anemia and adverse cardiovascular overweight/obesity. Data indicate that for obese patients, anemia outcomes. is an important risk factor for adverse outcomes that should not to In an attempt to improve the prognosis of patients with be ignored; however, future research on the roll of chronic kidney chronic diseases and anemia, stimulating with disease and possible iron deficiency in these overweight/obese -stimulating agents (ESA) has been used to high-risk patients is warranted to clarify future targets for correct anemia as a treatment strategy to improve prognosis. treatment. Small-scale studies in CHF patients have been shown in meta- analyses to be beneficial at reducing CHF-related hospitalization and all-cause mortality compared with controls, as well as at Strength and limitations increasing left ventricular function and improving the symp- Strengths of this study included the large cohort of almost 10 000 toms.32,33 However, each individual study reported that a small overweight or obese cardiovascular high-risk patients. Information number of events and results from long-term clinical outcomes on a wide range of measurements was available over a prolonged are needed, which have not yet been published.34 In a large, median follow-up time of 4.6 years. This analysis is limited by its randomized controlled trial of diabetes patients with chronic having been performed retrospectively, but being based on data kidney disease, correcting anemia with ESA has not been shown obtained prospectively. Another potential limitation in the to be beneficial, rather a two-fold increase in the rate of stroke presented study is the unknown cause of anemia in the patients and thromboembolic complications was found for the ESA arm and the lack of measurements of the body’s iron stores or with no benefit in mortality, which may have been due to erythropoietin; measures of , serum and serum increased hepcidin secretion.35,36 Therefore, even though we receptors could be interesting, as chronic low-grade did find a significant association between anemia and increased inflammation in obese individuals can be linked to iron deficiency. risks of cardiovascular disease and death, stimulating In addition, we did not have the measures of inflammation such as erythropoiesis with ESA in overweight/obese patients could, high-sensitivity c-reactive protein. Further, information on % body theoretically, be disadvantageous. fat was missing, which might have helped clarifying the possible

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