Abstract
Background
Anemia is associated with adverse cardiovascular outcomes in patients with ischemic heart disease and is more prevalent in women as compared to men. Prior studies have evaluated short-term outcomes in women with stable angina and relatively low rates of obstructive coronary artery disease (CAD). We investigated the long-term clinical significance of baseline anemia in this cohort.
Methods
We studied 885 women enrolled in the Women's Ischemia Syndrome Evaluation (WISE) undergoing clinically indicated coronary angiography for suspected ischemia. Anemia at enrollment was defined as hemoglobin (Hgb) level < 12 g/dL. Major adverse cardiovascular events (MACE) included cardiovascular death, non-fatal myocardial infarction, heart failure hospitalization, stroke, and vascular events. Cox regression models and Kaplan-Meier methods were used.
Results
Overall, the women, mean age 58.4 ± 11.7 years, were followed for an average of seven years (range 0–11 years). Anemia was present in 21.1%. They had higher creatinine levels with more frequent history of diabetes mellitus, hypertension, and HF (p < 0.05) but similar obstructive coronary artery disease compared to non-anemic women. Anemic women had higher long-term all-cause mortality and MACE rate. In multivariable analysis, anemia was independently associated with increased MACE risk (hazard ratio (HR): 1.5, 95% confidence interval [1.117–2.017, p = 0.007]) but not all-cause mortality (HR:1.2 [0.841, 1.727, p = 0.309]).
Conclusions
Among women evaluated for symptoms of ischemia, anemia is associated with and independently predicts long-term MACE. Further research targeting anemia management in women to mitigate these adverse outcomes is warranted.
Keywords: Ischemia, WISE, Cardiovascular, Anemia
1. Introduction
Anemia is relatively more prevalent in women as compared to men [1]. Women with symptoms and/or signs of ischemia most often have coronary endothelial and/or microvascular dysfunction [2], [3]. The impaired oxygen-carrying capacity due to anemia has the potential to worsen ischemia in such patients and patients with obstructive coronary disease (CAD).
Anemia is an independent predictor of worse cardiovascular outcomes in patients with the acute coronary syndrome (ACS), stable (CAD), or heart failure (HF) [4], [5], [6], [7]. Studies have reported that women with MI suffer from anemia more frequently than men, which were associated with increased 30-days and 2-year mortality [8], [9]. A preliminary analysis from the Women's Ischemia Syndrome Evaluation (WISE) observed that lower baseline hemoglobin levels predicted higher rates of major adverse outcomes (MACE) at a mean of three years in 939 women with signs and symptoms of ischemia undergoing clinically indicated coronary angiography [10]. However, the prognostic value of hemoglobin to predict long-term outcomes in these women has not been described.
2. Methods
2.1. Study design
The study cohort consisted of women enrolled in the National Heart, Lung, and Blood Institute (NHLBI)-sponsored WISE multicenter prospective study (NCT00000554). The design and protocol of the WISE study have been published previously [11]. Women (n = 939) referred for clinically indicated angiograms to evaluate suspected ischemia were enrolled from 1996to 2000. The Investigational Review Boards approved the protocol at each site, and all participants provided written informed consent. Of the women enrolled, 54 were excluded for missing/uninterpretable baseline data, resulting in 885 subjects that were included in this analysis.
Physical examination, clinical, and laboratory data were collected at the baseline visit. The WISE core laboratory analyzed invasive coronary angiography films to quantify the extent and severity of CAD. Each coronary artery was classified as non-obstructive CAD (<20% stenosis), minimal CAD (20–49% stenosis), or obstructive CAD (≥50%), as previously defined [12]. Additionally, a Sharaf-Gensini coronary artery severity score was calculated based on stenosis severity weighted by proximal location as previously published [12]. Hemoglobin levels were analyzed at the baseline visit, and anemia was defined using the World Health Organization definition; Hgb < 12 g/dL [13]. Standardized demographic, clinical, angiographic, and follow-up data forms were collected on-site and processed at the data coordinating center (University of Pittsburgh).
Measurement of inflammatory markers including high sensitivity C-reactive protein (hs-CRP), interleukin 6 (IL-6), and tumor necrosis factor-alpha (TNF-α) were added after enrollment began and were available in 594 women. These samples were stored at -70 °C and analyzed centrally by commercially available assays.
The follow-up data were collected at six weeks and then yearly by an experienced site nurse or physician. In the event of an adverse outcome, the documentation was requested, reviewed, and adjudicated by a physician team. In case of death, death certificates were requested and reviewed by the event review committee to determine cardiovascular etiology and supplemented by a search of the National Death Index Registry, as previously described [14].
2.2. Primary outcomes
Primary outcome focused on major adverse cardiac events (MACE). MACE was defined as cardiovascular death, non-fatal myocardial infarction, heart failure hospitalization, stroke, and vascular events. MI was defined as elevated creatinine kinase or troponin levels twice above the normal limit. Vascular events primarily included peripheral atherosclerosis-related events. Mortality data were obtained via the National Death Index search.
2.3. Secondary outcomes
The secondary outcome of interest was all cause-mortality. Mortality data were collected from patients' medical records, official death certificates, and contact with the patient families, supplemented by a search of the National Death Registry. The event adjudication committee then reviewed all the data.
2.4. Statistical analysis
Demographic and clinical characteristics were summarized by standard descriptive measures – frequency and percentage for categorical variables and mean (standard deviation) or median (range) for continuous variables. Tests for normality were assessed using the Shapiro-Wilk test. Bivariate comparison of anemic vs. non-anemic patients was then performed using Pearson's chi-square test or Fisher's exact test for categorical variables and the Student t-test or Wilcoxon-Mann-Whitney test for continuous variables where appropriate. Kaplan-Meier (KM) analysis was used to estimate survival probabilities, and the log-rank test was used to assess differences by hemoglobin level. Univariate and multivariable Cox proportional hazards regression was used to estimate unadjusted and adjusted hazard ratios of all-cause mortality and MACE in relation to anemic status. Multivariable Cox regression models were adjusted for known predictors of mortality and MACE as described in existing literature [10], including self-reported age, history of diabetes mellitus, history of hypertension, creatinine level, statin use, and the Sharaf-Gensini severity score. The proportional hazards assumption among all survival models was assessed by the scaled Schoenfeld residuals as well as the goodness-of-fit test [15].
Furthermore, Spearman correlation coefficients were used to explore the relationship between hemoglobin levels and inflammatory markers IL-6, TNF-α, and hs-CRP. All tests were two-sided, and p-values <0.05 were considered significant for all analyses. All statistical analyses were performed using SAS software (SAS, version 9.2, Carey, N.C.).
3. Results
3.1. Demographics
Among the 885 women with complete data, the mean age was 58.4 ± 11.7 years. The mean follow-up was seven years (range 0–11 years, median 9.7 years). Pertinent baseline characteristics are summarized in Table 1. 69% were white, 33% had diabetes mellitus, 12.8% were active smokers, and 70.1% had hypertension. More than 1 in 5 women (187/885, 21.1%) were anemic. Those with anemia had higher creatinine (Cr) (1.1 ± 0.9, p < 0.001), and prevalence of heart failure (HF) (p < 0.001), diabetes (p = 0.009), active smoking (p = 0.015) and hypertension (p = 0.001) versus non-anemic women. Despite this difference in the standard risk factor profile, there was no difference in the degree of obstructive vs. non-obstructive CAD among the two groups (p = 0.97): most (60.6%) of the women had non-obstructive CAD (<50% stenosis).
Table 1.
Baseline characteristics of the study cohort.
| Variable | All women (N = 885) |
Women with anemia (N = 187) |
Women without anemia (N = 698) |
P value |
|---|---|---|---|---|
| Age(yrs.) | 58.4 ± 11.7 | 58.8 ± 12.6 | 58.2 ± 11.4 | 0.50 |
| White | 716 (80.9) | 129 (69.0) | 587 (84.1) | <0.001 |
| Total cholesterol mg/dL (mean ± SD) | 212.3 ± 49.3 | 203.0 ± 50.5 | 214.7 ± 48.8 | 0.01 |
| LDL mg/dL (mean ± SD) | 126.3 ± 43.5 | 121.1 ± 43.5 | 127.6 ± 43.4 | 0.22 |
| Glucose mg/dL (mean ± SD) | 112.1 ± 63.1 | 107.8 ± 59.3 | 113.2 ± 64.1 | 0.55 |
| Creatinine mg/dL (mean ± SD) | 0.9 ± 0.5 | 1.1 ± 0.9 | 0.8 ± 0.3 | <0.001 |
| Systolic BP (mmHg) | 137.1 ± 22.8 | 139.5 ± 24.2 | 136.5 ± 22.3 | 0.20 |
| History of diabetes | 225 (25.6%) | 61 (33.0%) | 164 (23.6%) | 0.009 |
| Smoking status Active Former Non-smoker |
179 (20.3%) 299 (33.9%) 405 (45.9%) |
24 (12.8%) 72 (38.5%) 91 (48.7%) |
155 (22.3%) 227 (32.6%) 314 (45.1%) |
0.015 |
| History of CHF | 76 (8.7%) | 32 (17.2%) | 44 (6.4%) | <0.001 |
| Baseline EF EF < 30% EF30–39% EF 40–49% EF 50–69% EF ≥ 70% |
7 (1.0%) 14 (2.0%) 21 (2.9%) 407 (57.2%) 263 (36.9%) |
3 (2.3%) 6 (4.5%) 5 (3.8%) 69 (51.9%) 50 (37.6%) |
4 (0.7%) 8 (1.4%) 16 (2.8%) 338 (58.4%) 213 (36.8%) |
0.055 |
| Degree of obstructive CAD CAD < 20% CAD 20–49% CAD ≥ 50% |
319 (36.0%) 218 (24.6%) 348 (39.3%) |
69 (36.9%) 42 (22.5%) 76 (40.6%) |
250 (35.8%) 176 (25.2%) 272 (39.0%) |
0.74 |
| Sharaf-Gensini Severity Score | 14.9 ± 14.8 | 15.6 ± 16.1 | 14.8 ± 14.4 | 0.97 |
| ACEI use | 232 (26.3%) | 76 (40.6%) | 156 (22.4%) | <0.001 |
| Statins use | 223 (25.3%) | 47 (25.1%) | 176 (25.3%) | 0.97 |
| Beta blocker use | 349 (39.6%) | 86 (46.0%) | 263 (37.8%) | 0.04 |
| Aspirin use | 534 (60.6%) | 118 (63.1%) | 416 (59.9%) | 0.43 |
| Post-menopausal | 324 (38.6%) | 65 (37.4%) | 259 (38.9%) | 0.71 |
(N: number, Yrs.: years, SD: standard deviation, mmHg: millimeters of mercury, %: percentage: low density lipoprotein, BP: blood pressure, CHF: congestive heart failure, EF: ejection fraction, CAD: coronary artery disease, ACEI: angiotensin converting enzyme inhibitor)
3.2. Outcomes
Over eleven years of follow-up (median 8.3 years for mortality), 20.1% (178/885) died. Women with anemia had higher cardiovascular-related mortality than non-anemic women (17.1% vs. 11.0%, p < 0.025).
In univariate analysis, history of diabetes mellitus, hypertension, age, low Hgb level (< 12 g/dL), statin use, creatinine levels, and CAD > 20% were associated with adverse outcomes. Unadjusted Kaplan Meir curves showed higher rates of MACE in anemic women compared to non-anemic women (Fig. 1). Among the individual components of MACE, adverse outcomes for CV-related deaths (Supplement Fig. 1) were more frequently observed in anemic women than non-anemic women. Multivariable Cox regression models demonstrated low Hgb level < 12 g/dL as an independent predictor for higher risk for MACE [hazard ratio (HR): 1.5, 95% confidence interval 1.117–2.017, p = 0.007] (Fig. 2).
Fig. 1.
Kaplan-Meier curves for major adverse cardiac events (MACE).
Fig. 2.
Hazard Ratios from multivariable analysis including hemoglobin.
In unadjusted analysis, the Kaplan-Meier curve for mortality reflects that the anemic patients were at a higher all-cause mortality risk (Fig. 3). However, after adjustment for baseline covariates, there was no statistically significant difference among the two groups (HR:1.2 [0.841, 1.727, p = 0.309]) (Fig. 4).
Fig. 3.
Kaplan-Meier curves for all-cause mortality.
Fig. 4.
Hazard Ratios from multivariable analysis including hemoglobin.
The study did not have adequate power for subgroup analysis but showed no difference in outcomes based on the degree of severity (<50% CAD or > 50% CAD on invasive angiography) among the two groups; All-Cause Mortality (HR: 0.847 [95% CI 0.432, 1.661], p = 0.6285) and MACE (HR: 1.219 [95% CI 0.746, 1.992], p = 0.4295).
3.3. Inflammatory marker analysis
In the unadjusted analysis of inflammatory markers, we found higher baseline levels of TNFα, IL-6, and hs-CRP in anemic women. These inflammatory markers showed negative weak correlation with baseline Hgb levels: TNFα (r = −0.087, p = 0.03), IL-6 (r = −0.130, p = 0.001), and hs-CRP (r = −0.083, p = 0.03) (Supplement Table 2).
4. Discussion
This study highlights some significant findings that extend from our prior report. First, anemia is associated with long-term MACE risk in women with stable angina and relatively low rates of obstructive coronary artery disease (CAD). Second, anemia is an independent risk predictor regardless of traditional risk factor profile or CAD severity in such women. Third, the relation of elevated inflammatory markers with low hemoglobin levels fuels the hypothesis of potentially some novel mechanistic etiology for adverse outcomes in this cohort.
Low hemoglobin levels have been associated with adverse cardiac outcomes either by hypoxic injury, myocardial remodeling, perfusion mismatch, or impaired nitric oxide activity at lower Hgb levels [16], [17], [18]. Our study cohort did not differ in degree of obstruction, making epicardial disease severity alone an unlikely explanation for the adverse outcomes. A study by Suppogu et al. has reported an association of low hemoglobin levels with a higher baseline average peak velocity (bAPV) [19]. A Higher bAPV is frequently associated with low coronary flow reserve, a marker of underlying coronary microvascular dysfunction (CMD) in women with non-obstructive CAD. The underlying CMD has been well studied as a culprit for adverse clinical outcomes [20], [21], [22]. The microvasculature is also more sensitive to low-level declines in hemoglobin and can potentially lead to an impaired vasodilatory response in such women, which may play a role in symptoms manifestation and adverse clinical outcomes [23].
Our study showed the weak negative correlation of elevated inflammatory markers with anemia. Although the exact cause of anemia in our study is unknown due to the study's observational design, women's mean age was 58 years making iron blood loss anemia via menstruation or childbirth an unlikely culprit. One can hypothesize the role of anemia of chronic disease due to differences in baseline creatinine among anemic vs. non-anemic women. The strong association of anemia with inflammatory markers might points to the underlying CMD in such cohort, with is often associated with elevated markers [24], [25], [26], [27] due to ongoing ischemic damage. This phenomenon is often described as a culprit for adverse outcomes in diabetic and autoimmune disease patients [28], [29], [30].
Prior reports suggested improved clinical outcomes after correction of anemia in patients with acute coronary syndrome and HF [31], [32], [33], [34], [35], but no data is available in women in this regard. Our study has highlighted persistent long-term adverse MACE in anemic women and urges a need to investigate if treating anemia in such patients will improve clinical outcomes. This in the future can help improve the morbidity associated with ischemic heart disease in women. Moreover, further studies are needed to understand better the mechanisms involved in this process and the role of inflammatory markers in patients with anemia.
Our study has several strengths (multicenter, core labs, standardized data collection, and adequate power to study outcomes. It has some limitations, including observational design, lack of information about anemia's exact cause, and information regarding the correction of anemia at the follow-up. However, underestimating adverse events is possible due to a loss of follow-up due to death (survival bias), however the National. Death Registry search would likely have limited that issue.
5. Conclusions
Anemia was associated with and independently predicted long-term MACE among women evaluated for symptoms and/or signs of ischemia regardless of the degree of obstructive CAD. Further research targeting anemia treatment in women to mitigate these adverse outcomes is warranted.
Declaration of competing interest
Dr. C. Noel Bairey Merz, serves as Board of Director for iRhythm, fees paid through CSMC from Abbott Diagnostics and Sanofi. Dr. Janet Wei served on an advisory board for Abbott Vascular.
Acknowledgements
The work from this study was sponsored by University of Pittsburgh in collaboration with National Heart, Lung, and Blood Institute (NHLBI). ClinicalTrials.gov Identifier:NCT00000554. We would also like to recognize funding from The Barbra Streisand Women's Cardiovascular Research and Education Program (NBM), The Smidt Heart Institute. The Linda Joy Pollin Women's Heart Health Program, Edythe L. Broad and the Constance Austin Women's Heart Research Fellowships at Cedars-Sinai Medical Center, Los Angeles, California.
Footnotes
Supplementary data to this article can be found online at https://doi.org/10.1016/j.ahjo.2021.100059.
Appendix A. Supplementary data
Supplementary material
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