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J Am Coll Cardiol, 2004; 44:547-553, doi:10.1016/j.jacc.2004.03.080 © 2004 by the American College of Cardiology Foundation |














,*
* Cardiovascular Research Foundation, New York, New YorkUSA
Lenox Hill Heart and Vascular Institute, New York, New YorkUSA
William Beaumont Hospital, Royal Oak, MichiganUSA
Mid Carolina Cardiology, Charlotte, North CarolinaUSA
|| Hospital Gregorio Maranon, Madrid, Spain
¶ Duke Clinical Research Institute, Durham, North CarolinaUSA
# Virginia Beach General Hospital, Virginia Beach, VirginiaUSA
** Ospedali Riuniti di Bergamo, Bergamo, Italy

Moses Cone Memorial Hospital, Greensboro, North CarolinaUSA

Washington Adventist Hospital, Tacoma Park, MarylandUSA

Beth Israel Hospital, Boston, MassachusettsUSA
Manuscript received January 12, 2004; revised manuscript received February 24, 2004, accepted March 11, 2004.
* Reprint requests and correspondence: Dr. Gregg W. Stone, Cardiovascular Research Foundation, 55 East 59th Street, 6th Floor, New York, New York 10022 (Email: gstone{at}crf.org).
| Abstract |
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BACKGROUND: The prognostic importance of anemia on primary PCI outcomes is unknown.
METHODS: In the Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications (CADILLAC) trial, 2,082 patients of any age with AMI within 12 h onset undergoing primary PCI were randomized to balloon angioplasty versus stenting, each ± abciximab. Outcomes were stratified by the presence of anemia at baseline, as defined by World Health Organization criteria (hematocrit <39% for men and <36% for women).
RESULTS: Anemia was present in 260 (12.8%) of 2,027 randomized patients with baseline laboratory values. Patients with versus without baseline anemia more frequently developed in-hospital hemorrhagic complications (6.2% vs. 2.4%, p = 0.002), had higher rates of blood product transfusions (13.1% vs. 3.1%, p < 0.0001), and had a prolonged (median 4.1 vs. 3.5 days, p < 0.0001) and more expensive (median costs $12,434 vs. $11,603, p = 0.002) index hospitalization. Patients with versus without anemia had strikingly higher mortality during hospitalization (4.6% vs. 1.1%, p = 0.0003), at 30 days (5.8% vs. 1.5%, p < 0.0001), and at 1 year (9.4% vs. 3.5%, p < 0.0001). The rates of disabling stroke at 30 days (0.8% vs. 0.1%, p = 0.005) and at 1 year (2.1% vs. 0.4%, p = 0.0007) were also significantly higher in patients with anemia. By multivariate analysis, anemia was an independent predictor of in-hospital mortality (hazard ratio, 3.26; p = 0.048) and one-year mortality (hazard ratio, 2.38; p = 0.016).
CONCLUSIONS: Anemia at baseline in patients with AMI undergoing primary PCI is common, and is strongly associated with adverse outcomes and increased mortality.
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The primary composite end point included death from any cause, reinfarction, repeat target vessel revascularization (TVR) as a result of ischemia, or disabling stroke after the index procedure. The definitions of the primary end point have been previously described (9). Anemia was defined using World Health Organization (WHO) criteria as a hematocrit value at initial presentation <39% for men and <36% for women (10).
Clinical follow-up at 30 days, 6 months, and 1 year were performed in all patients. All events were adjudicated by an independent clinical events committee. Medical care costs were assessed for all U.S. patients using previously validated methodology (11). Detailed resource utilization data were recorded for all revascularization procedures, and procedural costs were based on measured resource utilization and 2001 unit costs. Nonprocedural hospital costs were estimated by converting hospital charges to costs according to hospital and cost-center specific cost-to-charge ratios. Costs for inpatient and outpatient physician services were calculated using the 2001 Massachusetts Medicare fee schedule.
Statistical analysis.
Categorical variables were compared with the Fisher exact test. Continuous variables are presented as medians with interquartile ranges, and were compared using the Kruskal-Wallis test. Survival data was estimated by the Kaplan-Meier method and compared by the log-rank test. Multivariate analysis of predictors of death at several time periods was performed using Cox proportional hazards regression with stepwise selection using entry and exit criteria of p < 0.1. The candidate variables entered in the model included age, gender, diabetes mellitus, hypertension, hypercholesterolemia, current smoking, history of prior myocardial infarction or coronary artery bypass graft surgery, Killip class
2 creatinine clearance, left anterior descending artery as an infarct vessel, triple-vessel disease, treatment with abciximab or stent, time from the symptom onset to the first balloon inflation, and baseline anemia (as a binary variable) or baseline hematocrit (as a continuous variable). Separate models were then generated adding in baseline medication use. All analyses were two-sided, and significance was established at the 0.05 level.
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| Discussion |
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In the present large trial of contemporary mechanical reperfusion strategies in AMI, anemia, as defined by WHO criteria, was common, occurring in 12.8% of patients. As patients with hemorrhagic diatheses and recent bleeding were excluded from the CADILLAC trial, the true incidence of anemia in a more general population of patients presenting for primary PCI is likely to be higher, especially given the increasing incidence of anemia as the population ages (7,12,13). Patients with anemia had an increased frequency of comorbid risk factors known to worsen prognosis after AMI, including advanced age, female gender, and diabetes mellitus (14,15). Despite similar rates of procedural success and infarct size, patients with baseline anemia had a significantly more complicated hospital course, including greater rates of hemorrhagic complications and blood product transfusion requirements. Hospitalization was significantly prolonged in patients with anemia, and costs were significantly greater. Most importantly, baseline anemia was strongly associated with an approximate three-fold increase in in-hospital, 30-day, and 1-year mortality. The impact of anemia on early and late death was present in both genders (though was especially profound in women), despite the different gender-based thresholds for anemia as established by WHO (10). Anemia was also strongly associated with an increased risk of disabling stroke, especially in women, a finding not previously reported.
The reasons for the worse outcomes in anemic patients with AMI treated with primary PCI are likely multifactorial. Anemia may by itself confer excess risk; decreased blood oxygen levels may be arrhythmogenic, directly exacerbate myocardial ischemia, activate the sympathetic nervous system, and result in cerebral hypoperfusion (46). Alternatively, anemia was a covariate with other high-risk features known to reduce survival after AMI. Patients with anemia were older, more commonly women, and had a higher prevalence of cardiovascular risk factors including diabetes and chronic renal insufficiency, factors known to worsen the prognosis of patients after AMI and primary PCI (1419). Peripheral arterial disease, which is a marker of diffuse atherosclerosis (20,21), was more prevalent in patients with anemia. Clinical congestive heart failure was also significantly more common at presentation in patients with anemia, although left ventricular ejection fraction was not measured to be different. Even after multivariate adjustment for the important confounders, anemia remained an independent predictor of in-hospital and one-year mortality. However, multivariate models cannot entirely account for the baseline differences, and adjusted effects may still be influenced by residual confounding. Additional clinical measurements not included in this analysis (e.g., certain comorbidities or inflammatory markers) may also interact with anemia.
Differences in pharmacologic treatment may also have contributed to the worse late prognosis in patients with anemia. Specifically, anemic patients were less likely to be treated with aspirin, beta-blockers, and statins, all of which are known to prolong survival after AMI (2225). When differences in medication use at the time of admission were considered in the multivariate model, aspirin continued to be an independent determinate of mortality both in-hospital and at one year. These models are unable to correct for postdischarge medication use, however, as approximately one-half of the deaths in patients with anemia occurred before hospital discharge. Notably, almost one-fifth of patients with anemia (18.8%) were not receiving aspirin at one-year follow-up, presumably due to their increased incidence of preadmission gastrointestinal bleeding, their greater rate of hemorrhagic events during the index hospitalization, and possible concerns about recurrent bleeding. Considering the impact of anemia on late survival in hospital survivors, the decreased mortality between the time of discharge and one year in patients with a reduced baseline hematocrit may be, at least partly, explained by the lower rate of aspirin prescription at discharge. Of note, prior studies demonstrating increased late mortality in patients with anemia and cardiovascular disorders did not examine the extent to which differences in medication usage may have contributed to the worse prognosis with this condition (8,26).
Study limitations. This post-hoc analysis was not prespecified and should, thus, be considered hypothesis-generating, and complementary to large, prospectively collected observational databases. The causes of anemia in the patients in our study were not known, and the prognostic importance of anemia may vary with different etiologies. The indications for and timing of blood product transfusions were not protocol-specified but, rather, left to local standards of care; whether a policy of early routine blood transfusion in anemic patients would improve their prognosis is unknown. Finally, no information was available regarding the correction of anemia at follow-up, or whether additional hemorrhagic events occurred.
Conclusions and clinical implications. Baseline anemia in patients with AMI undergoing primary PCI should be recognized as an important risk factor for prolonged hospitalization, increased hospital costs, and adverse short-term and late outcomes, including death and disabling stroke. Medications known to improve survival in AMI patients, including enteric-coated aspirin, beta-blockers, and statins should not be withheld from this high-risk population if at all possible. Further study is warranted to determine whether early red blood cell transfusions would improve the prognosis of patients with anemia and AMI undergoing primary PCI.
| Acknowledgments |
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