New-onset, hospital-acquired anemia (HAA) during acute myocardial infarction (AMI) is independently associated with poor outcomes. The patterns of recovery from HAA after AMI and their association with mortality and health status are unknown. In the prospective 24-center Translational Research Investigating Underlying disparities in acute myocardial infarction Patients’ Health Status (TRIUMPH) registry, we identified 530 patients with AMI and HAA (defined as normal hemoglobin at admission with the development of anemia by discharge) who had a repeat, protocol-driven hemoglobin measurement at 1 month after discharge. The 1-month measures were used to define persistent (persistent anemia) and transient (anemia resolved) HAA. The patients’ health status was assessed at 1, 6, and 12 months after AMI using the Short-Form 12 Physical Component Summary, and the health status of patients with persistent and transient HAA was compared using multivariate repeated measures regression analysis. Mortality was compared using the log-rank test and proportional hazards regression analysis. Overall, 165 patients (31%) developed persistent HAA. The adjusted mean Short-Form 12 Physical Component Summary scores at the follow-up visit were significantly lower in those with persistent HAA than in those with transient HAA (−2.0 points, 95% confidence interval −3.6 to −0.3; p = 0.02). During a median follow-up of 36 months, the crude mortality (13% vs 5%, p = 0.002) and multivariate-adjusted mortality (hazard ratio 2.08, 95% confidence interval 1.02 to 4.21, p = 0.04) was greater in patients with persistent HAA. In conclusion, HAA persists 1 month after discharge in nearly 1 of 3 patients and is associated with worse health status and greater mortality. Additional investigation is needed to understand whether HAA prevention, recognition, and treatment, particularly among those with persistent HAA, will improve outcomes.
Hospital-acquired anemia (HAA) develops in nearly 1 of 2 patients with acute myocardial infarction (AMI) who have normal hemoglobin at admission and is associated with greater mortality and worse health status. It is unclear to what extent HAA during AMI hospitalization resolves quickly during follow-up or persists after the acute episode of care. Moreover, it is unknown whether clinically important outcomes, such as mortality and health status, differ between patients with transient and persistent HAA. Understanding the patterns of HAA recovery after hospital discharge and their association with clinical outcomes would further support the importance of preventing and recognizing HAA. Furthermore, it might help identify patients at risk of a poor recovery after AMI who might benefit from more intensive follow-up. To address these gaps in knowledge, we studied patients enrolled in the Translational Research Investigating Underlying disparities in acute myocardial infarction Patients’ Health Status (TRIUMPH) study; a prospective 24-center observational registry of AMI treatment and outcomes. We identified patients with HAA at discharge and compared the 1-year health status and 3-year mortality of those with persistent and transient HAA at 1 month after an incident AMI.
Methods
The design and methods of the TRIUMPH study have been previously reported. In brief, a total of 4,340 patients were enrolled in TRIUMPH study from April 11, 2005 to December 31, 2008. The patients were ≥18 years old, with elevated cardiac biomarkers (troponin or creatine kinase-MB fraction assessed within 24 hours of admission) and supporting evidence of AMI (electrocardiographic ST-segment changes or prolonged ischemic signs/symptoms). The participants were required to present to the enrolling institution or to have been transferred to that hospital within 24 hours of presentation; thus, the primary clinical decision-making occurred at the enrolling center. Patients with elevated cardiac biomarkers from elective coronary revascularization were excluded. Trained data collectors performed detailed baseline chart abstractions to document patients’ medical history, the processes of inpatient care, laboratory results, and treatments. Each patient underwent a standardized interview by research staff to document their sociodemographic and clinical data. They were then contacted for follow-up interviews at 1, 6, and 12 months after AMI to reassess health status and interval events. All patients who agreed to follow-up laboratory assessment also underwent protocol-driven hemoglobin assessments 1 month after discharge. All patients provided written informed consent approved by the participating institution, and each participating center provided institutional review board approval.
Our goal was to describe the prevalence of persistent HAA and to assess the association between HAA persistence and subsequent outcomes. Accordingly, we first excluded 24 of the 4,340 patients in TRIUMPH who had died in the hospital. We then restricted the cohort to include only the 3,251 patients who were not anemic at admission and also restricted our analysis to those patients who developed HAA before discharge from the hospital (n = 1,599). Of these patients, 1,069 did not have the 1-month follow-up hemoglobin level collected because they had died (2%), were too ill (5%), refused the interview (5%), were lost to follow-up (31%), or had telephone interviews instead of in-home visits (57%), yielding an analytic cohort of 530 patients with AMI who were discharged with HAA and had had a follow-up hemoglobin assessment 1 month after discharge.
The admission hemoglobin was defined as the first in-hospital hemoglobin value available for each patient. If a patient was transferred to a TRIUMPH center from another hospital (n = 221), the initial hemoglobin at the transferring facility was obtained and used as the admission value. The discharge hemoglobin was defined as the last hemoglobin value obtained within 48 hours of discharge from the hospital. HAA was defined as the absence of anemia on admission with the development of anemia by discharge. Consistent with previous work, we defined anemia using the age-, gender-, and race-specific criteria described by Beutler and Waalen. Accordingly, a hemoglobin value of less than 13.7 g/dl for white men aged 20 to 59 years, 13.2 g/dl for white men ≥60 years old, 12.9 g/dl for black men aged 20 to 59 years, 12.7 g/dl for black men ≥60 years old, 12.2 g/dl for white women and 11.5 g/dl for black women was used to identify anemia. This classification has previously been shown to be more accurate than the World Health Organization definition.
Data abstractors, using the Thrombolysis In Myocardial Infarction (TIMI) classification, systematically recorded the bleeding episodes. TIMI major bleeding was defined as intracranial hemorrhage or a hemoglobin decline of ≥5 g/dl in the setting of overt bleeding. TIMI minor bleeding was assigned if the decrease in hemoglobin was 3 to 5 g/dl in the setting of observed bleeding. Any bleeding episode with a hemoglobin decline <3 g/dl was classified as TIMI minimal bleeding. All TIMI categories accounted for blood transfusion, with adjustment of the hemoglobin values by 1 g/dl for each unit transfused.
Health status was assessed using the Short Form-12 Physical Component Summary score (SF-12 PCS). The SF-12 is a valid and reliable instrument, with greater scores representing better health status. A score of 50 was normalized to the mean health status of the United States population and each 10 points represented 1 SD from that mean. Using criteria proposed by Cohen, the minimum clinically important difference on this scale is 2 points (0.2*SD).
The baseline characteristics, in-hospital treatments, in-hospital complications, and laboratory values of patients who had persistent HAA at 1 month were compared to those of the patients with transient HAA. We also described the proportion of patients with persistent HAA across the strata of HAA severity at discharge. For outcome analyses, we compared patients with persistent and transient HAA. For descriptive purposes, the categorical data are presented as the frequencies, and the differences between groups were compared using the chi-square or Fisher exact test, as appropriate. Continuous variables are reported as the mean ± SD, and differences were compared using independent Student’s t tests. The Wilcoxon rank sum test was used to compare patients’ length of stay owing to its skewed distribution, and the results are reported as the median and interquartile range.
The primary outcome of interest was health status, as assessed using the SF-12 PCS score. We used multivariate repeated measures linear regression analysis with an autoregressive covariance structure for SF-12 PCS that incorporated the 1-, 6-, and 12-month health status assessments. This model adjusted for the baseline SF-12 PCS score, age, gender, chronic kidney disease, and chronic heart failure, potential confounders identified in the previous data. Because patients discharged with more severe HAA might be more likely to develop persistent HAA, we also adjusted for patients’ discharge hemoglobin level. We then compared the mortality of patients with and without persistent HAA using Kaplan-Meier analyses and tested this relation using the log-rank test. The follow-up time was censored at the point of the most recent mortality update to the TRIUMPH database, with a mean follow-up of 3 years. We used Cox proportional hazards regression analysis to identify the relation of HAA persistence with mortality after adjusting for the Global Registry of Acute Coronary Events (GRACE) 6-month mortality risk score, age, and discharge hemoglobin. The GRACE 6-month mortality risk score is strongly predictive of long-term mortality and incorporates important potential confounders. The variables in the GRACE score include age, heart rate, systolic blood pressure, creatinine, history of congestive heart failure, previous myocardial infarction, in-hospital percutaneous coronary intervention or coronary artery bypass grafting, ST-segment depression on the initial electrocardiogram, and elevated cardiac biomarkers. We also adjusted for discharge hemoglobin values, because patients with severe HAA might be more likely to have persistent HAA at 1 month. The proportional hazards assumption was tested visually and using Schoenfeld residuals.
To assess the potential influence of missing 1-month follow-up data on our results, we developed a nonparsimonious propensity score for having 1-month follow-up data and conducted sensitivity analyses in which we weighted both the health status and mortality models with the reciprocal of this score. All analyses were conducted with SAS, version 9.2 (SAS Institute, Cary, North Carolina) and R, version 2.11.1.
Results
Of 530 patients with AMI discharged with HAA, 165 (31%) were persistently anemic at 1 month ( Table 1 ). A greater proportion of patients with more severe grades of HAA at discharge had persistent HAA ( Figure 1 ) . Of the patients with mild HAA at discharge, 82 (23%) had persistent HAA at 1 month, and patients discharged with moderate and severe HAA more frequently developed persistent HAA (65 patients [44%] and 18 patients [67%], respectively).
| Variable | HAA Status at 1 mo | p Value | |
|---|---|---|---|
| Transient (n = 365) | Persistent (n = 165) | ||
| Age | 60.2 ± 11.6 | 61.1 ± 11.9 | 0.41 |
| Men | 235 (64.4%) | 118 (71.5%) | 0.11 |
| White | 278 (76.6%) | 110 (67.1%) | 0.02 |
| Hemoglobin (g/dl) | |||
| At admission | 14.6 ± 1.3 | 14.1 ± 1.3 | <0.001 |
| At discharge | 11.8 ± 1.3 | 11.0 ± 1.4 | <0.001 |
| Change from initial to final during hospitalization | −2.7 ± 1.5 | −3.2 ± 1.9 | 0.004 |
| At 1 mo after discharge | 14.1 ± 1.1 | 12.0 ± 1.0 | <0.001 |
| Platelets at discharge (/μl) | 257 ± 76 | 262 ± 101 | 0.54 |
| Body mass index (kg/m 2 ) | 29.4 ± 6.3 | 29.3 ± 6.3 | 0.82 |
| Ejection fraction (%) | 49.4 ± 11.3 | 48.6 ± 12.4 | 0.50 |
| Killip class | |||
| I | 344 (94.8%) | 140 (86.4%) | 0.006 |
| II | 16 (4.4%) | 17 (10.5%) | |
| III | 2 (0.6%) | 3 (1.9%) | |
| IV | 1 (0.3%) | 2 (1.2%) | |
| Global Registry of Acute Coronary Events mortality risk score (g/dl) | 99.2 ± 25.9 | 106.0 ± 27.9 | 0.007 |
| Chronic heart failure | 15 (4.1%) | 9 (5.5%) | 0.49 |
| Dyslipidemia | 191 (52.3%) | 89 (53.9%) | 0.73 |
| Hypertension | 229 (62.7%) | 120 (72.7%) | 0.03 |
| History of cancer | 28 (7.7%) | 18 (10.9%) | 0.22 |
| Peripheral arterial disease | 19 (5.2%) | 6 (3.6%) | 0.43 |
| Previous myocardial infarction | 66 (18.1%) | 37 (22.4%) | 0.24 |
| Previous coronary artery bypass surgery | 30 (8.2%) | 24 (14.5%) | 0.03 |
| Previous stroke | 16 (4.4%) | 13 (7.9%) | 0.10 |
| Diabetes mellitus | 72 (19.7%) | 57 (34.5%) | <0.001 |
| Chronic kidney disease | 14 (3.8%) | 12 (7.3%) | 0.09 |
| Final diagnosis | |||
| ST-segment elevation myocardial infarction | 197 (54.0%) | 76 (46.1%) | 0.09 |
| Non–ST-segment elevation myocardial infarction | 168 (46.0%) | 89 (53.9%) | |
| In-hospital percutaneous coronary intervention | 263 (81.7%) | 81 (66.4%) | <0.001 |
| In-hospital renal failure | 7 (1.9%) | 6 (3.6%) | 0.24 |
| In-hospital bleeding | 51 (14.0%) | 27 (16.4%) | 0.47 |
| Thrombolysis In Myocardial Infarction bleeding severity | |||
| Major | 10 (19.6%) | 5 (18.5%) | 0.52 |
| Minor | 21 (41.2%) | 8 (29.6%) | |
| Minimum | 20 (39.2%) | 14 (51.9%) | |
| Length of stay | <0.001 | ||
| Median | 4.0 | 5.0 | |
| Interquartile range | 3.0–5.0 | 3.0–9.0 | |
| In-hospital iron supplementation | 3 (0.8%) | 5 (3.0%) | 0.12 |
| Aspirin at discharge | 350 (95.9%) | 154 (93.3%) | 0.21 |
| Thienopyridine at discharge | 304 (83.3%) | 106 (64.2%) | <0.001 |
| Warfarin at discharge | 34 (9.3%) | 17 (10.3%) | 0.72 |
| Angiotensin-converting enzyme inhibitor/angiotensin receptor blocker at discharge | 270 (74.0%) | 110 (66.7%) | 0.08 |
| β Blocker at discharge | 339 (92.9%) | 154 (93.3%) | 0.85 |
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