Red blood cell transfusion is common in patients with acute myocardial infarction (AMI). However, observational data suggest that this practice may be associated with worse clinical outcomes and data from clinical trials are lacking in this population. We conducted a prospective multicenter randomized pilot trial in which 45 patients with AMI and a hematocrit level ≤30% were randomized to a liberal (transfuse when hematocrit <30% to maintain 30% to 33%) or a conservative (transfuse when hematocrit <24% to maintain 24% to 27%) transfusion strategy. Baseline hematocrit was similar in those in the liberal and conservative arms (26.9% vs 27.5%, p = 0.4). Average daily hematocrits were 30.6% in the liberal arm and 27.9% in the conservative arm, a difference of 2.7% (p <0.001). More patients in the liberal arm than in the conservative arm were transfused (100% vs 54%, p <0.001) and the average number of units transfused per patient tended to be higher in the liberal arm than in the conservative arm (2.5 vs 1.6, p = 0.07). The primary clinical safety measurement of in-hospital death, recurrent MI, or new or worsening congestive heart failure occurred in 8 patients in the liberal arm and 3 in the conservative arm (38% vs 13%, p = 0.046). In conclusion, compared to a conservative transfusion strategy, treating anemic patients with AMI according to a liberal transfusion strategy results in more patients receiving transfusions and higher hematocrit levels. However, this may be associated with worse clinical outcomes. A large-scale definitive trial addressing this issue is urgently required.
In patients presenting with acute coronary syndromes (ACS) red blood cell (RBC) transfusion is a common yet highly variable practice with uncertain benefit. We conducted a randomized pilot trial in which anemic patients with acute myocardial infarction (AMI) were randomly assigned to a traditional liberal transfusion strategy or a more conservative transfusion strategy. The purpose of this study was to assess the effect of this randomization scheme on RBC usage rates, hematocrit levels, and clinical safety in a preliminary manner and thus to inform the design of a definitive large-scale trial.
Methods
This was a prospective multicenter parallel-group randomized pilot trial to compare 2 RBC transfusion strategies in anemic patients with AMI. Patients were randomly assigned in a 1:1 ratio to 1 of 2 treatment groups by the coordinating center using consecutively numbered opaque envelopes. Blinding of treatment assignment was not feasible.
Patients admitted to the Washington Hospital Center, Washington, DC VA Medical Center, or Durham VA Medical Center with AMI from May 2003 through October 2009 were considered for enrollment. AMI was defined as ischemic-type chest discomfort lasting ≥30 minutes and associated with a creatine kinase-MB (CK-MB) or cardiac troponin level above the upper limit of normal (determined locally). We included patients in whom the hematocrit was ≤30% within 72 hours of symptom onset. We excluded patients for the following reasons: (1) noncoronary cause for clinical syndrome; (2) active bleeding, defined as overt blood loss accompanied by a decrease in hematocrit of ≥5% in the preceding 12 hours; (3) inability or unwillingness to receive RBC transfusion; (4) RBC transfusion within 7 days of enrollment; (5) previous severe transfusion reaction; (6) imminent death; (7) decision to provide limited or comfort care; (8) age <21 years; (9) pregnancy; (10) participation in another clinical trial in which RBC transfusion was a requirement or a component of a primary or secondary end point; and (11) previous participation in the present study.
The protocol was approved by the institutional review board of each participating institution. Written informed consent was provided by the patient or an appropriate surrogate. An independent data and safety monitoring board monitored the study and performed 4 interim safety analyses during the course of the study. The study was supported by the Cardiovascular Research Institute of the Washington Hospital Center and received no external funding ( http://www.Clinicaltrials.gov , identifier NCT00126334 ).
Hematocrit was measured at least daily. Patients randomized to the liberal transfusion strategy underwent RBC transfusion when their hematocrit decreased <30% with the goal of maintaining a hematocrit from 30% to 33%. Patients randomized to the conservative transfusion strategy underwent RBC transfusion when their hematocrit decreased <24% with the goal of maintaining a hematocrit from 24% to 27%. In the 2 groups leukocyte-depleted packed RBCs were transfused 1 U at a time and hematocrit was measured again 1 hour later. Additional units were transfused as necessary to achieve a hematocrit within the target range. If the hematocrit was >5% below the target range, 2 U were transfused before the hematocrit was measured again. If a patient underwent a major surgical procedure, RBCs were subsequently transfused according to the judgment of the treating physician until discharge from the hospital and any such transfusions were excluded from the transfusion-related analyses (other patient outcomes were not excluded).
Patients could receive RBC transfusion for any of the following reasons at the discretion of the treating physician: (1) active bleeding as defined earlier; (2) persistent hypotension related to hypovolemia; (3) active ischemia; and (4) at any time it was determined that it was in a patient’s best interest to receive a transfusion. Once the active issue was resolved, transfusion was again administered according to the study protocol. In all cases patients were analyzed according to the randomization scheme (“intention to treat”).
Transfusion-related end points included the proportion of patients receiving ≥1 transfusion, number of transfusions received per patient, and average daily hematocrit. The primary clinical safety measurement was a composite of the first occurrence of in-hospital death, recurrent MI, or new or worsening heart failure (HF). Each additional exploratory clinical end point reported below was prespecified.
Patients were followed daily by study personnel during their hospitalization and contacted by telephone at 30 days from randomization. Events were determined by the local study investigator. Recurrent MI was defined for nonprocedure-related events as recurrent ischemic chest discomfort, new ischemic electrocardiographic changes, and CK-MB increase above the upper limit of normal and increased by ≥50% over the previous value. For patients with percutaneous coronary intervention <24 hours previously, CK-MB ≥3 times the upper limit of normal and increased by ≥50% over the previous value was required. For patients with coronary artery bypass grafting surgery <24 hours previously, CK-MB ≥5 times the upper limit of normal and increased by ≥50% over the previous value was required. New or worsening HF was defined as 1 of the following occurring ≥6 hours after randomization: cardiogenic shock or a physician’s decision to treat HF with an intravenous diuretic or intravenous vasoactive drug and evidence of pulmonary vascular congestion. Recurrent ischemia was defined as pain or discomfort considered probable or definite angina that was ≥5 minutes in duration.
The initial enrollment goal for the trial was 92 patients. After the fourth interim safety analysis, the data and safety monitoring board determined that an adequate number of patients had been enrolled to provide preliminary results with respect to transfusion-related end points and clinical safety. Therefore, in the face of slower-than-expected enrollment, the steering committee decided to halt further enrollment and the study was terminated after the last enrolled patient completed 30-day follow-up.
Between-group comparisons for continuous variables were made using t test or Wilcoxon rank-sum test and categorical variables were compared using a chi-square test or Fisher’s exact test as appropriate. Curves of daily hematocrit values were compared using a mixed linear model. A p value <0.05 was considered to represent statistical significance. Because of the preliminary nature of this pilot study, no corrections were made for multiple comparisons.
Results
We enrolled 45 patients, of whom 21 were randomized to the liberal transfusion strategy and 24 were randomized to the conservative transfusion strategy ( Figure 1 ) . Mean time from AMI symptom onset to trial enrollment was 1.6 ± 0.5 days. Baseline characteristics are presented in Table 1 and were generally similar in the 2 treatment groups. MI characteristics and therapies at time of enrollment are presented in Table 2 . There were 18 patients (40%) with ST-segment elevation MI and 27 patients (60%) with non–ST-segment elevation MI. Percutaneous coronary intervention had been performed in 25 patients (56%) before enrollment. Nearly all patients were receiving dual antiplatelet therapy.
| Characteristic | Liberal | Conservative |
|---|---|---|
| (n = 21) | (n = 24) | |
| Age (years), mean ± SD | 76.4 ± 13.5 | 70.3 ± 14.3 |
| Men | 48% | 54% |
| White | 76% | 61% |
| Smoker | 10% | 33% |
| Hypertension requiring drug treatment | 91% | 75% |
| Hyperlipidemia requiring drug treatment | 76% | 63% |
| Diabetes mellitus | 81% | 54% |
| End-stage renal disease | 19% | 17% |
| Previous coronary artery disease | 52% | 58% |
| Previous coronary artery bypass grafting | 29% | 17% |
| Previous percutaneous coronary intervention | 24% | 25% |
| Creatinine (mg/dl), mean ± SD | 2.9 ± 2.3 | 2.4 ± 2.3 |
| White blood cell count (1,000/μl), mean ± SD | 9.4 ± 5.0 | 10.5 ± 3.8 |
| Platelet count (1,000/μl), mean ± SD | 201 ± 84 | 249 ± 100 |
| Hematocrit (%), mean ± SD | 26.9 ± 1.9 | 27.5 ± 2.4 |
| Characteristic | Liberal | Conservative |
|---|---|---|
| (n = 21) | (n = 24) | |
| ST-segment elevation myocardial infarction | 33% | 46% |
| Non–ST-segment elevation myocardial infarction | 67% | 54% |
| ST-segment depression | 43% | 33% |
| Killip class | ||
| I | 52% | 67% |
| II | 24% | 8% |
| III | 0% | 13% |
| IV | 25% | 13% |
| Ejection fraction (%), mean ± SD | 47 ± 13 | 39 ± 15 |
| Percutaneous coronary intervention | 57% | 54% |
| Fibrinolysis | 5% | 4% |
| Aspirin | 100% | 100% |
| Clopidogrel | 81% | 88% |
| Heparin | 33% | 41% |
| Glycoprotein IIb/IIIa inhibitor | 5% | 8% |
| β Blocker | 62% | 79% |
| Angiotensin-converting enzyme inhibitor and/or angiotensin receptor blocker | 53% | 63% |
| Nitrate | 33% | 21% |
| Diuretic | 38% | 13% |
| Statin | 91% | 92% |
| Intravenous vasoactive drug | 29% | 13% |
| Intra-aortic balloon pump | 0% | 13% |
| Mechanical ventilation | 24% | 13% |
| Pulmonary artery catheter | 25% | 25% |
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