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Ann Thorac Surg 1996;62:1575-1577
© 1996 The Society of Thoracic Surgeons
Division of Thoracic Surgery, Department of Surgery, and Division of Biometry, Department of Community and Family Medicine, Duke University Medical Center, Durham, North Carolina
Although the efficacy of aprotinin in reducing transfusion requirements has been demonstrated for many subsets of cardiac surgical patients, the indications for its use remain controversial. There have been concerns regarding heparin management and safety since the initial United States randomized trial results were reported in 1992 [1]. Thoracic surgeons are also aware of safety concerns when aprotinin is employed with profound hypothermia and circulatory arrest [2, 3].
In this issue, Lemmer and associates [4] report the results achieved in the fourth published United States randomized, double-blind, placebo-controlled trial designed to establish the effectiveness of aprotinin in coronary artery bypass grafting (CABG). Both Food and Drug Administration-approved dosing schemes (regimen A, full-dose "Hammersmith"; regimen B, half-dose) as well as a nonapproved pump-prime–only dosing scheme were shown to be effective in reducing blood and blood component use in primary CABG. They noted no significant difference in myocardial infarction rate, as determined by a central laboratory using predefined enzyme and electrocardiographic criteria, when comparing full-dose and half-dose aprotinin with placebo. A significantly increased rate of the most sensitive expression of myocardial infarction (definite, probable, or possible) was noted in the pump-prime–only arm compared with placebo. There were no statistically significant differences in mortality.
As Lemmer and associates point out, it is perhaps not surprising that a nonlinear dose-response curve could exist for aprotinin. The drug appears to act in a complicated way to alter the balance of procoagulant and anticoagulant enzyme cascades as they are effected by operation and cardiopulmonary bypass. Currently available information reveals that the empirically derived
full-dose scheme coupled with specifically controlled heparinization is effective in reducing blood product use and reducing reexploration for bleeding without an increase in the rates of myocardial infarction, death, or other significant complications.
Lemmer and associates conclude that both the full-dose and half-dose aprotinin regimens are safe and effective, whereas the pump-prime–only regimen is not recommended because of association with an increased rate of myocardial infarction. They recommend that the half-dose regimen be employed in patients at high risk for postoperative bleeding as the cost of treatment is reduced while the bleeding-reduction benefit is maintained.
An alternative view is that this is the third consecutive randomized trial to report excess mortality and myocardial infarction when less than full-dose aprotinin is employed in primary or reoperative coronary operations. Because these trials have all been designed to detect effectiveness, they have individually been too small to definitively determine safety issues. In the present trial, pump-prime–only aprotinin resulted in sufficient excess myocardial infarction to be identified as significant. There was also an increased rate of mortality in this arm, which failed to achieve statistical significance. The half-dose arm also had increased mortality and myocardial infarction, but again this was not statistically significant.
In the only other trial with a pump-prime–only arm, in reoperative CABG [5], the pump-prime–only arm actually had less myocardial infarction and less mortality. Both reoperative coronary trials [1, 5] reported excess mortality in the half-dose arm, and excess myocardial infarction when determined by central laboratory criteria. Cosgrove and associates [1] raised concern over early graft thrombosis and mortality with aprotinin, but the excess mortality occurred in the half-dose arm, whereas mortality was equivalent with full-dose aprotinin. Levy and associates [5] noted increased mortality and myocardial infarction with half-dose aprotinin, but because statistical significance was not achieved within the study (p = 0.354 for mortality) it was not emphasized.
Because of these discrepancies, we have pooled raw data for coronary bypass patients from the four published United States trials with unpublished data from two other trials obtained from Bayer Corporation to permit a more powerful analysis of low-incidence outcomes such as myocardial infarction, stroke, renal failure, and death. The patient populations, randomization, and 30-day or in-hospital mortality outcome are presented in Table 1
. Because not all trials contain all study arms, and because individual trials contain primary CABG, reoperative CABG, or both distributed equally in the study arms, the placebo groups were matched for each aprotinin dose study group. Thus, although the randomization process assures validity of the aprotinin comparisons with placebo, it would not be correct to compare placebo groups or aprotinin groups with one another in our figures.
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illustrates mortality trends and 95% confidence intervals for the 2,283 CABG patients randomized to placebo, pump-prime, half-dose aprotinin, and full-dose aprotinin. Figure 2 illustrates myocardial infarction trends and 95% confidence intervals for the 1,861 CABG patients with central laboratory electrocardiographic and enzyme data. Figures 3 and 4 illustrate changes from baseline creatinine level and stroke incidence, respectively.
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The observed CABG mortality for the pump-prime–only arm was 2.9% compared with 3.2% with placebo. Definite, probable, or possible myocardial infarction was increased, but not significantly, with pump-prime–only aprotinin (17.6%) compared with placebo (14.8%).
The larger number of patients randomized to placebo or high-dose aprotinin, and their more equivalent mortality outcome (2.7% versus 2.8%), leaves us more confident in safety. A power analysis indicates that 422,000 patients would be required to detect such a small increase in mortality.
No clinically or statistically significant trends were noted in renal function, as measured by comparing the incidence of postoperative creatinine level increase of more than 0.5 mg/dL or of more than 2 mg/dL between aprotinin study arms and matched placebo groups.
The intriguing reduction in stroke incidence originally reported by Levy and associates [5] is confirmed by our analysis, achieving statistical significance for the full-dose regimen (1.0% versus 2.4% with placebo; p = 0.027). The mechanism of this reduction remains unexplained.
From these data, we conclude that full-dose aprotinin is safe and effective for indicated patients at risk for bleeding complications (reoperative CABG, primary CABG with impaired coagulation systems, and patients refusing blood and blood products for personal reasons).
We also conclude that more information is required to consider half-dose aprotinin to be safe for any patient. Given the known safety of full-dose aprotinin, and the knowledge that the cost of aprotinin is determined more by market forces than true production cost per kallekrein inhibiting unit, a superior rationale than cost effectiveness should be provided to study more patients. An initial strategy could be the complete study of all previously randomized patients, including long-term follow-up, to increase the number of mortality and morbidity end points for analysis. Such a study would confirm or refute our analysis, and elaborate an appropriate rationale for a study of less than full-dose aprotinin with sufficient size and appropriate patient safeguards. The relationship between aprotinin use and the incidence of cerebrovascular events warrants additional study.
Footnotes
Address reprint requests to Dr Smith, Department of Surgery, Duke University Medical Center, Box 3442, Durham, NC 27710.
References
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