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The safety of aprotinin and lysine-derived antifibrinolytic drugs in cardiac surgery: a meta-analysis
Henry D, Carless P, Fergusson D, Laupacis A
CMAJ: Canadian Medical Association Journal [Journal De L'association Medicale Canadienne]. 2009;180((2):):183-93.
Abstract
BACKGROUND Because of recent concerns about the safety of aprotinin, we updated our 2007 Cochrane review that compared the relative benefits and risks of aprotinin and the lysine analogues tranexamic acid and epsilon aminocaproic acid. METHODS We searched electronic databases, including CENTRAL, MEDLINE, EMBASE, Google and Google Scholar for trials of antifibrinolytic drugs used in adults scheduled for cardiac surgery. Searches were updated to January 2008. By comparing aprotinin and the 2 lysine analogues to control, we derived indirect head-to-head comparisons of aprotinin to the other drugs. We derived direct estimates of risks and benefits by pooling estimates from head-to-head trials of aprotinin and tranexamic acid or epsilon aminocaproic acid. RESULTS For indirect estimates, we identified 49 trials involving 182 deaths among 7439 participants. The summary relative risk (RR) for death with aprotinin versus placebo was 0.93 (95% confidence interval [CI] 0.69-1.25). In the 19 trials that included tranexamic acid, there were 24 deaths among 1802 participants. The summary RR was 0.55 (95% CI 0.24-1.25). From the risk estimates derived for individual drugs, we calculated an indirect summary RR of death with use of aprotinin versus tranexamic acid of 1.69 (95% CI 0.70-4.10). To calculate direct estimates of death for aprotinin versus tranexamic acid, we identified 13 trials with 107 deaths among 3537 participants. The summary RR was 1.43 (95% CI 0.98-2.08). Among the 1840 participants, the calculated estimates of death for aprotinin compared directly to epsilon aminocaproic acid was 1.49 (95% CI 0.98-2.28). We found no evidence of an increased risk of myocardial infarction with use of aprotinin compared with the lysine analogues in either direct or indirect analyses. Compared with placebo or no treatment, all 3 drugs were effective in reducing the need for red blood cell transfusion. The RR of transfusion with use of aprotinin was 0.66 (95% CI 0.61-0.72). The RR of transfusion was 0.70 (95% CI 0.61-0.80) for tranexamic acid, and it was 0.75 (95% CI 0.58-0.96) for use of epsilon aminocaproic acid. Aprotinin was also effective in reducing the need for re-operation because of bleeding (RR 0.48, 95% CI 0.34-0.67). INTERPRETATION The risk of death tended to be consistently higher with use of aprotinin than with use of lysine analogues. Aprotinin had no clear advantages to offset these harms. Either tranexamic acid or epsilon aminocaproic acid should be recommended to prevent bleeding after cardiac surgery.
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A decision aid for autologous pre-donation in cardiac surgery--a randomized trial
Laupacis A, O'Connor AM, Drake ER, Rubens FD, Robblee JA, Grant FC, Wells PS
Patient Education and Counseling. 2006;61((3):):458-66.
Abstract
OBJECTIVES The objective of this randomized, controlled study was to determine the usefulness of a decision aid on pre-donation of autologous blood before elective open heart surgery. METHODS The decision aid (DA) group received a tape and booklet which described the options for peri-operative transfusion in detail. The no decision aid (NDA) group received information usually given to patients about autologous donation. RESULTS A total of 120 patients were randomized. The DA group rated themselves better prepared for decision making and showed significant improvements in knowledge (p = 0. 001) and realistic risk perceptions (p = 0. 001). In both groups there was an increase in the proportion of patients choosing allogeneic blood between baseline and follow-up (p = 0. 001). Patients in the DA group were significantly more satisfied with the amount of information they received, how they were treated and with the decision they made, than patients in the NDA group. CONCLUSION The decision aid is useful in preparing patients for decision making. PRACTICE IMPLICATIONS The next stage is to explore strategies to make it available to all appropriate patients.
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Desmopressin use for minimising perioperative allogeneic blood transfusion
Carless PA, Henry DA, Moxey AJ, O'Connell D, McClelland B, Henderson KM, Sly K, Laupacis A, Fergusson D
Cochrane Database of Systematic Reviews. 2004;((1):):CD001884.
Abstract
BACKGROUND Public concerns regarding the safety of transfused blood have prompted re-consideration of the use of allogeneic (from an unrelated donor) red blood cell (RBC) transfusion, and of a range of techniques designed to minimise transfusion requirements. OBJECTIVES To examine the evidence for the efficacy of desmopressin acetate (1-deamino-8-D-arginine-vasopressin; DDAVP), in reducing perioperative blood loss and the need for red cell transfusion in patients who do not have congenital bleeding disorders. SEARCH STRATEGY Articles were identified by: computer searches of MEDLINE, EMBASE, Current Contents (to May 2003), and the Cochrane Central Register of Controlled Trials (CENTRAL) (Cochrane Library, Issue 1, 2003). References in the identified trials and review articles were searched and authors contacted to identify additional studies. SELECTION CRITERIA Controlled parallel group trials in which adult patients, scheduled for non-urgent surgery, were randomised to DDAVP, or to a control group, who did not receive the intervention. DATA COLLECTION AND ANALYSIS Trial quality was assessed using criteria proposed by Schulz et al. (Schulz 1995) and Jadad et al. (Jadad 1996). Main outcomes measured were: the number of patients exposed to allogeneic red cell transfusion, and the amount of blood transfused. Other outcomes measured were: re-operation for bleeding, blood loss, post-operative complications (thrombosis, infection, non-fatal myocardial infarction), mortality, and length of hospital stay (LOS). MAIN RESULTS Eighteen trials of DDAVP (n=1295) reported data on the number of patients transfused with allogeneic RBC transfusion. In subjects treated with DDAVP, the pooled relative risk of exposure to perioperative allogeneic RBC transfusion was 0.95 (95%CI = 0.86 to 1.06). The use of DDAVP did not significantly reduce blood loss; weighted mean difference (WMD) = -114.3ml: 95% confidence interval (95%CI) = -258.8 to 30.2ml per patient) or the volume of RBC transfused (WMD = -0.35 units: 95%CI = -0.70 to 0.01 units). In DDAVP-treated patients the relative risk of requiring re-operation due to bleeding was 0.69 (95%CI = 0.26 to 1.83). There was no statistically significant effect overall for mortality and non-fatal myocardial infarction in DDAVP-treated patients compared with control (RR = 1.72: 95%CI = 0.68 to 4.33) and (RR = 1.38: 95%CI = 0.77 to 2.50) respectively. AUTHORS' CONCLUSIONS There is no convincing evidence that desmopressin minimises perioperative allogeneic RBC transfusion in patients who do not have congenital bleeding disorders. These data suggest that there is no benefit from using DDAVP as a means of minimising perioperative allogeneic RBC transfusion. PLAIN LANGUAGE SUMMARY There is no convincing evidence that desmopressin reduces the need for blood transfusions in patients who do not suffer from congenital bleeding disorders.Risks of infection from transfused blood given by an unrelated donor are minimal when blood is screened by a competent transfusion service but concerns remain high. Other techniques are available to reduce the need for a transfusion. The review of trials found that there is no convincing evidence that desmopressin reduces the need for blood transfusion in patients undergoing elective surgery, who do not have congenital bleeding disorders. Other strategies, such as the use of anti-fibrinolytic agents may be more effective.
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Cost effectiveness of epoetin-alpha to augment preoperative autologous blood donation in elective cardiac surgery
Coyle D, Lee KM, Fergusson DA, Laupacis A
Pharmacoeconomics. 2000;18((2):):161-71.
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Platelet-rich plasmapheresis in cardiac surgery: a meta-analysis of the effect on transfusion requirements
Rubens FD, Fergusson D, Wells PS, Huang M, McGowan JL, Laupacis A
Journal of Thoracic and Cardiovascular Surgery. 1998;116((4):):641-7.
Abstract
OBJECTIVE Our purpose was to determine whether intraoperative platelet-rich plasmapheresis in cardiac surgery is effective in reducing the proportion of patients exposed to allogeneic red cell transfusions. METHODS A systematic search for prospective, randomized trials of platelet-rich plasmapheresis in cardiac surgery, using MEDLINE, HEALTHSTAR, Current Contents, Biological Abstracts, and EMBASE/Excerpta Medica up to August 1997, was completed. Trials were included if they reported either the proportion of patients exposed to allogeneic red cells or the units of allogeneic red cells transfused. Trials were abstracted by 2 independent investigators and the quality of trial design was assessed with the use of a validated scale. RESULTS Seventeen references met the inclusion criteria (1369 patients (675 control: 694 platelet-rich plasmapheresis)). Plateletrich plasmapheresis reduced the likelihood of exposure to allogeneic red cells in cardiac surgery (odds ratio 0.44; 95% confidence interval 0.27, 0.72, P = .001). Platelet-rich plasmapheresis had a small but statistically significant effect on both the volume of blood lost in the first 24 hours (weighted mean difference -102 mL; 95% confidence interval -148, -55 mL, P < .0001) and the mean units transfused (weighted mean difference -0.33 units; 95% confidence interval -0.43, -0.23, P < .0001). However, platelet-rich plasmapheresis was only marginally effective (odds ratio 0.83, 95% confidence interval 0.34, 2.01, P = .68) for good quality trials, whereas it appeared very effective in trials with poor methodologic quality (odds ratio 0.33, 95% confidence interval 0.17, 0.62, P = .0007). CONCLUSIONS Although platelet-rich plasmapheresis appeared effective in decreasing the proportion of patients receiving transfusions after cardiac operations, the quality of most of the supporting trials was low and the benefit was small in trials of good quality. Further clinical trials should be completed.
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Drugs to minimize perioperative blood loss in cardiac surgery: meta-analyses using perioperative blood transfusion as the outcome. The International Study of Peri-operative Transfusion (ISPOT) Investigators
Laupacis A, Fergusson D
Anesthesia and Analgesia. 1997;85((6):):1258-1267.
Abstract
Concern about the side effects of allogeneic red blood cell transfusion has increased interest in methods of minimizing perioperative transfusion. We performed meta-analyses of randomized trials evaluating the efficacy and safety of aprotinin, desmopressin, tranexamic acid, and epsilon-aminocaproic acid in cardiac surgery. All identified randomized trials in cardiac surgery were included in the meta-analyses. The primary outcome was the proportion of patients who received at least one perioperative allogeneic red cell transfusion. Sixty studies were included in the meta-analyses. The largest number of patients (5808) was available for the meta-analysis of aprotinin, which significantly decreased exposure to allogeneic blood (odds ratio [OR] 0.31, 95% confidence interval [CI] 0.25-0.39; P < 0.0001). The efficacy of aprotinin was not significantly different regardless of the type of surgery (primary or reoperation), aspirin use, or reported transfusion threshold. The use of aprotinin was associated with a significant decrease in the need for reoperation because of bleeding (OR 0.44, 95% CI 0.27-0.73; P = 0.001). Desmopressin was not effective, with an OR of 0.98 (95% CI 0.64-1.50; P = 0.92). Tranexamic acid significantly decreased the proportion of patients transfused (OR 0.50, 95% CI 0.34-0.76; P = 0.0009). Epsilon-aminocaproic acid did not have a statistically significant effect on the proportion of patients transfused (OR 0.20, 95% CI 0.04-1.12; P = 0.07). There were not enough patients to exclude a small but clinically important increase in myocardial infarction or other side effects for any of the medications. We conclude that aprotinin and tranexamic acid, but not desmopressin, decrease the number of patients exposed to perioperative allogeneic transfusions in association with cardiac surgery. Implications: Aprotinin, desmopressin, tranexamic acid, and epsilon-aminocaproic acid are used in cardiac surgery in an attempt to decrease the proportion of patients requiring blood transfusion. This meta-analysis of all published randomized trials provides a good estimate of the efficacy of these medications and is useful in guiding clinical practice. We conclude that aprotinin and tranexamic acid, but not desmopressin, decrease the exposure of patients to allogeneic blood transfusion perioperatively in relationship to cardiac surgery.