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.
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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.
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.
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.
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.
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.
Cost effectiveness of epoetin-alpha to augment preoperative autologous blood donation in elective cardiac surgery
Coyle D, Lee KM, Fergusson DA, Laupacis A
Economic analysis of erythropoietin use in orthopaedic surgery
Coyle D, Lee KM, Fergusson DA, Laupacis A
Transfusion Medicine. 1999;9((1):):21-30.
A meta-analysis of the effectiveness of cell salvage to minimize perioperative allogeneic blood transfusion in cardiac and orthopedic surgery. International Study of Perioperative Transfusion (ISPOT) Investigators
Huet C, Salmi LR, Fergusson D, Koopman-van-Gemert AW, Rubens F, Laupacis A
Anesthesia and Analgesia. 1999;89((4):):861-9.
Concern about risks of allogeneic transfusion has led to an interest in methods for decreasing perioperative transfusion. To determine whether cell salvage reduces patient exposure to allogeneic blood, we performed meta-analyses of randomized trials, evaluating the effectiveness and safety of cell salvage in cardiac or orthopedic elective surgery. The primary outcome was the proportion of patients who received at least one perioperative allogeneic red cell transfusion. Twenty-seven studies were included in the meta-analyses. Cell salvage devices that do not wash salvaged blood were marginally effective in cardiac surgery patients when used postoperatively (relative risk (RR) = 0.85, 95% confidence interval (CI) = 0.79-0.92). Devices that wash or do not wash salvaged blood considerably decreased the proportion of orthopedic surgery patients who received allogeneic transfusion (RR = 0.39, 95% CI = 0.30-0.51 and RR = 0.35, 95% CI 0.26-0.46, respectively). No studies of cell savers that wash salvaged blood during cardiac surgery were included. Cell salvage did not appear to increase the frequency of adverse events. We conclude that cell salvage in orthopedic surgery decreases the risk of patients' exposure to allogeneic blood transfusion perioperatively. Postoperative cell salvage in cardiac surgery, with devices that do not wash the salvaged blood, is only marginally effective. IMPLICATIONS This meta-analysis of all published randomized trials provides the best current estimate of the effectiveness of cell salvage and is useful in guiding clinical practice. We conclude that cell salvage in orthopedic surgery decreases the proportion of patients requiring allogeneic blood transfusion perioperatively, but postoperative cell salvage is only marginally effective in cardiac surgery.
Economic evaluations of technologies to minimize perioperative transfusion: a systematic review of published studies
Fergusson D, van Walraven C, Coyle D, Laupacis A, International Study of Peri-operative Transfusion investigators
Transfusion Medicine Reviews. 1999;13((2):):106-17.
Perioperative allogeneic blood transfusion does not cause adverse sequelae in patients with cancer: a meta-analysis of unconfounded studies
McAlister FA, Clark HD, Wells PS, Laupacis A
British Journal of Surgery. 1998;85((2):):171-8.
BACKGROUND There is controversy over whether perioperative allogeneic red blood cell transfusions are associated with an increased risk of cancer recurrence, postoperative infection or death in patients with cancer undergoing surgery. METHODS A systematic meta-analysis was performed to answer this question. Studies were identified from electronic databases (Medline 1966-1997, Cancerlit 1983-1997, Current Contents, Cinahl 1982-1996, Healthstar 1990-1997, Bioabstracts 1990-1996 and Embase), by hand search of the bibliographies of identified studies and relevant journals, and by contact with experts in the field. All randomized controlled trials or prospective cohort studies with active comparator controls (autologous or leucocytedepleted allogeneic blood) were eligible for inclusion if they reported on mortality, infection or recurrence rate in patients with cancer undergoing potentially curative surgical resection. The validity of the identified studies was assessed by means of a standardized scale, and data abstraction was carried out by two investigators independently. A random effects model was used for data synthesis. RESULTS Of the 2172 references identified, only 17 studies fulfilled the inclusion criteria. After exclusion of duplicate publications, six randomized controlled trials and two prospective cohort studies with appropriate concurrent controls were included in the analysis. The summary risk ratios were 0.95 (95 per cent confidence interval (c.i.) 0.79-1.15) for all-cause mortality and 1.06 (95 per cent c.i. 0.88-1.28) for cancer recurrence, the two endpoints that were appropriate to combine statistically. There was significant heterogeneity (explainable by differences in study design and patient characteristics) in the postoperative infection data and the summary risk ratio was 1.00 (95 per cent c.i. 0.76-1.32) for the four studies that were appropriate to subject to meta-analysis. Given the sample sizes of these eight studies, this meta-analysis had insufficient power to detect a relative difference of less than 20 per cent in the frequency of death, cancer recurrence or infection between the allogeneic and control transfusion arms. CONCLUSION Although more studies are required before a definitive statement can be made, at this time there is no evidence that allogeneic blood transfusion increases the risk of clinically important adverse sequelae in patients with cancer undergoing surgery.
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.
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.
Preoperative autologous donation decreases allogeneic transfusion but increases exposure to all red blood cell transfusion: results of a meta-analysis. International Study of Perioperative Transfusion (ISPOT) Investigators
Forgie MA, Wells PS, Laupacis A, Fergusson D
Archives of Internal Medicine. 1998;158((6):):610-616.
BACKGROUND Concern about risks associated with allogeneic red blood cell transfusion has led to interest in methods of decreasing patient exposure to perioperative transfusion. OBJECTIVE To perform a meta-analysis to determine the degree to which predonation of autologous blood reduces patients' exposure to allogeneic blood and all transfusions of red blood cells (allogeneic or autologous). METHODS We searched MEDLINE, EMBASE, bibliographies, annual reports, press releases, newsletters from organizations with interests in the blood system, and personal files for randomized studies and concurrent control cohort studies in which the control groups were patients excluded for nonmedical reasons. RESULTS Patients who predonated autologous blood were less likely to receive allogeneic blood in the 6 randomized studies (n = 933) (odds ratio [OR], 0.17; 95% confidence interval [CI], 0.08-0.32) and in the 9 cohort studies (n = 2351) (OR, 0.19; 95% CI, 0.14-0.26). However, autologous donors were more likely to undergo transfusion with allogeneic and/or autologous blood (for randomized studies: OR, 3.03; 95% CI, 1.70-5.39 and for cohort studies: OR, 12.32; 95% CI, 5.90-25.40). Studies that reported use of transfusion protocols found less benefit with preoperative autologous donation, although the difference was not statistically significant. CONCLUSIONS Preoperative autologous donation of blood decreases exposure to allogeneic blood but increases exposure to any transfusion (allogeneic and/or autologous). There is a direct relationship between the transfusion rate in the control group and the benefit derived from preoperative autologous donation. This suggests that other methods of decreasing blood transfusion, such as surgical technique and transfusion protocols, may be as important as preoperative autologous donation of blood.