Perioperative transfusion in anaemic patients undergoing coronary artery bypass

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*Ralf Baron, Joern Schattschneider, Andreas Binder, Dieter Siebrecht, Gunnar Wasner *Klinik für Neurologie, und Klinik für Anästhesiologie und Operative Intensivmedizin, Christian-Albrechts-Universität Kiel, 24105 Kiel, Germany (e-mail: [email protected]) 1

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Scadding JW. Complex regional pain syndrome. In: Wall PD, Melzack R, ed. Textbook of pain, 4th edn. Edinburgh: Churchill Livingstone, 1999: 835–50. Galer BS, Schwartz L, Allen RJ. Complex regional pain syndromes type I: reflex sympathetic dystrophy, and type II: causalgia. In: Loeser JD, ed. Bonica`s management of pain, 3rd edn. Philadelphia: Lippincott Williams and Wilkins, 2001: 388–411. Harden RN, Baron R, Jänig W, eds. Complex regional pain syndrome: progress in pain research and management, vol 22. Seattle: IASP Press, 2001. Price DD, Long S, Wilsey B, Rafii A. Analysis of peak magnitude and duration of analgesia produced by local anesthetics injected into sympathetic ganglia of complex regional pain syndrome patients. Clin J Pain 1998; 14: 216–26.

Perioperative transfusion in anaemic patients undergoing coronary artery bypass Sir—D Zindrou and colleagues (May 18, p 1747)1 report on preoperative haemoglobin concentration and mortality after coronary artery bypass surgery (CABG). We have some comments on their findings. They enrolled 2059 consecutive patients undergoing isolated CABG. We assume all patients underwent CABG under cardiopulmonary bypass. The mean number of grafts per patient is not given, although 96% of the patients received a graft from the internal mammary artery and, consequently, one graft to the anterior descending or right coronary arteries might have been done in some. If patients underwent off-pump CABG, the number should be noted because the postoperative course differs notably from that after on-pump surgery.2 If all patients underwent CABG under cardiopulmonary bypass, did any receive aprotinin? The number of treatments and the doses must be cited, since this drug can also modify patients’ outcomes.3 Zindrou and colleagues give no information about perioperative blood loss, blood-saving techniques, transfusion trigger, number of patients transfused in the non-anaemic group, number of units transfused per patient, or postoperative complications. This issue is important since there is a dosedependent association between blood transfusion and the development of severe postoperative infection and death

in patients undergoing cardiac surgery.4 For mortality, the crude data the investigators show in the figure are also confounded because discharged patients are not included. Despite this omission, the overall in-hospital mortality rate is slightly higher than that reported for a similar series of 2569 CABG patients, in whom transfusion trigger during cardiopulmonary bypass was a packed-cell volume of lower than 20%, and mortality was defined as death during hospital stay or within 30 days of surgery (3·37 vs 2·79%).5 In Zindrou and colleagues’ study, patients with a haemoglobin concentration less than 100 g/L had the pump primed with blood. Administration of blood during cardiopulmonary bypass may begin a cascade of events that contributes to postoperative organ dysfunction and morbidity associated with complement activation. Since low packed-cell volume during cardiopulmonary bypass is well tolerated, blood transfusion should be delayed until the intervention is stopped, when the packed-cell volume may need to be higher, thus reducing morbidity.5 Finally, we agree that disease severity and comorbidity had the greatest effect on mortality in the anaemic group, which may have been aggravated by transfusion of stored blood, and the anaemia being just a consequence of some of the disorders, such as renal failure. Hence, whenever possible, preoperative pharmacological but not transfusional treatment of anaemia should be used. *M Muñoz, J A García-Erce, S R Leal-Noval *GIEMSA (International Multidisciplinary Autotransfusion Study Group), University of Málaga School of Medicine. 29071 Málaga, Spain; Department of Hematology and Transfusion Medicine, Hospital Universitario Miguel Servet, Zaragoza; and Critical Care Division, Hospital Universitario Virgen del Rocio, Seville (e-mail: [email protected]) 1

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Zindrou D, Taylor KM, Bagger JP. Preoperative haemoglobin concentration and mortality rate after coronary artery bypass surgery. Lancet 2002; 359: 1747–48. Buffolo E, Andrade JC, Branco JN, Aguiar LF, Ribeiro EE, Jatene AD. Myocardial revascularization without extracorporeal circulation: seven-year experience in 593 cases. Eur J Cardiothorac Surg 1990; 4: 504–07. Levy M, Cromheecke ME, de Jonge E, et al. Pharmacological strategies to decrease excessive blood loss in cardiac surgery: a meta-analyses of clinically relevant end points. Lancet 1999; 354: 1940–47. Leal-Noval SR, Rincón-Ferrari MD, García-Curiel A, et al. Transfusion of blood components and postoperative infection in patients undergoing cardiac surgery. Chest 2001; 119: 1461–68. Utley JR, Wilde EF, Leyland SA, Morgan MS, Johnson HD. Intraoperative blood transfusion is a major risk factor for coronary artery bypass grafting in women. Ann Thorac Surg 1995; 60: 570–75.

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Authors’ reply Sir—No patient in the study underwent off-pump CABG. The mean number of grafts per patient was 2·8 (SD 0·5). Only 44 (2%) patients received one graft. These data do not alter the overall results. Perioperative blood loss was compensated for by autotransfusion. We have no systematic information on the amount of autotransfusion. We did report the preoperative transfusion trigger level. Perioperatively we gave transfusion if the packed-cell volume was lower than 20%. The recording of the number of transfusions given to patients with and without anaemia and complications among patients who actually received transfusions was beyond the scope of the study. However, 23 patients had reoperation because of postoperative bleeding, four of whom died. Aprotinin was given to about 20% of patients, mainly those at an increased risk of bleeding.1 The patients were not randomised for treatment with this drug and we did not attempt such subgroup analysis. For the endpoint, we assumed that patients with low haemoglobin concentrations would stay in hospital longer and sustain more complications after major surgery than those with higher concentrations. We therefore thought it fair to report on in-hospital mortality. We included three deaths that occurred later than 30 days after surgery. We showed crude survival only up to 30 days in the figure for practical reasons. Finally, we disagree with Muñoz and colleagues’ statement that there is a dose-dependent association between blood transfusion and development of severe postoperative infection and death. We do not think transfusions should be viewed in such an unambiguous way, at least in relation to death. Higher rates of perioperative bleeding complications will obviously lead to an increased rate of transfusions. However, transfusion per se is not necessarily a risk factor. The repeated operative trauma and raised risk of infection with repeated operations are probably more important for the outcome. Furthermore, patients with anaemia are more likely to have blood transfusions while undergoing bypass surgery than patients with no anaemia, despite use of blood-saving techniques. We suggested that anaemia was a marker of disease severity or comorbidity, and we believe that this relation probably has a greater effect on outcome than does transfusion. We are not, however, advocating that

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CORRESPONDENCE

transfusions are harmless. We believe they may add to morbidity and possibly mortality after surgery. Yet, these considerations do not preclude the fact that transfusion can be an independent predictor of outcome after surgery, as Utley and colleagues noted. We simply believe that transfusions are mainly the surrogate of a combination of operative difficulties, disease severity, and comorbidity.

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weekly interferon beta-1a for multiple sclerosis: results of a 2-year prospective randomised multicentre study (INCOMIN). Lancet 2002; 359: 1453–60. Durelli L, Ferrero B, Oggero A, et al. A multicentre trial comparing clinical and MRI efficacy of Interferon beta-1a and beta-1b in multiple sclerosis. J Neurol 2001; 248 (suppl): 62. ICH E6 consolidated guideline on good clinical practice: CPMP/ICH/135/95; London: European Agency for the Evaluation of Medicinal Products (EMEA), 1997.

D Zindrou, K M Taylor, *J P Bagger Cardiothoracic Directorate, Faculty of Medicine, Imperial College School of Science, Technology and Medicine, Hammersmith Hospital, London W12 0NN, UK (e-mail: [email protected]) 1

Taylor KM. Perioperative approaches to coagulation defects. Ann Thorac Surg 1993; 56 (suppl): S78–82.

Interferon beta-1a and beta1b for treatment of multiple sclerosis Sir—In their thoroughly planned and well done study, Luca Durelli and colleagues (April 27, p 1453)1 compare every-other-day interferon beta-1b with weekly interferon beta-1a for treatment of relapsing-remitting multiple sclerosis. In the MRI groups, patients on interferon beta-1a seem to have more proton density lesions, enhancing lesions, and Tl hypointense lesions at baseline. I would like to know whether these imbalances were corrected for when calculating the significance of differences during the trial. Durelli and colleagues state that no analysis of the results was done before the end of 2000. However, the 1-year results were presented in spring, 2001.2 Since the study was unblinded, I wonder what effect the early presentation had on the continuing assessment of patients, at least in the 2nd year of the study, for number of relapses and confirmed score on expanded disability status scale. I also do not understand how this 1-year analysis is compatible with the investigators’ statement that no interim analysis was planned and data were not monitored during the trial. Was there, therefore, no external quality control of the data provided by the participating centres, as is generally expected in studies done according to good clinical practice guidelines.3 L Kappos Neurologisch-Neurochirurgische Poliklinik, Kantonsspital Basel Universitätskliniken, CH-4031 Basel, Switzerland (e-mail: [email protected]) 1

Durelli L, Verdun E, Barbero P, et al. Everyother-day interferon beta-1b versus once-

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Sir—Luca Durelli and colleagues’ INdependent COMparison of INterferon (INCOMIN) study1 is important, but a word of caution is necessary before every-other-day highdose interferon beta-1b is generally accepted as more effective than weekly interferon beta-1a for treatment of multiple sclerosis. They report a prospective randomised trial in which patients received once-weekly injections of 6 MIU interferon beta-1a or injections of 8 MIU interferon beta-1b every other day. The primary clinical outcome was the proportion of patients who remained free from relapses for the 24-month duration of the study. The primary MRI outcome measure was the proportion of patients free from new proton-density or T2 hyperintense lesions. The MRI outcome measures were assessed in a blinded analysis, but clinical outcomes were not. The main reason for caution in accepting Durelli and colleagues’ results is that the findings are discrepant from those reported in the phase III clinical studies that established the efficacy of the interferons. Notably, the proportion of patients given interferon beta-1b who remained relapse free at 2 years was 51% in the INCOMIN study compared with 31% in the phase III study.2 The difference in yearly relapse rate between the two treatment groups in the INCOMIN study reflects a lower relapse rate in the interferon beta-1b group and a higher relapse rate in the interferon beta-1a rate than were reported in the respective phase III studies.2,3 The table shows these and other comparative data. The phase III trials were prospective, randomised, double-blind, placebocontrolled trials. INCOMIN was not. Durelli and colleagues do acknowledge

Porportion patients relapse-free Yearly relapse rate Proportion patients with ⭓1 point EDSS progression

the potential limitation of the lack of blinding for the clinical outcome, but argue that this limitation is unlikely to account for the differences they note in favour of interferon beta-1b. Blinded analysis of outcome is particularly important for subjective measures and, to their credit, the INCOMIN investigators made every effort to objectify the measurement of relapses by requiring independent confirmation of relapse by one of the investigators. The potentially confounding effect of the lack of blinding is illustrated by the randomised controlled trial of cyclophosphamide in multiple sclerosis, in which a significant treatment effect of cyclophosphamide was noted by the treating (unblinded) neurologists but not by the assessing (blinded) neurologists.4 I cannot be certain that the results of the phase III clinical trials more accurately represent the treatment effects of the interferons in multiple sclerosis than do those of the INCOMIN study. Nevertheless, I believe that the discrepancies between studies and the limitations in the methods of the INCOMIN study should lead to caution. Michael Benatar Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA 02215, USA (e-mail: [email protected]) 1

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Durelli L, Verdun E, Barbero P, et al. Everyother-day interferon beta-1b versus onceweekly interferon beta-1a for multiple sclerosis: results of a 2-year prospective randomised multicentre study (INCOMIN). Lancet 2002; 359: 1453–60. The IFNB Multiple Sclerosis Study Group. Interferon beta-1b is effective in relapsingremitting multiple sclerosis, I: clinical results of a multicenter, randomized, double-blind, placebo-controlled trial. Neurology 1993; 43: 655–61. Jacobs LD, Cookfair DL, Rudick RA, et al. Intramuscular interferon beta-1a for disease progression in relapsing multiple sclerosis. Neurology 1996; 39: 285–94. Noseworthy J, Ebers G, Vandervoort M, Farquhar R, Yetisir E, Roberts R. The impact of blinding on the results of a randomized, placebo-controlled multiple sclerosis clinical trial. Neurology 1994; 44: 16–20.

Author’s reply Sir—L Kappos notes that in the MRI analysis groups, interferon beta-1a patients have more proton density, enhancing, and T1 hypointense lesions at baseline. The two groups do not

Interferon beta-1a Phase III study INCOMIN 38% 36% 0·61*–0·67† 0·7 21·9*–21·2%† 30%

Interferon beta-1b Phase III study INCOMIN 31% 55% 0·84 0·5 27%‡ 13%

EDSS=expanded disability status scale. *Data from patients who completed 104 weeks follow-up. †All patients in study with 2-year data estimated from Kaplan-Meier curves. ‡Result from 3-year data since comparable 2-year data not available.

2-year outcome data from phase III and INCOMIN studies

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