Early Postoperative Anticoagulation: More Questions Than Answers?

Early Postoperative Anticoagulation: More Questions Than Answers?

Ann Thorac Surg 2006;82:1570 – 6 Ioannis K. Toumpoulis, MD Department of Cardiothoracic Surgery Attikon Hospital Center Georgiou Sisini 31 Athens, 11...

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Ann Thorac Surg 2006;82:1570 – 6

Ioannis K. Toumpoulis, MD Department of Cardiothoracic Surgery Attikon Hospital Center Georgiou Sisini 31 Athens, 11528 Greece, e-mail: [email protected] © 2006 by The Society of Thoracic Surgeons Published by Elsevier Inc

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References 1. Kaplan S, Bisleri G, Morgan JA, Cheema FH, Oz MC. Resveratrol, a natural red wine polyphenol, reduces ischemiareperfusion-induced spinal cord injury. Ann Thorac Surg 2005;80:2242–9. 2. Kiziltepe U, Turan NN, Han U, Ulus AT, Akar F. Resveratrol, a red wine polyphenol, protects spinal cord from ischemiareperfusion injury. J Vasc Surg 2004;40:138 – 45. 3. Toumpoulis IK, Anagnostopoulos CE, Drossos GE, MalamouMitsi VD, Pappa LS, Katritsis DG. Early ischemic preconditioning without hypotension prevents spinal cord injury caused by descending thoracic aortic occlusion. J Thorac Cardiovasc Surg 2003;125:1030 – 6. 4. Toumpoulis IK, Papakostas JC, Matsagas MI, et al. Superiority of early relative to late ischemic preconditioning in spinal cord protection after descending thoracic aortic occlusion. J Thorac Cardiovasc Surg 2004;128:724 –30. 5. Kakimoto M, Kawaguchi M, Sakamoto T, et al. Evaluation of rapid ischemic preconditioning in a rabbit model of spinal cord ischemia. Anesthesiology 2003;99:1112–7.

Early Postoperative Anticoagulation: More Questions Than Answers? To the Editor: We read with interest the report by Jones and colleagues [1] evaluating the hemorrhagic risk of postoperative unfractionated heparin and enoxaparin after cardiac surgery. Using data collected on 2,977 consecutive cardiac surgery patients treated in Salt Lake City, Utah, the authors reported that early postoperative use of enoxaparin and unfractionated heparin was associated with a significant increase in reexploration for postoperative bleeding. We recently reviewed the literature regarding the role of early anticoagulation after mechanical valve replacement [2], and we were enthusiastic to learn of the Salt Lake City experience. Yet given the paucity of methodological definitions, we found it difficult to interpret the study’s results. The authors suggested that early postoperative anticoagulation increased the risk of bleeding, but gave no time reference to the term early. Institutionally biased, the timing of anticoagulation initiation can vary from 6 to 48 hours after mechanical valve implantation. The majority of patients in Jones and colleagues’ [1] study were reexplored in the initial 3 days. However, without knowledge of the time interval between anticoagulation and reopening, it was difficult to discern whether the rate of reexploration was attributable to the anticoagulation strategy, or whether it was attributable to patient-related factors or surgery-related factors, or both. Furthermore, the dose and route of unfractionated heparin administration were not defined in the heparin group, and the specific indications for anticoagulation were not discussed. Bleeding and cardiac tamponade are serious complications after cardiac surgery, and both have been demonstrated to occur at higher rates in patients undergoing valve surgery compared with isolated coronary bypass grafting [3–5]. Table 1 in Jones and colleagues’ [1] article clearly illustrated that the heparin and enoxaparin groups underwent more complex and longer operations than the control group [1]. The proportion of redo operations among this cohort was not stated. The authors performed a Cox regression analysis to evaluate the effect of postoperative anticoagulation while controlling for the covariates of age, gender, type of preoperative and perioperative anticoagulant, warfarin, and antiplatelet therapy. However, the type and length of surgical procedure were not factored into the analysis. Although an attempt was made to factor warfarin into 0003-4975/06/$32.00

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nal Cord Injury” [1]. I congratulate Kaplan and colleagues [1] on their study of resveratrol use to provide ischemic spinal cord protection. In this study the authors evaluated the effect of resveratrol (100 ␮g/kg) on the spinal cord in a rabbit experimental model of 30-minute infrarenal aortic cross clamping. They used 16 rabbits assigned either to a treated group (n ⫽ 8, resveratrol was infused 15 minutes before aortic occlusion) or a control group (n ⫽ 8, untreated group). All animals were sacrificed at 24 hours and groups were compared clinically using the Tarlov score, while histopathologic assessment and measurements of malondiadehyde levels and myeloperoxidase activity were performed. Neurologic impairment, reduction of the number of motor neurons, malondiadehyde levels and myeloperoxidase activity were significantly lower in the resveratrol group. In a previous published study, Kiziltepe and colleagues [2] used almost the same experimental rabbit model and evaluated the effect of resveratrol on the spinal cord using two different doses (1 mg/kg and 10 mg/kg of resveratrol, which were administered 30 minutes before infrarenal aortic occlusion). The protected effect of resveratrol in this study was not prominent in animals that received 1 mg/kg, and only animals that received 10 mg/kg resveratrol experienced spinal cord protection. In our recently published studies [3, 4], we have demonstrated that immediate ischemic preconditioning without hypotension prevents spinal cord injury in a porcine model of descending thoracic aortic occlusion. In our studies it was very important to maintain the arterial systolic blood pressure ⬎ 100 mm Hg during the reperfusion interval, while we have underscored that hypotensive animals (80 to 90 mm Hg arterial systolic blood pressure) during the reperfusion interval became paraplegic at 48 hours postoperatively. Kaplan and colleagues [1] observed significantly increased proximal aortic blood pressure in the resveratrol group as well as distal aortic blood pressure during cross clamping. This phenomenon itself may explain the protective effect on the spinal cord in this group. How did the authors explain the previously mentioned increased arterial blood pressures and what would have been the results if the two groups had similar arterial blood pressures? A possible reply could be extracted from the study of Kiziltepe and colleagues [2] in which they used a 10 times higher dose (1 mg/kg instead of 100 ␮g/kg in the study of Kaplan and colleagues [1]) and there was no elevation in arterial blood pressure during the reperfusion interval in the resveratrol group, and there was no difference found when compared with the controls. Kaplan and colleagues [1] claimed in the Comment section of their article that a detailed Medline research regarding resveratrol was performed to determine the dose of resveratrol. The study of Kiziltepe and colleagues [2] (published in 2004) is not referenced by Kaplan and colleagues [1]. Were the authors aware of this study and the used doses of resveratrol? Finally, why did the authors choose to follow-up the animals for only 24 hours postoperatively? It is well-known that among such studies an appropriate time interval for follow-up should be 5 or 7 days postoperatively to exclude any transient protection or the effect of delayed paraplegia [3–5].

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the analysis, we do not believe that Cox regression analysis can eliminate the confounding created by differing rates of postoperative warfarin therapy in the groups (enoxaparin patients, 25%; control patients, 12%). Given the number of differences between the groups, some controlled for and others not, we find it difficult to agree with the conclusion that the higher reexploration rate was solely attributable to enoxaparin. Unlike Jones and colleagues [1], in our systematic review we found that the bleeding risk associated with low molecular weight heparin was less than that associated with intravenous heparin (hemorrhage risk with oral anticoagulation alone, 3.3%; oral anticoagulation with intravenous unfractionated heparin, 7.2%; oral anticoagulation with low molecular weight heparin, 4.8%) [2]. Although we may argue this study’s methodology and results, we wholeheartedly agree with the authors that prospective randomized studies are necessary to fully ascertain the relative risks and benefits of different anticoagulation regimens with a variety of clinical circumstances after cardiac surgery. Alexander Kulik, MD Fraser D. Rubens, MD, MS Thierry G. Mesana, MD, PhD B-Khanh Lam, MD, MPH Division of Cardiac Surgery University of Ottawa Heart Institute 40 Ruskin Street, Suite H3204 Ottawa, Ontario, K1Y 4W7 Canada e-mail: [email protected]

References

MISCELLANEOUS

1. Jones HU, Muhlestein JB, Jones KW, et al. Early postoperative use of unfractionated heparin or enoxaparin is associated with increased surgical re-exploration for bleeding. Ann Thorac Surg 2005;80:518 –22. 2. Kulik A, Rubens FD, Wells PS, et al. Early postoperative anticoagulation after mechanical valve replacement: a systematic review. Ann Thorac Surg 2005; (in press). 3. Meurin P, Weber H, Renaud N, et al. Evolution of the postoperative pericardial effusion after day 15: the problem of the late tamponade. Chest 2004;125(6):2182–7. 4. Pepi M, Muratori M, Barbier P, et al. Pericardial effusion after cardiac surgery: incidence, site, size, and haemodynamic consequences. Br Heart J 1994;72(4):327–31. 5. Unsworth-White MJ, Herriot A, Valencia O, et al. Resternotomy for bleeding after cardiac operation: a marker for increased morbidity and mortality. Ann Thorac Surg 1995;59(3):664 –7.

Reply To the Editor: We appreciate the interest that Kulik and colleagues [1] have shown in our article describing our observational findings of the hemorrhagic risk associated with postoperative anticoagulation after cardiac surgery [2]. We appreciate their careful critique and have performed further analysis, and we would like to respond to their comments. In our study, we included all patients who received postoperative anticoagulation any time during the postsurgical hospital stay. Our database does not contain individual postoperative anticoagulation initiation times, but in general our institutional practice has been to initiate anticoagulation 24 to 48 hours after surgery. In most instances, among patients receiving postoperative anticoagulation, return to surgery occurred after the first 24 to 48 hours. Therefore we expect that this is after reinitiation of

Ann Thorac Surg 2006;82:1570 – 6

anticoagulation therapy. Unfortunately our database did not show the exact dose and route of unfractionated heparin administration, nor did it provide specific physician-reported indications for anticoagulation. The proportions of re-do operations among this cohort were 13%, 15%, and 17% in the none, unfractionated heparin, and enoxaparin groups, respectively (p ⫽ 0.09), but in the Cox regression adjustment for re-do operation, there is no meaningful confounding effect on the association of postoperative anticoagulants to reoperation. We also performed additional Cox regression adjusting for length of surgical procedure, and it had no meaningful effect on the association either. Adjustment for type of surgery did influence the association with changes in the hazard ratio for unfractionated heparin compared with none, from 2.46 before to 2.42, and for enoxaparin, from 2.31 before to 2.52. These changes did not provide a statistically significant change in the fit of the model. Therefore, after the additional adjustments recommended by Kulik and colleagues [1] we still reach the same conclusion reported in our original article (ie, early postoperative use of anticoagulation therapy [either unfractionated heparin or enoxaparin] is associated with a significant increase in surgical re-exploration for bleeding. However, certainly the presence of this modest but significant increased risk does not preclude the use of postoperative anticoagulation in special circumstances. It merely implies an imperative to perform an appropriate riskbenefit analysis regarding the question. Our findings do not reveal significant differences in the overall incidence of re-exploration between enoxaparin and unfractionated heparin. Therefore we do not conclude that the higher re-exploration rate is solely attributable to enoxaparin. We merely commented on the interesting finding that patients receiving enoxaparin who required surgical exploration tended to present later than those receiving unfractionated heparin. Finally, because of the significant limitations associated with any retrospective observational study such as ours, and as we acknowledge in the article, our findings should only be considered as generating hypotheses. We agree that prospective randomized studies are necessary to fully ascertain the relative risks and benefits of different anticoagulation regimens under a variety of clinical circumstances after cardiac surgery. We appreciate the efforts of Kulik and colleagues [1] in providing a systematic review of the available literature regarding early anticoagulation after mechanical valve replacement [3], and we look forward to reading it when it is published in The Annals of Thoracic Surgery. Heath U. Jones, BS Joseph B. Muhlestein, MD Kent W. Jones, MD Dale G. Renlund, MD Tami L. Bair, BS Thomas Jared Bunch, MD Benjamin D. Horne, PhD, MPH Donald L. Lappé, MD Jeffrey L. Anderson, MD Donald B. Doty, MD Cardiovascular Department LDS Hospital and University of Utah Salt Lake City, UT 84143 Department of Medicine Mayo Clinic Mayo Foundation Rochester, MN 55905 e-mail: [email protected]