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Ann Thorac Surg 2000;69:762-764
© 2000 The Society of Thoracic Surgeons

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Original Articles

Effect of low molecular weight heparin (Fragmin) on bleeding after cardiac surgery

^a Regional Cardiothoracic Centre, Freeman Hospital, Newcastle upon Tyne, England, UK

Address reprint requests to Dr Clark, Regional Cardiothoracic Centre, Freeman Hospital, Newcastle upon Tyne NE7 7DN, England
e-mail: s.c.clark{at}ncl.ac.uk

	Abstract

Top Abstract Introduction Material and methods Results Comment References

 
Background. Fragmin (Dalteparin, Pharmacia Ltd, Milton Keynes, UK), a low molecular weight heparin, is now recommended in the treatment of unstable angina. Due to the greater bioavailability and longer half-life of Fragmin compared with conventional heparin we postulated that this may influence postoperative bleeding after cardiac surgery for unstable angina.

Methods. We investigated the influence of the agent on postoperative bleeding after cardiac surgery. Patients undergoing first-time coronary artery bypass grafting were prospectively studied in four groups: group A (n = 100) were elective patients; group B (n = 60) had unstable angina and received conventional heparin intravenously until operation; group C (n = 115) received Fragmin with the last dose administered more than 12 hours before surgery; and group D (n = 115) received Fragmin within 12 hours of operation.

Results. Patients in group D had significantly greater blood loss (p < 0.001) and increased blood transfusion than groups A, B, and C (p = 0.047). Patients receiving Fragmin more than 12 hours before surgery (group C) had similar rates of blood loss and transfusion to group B (p > 0.05) but greater than in group A (p = 0.021). There were no differences in reopening rate.

Conclusions. The risks of bleeding and transfusion must be weighed against the risks of acute ischemic events if Fragmin is stopped more than 12 hours before operation.

	Introduction

Top Abstract Introduction Material and methods Results Comment References

 
Conventional unfractionated heparin is known to be effective in preventing new cardiac-related events after an episode of unstable angina [1]. Low molecular weight heparins, typified by Fragmin (Dalteparin, Pharmacia Ltd, Milton Keynes, UK), have similar antithrombotic properties but can be given subcutaneously for convenience in long-term therapy as they have high bioavailability and thus a prolonged half-life. This avoids the difficulties of intravenous administration and regular monitoring of anticoagulation.

Because of these advantages, Fragmin and other low molecular weight heparins have been advocated recently as the optimal anticoagulant for patients with unstable angina when in combination with aspirin and administered twice daily at a dose of 120 units/kg body weight [2, 3].

As there are no reports on the effects of Fragmin on bleeding after cardiac surgery, we conducted a study to determine whether this change in cardiologic practice influenced postoperative bleeding in patients subsequently undergoing myocardial revascularization for unstable angina.

	Material and methods

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Three hundred ninety consecutive patients undergoing first-time coronary artery bypass grafting were studied prospectively and divided into four groups. The study complied with the requirements of our institutional review board regarding clinical research on humans.

Group A were routine elective patients (n = 100) who stopped aspirin 5 days before operation. Group B (n = 60) consisted of unstable angina patients maintained on aspirin and a conventional heparin infusion to keep the kaolin clotting time (KCT) ratio more than 2.0. Group C patients (n = 115) had unstable angina and were maintained on aspirin and Fragmin (120 units/kg bid subcutaneously) but their Fragmin was stopped at least 12 hours before surgery. In group D (n = 115), Fragmin was administered within 12 hours of cardiac surgery. The administration of Fragmin or conventional heparin for unstable angina was dictated by the preference of the patient’s cardiologist.

All patients were operated on by the same group of surgeons using a standard operative technique involving nonpulsatile cardiopulmonary bypass with systemic cooling to 28°C. Cardiopulmonary bypass was undertaken after administration of 300 units/kg of heparin to maintain an activated clotting time (ACT; a measure of the clotting time of fresh blood activated by surface contact) of more than 450 seconds (Medtronic Europe, Lausanne, Switzerland). Cold antegrade blood cardioplegia was used in all cases. Heparin reversal was by administration of 1 mg protamine per 100 units of heparin administered to achieve an ACT of less than 120 seconds. Aprotinin, aminocaproic acid, and tranexamic acid were not used in any case.

Postoperatively, blood loss into the mediastinal drains at 12 hours and the administration of blood and blood products were assessed by the intensive care staff caring for the patient. Blood transfusion was indicated to maintain a hematocrit of 0.28 according to our unit policy. In patients with excessive blood loss the administration of blood products was governed by an abnormal clotting screen (prothrombin time > 1 second, KCT > 45 seconds) or platelet count. Products were administered only after review by the intensive care medical staff.

In addition, the ACT was measured at arrival on the intensive care unit (ITU) 2, 4, 6, and 12 hours postoperatively. To avoid confounding measurements of ACT and clotting screen, all patients returning to ITU with heparinized cardiotomy blood being administered were excluded, ie, residual blood from the cardiopulmonary bypass circuit. Resternotomy rate for hemorrhage or cardiac tamponade was also measured.

Groups were analyzed using analysis of variance (ANOVA) for nonrandomized groups. Data are presented as means ± standard deviation. A value of p less than 0.05 indicated statistical significance at a power of 90%.

	Results

Top Abstract Introduction Material and methods Results Comment References

 
There were no differences in patient demographics such as age, sex, or weight (p > 0.05; Table 1). Patient groups were similar with regard to the incidence of intercurrent disease such as hypertension, cerebrovascular disease, renal dysfunction, or diabetes and the type of antianginal drug therapy. The were no differences in preoperative platelet count, hematocrit, or coagulation tests. Similarly, there were no differences in preoperative ejection fraction, cross-clamp time, or cardiopulmonary bypass time between groups (p > 0.05; Table 1). There were no postoperative deaths in this series and equivalent numbers of patients required intraaortic balloon pumping and inotropic support in each of the study groups.

View larger version (16K): [in this window] [in a new window]   Fig 1. Postoperative blood loss after 12 hours (mL). Error bars indicate the standard deviation.

View larger version (33K): [in this window] [in a new window]   Fig 2. Volumes of blood, fresh frozen plasma (FFP), and platelets transfused (Tx) during intensive care stay (mL). Error bars indicate the standard deviation.

View larger version (48K): [in this window] [in a new window]   Fig 3. Activated clotting times (ACT) on arrival at the intensive care unit (Adm ITU) and at 2, 4, 6, and 12 hours postoperatively. Error bars indicate the standard deviation.

	Comment

Top Abstract Introduction Material and methods Results Comment References

Little is known of the potential effects of this regimen adopted by cardiologists on postoperative bleeding in patients undergoing first-time myocardial revascularization. Our data indicate that administration of Fragmin significantly promotes bleeding postoperatively compared with our control group of routine cases. The influence of aspirin administration in the unstable angina patients, however, must be taken into account. Although bleeding is comparable to that seen in patients receiving conventional heparin infusion if Fragmin is stopped at least 12 hours before surgery, the significant increase in bleeding seen when Fragmin is given within 12 hours of operation is of concern. This did not manifest itself as an increase in reopening rate, but the significantly increased volumes of packed red cells administered to these patients over the first 12 hours on ITU is a concern as the number of donors to which the patient is exposed is increased along with the chances of infective agent transmission. There is also evidence that blood transfusion increases postoperative infections [4–6] and increased blood transfusion may have cost implications in this subset of unstable angina patients undergoing operation.

We acknowledge that although the patient groups are broadly comparable, some type of selection bias is possible as patient therapy is designated by the practice philosophy of individual cardiologists.

The increased blood loss encountered and risks of increased transfusion in patients on Fragmin within 12 hours of operation must be balanced against the theoretical risks of acute myocardial events if Fragmin were stopped at least 12 hours before surgery. This aspect requires careful future study.

	References

Top Abstract Introduction Material and methods Results Comment References

 

1. Oler A., Whooley M.A., Oler J., Grady D. Adding heparin to aspirin reduces the incidence of myocardial infarction and death in patients with unstable angina. A meta-analysis. JAMA 1996;276:811-815.[Abstract/Free Full Text]
2. FRISC Study Group. Low molecular weight heparin during instability in coronary artery disease. Lancet 1996;347:561-568.[Medline]
3. Klein W., Buchwald A., Hillis S.E., et al. Comparison of low molecular weight heparin with unfractionated heparin acutely and with placebo for 6 weeks in the management of unstable coronary artery disease. Circulation 1997;96:61-68.[Abstract/Free Full Text]
4. Jensen L.S., Anderson A.J., Christiansen P.M., et al. Postoperative infection and NK cell function following blood transfusion in patients undergoing elective colorectal surgery. Br J Surg 1992;79:513-516.[Medline]
5. Jensen L.S., Grunnet N., Hanberg-Sorensen F., Jorgensen J. Cost effectiveness of blood transfusion and white cell reduction in elective colorectal surgery. Transfusion 1995;35:719-722.[Medline]
6. Triulzi D.J., Vanek K., Ryan D.H., Blumberg N. A clinical and immunologic study of blood transfusion and postoperative infection in spinal surgery. Transfusion 1992;35:517-524.

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Stephen C. Clark Nicola Vitale Joseph Zacharias Jonathan Forty Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Clark, S. C. Articles by Forty, J. Search for Related Content PubMed PubMed Citation Articles by Clark, S. C. Articles by Forty, J. Related Collections Related Article