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Brief Communication: Preoperative Anticoagulant Activity after Bridging Low-Molecular-Weight Heparin for Temporary Interruption of Warfarin

Martin J. O'Donnell, MB; Clive Kearon, MB, PhD; Judy Johnson, RN; Marlene Robinson, RN, BScN; Michelle Zondag, RN; Irene Turpie, MB, MSc; and Alexander G. Turpie, MB
[+] Article and Author Information

From McMaster University and Hamilton Health Sciences Foundation, Hamilton, Ontario, Canada.


Grant Support: This project was funded by an unrestricted grant from the Hamilton Health Sciences Foundation, Hamilton, Ontario, Canada. Drs. Kearon and O'Donnell are supported by the Canadian Institutes of Health Research.

Potential Financial Conflicts of Interest: None disclosed.

Requests for Single Reprints: Martin J. O'Donnell, MB, Henderson Research Centre, McMaster University, 70 Wing, Room 220, 711 Concession Street, Hamilton, Ontario L8V 1C3, Canada; e-mail, odonnm@mcmaster.ca.

Current Author Addresses: Dr. O'Donnell: Henderson Research Centre, 70 Wing, Room 220, 711 Concession Street, Hamilton, Ontario L8V 1C3, Canada.

Dr. Kearon: Henderson General Hospital, 70 Wing, Room 39, 711 Concession Street, Hamilton, Ontario L8V 1C3, Canada.

Dr. A.G. Turpie, Ms. Zondag, Ms. Robinson, and Ms. Johnson: Thrombosis Clinic, McMaster Clinic Building, 6th Floor, Hamilton General Hospital, 237 Barton Street East, Hamilton, Ontario L8L 2X2, Canada.

Dr. I. Turpie: St. Joseph's Centre for Ambulatory Health Services, 2757 King Street East, Hamilton, Ontario L8G 5E4, Canada.

Author Contributions: Conception and design: M.J. O'Donnell, C. Kearon, I. Turpie, A.G. Turpie.

Analysis and interpretation of the data: M.J. O'Donnell, C. Kearon.

Drafting of the article: M.J. O'Donnell, C. Kearon, I. Turpie, A.G. Turpie.

Critical revision of the article for important intellectual content: M.J. O'Donnell, C. Kearon, A.G. Turpie.

Final approval of the article: M.J. O'Donnell, J. Johnson, C. Kearon, M. Robinson, I. Turpie, A.G. Turpie, M. Zondag.

Collection and assembly of data: J. Johnson, M. Robinson, M. Zondag.


Ann Intern Med. 2007;146(3):184-187. doi:10.7326/0003-4819-146-3-200702060-00007
Text Size: A A A

One hundred two patients were enrolled from March 2003 to February 2005. Eight were subsequently excluded because their procedure was canceled. The Table shows the baseline characteristics of the 94 patients who received preoperative bridging LMWH. Mean age was 68 years, and 76% of patients were men. The most common indication for warfarin therapy was atrial fibrillation (n = 62), and the most common reasons for temporary interruption of warfarin therapy were endovascular procedures (n = 73). Ninety-three (99%) patients completed clinical follow-up at 4 to 6 weeks; 1 patient was lost to follow-up.

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Figures

Grahic Jump Location
Figure.
Association between residual anti-Xa level and interval from last dose of low-molecular-weight heparin.

R2 = 0.14.

Grahic Jump Location

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Bridging low-molecular weight heparin for temporary interruption of warfarin
Posted on February 25, 2007
Abdol Majid Shojania
St. Boniface General Hospital
Conflict of Interest: None Declared

To THE EDITOR: O'Donnell et al (1) have indicated that" warfarin was withheld 4-5 days before the planned procedure and that patients were started on enoxaparin 1 mg/kg of body weight twice daily starting 3 days before surgery. The final dose of enoxaparin was given the night before surgery". They conclude that because the mean anti-Xa level prior to surgery was 0.6 U/ml and that in 68% of the patients, anti-Xa levels were 0.5 or greater, preoperative bridging will results in high residual anti- Xa level, if the last dose is given in the evening before surgery. They recommend that if a twice daily regimen of LMWH (low-molecular-weight heparin) is used, the final dose should be given on the morning of the day before surgery. I do not think that such a recommendation can be made, merely because the residual anti-Xa levels prior to procedure were high.

The therapeutic range of anti-Xa for monitoring of LMWH has not been established. The product insert for enoxaparin states that for 100 U/Kg (1mg/kg) b.i.d. the expected anti-Xa 3-4 h post dose is less than 1.15 U/ml. Hirsh and Raschke (2) state "a conservative therapeutic range for peak effect with twice-daily administration of enoxaparin is 0.6-1.0 IU/ml".

There is a great variability in the results of anti-Xa heparin levels measured by different laboratories (3). In the CAP survey (3), 87 laboratories used the chromogenic assay and LMWH as a standard for assay of the same sample. The mean anti-Xa assay by these 87 laboratories was 1.427 U/ml (SD =0.449, range: 0.34- 2.60). O'Donnell and colleagues (1) report that the mean anti-Xa at mid-dosing interval was 1.3 U/ml. Ferreira et al (4) using twice daily enoxaparin (1 mg/kg) and chromogenic assay for anti-Xa heparin level (the same as O'Donnell et al) aiming at anti Xa-level of 0.5-1.0 U/ml, reported that the mean anti-Xa heparin level at mid-dosing interval for 67 patients was 0.58 U/ml.

If O' Donnell and colleagues believe that the mean residual heparin of 0.6 U/ml prior to surgery is too high, then they also have to conclude that the enoxamarin dose of 1 mg/kg twice daily that they used was too high; because the mean anti-Xa heparin level of 1.3 U/ml at mid-dosing point that they found is higher than recommended therapeutic range for enoxaparin.

The method that I have used successfully, in the past 10 years, for preoperative management of anticoagulation, seems to be simpler and require less LMWH following temporarily withdrawal of warfarin. Patients are instructed to continue with warfarin therapy until the day before surgery. On the day before surgery, the patient comes to the clinic in the morning for an INR check. Depending on the INR, the patient is given 1-2 mg of vitamin K (using parenteral preparation) orally, while the patient is in the clinic. This dose of vitamin K is adequate to bring the INR to less than 1.5 which is safe for general surgery. The patient is then told not to take any warfarin until after surgery. Post operatively the patient start taking warfarin as soon as he/she can take oral feeding and the patient is started on Dalteparin (200 U/kg SC daily), 8 hours after surgery, if the patient has no active bleeding. This method, not only requires shorter duration of LMWH therapy, but also reduces the chance of an unnecessary interruption of warfarin preoperatively in case, for any reason, a patient's surgery is cancelled.

A.M. Shojania, MD St. Boniface General Hospital Winnipeg, Manitoba, Canada, R2H 2A6

1. O'Donnell MJ, Kearon C, Johnson J, Robinson M, Zondag M, Turpie I et al. Ann Intern Med 2007; 146:184-90.

2. Hirsk J, Raschke R. Heparin and Low-molecular-weight heparin. The Seventh ACCP Conference on Antithrombotic Therapy. CHEST 2004; 126:188S- 203S.

3. Shojania AM. More on: is laboratory monitoring of low-molecular weight heparin necessary? J Thromb Haemost 2004;2: 2276-7.

4. Ferreira I, Dos L, Tornos P, Nicolau I, Permanyer-Miralda G , Soler-Soler J. Experience with enoxaparin in patients with mechanical heart valves who must withhold acecumarol. Heart 2003; 89:527-530.

Conflict of Interest:

None declared

Preoperative Anticoagulant Activity After Bridging Low-Molecular-Weight Heparin
Posted on April 9, 2007
Martin J O'Donnell
McMaster University
Conflict of Interest: None Declared

We appreciate the opportunity to respond to issues raised by Dr. Shojania. We agree that the therapeutic anti-Xa heparin level range for low-molecular-weight heparins has not been rigorously evaluated, however, the high residual anti-Xa heparin activity observed in our study is a cause for concern as it is likely to increase bleeding during surgery. (1) We believe that when physicians stop warfarin therapy before surgery it is not their intention to substitute another anticoagulant during the surgical procedure. The difference in mean anti-Xa heparin levels between our study and the study by Ferreria et al (2) is not surprising as their patient population was younger and, in response to anti-Xa measurements, enoxaparin dose was adjusted to target anti-Xa heparin levels of 0.5"“1 IU/ml. While the preoperative management outlined by Dr. Shojania sounds reasonable, we are aware of no published cohort studies or clinical trials evaluating the safety of this approach.

Yours Sincerely,

Martin J O'Donnell MB Clive Kearon MB PhD Alexander G. Turpie MB

1. O'Donnell MJ, Kearon C, Johnson J, Robinson M, Zondag M, Turpie I, Turpie AG. Ann Intern Med 2007; 146:184-90.

2. Ferreira I, Dos L, Tornos P, Nicolau I, Permanyer-Miralda G , Soler-Soler J. Experience with enoxaparin in patients with mechanical heart valves who must withhold acecumarol. Heart 2003; 89:527-530.

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Summary for Patients

Safety of Surgery during Bridging Anticoagulation Therapy with Low-Molecular-Weight Heparin

The summary below is from the full report titled “Brief Communication: Preoperative Anticoagulant Activity after Bridging Low-Molecular-Weight Heparin for Temporary Interruption of Warfarin.” It is in the 6 February 2007 issue of Annals of Internal Medicine (volume 146, pages 184-187). The authors are M.J. O'Donnell, C. Kearon, J. Johnson, M. Robinson, M. Zondag, I. Turpie, and A.G. Turpie.

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