Correspondence

Dalteparin Compared with an Oral Anticoagulant for Thromboprophylaxis in Patients with Cancer

N Engl J Med 2003; 349:1385-1387October 2, 2003

Article

To the Editor:

Lee and colleagues (July 10 issue)1 provide strong and pertinent data indicating the benefit of prolonged treatment with low-molecular-weight heparin for the prevention of recurrent venous thromboembolism in patients with cancer. Nevertheless, among the patients who received an oral anticoagulant, the international normalized ratio (INR) was above the therapeutic range 24 percent of the time. This could be a source of bias in evaluating the effect of the coumarin derivative. In addition, we wonder whether the authors found that the number of patients with clinically relevant thrombocytopenia was higher after long-term treatment with low-molecular-weight heparin than it was after long-term treatment with an oral anticoagulant.

Emmanuel Blot, M.D.
Fabrice Gutman, M.D.
Alexia Thannberger
Centre Henri Becquerel, 76038 Rouen CEDEX, France

1 References

1
Lee AYY, Levine MN, Baker RI, et al. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med 2003;349:146-153
Full Text | Web of Science | Medline

To the Editor:

The findings reported by Lee et al. are evidence of yet another clinical indication for the use of dalteparin. What remains unclear, however, is the patient's perspective and compliance with this type of treatment. In our clinical practice, a considerable proportion of patients are not prepared to give themselves subcutaneous injections. Harrison et al. found that almost one third of patients are uncomfortable self-injecting low-molecular-weight heparin.1 The cost–benefit analysis is substantially altered if daily attendance by health care professionals is taken into account. Furthermore, the need to arrange attendance often results in delays or lapses in treatment.

Lee et al. trained patients, family members, or both to administer dalteparin, but nursing services were arranged, if necessary. In their discussion, they comment that long-term self-injection was acceptable to their patients. Modern practice is moving increasingly toward patient-centered approaches, and we would therefore be very interested to see objective data substantiating this comment.

James H.K. Hull, M.R.C.P.
St. George's Hospital, London SW17 0QT, United Kingdom

Peter J. Hull, M.R.C.P.
Abbotsbury Road Primary Care Center, Weymouth DT3 5NQ, United Kingdom

1 References

1
Harrison L, McGinnis J, Crowther M, Ginsberg J, Hirsch J. Assessment of outpatient treatment of deep-vein thrombosis with low-molecular-weight heparin. Arch Intern Med 1998;158:2001-2003
CrossRef | Web of Science | Medline

To the Editor:

Did Lee et al. compare the cost of the more expensive treatment with dalteparin by injection with the total cost of warfarin and laboratory testing to monitor anticoagulation? Cost data are important, because many patients with hypercoagulability take anticoagulants for life, not for a six-month period, as in this study.

Jeffrey L. Kaufman, M.D.
Vascular Services of Western New England, Springfield, MA 01107

To the Editor:

In his Perspective article, Bick1 states that the low-molecular-weight heparin dalteparin, “unlike others of its type that are available in North America, has been deemed safe for use in the elderly (those older than 65 years of age) by the Food and Drug Administration [FDA].” This is incorrect. On comparison, the prescribing information for enoxaparin, tinzaparin, and dalteparin — specifically, the information given in the “Precautions: Geriatric Use” subsection — is very similar. For all three, efficacy in the elderly has been reported to be similar to that seen in younger patients, and studies have shown that the risk of bleeding increases with age. Therefore, all these agents should be used with care, particularly with regard to dosing intervals and concomitant medications, in elderly patients.

The meta-analysis cited by Bick does not show a significant safety benefit in favor of dalteparin. The authors of the meta-analysis (Dolovich et al.) state, “Based on pooled results, there are no major differences among preparations. This suggests that the use of any of the products in the dosages evaluated in the trials is reasonable.”2

François Nader, M.D.
Aventis Pharmaceuticals, Bridgewater, NJ 08807

2 References

1
Bick RL. Cancer-associated thrombosis. N Engl J Med 2003;349:109-111
Full Text | Web of Science | Medline

2
Dolovich LR, Ginsberg JS, Douketis JD, Holbrook AM, Cheah G. A meta-analysis comparing low-molecular-weight heparins with unfractionated heparin in the treatment of venous thromboembolism: examining some unanswered questions regarding location of treatment, product type, and dosing frequency. Arch Intern Med 2000;160:181-188
CrossRef | Web of Science | Medline

Author/Editor Response

Dr. Blot and colleagues are concerned about potential bias in our trial, specifically with regard to excessive anticoagulation in the patients who received long-term treatment with coumarin derivatives. Such treatment bias is possible, but it would favor the control group by reducing the likelihood of recurrent venous thromboembolism. In our study, as in other clinical trials, an association between recurrent thrombotic events and the achieved INR was not observed in patients with cancer.1 The INR control that was achieved and the rate of recurrent venous thromboembolism in the oral-anticoagulant group were similar to the results that have been reported in randomized, controlled trials and prospective cohort studies.1,2

As for the risk of clinically relevant thrombocytopenia, we did not detect any significant difference between the two treatment groups on the basis of platelet counts recorded at follow-up visits. During the six-month study period, there were two reported cases of suspected heparin-induced thrombocytopenia while patients were receiving dalteparin; one case was reported after 11 days of treatment in a patient who had received intravenous unfractionated heparin before enrollment in the study and the other in a patient in whom thrombocytopenia developed after 12 days.

In response to Drs. Hull and Hull: we did not administer a formal questionnaire to determine the patients' acceptance of or satisfaction with subcutaneous injections. However, 78 percent of all the eligible patients consented to be randomly assigned to long-term dalteparin injections or oral administration of an anticoagulant. Furthermore, only 21 patients (6 percent) in the dalteparin group, as compared with 15 (4 percent) in the coumarin group, chose to stop taking the study medication before the planned end of the treatment period.

We agree with Dr. Kaufman that cost is an important consideration in the long-term use of low-molecular-weight heparin. A formal cost-effectiveness comparison of low-molecular-weight heparin and coumarin derivatives is planned. Given the high mortality rate in our trial, we believe that six months is a reasonable estimate of the duration of treatment for the majority of patients.

Agnes Y.Y. Lee, M.D.
Mark N. Levine, M.D.
Michael Gent, D.Sc.
McMaster University, Hamilton, ON L8V 1C3, Canada

2 References

1
Hutten BA, Prins MH, Gent M, Ginsberg J, Tijssen JG, Buller HR. Incidence of recurrent thromboembolic and bleeding complications among patients with venous thromboembolism in relation to both malignancy and achieved international normalized ratio: a retrospective analysis. J Clin Oncol 2000;18:3078-3083
Web of Science | Medline

2
Prandoni P, Lensing AW, Piccioli A, et al. Recurrent venous thromboembolism and bleeding complications during anticoagulant treatment in patients with cancer and venous thrombosis. Blood 2002;100:3484-3488
CrossRef | Web of Science | Medline

Author/Editor Response

In response to Dr. Nader: I refer readers to the FDA MedWatch alert posted on May 30, 2000, regarding the safety of enoxaparin in the elderly.1 An additional FDA MedWatch alert, regarding the use of enoxaparin in patients with heart valves, pregnant patients (including those with maternal or fetal hemorrhage or potential teratogenicity), and patients with epidural bleeding was posted on January 9, 2002.2

I also refer readers to Figure 4 and Table 6 of the meta-analysis by Dolovich et al.,3 which shows that the relative risk of major hemorrhage with the use of dalteparin, as compared with unfractionated heparin, is 0.31, and with enoxaparin, the relative risk is 1.60.

Rodger L. Bick, M.D., Ph.D.
University of Texas Southwestern Medical School, Dallas, TX 75231
rbick@thrombosis.com

3 References

1
FDA MedWatch. LOVENOX (enoxaparin sodium) injection [May 30, 2000: Aventis Pharmaceuticals]: precautions: geriatric use: new subsection. (Accessed September 11, 2003, at http://www.fda.gov/medwatch/safety/2000/may00.htm#loveno.)

2
FDA MedWatch. LOVENOX (enoxaparin sodium) injection [January 9, 2002: Aventis]: warnings. (Accessed September 11, 2003, at http://www.fda.gov/medwatch/SAFETY/2002/jan02.htm#loveno.)

3
Dolovich LR, Ginsberg JS, Douketis JD, Holbrook AM, Cheah G. A meta-analysis comparing low-molecular-weight heparins with unfractionated heparin in the treatment of venous thromboembolism: examining some unanswered questions regarding location of treatment, product type, and dosing frequency. Arch Intern Med 2000;160:181-188
CrossRef | Web of Science | Medline

Citing Articles (3)

Citing Articles

1
Brigitte AB Essers, Martin H Prins. (2010) Methods to measure treatment satisfaction in patients with pulmonary embolism or deep venous thrombosis. Current Opinion in Pulmonary Medicine 16:5, 437-441
CrossRef
2
W.Z. Xie, M. Leibl, M.R. Clark, P. Dohrmann, T. Kunze, F. Gieseler. (2005) Activation of the coagulation system in cancerogenesis and metastasation. Biomedicine & Pharmacotherapy 59:3, 70-75
CrossRef
3
Marcello Di Nisio, Alessandro Squizzato, Clara P.W Klerk, Dick J Richel, Harry R B??ller. (2004) Antithrombotic therapy and cancer. Current Opinion in Hematology 11:3, 187-191
CrossRef