Correspondence
Prophylaxis for Thromboembolism in Hospitalized Medical Patients
N Engl J Med 2007; 357:304-306July 19, 2007
- Article
To the Editor:
Francis (April 5 issue)1 states that an 8-hour dosing schedule of unfractionated heparin may be preferable to a 12-hour dosing schedule. However, a recent meta-analysis that included 12 studies and 7978 patients has shown that a regimen of 5000 U of unfractionated heparin every 8 hours is associated with a significant risk of major bleeding, as compared with a regimen of unfractionated heparin given every 12 hours (96% vs. 35%, P<0.001).2 Furthermore, 8-hour doses of unfractionated heparin are associated with an increased risk of heparin-induced thrombocytopenia.3,4 It is also important to consider that, according to another meta-analysis,5 the number of patients who would need to be treated (number needed to treat) to prevent one fatal pulmonary embolism among hospitalized medical patients is approximately 400, and the number needed to treat to prevent a nonfatal embolic event is 345. These data underscore the suggestion that the 8-hour dosing regimen of unfractionated heparin be used only in patients who have significant risk factors for venous thromboembolism with a minimal risk of bleeding. Otherwise, the small benefit of preventing venous thromboembolism may be surpassed by the risk of bleeding complications.
5 ReferencesWalter Calderón-Gerstein, M.D.
EsSalud Regional Hospital, Huancayo, Peru
waltercalderon27@yahoo.com 1
Francis CW . Prophylaxis for thromboembolism in hospitalized medical patients. N Engl J Med 2007;356:1438-1444
Full Text | Web of Science | Medline2
King CS ,Holley AB ,Jackson JL ,Shorr AF ,Moores LK . Twice vs three times daily heparin dosing for thromboembolism prophylaxis in the general medical population: a meta-analysis. Chest 2007;131:507-516
CrossRef | Web of Science | Medline3
Warkentin TE ,Roberts RS ,Hirsh J ,Kelton JG . An improved definition of immune heparin-induced thrombocytopenia in postoperative orthopedic patients. Arch Intern Med 2003;163:2518-2524
CrossRef | Web of Science | Medline4
Greinacher A ,Eichler P ,Lietz T ,Warkentin TE . Replacement of unfractionated heparin by low-molecular weight heparin for postorthopedic surgery antithrombotic prophylaxis lowers the overall risk of symptomatic thrombosis because of a lower frequency of heparin-induced thrombocytopenia. Blood 2005;106:2921-2922
CrossRef | Web of Science | Medline5
Dentali F ,Douketis JD ,Gianni M ,Lim W ,Crowther MA . Meta-analysis: anticoagulant prophylaxis to prevent symptomatic venous thromboembolism in hospitalized medical patients. Ann Intern Med 2007;146:278-288
Web of Science | Medline
To the Editor:
The conclusion by Francis that fondaparinux and low-molecular-weight heparins are equally useful as prophylaxis against venous thromboembolism in hospitalized medical patients is questionable. The risk of bleeding with a glomerular filtration rate of 30 to 50 ml per minute per 1.73 m2 of body-surface area is increased with the use of fondaparinux because of its longer half-life (17 hours)1 as compared with that of enoxaparin (<10 hours).2 This means that most patients 75 years of age or older, who represent the large majority of hospitalized patients with medical disorders, may be exposed to an unacceptably elevated risk of bleeding with fondaparinux. Furthermore, even patients with a body weight of less than 50 kg have reduced fondaparinux clearance.1,3 We have no antidote against fondaparinux, which is most problematic when rapid reversal is required,3 and fondaparinux is also much more expensive than unfractionated heparin or low-molecular-weight heparins. On the basis of these considerations, we do not believe that fondaparinux may stand on its own as prophylaxis against thromboembolism in medical patients; instead, it appears to be reasonable to limit its use among such patients to those with a history of heparin-induced thrombocytopenia.4
4 ReferencesGiuseppe Famularo, M.D., Ph.D.
Giovanni Minisola, M.D.
San Camillo Hospital, 00152 Rome, Italy
gfamularo@scamilloforlanini.rm. it Claudio De Simone, M.D.
University of L'Aquila, 67100 L'Aquila, Italy1
Donat F ,Duret JP ,Santoni A , et al. The pharmacokinetics of fondaparinux sodium in healthy volunteers. Clin Pharmacokinet 2002;41:Suppl 2:1-9
CrossRef | Web of Science | Medline2
Hulot JS ,Vantelon C ,Urien S , et al. Effect of renal function on the pharmacokinetics of enoxaparin and consequences on dose adjustment. Ther Drug Monit 2004;26:305-310
CrossRef | Web of Science | Medline3
Reverter JC . Fondaparinux sodium. Drugs Today (Barc) 2002;38:185-194
CrossRef | Web of Science | Medline4
Girolami B ,Girolami A . Heparin-induced thrombocytopenia: a review. Semin Thromb Hemost 2006;32:803-809
CrossRef | Web of Science | Medline
Author/Editor Response
Dr. Calderón-Gerstein raises the important issue of balancing the risks and benefits of prophylaxis. Serious bleeding can occur with pharmacologic prophylaxis but is very uncommon. The meta-analysis cited1 studied the outcomes with unfractionated heparin given every 8 hours as compared with every 12 hours for prophylaxis in medical patients and found an increase in major bleeding with 8-hour dosing. However, there were major flaws in the study. Criteria for major bleeding were not well defined in 7 of the 12 studies, and 5776 of the 6314 patients in the 12-hour group (91%) were enrolled in a single study in which major bleeding was diagnosed only at autopsy.2 This would result in underreporting of nonfatal bleeding events. The authors suggest that results eliminating this study “are likely more meaningful to current practicing physicians,” and note that “doing so eliminated the difference in bleeding rates, while suggesting that TID heparin is superior for all outcomes evaluated.” On the basis of the available data, I suggest that unfractionated heparin administered every 8 hours is better than that administered every 12 hours.
Famularo et al. express concern about bleeding complications with the use of prophylactic fondaparinux in older patients and those with reduced renal function because of the renal clearance of the drug. The best information regarding this comes from the Arixtra for Thromboembolism Prevention in a Medical Indications Study (ARTEMIS),3 which included 849 subjects with a mean age of 75 years who were randomly assigned to receive prophylaxis with fondaparinux or placebo. Patients with severely reduced renal function (serum creatinine, >180 μmol per liter) were excluded. The rate of major bleeding in both treatment groups was low, at 0.2%. This indicates that fondaparinux has a favorable balance of benefit to risk but should be avoided in patients with severe renal compromise. Famularo et al. also raise the issue of cost, which can be an important determinant in drug choice. However, the cost varies from one market to another and changes with competition, as new drugs become available.
3 ReferencesCharles W. Francis, M.D.
University of Rochester Medical Center, Rochester, NY 14642
charles_francis@urmc.rochester. edu 1
King CS ,Holley AB ,Jackson JL ,Shorr AF ,Moores LK . Twice vs three times daily heparin dosing for thromboembolism prophylaxis in the general medical population: a metaanalysis. Chest 2007;131:507-516
CrossRef | Web of Science | Medline2
Gardlund B . Randomised, controlled trial of low-dose heparin for prevention of fatal pulmonary embolism in patients with infectious diseases. Lancet 1996;347:1357-1361
CrossRef | Web of Science | Medline3
Cohen AT ,Davidson BL ,Gallus AS , et al. Efficacy and safety of fondaparinux for the prevention of venous thromboembolism in older acute medical patients: randomised placebo controlled trial. BMJ 2006;332:325-329
CrossRef | Web of Science | Medline
