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Clive Kearon, MB, PhD; Elie A. Akl, MD, MPH, PhD
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From the Department of Medicine (Dr Kearon) and Department of Clinical Epidemiology & Biostatistics (Drs Kearon and Akl), Michael De Groote School of Medicine, McMaster University; and the Departments of Medicine, Family Medicine and Social & Preventive Medicine (Dr Akl), State University of New York at Buffalo (Buffalo, NY).

Correspondence to: Clive Kearon, MB, PhD, Hamilton Health Sciences, Juravinski Hospital Division, 711 Concession St, Hamilton, ON, L8V 1C3, Canada; e-mail: kearonc@mcmaster.ca


Financial/nonfinancial disclosures: The authors of this guideline provided detailed conflict of interest information related to each individual recommendation made in this article. A grid of these disclosures is available online. In summary, the authors have reported to CHEST the following conflicts of interest: Dr Kearon is a consultant to Boehringer Ingelheim GmbH and has received peer-reviewed funding for studies in the treatment of VTE. Dr Akl is a member of and prominent contributor to the GRADE Working Group.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2012;142(4):1075-1076. doi:10.1378/chest.12-1303
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To the Editor:

With this reply, we appreciate the opportunity to (1) reiterate the points made by Drs Miesner and Trewet, (2) identify that the question that they raise about treatment of pulmonary embolism also applies to the treatment of DVT (Recommendation 2.5.2), and (3) expand on our published explanation for the highlighted recommendations.1 We identified five randomized trials that compared daily and bid regimens. In four of the five trials, patients in the two treatment groups received the same total dose of low-molecular-weight heparin (LMWH) in a 24-h period (ie, each once-daily dose of LMWH had twice the number of units of LMWH as each of the bid doses). In the fifth trial by Merli et al,2 the once-daily LMWH dose (ie, enoxaparin 1.5 mg/kg) was less than double each of the bid doses (ie, enoxaparin 1.0 mg/kg); therefore, the once-daily LMWH group received a lower total dose of LMWH over a 24-h period than the bid LMWH group.

As we noted, these trials provide low-quality evidence (hence, the grade C) that treatment of VTE (DVT or pulmonary embolism) with once-daily LMWH is associated with similar outcomes as treatment with bid LMWH. We judged the quality of evidence as low for two reasons. First, there is imprecision, as reflected by the wide 95% CI for the calculated risk ratios, and, consequently, we cannot exclude important differences in favor of either once-daily or bid LMWH. Second, there was an inconsistency of findings between the only two studies that assessed the effect on recurrent VTE at 3 months; one study appeared to favor the once-daily LMWH regimen (once-daily dose equal to the sum of the two bid doses),3 whereas the other (once-daily dose less than the sum of the two bid doses) favored the bid regimens.2 The difference in dosing may have accounted for this inconsistency.

We made a weak recommendation (hence grade 2) in favor of once-daily LMWH over bid LMWH because (1) “we placed value on avoiding an extra injection per day” of LMWH and (2) the overall evidence suggested that once-daily regimens are as effective and safe as bid regimens. However, because recurrent VTE may have been higher with once-daily LMWH in the single study that treated patients with a lower 24-h total dose of LMWH in the once daily compared with the bid group, we only encourage (ie, express a preference for) once-daily regimens “when the approved once-daily regimen uses the same daily dose as the twice-daily regimen.”1 We reinforce what Drs Miesner and Trewet have stated: It is not acceptable to treat VTE with enoxaparin 2.0 mg/kg once daily because this regimen has not been evaluated and is not approved for the treatment of DVT or pulmonary embolism.

Kearon C, Akl EA, Comerota AJ, et al. Antithrombotic therapy for VTE disease: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012;141((2)):supple419S-e494S. [PubMed] [CrossRef]
 
Merli G, Spiro TE, Olsson CG, et al;; Enoxaparin Clinical Trial Group Enoxaparin Clinical Trial Group. Subcutaneous enoxaparin once or twice daily compared with intravenous unfractionated heparin for treatment of venous thromboembolic disease. Ann Intern Med. 2001;134(3):191-202.
 
Charbonnier BA, Fiessinger JN, Banga JD, Wenzel E, d’Azemar P, Sagnard L. Comparison of a once daily with a twice daily subcutaneous low molecular weight heparin regimen in the treatment of deep vein thrombosis. FRAXODI group. Thromb Haemost. 1998;79(5):897-901.
 

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References

Kearon C, Akl EA, Comerota AJ, et al. Antithrombotic therapy for VTE disease: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012;141((2)):supple419S-e494S. [PubMed] [CrossRef]
 
Merli G, Spiro TE, Olsson CG, et al;; Enoxaparin Clinical Trial Group Enoxaparin Clinical Trial Group. Subcutaneous enoxaparin once or twice daily compared with intravenous unfractionated heparin for treatment of venous thromboembolic disease. Ann Intern Med. 2001;134(3):191-202.
 
Charbonnier BA, Fiessinger JN, Banga JD, Wenzel E, d’Azemar P, Sagnard L. Comparison of a once daily with a twice daily subcutaneous low molecular weight heparin regimen in the treatment of deep vein thrombosis. FRAXODI group. Thromb Haemost. 1998;79(5):897-901.
 
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