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Electronic letters published:
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Substantially Misleading
Efficacy of thromboprophylaxis in medical patients
Anticoagulant Prophylaxis for Hospitalized Medical Patients
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Steven L. Shumak, MD, FRCPC University of Toronto
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steven.shumak{at}sunnybrook.ca Steven L. Shumak
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The Editors' notes for this article state that "anticoagulant prophylaxis substantially reduces the risk for venous thromboembolism . . .". Although, by their nature, adverbs such as 'substantially' can have no objective, 'gold standard' to which they are compared, it is still difficult for me to reconcile the word "substantially" with an absolute risk reduction of a mere 0.29 percent (an NNT of 345). Moreover, Dentali et al did NOT, in fact, demonstrate a sigificant reduction in symptomatic venous thromboembolism - a fact which further belies the Editor's use of the word "substantially". Indeed, the putative benefits of anticoagulant prophylaxis remain controversial (1). 1. D'Costa DF. Prophylaxis for medical inpatients is not entirely proven. Br Med J 2007; 334:1127. Conflict of Interest:None declared |
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Mark A. Crowther, MD, MSc McMaster University, Francesco Dentali, Wendy Lim and James Douketis
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crowthrm{at}mcmaster.ca Mark A. Crowther, et al.
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Dear Editor, Lederle and associates question our conclusion that symptomatic venous thromboembolism (VTE) in medical patients is reduced during treatment with prophylactic anticoagulants. We acknowledge that a discussion of these matters is important as our findings could influence the care of a large number of patients. First, they indicate that Cohen et al. (1) did not confirm, with autopsy, all fatal pulmonary emboli (PE). They propose this would overestimate the risk of such events. We included these events because, in accordance with our pre-specified criteria, they were independently adjudicated as fatal PE. Secondly, they questioned our decision to only extract only data from the first 21 days of follow-up data in the study by Gardlund et al. (2). We did this because, in accordance with our analysis plan, we were assessing the impact of prophylaxis during anticoagulant treatment; in this study, prophylaxis was given for up to 21 days. Nonetheless, we agree with their questioning the efficacy of anticoagulant prophylaxis after treatment is stopped. Indeed, we state "the risk for VTE after prophylaxis is stopped remains to be clarified and should be evaluated in future studies" (3). Thirdly, they criticized our extraction of data of the study by Mahe et al. (4) because we counted all fatal PE events whereas in the study by Gardlund we counted only 'clinically relevant fatal PE'. This was not done by choice, as Lederle et al. infer, but based on our pre-specified decision to extract primary outcome data as reported in each study. Though it would be ideal to have a standardized definition of 'clinically relevant' PE, this definition does not exist. To account for the differences across studies in their methods of outcome determination we compared outcomes within each study in an attempt to provide a consistent and non-biased assessment of the efficacy of anticoagulants to prevent symptomatic VTE. Although Lederle and associates state that our findings would be rendered null by a more circumspect reporting of outcomes, we disagree. We stand by our conclusion that anticoagulant prophylaxis reduces symptomatic VTE based on the totality of evidence: across-study consistency of risk reduction for PE (3); risk reduction for symptomatic deep vein thrombosis (OR = 0.47; 95% CI: 0.22-1.00; P = 0.05) (3); and supportive evidence from other studies that anticoagulant prophylaxis reduces asymptomatic deep vein thrombosis in medical patients (5). References 1. Cohen AT, Davidson BL, Gallus AS, Lassen MR, Prins MH, Tomkowski W, et al. for the ARTEMIS investigators. Efficacy and safety of fondaparinux for the prevention of venous thromboembolism in older acute medical patients: randomized placebo controlled trial. BMJ 2006;11:332:325 -9. 2. Gardlund B. Randomised, controlled trial of low-dose heparin for prevention of fatal pulmonary embolism in patients with infectious diseases. The Heparin Prophylaxis Study Group. Lancet 1996;347:1357-61. 3. Dentali et al. 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;146:278-88. 4. Mahe I, Bergmann JF, d'Azemar P, Vaissie JJ, Caulin C. Lack of effect of a low-molecular-weight heparin (nadroparin) on mortality in bedridden medical in-patients: a prospective randomised double-blind study. Eur J Clin Pharmacol 2005;61:347-51. 5. Mismetti P, Laporte-Simitsidis S, Tardy B, Cuchurat M, Buchmuller A, Juillard-Delsart D, et al. Prevention of venous thromboembolism in internal medicine with unfractionated or low-molecular-weight heparins: a meta-analysis of randomised clinical trials. Thromb Haemost 2000;831:14-9. Conflict of Interest:None declared |
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Frank A. Lederle, MD Minneapolis VA Center for Chronic Disease Outcomes Research, Roderick MacDonald, MS, and Timothy J. Wilt, MD MPH
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frank.lederle{at}va.gov Frank A. Lederle, et al.
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Dentali et al (1) base their conclusion that anticoagulant prophylaxis is effective in hospitalized medical patients on two overlapping significant findings, namely reductions in any pulmonary emboli (PE) and in fatal PE. The two significant differences were largely driven by the results of three studies, by Cohen (2), Gårdlund (3), and Mahe (4). The devil is in the details, and closer examination of these data calls Dentali’s conclusion into question. First, the trial by Cohen reports no PE in the Fondaparinux group and 5 “fatal PE” in the control group at 15 days, but as Cohen et al state: “Two of the five were confirmed by autopsy, the others were assumed to be due to pulmonary emboli, as no other plausible cause was found”. As Dentali et al state that “We only considered objectively documented and independently adjudicated outcomes”, the three “assumed” PE should clearly not have been counted. Second, for the Gårdlund study, which had fatal PE at 60 days as its primary outcome, Dentali et al list 3 fatal PE in the heparin group and 12 in the control group, numbers very different from the 15 and 16 reported by Gårdlund. Dentali et al appear to have taken events at 21 days from Gårdlund’s figure, presumably out of desire to consider only events occurring “during anticoagulant prophylaxis”. Prophylaxis was given for up to 21 days in the Gårdlund study though the mean duration was 8.2 days. However, Gårdlund’s figure shows that the four-fold difference in fatal PE at 21 days had completely disappeared two weeks later. Heparin thus may have delayed some events by a few days in this study, but it did not prevent events, and selection of the 21-day timepoint dramatically distorts the study’s overall findings. Dentali et al never mention their alteration of the original data. Third, the study by Mahe reported 27 PE (10 heparin, 17 control) “discovered at autopsy” with no indication that any were clinically important. Dentali et al included these cases, which favor heparin, as “fatal” PE, but excluded identical cases from Gårdlund, which favor control (33 heparin, 26 control). If the meta-analyses are re-calculated with the corrections described above, there are no significant findings in the article by Dentali et al. The value of anticoagulant prophylaxis in hospitalized medical patients remains uncertain. References 1. 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;146:278-88. 2. Cohen AT, Davidson BL, Gallus AS, Lassen MR, Prins MH, Tomkowski W, Turpie AG, Egberts JF, Lensing AW; ARTEMIS Investigators. Efficacy and safety of fondaparinux for the prevention of venous thromboembolism in older acute medical patients: randomised placebo controlled trial. BMJ 2006;332:325-9. 3. Gårdlund B, for the Heparin Prophylaxis Study Group. Randomized, controlled trial of low-dose heparin for prevention of fatal pulmonary embolism in patients with infectious diseases. Lancet 1996;347:1357-61. 4. Mahe I, Bergmann JF, d'Azemar P, Vaissie JJ, Caulin C. Lack of effect of a low-molecular-weight heparin (nadroparin) on mortality in bedridden medical in-patients: a prospective randomised double-blind study. Eur J Clin Pharmacol 2005;61:347-51. Conflict of Interest:None declared |
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