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Meta-analysis: Anticoagulant Prophylaxis to Prevent Symptomatic Venous Thromboembolism in Hospitalized Medical Patients

Francesco Dentali, MD; James D. Douketis, MD; Monica Gianni, MD; Wendy Lim, MD; and Mark A. Crowther, MD, MSc
[+] Article and Author Information

From McMaster University and St. Joseph's Healthcare, Hamilton, Ontario, Canada.


Acknowledgments: The authors thank Dr. Qilong Yi for his helpful review of and contribution to the manuscript.

Grant Support: Dr. Crowther is a Career Investigator of the Heart and Stroke Foundation of Ontario. Dr. Lim holds a Mentorship award from the Canadian Institutes of Health Research.

Potential Financial Conflicts of Interest: Consultancies: J.D. Douketis (Agen Biomedical), M.A. Crowther (Sanofi-Aventis, Pfizer Inc., Leo Laboratories, GlaxoSmithKline, Organon, Artisian Therapeutics); Honoraria: J.D. Douketis (Sanofi-Aventis, Pfizer Inc., Leo Pharma), M.A. Crowther (Sanofi-Aventis, Pfizer Inc., Leo Laboratories, GlaxoSmithKline, Organon Artisian Therapeutics); Grants received: M.A. Crowther (Sanofi-Aventis, Pfizer Inc., Leo Laboratories, GlaxoSmithKline, Organon, Artisian Therapeutics).

Requests for Single Reprints: James D. Douketis, MD, St. Joseph's Hospital, Room F-544, 50 Charlton Avenue East, Hamilton L8N 4A6, Ontario, Canada; e-mail, jdouket@mcmaster.ca.

Current Author Addresses: Drs. Dentali and Gianni: Inusbria University, Viale Borri 57, 21100 Varese, Italy.

Drs. Douketis, Lim, and Crowther: McMaster University, 50 Charleton Avenue East, Hamilton L8N 4A6, Ontario, Canada.


Ann Intern Med. 2007;146(4):278-288. doi:10.7326/0003-4819-146-4-200702200-00007
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Background: Underutilization of anticoagulant prophylaxis may be due to lack of evidence that prophylaxis prevents clinically important outcomes in hospitalized medical patients at risk for venous thromboembolism.

Purpose: To assess the effects of anticoagulant prophylaxis in reducing clinically important outcomes in hospitalized medical patients.

Data Sources: MEDLINE, EMBASE, and Cochrane databases were searched to September 2006 without language restrictions.

Study Selection: Randomized trials comparing anticoagulant prophylaxis with no treatment in hospitalized medical patients.

Data Extraction: Any symptomatic pulmonary embolism (PE), fatal PE, symptomatic deep venous thrombosis, all-cause mortality, and major bleeding. Pooled relative risks and associated 95% CIs were calculated. For treatment effects that were statistically significant, the authors determined the absolute risk reduction and the number needed to treat for benefit (NNTB) to prevent an outcome.

Data Synthesis: 9 studies (n = 19 958) were included. During anticoagulant prophylaxis, patients had significant reductions in any PE (relative risk, 0.43 [CI, 0.26 to 0.71]; absolute risk reduction, 0.29%; NNTB, 345) and fatal PE (relative risk, 0.38 [CI, 0.21 to 0.69]; absolute risk reduction, 0.25%; NNTB, 400), a nonsignificant reduction in symptomatic deep venous thrombosis (relative risk, 0.47 [CI, 0.22 to 1.00]), and a nonsignificant increase in major bleeding (relative risk, 1.32 [CI, 0.73 to 2.37]). Anticoagulant prophylaxis had no effect on all-cause mortality (relative risk, 0.97 [CI, 0.79 to 1.19]).

Limitations: 2 of 9 included studies were not double-blind.

Conclusions: Anticoagulant prophylaxis is effective in preventing symptomatic venous thromboembolism during anticoagulant prophylaxis in at-risk hospitalized medical patients. Additional research is needed to determine the risk for venous thromboembolism in these patients after prophylaxis has been stopped.

Figures

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Figure 1.
Identification of eligible studies.

LMWH = low-molecular-weight heparin; UFH = unfractionated heparin.

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Figure 2.
Any pulmonary embolism during anticoagulant prophylaxis.

RR = relative risk.

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Figure 3.
Fatal pulmonary embolism during anticoagulant prophylaxis.

RR = relative risk. *One patient in the prophylaxis group died of myocardial infarction, but autopsy also revealed a pulmonary embolism. Therefore, the patient was included as having a fatal pulmonary embolism.

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Figure 4.
Symptomatic deep venous thrombosis during anticoagulant prophylaxis.

RR = relative risk.

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Figure 5.
All-cause mortality during anticoagulant prophylaxis.

RR = relative risk.

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Figure 6.
Major bleeding during anticoagulant prophylaxis.

RR = relative risks.

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Appendix Figure.
Funnel plot of studies for outcome of symptomatic pulmonary embolism (top) and major bleeding (bottom).

RR = relative risk; SE = standard error.

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Anticoagulant Prophylaxis for Hospitalized Medical Patients
Posted on February 27, 2007
Frank A. Lederle
Minneapolis VA Center for Chronic Disease Outcomes Research
Conflict of Interest: None Declared

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), GÃ¥rdlund (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 GÃ¥rdlund 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 GÃ¥rdlund. Dentali et al appear to have taken events at 21 days from GÃ¥rdlund's figure, presumably out of desire to consider only events occurring "during anticoagulant prophylaxis". Prophylaxis was given for up to 21 days in the GÃ¥rdlund study though the mean duration was 8.2 days. However, GÃ¥rdlund'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 GÃ¥rdlund, 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. GÃ¥rdlund 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

Efficacy of thromboprophylaxis in medical patients
Posted on May 29, 2007
Mark A. Crowther
McMaster University
Conflict of Interest: None Declared

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

Substantially Misleading
Posted on May 31, 2007
Steven L. Shumak
University of Toronto
Conflict of Interest: None Declared

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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