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Venous Thromboembolism Prophylaxis in Hospitalized Medical Patients and Those With Stroke: A Background Review for an American College of Physicians Clinical Practice Guideline

Frank A. Lederle, MD; Dylan Zylla, MD; Roderick MacDonald, MS; and Timothy J. Wilt, MD, MPH
[+] Article and Author Information

From the Minnesota Evidence-based Practice Center and Minneapolis Veterans Affairs Medical Center, Minneapolis, Minnesota.


Acknowledgment: The authors thank Indy Rutks and James Tacklind for their assistance in the literature search.

Grant Support: By the American College of Physicians.

Potential Conflicts of Interest: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M10-1375.

Requests for Single Reprints: Frank A. Lederle, MD, Center for Chronic Disease Outcomes Research, Minneapolis Veterans Affairs Medical Center (111-O), One Veterans Drive, Minneapolis, MN 55417; e-mail, frank.lederle@va.gov.

Current Author Addresses: Drs. Lederle and Wilt and Mr. MacDonald: Center for Chronic Disease Outcomes Research, Minneapolis Veterans Affairs Medical Center (111-O), One Veterans Drive, Minneapolis, MN 55417.

Dr. Zylla: Hematology Section, Minneapolis Veterans Affairs Medical Center (111-O), One Veterans Drive, Minneapolis, MN 55417.

Author Contributions: Conception and design: F.A. Lederle, T.J. Wilt.

Analysis and interpretation of the data: F.A. Lederle, D. Zylla, R. MacDonald, T.J. Wilt.

Drafting of the article: F.A. Lederle, R. MacDonald, D. Zylla.

Critical revision of the article for important intellectual content: F.A. Lederle, T.J. Wilt.

Final approval of the article: F.A. Lederle, D. Zylla, R. MacDonald, T.J. Wilt.

Statistical expertise: R. MacDonald, T.J. Wilt.

Obtaining of funding: T.J. Wilt.

Administrative, technical, or logistic support: T.J. Wilt.

Collection and assembly of data: F.A. Lederle, D. Zylla, T.J. Wilt.


Ann Intern Med. 2011;155(9):602-615. doi:10.7326/0003-4819-155-9-201111010-00008
Text Size: A A A

Background: Venous thromboembolism prophylaxis has been recommended for nonsurgical patients, but its effectiveness remains uncertain.

Purpose: To assess the benefits and harms of prophylaxis in hospitalized adult medical patients and those with acute stroke.

Data Sources: MEDLINE and the Cochrane Library from 1950 through April 2011, reference lists, and study authors.

Study Selection: English-language randomized trials were included if they provided clinical outcomes and evaluated therapy with low-dose heparin or related agents or mechanical measures compared with placebo, no treatment, or other active prophylaxis in the target population.

Data Extraction: Two independent investigators extracted data on study characteristics and clinical outcomes up to 120 days after randomization. The primary outcome was total mortality.

Data Synthesis: In medical patients, heparin prophylaxis did not reduce total mortality but did result in fewer pulmonary embolisms (PEs) (odds ratio [OR], 0.69 [95% CI, 0.52 to 0.90], but with evidence of publication bias) and an increase in all bleeding events (risk ratio [RR], 1.34 [CI, 1.08 to 1.66]). Heparin prophylaxis had no statistically significant effect on any outcome in patients with acute stroke except for an increase in major bleeding events (OR, 1.66 [CI, 1.20 to 2.28]). When trials of medical patients and those with stroke were considered together (18 studies; 36 122 patients), heparin prophylaxis reduced the incidence of PE (OR, 0.70 [CI, 0.56 to 0.87]; absolute reduction, 3 events per 1000 patients treated [CI, 1 to 5 events]) but increased the incidence of all bleeding (RR, 1.28 [CI, 1.05 to 1.56]) and major bleeding events (OR, 1.61 [CI, 1.23 to 2.10]), with an absolute increase of 9 bleeding events per 1000 patients treated (CI, 2 to 18 events), 4 of which were major (CI, 1 to 7 events). A reduction in total mortality approached statistical significance (RR, 0.93 [CI, 0.86 to 1.00]; P = 0.056; absolute decrease, 6 deaths per 1000 patients treated [CI, 0 to 11 deaths]). No statistically significant differences in clinical outcomes were observed in the 14 trials that compared unfractionated heparin with low-molecular-weight heparin. No improvements in clinical outcomes were seen in the 3 studies of mechanical prophylaxis in patients with stroke, but more patients had lower-extremity skin damage (RR, 4.02 [CI, 2.34 to 6.91])—an increase of 39 events per 1000 patients treated (CI, 17 to 77 events).

Limitation: Non−English-language studies were not included, but these were few and small.

Conclusion: Heparin prophylaxis had no significant effect on mortality, may have reduced PE in medical patients and all patients combined, and led to more bleeding and major bleeding events, thus resulting in little or no net benefit. No differences in benefits or harms were found according to type of heparin used. Mechanical prophylaxis provided no benefit and resulted in clinically important harm to patients with stroke.

Primary Funding Source: American College of Physicians.

Figures

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Appendix Figure 1.
Summary of evidence search and selection.

VTE = venous thromboembolism.

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Appendix Figure 2.
Risk-for-bias graphs for trials of heparin prophylaxis versus no heparin, low-molecular-weight versus unfractionated heparin prophylaxis, and mechanical versus no mechanical prophylaxis.
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Figure 1.
Forest plots for outcomes of death, pulmonary embolism, and major bleeding events in studies of heparin prophylaxis versus no heparin.
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Figure 1—
Continued

* Mantel–Haenszel risk ratio (random) and Peto odds ratio (fixed).

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Figure 2.
Forest plots for outcomes of death, pulmonary embolism, and major bleeding events in studies of low-molecular-weight versus unfractionated heparin prophylaxis.
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Figure 2—
Continued

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

* Mantel–Haenszel risk ratio (random) and Peto odds ratio (fixed).

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Figure 3.
Forest plot for outcome of death in studies of mechanical versus no mechanical prophylaxis.

* Mantel–Haenszel risk ratio (fixed).

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Comments

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Skeptical About the Sweeping Recommendations
Posted on November 7, 2011
RaghavendraAllareddy, MBBS, MD
Cleveland Clinic
Conflict of Interest: None Declared

I read the article "Venous Thromboembolism prophylaxis in hospitalized medical patients and those with stroke: Background review for an American College of Physicians clinical practice guideline" from the annals with great interest, along with accompanying guidelines and the editorial (1).

The articles generates a lot of enthusiasm in many physicians--I am one among them--who are skeptical about the sweeping recommendations of the of Joint Commission of advocating for VTE prophylaxis against most of surgical, hospitalized medical patients as performance measure.(2)

We all agree about the high incidence and significant mortality and morbidity of VTE (3). But the data quoted as the 2nd reference in VTE guidelines "Twenty-six percent of patients with undiagnosed and untreated PE will have a subsequent fatal embolic event, whereas another 26% will have a nonfatal recurrent embolic event" [which is actually from a study in 1960s (4), quoted as from a different article (5)] was historical and misleading as has data which was old with questionable diagnostic accuracy for PE in the absence of definitive diagnostic procedures like pulmonary angiogram or CT pulmonary angiogram in that era in comparison to the contemporary scene.

In addition, several of the studies quoted in heparin prophylaxis vs placebo group and most from the UFH and LMWH comparison were from before 1998, the year when the CT pulmonary angiogram(CTPA) was started being used widely. More over the Pulmonary Embolism as a cause of death is 'overemphasized'--forgetting the fact that spectrum of PE presentation varies from 'massive PE' with its high mortality and morbidity to 'asymptomatic PE', which is incidentally found in CT scans--and may not be any more valid in the newer circumstances where PE is diagnosed more frequently by use of CTPA than by previous older methods like V/Q scan or Pulmonary Angiogram as quoted by Wiener RS et al (6). The same article generates questions about the need to treating asymptomatic PEs, making even the 'strong' 2nd recommendation--recommending the pharmacological prophylaxis in medical patients and those with stroke at risk with heparin or related drugs if bleeding risk is low--questionable.

These articles, guidelines also generate interest in possible new ideas--do we need to take a different approach in our aggressiveness in dealing with at least some of the categories of DVTs like the below the knee DVTs (may be the upper extremity /line related DVTs too)?. In fact many of physicians have reservations about treating the below knee DVTs. As we are all aware, they are, at present, recommended to be treated like above knee DVTs with full anti-coagulation.

So we need to move forward from questioning the sweeping recommendation for VTE prophylaxis--which these articles support--to questioning the recommendations for therapeutic anticoagulation of low risk DVTs ( below knee) and PEs (those which are incidental and asymptomatic).

References:

1. Lederle FA, Zylla D, MacDonald R, Wilt T. Venous thromboembolism prophylaxis in hospitalized medical patients and those with stroke: background review for an American College of Physicians clinical practice guideline. Ann Intern Med. 2011;155:602-615. 2. The Joint Commission. Venous thromboembolism. Accessed at www.jointcommission.org/venous_thromboembolism/ on 4 August 2011.

3. Geerts WH, Pineo GF, Heit JA, Bergqvist D, Lassen MR, Colwell CW, et al. Prevention of venous thromboembolism: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004;126:338S-400S.

4. Barritt DW, Jordan SC. Anticoagulant drugs in the treatment of pulmonary embolism. A controlled trial. Lancet. 1960;1:1309-12. [PMID: 13797091]

5. Qaseem A, Snow V, Barry P, Hornbake ER, Rodnick JE, Tobolic T, et al; Joint American Academy of Family Physicians/American College of Physicians Panel on Deep Venous Thrombosis/Pulmonary Embolism. Current diagnosis of venous thromboembolism in primary care: a clinical practice guideline from the American Academy of Family Physicians and the American College of Physicians. Ann Intern Med. 2007;146:454-8.

6. Renda Soylemez Wiener, Lisa M. Schwartz, and Steven Woloshin, et al; Time Trends in Pulmonary Embolism in the United States: Evidence of Overdiagnosis. Arch Intern Med, May 2011; 171: 831 - 837.

Conflict of Interest:

None declared

Re: Systematic review of VTE prophylaxis in Hospitalized Medical Patients
Posted on December 4, 2011
Todd E. H.Hecht, Associate Professor of Clinical Medicine
University of Pennsylvania
Conflict of Interest: None Declared

I read with great interest the systematic review of VTE prophylaxis authored by Lederle et al. in the November 1, 2011 issue (1). The authors conclude that heparin prophylaxis resulted "in little or no net benefit." This is in contrast to an earlier meta-analysis by Wein et al. that employed many of the same studies in medical and stroke patients (2). I believe the authors of the current analysis reached this conclusion erroneously.

First, the authors' decision to eliminate asymptomatic DVT from their analysis accounts for a significant slant against the efficacy of VTE prophylaxis. The authors do not provide the total number of asymptomatic DVTs in the studies included. However, if the DVT outcomes from the Wein meta-analysis were used, the point estimate for the absolute effect per 1000 patients would be 62 fewer DVTs, which is seven-fold and 15-fold greater than the rates of all bleeding and major bleeding per 1000 in all medical and stroke patients in the Lederle analysis.

Second, by eliminating the outcome of asymptomatic DVT, the authors are underestimating the effect of prophylaxis on symptomatic VTE. Since trial patients that developed asymptomatic DVT would likely have undergone treatment with systemic anticoagulation, it is reasonable to expect that the rate of symptomatic events may very well have been reduced by this early detection. This is strongly suggested by the fact that the symptomatic DVT rate in the present analysis is actually lower than the symptomatic PE rate, a finding that is quite different from that found in other trials targeting only symptomatic endpoints (3,4).

Third, the authors emphasize some of their adverse effect data while simultaneously de-emphasizing the VTE outcome data. For medical patients, the point estimates for the absolute effect per 1000 patients suggest 10 fewer deaths, PEs, or symptomatic DVTs against 1 major bleed. I think most patients and providers would accept this tradeoff. Further, while heparin appears to be associated with an increase in all bleeds, these are overwhelmingly minor bleeds as is shown with a major bleeding rate that is one-tenth the rate of all bleeding. If the authors are prepared to discount asymptomatic DVT, they should be willing to discount minor bleeds as well.

I sincerely hope that this misleading systematic review does not impair the many efforts being undertaken around the world to improve the use of VTE prophylaxis in hospitalized patients.

References

1. Lederle FA, Zylla D, Macdonald R, Wilt TJ. Venous thromboembolism prophylaxis in hospitalized medical patients and those with stroke: a background review for an american college of physicians clinical practice guideline. Ann Intern Med;155:602-15.

2. Wein L, Wein S, Haas SJ, Shaw J, Krum H. Pharmacological venous thromboembolism prophylaxis in hospitalized medical patients: a meta- analysis of randomized controlled trials. Arch Intern Med 2007;167:1476- 86.

3. Lederle FA, Sacks JM, Fiore L, Landefeld CS, Steinberg N, Peters RW, Eid AA, Sebastian J, Stasek JE, Jr., Fye CL. The prophylaxis of medical patients for thromboembolism pilot study. Am J Med 2006;119:54-9.

4. Prevention of pulmonary embolism and deep vein thrombosis with low dose aspirin: Pulmonary Embolism Prevention (PEP) trial. Lancet 2000;355:1295-302.

Conflict of Interest:

None declared

Response to Hecht and Allareddy
Posted on December 12, 2011
Frank A.Lederle, MD, Roderick MacDonald, MS, Timothy J. Wilt, MD, MPH
Center for Chronic Disease Outcomes Research, Veterans Affairs Medical Center, Minneapolis MN 55417
Conflict of Interest: None Declared

Hecht objects to our decision not to include asymptomatic deep venous thrombosis (DVT) in our systematic review (1). As noted in our Introduction, asymptomatic DVT is a surrogate outcome that is much more common than clinically evident venous thromboembolism, and its value has been repeatedly questioned (1). We stand by our decision, but we agree with Hecht that screening and treatment for asymptomatic DVT, which occurred in some trials in our review, may have reduced the number of symptomatic DVTs. Treating asymptomatic DVT is analogous to increasing the crossover rate, and so could reduce the effect of prophylaxis on all measures of benefit and harm, including pulmonary embolism and bleeding. While we consider the practice misguided, we do not consider it a reason to include a surrogate outcome in our review. To assess its impact in medical patients, we compared the effect of heparin prophylaxis on symptomatic DVT in studies that screened for asymptomatic DVT (OR 0.79, 95% CI: 0.41 to 1.51) vs. those that did not (OR 0.87, 95% CI: 0.51 to 1.49). The effect did not differ substantially or significantly (p = 0.83), suggesting that our findings were not much affected by this practice. The data are insufficient to conduct a similar analysis in patients with stroke. The foregoing analysis includes symptomatic DVT from Mahe (2) that were omitted from the original review (1). With their inclusion, the odds ratio in the original Table under heparin vs no heparin for symptomatic DVT in medical patients changes slightly to 0.83 [0.55 to 1.26], with the same absolute effect of 2 fewer [-5 to 3].

Hecht also criticizes our emphasis regarding outcomes in medical patients, based on differences in mortality and symptomatic DVT that were not significant, and a difference in pulmonary embolism for which evidence of publication bias was detected. Weighing these uncertainties against the significant increase in bleeding, we stand by our characterization of heparin prophylaxis as demonstrating little or no net benefit. We agree with Hecht’s suggestion that the most appropriate comparison of morbidities is between symptomatic venous thromboembolism and major bleeding, and to this end we twice cited the paper by Carrier (3), which provides quantitative support for that comparison.

We cannot dispute Allareddy’s point that recommending prophylaxis “if bleeding risk is low” is “questionable” because, as noted in our Discussion, we did not find trial data that identified patient subgroups more likely to benefit from prophylaxis, with the possible exception of those older than 75.  

References

1. Lederle FA, Zylla D, MacDonald R, Wilt TJ. Venous thromboembolism prophylaxis in hospitalized medical patients and those with stroke: a background review for an American College of Physicians clinical practice guideline. Ann Intern Med 2011;155:602-15.

2. 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.

3. Carrier M, Le Gal G, Wells PS, Rodger MA. Systematic review: case- fatality rates of recurrent venous thromboembolism and major bleeding events among patients treated for venous thromboembolism. Ann Intern Med 2010;152:578-89.

Conflict of Interest:

None declared

Disagree with Authors' Conclusion
Posted on January 3, 2012
Michael B.Streiff, MD, FACP, Associate Professor of Medicine, Amer Zeidan, MD, Postdoctoral Fellow in Hematology, Elliott R. Haut, MD FACS, Associate Professor of Surgery and Anesthesiology and Critical Care Medicine, Division of Acute Care Surgery, Department of Surgery
Division of Hematology, Medical Director, Johns Hopkins Anticoagulation Management Service and Outpa
Conflict of Interest: None Declared

Dear Editor, We read with interest the systematic review of venous thromboembolism (VTE) prophylaxis by Lederle et al. (1) While we agree with their emphasis on risk assessment, we disagree with their conclusion that VTE prophylaxis is associated with "little or no net benefit". We are concerned that this conclusion may mislead policy makers and jeopardize recent improvements in VTE prophylaxis causing unintended patient harm.

In our opinion, these conclusions are largely a product of their study design. Observation #1- Randomized clinical trials (RCT) using routine DVT surveillance underestimate the impact of prophylaxis on symptomatic VTE. Routine DVT surveillance reduces the incidence of symptomatic thrombotic events by identifying events prior to symptoms. This "surveillance effect" explains the curious finding that symptomatic PE outnumbered symptomatic DVT in the systematic review whereas symptomatic DVT is 2-3 fold more common in population-based observational studies (2, 3). Observation #2- Major bleeding is the most relevant measure of harm from VTE prophylaxis. Major bleeding during therapeutic anticoagulation is associated with a similar case fatality rate as recurrent VTE (4). In contrast, all bleeding during VTE prophylaxis typically includes events such as injection site bruising which have negligible health consequences. Therefore, major bleeding not all bleeding should be the primary measure of harm from VTE prophylaxis.

Observation #3- Clinical outcomes are best measured during the treatment period Subcutaneous heparin has a half-life of several hours. Therefore, VTE prophylaxis outcomes in the systematic review should focus on the 6-21 days of administration not 120 days after randomization.. During VTE prophylaxis, 32/ 10,060 (0.31%) heparin patients and 27/10,188 placebo recipients (0.27%) suffered major bleeding. Symptomatic VTE occurred in 209/9842 placebo patients (2.12%) and 125/9705 heparin patients (1.29%), a reduction well worth the 0.04% increase in major bleeding. Observation #4- Fatal PE is the best VTE prophylaxis mortality measure.

Autopsy data indicate that fatal PE occurs in 3.9% of hospitalized patients (5). Therefore, VTE prophylaxis is unlikely to impact all-cause mortality. Fatal PE occurred in 43/10,023 (0.43%) placebo recipients and 26/9887 (0.26%) heparin recipients during prophylaxis, a 40% relative risk reduction.

Despite our differing view, we think that Lederle et al have focused necessary attention on the importance of risk assessment in hospitalized medical patients. VTE prophylaxis should be applied in a risk-appropriate fashion not universally without regard to potential harm. Nevertheless, we strongly believe that prescription of risk-appropriate VTE prophylaxis is a practice that should be encouraged rather than discouraged.

Sincerely,

Michael B. Streiff, MD FACP Associate Professor of Medicine Division of Hematology Medical Director, Johns Hopkins Anticoagulation Management Service and Outpatient Clinics

Amer Zeidan, MD Postdoctoral Fellow in Hematology

Elliott R. Haut, MD FACS Associate Professor of Surgery and Anesthesiology and Critical Care Medicine Division of Acute Care Surgery, Department of Surgery

For the Johns Hopkins VTE Collaborative and the Armstrong Institute for Patient Safety and Quality, Johns Hopkins Medical Institutions, Baltimore, MD

References:

1. Lederle FA, Zylla D, MacDonald R, Wilt TJ. Venous thromboembolism prophylaxis in hospitalized medical patients and those with stroke: a background review for an American College of Physicians Clinical Practice Guideline. Ann Intern Med. 2011;155(9):602-15.

2. Stein PD, Beemath A, Olson RE. Trends in the incidence of pulmonary embolism and deep venous thrombosis in hospitalized patients. Am J Cardiol. 2005;95(12):1525-6.

3. Spencer FA, Emery C, Joffe SW, Pacifico L, Lessard D, Reed G, et al. Incidence rates, clinical profile, and outcomes of patients with venous thromboembolism. The Worcester VTE study. J Thromb Thrombolysis. 2009;28(4):401-9.

4. Carrier M, Le Gal G, Wells PS, Rodger MA. Systematic review: case- fatality rates of recurrent venous thromboembolism and major bleeding events among patients treated for venous thromboembolism. Ann Intern Med. 2010;152(9):578-89.

5. Alikhan R, Peters F, Wilmott R, Cohen AT. Fatal pulmonary embolism in hospitalised patients: a necropsy review. J Clin Pathol. 2004;57(12):1254-7.

Conflict of Interest:

None declared

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Summary for Patients

Preventing Venous Thromboembolism in Hospitalized Patients: Recommendations From the American College of Physicians

The full reports are titled “Venous Thromboembolism Prophylaxis in Hospitalized Patients: A Clinical Practice Guideline From the American College of Physicians” and “Venous Thromboembolism Prophylaxis in Hospitalized Medical Patients and Those With Stroke: A Background Review for an American College of Physicians Clinical Practice Guideline.” They are in the 1 November 2011 issue of Annals of Internal Medicine (volume 155, pages 625-632 and pages 602-615). The first report was written by A. Qaseem, R. Chou, L.L. Humphrey, M. Starkey, and P. Shekelle, for the Clinical Guidelines Committee of the American College of Physicians; the second report was written by F.A. Lederle, D. Zylla, R. MacDonald, and T.J. Wilt.

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