Amir Qaseem, MD, PhD, MHA; Roger Chou, MD; Linda L. Humphrey, MD, MPH; Melissa Starkey, PhD; Paul Shekelle, MD, PhD; for the Clinical Guidelines Committee of the American College of Physicians
The American College of Physicians (ACP) developed this guideline to present the evidence and provide clinical recommendations on prophylaxis of venous thromboembolism for hospitalized nonsurgical patients (medical patients and patients with acute stroke).
This guideline is based on published literature on the topic from 1950 through April 2011 that was identified by using MEDLINE, the Cochrane Library, and reference lists of pertinent randomized trials and systematic reviews to identify additional reports. Searches were limited to randomized trials and English-language publications. The primary outcome for this guideline was total mortality up to 120 days after randomization. Secondary outcomes included symptomatic deep venous thrombosis; all pulmonary embolisms; fatal pulmonary embolism; all bleeding events; major bleeding events; and, for mechanical prophylaxis, effects on skin. This guideline grades the evidence and recommendations by using the ACP's clinical practice guidelines grading system.
ACP recommends assessment of the risk for thromboembolism and bleeding in medical (including stroke) patients prior to initiation of prophylaxis of venous thromboembolism (Grade: strong recommendation, moderate-quality evidence).
ACP recommends pharmacologic prophylaxis with heparin or a related drug for venous thromboembolism in medical (including stroke) patients unless the assessed risk for bleeding outweighs the likely benefits (Grade: strong recommendation, moderate-quality evidence).
ACP recommends against the use of mechanical prophylaxis with graduated compression stockings for prevention of venous thromboembolism (Grade: strong recommendation, moderate-quality evidence).
ACP does not support the application of performance measures in medical (including stroke) patients that promotes universal venous thromboembolism prophylaxis regardless of risk.
ACP = American College of Physicians; DVT = deep venous thrombosis; PE = pulmonary embolism; VTE = venous thromboembolism.
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Dr. Amir Qaseem discusses ACP's clinical practice guideline to prevent venous thromboembolism in hospitalized patients.
David K.Cundiff, Physician (Retired)
LA County USC Medical Center
November 6, 2011
Declare anticoagulants as VTE prophylaxis for medical patients ... CONTRAINDICATED
The background review and ACP Venous Thromboembolism Prophylaxis guidelines by Lederle, Qaseem, and colleagues(1, 2) concluded that heparin prophylaxis for medical patients does not reduce mortality and does increase major bleeding. Additionally, heparin prophylaxis hurts patients with repeated needle sticks and subcutaneous hematomas, takes valuable clinician time, and costs money. Heparin significantly reduces the risks of asymptomatic PE and DVT but not symptomatic VTE. The ACP recommends that physicians prescribe heparin if the risk for VTE is greater than the risk for bleeding. However, there is no validated process of determining if the risk of VTE is greater than the risk for bleeding.
With three coauthors, my review of the literature of anticoagulant prophylaxis against hospital acquired VTE showed that anticoagulants increase the risk of death in medical patients.(3) Our review included an important study not referenced in the ACP review because it was not an RCT. Goldhaber and colleagues reviewed charts to find the incidence of developing DVT, PE, and fatal PE (FPE) during hospitalization and within 30 days after hospital discharge in about 80,000 medical, surgical, neurological, obstetrical, and pediatric patients admitted over a two year period in Boston's Brigham and Women's Hospital.(4) Out of 384 patients with hospital-acquired VTE (about 1 per 200 admissions), less than 25% came from general surgical or orthopedic surgical services and the rest came from medical or oncology services. Only 318 hospital acquired VTE patients (82.8%) were potential candidates for prophylaxis (i.e., they had two or more VTE risk factors). Of prophylaxis candidates, 170 (53%) had received anticoagulants. Out of 13 patients with FPE (all on medical or oncology wards and no stroke patients), 12 had received anticoagulant prophylaxis. Estimating that 32% of the hospitalized patients were at risk for VTE and that 50% of all patients at increased risk for VTE received anticoagulants,(3) anticoagulation prophylaxis was associated with a 12- fold increase in FPE (OR: 12.0; 95% CI, 1.6-92). Notably, the rate of FPE estimated in anticoagulated and unanticoagulated high VTE risk patients in the Goldhaber patient chart study was an order of magnitude less than the rate in the largely industry funded RCTs included in the ACP review (heparin: 12/12 300 (0.10%) versus 46/13 839 (0.33%); no heparin: 1/12 300 (0.008%) versus 66/18 462 (0.36%)).(1, 3)
To reduce deaths and vascular complications of heparin and other anticoagulants, the ACP guidelines should declare prophylactic anticoagulation of medical inpatients contraindicated.
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 10.1059/0003-4819-155-9-201111010-00008. Annals of Internal Medicine. 2011;155(9):602-615.
2. Qaseem A, Chou R, Humphrey LL, Starkey M, Shekelle P. Venous Thromboembolism Prophylaxis in Hospitalized Patients: A Clinical Practice Guideline From the American College of Physicians 10.1059/0003-4819-155-9- 201111010-00011. Annals of Internal Medicine. 2011;155(9):625-632.
3. Cundiff D, Agutter P, Malone P, Pezzullo J. Diet as prophylaxis and treatment for venous thromboembolism? Theoretical Biology and Medical Modelling. 2010(1):http://www.tbiomed.com/content/7/1/31/comments.
4. Goldhaber S, Dunn K, MacDougall R. New onset of venous thromboembolism among hospitalized patients at Brigham and Women's Hospital is caused more often by prophylaxis failure than by withholding treatment. Chest. 2000;118:1680-4.
Paul S.Agutter, Director, P. Colm Malone
Theoretical Medicine and Biology Group
November 8, 2011
ACP VTE guideline: a comment
The recent review supporting the ACP guideline for hospitalized medical and stroke patients (1) showed that heparin, both LMW and unfractionated, fails to reduce mortality from VTE and DVT-related morbidity in patients overall, but increases the likelihood of major bleeding. Our recent article (2) yielded the same inferences but surprisingly was not cited in (1). The authors of (1) recommend that, for most patients, heparin prophylaxis should be used only when the VTE risk exceeds the bleeding risk, but it is not clear how these risks are to be computed and compared. In (2) we suggested that certain diets (Mediterranean, vegetarian or vegan) could be prophylactic against VTE, citing independent support for this proposal; it would entail no bleeding risk, though a large trial would be required to validate it (2). The necessary trial for medical and post-stroke patients need not have a heparin prophylaxis control arm since this ACP review (1) demonstrated that heparin does not benefit patients.
The new ACP VTE prophylaxis guideline recommends against mechanical prophylaxis with graduated compression stockings because of limited benefit and deleterious effects on the skin, though the authors admit their evidence is sparse and of moderate quality (1). One argument for early mobilization and mechanical prophylaxis is that these measures were infrequently utilized before the 1980s; since then they have become widely practiced, and the incidence of hospital-acquired VTE has decreased around four-fold (2). Our understanding of the etiology of DVT and VTE (3) indicates that the most effective form of mechanical prophylaxis would be intermittent pneumatic compression with pulses at 30-60 minute intervals. This would suffice to empty the valve pockets during non-pulsatile venous flow at frequent enough intervals to preclude the suffocating hypoxemia that initiates thrombogenesis. The experiments that confirmed our account of DVT etiology (4) imply that this approach to prophylaxis would be valuable, but further animal experiments followed by clinical trials are needed to test the implication. In view of the continuing high incidence of DVT/VTE in hospitals, such studies should receive priority. The authors of (1) have made clear the paucity of evidence in this area.
Paul S. Agutter: Theoretical Medicine and Biology Group, Glossop, Derbyshire, UK; firstname.lastname@example.org P. Colm Malone: email@example.com
1. Qaseem A, Chou R, Humphrey LL, Starkey M, Shekelle P. Venous thromboembolism prophylaxis in hospitalized patients: a clinical practice guideline from the American College of Physicians. Ann Intern Med. 2011;155:625-32. [PMID: 22041951]
2. Cundiff DK, Agutter PS, Malone PC, Pezzullo J. Diet as prophylaxis and treatment for venous thromboembolism? Theor Biol Med Model 2010;7:31. [PMID: 20701748] http://www.tbiomed.com/content/7/1/31/comments.
3. Malone PC, Agutter PS. The Aetiology of Deep Venous Thrombosis. Dordrecht: Springer; 2008.
4. Hamer JD, Malone PC. Experimental deep vein thrombosis by a non- invasive method. Ann R Coll Surg Engl. 1984;66:416-9. [PMID: 6508162]
Graham DMills, General Physician
Waikato Hospital, Hamilton, New Zealand
December 1, 2011
Show me the evidence - VTE prophylaxis
There appears to be a disconnect in the evidence based guidelines from the American College of Physicians. It is pleasing to see the background review for the VTE guidelines by Lederle et al has been copublished by the editors, but this appears to have been ignored (at least in part) by the clinical guideline committee of the American College of Physicians when making their clinical practice guidelines. Specifically, recommendation 2 states that pharmacologic prophylaxis with heparin is recommended for VTE prophylaxis in medical patients unless the assessed risk for bleeding outweighs the likely benefits and grades this as a strong recommendation with moderate-quality evidence. The discussion then states that "the clinical benefit of reduction of PEs outweighs the harm of increased risk for bleeding events." Yet, Lederle et al caution about the validity of the PE data as "the funnel plot and Egger analyses suggested that the decrease in PE incidence may have been exaggerated by publication bias."
Given this caution, the lack of mortality benefit, and the increased risk of bleeding, why has the position been taken that VTE prophylaxis with heparin adds anything to the clinical management of the standard "higher risk" medical patient which is the population included in the background meta-analysis by Lederle? Where is the moderate-quality evidence to make such a strong recommendation? Is their any scenario that is readily identifiable when the risk of VTE is greater than the risk for bleeding? Surely, the normative approach based on the evidence is to only consider prophylaxis in specific circumstances (yet what they are is yet to be determined), rather than as the routine. Primum non nocere!
EugeneCarpenter, Forensic Pathologist
L.A. County Coroner
December 24, 2011
Subdural Hematomas and Death In Older People With Minor Tauma, On Anticoagulants
Here at Los Angeles Dept. of Coroner it seems that we have ten to twenty such deaths per month. Most often the use of "blood thinners" is not listed on the death certificate and the type of trauma has not been made clear. A good reseach project would be to collect all the many cases of deaths by blunt head trauma/and or subdural hematomas from the death certificate statistics and then clarify how many are due to minor head trauma while on anticoagulants. I think the results would be shocking and turn "weighing the benefits and risks" of administering such therapies into a whole new ball game. Just about everytime I fill out the worksheets for the mortuary external examinations to be done by our deputy coroners I see several such cases. I do this several times per month and other doctors cover this duty the other twenty seven days of the month. It seems epidemic. It is truely alarming to me. Even just interviewing coroner/medical examiners of the major cities should produce a very ugly hypothesis of a very real problem ignored far too long.
AmirQaseem, , Roger Chou, Linda Humphrey, Paul Shekelle
American College of Physicians
January 11, 2012
We thank Drs. Agutter, Cundiff, and Mills for their comments regarding the American College of Physicians' recent clinical guideline on venous thromboembolism (VTE) prophylaxis in hospitalized patients (1).
In response to Dr. Mills, the pooled results from medical patients showed that prophylaxis with heparin is associated with a statistically significant reduction in PEs (absolute decrease, 4 events per 1000 persons treated) but a non-statistically significant increase in major bleeding events (absolute increase, 1 event per 1000 persons treated), and no effect on mortality or symptomatic DVT. Hence, there is more benefit from potential reduction in PE events relative to the risk of bleeding events. As far as the rating of our evidence goes, according to the GRADE system, publication bias is just one of the factors in addition to others such as the number of trials, quality, consistency between trials, and precision of estimates that should be considered when rating the quality of evidence and grading the strength of recommendations. Funnel plots can be helpful in understanding the risk of publication bias, but results must be interpreted cautiously, because the small sample effects evaluated in funnel plots can be due to factors other than publication bias (such as differences in study quality, populations, or outcomes) (2, 3). Other approaches for examining the likelihood of publication bias have similar limitations (4). In addition, the possibility of publication bias by itself does not necessarily invalidate estimates of treatment effects. In this case, many unpublished small trials of heparin prophylaxis showing no reduced risk of PE would have to exist in order to lower the absolute decrease in events from 4 events per 1000 persons treated to 1 or fewer events per 1000 persons treated, and result in no net benefit relative to the risk of major bleeding. This is unlikely. Therefore we stand by our original recommendation and grading of evidence.
As far as Drs. Cundiff's and Agutter's comments are concerned, our literature review only included evidence from randomized controlled trials because they are less susceptible to bias than observational studies when designed and carried out correctly. Both Drs. Agutter and Cundiff refer to a review focusing on diet and VTE. Their review included no studies that actually evaluated the association between a prophylactic intervention and clinical outcomes. Rather it discussed possible mechanisms for benefit and epidemiological studies and proposed a possible dietary intervention for future research (5). Hence this paper was not included in the review for our guideline.
Authors: Amir Qaseem, MD, PhD, MHA American College of Physicians, 190 N. Independence Mall West, Philadelphia, PA 19106
Roger Chou, MD Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Mail Code: BICC, Portland, OR 97239.
Linda Humphrey, MD Oregon Health and Science University, 3710 SW US Veterans Hospital Road, Portland, OR 97201
Paul Shekelle, MD, PhD Greater Los Angeles VA Health Center/RAND, 1776 Main Street, Santa Monica, CA 90401
1. Qaseem A, Chou R, Humphrey LL, Starkey M, Shekelle P. Venous Thromboembolism Prophylaxis in Hospitalized Patients: A Clinical Practice Guideline From the American College of Physicians. Annals of Internal Medicine. 2011;155(9):625-32. 2. Lau J, Ioannidis JP, Terrin N, Schmid CH, Olkin I. The case of the misleading funnel plot. BMJ. 2006;333(7568):597-600. 3. Terrin N, Schmid CH, Lau J. In an empirical evaluation of the funnel plot, researchers could not visually identify publication bias. J Clin Epidemiol. 2005;58(9):894-901. 4. Guyatt GH, Oxman AD, Montori V, Vist G, Kunz R, Brozek J, et al. GRADE guidelines: 5. Rating the quality of evidence--publication bias. J Clin Epidemiol. 2011;64(12):1277-82. 5. Cundiff DK, Agutter PS, Malone PC, Pezzullo JC. Diet as prophylaxis and treatment for venous thromboembolism? Theor Biol Med Model. 2010;7:31.
Qaseem A, Chou R, Humphrey LL, Starkey M, Shekelle P, for the Clinical Guidelines Committee of the American College of Physicians. Venous Thromboembolism Prophylaxis in Hospitalized Patients: A Clinical Practice Guideline From the American College of Physicians. Ann Intern Med. ;155:625–632. doi: 10.7326/0003-4819-155-9-201111010-00011
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Published: Ann Intern Med. 2011;155(9):625-632.
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