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Correspondence |

Deep Vein Thrombosis Prophylaxis FREE TO VIEW

Kristy L. Weber, MD; Joseph D. Zuckerman, MD; William C. Watters, III, MD; Charles M. Turkelson, PhD
Author and Funding Information

Affiliations: Dr. Weber is affiliated with the Department of Orthopedics, Johns Hopkins University, and is Chair, Council on Research, Quality Assessment, & Technology, American Academy of Orthopaedic Surgeons. Dr. Zuckerman is affiliated with the New York University Hospital for Joint Diseases, and is President, American Academy of Orthopaedic Surgeons. Dr. Watters is affiliated with the Bone and Joint Clinic of Houston, and is Chair, Guidelines and Technology Oversight Committee, American Academy of Orthopaedic Surgeons. Dr. Turkelson is Director, Research and Scientific Affairs Department, American Academy of Orthopaedic Surgeons.

Correspondence to: Charles M. Turkelson, PhD, American Academy of Orthopaedic Surgeons, Research and Scientific Affairs, 6300 N River Rd, Rosemont, IL 60018; e-mail: turkelson@aaos.org


Financial/nonfinancial disclosures: The authors have reported to the ACCP that no significant conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal.org/site/misc/reprints.xhtml).


© 2009 American College of Chest Physicians


Chest. 2009;136(6):1699-1700. doi:10.1378/chest.09-1218
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To the Editor:

We appreciate the comments made in a recent issue of CHEST (February 2009) by Eikelboom et al1 about the American Academy of Orthopaedic Surgeons (AAOS) clinical practice guideline “Prevention of Symptomatic Pulmonary Embolism in Patients Undergoing Total Hip or Knee Arthroplasty.” The AAOS welcomes continued professional dialogue on the topic of prophylaxis and will consider all such comments when it performs its scheduled update of its guideline in 2010. However, we would like to reiterate that we remain concerned about the use of deep vein thrombosis (DVT) as a surrogate marker for pulmonary embolism (PE), and about the potential in the joint replacement patient for iatrogenic hemorrhage (with its associated complications) that can result from PE prophylaxis.

Part of the difficulty of using DVT as an outcome of choice is that it may not be an outcome that is as important to patients as PE or hemorrhage, particularly when the DVT is asymptomatic. The AAOS represents practicing orthopedic surgeons who are often ambivalent about administering a prophylactic regimen that, in large part, has been validated by its proven ability to lower the risk of asymptomatic DVT. This is not viewed as being an acceptable tradeoff when considering the risk of patient harm associated with major hemorrhage. The common perception is that relatively aggressive attempts to prevent DVT underestimate the risk of bleeding.

To be a valid surrogate measure, a surrogate must meet strict criteria. First, the measure should have a well-established relationship (ie, correlation) with the relevant clinical end point. Eikelboom et al1 nicely summarized data showing that such a correlation exists between DVT and PE. However, it is also important to note that one has greater confidence in the validity of a surrogate if the correlation is large,2,3 and it is not clear that the relative risks presented by Eikelboom et al,1 which range from approximately 0.3 to 0.5, are, in fact, large.

Furthermore, for a surrogate to be valid, it should also be possible to use the effect of the treatment on the surrogate to estimate the amount of clinical benefit a patient will experience. Eikelboom et al1 have again presented correlations to suggest that such an estimate can be derived and, again, it is not clear that these correlations are sufficiently large. However, even large correlations are not sufficient to demonstrate the validity of a surrogate, because even a perfect correlation between the treatment-induced effects on a potential surrogate and a patient-oriented outcome does not guarantee the utility of that potential surrogate.4 Further, summary metaanalytic data, such as those reported by Eikelboom et al,1 can be misleading. Data that allow for a correct metaanalytic interpretation of the validity of surrogate measures do not appear to be available, but it is worth noting that the desired analysis would involve regressing the effect of an intervention on PE, and also regressing the effect of that intervention on DVT for each trial. One would treat the coefficients from these two regressions as random variables with a joint distribution over all trials. The estimated parameters from this joint distribution would then be used to predict mean PE rates from the expected DVT rates.5 A correct interpretation of the results of single studies requires similar analytic considerations.

Although meeting these two criteria is necessary to establish a surrogate as valid, meeting these two criteria is not sufficient to establish the surrogate as valid. For a valid surrogate, the treatment effect on the clinical outcome must also be entirely explained by the treatment effect on the surrogate, a criterion known as the “capture criterion.”6 This criterion was not specifically addressed by Eikelboom et al,1 but others7 have found that there is insufficient evidence to conclude that DVT meets this criterion.

In the absence of meeting all three of these criteria, we remained concerned about the use of DVT as a surrogate outcome. We are particularly concerned because the use of surrogate outcomes has caused harm to patients.3,8,9 Hemorrhage, which can be fatal, is a noteworthy harm of DVT prophylaxis. Unfortunately, the impact that this harm has on medical decision making was not addressed by Eikelboom et al1 and, as shown in the AAOS guideline,10 may occur in 1.8% of all patients who receive systemic prophylaxis. To date, there has been no formal consideration of the tradeoffs between the benefits and the harms of DVT prophylaxis, as might be accomplished with a decision analysis.

At the same time, the AAOS recognizes that having two different guidelines reach different conclusions can be confusing. To resolve this confusion, we would welcome the opportunity to work with the American College of Chest Physicians when we update our clinical practice guideline on preventing PE.

Eikelboom JW, Karthikeyan G, Fagel N, et al. American Association of Orthopedic Surgeons and American College of Chest Physicians guidelines for venous thromboembolism prevention in hip and knee arthroplasty differ: what are the implications for clinicians and patients? Chest. 2009;135:513-520. [PubMed] [CrossRef]
 
Lassere MN, Johnson KR, Boers M, et al. Definitions and validation criteria for biomarkers and surrogate endpoints: development and testing of a quantitative hierarchical levels of evidence schema. J Rheumatol. 2007;34:607-615. [PubMed]
 
Bucher HC, Guyatt GH, Cook DJ, et al. Users' guides to the medical literature: XIX. Applying clinical trials results: A. How to use an article measuring the effect of an intervention on surrogate end points. JAMA. 1999;282:771-778. [PubMed]
 
Baker SG, Kramer SB. A perfect correlate does not a surrogate make. BMC Med Res Methodol. 2003;3:16-20. [PubMed]
 
Gail MH, Pfeiffer R, Houwelingen HC, et al. On meta-analytic assessment of surrogate outcomes. Biostatistics. 2001;3:231-246
 
Prentiss RL. Surrogate endpoints in clinical trials: definition and operational criteria. Stat Med. 1989;8:431-440. [PubMed]
 
Kassai B, Shah NR, Leizorovicza A, et al. The true treatment benefit is unpredictable in clinical trials using surrogate outcome measured with diagnostic tests. J Clin Epidemiol. 2005;58:1042-1051. [PubMed]
 
Grimes DA, Schulz KF. Surrogate end points in clinical research: hazardous to your health. Obstet Gynecol. 2006;105:1114-1118
 
Fleming TR, DeMets DL. Surrogate end points in clinical trials: are we being misled? Ann Intern Med. 1996;125:605-613. [PubMed]
 
American Academy of Orthopaedic Surgeons Guideline on the prevention of symptomatic pulmonary embolism in patients undergoing total hip or knee arthroplasty.Accessed October 28, 2009 Available at:http://www.aaos.org/research/guidelines/PEguide.asp.
 

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References

Eikelboom JW, Karthikeyan G, Fagel N, et al. American Association of Orthopedic Surgeons and American College of Chest Physicians guidelines for venous thromboembolism prevention in hip and knee arthroplasty differ: what are the implications for clinicians and patients? Chest. 2009;135:513-520. [PubMed] [CrossRef]
 
Lassere MN, Johnson KR, Boers M, et al. Definitions and validation criteria for biomarkers and surrogate endpoints: development and testing of a quantitative hierarchical levels of evidence schema. J Rheumatol. 2007;34:607-615. [PubMed]
 
Bucher HC, Guyatt GH, Cook DJ, et al. Users' guides to the medical literature: XIX. Applying clinical trials results: A. How to use an article measuring the effect of an intervention on surrogate end points. JAMA. 1999;282:771-778. [PubMed]
 
Baker SG, Kramer SB. A perfect correlate does not a surrogate make. BMC Med Res Methodol. 2003;3:16-20. [PubMed]
 
Gail MH, Pfeiffer R, Houwelingen HC, et al. On meta-analytic assessment of surrogate outcomes. Biostatistics. 2001;3:231-246
 
Prentiss RL. Surrogate endpoints in clinical trials: definition and operational criteria. Stat Med. 1989;8:431-440. [PubMed]
 
Kassai B, Shah NR, Leizorovicza A, et al. The true treatment benefit is unpredictable in clinical trials using surrogate outcome measured with diagnostic tests. J Clin Epidemiol. 2005;58:1042-1051. [PubMed]
 
Grimes DA, Schulz KF. Surrogate end points in clinical research: hazardous to your health. Obstet Gynecol. 2006;105:1114-1118
 
Fleming TR, DeMets DL. Surrogate end points in clinical trials: are we being misled? Ann Intern Med. 1996;125:605-613. [PubMed]
 
American Academy of Orthopaedic Surgeons Guideline on the prevention of symptomatic pulmonary embolism in patients undergoing total hip or knee arthroplasty.Accessed October 28, 2009 Available at:http://www.aaos.org/research/guidelines/PEguide.asp.
 
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