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Elie A. Akl, MD, PhD; M. Hassan Murad, MD, MPH; Gordon H. Guyatt, MD; Susan R. Kahn, MD
Author and Funding Information

From the Department of Medicine (Dr Akl), University of Buffalo; the Division of Preventive Medicine (Dr Murad), Mayo Clinic; the Department of Clinical Epidemiology and Biostatistics (Dr Guyatt), McMaster University; and the Department of Internal Medicine (Dr Kahn), SMBD Jewish General Hospital.

Correspondence to: Mohammad Hassan Murad, MD, MPH, Division of Preventative Medicine, Mayo Clinic, 200 1st St, Rochester, MN 55905; e-mail: murad.mohammad@mayo.edu

Funding/Support: The Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines received support from the National Heart, Lung, and Blood Institute [R13 HL104758] and Bayer Schering Pharma AG. Support in the form of educational grants were also provided by Bristol-Myers Squibb; Pfizer, Inc; Canyon Pharmaceuticals; and Sanofi-Aventis US.

Financial/nonfinancial disclosures: The authors of this guideline provided detailed conflict of interest information related to each individual recommendation made in this article. A grid of these disclosures is available online. In summary, the authors have reported to CHEST the following conflicts of interest: Dr Akl is a prominent contributor to the GRADE Working Group. Dr Kahn has received peer-reviewed and investigator-initiated industry research funding for projects related to venous thrombosis and postthrombotic syndrome prevention and treatment. She has received honoraria for industry-sponsored talks pertaining to venous thrombosis. Dr Murad is a member of the GRADE Working Group. Dr Guyatt has reported that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.


Funding/Support: The Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines received support from the National Heart, Lung, and Blood Institute [R13 HL104758] and Bayer Schering Pharma AG. Support in the form of educational grants were also provided by Bristol-Myers Squibb; Pfizer, Inc; Canyon Pharmaceuticals; and Sanofi-Aventis US.

Financial/nonfinancial disclosures: The authors of this guideline provided detailed conflict of interest information related to each individual recommendation made in this article. A grid of these disclosures is available online. In summary, the authors have reported to CHEST the following conflicts of interest: Dr Akl is a prominent contributor to the GRADE Working Group. Dr Kahn has received peer-reviewed and investigator-initiated industry research funding for projects related to venous thrombosis and postthrombotic syndrome prevention and treatment. She has received honoraria for industry-sponsored talks pertaining to venous thrombosis. Dr Murad is a member of the GRADE Working Group. Dr Guyatt has reported that no potential 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. See online for more details.


Chest. 2012;142(1):266-267. doi:10.1378/chest.12-0702
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We thank Dr Khorana and his colleagues for their thoughtful comments on our article.1 As a point of clarification, our recommendation does not suggest that patients “should receive” prophylactic-dose heparin. In fact, it is a weak (level 2) recommendation, only suggesting the use of a prophylactic dose of heparin and only in subgroups of patients with cancer at high risk of VTE and low risk of bleeding. Indeed, within the Grading of Recommendation, Assessment, Development, and Evaluation framework, panel members make a weak recommendation when they conclude that the desirable effects of adherence to the recommendation probably outweigh the undesirable effects.2 In those cases, the best action may differ depending on patient circumstances,3 and clinicians need to help each patient make a decision consistent with her or his values and preferences.2

The authors suggest that the recommendation is formulated without scientific evidence. The scientific evidence the panel considered is summarized in Table 15 of the article and in Table S18 of the online supplement.1 It is based on a Cochrane systematic review,4 with a meta-analysis of nine trials at low risk of bias, enrolling 2,857 patients. The quality of evidence was rated high for symptomatic VTE; moderate for mortality, major bleeding, and minor bleeding; and low for quality of life. The recent publication of two trials5,6 has further increased the quality of evidence and the precision of effect estimates.7

The guideline panel carefully considered the balance of benefits and harms for this recommendation. According to the data in Table 15,1 if 1,000 patients with cancer were to use a prophylactic dose of heparin, over a follow-up period of 12 months death would likely be averted in approximately 45 patients, symptomatic VTE would be averted in 13, and two would have a major bleeding episode. Considering this trade-off, along with the burden of a daily injection of heparin over a prolonged period of time, the panel made the judgment that patients are more likely to benefit than be harmed and issued a weak recommendation in favor.

The guideline panel was also very concerned with the issue raised by the authors (ie, the identification of patients who are more likely to benefit from heparin prophylaxis). Indeed, as we point out in the article, “the substantial clinical heterogeneity of the patients studied (different cancer types, different cancer treatments, and different durations of prophylaxis) raises questions about which groups of outpatients with cancer will benefit.”1 Therefore, the panel issued a first recommendation (recommendation 4.2.1) that advises against routine prophylaxis with heparin in outpatients with cancer who have no additional risk factors for VTE. It then issued a second recommendation (recommendation 4.2.2) suggesting prophylactic dose heparin in a well-defined subgroup of patients with solid tumors who are at high risk of VTE and at low risk of bleeding.

The panel referred to the eligibility criteria of the nine trials to identify the group of patients at a higher risk and who are likely to benefit. We welcome and strongly support the suggestion of the authors for clinicians to use structured and validated tools to risk stratify patients.8 An ideal tool would predict not only VTE but also major bleeding and mortality, the latter being the most important outcome for this specific intervention in this specific population.

The authors state, “It is quite possible that institutional review boards may identify these suggestions as a standard of care.” Such misinterpretation would reflect a grave misunderstanding of guideline methodology as laid out clearly in relevant publications.2,3

Finally, we hope that the transparency with which the panel made and reported its judgments will allow clinicians to interpret the recommendation in the individual patients’ specific context and help them make the decisions that are appropriate for them.

Role of sponsors: The sponsors played no role in the development of these guidelines. Sponsoring organizations cannot recommend panelists or topics, nor are they allowed prepublication access to the manuscripts and recommendations. Guideline panel members, including the chair, and members of the Health & Science Policy Committee are blinded to the funding sources. Further details on the Conflict of Interest Policy are available online at http://chestnet.org.

Kahn SR, Lim W, Dunn AS, et al. Prevention of VTE in nonsurgical patients: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012;141(2)(suppl):e195S-e226S. [PubMed] [CrossRef]
 
Guyatt GH, Oxman AD, Kunz R, et al; GRADE Working Group GRADE Working Group. Going from evidence to recommendations. BMJ. 2008;336(7652):1049-1051.
 
Guyatt GH, Norris SL, Schulman S, et al. Methodology for the development of antithrombotic therapy and prevention of thrombosis guidelines: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012;141(2)(suppl):53S-70S.
 
Akl EA, Gunukula S, Barba M, et al. Parenteral anticoagulation in patients with cancer who have no therapeutic or prophylactic indication for anticoagulation. Cochrane Database Syst Rev. 2011:CD006652.
 
Agnelli G, George DJ, Kakkar AK, et al; SAVE-ONCO Investigators SAVE-ONCO Investigators. Semuloparin for thromboprophylaxis in patients receiving chemotherapy for cancer. N Engl J Med. 2012;366(7):601-609.
 
van Doormaal FF, Di Nisio M, Otten HM, et al. Randomized trial of the effect of the low molecular weight heparin nadroparin on survival in patients with cancer. J Clin Oncol. 2011;29(15):2071-2076.
 
Akl EA, Schünemann HJ. Routine heparin for patients with cancer? One answer, more questions. N Engl J Med. 2012;366(7):661-662.
 
Khorana AA, Kuderer NM, Culakova E, Lyman GH, Francis CW. Development and validation of a predictive model for chemotherapy-associated thrombosis. Blood. 2008;111(10):4902-4907.
 

Figures

Tables

References

Kahn SR, Lim W, Dunn AS, et al. Prevention of VTE in nonsurgical patients: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012;141(2)(suppl):e195S-e226S. [PubMed] [CrossRef]
 
Guyatt GH, Oxman AD, Kunz R, et al; GRADE Working Group GRADE Working Group. Going from evidence to recommendations. BMJ. 2008;336(7652):1049-1051.
 
Guyatt GH, Norris SL, Schulman S, et al. Methodology for the development of antithrombotic therapy and prevention of thrombosis guidelines: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012;141(2)(suppl):53S-70S.
 
Akl EA, Gunukula S, Barba M, et al. Parenteral anticoagulation in patients with cancer who have no therapeutic or prophylactic indication for anticoagulation. Cochrane Database Syst Rev. 2011:CD006652.
 
Agnelli G, George DJ, Kakkar AK, et al; SAVE-ONCO Investigators SAVE-ONCO Investigators. Semuloparin for thromboprophylaxis in patients receiving chemotherapy for cancer. N Engl J Med. 2012;366(7):601-609.
 
van Doormaal FF, Di Nisio M, Otten HM, et al. Randomized trial of the effect of the low molecular weight heparin nadroparin on survival in patients with cancer. J Clin Oncol. 2011;29(15):2071-2076.
 
Akl EA, Schünemann HJ. Routine heparin for patients with cancer? One answer, more questions. N Engl J Med. 2012;366(7):661-662.
 
Khorana AA, Kuderer NM, Culakova E, Lyman GH, Francis CW. Development and validation of a predictive model for chemotherapy-associated thrombosis. Blood. 2008;111(10):4902-4907.
 
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