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Correspondence |

Warfarin for Atrial Fibrillation in Patients With End-Stage Renal Disease: The Problem of Observational Studies FREE TO VIEW

Christiaan Lucas Meuwese, MD, PhD; Judith Kooiman, MD, PhD; Merel van Diepen, PhD; Juan Jesus Carrero, PhD
Author and Funding Information

FINANCIAL/NONFINANCIAL DISCLOSURES: None declared.

aDepartment of Cardiology, University Medical Center Utrecht, Utrecht, The Netherlands

bDepartment of Thrombosis and Hemostasis, Leiden University Medical Center, Leiden, The Netherlands

cDepartment of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands

dDepartment of Renal Medicine, CLINTEC, Karolinska Institutet, Stockholm, Sweden

CORRESPONDENCE TO: Christiaan Meuwese, MD, PhD, University Medical Center Utrecht Heidelberglaan 100, Utrecht, The Netherlands 3584 CX


Copyright 2016, . All Rights Reserved.


Chest. 2016;150(4):981. doi:10.1016/j.chest.2016.07.021
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The recent meta-analysis by Dahal et al concludes that warfarin therapy for atrial fibrillation (AF) may have an unfavorable risk/benefit ratio in patients with end-stage renal disease. Although meta-analyses represent the highest level of evidence for formulating recommendations for clinical practice, the robustness of conclusions depends on the quality of available studies. The design and observational nature of studies included in this meta-analysis portend important biases that must be brought to the front in the interpretation of their conclusions.

An important source of systematic error, which in our eyes was not sufficiently acknowledged by the authors, is confounding by indication. The physician’s decision to allocate patients to warfarin therapy is influenced by many factors, including patient characteristics, social contexts, prognostic expectations, the physician’s traditions/experience, reimbursements, and hospital policies. Treatment and nontreatment groups therefore differ in their probability distribution for their (hoped as well as feared) clinical outcomes to the point that meta-analyses comparing results from randomized trials vs nonrandomized trials can find opposite results. Such bias may be magnified if only unadjusted (crude) treatment effects are meta-analyzed. Although various statistical approaches may be used in an attempt to mitigate this bias, adjustment for administrative records are unlikely to fully reflect the prescription behavior of physicians.

A second systematic error is introduced by survival bias. Several of the studies considered in the meta-analysis included patients with prevalent AF who were already receiving warfarin treatment at the time of inclusion. Prevalent patients are, by definition, required to have survived an unknown time with their disease and treatment. Patients with prevalent AF not receiving warfarin may represent a selection of healthy survivors, who are less prone to coagulation and inherently have a better prognosis. In contrast, the prevalent group of warfarin users likely contains patients who would have died before inclusion if they had not received treatment, yielding a group with a worse prognosis. This selection by survival could explain an absence or even complete reversal of observed effects. One study that attempted to mitigate this bias by using patients with incident AF undergoing dialysis observed a net clinical benefit for warfarin use in end-stage renal disease.

Because of problems with confounding and selection bias, we call for caution in the interpretation of this meta-analysis and concur with the authors about the need for undertaking adequately powered randomized trials to solve this conundrum.

References

Dahal K. .Kunwar S. .Rijal J. .et al Stroke, major bleeding, and mortality outcomes in warfarin users with atrial fibrillation and chronic kidney disease, a meta-analysis of observational studies. Chest. 2016;149:951-959 [PubMed]journal. [CrossRef] [PubMed]
 
Jager K.J. .Zoccali C. .Macleod A. .Dekker F.W. . Confounding: what it is and how to deal with it. Kidney Int. 2008;73:256-260 [PubMed]journal. [CrossRef] [PubMed]
 
Kunz R. .Oxman A.D. . The unpredictability paradox: review of empirical comparisons of randomised and non-randomised clinical trials. BMJ. 1998;317:1185-1190 [PubMed]journal. [CrossRef] [PubMed]
 
Hernan M.A. .Hernandez-Diaz S. .Robins J.M. . A structural approach to selection bias. Epidemiology. 2004;15:615-625 [PubMed]journal. [CrossRef] [PubMed]
 
Olesen J.B. .Lip G.Y. .Kamper A.L. .et al Stroke and bleeding in atrial fibrillation with chronic kidney disease. N Engl J Med. 2012;367:625-635 [PubMed]journal. [CrossRef] [PubMed]
 

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References

Dahal K. .Kunwar S. .Rijal J. .et al Stroke, major bleeding, and mortality outcomes in warfarin users with atrial fibrillation and chronic kidney disease, a meta-analysis of observational studies. Chest. 2016;149:951-959 [PubMed]journal. [CrossRef] [PubMed]
 
Jager K.J. .Zoccali C. .Macleod A. .Dekker F.W. . Confounding: what it is and how to deal with it. Kidney Int. 2008;73:256-260 [PubMed]journal. [CrossRef] [PubMed]
 
Kunz R. .Oxman A.D. . The unpredictability paradox: review of empirical comparisons of randomised and non-randomised clinical trials. BMJ. 1998;317:1185-1190 [PubMed]journal. [CrossRef] [PubMed]
 
Hernan M.A. .Hernandez-Diaz S. .Robins J.M. . A structural approach to selection bias. Epidemiology. 2004;15:615-625 [PubMed]journal. [CrossRef] [PubMed]
 
Olesen J.B. .Lip G.Y. .Kamper A.L. .et al Stroke and bleeding in atrial fibrillation with chronic kidney disease. N Engl J Med. 2012;367:625-635 [PubMed]journal. [CrossRef] [PubMed]
 
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