NEWS & VIEWS CARDIOVASCULAR DISEASE
Still unresolved: warfarin in ESRD with atriai fibrillation Wolfgang C. Winkeimayer
Well-controlled oral anticoagulation lowers the risk of ischaemic stroke in patients with atriai fibriilation; however, confiicting evidence exists on its benefits and risks in patients with end-stage renai disease. Shah and coileagues examined this question in a large cohort of patients on diaiysis who were diagnosed with atriai fibrillation. Winkeimayer. W. C. Nat. Rev. Nephroi. 10, 244-245 (2014); published orniine 18 March 2014; d0i:10.1038/nrneph.2014.48
Atriai fibrillation is increasingly common in patients with end-stage renal disease (ESRD). Indeed, >10% of patients with ESRD undergoing haemodialysis in the USA have been diagnosed with the condition.' Ischaemic stroke is the most dreaded complication of atriai fibrillation, but its risk can be lowered substantially by oral anticoagulation using vitamin K antagonists (such as warfarin), direct thrombin inhibitors or factor Xa antagonists. Although oral anticoagulation confers an additional risk of bleeding, which can be severe and consequential, the benefits of oral anticoagulation exceed the bleeding risks in most population subgroups. However, adequate evidence on the effectiveness and safety of oral anticoagulation is lacking in patients with advanced kidney disease, especially those on dialysis. A recent study by Shah et al.^ reported in Cireulation has presented some new data on this issue. Several previous studies investigated the association of oral anticoagulation using vitamin K antagonists (predominantly warfarin) with ischaemic stroke and major
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bleeding outcomes in patients with atriai fibrillation receiving maintenance dialysis, albeit with rather mixed results.''^ Although most of these studies found increased risks of bleeding in warfarin-treated patients, the associations between warfarin use and the risks of ischaemic stroke and/or death ranged from decidedly protective to strongly detrimental. Differences in databases, study design and analytical approaches might have contributed to the heterogeneity of these findings. Shah et aP used two large provincial databases from Canada (Ontario and Québec) with integrated information from several sources, namely, data on hospitalizations, outpatient encounters, dispensed prescription drugs and vital status of individuals >65 years of age. In general, the researchers rephcated (with minor modifications) the approach taken in an earlier smaller study reported in the Clinical Journal of the American Society ofNephrology.^ That is, they identified patients with new diagnoses of atriai fibrillation from hospitalization claims records, identified those who were on dialysis, identified those who filled a prescripfion for warfarin among those who survived 30 days from discharge and followed-up warfarin users and nonusers for the relevant outcomes of ischaemic stroke and major bleeding. In formally comparing adjusted or propensity-matched time-to-event models, the relative rates of the study events using an intention-to-treat approach were determined while controlling for differences in observed characteristics between warfarin users and nonusers. Their results confirmed the finding of the earlier study' that warfarin users had a significantly increased risk of a major bleeding event, but no conclusive
evidence supported a reduced risk of stroke with warfarin. Although, ischaemic stroke rates were not different between users of warfarin and nonusers, the study was rather underpowered: the 95% confidence limits were compatible with both a 22% reduction and a 67% increase in stroke risk among warfarin users.^
• • ...the cohort of "dialysis patients" might have been substantially diluted by patients who did not have ESRD... W Several interesting points deserve mention. Firstly, 46.5% of patients received warfarin within 30 days of their initial atriai fibrillation hospitalization. In the context of the literature, this proportion is unusually large. Although not explicitly stated, the cohort possibly included patients who had used warfarin prior to their first atriai fibrillation hospitalization. If correct, inclusion of these patients in the analysis is problematic as it might introduce a bias that can be avoided by restricting the cohort to new users.' In addition, one might wonder about the indication for warfarin in these ongoing users: did they already have atriai fibrillation? Did they have another established indication for warfarin (for example, deep venous thrombosis or pulmonary embolism) or reason for off-label use (for example, haemodialysis catheter issues) that remained unrecorded or unascertained from the data? Arguably, if patients previously on warfarin had these or other indications, their prognoses would be worse, which would be indicative of residual confounding that favours the nonuser group.
www.nature.com/nrneph
NEWS & VIEWS Secondly, no information was given on the duration of warfarin treatment in those who used it in the first 30 days, or on the time spent in the therapeutic international normalized ratio range. Persistence of initiated warfarin treatment in patients receiving dialysis is low and treatment can certainly only work if faithfully taken and can only provide optimal benefit if well controlled with regards to the coagulation metric target. Correspondingly, no information was given on the proportion of patients unexposed at baseline who initiated warfarin after the 30-day threshold. Even though data on international normalized ratio measurements were unavailable in the study, treatment cross-overs could have been quantified and lag-censored analyses conducted. Thirdly, to the nephrology audience, it seems that none of the authors have a background in our clinical discipline, which might have contributed to several potential shortcomings in their analyses. Indeed, their algorithm to identify patients on dialysis—which used any three haemodialysis or peritoneal dialysis procedure codes in the past year—seems more likely to identify patients with past acute kidney injury than patients with ESRD requiring maintenance dialysis. No requirement was noted in the article for these codes to have been spread out over time (one or more each in three consecutive months) or in close proximity to the index hospitalization, which would have made it more plausible that the identified patients fit the intended disease-specific inclusion criterion. Further support of my concern comes from the reported rates of stroke in "dialysis patients" compared with nondialysis patients (data for whom were also reported), which were very similar at 3.12 and 2.35 per 100 personyears, respectively.- Previous research has demonstrated that stroke rates differ fourfold to tenfold between older patients with ESRD receiving dialysis and age-matched individuals from the general population depending on sex and race,* further affirming the suspicion that the cohort of "dialysis patients" might have been substantially diluted by patients who did not have ESRD requiring maintenance treatment. Finally, the nephrologist reader would want to see information on dialysis modality, kidney transplant status, dialysis catheter use, time since ESRD and other potentially confounding characteristics for the association under investigation specific to a dialysis population.
NATURE REVIEWS | NEPHROLOGY
Whether use of warfarin or any other oral anticoagulant is beneficial in patients receiving dialysis who have atrial fibrillation remains unknown. Clinical trials elucidating this common therapeutic dilemma would be desirable, but I am skeptical that such trials using oral vitamin K antagonists will be conducted. Perhaps the arrival of the newer (and more expensive) oral anticoagulants, direct thrombin inhibitors and factor Xa antagonists will ignite interest and make funds available tofinallytackle— through high-quality placebo-controlled trials—the open question of stroke prevention in patients with atrialfibrillationwho are on dialysis. Stanford University School of Medicine, Division of Nephrology, 1070 Arastradero Road, Suite 311, Palo Alto, CA 94304, USA. wcwl
Still unresolved: warfarin in ESRD with atriai fibrillation Wolfgang C. Winkeimayer
Well-controlled oral anticoagulation lowers the risk of ischaemic stroke in patients with atriai fibriilation; however, confiicting evidence exists on its benefits and risks in patients with end-stage renai disease. Shah and coileagues examined this question in a large cohort of patients on diaiysis who were diagnosed with atriai fibrillation. Winkeimayer. W. C. Nat. Rev. Nephroi. 10, 244-245 (2014); published orniine 18 March 2014; d0i:10.1038/nrneph.2014.48
Atriai fibrillation is increasingly common in patients with end-stage renal disease (ESRD). Indeed, >10% of patients with ESRD undergoing haemodialysis in the USA have been diagnosed with the condition.' Ischaemic stroke is the most dreaded complication of atriai fibrillation, but its risk can be lowered substantially by oral anticoagulation using vitamin K antagonists (such as warfarin), direct thrombin inhibitors or factor Xa antagonists. Although oral anticoagulation confers an additional risk of bleeding, which can be severe and consequential, the benefits of oral anticoagulation exceed the bleeding risks in most population subgroups. However, adequate evidence on the effectiveness and safety of oral anticoagulation is lacking in patients with advanced kidney disease, especially those on dialysis. A recent study by Shah et al.^ reported in Cireulation has presented some new data on this issue. Several previous studies investigated the association of oral anticoagulation using vitamin K antagonists (predominantly warfarin) with ischaemic stroke and major
244
MAY 2014
VOLUME 10
bleeding outcomes in patients with atriai fibrillation receiving maintenance dialysis, albeit with rather mixed results.''^ Although most of these studies found increased risks of bleeding in warfarin-treated patients, the associations between warfarin use and the risks of ischaemic stroke and/or death ranged from decidedly protective to strongly detrimental. Differences in databases, study design and analytical approaches might have contributed to the heterogeneity of these findings. Shah et aP used two large provincial databases from Canada (Ontario and Québec) with integrated information from several sources, namely, data on hospitalizations, outpatient encounters, dispensed prescription drugs and vital status of individuals >65 years of age. In general, the researchers rephcated (with minor modifications) the approach taken in an earlier smaller study reported in the Clinical Journal of the American Society ofNephrology.^ That is, they identified patients with new diagnoses of atriai fibrillation from hospitalization claims records, identified those who were on dialysis, identified those who filled a prescripfion for warfarin among those who survived 30 days from discharge and followed-up warfarin users and nonusers for the relevant outcomes of ischaemic stroke and major bleeding. In formally comparing adjusted or propensity-matched time-to-event models, the relative rates of the study events using an intention-to-treat approach were determined while controlling for differences in observed characteristics between warfarin users and nonusers. Their results confirmed the finding of the earlier study' that warfarin users had a significantly increased risk of a major bleeding event, but no conclusive
evidence supported a reduced risk of stroke with warfarin. Although, ischaemic stroke rates were not different between users of warfarin and nonusers, the study was rather underpowered: the 95% confidence limits were compatible with both a 22% reduction and a 67% increase in stroke risk among warfarin users.^
• • ...the cohort of "dialysis patients" might have been substantially diluted by patients who did not have ESRD... W Several interesting points deserve mention. Firstly, 46.5% of patients received warfarin within 30 days of their initial atriai fibrillation hospitalization. In the context of the literature, this proportion is unusually large. Although not explicitly stated, the cohort possibly included patients who had used warfarin prior to their first atriai fibrillation hospitalization. If correct, inclusion of these patients in the analysis is problematic as it might introduce a bias that can be avoided by restricting the cohort to new users.' In addition, one might wonder about the indication for warfarin in these ongoing users: did they already have atriai fibrillation? Did they have another established indication for warfarin (for example, deep venous thrombosis or pulmonary embolism) or reason for off-label use (for example, haemodialysis catheter issues) that remained unrecorded or unascertained from the data? Arguably, if patients previously on warfarin had these or other indications, their prognoses would be worse, which would be indicative of residual confounding that favours the nonuser group.
www.nature.com/nrneph
NEWS & VIEWS Secondly, no information was given on the duration of warfarin treatment in those who used it in the first 30 days, or on the time spent in the therapeutic international normalized ratio range. Persistence of initiated warfarin treatment in patients receiving dialysis is low and treatment can certainly only work if faithfully taken and can only provide optimal benefit if well controlled with regards to the coagulation metric target. Correspondingly, no information was given on the proportion of patients unexposed at baseline who initiated warfarin after the 30-day threshold. Even though data on international normalized ratio measurements were unavailable in the study, treatment cross-overs could have been quantified and lag-censored analyses conducted. Thirdly, to the nephrology audience, it seems that none of the authors have a background in our clinical discipline, which might have contributed to several potential shortcomings in their analyses. Indeed, their algorithm to identify patients on dialysis—which used any three haemodialysis or peritoneal dialysis procedure codes in the past year—seems more likely to identify patients with past acute kidney injury than patients with ESRD requiring maintenance dialysis. No requirement was noted in the article for these codes to have been spread out over time (one or more each in three consecutive months) or in close proximity to the index hospitalization, which would have made it more plausible that the identified patients fit the intended disease-specific inclusion criterion. Further support of my concern comes from the reported rates of stroke in "dialysis patients" compared with nondialysis patients (data for whom were also reported), which were very similar at 3.12 and 2.35 per 100 personyears, respectively.- Previous research has demonstrated that stroke rates differ fourfold to tenfold between older patients with ESRD receiving dialysis and age-matched individuals from the general population depending on sex and race,* further affirming the suspicion that the cohort of "dialysis patients" might have been substantially diluted by patients who did not have ESRD requiring maintenance treatment. Finally, the nephrologist reader would want to see information on dialysis modality, kidney transplant status, dialysis catheter use, time since ESRD and other potentially confounding characteristics for the association under investigation specific to a dialysis population.
NATURE REVIEWS | NEPHROLOGY
Whether use of warfarin or any other oral anticoagulant is beneficial in patients receiving dialysis who have atrial fibrillation remains unknown. Clinical trials elucidating this common therapeutic dilemma would be desirable, but I am skeptical that such trials using oral vitamin K antagonists will be conducted. Perhaps the arrival of the newer (and more expensive) oral anticoagulants, direct thrombin inhibitors and factor Xa antagonists will ignite interest and make funds available tofinallytackle— through high-quality placebo-controlled trials—the open question of stroke prevention in patients with atrialfibrillationwho are on dialysis. Stanford University School of Medicine, Division of Nephrology, 1070 Arastradero Road, Suite 311, Palo Alto, CA 94304, USA. wcwl
