Table 5.

Observational studies on anticoagulants for stroke prevention in CKD stage 5 on dialysis with atrial fibrillation

Study Characteristics and PublicationIntervention, Control, and Type of AnalysisEffectiveness and Harm OutcomesaConclusion
Retrospective population analysis Denmark, 1997–2008. Follow-up yr not given, n=901, CKD stage 5 on dialysis, Olesen, NEJM 2012Warfarin±aspirin (n=178) versus no nonwarfarin±aspirin (n=723). As treated.Rates of all-cause stroke or thromboembolism per 100 person yr 5.6. Reduced risk in warfarin compared with no warfarin, HR, 0.44 (95% CI, 0.26 to 0.74). Rates of major bleeding per 100 person yr 8.9b. Increased risk with warfarin compared with no warfarin, HR, 1.27 (95% CI, 0.91 to 1.77).Warfarin associates with reduced risk of stroke or systemic thromboembolism and increased risk of bleeding compared with no anti-coagulation in patients on dialysis.
Retrospective population analysis Denmark, 1997–2011. Median follow-up 1.65 yr, n=1728, CKD stage 5 on dialysis, Bonde, JACC 2014Warfarin±aspirin (n=186) versus no warfarin±aspirin (n=1129). As treated.“Net clinical benefit” defined as composite of fatal all-cause stroke/fatal bleedingc. 130 fatal all-cause stroke/fatal bleeding events. Risk was nonsignificantly higher with warfarin compared with no warfarin, HR, 1.30 (95% CI, 0.77 to 2.20).No conclusions can be made on the net clinical benefit of warfarin in regard to risk of fatal all-cause stroke/fatal bleeding in patients on dialysis.
Retrospective population analysis Quebec, Canada, 1998–2007. Follow-up yr not given, n=1626, CKD stage 5 on HD, age>65 yr, Shah, Circulation 2014Warfarin±aspirin (n=756) versus nonwarfarin±aspirin (n=870). Intention to treat.Incidence rates per 100 person yr of ischemic stroke were 3.37 on warfarin and 2.91 not on warfarin. Nonsignificant increased risk with warfarin in comparison with no-warfarin use, HR, 1.14 (95% CI, 0.78 to 1.67). Incidence rates per 100 person yr of major bleedingd were 10.88 on warfarin and 7.31 not on warfarin. Increased risk of major bleeding, HR, 1.44 (95% CI, 1.13 to 1.85) with warfarin in comparison with no warfarin use.Warfarin does not associate with reduced risk of ischemic stroke but associates with increased risk of bleeding in older adult patients on dialysis.
Prospective cohort study ≥1500 dialysis clinics in North America, 2010–2014. Follow-up 3839 patient yre, n=8589, CKD stage 5 on HD, Chan, Circulation 2015Warfarin (n=8064), dabigatran (n=281), rivaroxaban (n=244)±aspirin. As treated.Dabigatran rate ratio 1.78 (95% CI, 1.18 to 2.68) and rivaroxaban rate ratio 1.71 (95% CI 0.94, 3.12) were associated with a higher risk of hemorrhagic death relative to warfarin and higher risk of hospitalization or death from bleeding compared with warfarin (dabigatran rate ratio, 1.48; 95% CI, 1.21 to 1.81; rivaroxaban rate ratio, 1.38; 95% CI, 1.03 to 1.83).The risk of mortality from bleeding and hospital-related bleeding is higher with dabigatran and rivaroxaban compared with warfarin in patients on dialysis. There were too few events of stroke and TE to detect meaningful differences.
Retrospective observational cohort United States Renal Data System, 2007–2011. Mean follow-up 1.41 yr, n=12,284, Shen, AJKD 2015Warfarin±aspirin (n=1838) versus no anti-coagulation±aspirin (n=10,466). Intention to treatf.Rate of ischemic stroke per 100 person yr 2.3 on warfarin and 3.4 not on warfarin. Reduced risk of ischemic stroke on warfarin compared with no warfarin, HR, 0.68 (95% CI, 0.47 to 0.99). Rate of hemorrhagic stroke per 100 person yr 1.09 warfarin and 1.05 not on warfarin. Rates of GIB per 100 person yr 0.97 on warfarin and 0.98 not on warfarin. No difference in risk of hemorrhagic stroke, HR, 0.82 (95% CI, 0.37 to 1.81) or GIB, HR, 1.00 (95% CI, 0.69 to 1.44) with warfarin compared with no anti-coagulation.In patients on maintenance HD, warfarin modestly reduced the risk of ischemic stroke.
Retrospective observational cohort in the United States Renal Data System, 2010–2015. Follow-up time not givenf, n=9404, Siontis, Circulation 2018Apixaban (n=2351) standard dose 5 mg twice daily (n=1034) and (n=1317) reduced dose 2.5 mg twice daily, matched 3:1 with warfarin (n=7053). As treated.Ischemic stroke event rates per 100 person yr 8.8 in apixiban versus 11.8 in warfarin users, HR, 0.88 (95% CI, 0.69 to 1.12). Ischemic stroke event rates per 100 person yr 8.8 in apixiban standard dose versus 15.3 in reduced dose, HR, 0.61 (95% CI, 0.37 to 0.98). Bleeding eventg rates per 100 person yr 18.3 bleeding apixiban versus 21.9 in warfarin users, HR, 0.72 (95% CI, 0.59 to 0.87). Major bleeding event rate per 100 person yr 18.3 in apixiban standard dose versus 20.3 in reduced dose, HR, 0.98 (95% CI, 0.68 to 1.42).Apixaban at the standard 5 mg twice a day dose associated with lower risk of major bleeding compared with warfarin and no difference in ischemic stroke/systemic embolism.
  • As-treated analysis refers to time on drug as often done with statistical techniques using time-varying exposures (e.g., time-dependent Cox proportional hazards models) or censoring if there is no anticoagulant prescription refill within a defined period of time. Intention-to-treat analyses use exposure (e.g., warfarin versus no anticoagulation) as a time-fixed binary variable. Only the primary analysis is reported. NEJM, New England Journal of Medicine; HR, hazard ratio; 95% CI, 95% confidence interval; JACC, Journal of the American College of Cardiology; HD, hemodialysis; TE, thromboembolic; GIB, gastrointestinal bleed; TIA, transient ischemic attack; AJKD, American Journal of Kidney Disease.

  • a Adjusted analyses are reported.

  • b Hospitalization or death from all-cause stroke (ischemic and or hemorrhagic) or systemic thromboembolism (peripheral-artery embolism, ischemic stroke, and TIA). Hospitalization or death from major bleeding (gastrointestinal, intracranial, urinary tract, or airway). Outcome events were not separated by treatment group.

  • c This study was designed to evaluate net clinical benefit; outcomes of stroke/systemic thromboembolism/all bleeding, and fatal stroke/fatal bleeding were not reported separately. The numbers of outcome events were not separated by treatment group.

  • d Stroke defined as hospitalization or emergency department visit for ischemic cerebrovascular disease, TIA, or retinal infarct. Bleeding defined as hospitalization or emergency department visit for intracerebral bleeding, gastrointestinal bleeding, intraocular bleeding, hematuria, and unspecified location of bleeding.

  • e Follow up in patient years; 3226 for no anticoagulation, 123 for dabigatran, and 72 for rivaroxaban.

  • f As-treated analyses were also done for each outcome.

  • g Bleeding events included GIB, intracranial bleeding or major bleeding was defined by a critical site (such as intracranial), need for blood transfusion, or death.