Anticoagulation, atrial fibrillation in elderly patients with chronic kidney disease

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1 Anticoagulation, atrial fibrillation in elderly patients with chronic kidney disease Zbigniew Heleniak M.D. Ph.D. Department of Nephrology, Transplantology and Internal Medicine Medical University of Gdansk Head of Department: prof. Alicja Dębska-Ślizień

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3 Cardiovascular morbidity and mortality associatied with AF

4 Cardiovascular and other conditions associatied with AF

5 Cardiovascular and other conditions associatied with AF

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7 Clinical risk factor for stroke, TIA and systemic embolism

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9 AF in general population 1. In general population, oral anticoagulation is recommended in patients with AF, depending on the risk of ischemic incident and systematic embolism with risk quantification using CHA 2 DS 2 VASC score. 2. There is general consensus that the hemorrhage under oral anticoagulation is lower than the prognostic benefit of anticoagulation. 3. Proper anticoagulation reduces the risk of ischemic stroke and systemic embolism by two-thirds in randomized trial. 4. Anticoagulation should be started at CHA 2 DS 2 VASC score of two points.

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11 Cardiovascular disease in CKD patients

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16 The increased incidence of AF among those with worsening renal function

17 Predictors of new-onset AF in ESRD patients the incidence of AF development is 12.1/1,000 patient-years in ESRD compared with 5.0/1,000 patient-years in controls

18 AF in ESRD patients 6 risk factors

19 Risk of AF in the first 20 days after kidney transplantation Transplantation. 96(11): , December 15, 2013

20 AF- group, 1- and 5- year patient survival rates: 94.4% and 80.2% respectively AF + group 1- and 5-year patient survival rates: 85.7% and 59.3%, respectively.

21 Graft survival AF + group 1- and 5-year graft survival rates 79.4% and 51.7% respectively AF group 1- and 5-year graft survival 89.1% and 67.6% respectively

22 The USRDS estimates that approximately 7% of all cardiovascular hospitalizations are primarily because of atrial fibrillation in the first 2 years after kidney transplantation ( The highest risk of incident atrial fibrillation after kidney transplantation is among kidney transplant recipients who were: - older - male - white - hypertension - coronary heart disease. Transplantation. 96(11): , December 15, 2013

23 a new diagnosis of AF not only heralds the progression of CKD but also hastens the development of ESRD AF also leads to the progression of CKD, even among those with relatively normal renal function, with no detectable proteinuria on dipstick test at baseline

24 Incidence of kidney dysfunction and AF

25 Incidence of proteinuria and AF

26 Potential mechanisms of increased thromboembolic risk in patients with chronic kidney disease stages 3 5 nondialysis

27 Although, it significantly increases the risk of thromboembolism and ischemic stroke in AF, CKD also paradoxically results in an increased risk of hemorrhagic events. Evidence from both the Rotterdam study and the Japanese CIRCS (Circulatory Risk in Communities Study) trial shows that the presence of reduced renal function (GFR <60 ml/min/1.73 m2) results in a more than 4-fold increased risk of hemorrhagic stroke in men and a 7-fold increased risk in women Stroke, 2011;42:

28 Atrial fibrillation in CKD: balancing the risks and benefits of anticoagulation The pathophysiological causes of the increased risk of hemorrhagic events are clearly multifactorial: -uremia-related platelet dysfunction -impaired platelet adhesion and aggregation -impaired platelet glycoprotein IIb or IIIa receptor activation -altered von Willebrand factor; -impaired nitric oxide metabolism -use of antiplatelet agents or nonsteroidal anti-inflammatory and invasive strategies, such as central venous access and hemodialysis - frequent heparin exposure Am J Kidney Dis 2013;62:

29 R2CHA2DS2 score the addition of renal impairment for stroke risk stratification proposed the R2CHADS2 score (the additional R was for impaired renal function (creatinine clearance <60ml/min) and given 2 points). patients with creatinine clearance <30ml/min were exluded Circulation 2013;127:

30 CONCLUSIONS: In patients with nonvalvular AF at moderate to high risk of stroke, impaired renal function is a potent predictor of stroke and systemic embolism. Stroke risk stratification in patients with AF should include renal function. Circulation 2013;127:

31 R2CHADS2 vs CHADS vs CHADS2VASC NO DIFFERENNCES in patients with creatinine clearance <30ml/min

32 Oral anticoagulation in atrial fibrillation patients with chronic kidney disease Anticoagulation can be safely used in AF patients with moderate or moderate-to-severe CKD (GFR) 15mL/min In a meta-analysis of the major NOAC trials, patients with mild or moderate CKD suffered fewer strokes, systemic emboli or major bleeding events on NOACs than on warfarin. Kidney function should be regularly monitored in AF patients on OACs to allow dose adaptation for those on NOACs and to refine risk estimation European Heart Journal (2016) 37,

33 Oral anticoagulation in atrial fibrillation patients on dialysis - there are no randomized trials assessing OAC in hemodialysis patients -no controlled trials of NOACs in patients with severe CKD (CrCl,25 30 ml/min). European Heart Journal (2016) 37,

34 Patients with atrial fibrillation requiring kidney transplantation -there are no randomized trials assessing OAC in patients after kidney transplantation. - the prescription of NOAC therapy should be guided by the estimated GFR of the transplanted kidney. - potential pharmacokinetic interactions of NOAC immunosuppressive agents should be considered. European Heart Journal (2016) 37,

35 Possible drug-drug interactions : effect on NOAC plasma levels

36 Primary Outcome Measures: apixaban accumulation after an 8-day administration Dose 2 x 2,5mg/day n-7

37 CLINICAL MANAGEMENT OF AF AND CKD In general, the management of AF is patient-centered and symptom-directed when it comes to deciding on rate or rhythm control strategies. Limited data are available on the differential management of AF in patients with CKD. Drug pharmacokinetics of antiarrhythmic agents and some anticoagulants may be influenced by CKD and dosages may need adjustment due to the prolonged half-lives of various drugs and reduced clearance. Some drugs can even be removed by dialysis. Boriani G, Savelieva I, Dan GA, et al. Europace 2015;17:

38 41 cardiology centers (Serbia, France. Poland, Denmark, Germany, Norway)

39 preference for specific oral anticoagulant drug oral anticoagulants (essentially VKAs) among patients with significant renal impairment varies from as low as 2% in Germany to as high as 37% in Canada

40 ischemic stroke, intracranial bleedings and death from any cause in atrial fibrillation patients in relation to renal failure.

41 Elderly patients with CKD (>75 years of age) appear to be particularly at risk compared with those below 65 years of age. At the same time, those taking VKA while receiving hemodialysis may have a higher risk of hemorrhagic stroke than of thromboembolic events. Explanations for the lack of efficacy of VKA in protection may be: - the poor quality of anticoagulation control (a low time in therapeutic range for patients receiving renal replacement therapy) - dependent on the modality used in renal replacement therapy J A C C VO L. 6 8, N O. 1 3,

42 Hong Kong AF cohort suggested that ESRD patients receiving peritoneal dialysis had a thrombotic risk similar to that of their nonperitoneal dialysis counterparts.

43 Warfarin use in this particular patient group not only provided protection against ischemic stroke but there was no increased risk of intracranial hemorrhage.

44 Rivaroxaban preserved the benefit of warfarin in preventing stroke and systemic embolus. Bleeding rates with the reduced dose of rivaroxaban were similar to those on warfarin therapy and there were fewer fatal bleeds with rivaroxaban.

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46 ENGAGE -TIMI 48 Trial Epixaban dose 30mg 60mg 60mg The prescribing label for edoxaban in Europe and elsewhere does not have the FDA caution/restriction for use in AF patients with CrCl >95 ml/min.

47 Proportion of patients in different time-in-therapeutic ranges across worsening egfr strata. J Am Heart Assoc. 2017

48 a composite of intracranial hemorrhage/ischemic stroke/myocardialinfarction/death J Am Heart Assoc. 2017

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51 N = 375, CHA2DS2-VASc: 4.9 ± 1.5, HASBLED: 3.4 ± 1.3), mean age 74 years old -stroke reduction is very high and persistent in all stages of CKD - reduction of bleeding risk

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53 Summary of current evidence on oral anticoagulant therapy (OAT)for patients with atrial fibrillation (AF) across the spectrum of chronic kidney disease(ckd).

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55 Thank you for your attention

56 Warfarin inhibits hepatic and peripheral carboxylation. Warfarin prevents vitamin K from participating in the carboxylation process, inhibiting both hepatic and peripheral production of VKDPs. However, warfarin also inhibits activation of MGP and Gas-6, interrupting the protective mechanisms of these proteins. Vascular smooth muscle cells are unable to respond to injury in a normal manner, and potentially, cell death and eventual calcification ensue. Deficiency of vitamin K nutritional deficiency, malabsorptive states, or alteration of indigenous intestinal flora, may potentially lead to vascular injury.