Anticoagulants in kidney disease

Abstract: Background: Patients with chronic kidney disease (CKD) and atrial fibrillation (AF) are at high risk of ischemic stroke. Evidence is lacking if patients with advanced CKD or on dialysis benefit from oral anticoagulants (OAC) as stroke prophylaxis. There is also no clear evidence on the safety and efficacy of prophylactic anticoagulants (PAC) in the prothrombotic state nephrotic syndrome (NS).Aims:To investigate effectiveness and risks of oral anticoagulants as stroke prophylaxis in chronic kidney disease with atrial fibrillationTo examine the role of warfarin treatment quality as a predictor for ischemic stroke and bleeding in CKDTo investigate benefits and risks with prophylactic anticoagulants in patients with nephrotic syndrome and elucidate risk factors for thrombosis and bleedingMethods: A cohort of patients with non-valvular atrial fibrillation (NVAF) and CKD GFR category 3–5 (G3–G5) or on dialysis (G5D) was created by combining data from national health care- and quality registries between 2009-2018. Included registries were the Swedish Renal Registry, AuriculA, The Stroke Register and The Swedish National Patient Register. G3 was defined as GFR 30-59ml/min/1.73m2, G4: 15-29, G5:<15, G5D: on dialysis. Paper I compared patient time on warfarin with patient time on no OAC treatment using Cox regression. Paper II compared DOAC and warfarin using the same methods. Paper III investigated the effect of increasing warfarin treatment quality, measured as individual time in therapeutic range (iTTR). Primary outcomes in paper I-III were ischemic stroke and major bleeding. Paper IV, a retrospective medical records study included adults with NS between 2010-2019 in the county of Västernorrland, Sweden. Outcomes were venous thromboembolism (VTE), bleeding and death. Patients divided into PAC- and no PAC group were compared using Fisher’s exact test. Patient time was divided into serum/plasma (S/P)-albumin intervals and VTE- and bleeding rates were calculated. Results: Paper I: At study start 12106 patients were included, 21.4% had G3, 43.5% G4, 11.6% G5 and 23.6% G5D.Warfarin, TTR 70%, compared to no treatment conferred lower risk for ischemic stroke in all patients, hazard ratio 0.51 (95% confidence interval 0.41-0.64). Warfarin was associated with higher risk of bleeding, 1.28 (1.14-1.43) in G3-G5D. Major bleedings were more than twice as common as ischemic stroke in G5-5D, irrespective of warfarin or no OAC treatment. Death was more than halved on warfarin compared to no treatment in all patients, 0.46 (0.42-0.50).Paper II: For comparing DOAC and warfarin, 2453 patients were included. DOAC compared to warfarin, TTR 67%, was associated with lower hazard of major bleeding, HR 0.71 (95%CI 0.53-0.96) but no difference in the risk of ischemic stroke. Mortality was higher during DOAC treatment, 1.24 (1.01-1.53), presumably not a causal association since less fatal bleedings on DOAC occurred. Paper III: Of 2379 patients on warfarin 21.9% had G3, 47.5% G4, 10.8% G5 and 19.8% G5D. TTR in G3 was 75.6%, G4 72.2%, G5 67.6% and G5D 62.0%. Increase by 10 percentage points iTTR conferred lower risk of major bleeding, ischemic stroke and death for all patients, HR 0.91 (95%CI 0.87-0.94), 0.92 (0.85-0.99) and 0.88 (0.85-0.90). Paper IV: Of 95 included patients with NS, 40 patients had PAC and 55 patients had no PAC. Seven VTE (7.4%) and 17 bleedings (18%) were found, 4 patients (4.2%) experienced major bleedings. Outcomes didn’t differ significantly between the PAC and no PAC group. Time with S/P-albumin <20g/L conferred higher rates/100 years of VTE with incidence rate ratio, IRR, 21.7 (95%CI 4.5–116.5) and bleeding, IRR 5.0 (1.4 –14.7), compared to time with S/P-albumin>20g/L.  Conclusions: High quality warfarin treatment compared to no OAC is associated with lower risk of ischemic stroke but higher risk of bleeding in patients with NVAF and CKD G3-G5D. Improved warfarin treatment quality seems beneficial regarding the risk of both bleeding and ischemic stroke. DOAC treatment is associated with lower risk of bleeding compared to warfarin in G3-G5D. The rate of major bleeding exceeds the rate of ischemic stroke in both OAC-treated and untreated patients. The risk of bleeding is particularly high in G5-5D and therefore, anticoagulants should not be prescribed by routine in these patients with AF. Larger randomised controlled trials (RCTs) need to confirm the possible benefit of DOAC compared to warfarin and establish whether anticoagulants are warranted in patients with NVAF and advanced CKD or on dialysis. Awaiting RCTs it might be reasonable to use OAC in selected patients on dialysis, with low risk of bleeding and high risk of ischemic stroke. If choosing warfarin, close monitoring is recommended. DOAC seems to be an appealing alternative to warfarin. Patients with NS have high risk of both VTE and bleeding, especially during time with S/P-albumin<20g/L. RCTs could elucidate whether PAC is warranted in NS.