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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 fibrillation
• To examine the role of warfarin treatment quality as a predictor for ischemic stroke and bleeding in CKD
• To investigate benefits and risks with prophylactic anticoagulants in patients with nephrotic syndrome and elucidate risk factors for thrombosis and bleeding

Methods: 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.

Background: Nephrotic syndrome (NS) is associated with increased risk of venous thromboembolism (VTE). Guidelines suggest prophylactic anticoagulants to patients with high risk of thrombosis and low risk of bleeding, but the evidence behind this is poor. This study aims to investigate the effectiveness and risks of prophylactic anticoagulants (PAC) and investigate risk factors for VTE and bleeding in NS.

Methods: A retrospective medical records study including adults with NS, biopsy proven glomerular disease in the county of Västernorrland, Sweden. Outcomes were 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 (<20g/L and ≥20g/L) and VTE- and bleeding rates were calculated.

Results: In 95 included NS patients (PAC = 40, no PAC = 55), 7 VTE (7.4%) and 17 bleedings (18%) were found. 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 (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.

Conclusion: Duration of severe hypoalbuminemia (S/P-albumin <20g/L) in NS is a risk factor for both VTE and bleeding. There is a need for randomized controlled studies regarding the benefit of PAC in NS as well as risk factors of thrombosis and bleeding in NS.

Background: The use of direct oral anticoagulants (DOAC) in patients with non-valvular atrial fibrillation (NVAF) and advanced chronic kidney disease (CKD) including dialysis is growing. Several studies have shown favorable results of DOAC compared with warfarin regarding bleeding risk but no difference in stroke protection. However, these studies had poor time in therapeutic range (TTR), in the warfarin comparison group.

Methods: This was a Swedish national cohort study investigating the risk of ischemic stroke and major bleeding on DOAC compared with warfarin in patients with NVAF, glomerular filtration rate category 3-5D (G3-G5D), kidney transplant recipients excluded, between 2009 and 2018. Data extracted from high-quality national healthcare registries including the Swedish Renal Registry, AuriculA (the Swedish national quality register for AF and anticoagulation) and The Stroke Register.

Results: At enrolment, of 2453 patients 59% were treated with warfarin (mean TTR 67%) and 41% with DOAC. Overall, 693 (28.3%) had G3, 1113 (45.4%) G4, 222 (9.1%) G5 and 425 (17.3%) G5D. DOAC compared with warfarin showed lower hazard of major bleeding [hazard ratio 0.71 (95% confidence interval 0.53-0.96)] but no difference in ischemic stroke risk. Mortality was increased during DOAC treatment [1.24 (1.01-1.53)], presumably not a causal association since fewer fatal bleedings occurred on DOAC.

Conclusions: DOAC treatment, compared with warfarin, is associated with almost 30% lower risk of bleeding in patients with NVAF and CKD G3-G5D. The stroke risk is comparable between the treatments. This is the first study comparing DOAC and well-managed warfarin (TTR 67%) in advanced CKD. Ongoing and planned randomized controlled trials need to confirm the possible benefit of DOAC.

Background: Observational data comparing warfarin with no treatment for patients with non-valvular atrial fibrillation (NVAF) and severely reduced glomerular filtration rate (GFR) are conflicting and randomized controlled trials (RCTs) are lacking. Most studies do not provide information on warfarin treatment quality, making them difficult to compare.

Methods: This national cohort study investigates the risk of ischaemic stroke and major bleeding during warfarin treatment compared with no oral anticoagulants in patients with NVAF, GFR category 3-5 (G3-G5) or on dialysis (G5D), with kidney transplant recipients excluded, between 2009 and 2018. Data extracted from high-quality Swedish national healthcare registries, including the Swedish Renal Registry, AuriculA-the Swedish national quality registry for atrial fibrillation and anticoagulation- A nd the Stroke Registry.

Results: At enrolment of 12 106 patients, 21.4% were G3, 43.5% were G4, 11.6% were G5 and 23.6% were G5D. The mean time in the therapeutic range was 70%. Warfarin compared with no treatment showed a lower risk for ischaemic stroke for G3 {hazard ratio [HR] 0.37 [95% confidence interval (CI) 0.18-0.76]}, G4 [0.53 (0.38-0.74)] and G5 [0.49 (0.30-0.79)] and an increased risk of major bleeding in G4 [HR 1.22 (1.02-1.46)], G5 [1.52 (1.15-2.01)] and G5D [1.23 (1.00-1.51)]. All-cause mortality was more than halved on warfarin compared with no treatment in all GFR categories.

Conclusions: Warfarin treatment is associated with a lower risk of ischaemic stroke for patients with NVAF and G3, G4 and G5D at the cost of a higher risk of major bleeding for G4-G5D. Existing observational data are conflicting, stressing the need for RCTs on warfarin compared with no treatment in G4-G5D. Awaiting RCTs, it seems reasonable to treat selected patients on dialysis and NVAF with warfarin.

Introduction: Warfarin treatment quality is calculated as time in therapeutic range (TTR). TTR ≥ 70 % is considered reducing the risk of adverse events for patients with atrial fibrillation (AF). The association of TTR and adverse events in chronic kidney disease (CKD) is however poorly investigated. The aim is to explore this further.

Materials and methods: Swedish cohort study based on national healthcare registers between 2009 and 2018, including Swedish Renal Registry, Swedish Stroke Register and AuriculA - the Swedish national quality register for AF and anticoagulation. Investigating the effect of individual TTR (iTTR) and iTTR ≥ 70 % versus <70 % on the risk of ischemic stroke, major bleeding and death for patients with CKD GFR category 3–5 (G3-G5) including patients on dialysis (G5D) and non-valvular AF (NVAF).

Results: Of 2379 included patients 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 (hazard ratio 0.91 (95 % Confidence interval 0.87–0.94), 0.92 (0.85–0.99) and 0.88 (0.85–0.90)). iTTR≥ 70 % versus <70 % was associated with lower risk of bleeding and death in all patients (0.63 (0.51–0.77) and (0.51 (0.43–0.61)), and a non-significant tendency towards lower stroke risk (0.67 (0.43–1.06)).

Conclusions: Warfarin treatment quality worsens with decreasing GFR. Higher iTTR confers lower risk of bleeding, ischemic stroke and death in patients with NVAF and G3-G5D. iTTR ≥ 70 % was associated with better safety profile. Close monitoring of patients with CKD on warfarin is recommended.

Background: Patients with chronic kidney disease (CKD) and atrial fibrillation (AF) on oral anticoagulants (OACs) are at high risk of bleeding. Determinants of major bleeding risk in OAC users with AF and CKD are not well established and available bleeding score systems do not perform well in CKD. This study aims to present risk factors associated with major bleeding in a Swedish cohort of OAC-treated patients with CKD G3–5D.

Methods: We conducted a Swedish register-based cohort study including patients with AF and CKD G3–5D on warfarin or direct OACs (DOACs) between 2009 and 2018. Data were collected from high-quality registers including the Swedish Renal Registry and Auricula, a register for AF and OACs. Risk factors for major bleeding were investigated with Cox regression analysis.

Results: Of 2453 included patients, 59% were on warfarin (time in therapeutic range 67%) and 41% on DOACs. Major bleeding rates were 8.9/100 patient-years. Factors associated with increased bleeding risk were glomerular filtration rate category, G5/5D versus G3 {hazard ratio [HR] 1.92 [95% confidence interval (CI) 1.43–2.56]}, previous gastrointestinal bleeding [HR 1.77 (95% CI 1.39–2.25)], previous other bleeding [HR 1.33 (95% CI 1.09–1.62)], congestive heart failure [HR 1.36 (95% CI 1.11–1.68)], male sex [HR 1.28 (95% CI 1.03–1.60)] and vascular disease [HR 1.35 (95% CI 1.01–1.79)].

Conclusion: Patients with AF and G3–5D on OACs are at a high risk of bleeding. Previous major bleeding and kidney failure are strongly associated with major bleeding. The present study also shows an association between OAC-associated bleeding and male sex, congestive heart failure and vascular disease. Knowledge about determinants of bleeding in advanced CKD is essential when deciding on when to anticoagulate or not.