Table 6.
Risk of thromboembolic and bleeding events in AF patients with renal impairment
| Author, year, country | Study population | Definition of renal impairment | ATT therapy | Thromboembolic events | Bleeding events |
|---|---|---|---|---|---|
| Providência, 201481 | Meta-analysis 19 studies 379 506 patients AF patients with CKD |
Cockroft–Gault (n = 5) MDRD (n = 5) CKD-EPI (n = 2) Coding |
Warfarin, NOACs, aspirin, or none | CKD ↑ TE risk [HR (95% CI) 1.46 (1.20–1.76); P = 0.0001] End-stage CKD ↑ TE risk [HR (95% CI) 1.83 (1.56–2.14); P < 0.00001] Warfarin ↓TE in non-end-stage CKD patients [HR (95% CI) 0.39 (0.18–0.86); P < 0.00001] NOACs ↓TE compared with warfarin [HR (95% CI) 0.80 (0.66–0.96); P = 0.02] and aspirin [HR (95% CI) 0.32 (0.19–0.55); P < 0.0001] in non-end-stage CKD patients |
|
| Shah, 2014, Canada82 | Retrospective population-based cohort study Patients aged ≥65 years admitted to the hospital with primary/secondary diagnosis of AF from 1998 to 2007 |
Dialysis: n = 1626 Mean (SD) age: 75 (8) years; 634 (39.0%) women Non-dialysis: n = 204 210 Mean (SD) age: 78 (10); 104 652 (51.2%) women |
Warfarin vs. no warfarin OAC: 756 (46.4%) dialysis vs. 103 473 (50.7%) non-dialysis |
No. of events (incidence rate per 100 patient-years) Dialysis patients: 107 (3.12) On warfarin vs. off-warfarin: 52 (3.37) vs. 55 (2.91) Non-dialysis patients: 19 489 (2.35) On warfarin vs. off-warfarin: 9241 (2.19) vs. 10 248 (2.51) Warfarin use not associated with ↓stroke risk in dialysis patients [adjusted HR (95% CI) 1.14 (0.78–1.67) ↓Stroke risk with warfarin use in non-dialysis patients [adjusted HR (95% CI) 0.87 (0.85–0.90)] |
No. of events (incidence rate per 100 patient-years) Dialysis patients: 275 (8.89) On warfarin vs. off-warfarin: 149 (10.88) vs. 126 (7.31) Non-dialysis patients: 34 035 (4.32) On warfarin vs. off-warfarin: 18 340 (4.64) vs. 15 695 (4.00) Warfarin use ↑bleeding risk in dialysis [adjusted HR (95% CI) 1.44 (1.13–1.85)] and non-dialysis [HR (95% CI) 1.19 (1.13–1.85)] patients |
| Kooiman, 2014, The Netherlands83 | 724 AF patients without CKD or non-dialysis-dependent CKD on OAC attending the Leiden clinic between 1997 and 2005 Follow-up: 31 December 2010 Median follow-up 2.1 years for stroke/TIA and 2.3 years for major bleeding events Mean (SD) age 75 (10); 43.5% women |
Abbreviated MDRD formula No CKD (eGFR >60 mL/min): n = 300 Moderate CKD (30–60 mL/min): n = 294 Severe CKD (eGFR <30 mL/min) = 130 |
All OACs | 45/724 (6.2%) (1.67/100 patient-years) stroke/TIA ↑Stroke/TIA risk in patients with severe CKD vs. those without CKD [HR (95% CI) 2.75 (1.25–6.05)] vs. those with moderate CKD [HR (95% CI) 3.93 (1.71–9.00)] Similar stroke/TIA risk for patients with moderate CKD vs. without CKD (data not reported) |
ISTH criteria for major bleeding 113/724 (15.6%) (4.8/100 patient-years) Non-significant ↑ in major bleeding risk with severe CKD vs. no CKD [HR (95% CI) 1.66 (0.97–2.86)] and those with moderate CKD [HR (95% CI) 1.86 (1.08–3.21)] Similar risk of major bleeding for patients with moderate CKD vs. no CKD (data not reported) |
| Friberg, 2014, Sweden*84 | Retrospective analysis of Swedish AF national registry 307 351 patients with hospital diagnosis of AF between 1 July 2005 and 31 December 2010 13 435 (4.4%) with previous diagnosis of renal failure |
ICD-10 codes (N17-19) or local codes for dialysis or renal transplantation Mean (SD) age; % women Renal failure: 78.4 (10.3); 4802 (35.7%) No renal failure: 74.8 (12.5); 123 333 (45.6%) |
Warfarin at baseline Renal failure: 3766 (28.0%) No renal failure: 10 794 (39.9%) |
↑ Annual rate of ischaemic stroke [3.9 vs. 2.9%; HR (95% CI) 1.25 (1.16–1.34)] and TE [8.2 vs. 5.2%; HR (95% CI) 1.42 (1.35–1.49)] with renal failure; however, no significant difference after full adjustment for confounders [adjusted HR (95% CI) 1.02 (0.95–1.10) and 1.12 (1.07–1.18) for ischaemic stroke and TE, respectively] Irrespective of renal function, patients on warfarin at baseline had ↓ stroke and TE than those not on warfarin at baseline [HR 0.69 vs. 0.70 in patients with and without renal failure; P-value for interaction P = 0.865] |
↑ Annual rate of any bleeding [9.8 vs. 4.1%; HR (95% CI) 2.24 (2.14–2.35)] and ICH [0.8 vs. 0.5%; HR (95% CI) 1.50 (1.28–1.74)] with renal failure Renal failure-independent risk factor for any bleeding [adjusted HR (95% CI) 1.56 (1.48–1.63)] and ICH [adjusted HR 1.27 (1.09–1.49)] |
| Chao, 2014, Taiwan85 | Retrospective analysis of Taiwan's National Health Insurance Research Database between 1 January 1996 and 31 December 2011 10 999 AF patients with ESRD undergoing renal replacement therapy, not on OAC or APT Mean (SD) age 71.0 (11.1) years; 5913 (53.8%) women |
ESRD defined by ICD-9-CM codes | None | Ischaemic stroke 1217 pts. (11.7%); incidence rate of 6.9 per 100 patient-years |
† 9.7% severe bleeding (bleeding not defined) |
| Roldán, 2013, Spain*86 | 978 consecutive stable anticoagulated (INR 2.0–3.0 within previous 6 months) AF patients from outpatient clinic Median (IQR) age 76 (70–81); 482 (49.3%) women Median (IQR) follow-up: 875 (706–1059) days |
MDRD Renal impairment: eGFR <60 mL/min/1.73 m2 |
OAC | CV events (stroke, TIA, peripheral embolism, ACS, acute HF, and cardiac death) 113 patients (4.82%/year) adverse CV events; 39 (1.66%/year) strokes eGFR (categorical variable per 30 mL/min/1.73 m2 decrease) was significantly associated with thrombotic/vascular events [unadjusted HR (95% CI) 1.42 (1.11–1.83); P = 0.006] Adjusted for ‘high-risk’ (CHA2DS2-VASc score ≥2) eGFR (per 30 mL/min/1.73 m2 decrease) was significantly associated with thrombotic/vascular events [adjusted HR (95% CI) 1.37; 1.07–1.76; P = 0.012] |
ISTH criteria for major bleeding 81 patients (3.46%/year) haemorrhagic events 16 ICH (0.68%/year) eGFR (categorical variable per 30 mL/min/1.73m2 decrease) ↑ risk of bleeding (HR 1.44; 1.08–1.94; P = 0.015) Adjusted for ‘high-risk’ (HAS-BLED ≥3) eGFR (per 30 mL/min/1.73 m2 decrease) was significantly ↑ risk of bleeding [adjusted HR (95% CI) 1.34 (1.00–1.80); P = 0.046] |
| Banerjee, 2013, France*87 | Loire Valley cohort 5912 patients with first recorded AF diagnosis in hospital between 1 January 2000 and December 2010 with baseline serum creatinine data Mean follow-up: 2.45 (3.56) years |
History of renal failure or baseline serum creatinine level >133 µmol/L (men) or >115 µmol/L (women) eGFR (mL/min/1.73m2) three groups: ≥60 (n = 4375) 30–59 (n = 1196) <30 (n = 341) |
TE (ischaemic stroke, TIA, and peripheral artery embolism) No. TE events and rate (95% CI) at 1 year eGFR ≥60: 64; 3.4 (2.4–4.8) eGFR 30–59: 92; 5.7 (4.2–7.8) eGFR <30: 15; 7.7 (4.3–13.6) Normal: 119; 4.4 (3.2–5.9) As a categorical variable only, eGFR was an independent predictor of TE after adjustment for age, sex, and CHADS2 risk factors but not for baseline characteristics |
† | |
| Apostolakis, 2013, multicentre88 | AMADEUS cohort 4576 AF patients. receiving OAC Mean (SD) age 70 (9) years; 1526 (33.4%) women Mean (SD) follow-up: 325 (164) days |
Baseline serum creatinine available in 4554 (99.5%) Three most widely used equations to calculate renal function CrCl (Cockroft–Gault formula), MDRD and CKD-EPI Based on CrCl: 1470 (32.35) <60 mL/min 68 (1.5%) <30 mL/min |
Warfarin or idraparinux | Composite of all stroke/non-CNS SE 45 strokes/non-CNS SE (1.1 events per 100 patient-years) Only data for CrCl and MDRD reported here (number of events (n/100 patient-years) CrCl ≥90: 6 (0.6) 60–89: 13 (0.8) 30–59: 26 (2.2) <30: 0 MDRD ≥90: 2 (0.4) 60–89: 17 (0.8) 30–59: 25 (1.9) <30: 1 (1.9) Adjustment for demographic characteristics and co-morbidities, patients with CrCl <60 mL/min had double the risk of risk/SE compared with those with CrCl ≥60 mL/min [adjusted HR (95% CI) 2.27 (1.14–4.52)] |
ISTH criteria for major bleeding 103 major bleeds (2.5 events per 100 patient-years) CrCl ≥90: 15 (1.3) 60–89: 38 (2.4) 30–59: 48 (3.8) <30: 2 (3.2) MDRD ≥90: 7 (1.6) 60–89: 53 (2.4) 30–59: 42 (3.2) <30: 1 (1.9) Patients with CrCl <60 mL/min had ↑ risk of major bleeding compared with patients with CrCl ≥60 mL/min [adjusted HR (95% CI) 1.58 (1.05–2.39); P = 0.027] |
| Olesen, 2012, Denmark*55 | Retrospective analysis of Danish national registries 132 372 patients with hospital discharge diagnosis of AF between 1997 and 2008 |
ICD codes No renal disease at baseline: 127 884 (96.6%) Mean (SD) age 73.2 (12.9); 46.9% women Non-end-stage CKD: 3587 (2.7%) Mean (SD) age 76.5 (11.0); 41.0% women end-stage CKD (dialysis or previous kidney transplant): 901 (0.7%) Mean (SD) age 66.8 (11.7); 33.6% women |
OAC ± ASA, ASA, or none | No. of stroke/TE events; event rate per 100 patient-years (95% CI) No renal disease: 16 648; 3.61 (3.55–3.66) Non-end-stage CKD: 842; 6.44 (6.02–6.89) End-stage CKD: 164; 5.61 (4.82–6.54) Compared with patients with no renal disease, non- end-stage CKD patients [HR (95% CI) 1.49 (1.38–1.59; P < 0.001)] and those on renal replacement [HR (95% CI) 1.83 (1.57–2.14; P < 0.001] had ↑ risk of stroke/TE Warfarin ↓ stroke/TE risk in both groups [adjusted HR (95% CI)] No renal disease: ASA: 0.59 (0.56–0.61) OAC: 1.10 (1.06–1.14) OAC + ASA: 0.69 (0.64–0.74) Non-end-stage CKD: ASA: 0.84 (0.69–1.01) OAC: 1.25 (1.07–1.47) OAC + ASA: 0.76 (0.56–1.03) Renal replacement: ASA: 0.44 (0.26–0.74) OAC: 0.88 (0.59–1.32) OAC + ASA: 0.82 (0.37–1.80) |
No. of major bleeding events; event rate per 100 patient-years (95% CI) No renal disease: 16 195; 3.54 (3.48–3.59) Non-end-stage CKD: 1097; 8.77 (8.26–9.30) Renal replacement: 243 8.89 (7.84–10.08) Adjusted HR (95% CI) No renal disease: ASA: 1.28 (1.23–1.33) OAC: 1.21 (1.16–1.26) OAC + ASA: 2.18 (2.07–2.30) Non-end-stage CKD: ASA: 1.36 (1.17–1.59) OAC: 1.12 (0.96–1.30) OAC + ASA: 1.63 (1.32–2.02) Renal replacement: ASA: 1.27 (0.91–1.77) OAC: 1.63 (1.18–2.26) OAC + ASA: 1.71 (0.98–2.99) |
| Go, 2009, USA*90 | ATRIA cohort 13 535 AF patients diagnosed between 1 July 1996 and 31 December 1997 Mean age of ATRIA cohort 71.6 years; 42.8% women Follow-up until 30 September 2003 |
MDRD Baseline serum creatinine not available in 2627 (19.4%) patients eGFR ≥60 mL/min/1.73 m2: n = 7690 45–59 mL/min/1.73m2: n = 2499 <45 mL/min/1.73m2: n = 1338 |
None 33 165 patient-years off-OAC among 10 908 AF patients |
676 TE events (637 ischaemic strokes) during periods off-warfarin eGFR ≥60 mL/min/1.73 m2: 344 events 45–59 mL/min/1.73 m2: 168 events <45 mL/min/1.73 m2: 149 events 15 events in patients with unknown kidney function Crude rates of TE off-warfarin by eGFR eGFR ≥60: 1.63 45–59 : 2.76 <45: 4.22 Rate of TE off-warfarin ↑ significantly with lower eGFR Adjusted (for age, sex, ethnicity, education, income, previous stroke, HF, DM, hypertension, and CHD) HR (95% CI) for TE compared with eGFR ≥60 eGFR 45–59: 1.16 (0.95–1.40) eGFR <45: 1.39 (1.13–1.71) Graded increased independent risk of TE with eGFR <45 mL/min/1.73 m2 |
† |
AMADEUS, Atrial fibrillation trial of Monitored, Adjusted Dose vitamin K antagonist, comparing Efficacy and safety with Unadjusted SanOrg 34006/idraparinux study; ACS, acute coronary syndrome; AF, atrial fibrillation; ASA, aspirin; ATRIA, AnTicoagulation and RIsk factors in Atrial fibrillation; ATT, antithrombotic therapy; CI, confidence interval; CKD, chronic kidney disease; CKD-EPI, chronic kidney disease epidemiology collaboration equation; CNS, central nervous system; CrCl, creatinine clearance; CV, cardiovascular; eGFR, estimated glomerular filtration rate; CKD, chronic kidney disease; ESRD, end-stage renal disease; HF, heart failure; HR, hazard ratio; ICD, International Classification of Disease; ICH, intracranial haemorrhage; IQR, interquartile range; ISTH, International Society of Thrombosis and Haemostasis; MDRD, Modification of Diet in Renal Diet; min, minute; mL, millilitres; NOAC, non-vitamin K antagonist oral anticoagulant; OAC, oral anticoagulation; SD, standard deviation; TE, thromboembolism; TIA, transient ischaemic attack; vs., versus.
†, not reported; *, included in meta-analysis81; ↑, increase; ↓, decrease.