Appendix Table 4.
Summary of Results Evaluating Individual Risk Factors
| Study Design |
No. of Patients |
Followup | Bleeding Risk | Risk of Bias |
|---|---|---|---|---|
| Presence and severity of CKD | ||||
| Apostolakis, 201350 Observational |
2293 | NR | Major Bleeding Patients with more than mild CKD (CrCl 60 mL/min) had higher risk of major bleeding compare with patients with CrCl ≥60 mL/min: HR 1.58 (95% CI 1.05 to 2.39)* |
Low |
| Bassand, 2018117 | 28,628 | 2 years | Major Bleeding HR 1.74 (95% CI 1.34 to 2.26) |
Low |
| Friberg, 201571 Observational |
283,969 | Total: Median 2.1 years | Intracranial Bleeding Presence and severity of CKD: HR 1.50 (95% CI 1.28 to 1.74)* Any Bleeding Presence and severity of CKD: HR 2.24 (95% CI 2.14 to 2.35)* |
Low |
| Jun, 201770 Observational |
14,892 | 1 year | Compared to nonuse, warfarin therapy was not associated with higher risk for major bleeding except for those with eGFRs of 60 to 89 mL/min/1.73 m2 (HR 1.36; 95% CI 1.13 to 1.64). | Low |
| McAlister, 2017115 Observational |
58,451 | Median 31 months | eGFR, mL/min/1.732 ≥60 = 1.00 45-59 = 1.13 (95% CI 1.04 to 1.22) 30-44 = 1.25 (95% CI 1.14 to 1.37) <30 = 1.50 (95% CI 1.33 to 1.68) |
Low |
| Friberg, 201218 Observational |
182,678 | Total: Median 1.4 year (IQR 1.8) | Multivariable Analysis Major Bleeding HR 1.59 (95% CI 1.41 to 1.79)* |
Low |
| Pisters, 20109 Observational |
3456 | 1 year | Major Bleeding OR 2.86 (95% CI 1.33 to 6.18)* |
Low |
| Sherwood, 2015118 Observational |
14,263 | NR | Creatinine clearance (for each 5-U decrease to <60 ml/min) HR 1.06 (95% CI 1.01 to 1.12)* |
Low |
| Cognitive impairment | ||||
| Orkaby, 2017119 Observational |
2,572 | Mean 2.2 person-years following diagnosis of dementia | After diagnosis of dementia no statistically significant decrease in risk of major bleeding (HR 0.78, 95% CI 0.61 to 1.01, P = .06). |
Medium |
| INR | ||||
| An, 2017120 Observational |
32,074 | Total: 5 years Median 3.8 years |
Patients whose TTRs were < 65%, had a 2 times higher risk of major bleeding (HR 2.10, 95% CI 1.96 to 2.24) compared with patients with the highest TTR quartile (≥ 73%) | Low |
| Haas, 201647 Observational |
9,934 | 1 year | TTR <65% vs. ≥65% bleeding risk HR 1.54 (95% CI 1.04 to 2.26) | Low |
| Lind, 201267 Observational |
19,179 | 34718.9 patient-years | The bleeding risk HR for the SDTINR variable was 1.27 (95% CI 1.20 to 1.35), and the HR for TTR was 1.07 (95% CI 1.01 to 1.14) | High |
| Phelps, 2018121 Observational |
8,405 | 1 year | Major Bleeding OR 0.62 (95% CI 0.43 to 0.89) |
Moderate |
| Rivera-Caravaca, 2018122 Observational |
1,361 | 6 months Median follow-up 214 days | Major bleeding rates per year: TTR <20% = 1.47 and ≥20% = 2.93; TTR <65% = 3.03 and ≥65% = 2.10 |
Low |
| Age | ||||
| Bassand, 2018117 | 28,628 | 2 years | Major Bleeding (HRs) <65 = referent 65-69 = 1.30 (95% CI 0.86 to 1.96) 70-74=1.88 (95% CI 1.30 to 2.74) 75+=2.49 (95% CI 1.81 to 3.42) |
Low |
| Friberg, 201218 Observational |
182,678 | Total: Median 1.4 year (IQR 1.8) | Multivariable Analysis Major Bleeding Age: 65-74 yr HR 2.33 (95% CI 1.96 to 2.77)* >75yr HR 3.28 (95% CI 2.80 to 3.83)* |
Low |
| Goodman, 2014123 Observational |
14,264 | NR | Multivariable analysis Major Bleeding Age (per 5y increase) HR 1.17 (95% CI 1.12 to 1.23)* |
Low |
| Hankey, 2014124 Observational |
14,264 | NR | Intracranial Bleeding Age: HR for 10 years increase 1.35 (95% CI 1.13 to 1.63)* |
Medium |
| Olesen, 201217 Observational |
6348 | NR | Major Bleeding Age <65: Event Rate 0.39 (0.16 to 0.94) Age 65-74y: Event Rate 1.34 (0.60 to 2.97) Age>75: Event Rate 1.98 (1.10 to 3.58) |
Medium |
| Pisters, 20109 Observational |
3456 | 1 year | Major Bleeding Age >65: OR 2.66 (1.33-5.32)* |
Low |
| Renoux, 2017125 Observational |
147,622 | Mean follow up period 2.9 years | Female vs. Male for Major Bleeding <75 = HR 0.91 (95% CI 0.88 to 0.95) ≥75 = HR 0.96 (95% CI 0.89 to 1.02) |
Low |
| Sherwood, 2015118 Observational |
14,263 | NR | Major Bleeding (Gastrointestinal) Age (for each 5-yr increase): HR 1.11 (1.06 to 1.17)* |
Low |
| Prior stroke | ||||
| Bassand, 2018117 | 28,628 | 2-years | Major Bleeding HR 1.36 (95% CI 1.04 to 1.78) |
Low |
| Friberg, 201218 Observational |
182,678 | Total: Median 1.4 year (IQR 1.8) | Multivariable Analysis Major Bleeding HR 1.14 (95% CI 1.04 to 1.24)* |
Low |
| Hankey, 2014124 Observational |
14,264 | NR | Intracranial Bleeding HR 1.42 (95% CI 1.02 to 1.96)* |
Medium |
| Pisters, 20109 Observational |
3456 | 1 year | Major Bleeding Prior stroke: OR 0.94 (95% CI 0.32 to 2.86) |
Low |
| Hilkens, 2017126 Observational |
3623 | 2 years | C-statistic (95% CI) of risk scores for major bleeding in patients with a TIA or stroke on oral anticoagulants at 2 years HEMORR2 HAGES 0.63 (0.59 to 0.66) HAS-BLED 0.62 (0.58 to 0.65) ATRIA 0.66 (0.62 to 0.69) |
Low |
| Presence of heart disease | ||||
| Bassand, 2018117 | 28,628 | 2-years | Major Bleeding HR 1.07 (95% CI 0.84 to 1.36) |
Low |
| Friberg, 201218 Observational |
182,678 | Total: Median 1.4 year (IQR 1.8) | Multivariable Analysis Major Bleeding Presence of heart disease (Heart Failure): HR 1.15 (95% CI 1.07 to 1.24)* (Hypertension) HR 1.25 (95% CI 1.16 to 1.33)* |
Low |
| Goodman, 2014123 Observational |
14,264 | NR | Multivariable Model Major Bleeding Presence of heart disease (Hypertension): DBP >90 mm Hg (per 5-mm Hg increase) HR 1.28 (1.11 to 1.47)* |
Low |
| Hankey, 2014124 Observational |
14,264 | NR | Intracranial Bleeding HR 0.65 (95% CI 0.47 to 0.89)* |
Medium |
| Pisters, 20109 Observational |
3456 | 1 year | Major Bleeding Presence of heart disease (PA>160mmHg): OR 0.60 (95% CI 0.21 to 1.72) |
Low |
| Diabetes | ||||
| Bassand, 2018117 | 28,628 | 2-years | Major Bleeding HR 0.92 (95% CI 0.71 to 1.18) |
Low |
| Friberg, 201218 Observational |
182,678 | Total: Median 1.4 yr (IQR 1.8) | Multivariable Analysis Major Bleeding HR 1.01 (95% CI 0.92 to 1.11) |
Low |
| Sex | ||||
| Bassand, 2018117 | 28,628 | 2 years | Major Bleeding HR (Women) 1.14 (95% CI 0.90 to 1.45) |
Low |
| Friberg, 201218 Observational |
182,678 | Total: Median 1.4 yr (IQR 1.8) | Multivariable Analysis Major Bleeding Female HR 0.79 (95% CI 0.73 to 0.85)* |
Low |
| Goodman, 2014123 Observational |
14,264 | NR | Multivariable Model Major Bleeding Female vs. Male HR 0.82 (95% CI 0.70 to 0.95)* |
Low |
| Renoux, 2017125 Observational |
147,622 | Mean follow up period 2.9 years | Female vs. Male for Major Bleeding <75 = HR 0.91 (95% CI 0.88 to 0.95) ≥75 = HR 0.96 (95% CI 0.89 to 1.02) |
Low |
| Sherwood, 2015118 Observational |
14,263 | NR | Major Bleeding (Gastrointestinal) Male HR 1.21 (95% CI 1.01 to 1.44)* |
Low |
| Cancer | ||||
| Friberg, 201218 Observational |
182,678 | Total: Median 1.4 yr (IQR 1.8) | Multivariable Analysis Major Bleeding Cancer <3 years: HR 1.15 (95% CI 1.04 to 1.27)* |
Low |
| Race/Ethnicity | ||||
| Bassand, 2018117 | 28,628 | 2-years | Major Bleeding (HRs) Caucasian / Hispanic / Latino (referent) Asian = 0.61 (95% CI 0.44 to 0.84) Other = 0.51 (95% CI 0.16 to 1.61) |
Low |
| Hankey, 2014124 Observational |
14,264 | NR | Intracranial Bleeding Asian HR 2.02 (95% CI1.39 to 2.94) Black HR 3.25 (95% CI 1.43 to 7.41)* |
Medium |
*
p value<0.05
Abbreviations: ATRIA=Anticoagulation and Risk Factors in Atrial Fibrillation; BRI=Bleeding Risk Index; CI=confidence interval; CKD=chronic kidney disease; HAS-BLED=Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile international normalized ratio, Elderly (> 65 years), Drugs/alcohol concomitantly; HR=hazard ratio; HEMORR2HAGES=Hepatic or renal disease, Ethanol abuse, Malignancy, Older (age >75 years), Reduced platelet count or function, Re-bleeding risk (2 points), Hypertension (uncontrolled), Anemia, Genetic factors, Excessive fall risk, Stroke; SE=standard error; INR=international normalized ratio; TIA=transient ischemic attack; TTR=time in therapeutic range; SDTinr=standardized deviation of transformed INF