Are the risk factors listed in warfarin prescribing information associated with anticoagulation-related bleeding? A systematic literature review

Abstract

Warfarin significantly reduces thromboembolic risk, but perceptions of associated bleeding risk limit its use. The evidence supporting the association between bleeding and individual patient risks factors is unclear. This systematic review aims to determine the strength of evidence supporting an accentuated bleeding risk when patients with risk factors listed in the warfarin prescribing information are prescribed the drug. A systematic literature search of MEDLINE and Cochrane CENTRAL was conducted to identify studies reporting multivariate relationships between prespecified covariates and the risk of bleeding in patients receiving warfarin. The prespecified covariates were identified based on patient characteristics for bleeding listed in the warfarin package insert. Each covariate was evaluated for its association with specific types of bleeding. The quality of individual evaluations was rated as 'good', 'fair' or 'poor' using methods consistent with those recommended by the Agency for Healthcare Research and Quality (AHRQ). Overall strength of evidence was determined using the Grading of Recommendations Assessment, Development (GRADE) criteria and categorised as 'insufficient', 'very low', 'low', 'moderate' or 'high'. Thirty-four studies, reporting 134 multivariate evaluations of the association between a covariate and bleeding risk were identified. The majority of evaluations had a low strength of evidence for the association between covariates and bleeding and none had a high strength of evidence. Malignancy and renal insufficiency were the only two covariates that had a moderate strength of evidence for their association with major and minor bleeding respectively. The associations between covariates listed in the warfarin prescribing information and increased bleeding risk are not well supported by the medical literature.

Identifying the Risks of Anticoagulation in Patients with Substance Abuse

“…[19][20][21][22] In particular, warfarin is underutilized in patients with atrial fibrillation with co-morbid substance abuse, 23 but evidence to support this decision has been sparse. 24 , 25 A recent systematic review found a statistically significant increase in hemorrhages in alcohol abusers in less than half of the studies and reported overall strength of the evidence as low. 25 Poorer anticoagulation control in substance-abusing patients is concerning, since improved control is associated with fewer adverse events.…”

International Warfarin Genotype-Guided Dosing Algorithms in the Turkish Population and Their Preventive Effects on Major and Life-Threatening Hemorrhagic Events

“…Relevant risk reductions are also observed for the other warfarin indications [5]. Although it has a significant thromboembolism risk reduction, incorrect warfarin dosing can be associated with thromboembolic events (in the case of underdosing) or bleeding complications (in the case of overdosing) [6]. Warfarin is the first cause of emergency room visits for adverse drug events in older adults in the USA [7].…”

Bleeding risk with oral anticoagulation - new frontiers and new questions

“…In this issue of the International Journal of Clinical Practice , Chen et al. report the results of a systematic review to determine the strength of evidence supporting an accentuated bleeding risk when patients with risk factors listed in the warfarin prescribing information (in terms of contraindications, warnings, and precautions) are prescribed warfarin (7). Risk factors for bleeding include ‘haemorrhagic tendencies, blood dyscrasias, characteristics listed in the black box warning, unsupervised patients with senility or alcoholism, severe heart disease, and anaemia’ (7).…”

“…The review by Chen et al. (7) is comprehensive and includes 35 articles published between 1988 and 2009, from 34 unique studies (two post hoc analyses of randomised controlled trials, 11 prospective observational studies, 18 retrospective observational studies, two mixed prospective and retrospective studies, and one study of unclear study design). The total sample size was 148,443 patients (80–66,988 within individual studies), with a median duration of follow‐up of 1247 patient‐years (221–133,976 patient‐years).…”

“…The comprehensive systematic review found that only malignancy and renal insufficiency were associated with bleeding risk and this association was supported by a ‘moderate strength of evidence’. For all other risk factors listed in the warfarin package insert, they concluded that bleeding risk was ‘low to very low’ (7).…”