The importance of mean time in therapeutic range for complication rates in warfarin therapy of patients with atrial fibrillation: A systematic review and meta-regression analysis

Abstract

Background\Anticoagulation is used for stroke prophylaxis in non-valvular atrial fibrillation, amongst other by use of the vitamin K antagonist, warfarin. Quality in warfarin therapy is often summarized by the time patients spend within the therapeutic range (percent time in therapeutic range, TTR). The correlation between TTR and the occurrence of complications during warfarin therapy has been established, but the influence of patient characteristics in that respect remains undetermined. The objective of the present papers was to examine the association between mean TTR and complication rates with adjustment for differences in relevant patient cohort characteristics.MethodsA systematic literature search was conducted in MEDLINE and Embase (2005–2015) to identify eligible studies reporting on use of warfarin therapy by patients with non-valvular atrial fibrillation and the occurrence of hemorrhage and thromboembolism. Both randomized controlled trials and observational cohort studies were included. The association between the reported mean TTR and major bleeding and stroke/systemic embolism was analyzed by random-effects meta-regression with and without adjustment for relevant clinical cohort characteristics. In the adjusted meta-regressions, the impact of mean TTR on the occurrence of hemorrhage was adjusted for the mean age and the proportion of populations with prior stroke or transient ischemic attack. In the adjusted analyses on thromboembolism, the proportion of females was, furthermore, included.ResultsOf 2169 papers, 35 papers met pre-specified inclusion criteria, holding relevant information on 31 patient cohorts. In univariable meta-regression, increasing mean TTR was significantly associated with a decreased rate of both major bleeding and stroke/systemic embolism. However, after adjustment mean TTR was no longer significantly associated with stroke/systemic embolism. The proportion of residual variance composed by between-study heterogeneity was substantial for all analyses.ConclusionsAlthough higher mean TTR in warfarin therapy was associated with lower complication rates in atrial fibrillation, the strength of the association was decreased when adjusting for differences in relevant clinical characteristics of the patient cohorts. This study suggests that mainly the safety of warfarin therapy increases with higher mean TTR, whereas effectiveness appears not to be substantially improved.Due to the limitations immanent in the meta-regression methods, the results of the present study should be interpreted with caution. Further research on the association between the quality of warfarin therapy and risk of complications is warranted with adjustment for clinically relevant characteristics.

Incidence, risk factors, and outcomes of warfarin‐associated major bleeding in Thai population

“…It is well known that a myriad of factors can affect warfarin therapy . Among these factors, the quality of anticoagulation control has been shown to directly influence both efficacy and safety of warfarin . For Thailand, limited local data suggested that quality of anticoagulation control, as expressed by time in therapeutic range (TTR), is still suboptimal .…”

“…1 Among these factors, the quality of anticoagulation control has been shown to directly influence both efficacy and safety of warfarin. 17 For Thailand, limited local data suggested that quality of anticoagulation control, as expressed by time in therapeutic range (TTR), is still suboptimal. 8 In addition, racial difference, higher level of anticoagulation needed for SPMVR, patterns of comorbidities, and overall health system quality may affect in the development of WAMB.…”

Impact of Aspirin on Warfarin Control as Measured by Time in Therapeutic Range

“…Warfarin requires ongoing monitoring of Internationalised Normalised Ratio (INR) due to a narrow therapeutic index and interactions with numerous drugs . The time in therapeutic range (TTR) is often used to indicate the quality of warfarin therapy due to the established correlation between higher mean TTR and reduced complications such as bleeding and thromboembolism . TTR is strongly associated with bleed risk, but increased bleeding with warfarin has also been associated with patient comorbidities and concurrent administration of other medication linked to bleeding including antiplatelet agents and non‐steroidal anti‐inflammatories (NSAIDs) .…”

Rationale, design, and preliminary results of the Quebec Warfarin Cohort Study

“…It is a strong predictor of adverse events in warfarin-treated patients such that lower TTR (<60%) is associated with an increased risk of major bleeding and thromboembolism. [14][15][16][17][18] TTR was calculated using the Rosendaal method as previously described 19 based on linear interpolation to infer the proportion of days a patient spent within his or her respective therapeutic range.…”