Do the Safety and Efficacy Outcomes Reported in the Clinical Trials of Direct Oral Anticoagulants (DOAC) Translate to the Real-World?

Abstract

Do the safety and efficacy outcomes reported in the clinical trials of direct oral anticoagulants (DOAC) translate to the 'real-world'?Background: A number of DOACs are now available for clinicians to prescribe in clinical practice. Whilst the results from large clinical trials demonstrate that these agents are as effective as vitamin K antagonists, there is some concern that the patients studied in the trials were not representative of patients, clinicians encounter in everyday practice. The aim of our study was to compare the real-world clinic population commenced on a DOAC to that from the clinical trials for these agents, in order to assess potential differences in safety and efficacy.Patients and methods: A retrospective observational cohort study was undertaken. Patients who were initiated on a DOAC (apixaban, dabigatran and rivaroxaban) at a large teaching hospital in South East London between 1st August 2012 and 31st July 2014 were identified through pharmacy issue data with those followed-up for a minimum of 6 months included. Baseline demographic data, rates of stroke/VTE and rates of major/non-major clinically relevant (NMCR) (ISTH definition) bleeding were assessed and compared to pooled data reported from the corresponding Phase III trials. Differences between groups were compared using t-tests or chi-squared tests.Results: During the review period, 748 patients were initiated on a DOAC, 365 for atrial fibrillation (AF) and 383 for venous thromboembolism (VTE). In terms of demographic differences, the real-world AF population comprised more females, were significantly older, had poorer renal function and a lower body weight. In contrast, the real-world VTE population typically had a higher body weight and poorer renal function, compared to the trial population, (table 1). Efficacy of DOACs was found to be similar across both the VTE and AF populations. With respect to safety, the real-world AF population experienced similar rates of major bleeding and a significantly lower rate of NMCR bleeding compared to the trial populations. In contrast, the real-world VTE population experienced a significantly higher rate of major bleeding, particularly gastrointestinal bleeding. Although the rate of NMCR bleeding was similar, there was a significantly higher rate of urogenital bleeding in the real-world VTE population, specifically heavy menstrual bleeding in women.Conclusions: The efficacy outcomes of DOAC use in a real-world AF and VTE population are consistent with the Phase III trials, despite some significant differences in baseline characteristics. However, a significantly increased rate of major bleeding was observed in the real-world VTE population, which requires further investigation.Table 1Baseline demographic characteristics, efficacy and safety outcomes in the real-world population versus the trial populationAtrial FibrillationVenous ThromboembolismTrial population+N=28,342Real-world populationTrial population++Real-world populationN=365N=8,716N=383Baseline Demographics, mean (SD) unless otherwise specifiedAge, years72(9.6)76.8 *(12.1)56.9(14.2)55.6(18.7)Female (%)10451(36.9)215 *(58.9)3753(43.1)184(48.0)Weight, kg82.7(19.5)77.3 *(22.6)84.9(19.6)88.2 *(23.0)Creatinine clearance, mL/min69(26.7)58.1 *(26.9)105.8(40.7)91.1 *(37.6)Concomitant aspirin therapy10341(36.5)49 *(13.4)-0(0)Previous VKA use (%)15711(55.4)193(52.9)-85(22.2)Efficacy (%)All-cause mortality1695(6.0)37 *(9.1)160(1.8)10(2.5)Stroke676(2.4)8(2.0)-1(0.3)VTE39(0.1)1(0.2)192(2.2)7(1.8)Safety (%)Major Bleeding1419(5.0)17(4.2)79(0.9)15 *(3.8)Intracranial170(0.6)1(0.2)6(0.1)2 *(0.5)Gastrointestinal644(2.3)8(2.0)8(0.1)8 *(2.0)Non-major Clinically relevant (NMCR) bleeding4824(17.0)30 *(7.4)540(6.2)26(6.6)Gastrointestinal-9(2.2)53(4.2)10(2.5)Urogenital296(4.2)16(3.9)100(2.5)38 *(9.6)+Pooled data from ARISTOTLE, RE-LY and ROCKET-AF trials++Pooled data from AMPLIFY, RE-COVER and EINSTEIN-PE/DVT trials*p<0.05 DisclosuresPatel:Bayer plc: Research Funding. Auyeung:Bayer PLC: Research Funding. Arya:Bayer plc: Research Funding.