Adverse Drug Reactions during Real-Life Use of Direct Oral Anticoagulants in Italy: An Update Based on Data from the Italian National Pharmacovigilance Network

Abstract

Background: The availability of direct oral anticoagulants (DOAC) in clinical practice has transformed the health care provided to patients for the prevention and treatment of thromboembolism. Safety and efficacy data guide clinicians in the choice of the drug used. To date, no evidence is available from head-to-head trials comparing different DOAC with regard to safety and efficacy; information is mainly derived from several meta-analyses and real-life studies. Conclusions from these studies are inconsistent and unsatisfactory. The evaluation of self-reported adverse drug reactions (ADR) available from databases of drug-regulatory agencies such as the Italian Medicines Agency (AIFA) pharmacovigilance database represents a novel aid to guide decision-making. Objective: To analyze potential suspected ADR of DOAC using a previously described risk index (RI) in daily clinical practice in Italy. Methods: The National Pharmacovigilance Network database (from the AIFA website) was searched in order to retrieve information on all ADR related to oral anticoagulants occurring from 2013 to 2018. The ADR RI for each drug was calculated, where an RI = 1 indicates a balance between the percentage of ADR share and the percentage of market share for each DOAC; and an RI < 1 indicates a rate of ADR lower than the rate of market share (safer DOAC). The following DOAC molecules were considered: dabigatran, rivaroxaban, apixaban, and edoxaban. Results: The results showed that rivaroxaban is the DOAC with the lowest RI among the 4 molecules available today in Italy. Conclusions: Based on the RI, we identified rivaroxaban as the DOAC having the best safety profile.The studies analyzed meet the requirements regulatory authorities (e.g., EMA) usually demand of pharmaceutical companies for primary endpoint completion (e.g., assessment of drug safety).

Thromboembolic and Bleeding Risk in Atrial Fibrillation Patients with Chronic Kidney Disease: Role of Anticoagulation Therapy

“…Randomized controlled trials demonstrated that direct oral anticoagulants (DOACs) are not inferior to warfarin for stroke or systemic embolism; however, these studies excluded patients on dialysis, those with an eGFR < 25-30 mL/min and those treated with vitamin K antagonists (VKA) other than warfarin [20][21][22][23][24][25]. Consequently, all data concerning use of DOACs in patients with eGFR < 30 mL/min came from observational studies, and the evidence in favor of DOACs in patients with advanced or ESRD is still very limited [26][27][28][29][30][31]. The aim of this review is to evaluate how treatment with DOACs affects stroke and bleeding outcomes compared with warfarin in a CKD population.…”

Adverse drug reactions with oral anticoagulants: data from sicilian spontaneous reporting system database

“…Other studies reported that elderly people were more affected in both groups 50,51 . As is already reported in the literature, acenocoumarol was associated with the onset of SADRs, while dabigatran was mostly related to non‐SADRs 1,8,52‐57 . Moreover, even though there was a higher proportion of reports with an improved outcome for VKAs, DOAC reports were more associated with ADRs from which patients fully recovered 21,53,58 …”

Direct Oral Anticoagulants: From Randomized Clinical Trials to Real-World Clinical Practice

“…Therefore, despite the overall favorable safety profile, bleeding risk remains a critical issue in the selection of the appropriate oral anticoagulant drug. Indeed, there are no head-to-head studies comparing safety and efficacy of different DOACs, and bearing in mind the differences in clinical trial designs as well as patient characteristics enrolled, definitive conclusions cannot be stated due to numerous biases ( Lavalle et al, 2020 ).…”

“…A sequence symmetry analysis using nationwide data from the French National Healthcare databases has shown, besides the well-known and specific increased bleeding risk, a severe drug-induced liver injury (especially rivaroxaban) and nonbleeding gastrointestinal disorders associated with DOAC treatments ( Maura et al, 2018 ). In contrast, rivaroxaban has demonstrated the best safety profile (lowest ratio between the serious TEAEs rate and the utilization rate of the active principle) in a data analysis from the Italian National Pharmacovigilance Network ( Lavalle et al, 2020 ). In brief, in the whole cohort of 959,231 patients treated with DOACs for several indications, 7,273 have experienced a TEAE, in particular dabigatran 3,342/249,976; rivaroxaban 2,032/317,359; apixaban 1,492/294,721; and edoxaban 407/97,175 (data limited to the biennium 2017–18 for edoxaban).…”

“…In brief, in the whole cohort of 959,231 patients treated with DOACs for several indications, 7,273 have experienced a TEAE, in particular dabigatran 3,342/249,976; rivaroxaban 2,032/317,359; apixaban 1,492/294,721; and edoxaban 407/97,175 (data limited to the biennium 2017–18 for edoxaban). The most common TEAE reported was gastrointestinal disorders (41.2%); to note, 57% were related to gastrointestinal hemorrhages, 8.30% upper abdominal pain, 7.3% rectal hemorrhages, and 5.1% dyspepsia ( Lavalle et al, 2020 ).…”