Adverse events associated with the use of direct-acting oral anticoagulants in clinical practice: beyond bleeding complications

Abstract

Non-vitamin K oral anticoagulants, also known as direct-acting oral anticoagulants (DOACs), have entered the market in 2008 with the expected breakthrough potential of circumventing limitations related to treatment with vitamin K antagonists (eg, warfarin) by virtue of their pharmacological properties. Although data derived from premarketing randomized clinical trials have largely demonstrated the clinical benefit of DOACs, especially in terms of reduced risk of intracranial bleeding, it is important to monitor the safety in the postmarketing phase, which better reflects real-world patients with comorbidities and polypharmacotherapy, in order to assess the actual risk-benefit profile. In this critical review, we aimed to evaluate the evidence on the latest debated safety issues. In the first section, we will discuss: 1) the need for pharmacovigilance (ie, the science and activities relating to the detection, assessment, understanding, and prevention of adverse effects or any other drug-related problems in the real-world setting), and 2) the importance of properly interpreting postmarketing data to avoid unnecessary alarm. In the second section, emerging and debated safety issues potentially associated with the use of DOACs in the postmarketing setting will be assessed: 1) the potential coronary risk (which emerged during the preapproval period); 2) the occurrence of liver injury (a risk undetected in clinical trials and highlighted by case reports or series); and 3) the potential for renal damage (a still unclear safety issue). It is anticipated that hepatic and renal issues still require dedicated postauthorization safety studies to ultimately assess causality.

Risk–Benefit Profile of Direct-Acting Oral Anticoagulants in Established Therapeutic Indications: An Overview of Systematic Reviews and Observational Studies

“…As expected, our review did not identify these rare safety signals. A recent literature review, comprising case reports, concluded that, while the coronary risk (described for dabigatran) is not supported by a critical evaluation of the evidence, the unpredictable occurrence of liver injury and the potential for renal damage warrant a more precise characterization and call for awareness by clinicians (see below) [80]. …”

“…However, the time to onset from published case reports suggests that early evaluation of hepatic enzymes (i.e. within the first month) may be considered, at least in patients under complex treatment regimens with comorbidities; subsequently, liver function can be monitored on a yearly basis [80]. Therefore, vigilance should be maintained by both clinicians, pharmacovigilance experts and patients, who should timely communicate early clinical signs/symptoms, consider on a case-by-case basis the role of DOACs as well as concomitant therapies, and report suspect cases to the national pharmacovigilance services [99].…”

Liver injury with direct-acting anticoagulants: has the fog cleared?

“…We encourage additional observational studies to replicate these findings, especially in different contexts, such as the European scenario and in patients with venous thromboembolism, who might be more prone to develop liver injury 3. Hopefully, collaborative multidisciplinary consortia will fill the mechanistic and clinical gaps to establish actual drug–event relationship and support risk stratification.…”

Drug-induced liver injury: Towards early prediction and risk stratification

“…The majority of data are derived from case reports/series, which emphasized the relatively rapid time-to-onset and the concomitant reporting of drug that are implicated in liver damage or have the potential to result in drug interactions[39]. In particular, the time-to-onset from published case reports suggests that early evaluation of hepatic enzymes ( i.e ., within the first month) may be considered at least in patients under complex treatment regimen with comorbidities; subsequently, liver function can be monitored on a yearly basis[40]. This is especially the case of rivaroxaban, for which a probable but unquantified association is likely to exist.…”

“…However, among DOACs, it is difficult to discriminate the agent with the highest risk, keeping in mind that post-marketing data have reported rivaroxaban to be most likely associated with DILI[40]. Therefore, these data suggested that current performance of this risk stratification tool is still suboptimal.…”