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

Abstract

Since 2008, the direct-acting oral anticoagulants (DOACs) have expanded the therapeutic options of cardiovascular diseases with recognized clinical and epidemiological impact, such as non-valvular atrial fibrillation (NVAF) and venous thromboembolism (VTE), and also in the preventive setting of orthopedic surgical patients. The large body of evidence, not only from pivotal clinical trials but also from ‘real-world’ postmarketing observational findings (e.g. analytical epidemiological studies and registry data) gathered to date allow for a first attempt at verifying a posteriori whether or not the pharmacological advantages of the DOACs actually translate into therapeutic innovation, with relevant implications for clinicians, regulators and patients. This review aims to synthesize the risk–benefit profile of DOACs in the aforementioned consolidated indications through an ‘evidence summary’ approach gathering the existent evidence-based data, particularly systematic reviews with meta-analyses of randomized controlled trials, as well as observational studies, comparing DOACs with vitamin K antagonists. Clinical evidence will be discussed and compared with major international guidelines to identify whether an update is needed. Controversial clinically relevant safety issues will be also examined in order to highlight current challenges and unsettled questions (e.g. actual bleeding risk in susceptible populations). It is anticipated that the large number of publications on NVAF or VTE (44 systematic reviews with meta-analyses and 12 observational studies retained in our analysis) suggests the potential existence of overlapping studies and calls for common criteria to qualitatively and quantitatively assess discordances, thus guiding future research.Electronic supplementary materialThe online version of this article (doi:10.1007/s40264-016-0464-3) contains supplementary material, which is available to authorized users.

Pharmacological profile of non-vitamin K antagonist oral anticoagulants

“…Meta-analyzes with up to 50,578 patients using NOACs showed reduction of stroke, intracranial hemorrhage and mortality, but there was a higher gastrointestinal bleeding rate compared to the group using warfarin (Miller et al, 2012;Capodanno et al, 2013;Ruff et al, 2014). Recent systematic review, including meta-analyzes and observational studies, with overlapping studies, comparing patients on NOACs and those using warfarin, for the consolidated indications (non-valvular AF and deep venous thrombosis/pulmonary thromboembolism), showed results similar to those described above (Raschi et al, 2016). Post-marketing studies are non-randomized, retrospective studies, but reflect the real-world clinical practice.…”

Non-bleeding Adverse Events with the Use of Direct Oral Anticoagulants: A Sequence Symmetry Analysis

“…The relative safety of DOACs versus warfarin in non-valvular AF patients [ 9 – 11 ], or versus heparin in the treatment and prevention of recurrence of venous thromboembolism [ 12 – 14 ], has been demonstrated in large-scale randomized clinical trials (RCTs), and has been confirmed globally by observational studies [ 15 , 16 ]; however, both clinical trials and observational studies have mainly focussed on bleeding adverse events to date [ 17 ]. Postmarketing data, including pharmacovigilance reports [ 18 ] and case reports, have raised concerns about other, albeit rarer, non-bleeding adverse events that could not be detected by RCTs due to intrinsic limitations, such as small sample size and short follow-up.…”

Management of venous thromboembolism with non–vitamin K oral anticoagulants: A review for nurse practitioners and pharmacists

“…VKAs have also been the cornerstone for long-term prevention of recurrent VTE (Kearon et al, 2012). However, recent evidence suggests that non-vitamin K oral anticoagulants (NOACs), including apixaban, dabigatran, edoxaban, and rivaroxaban, may offer an improved benefitrisk profile than VKAs for patients with VTE (Raschi, Bianchin, Ageno, De Ponti, & De Ponti, 2016). A new entrant to the NOAC therapeutics class is betrixaban, which was recently approved for VTE prophylaxis in adult patients with acute illness.…”