Safety of direct oral anticoagulants in real–world clinical practice: translating the trials to everyday clinical management

ABSTRACT

Introduction: Direct oral anticoagulants (DOACs) may be regarded as some of the most successful innovations in recent times. These drugs which were specifically developed to overcome the challenges posed by warfarin did just that and in the process, have changed the outlook towards stroke prevention with anticoagulation. The decade of experience with these drugs that has resulted in the availability of large scale data on their safety profile has aided this.

Areas covered: This review examines existing real-world studies (RWS) and their interpretation to better appreciate how they either complement or contradict findings from the hallmark trials. Specific focus has been made on the safety of DOACs, on their risks of major bleeding, intra-cranial haemorrhage (ICH), gastro-intestinal (GI) bleeding and all-cause mortality compared to warfarin and each other. DOAC use in the elderly and other sub-groups are briefly discussed.

Expert opinion: Results for safety outcomes according to ‘real world evidence’ (RWE) are in-keeping with randomised controlled trials (RCTs) and currently, all 4 DOACs have been deemed at least as effective as warfarin, while demonstrating superiority in some aspects. While real world studies act as a complementary source of knowledge, traditional RCTs remain the gold standard for determining cause-effect relationships.

KEYWORDS:

• Oral anti-coagulants
• atrial fibrillation
• randomised controlled trials
• DOACs
• safety
• real world evidence
• dabigatran
• rivaroxaban
• apixaban
• edoxaban

Article highlights

• Randomised controlled trials (RCTs) are the gold-standard for inferring cause and effect conclusively.

• Real world evidence (RWE) is beneficial for validating RCT findings. They can be used to identify links and associations but caution is warranted when interpreting their results.

• Complementary data from both RCTs and RWE is required for the implementation of guidelines relevant to the wider population.

• Overall, observational studies evaluating the effects of direct oral anticoagulants (DOACs) have strengthened the findings of the corresponding RCTs. For the standard population, DOACs are relatively safe and are at least as effective as vitamin K antagonists (VKAs), although some drugs have worse profiles for GI bleeding,

• Prior to prescription of DOACs, pre-existing evidence, the properties of each of the drugs and patient characteristics need to be considered to maximise benefits and ensure safety.

This box summarizes key points contained in the article.

Declaration of interest

G Lip is a consultant for Bayer/Janssen, Bristol-Myers Squibb/Pfizer, Medtronic, Boehringer Ingelheim, Novartis, Verseon and

Daiichi-Sankyo. G Lip is also a speaker for Bayer, Bristol-Myers Squibb/Pfizer, Medtronic, Boehringer Ingelheim, and Daiichi-Sankyo. No fees are directly received personally. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded