In this prospective cohort study, our principal findings are as follows: (i) one-third of AF patients met some common RCT exclusion criteria, and thus, these patients would be systematically excluded from RCT participation; (ii) patients who met exclusion criteria in RCTs had a higher risk profile, and greater comorbidities; and (iii) the presence of exclusion criteria was associated with an increased risk of major bleeding, MACE, and mortality, which was even higher per with each additional exclusion criteria.

Stroke prevention with OAC is an essential part of the management of AF [8, 9]. However, there remains a significant proportion of patients in whom the management of OAC is particularly challenging. This may be because many of the studies and clinical trials on OAC established strict inclusion and exclusion criteria, resulting in under-representation of such patients who are usually managed in everyday clinical practice with limited evidence-based support, but leading to uncertainties and lack of information when trying to extrapolate the results of RCTs to everyday clinical practice.

Therefore, although RCTs provide the highest level of scientific evidence, observational studies would supplement the evidence gap in this field. For this reason, there should be an increase in the number of pragmatic clinical trials where participants resemble the less selected populations that would benefit from the treatments and interventions under investigation. In pragmatic trials, inclusion and exclusion criteria should be reduced as much as possible, and both the number of reviews and the completeness of patient follow-up should be increased, given the trends toward more personalized medicine. This approach allows the results of pragmatic trials to closely resemble daily clinical practice [16].

Undoubtedly, the presence of cardiovascular risk factors adds to the clinical complexity and challenges of AF management. Conditions such as thrombocytopenia may indicate the presence of comorbidities associated with poor survival in AF [17], and acts as an independent risk factor for bleeding [18]. There are even additional exclusion criteria beyond those considered in this study. For instance, patients with liver dysfunction were excluded from all RCTs comparing DOACs to warfarin due to their higher risk of both thrombosis and bleeding compared to AF patients without liver disease, thereby creating a significant knowledge gap [19]. Indeed, liver disease and fibrosis have shown to increase the risk of worse clinical outcomes, particularly in VKA users [20,21,22]. Despite the high risk of adverse outcomes in these complex patients, anticoagulation is under-prescribed and discontinuations are common [3]. DOACs offer a better safety and effectiveness profile, but the scientific evidence from RCTs is limited as these patients are less likely to have been included in a clinical trial.

The insights gleaned from post-authorization studies provide several significant benefits for patients undergoing treatment with DOACs. These studies serve as valuable complements to earlier-phase clinical trials, providing additional data on the safety and efficacy of these medications in less restricted scenarios. For example, the ETNA-AF and XANTUS studies confirmed the safety and efficacy of edoxaban and rivaroxaban over warfarin in clinical practice settings. Notably, their findings are even more reassuring than those from their respective pivotal trials. The broader patient profiles observed in these studies suggest a wider applicability of DOACs compared to the more stringent inclusion criteria of phase III trials [23]. Moreover, the comorbidity profiles of patients in these studies closely resemble those in our own research.

We previously demonstrated that everyday clinical practice patients have inherent factors that make them different from patients included in an RCT, and are at a higher risk of adverse events when compared to RCT patients, even if differences are appropriately adjusted using statistical methods [24]. Similarly, a study showed that risk profiles are higher in AF patients included in observational studies compared to patients included in RCTs, and the higher rates of bleeding and mortality not attributable to thromboembolism in these patients suggest that there are additional differences in their characteristics that are important contributors to this difference in event rates [25]. Another recent study showed that in elderly patients with venous thromboembolism, those with ≥ 2 exclusion criteria had a twofold (sHR 2.16, 95% CI 1.38–3.39) increased risk of major bleeding compared to eligible patients, and the bleeding risk increases significantly with the number of exclusion criteria present [26]. On the contrary, Steinberg et al. found that patients treated with OACs and contraindication to anticoagulation had a lower risk of stroke, hospitalization, and death although there was an increased risk of intracranial hemorrhage. In addition, they showed that even in cases of blood dyscrasias and intracranial bleeding, the net clinical benefit was still positive, hence demonstrating that a high risk of bleeding should not be an absolute contraindication to OAC as many of the risk factors for bleeding are also risk factors for stroke [27].

Certainly, many comorbidities, including anemia, thrombocytopenia, renal failure, or uncontrolled hypertension do not represent an absolute contraindication to OAC. Therefore, future RCTs should reduce the number of exclusion criteria so that they can provide a more objective and less restrictive scenario, thus providing a more realistic picture and broadening the generalizability of study results. In parallel, it would be desirable to investigate which specific exclusion criteria are associated with a higher risk of events, in order to design specific studies in such populations.

There are some limitations in relation to this study that should be acknowledged. The main one lies in its observational nature, with a Caucasian-based population and single-center design. Another potential limitation is patient selection because only those patients who initiated VKA therapy were included as this was the only OAC authorized for OAC-naïve patients in Spain. Thus, we need to recognize that our results could not apply to a DOAC-treated population, where the risk of several outcomes could be attenuated by the greater effectiveness and safety of DOACs.

In addition, we acknowledge that the definitions of stroke exclusion criteria are not exactly the same between the four DOAC RCTs (RE-LY: strokes within the previous 14 days were excluded [6 months for severe stroke]; ARISTOTLE: strokes within the previous 7 days were excluded; ROCKET AF: strokes within the previous 14 days were excluded [3 months for severe stroke]; ENGAGE TIMI AF: strokes within the previous 30 days were excluded). Hence, we decided to use the 6 months timing for severe strokes.

Finally, although we included severe frailty condition as a criterion, we did not consider other subjective exclusion criteria such as “the investigator’s opinion that a subject would have an unacceptable risk from study participation, a suboptimal compliance, or any condition precluding successful study completion”. It is therefore likely that the real proportion of non-eligible patients for a RCT would be even higher.