The objective of this study was to analyse the potential clinical and economic impact of DOAC therapy in ESUS patients proven not to have AF, across multiple international settings. The outcomes of our analyses and simulations show that the use of DOACs in ESUS patients without documented AF may come at an excessive risk of additional bleeds or costs or both, with no clear evidence of providing any benefit. The higher costs associated with additional bleeding events and pharmaceuticals may outweigh possible cost savings associated with reductions in the absolute ischaemic stroke risk, which was found to be orders of magnitude lower than the one observed in the presence of AF. These data provide a potential explanation for the recent NAVIGATE ESUS and RE-SPECT ESUS clinical trial results. The hypotheses driving these studies included that AF was frequently undetected and also that patients without proven AF were at increased risk of (embolic) stroke through other pathways. The former hypothesis was confirmed in CRYSTAL-AF and a recent meta-analysis where one-third of continuously monitored ESUS patients had AF.7,27
The second hypothesis driving the concept of anticoagulation for all ESUS patients was the debate on whether AF is the only or main culprit behind CS/ESUS driven by lack of knowledge of the mechanisms underpinning the relationship between AF and stroke,28 and the role of the left atrial appendage (LAA) as a site of thrombus formation29, especially in CS. Moreover, several other non-AF mechanisms of stroke potentially benefiting from anticoagulation had been proposed including stasis due to an atrial cardiopathy27 and artery-to-artery embolism.30,31
Pre-DOAC-era studies
Prior to the development of the DOACs, numerous studies had shown that warfarin did not reduce embolic strokes in patients without clinically-evident AF.11,12,13 The Warfarin–Aspirin Recurrent Stroke Study (WARSS) in patients with recent non-cardioembolic ischaemic stroke (including 26% with CS) showed no additional benefit over aspirin in preventing recurrent ischaemic stroke or death, while the rate of minor haemorrhagic events was greater with warfarin11. A common criticism of WARSS was that the study’s INR target range of 1.4 to 2.8 included INR values below that considered as therapeutic (typically 2.0-3.0). Whilst it does seem to be case that patients outside the 2.0-3.0 therapeutic range gain less benefit in terms of stroke prevention and suffer more bleeds,32 the Warfarin–Aspirin Symptomatic Intracranial Disease (WASID) trial in patients with stroke or TIA due to intracranial atherosclerotic stenosis also reported no benefit of warfarin in preventing ischaemic stroke, or death, but described higher rates of major haemorrhage despite more accepted INR levels12. However, the hazard ratio for ischaemic stroke risk in WASID was directionally supportive.
Subsequently, the Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction (WARCEF) trial provided additional data in patients with heart failure in sinus rhythm.13 Here also, despite no difference between warfarin and aspirin in the composite primary endpoint of ischaemic stroke, intracerebral haemorrhage, or death, there was a 52% lower rate of ischaemic stroke in the warfarin arm, albeit offset by an increased risk of major haemorrhage. Although the Aortic Arch Related Cerebral Hazard (ARCH) trial33 did not show the same trend, overall, these data hinted at the promise of net clinical benefit in a broad spectrum of patients if bleeding risk could be reduced.
Post-DOAC-era studies
The promising pre-DOAC-era data led to the development of two large studies using dabigatran and rivaroxaban in patients with ESUS. NAVIGATE ESUS20, comparing rivaroxaban to aspirin, was halted early for futility due to a higher risk of bleeding in the rivaroxaban arm and no evidence of efficacy in preventing either the primary efficacy outcome of recurrent stroke or systemic embolism, or secondary efficacy outcomes. The increased risk conferred by rivaroxaban (6.5x that of aspirin for haemorrhagic stroke and 2.34x for life-threatening and major bleeding in general) was higher than found in our modelling, suggesting that the ESUS population may be at higher bleeding risk than the stroke-free populations with underlying AF collated by Tawfik et al.24 Another possible explanation is that because follow-up was incomplete when those findings emerged and the decision was reached to stop the trial, the results may have ultimately been less extreme if more follow-up had accrued. On the other hand, the rates of recurrent ischaemic stroke were identical (4.7%) in the rivaroxaban and aspirin arms. The RE-SPECT ESUS trial21, comparing dabigatran to aspirin, also found no significant reduction in the primary efficacy endpoint of recurrent stroke which was reduced by 16% (rather than the anticipated 30%), but a significant increase in major and CRNM bleeds in the dabigatran arm.
Our analysis of ESUS patients from CRYSTAL-AF7 who were free of AF at 3 years (representing approximately two-thirds of the enrolled ESUS population) showed an annual ischaemic stroke risk of 0.0127 per patient-year, very close to that of the aspirin arm of WARCEF (0.0136 per patient per year). Whereas the control arms of WARSS and WASID had rates of 0.08 and 0.207 ischaemic stroke rates respectively, the aspirin arms of NAVIGATE ESUS and RESPECT-ESUS reported 0.047 per year. There is therefore considerable variability in event rates, implying differences between patients that have not yet been fully explored. Overall however, the data from CRYSTAL-AF suggest that the stroke recurrence rate is very low in the absence of AF, such that the opportunity to reduce stroke via anticoagulation may be limited. Our results demonstrate that DOACs would generally be cost-additive and with the very low rate of stroke, combined with the risk of bleeding, this raises uncertainty on the use of these medications for patients without AF, even if clinical efficacy could be shown.
Personalised care
On the whole, personalised care, if achievable, leads to heightened outcomes compared to imprecise approaches to therapy and our modelling, the data from NAVIGATE-ESUS and RESPECT-ESUS, and recent meta-analysis34 and observational data35 on outcomes in patients with long-term monitoring suggest that this paradigm also holds for anticoagulation in patients with CS. For example, whilst implantable cardiac monitors are a cost-effective tool to diagnose occult AF and guide appropriate treatment in a CS population,22 this approach is likely to be even more effective when focused on subgroups with a high incidence of AF such as ESUS.
Limitations
The most important limitation to this analysis is that our findings are based on a small sample size with relatively limited follow-up and rely on linked evidence about benefits and harms. Furthermore, the ESUS criteria were applied retrospectively to the CRYSTAL-AF population.7 However, the necessary diagnostic information was available to perform this re-classification, as a comprehensive stroke work-up was performed at trial entry.
Due to structural constraints, the model is only able to simulate the risk of up to one recurrent ischaemic stroke event after the original ESUS event. Thus, it is possible that patients could experience multiple ischaemic strokes that could be prevented by anticoagulation, which we have not been able to account for. The influence of this would be to reduce the benefit of the treatment effect of empiric anticoagulation, by underestimating the impact of the hypothetical 30% relative risk reduction. However, with the low observed rate of incident stroke, we expect the actual impact to be small and the direction of our conclusions not to change.