Discussion
The primary finding of the prospective, observational HEBRAS study is that enhanced diagnostic workup significantly improves the detection of pathological findings after AIS, proving the prespecified study hypothesis. Taken together, application of CMR and prolonged Holter-monitoring (in-hospital and up to 5 days after discharge vs routine monitoring in-hospital) increased the rate of prespecified pathological findings relevant to stroke aetiology by 17%. Subsequently, enhanced diagnostic workup led to a significant decrease of patients with AIS diagnosed with cryptogenic stroke according to TOAST criteria at hospital discharge.
In HEBRAS, CMR could be performed in 82% of the included patients who had a stroke, which is well in line with previously reported rates.14 CMR was able to detect more cardiac pathologies such as intracardiac thrombi or tumours, and revealed a higher rate of akinetic myocardial segments compared with routine diagnostic care. However, we cannot draw definite conclusions on implications for improved secondary stroke prevention. Future trials are needed to investigate a possible therapeutic relevance of an enhanced diagnostic approach. Moreover, assessing LVEF by CMR analysis found a significantly higher rate of reduced LVEF both according to the definition of the study protocol (LVEF <45%) and to define ESUS (<30%).18 Indeed, a reduced LVEF was the most frequent pathological finding using CMR (online supplemental table 3). It has been shown that both the presence of akinetic myocardial segments as well as reduced LVEF promotes intracardiac thrombus formation.22 However, there is no clear recommendation on the therapeutic consequences of these conditions in the absence of thrombus or AF.23 This might change in the future, as a subgroup analysis of the NAVIGATE ESUS trial found rivaroxaban to be superior to acetylsalicylic acid in reducing the risk of recurrent stroke or systemic embolism.24 Nevertheless, identification of an akinetic myocardial segment and/or reduced LVEF may already have therapeutic consequences in terms of additional diagnostics (ie, coronary angiography) or change of medication.25 From our perspective, the HEBRAS findings support the notion to consider advanced cardiac imaging like CMR in selected patients with stroke or TIA due to presumed cardioembolism and no identifiable cardioembolic source after routine diagnostic care.
In our analysis, the detection rate of a first AF episode in patients with AIS was more than doubled by the study-specific prolonged Holter-ECG monitoring. In detail, the study-specific Holter-ECG led to an absolute increase in AF detection after stroke of 2.5%. This is in line with the randomised MonDAFIS trial, which demonstrated an absolute increase in AF detection of 1.8% by prolonged Holter-monitoring in-hospital compared with routine monitoring.16 Notably, all first episodes of AF were detected by the study-specific Holter-ECG during the in-hospital stay. Therefore, one might argue that the more thorough the search for AF is performed in-hospital, the less likely might be an additional diagnostic benefit of out-of-hospital rhythm monitoring after AIS.
From a pathophysiological perspective, early assessment and better understanding of stroke aetiology may improve secondary stroke prevention and thereby help to reduce the rate of stroke recurrence. Overall, exclusive findings of HEBRAS would have warranted changes in antithrombotic medication (ie, indication for oral anticoagulation (OAC)) in accordance with current guidelines in 13 (3.7%) patients (due to detection of AF or intracardiac thrombi) and an intensified LDL target in one patient (due to a severe aortic plaque). Regarding AF, we are unable to answer the question whether AF first detected after the index stroke was causal for the index stroke, was present but unnoticed before the stroke or was induced by the index stroke itself.5 26 27 Whether or not enhanced diagnostic workup would translate into improved secondary stroke prevention and subsequent reduction of stroke recurrence was not an aim of the HEBRAS study,18 and deserves further investigation in a large prospective multicentre trial.
Of note, the proportion of patients with AIS classified as ‘competing aetiology’ increased following the enhanced workup in the HEBRAS study, as an additional stroke aetiology was identified in patients who had a stroke already diagnosed with a definite aetiology following routine diagnostic care. It has been repeatedly pointed out that the original TOAST classification comprises three very heterogeneous groups of patients with cryptogenic stroke, namely those with incomplete diagnostics, those with more than one identified cause of stroke and those with no identified cause despite complete investigation.2 28 Therefore, we differentiated between cryptogenic strokes with competing aetiology and cryptogenic strokes without an identified cause.
The following limitations have to be addressed and might mitigate the validity of our results. First, our findings cannot be generalised to all patients with AIS, as patients unable to provide informed consent or patients with previously detected AF were excluded. This indicates a selection bias and might have resulted in the inclusion of younger, less severely affected patients who had a stroke. In addition, 18% of all study participants did not receive CMR. Second, with a median time of 30 hours from hospital admission to the start of the study-specific Holter-ECG, there is a chance that we might have missed the diagnosis of AF in some patients. Third, not all study patients underwent TTE and/or TEE and we cannot exclude a respective selection bias. However, this reflects routine diagnostic care in clinical practice, even in developed countries with a nationwide stroke unit system like Germany.7 8 29 Notably, neither stroke unit certification requirements according to the German nor the European Stroke Organisation include specific recommendations on the use of echocardiography.30 31 Fourth, one might argue that the chosen LVEF threshold (<45% or even <30%) defining a high-risk cardioembolic source is debatable in the absence of a cardiac thrombus.32 Based on a risk model including history of ischaemic stroke, a recent meta-analysis including >20 000 heart failure patients with reduced LVEF and sinus rhythm identified a subgroup of patients with a similar stroke risk to AF patients without OAC.33 Nevertheless, there are no randomised controlled trials demonstrating a benefit of OAC in this population. The same holds true for left ventricular akinetic segments, despite the fact that this finding goes along with a higher chance of thrombus formation.34 However, the recently updated German guidelines on secondary stroke prevention recommend to consider OAC instead of antiplatelet therapy in patients who had an ischaemic stroke with an LVEF <35% and sinus rhythm.35 The relevance of an interatrial septal abnormality for secondary stroke prevention was low at the time the HEBRAS study was designed, as randomised controlled trials (like CLOSURE I, PC trial and RESPECT PFO) did not demonstrate a significant reduction of stroke recurrence in PFO patients and otherwise cryptogenic stroke.36 According to current guidelines, PFO closure should be considered in patients 18–60 years who do not have another identifiable cause of stroke after comprehensive workup. Therefore, TTE is essential in these patients.37 Fifth, besides feasibility, timing and cost-effectiveness are major considerations for CMR.12 14 Prolonged non-invasive ambulatory ECG monitoring for 14 as well as 30 days after cryptogenic stroke was estimated to be highly cost-effective based on data from the EMBRACE trial.38 However, as a cost–benefit analysis was not aim of the HEBRAS study, it is very difficult to draw definitive conclusions on that matter. To the best of our knowledge, no such analysis has been performed on the use of CMR in patients who had a stroke. CMR may be cost-effective in patients with AIS undergoing brain MRI and CMR immediately afterwards, subsequently shortening the in-hospital stay after AIS. Additionally, CMR might be reasonable in a subset of patients with AIS with a high presumed risk of cardioembolic stroke or (undetected) coronary heart disease.