LAUSR

In Response: We thank Gutierrez and Wu et al for their interest in our study regarding dual antiplatelet therapy in progressive lacunar strokes and welcome the opportunity to clarify some of the questions in their correspondences, which we were not able to address within the Brief Report because of its short format. Both letters commented on the exclusion of patients with evidence of extraor intracranial stenosis in view of potential bias regarding various degrees of stenosis and heterogeneous physiopathology of lacunar strokes including large artery disease in some cases. The aim of our study was not to evaluate the efficacy of dual antiplatelet therapy (DAPT) in the entire stroke population. In our institution it is standard of care for many years to treat patients with severe intracranial stenosis with DAPT, and to operate or stent patients with extracranial symptomatic stenosis very soon. Our aim was to specially look for patients with presumable microangiopathic lacunar strokes. Therefore, we intentionally excluded patients with any relevant extraor intracranial carotid stenosis from our analysis to minimize the bias of DAPT efficacy attributed to potential effects on carotid stenosis. Still, effects on arteriosclerosis of small vessels might play a role for efficacy of DAPT especially as treatment with systemic thrombolysis did not prevent the occurrence of early neurological deterioration (END), implying that vessel occlusion might not be the main pathomechanism for progressive lacunar strokes. Although further insights into pathomechanisms of progressive lacunar strokes are important to understand and potentially even prevent the occurrence of END, we did not further focus on this question by, for example analyzing changes in diameter of ischemic lesion before and after END within the Brief Report. Regarding the time point of initiation of DAPT in patients with prior systemic thrombolysis, 9 of the 17 patients (53%) received DAPT within 24 hours after administration of systemic thrombolysis and further 2 patients exactly after 24 hours. As none of these patients experienced symptomatic intracerebral bleeding complications, early initiation of DAPT after administration of systemic thrombolysis was safe and resulted in improvement of functional outcome (primary end point) and reduction of further clinical fluctuation (secondary end point) in 10 of the 11 patients. Further comments of Gutierrez and Wu et al refer to the performance of analysis and limitations of the retrospective study. Regarding the decisions of initiation of DAPT or not, our institutional standard operating procedures recommend the initiation of DAPT in patients with progressive lacunar strokes. However, as no data about efficacy of DAPT in these patients existed to date, the initiation was not mandatory and therefore based on individual decisions of treating physicians. As mentioned in the limitations of the study, reasons for individual treatment decisions were retrospectively not determinable, but patients with objective contraindications against DAPT were excluded from the study. In addition, there was no mandatory loading dose for clopidogrel. Therefore, clopidogrel was administered in different starting doses of 300 mg in 51 patients, 600 mg in 5 patients, and 75 mg in 37 patients. Four patients received clopidogrel as single antiplatelet treatment before admission and were additionally treated with aspirin after END occurred. Primary end point was fulfilled in 34 (61%) of the 56 patients with a loading dose of 300 to 600 mg clopidogrel and in 30 (81%) of the 37 patients with an initial clopidogrel dose of 75 mg. Based on these numbers, the overall efficacy of DAPT seemed not to be hampered by the shortly delayed onset of efficacy due to the lower initial clopidogrel dose. Wu et al stated that the part of the definition of END based on description of fluctuating clinical symptoms in medical reports may be subjective and introduce bias to the study. We were aware of this limitation but decided to keep this part of the definition to include also patients with fluctuating clinical symptoms, which might not well be reflected by the National Institutes of Health Stroke Scale score such as the fluctuation of distal arm paresis. Although including these patients might introduce bias to the study, excluding these patients due to limitations of National Institutes of Health Stroke Scale scoring might do the same. Furthermore, it was questioned if lacunar infarction can be clearly detected in patients receiving only computed tomographic scan as neuroimaging. Here, these patients received either follow-up computed tomography scan clearly demonstrating lacunar infarction, or primary computed tomography imaging was performed late enough after clinical onset to detect lacunar stroke. Finally, we demonstrated that DAPT initiated after END was associated with improved functional outcomes and no observed increased risk for symptomatic intracerebral bleeding in patients with progressive lacunar strokes including those patients with early neurological deterioration after treatment with systemic thrombolysis. We agree with the authors of the letters that the results need further testing in randomized trials, and further studies on pathomechanisms and potential risk factors would be helpful for early identification of patients with a high risk for early neurological deterioration.