Effects of Clopidogrel Added to Aspirin in Patients with Recent Lacunar Stroke Oscar R. Benavente, University of British Columbia, Vancouver, Canada; Robert G. Hart, Population Health Research Institute, Hamilton, ON, Canada; Leslie A. McClure and Jeffrey M. Szychowski, University of Alabama at Birmingham, Birmingham; Christopher S. Coffey, N Engl J Med 2012;367:817-825 R3 Kim seung min / Prof. Kim Woo-Shik Good morning. The journal that I’m going to present deals with the study about Safety and Efficacy of INCB018424, a JAK1 and JAK2 Inhibitor, in Myelofibrosis My name is ko weonjin, my modulator is prof. 조경삼

Background small subcortical brain infarcts, commonly known as lacunar strokes, constitute about 25% of ischemic strokes This underlying disorder is the most frequent cause of covert brain infarcts and vascular cognitive impairment Lacunar infarcts are a frequent type of stroke caused mainly by cerebral small-vessel disease. The effectiveness of antiplatelet therapy for secondary prevention has not been defined Let me turn a page to introduce background - Myelofibrosis is a Philadelphia chromosome–negative myeloproliferative neoplasm associated with cytopenias, splenomegaly, poor quality of life, and shortened survival - About half of patients with myelofibrosis carry a gain-of-function mutation in the Janus kinase 2 gene that contributes to the pathophysiology of the disease - INCB018424 is a potent and selective JAK1 and JAK2 inhibitor common in elderly persons

Background Aspirin is accepted as standard antiplatelet therapy in patients with lacunar infarcts clopidogrel + aspirin has been shown to reduce the risk of stroke among patients with atrial fibrillation and those with acute coronary syndromes dual antiplatelet therapy has been associated with increased bleeding. The Secondary Prevention of Small Subcortical Strokes (SPS3) trial tested two randomized interventions, in a 2-by-2 factorial design Let me turn a page to introduce background - Myelofibrosis is a Philadelphia chromosome–negative myeloproliferative neoplasm associated with cytopenias, splenomegaly, poor quality of life, and shortened survival - About half of patients with myelofibrosis carry a gain-of-function mutation in the Janus kinase 2 gene that contributes to the pathophysiology of the disease - INCB018424 is a potent and selective JAK1 and JAK2 inhibitor common in elderly persons

Methods SPS3 was a randomized, multicenter clinical trial 82 clinical centers in North America, Latin America, and Spain double-blind, multicenter trial involving 3020 patients Recent symptomatic lacunar infarcts identified by magnetic resonance imaging. clopidogrel (75mg) + aspirin (35mg) VS placebo + aspirin (35mg) The primary outcome  recurrent stroke (ischemic stroke and intracranial hemorrhage) Let me show you the Method Patients 18 years of age or older with primary myelofibrosis were eligible for enrollment if they required therapy Additional eligibility criteria included ECOG performance status of 2 or less

Selection of Patients 30 years of age or older symptomatic lacunar stroke within the preceding 180 days not surgically amenable ipsilateral carotid artery disease Not cardio-embolic sources of stroke. meet MRI criteria lesion measuring 2.0 cm or less in diameter on DWI recent or remote cortical infarct, a large subcortical infarct , history of intracerebral hemorrhage were excluded Let me show you the Method Patients 18 years of age or older with primary myelofibrosis were eligible for enrollment if they required therapy Additional eligibility criteria included ECOG performance status of 2 or less

outcome primary hypothesis clopidogrel + aspirin would be superior to aspirin alone in reducing the primary outcome of stroke recurrence ? (ischemic stroke or intracranial hemorrhage) Ischemic stroke focal neurologic deficit of sudden onset persisting for >24 hours, without evidence of hemorrhage Secondary outcomes (acute myocardial infarction and death) vascular, nonvascular, or unknown cause. The primary safety outcome was major extracranial hemorrhage, they conducted a phase 1−2 trial in patients with JAK2 V617F−positive or JAK2 −negative primary myelofibrosis Patients were followed for a median of 14.7 months.

Result Now I’m going to show you some tables ,figures which is related results..

Between 2003 and 2011, a total of 3020 patients were enrolled in the study: 1503 in the group treated with aspirin plus placebo and 1517 in the group treated with aspirin plus clopidogrel. A total of 1960 of the participants (65%) were from North America, 694 (23%) from Latin America, and 366 (12%) from Spain. Participants had been followed for a mean of 3.4 years (range, 0 to 8.2) at the time of termination of the antiplatelet component of the study in August 2011 (see Fig. S1 in the Supplementary Appendix, available at NEJM.org)

The starting dose was 25 mg twice daily followed by escalation to 50 mg twice daily. Subsequently, once-daily doses were also evaluated, from 25 mg up to 200 mg once daily. In the phase 2 part of the study with defined enrollment targets and additional evaluations To identify an effective dosing schedule with a reduced incidence of thrombocytopenia. 25 mg twice daily, with a reduction to 10 mg twice daily after two cycles of therapy; 10 mg twice daily, with allowance for dose escalation after three cycles with allowance for dose increases up to 25 mg twice daily,

The starting dose was 25 mg twice daily followed by escalation to 50 mg twice daily. Subsequently, once-daily doses were also evaluated, from 25 mg up to 200 mg once daily. In the phase 2 part of the study with defined enrollment targets and additional evaluations To identify an effective dosing schedule with a reduced incidence of thrombocytopenia. 25 mg twice daily, with a reduction to 10 mg twice daily after two cycles of therapy; 10 mg twice daily, with allowance for dose escalation after three cycles with allowance for dose increases up to 25 mg twice daily,

The starting dose was 25 mg twice daily followed by escalation to 50 mg twice daily. Subsequently, once-daily doses were also evaluated, from 25 mg up to 200 mg once daily. In the phase 2 part of the study with defined enrollment targets and additional evaluations To identify an effective dosing schedule with a reduced incidence of thrombocytopenia. 25 mg twice daily, with a reduction to 10 mg twice daily after two cycles of therapy; 10 mg twice daily, with allowance for dose escalation after three cycles with allowance for dose increases up to 25 mg twice daily,

The starting dose was 25 mg twice daily followed by escalation to 50 mg twice daily. Subsequently, once-daily doses were also evaluated, from 25 mg up to 200 mg once daily. In the phase 2 part of the study with defined enrollment targets and additional evaluations To identify an effective dosing schedule with a reduced incidence of thrombocytopenia. 25 mg twice daily, with a reduction to 10 mg twice daily after two cycles of therapy; 10 mg twice daily, with allowance for dose escalation after three cycles with allowance for dose increases up to 25 mg twice daily,

Conclusion the addition of clopidogrel to aspirin did not significantly reduce the risk of recurrent stroke among patients with recent lacunar strokes the addition of clopidogrel to aspirin did significantly increase the risk of bleeding and death among patients with recent lacunar strokes A post hoc subgroup analysis showed that the proportion of patients with a response in the pooled groups of patients who received 15 mg and 25 mg was similar among the 61 patients