Efficacy of Clopidogrel for Prevention of Stroke Based on CYP2C19 Allele Status in the POINT Trial.

BACKGROUND AND PURPOSE: Clopidogrel is an antiplatelet drug that is metabolized to its active form by the CYP2C19 enzyme. The CHANCE trial (Clopidogrel in High-Risk Patients With Acute Nondisabling Cerebrovascular Events) found a significant interaction between loss-of-function allele status for the CYP2C19 gene and the effect of dual antiplatelet therapy with aspirin and clopidogrel on the rate of early recurrent stroke following acute transient ischemic attack/minor stroke. The POINT (Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke Trial), similar in design to CHANCE but performed largely in North America and Europe, demonstrated a reduction in early recurrent stroke with dual antiplatelet therapy compared with aspirin alone. This substudy was done to evaluate a potential interaction between loss-of-function CYP2C19 alleles and outcome by treatment group in POINT. METHODS: Of the 269 sites in 10 countries that enrolled patients in POINT, 134 sites participated in this substudy. DNA samples were genotyped for CYP2C19 *2, *3, and *17 alleles and classified as being carriers or noncarriers of loss-of-function alleles. Major ischemia consisted of ischemic stroke, myocardial infarction, or ischemic vascular death. RESULTS: Nine hundred thirty-two patients provided analyzable DNA. The rates of major ischemia were 6.7% for the aspirin group versus 2.3% for the dual antiplatelet therapy group (hazard ratio, 0.33 [95% CI, 0.09-1.21]; P=0.09) among carriers of loss-of-function allele. The rates of major ischemia were 5.6% for the aspirin group versus 3.7% for the dual antiplatelet therapy group (hazard ratio, 0.65 [95% CI, 0.32-1.34]; P=0.25) among noncarriers. There was no significant interaction by genotype for major ischemia (P=0.36) or stroke (P=0.33). CONCLUSIONS: This substudy of POINT found no significant interaction with CYP2C19 loss-of-function carrier status and outcome by treatment group. Failure to confirm the findings from the CHANCE trial may be because the loss-of-function alleles tested are not clinically important in this context or because the 2 trials had differences in racial/ethnic composition. Additionally, differences between the 2 trials might be due to chance as our statistical power was limited to 50%. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00991029.

Intravenous Thrombolysis for Acute Ischemic Stroke in Patients with Thrombocytopenia.

OBJECTIVE: To determine the safety of intravenous (IV) recombinant tissue plasminogen activator (rtPA) in patients with acute ischemic stroke (AIS) who had a platelet count <100,000 /mm3. METHODS: We reviewed the charts of all patients who received IV rtPA for AIS during a 9.6-year period at our stroke center. Those with platelets <100,000/mm3 were identified. Head computed tomography scans performed in 24-36 hours postthrombolysis were reviewed to evaluate the rate of symptomatic intracranial hemorrhage (sICH). RESULTS: A total of 835 patients received IV rtPA for AIS during this period. A total of 5 patients were identified to have a platelet count <100,000/mm3. One of them (20%) developed sICH post-IV tPA administration .The mean platelet count of those 5 patients was 63,000 ± 19,000/mm3. To the best of our knowledge, only 21 thrombocytopenic patients have been reported to receive IV rtPA for AIS in the medical literature. Combining our 5 cases with 21 patients previously reported, we have 26 AIS patients who had a platelet count <100,000/mm3 and received IV rtPA, with 2 of them developing sICH (7.7 %). Comparing the rate of sICH among this group with the patients with normal platelet count in our cohort, there was no statistically significant difference (7.7% versus 6.04%, P value = .73). CONCLUSION: IV rtPA for AIS might be safe in patients with platelet count <100,000/mm3 and it is reasonable not to delay IV rtPA administration while waiting for the platelet count result, unless there is strong suspicion for abnormal platelet count.

Relationship between Inflammation and Aspirin and Clopidogrel Antiplatelet Responses in Acute Ischemic Stroke.

OBJECTIVE: We measured serum levels of proinflammatory/prothrombotic markers P-selectin, CD40L, matrix metalloproteinase 9 (MMP-9), intracellular adhesion molecule 1 (ICAM-1), and interleukin (IL)-6 in ischemic stroke patients, correlating their levels with the results of aspirin (ASA) and clopidogrel antiplatelet responses, using 3 "point of care" platelet function instruments, thromboelastograph (TEG), Accumetrics (ACU), and impedance aggregometer (IMP). METHODS: Patients on chronic ASA regimen at the time of stroke were switched to 300 mg clopidogrel loading dose and 75 mg clopidogrel maintenance dose. Serum levels of the aforementioned inflammatory mediators were measured in 51 patients at baseline (on ASA regimen), and at 26 ± 5 hours and 64 ± 18 hours postclopidogrel administration by enzyme-linked immunosorbent assay. RESULTS: P-selectin, CD40L, and MMP-9 serum levels were reduced; ICAM-1 and IL-6 serum levels showed no difference postclopidogrel administration relative to baseline. Patients' stratification based on ASA dose showed more significant reductions in P-selectin, CD40L, and MMP-9 serum levels postclopidogrel administration in patients who were on baseline 81 mg ASA, as compared to patients on 325 mg ASA. Measurement with TEG was sensitive for correlating ASA antiplatelet responses to serum levels of inflammatory markers, whereas measurements with ACU and IMP were sensitive for correlating clopidogrel antiplatelet responses to serum levels of inflammatory markers. CONCLUSION: Clopidogrel exerts both platelet-dependent and platelet-independent anti-inflammatory effects. The association between platelet function and inflammation depends on the platelet function analyzer, the type of antiplatelet agent, the nature of the inflammatory marker, and the time of measurement relative to the time of drug administration.

Prior Asymptomatic Parenchymal Hemorrhage Does Not Increase the Risk for Intracranial Hemorrhage after Intravenous Thrombolysis.

BACKGROUND: The NINDS trial demonstrated the efficacy of intravenous (IV) recombinant tissue plasminogen activator (rtPA) in improving the neurologic outcome in patients presenting with acute ischemic strokes. Patients who had a prior history of intracranial hemorrhage (ICH) were excluded from this trial, possibly due to a hypothetical increase in the subsequent bleeding risk. Thus, there is little data available, whether against or in favor of, the use of IV rtPA in patients with prior ICH. We aim to aid in determining the safety of IV rtPA in such patients through a retrospective hospital-based single center study. METHODS: We reviewed the brain imaging of all patients who received IV rtPA at our comprehensive stroke center from January 2006 to April 2014 for evidence of prior ICH at the time of IV rtPA administration. Their outcomes were determined in terms of subsequent development of symptomatic ICH as defined by the NINDS trial. RESULTS: Brain imaging for 640 patients was reviewed. A total of 27 patients showed evidence of prior ICH at the time of IV thrombolysis, all intra-parenchymal. Only 1 patient (3.7%) developed subsequent symptomatic ICH after the administration of IV rtPA. Of the remaining 613 patients who received IV rtPA, 25 patients (4.1%) developed symptomatic ICH. CONCLUSION: This retrospective study provides Level C evidence that patients with imaging evidence of prior asymptomatic intra-parenchymal hemorrhage presenting with an acute ischemic stroke do not show an increased risk of developing symptomatic ICH after IV thrombolysis.

Clopidogrel responsiveness in stroke patients on a chronic aspirin regimen.

This study evaluated the antiplatelet effects of clopidogrel (CPG) in patients sustaining acute ischemic stroke who were already receiving chronic outpatient aspirin therapy (81-325 mg/day). Platelet function was measured using 3 different "point-of-care" platelet function analyzers: the Thrombelastograph hemostasis system, the Accumetrics VerifyNow system, and the Chronolog 570VS impedance aggregometer. Platelet function was assessed before administration of a 300-mg CPG loading dose and again at 26 hours and 64 hours after this loading dose along with a 75-mg daily maintenance dose. All 3 instruments detected marked inhibition of platelet function at 26 hours and 64 hours after CPG administration. There were significant variations among the 3 instruments in monitoring antiplatelet responses to aspirin and CPG; however, these variations were eliminated when the platelet function results were corrected for baseline platelet variability. The percentage of patients who were poor responders to CPG after switching from aspirin depended on the measurement instrument used, but was higher at 26 hours after CPG administration than at 64 hours after CPG administration. Our findings indicate that poor response to antiplatelet agents in general, and to CPG in particular, is a function of the measuring instrument. The correction for baseline platelet variability results in similar levels of platelet inhibition measured by the 3 platelet function analyzers. Future studies are warranted to examine the association between ex vivo CPG-induced platelet inhibition and clinical outcomes in patients with ischemic stroke.

Long-term functional and neurocognitive recovery in patients who had an acute cerebrovascular event secondary to catheter ablation for atrial fibrillation.

INTRODUCTION: Cerebral thromboembolic event (CTE) is a possible complication of pulmonary vein antrum isolation (PVAI). The objective of this study was to report long-term functional and neurocognitive recovery in patients who had a CTE during or within 48 hours of catheter ablation. METHODS AND RESULTS: We screened 3,060 patients who underwent PVAI between January 2000 and June 2007. Out the 3,060 patients, 26 patients (0.8%) (61 +/- 8 years, 88% males) had a CTE during or within 48 hours of the procedure. We followed these 26 patients (study group) over time and assessed their functional and neurocognitive recovery status. No preferential vascular territory for the site of obstruction was found; right anterior circulation-5 patients (26%), left anterior circulation-5 patients (26%), posterior circulation-3 patients (16%), and 2 or more territories-6 patients (32%), (P-value = 0.8). The average international normalized ratio at the time of CTE was 1.33 +/- 0.4. Two patients died during the study period. At the end of 38.4 +/- 24 months follow-up, most surviving patients had complete neurocognitive and functional recovery irrespective of the severity of periprocedural stroke. CONCLUSIONS: Periprocedural stroke in the setting of catheter ablation for atrial fibrillation is relatively rare. When it occurs, complete functional and neurocognitive recovery over time is the likely outcome for most patients.

Delays in door-to-needle time for acute ischemic stroke in the emergency department: A comprehensive stroke center experience.

BACKGROUND: Current American Stroke Association guidelines recommend initiating intravenous thrombolysis (IVT) for acute ischemic stroke (AIS) within 60min of patient arrival, given the benefits of IVT for AIS are time dependent. This study aimed to identify the delaying factors in door-to-needle time (DTN) in the emergency department of one of the largest comprehensive stroke centers in New York State. We also recommended measures to reduce the delays. METHODS: We retrospectively reviewed the medical charts of all AIS patients who received IVT in our emergency department patients between April 1, 2012 and December 31, 2015 to identify those with a DTN time of >60min. We categorized the factors causing the delay into different groups. For each group, we recommended measures to reduce the treatment delays. RESULTS: A total of 487 patients received IVT for AIS during the 3.7-year period. Of these, 96 patients (20.4%) met our DTN time delay criteria. Delays for obtaining stroke imaging and hypertension control were the most common factors. Thirty eight patients (39.5%) had delay in obtaining CT-based stroke imaging. Twenty-two patients (22.9%) required control of elevated blood pressure prior to IVT. Other causes for delay in DTN time included delay in stroke triage and paging (11.4%), fluctuating neurological symptoms (7.2%), uncertainty about diagnosis (12.5%), delays associated with obtaining consent (9.3%), and uncertainty about the time of symptom onset (5.2%). CONCLUSION: Important and common causes of delay in IVT for AIS were identified in a review of charts at our comprehensive stroke center. The authors recommend strategies to achieve faster DTN time for each of the delaying factor categories including faster acquisition and interpretation of stroke imaging, more effective triage protocols and faster blood pressure control for AIS patients who are eligible for IVT.

Is acute reperfusion therapy safe in acute ischemic stroke patients who harbor unruptured intracranial aneurysm?

BACKGROUND: Intracranial aneurysms are currently considered as contraindication for intravenous thrombolysis in acute ischemic stroke, very likely due to a possible increase in the risk of bleeding from aneurysm rupture; however, there is limited data available on whether intravenous thrombolysis is safe for acute ischemic stroke patients with pre-existing intracranial aneurysms. AIMS AND/OR HYPOTHESIS: To find out the safety of intravenous thrombolysis in acute ischemic stroke patients who harbor unruptured intracranial aneurysms. METHODS: We retrospectively reviewed the medical records and cerebrovascular images of all the patients treated with intravenous thrombolysis for acute ischemic stroke in our center from the beginning of 2006 till the end of April 2014. Those with unruptured intracranial aneurysm present on cerebrovascular images prior to acute reperfusion therapy were identified. Post-thrombolysis brain imaging was reviewed to evaluate for any intraparenchymal or subarachnoid hemorrhage related or unrelated to the aneurysm. RESULTS: A total of 637 patients received intravenous thrombolysis for acute ischemic stroke in our center during an 8·3-year period. Thirty-three (5·2%) were found to have at least one intracranial aneurysms. Twenty-three (70%) of those received only intravenous thrombolysis, and 10 patients received combination of intravenous and intra-arterial thrombolysis. The size of the largest aneurysm was 10 mm in maximum diameter (range: 2-10 mm). The mean size of aneurysms was 4·8 mm. No symptomatic intracranial hemorrhage occurred among the 23 patients receiving only intravenous thrombolysis. Out of those who received a combination of intravenous and intra-arterial thrombolysis, one developed symptomatic intracranial hemorrhage in the location of acute infarct, distant to the aneurysm location. CONCLUSION: Our findings suggest that neither intravenous thrombolysis nor combination of intravenous and intra-arterial thrombolysis increases the risk of aneurysmal hemorrhage in acute ischemic stroke patients who harbor unruptured intracranial aneurysms less than 10 mm in diameter. Their listing in exclusion criteria for intravenous thrombolysis should be reconsidered to assure appropriate use of acute reperfusion therapy in this group of patients.

Cerebral small vessel disease: cognition, mood, daily functioning, and imaging findings from a small pilot sample.

Cerebral small vessel disease, a leading cause of cognitive decline, is considered a relatively homogeneous disease process, and it can co-occur with Alzheimer's disease. Clinical reports of magnetic resonance imaging (MRI)/computed tomography and single photon emission computed tomography (SPECT) imaging and neuropsychology testing for a small pilot sample of 14 patients are presented to illustrate disease characteristics through findings from structural and functional imaging and cognitive assessment. Participants showed some decreases in executive functioning, attention, processing speed, and memory retrieval, consistent with previous literature. An older subgroup showed lower age-corrected scores at a single time point compared to younger participants. Performance on a computer-administered cognitive measure showed a slight overall decline over a period of 8-28 months. For a case study with mild neuropsychology findings, the MRI report was normal while the SPECT report identified perfusion abnormalities. Future research can test whether advances in imaging analysis allow for identification of cerebral small vessel disease before changes are detected in cognition.