Newly Diagnosed Atrial Fibrillation After Transient Ischemic Attack Versus Minor Ischemic Stroke in the POINT Trial.

Background Atrial fibrillation/flutter (AF) after transient ischemic attack (TIA) has not been well studied. We compared the likelihood of new AF diagnosis after ischemic stroke versus TIA. Methods and Results The POINT (Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke) trial enrolled adults within 12 hours of minor ischemic stroke or high-risk TIA. Our exposure was index event type (ischemic stroke versus TIA). The primary analysis used the original trial definition of TIA (resolution of symptoms/signs). In secondary analyses, TIA cases with infarction on neuroimaging were reclassified as strokes. Our primary outcome was a new AF diagnosis, ascertained from adverse event and treatment interruption/discontinuation reports. We calculated C-statistics for variables associated with newly diagnosed AF. We used Kaplan-Meier survival statistics and Cox models adjusted for demographics and vascular risk factors. Excluding 49 subjects with baseline AF, 2746 patients had index stroke and 2086 patients had index TIA. During the 90-day follow-up, 106 patients had newly diagnosed AF. Cumulative risks of AF were 2.7% (95% CI, 2.1%-3.4%) after stroke and 2.0% (95% CI, 1.5%-2.7%) after TIA (P=0.15). After reclassifying index events by neuroimaging, cumulative AF risk was higher after stroke (2.7%; 95% CI, 2.2%-3.4%) than TIA (1.8%; 95% CI, 1.3%-2.5%) (P=0.04). Index event type had negligible predictive utility (C-statistic, 0.54). Conclusions Among patients with cerebral ischemia, the distinction between TIA versus minor stroke did not stratify the risk of subsequent AF diagnosis, implying that patients with TIA should undergo similar heart-rhythm monitoring strategies as patients with ischemic stroke.

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.

Assessment of the End Point Adjudication Process on the Results of the Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke (POINT) Trial: A Secondary Analysis.

Importance: Debate continues about the value of event adjudication in clinical trials and whether independent centralized assessments improve reliability and validity of study results in masked randomized trials compared with local, investigator-assessed end points. Objective: To assess the results of the adjudicated end point process in the Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke (POINT) trial by comparing end points assessed by local site investigators with centrally adjudicated end points. Design, Setting, and Participants: This is an ad hoc secondary analysis of a randomized, double-blind clinical trial comparing safety and effectiveness of clopidogrel bisulphate plus aspirin vs placebo plus aspirin. Patients received either 600 mg of clopidogrel bisulphate on day 1, then 75 mg per day through day 90 plus 50 to 325 mg of aspirin per day, or the same range of dosages of placebo plus aspirin. Investigators reported all potential end points; independent masked adjudicators were randomly assigned to review using definitions specified in the study protocol. This was a multicenter study; 269 international sites in 10 countries enrolled from May 28, 2010, to December 19, 2017. The study enrolled 4881 patients 18 years or older with transient ischemic attack or minor acute ischemic stroke within 12 hours of symptom onset and followed for 90 days from randomization; last follow-up was completed in March 2018. Main Outcomes and Measures: Independent adjudicators external to the study and masked to study treatment assignment adjudicated 467 primary and secondary effectiveness outcomes and major and minor bleeding events, including the primary composite end point, which was the risk of a composite of major ischemic events at 90 days, defined as ischemic stroke, myocardial infarction, or death from an ischemic vascular event. The primary safety end point was major hemorrhage. All components of the primary and safety outcomes were adjudicated. Results: In this secondary analysis of an international randomized clinical trial, a total of 269 sites worldwide randomized 4881 patients (median age, 65.0 years; interquartile range, 55-74 years); 55.0% were male. The primary results have been published previously. The hazard ratios for clopidogrel plus aspirin vs placebo plus aspirin for the primary composite end point were 0.75 (95% CI, 0.59-0.95) for adjudicator-assessed events and 0.76 (95% CI, 0.60-0.95) for investigator-assessed events. Agreement between adjudicator and investigator assessments was 90.7%. The hazard ratios for clopidogrel plus aspirin vs placebo plus aspirin for the primary safety end point were 2.32 (95% CI, 1.10-4.87) for adjudicator-assessed events and 2.58 (95% CI, 1.19-5.58) for investigator-assessed events, with an agreement rate of 77.5%. Conclusions and Relevance: Independent end point adjudication did not substantially alter estimates of the primary treatment effectiveness in the POINT trial. Trial Registration: ClinicalTrials.gov identifier: NCT00991029.

Outcomes Associated With Clopidogrel-Aspirin Use in Minor Stroke or Transient Ischemic Attack: A Pooled Analysis of Clopidogrel in High-Risk Patients With Acute Non-Disabling Cerebrovascular Events (CHANCE) and Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke (POINT) Trials.

Importance: Dual antiplatelet therapy with clopidogrel and aspirin is effective for secondary prevention after minor ischemic stroke or transient ischemic attack (TIA). Uncertainties remained about the optimal duration of dual antiplatelet therapy for minor stroke or TIA. Objective: To obtain precise estimates of efficacy and risk of dual antiplatelet therapy after minor ischemic stroke or TIA. Design, Setting, and Participants: This analysis pooled individual patient-level data from 2 large-scale randomized clinical trials that evaluated clopidogrel-aspirin as a treatment to prevent stroke after a minor stroke or high-risk TIA. The Clopidogrel in High-Risk Patients With Acute Non-Disabling Cerebrovascular Events (CHANCE) trial enrolled patients at 114 sites in China from October 1, 2009, to July 30, 2012. The Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke (POINT) trial enrolled patients at 269 international sites from May 28, 2010, to December 19, 2017. Both were followed up for 90 days. Data analysis occurred from November 2018 to May 2019. Interventions: In the 2 trials, patients with minor stroke or high-risk TIA were randomized to clopidogrel-aspirin or aspirin alone within 12 hours (POINT) or 24 hours (CHANCE) of symptom onset. Main Outcomes and Measures: The primary efficacy outcome was a major ischemic event (ischemic stroke, myocardial infarction, or death from ischemic vascular causes). The primary safety outcome was major hemorrhage. Results: The study enrolled 5170 patients (CHANCE) and 4881 patients (POINT). Analysis included individual data from 10 051 patients (5016 in the clopidogrel-aspirin treatment group and 5035 in the control group) with a median age of 63.2 (interquartile range, 55.0-72.9) years; 6106 patients (60.8%) were male. Clopidogrel-aspirin treatment reduced the risk of major ischemic events at 90 days compared with aspirin alone (328 of 5016 [6.5%] vs 458 of 5035 [9.1%]; hazard ratio [HR], 0.70 [95% CI, 0.61-0.81]; P < .001), mainly within the first 21 days (263 of 5016 [5.2%] vs 391 of 5035 [7.8%]; HR, 0.66 [95% CI, 0.56-0.77]; P < .001), but not from day 22 to day 90. No evidence of heterogeneity of treatment outcome across trials or prespecified subgroups was observed. Major hemorrhages were more frequent in the clopidogrel-aspirin group, but the difference was nonsignificant. Conclusions and Relevance: In this analysis of the POINT and CHANCE trials, the benefit of dual antiplatelet therapy appeared to be confined to the first 21 days after minor ischemic stroke or high-risk TIA.

Time Course for Benefit and Risk of Clopidogrel and Aspirin After Acute Transient Ischemic Attack and Minor Ischemic Stroke.

BACKGROUND: In patients with acute minor ischemic stroke or high-risk transient ischemic attack enrolled in the POINT trial (Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke [POINT] Trial), the combination of clopidogrel and aspirin for 90 days reduced major ischemic events but increased major hemorrhage in comparison to aspirin alone. METHODS: In a secondary analysis of POINT (N=4881), we assessed the time course for benefit and risk from the combination of clopidogrel and aspirin. The primary efficacy outcome was a composite of ischemic stroke, myocardial infarction, or ischemic vascular death. The primary safety outcome was major hemorrhage. Risks and benefits were estimated for delayed times of treatment initiation using left-truncated models. RESULTS: Through 90 days, the rate of major ischemic events was initially high then decreased markedly, whereas the rate of major hemorrhage remained low but relatively constant throughout. With the use of a model-based approach, the optimal change point for major ischemic events was 21 days (0-21 days hazard ratio 0.65 for clopidogrel-aspirin versus aspirin; 95% CI, 0.50-0.85; P=0.0015, in comparison to 22-90 days hazard ratio, 1.38; 95% CI, 0.81-2.35; P=0.24). Models showed benefits of clopidogrel-aspirin for treatment delayed as long as 3 days after symptom onset. CONCLUSIONS: The benefit of clopidogrel-aspirin occurs predominantly within the first 21 days, and outweighs the low, but ongoing risk of major hemorrhage. When considered with the results of the CHANCE trial (Clopidogrel in High-Risk Patients With Non-disabling Cerebrovascular Events), a similar trial treating with clopidogrel-aspirin for 21 days and showing no increase in major hemorrhage, these results suggest that limiting clopidogrel-aspirin use to 21 days may maximize benefit and reduce risk after high-risk transient ischemic attack or minor ischemic stroke. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00991029.

Risk for Major Hemorrhages in Patients Receiving Clopidogrel and Aspirin Compared With Aspirin Alone After Transient Ischemic Attack or Minor Ischemic Stroke: A Secondary Analysis of the POINT Randomized Clinical Trial.

Importance: Results show the short-term risk of hemorrhage in treating patients with acute transient ischemic attack (TIA) or minor acute ischemic stroke (AIS) with clopidogrel plus aspirin or aspirin alone. Objective: To characterize the frequency and kinds of major hemorrhages in the Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke (POINT) trial. Design, Setting, and Participants: This secondary analysis of the POINT randomized, double-blind clinical trial conducted in 10 countries in North America, Europe, and Australasia included patients with high-risk TIA or minor AIS who were randomized within 12 hours of symptom onset and followed up for 90 days. The total enrollment, which occurred from May 28, 2010, through December 17, 2017, was 4881 and constituted the intention-to-treat group; 4819 (98.7%) were included in the as-treated analysis group. The primary safety analyses were as-treated, classifying patients based on study drug actually received. Intention-to-treat analyses were performed as secondary analyses. Data were analyzed in April 2018. Interventions: Patients were assigned to receive clopidogrel (600 mg loading dose on day 1 followed by 75 mg daily for days 2-90) or placebo; all patients also received open-label aspirin, 50 to 325 mg/d. Main Outcomes and Measures: The primary safety outcome was all major hemorrhages. Other safety outcomes included minor hemorrhages. Results: A total of 269 sites worldwide randomized 4881 patients (median age, 65.0 years [interquartile range, 55-74 years]; 2195 women [45.0%]); the primary results have been published previously. In the as-treated analyses, major hemorrhage occurred in 21 patients (0.9%) receiving clopidogrel plus aspirin and 6 (0.2%) in the aspirin alone group (hazard ratio, 3.57; 95% CI, 1.44-8.85; P = .003; number needed to harm, 159). There were 4 fatal hemorrhages (0.1%; 3 in the clopidogrel plus aspirin group and 1 in the aspirin alone group); 3 of the 4 were intracranial. There were 7 intracranial hemorrhages (0.1%); 5 were in the clopidogrel plus aspirin group and 2 in the aspirin plus placebo group. The most common location of major hemorrhages was in the gastrointestinal tract. Conclusions and Relevance: The risk for major hemorrhages in patients receiving either clopidogrel plus aspirin or aspirin alone after TIA or minor AIS was low. Nevertheless, treatment with clopidogrel plus aspirin increased the risk of major hemorrhages over aspirin alone from 0.2% to 0.9%. Trial Registration: ClinicalTrials.gov identifier: NCT00991029.

Clopidogrel and Aspirin in Acute Ischemic Stroke and High-Risk TIA.

BACKGROUND: Combination antiplatelet therapy with clopidogrel and aspirin may reduce the rate of recurrent stroke during the first 3 months after a minor ischemic stroke or transient ischemic attack (TIA). A trial of combination antiplatelet therapy in a Chinese population has shown a reduction in the risk of recurrent stroke. We tested this combination in an international population. METHODS: In a randomized trial, we assigned patients with minor ischemic stroke or high-risk TIA to receive either clopidogrel at a loading dose of 600 mg on day 1, followed by 75 mg per day, plus aspirin (at a dose of 50 to 325 mg per day) or the same range of doses of aspirin alone. The dose of aspirin in each group was selected by the site investigator. The primary efficacy outcome in a time-to-event analysis was the risk of a composite of major ischemic events, which was defined as ischemic stroke, myocardial infarction, or death from an ischemic vascular event, at 90 days. RESULTS: A total of 4881 patients were enrolled at 269 international sites. The trial was halted after 84% of the anticipated number of patients had been enrolled because the data and safety monitoring board had determined that the combination of clopidogrel and aspirin was associated with both a lower risk of major ischemic events and a higher risk of major hemorrhage than aspirin alone at 90 days. Major ischemic events occurred in 121 of 2432 patients (5.0%) receiving clopidogrel plus aspirin and in 160 of 2449 patients (6.5%) receiving aspirin plus placebo (hazard ratio, 0.75; 95% confidence interval [CI], 0.59 to 0.95; P=0.02), with most events occurring during the first week after the initial event. Major hemorrhage occurred in 23 patients (0.9%) receiving clopidogrel plus aspirin and in 10 patients (0.4%) receiving aspirin plus placebo (hazard ratio, 2.32; 95% CI, 1.10 to 4.87; P=0.02). CONCLUSIONS: In patients with minor ischemic stroke or high-risk TIA, those who received a combination of clopidogrel and aspirin had a lower risk of major ischemic events but a higher risk of major hemorrhage at 90 days than those who received aspirin alone. (Funded by the National Institute of Neurological Disorders and Stroke; POINT ClinicalTrials.gov number, NCT00991029 .).

Screen failure data in clinical trials: Are screening logs worth it?

BACKGROUND: Clinical trials frequently spend considerable effort to collect data on patients who were assessed for eligibility but not enrolled. The Consolidated Standards of Reporting Trials (CONSORT) guidelines' recommended flow diagram for randomized clinical trials reinforces the belief that the collection of screening data is a necessary and worthwhile endeavor. The rationale for collecting screening data includes scientific, trial management, and ethno-socio-cultural reasons. PURPOSE: We posit that the cost of collecting screening data is not justified, in part due to inability to centrally monitor and verify the screening data in the same manner as other clinical trial data. METHODS: To illustrate the effort and site-to-site variability, we analyzed the screening data from a multicenter, randomized clinical trial of patients with transient ischemic attack or minor ischemic stroke (Platelet-Oriented Inhibition in New Transient Ischemic Attack and Minor Ischemic Stroke (POINT)). RESULTS: Data were collected on over 27,000 patients screened across 172 enrolling sites, 95% of whom were not enrolled. Although the rate of return of screen failure logs was high overall (95%), there were a considerable number of logs that were returned with 'no data to report' (23%), often due to administrative reasons rather than no patients screened. CONCLUSION: In spite of attempts to standardize the collection of screening data, due to differences in site processes, multicenter clinical trials face challenges in collecting those data completely and uniformly. The efforts required to centrally collect high-quality data on an extensive number of screened patients may outweigh the scientific value of the data. Moreover, the lack of a standardized definition of 'screened' and the challenges of collecting meaningful characteristics for patients who have not signed consent limits the ability to compare across studies and to assess generalizability and selection bias as intended.

Platelet-oriented inhibition in new TIA and minor ischemic stroke (POINT) trial: rationale and design.

BACKGROUND: Ischemic stroke and other vascular outcomes occur in 10-20% of patients in the three-months following a transient ischemic attack or minor ischemic stroke, and many are disabling. The highest risk period for these outcomes is the early hours and days immediately following the ischemic event. Aspirin is the most common antithrombotic treatment used for these patients. AIM: The aim of POINT is to determine whether clopidogrel plus aspirin taken <12 h after transient ischemic attack or minor ischemic stroke symptom onset is more effective in preventing major ischemic vascular events at 90 days in the high-risk, and acceptably safe, compared with aspirin alone. DESIGN: POINT is a prospective, randomized, double-blind, multicenter trial in patients with transient ischemic attack or minor ischemic stroke. Subjects are randomized to clopidogrel (600 mg loading dose followed by 75 mg/day) or matching placebo, and all will receive open-label aspirin 50-325 mg/day, with a dose of 162 mg daily for five-days followed by 81 mg daily strongly recommended. STUDY OUTCOMES: The primary efficacy outcome is the composite of new ischemic vascular events - ischemic stroke, myocardial infarction, or ischemic vascular death - by 90 days. The primary safety outcome is major hemorrhage, which includes symptomatic intracranial hemorrhage. DISCUSSION: Aspirin is the most common antithrombotic given to patients with a stroke or transient ischemic attack, as it reduces the risk of subsequent stroke. This trial expects to determine whether more aggressive antithrombotic therapy with clopidogrel plus aspirin, initiated acutely, is more effective than aspirin alone.

Prospective validation of the ICH Score for 12-month functional outcome.

BACKGROUND: The ICH Score is a commonly used clinical grading scale for outcome after acute intracerebral hemorrhage (ICH) and has been validated for 30-day mortality, but not long-term functional outcome. The goals of this study were to assess whether the ICH Score accurately stratifies patients with regard to 12-month functional outcome and to further delineate the pace of recovery of patients during the first year post-ICH. METHODS: We performed a prospective observational cohort study of all patients with acute ICH admitted to the emergency departments of San Francisco General Hospital and UCSF Medical Center from June 1, 2001, through May 31, 2004. Components of the ICH Score (admission Glasgow Coma Scale score, initial hematoma volume, presence of intraventricular hemorrhage, infratentorial ICH origin, and age) were recorded along with other clinical characteristics. Patients were then assessed with the modified Rankin Scale (mRS) at hospital discharge, 30 days, and 3, 6, and 12 months post-ICH. RESULTS: Of 243 patients, 95 (39%) died during initial acute hospitalization. The ICH Score accurately stratified patients with regard to 12-month functional outcome for various dichotomous cutpoints along the mRS (p < 0.05). Many patients continued to improve across the first year, with a small number of patients becoming disabled or dying due to late events unrelated to the initial ICH. CONCLUSIONS: The ICH Score is a valid clinical grading scale for long-term functional outcome after acute intracerebral hemorrhage (ICH). Many ICH patients improve after hospital discharge and this improvement may continue even after 6 months post-ICH.

Brain tissue oxygen monitoring in intracerebral hemorrhage.

INTRODUCTION: Brain tissue oxygen (PbrO2) monitoring is an emerging technique for detection of secondary brain injury in neurocritical care. Although it has been extensively reported in traumatic brain injury and aneurysmal subarachnoid hemorrhage, its use in nontraumatic intracerebral hemorrhage (ICH) has not been well described. We report complementary preliminary studies in a large animal model and in patients that demonstrate the feasibility of PbrO2 monitoring after ICH. METHODS: To assess early events after ICH, Licox Clark-type oxygen probes were inserted in the bilateral frontal white matter of four anesthetized swine that subsequently underwent right parietal hematoma formation in an experimental model of ICH. Intracranial pressure (ICP) was monitored as well. Seven patients with acute ICH, who were undergoing ICP monitoring as part of standard neurocritical care, had placement of a frontal oxygen probe, with subsequent monitoring for up to 7 days. RESULTS: In the swine ICH model, a rise in ICP early after hematoma formation was accompanied by a decrease in ipsilateral and contralateral PbrO2. Secondary increases in hematoma volume resulted in further decreases in PbrO2 over the first hour after ICH. In patients undergoing oxygen monitoring, low PbrO2 (<15 mmHg) was common. In these patients, changes in FiO2, mean arterial pressure, and cerebral perfusion pressure (but not ICP) predicted subsequent change in PbrO2. CONCLUSION: Brain tissue oxygen monitoring is feasible in ICH patients, as well as in a swine model of ICH. Translational research that emphasizes complementary information derived from human and animal studies may yield additional insights not available from either alone.

External validation of the ICH score.

INTRODUCTION: The ICH score is a clinical grading scale that is composed of five components related to outcome after nontraumatic intracerebral hemorrhage (ICH): Glasgow Coma Scale score, ICH volume, presence of intraventricular hemorrhage, infratentorial origin, and age. The ICH score accurately risk-stratifies patients in the cohort from which it was developed, but it has not yet been fully externally validated. The purpose of this study was to determine whether the ICH score accurately risk-stratifies patients in an independent cohort. METHODS: Records of all patients with acute ICH presenting to Stanford Medical Center and Santa Clara Valley Medical Center from 1998 through 2000 were reviewed. Outcome was assessed as mortality at 30 days. RESULTS: A total of 175 patients formed the cohort for analysis. Thirty-day mortality for the entire cohort was 40%. ICH scores ranged from 0 to 5, and each increase in the ICH score was associated with an increase in 30-day mortality (p<0.01 for trend); 4 of 41 patients with an ICH score of 0 died, whereas all 5 patients with a score of 5 died. Receiver operating characteristic curves for the ICH score were similar for this cohort and for the initial ICH score cohort. CONCLUSION: The ICH score accurately stratifies outcome in an external patient cohort. Thus, the ICH score is a validated clinical grading scale that can be easily and rapidly applied at ICH presentation. Ascale such as the ICH score could be used to standardize clinical treatment protocols or clinical studies.