Mary Farrant’s research while affiliated with University of California, San Francisco and other places

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.

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.

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

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.

Background: In patients with acute minor ischemic stroke or high-risk transient ischemic attack enrolled in the POINT trial, the combination of clopidogrel and aspirin for 90 days reduced major ischemic events but increased major hemorrhage compared to aspirin alone. Methods: In a secondary analysis of POINT (N=4,881), 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, while the rate of major hemorrhage remained low but relatively constant throughout. Using a model-based approach, the optimal change-point for major ischemic events was 21 days (0-21 days HR 0.65 for clopidogrel-aspirin vs. aspirin, 95% CI 0.50-0.85, p=0.0015, compared to 22-90 days HR 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 CHANCE, a similar trial treating with clopidogrel-aspirin for 21 days and showing no increase in major hemorrhage, these results suggest limiting clopidogrel-aspirin use to 21 days may maximize benefit and reduce risk after high-risk TIA or minor ischemic stroke. Clinical trial registration: URL: https://clinicaltrials.gov Unique Identifier: NCT00991029.

Background and Purpose In randomized stroke trials, central adjudication of a trial’s primary outcome is regularly implemented. However, recent evidence questions the importance of central adjudication in randomized trials. The aim of this review was to compare outcomes assessed by central adjudicators with outcomes assessed by site investigators. Methods We included randomized stroke trials where the primary outcome had undergone an assessment by site investigators and central adjudicators. We searched MEDLINE, EMBASE, CENTRAL (Cochrane Central Register of Controlled Trials), Web of Science, PsycINFO, and Google Scholar for eligible studies. We extracted information about the adjudication process as well as the treatment effect for the primary outcome, assessed both by central adjudicators and by site investigators. We calculated the ratio of these treatment effects so that a ratio of these treatment effects >1 indicated that central adjudication resulted in a more beneficial treatment effect than assessment by the site investigator. A random-effects meta-analysis model was fitted to estimate a pooled effect. Results Fifteen trials, comprising 69 560 participants, were included. The primary outcomes included were stroke (8/15, 53%), a composite event including stroke (6/15, 40%) and functional outcome after stroke measured on the modified Rankin Scale (1/15, 7%). The majority of site investigators were blind to treatment allocation (9/15, 60%). On average, there was no difference in treatment effect estimates based on data from central adjudicators and site investigators (pooled ratio of these treatment effects=1.02; 95% CI, [0.95–1.09]). Conclusions We found no evidence that central adjudication of the primary outcome in stroke trials had any impact on trial conclusions. This suggests that potential advantages of central adjudication may not outweigh cost and time disadvantages in stroke studies if the primary purpose of adjudication is to ensure validity of trial findings.

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

Introduction: An online process for eliciting and assessing information from stroke patients to prescreen for stroke recovery studies holds potential to accelerate enrollment, but the validity of using self-reported information for online pre-screening is uncertain. Methods: Among patients in the UCSF Stroke Recovery Initiative, a nationwide, online participant recruitment registry of stroke patients that have expressed an interest in stroke recovery studies (strokerecoveryinitiative.ucsf.edu; NCT03318432), we compared self-reported information on stroke subtype (ischemic vs. hemorrhagic), location (MCA, cerebellar, brainstem), and functional status (modified Rankin Scale) elicited online to final validated responses as determined by follow-up semi-structured telephone interviews. We used descriptive statistics and Cohen’s kappa to evaluate the concordance of self-reported information against validated responses. Results: A total of 1,283 of the 3,959 participants in the recruitment registry were selected for semi-structured telephone follow-up (mean age 56; 55% male; average of 2.6 years after the index stroke). There was moderate agreement between self-report and telephone-validated responses for stroke subtype (84.4% agreement, kappa=0.68 for ischemic stroke; 83.0% agreement, 0.70 for hemorrhagic stroke) and similar performance for stroke location (86.1% agreement, kappa=0.75 for MCA location; 81.1% agreement, 0.66 for cerebellar location; 86.9% agreement, 0.78 for brainstem location). Agreement for the modified Rankin Scale for functional status was somewhat lower overall (66.7% agreement, kappa=0.53) but self-reported scores were within 1 point of the validated score 94% of the time. Conclusion: Using self-reported information to prescreen patients for stroke recovery studies requires a permissive approach to basic eligibility criteria to flag potentially-eligible candidates for additional follow-up. The efficiency and high-throughput of an online prescreening process would benefit from having studies with eligibility criteria that are developed with an efficient prescreening process in mind as well as high-throughput pre-screening instruments that are optimized for self-report.

Introduction: Misclassification of outcome events can potentially lead to biased treatment effect estimates. Efforts to avoid endpoint misclassification in large-scale multicenter randomized clinical trials such as POINT have included an independent adjudication committee blinded to study treatments to standardize assessment of outcomes and reduce risk of ascertainment bias of main study endpoints. Debate continues about the scientific value of such committees and whether independent assessments improve reliability of study results, particularly when compared to the considerable time and resources consumed by the process. Methods: An independent adjudication committee adjudicated 467 primary and secondary efficacy outcomes and major and minor bleeding events, including the primary efficacy endpoint, a composite of new ischemic vascular events: ischemic stroke, myocardial infarction or ischemic vascular death at 90 days. The impact of the adjudicated endpoint process was studied by comparing the primary results using site-assessed endpoints versus adjudicator-assessed endpoints. Time from randomization to first endpoint of interest was calculated using the log-rank test and the hazard ratio and 95% CI were computed using a Cox proportional hazards model. Rate of agreement between site-assessed and adjudicator-assessed outcomes was also calculated. All analyses were completed according to the intention-to-treat principle. Results: The primary results of POINT have been published. The hazard ratios (HRs) (95% confidence interval [CI]) for clopidogrel versus aspirin therapy for the primary composite endpoint were 0.75 (0.59-0.95) for adjudicator-assessed events and 0.76 (0.60-0.95) for investigator-assessed events. Agreement between the composite endpoint for adjudicated-assessed and investigator-assessed events was 90.7%. Conclusion: Independent endpoint adjudication did not significantly impact estimates of the primary efficacy treatment effect in POINT compared to site-assessed endpoints. If misclassification of outcome events is infrequent, and careful site selection, study design and outcome definitions are in place, independent adjudication may have no meaningful impact on estimates of treatment effect.