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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.

ABSTRACT: 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.

SUBMITTER: Farrant M

PROVIDER: S-EPMC6735409 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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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.

Farrant Mary M Easton J Donald JD Adelman Eric E EE Cucchiara Brett L BL Barsan William G WG Tillman Holly J HJ Elm Jordan J JJ Kim Anthony S AS Lindblad Anne S AS Palesch Yuko Y YY Zhao Wenle W Pauls Keith K Walsh Kyle B KB Martí-Fàbregas Joan J Bernstein Richard A RA Johnston S Claiborne SC

JAMA network open 20190904 9

<h4>Importance</h4>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.<h4>Objective</h4>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 wi ...[more]

PMID: 31490536

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Project description:ImportanceDual 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.ObjectiveTo obtain precise estimates of efficacy and risk of dual antiplatelet therapy after minor ischemic stroke or TIA.Design, setting, and participantsThis 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.InterventionsIn 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 measuresThe 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.ResultsThe 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 relevanceIn 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.

Project description:ImportanceElevated systolic blood pressure (SBP) after acute ischemic stroke and transient ischemic attack (TIA) is associated with future stroke risk.ObjectiveTo explore the association of dual antiplatelet therapy (DAPT) with stroke recurrence among patients with acute ischemic stroke and TIA with or without elevated baseline SBP.Design, setting, and participantsThis cohort study performed a post hoc subgroup analysis of the Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke (POINT) trial, which was a multicenter trial conducted from 2010 to 2018 at 269 sites in 10 countries in North America, Europe, Australia, and New Zealand. Patients enrolled in POINT with available blood pressure and outcome data were included in this cohort. Statistical analysis was performed from November 2020 to January 2021.ExposuresBaseline SBP less than 140 mm Hg vs greater than or equal to 140 mm Hg and the interaction term of SBP (<140 mm Hg vs ≥140 mm Hg) × treatment group (aspirin vs DAPT).Main outcomes and measuresThe primary outcome was ischemic stroke during 90 days of follow-up. The statistical analysis fit Cox proportional hazards models adjusted for patient age, race, premorbid hypertension, diabetes, and final diagnosis of the qualifying event (stroke vs TIA).ResultsAmong 4781 patients in the cohort, the mean (SD) age was 64.6 (13.1) years; 2142 (44.8%) were male individuals, 3487 (72.9%) were White individuals, and 266 (5.6%) had a primary outcome of ischemic stroke during follow-up. There were 946 patients (19.8%) with baseline SBP less than 140 mm Hg and 3835 (80.2%) with SBP greater than or equal to 140 mm Hg. The interaction term (SBP × treatment) was significant (P for interaction = .03). In the subgroup of patients with SBP less than 140 mm Hg, the hazard ratio (HR) of DAPT vs aspirin alone for ischemic stroke was 0.36 (95% CI, 0.18-0.72; P = .004), whereas the HR in the subgroup with SBP greater than or equal to 140 mm Hg was 0.79 (95% CI, 0.60-1.02; P = .08). When evaluating the outcome of ischemic stroke within 7 days of randomization, the interaction term was significant (P for interaction = .02), and the HR for patients with DAPT with SBP less than 140 mm Hg was 0.19 (95% CI, 0.07-0.55; P = .002).Conclusions and relevanceIn the POINT trial, patients with SBP less than 140 mm Hg at presentation received a greater benefit from 90 days of DAPT than those with higher baseline SBP, particularly for reduction of early ischemic stroke recurrence. Additional research is needed to replicate these findings and potentially test whether mild SBP reduction and DAPT within 12 hours of stroke onset lowers early risk of stroke recurrence.

Project description:Background: The combination of clopidogrel and aspirin is recommended for the treatment of patients with acute minor stroke or transient ischemic attack (TIA). However, with varied clopidogrel resistance (often due to CYP2C19 loss-of-function (LOF) alleles), alternatives like ticagrelor have been suggested. Previous studies showed that ticagrelor had a lower platelet reactivity assessed by VerifyNow P2Y12 assay than clopidogrel. We aimed to compare the effect of ticagrelor vs. clopidogrel on platelet reactivity assessed by a different method (Aggrestar platelet function analyzer) and analyze whether CYP2C19 genotypes were involved. Methods: A pre-specified subgroup analysis of a randomized controlled trial- Platelet Reactivity in Acute Non-disabling Cerebrovascular Events (PRINCE) was conducted. Patients with minor stroke or TIA were randomized for treatment with ticagrelor plus aspirin or clopidogrel plus aspirin. Platelet reactivity was assessed by Aggrestar (PL) platelet function analyzer and high on-treatment platelet reactivity (HOPR) on ticagrelor or clopidogrel was compared. Clinical outcomes included any stroke, composite vascular events and bleeding events within 90 days. Patients were categorized into carriers and non-carriers according to the carrier status of CYP2C19 LOF alleles. Results: Among 675 patients enrolled in the PRINCE trial, 387 patients were included in this subgroup: 197 were randomized to ticagrelor plus aspirin and 190 to clopidogrel plus aspirin. At 90 ± 7 days, compared with clopidogrel/aspirin group, the proportion of HOPR in ticagrelor/aspirin group was significantly lower (19.6 vs. 40.8%, P < 0.001). No significant treatment-by-genotype interactions were found (P for interaction = 0.12). Within 90 days, a trend toward a lower risk of new stroke in ticagrelor/aspirin compared to clopidogrel/aspirin was observed (4.6 vs. 9.5%, HR 0.47, 95% CI 0.21-1.05, P = 0.06). Conclusions: Ticagrelor is superior to clopidogrel in inhibiting platelet reactivity measured by the PL platelet function analyzer among patients with acute minor stroke or TIA. Our study confirmed the finding of the main analysis of PRINCE trial in a different assay. Large randomized controlled trials are needed to evaluate our findings. Clinical Trial Registration: Clinicaltrials.gov NCT02506140.

Project description:ImportanceStroke incidence is higher among black than white individuals in the United States. It is unclear whether black individuals have a higher risk of stroke recurrence after a minor ischemic stroke or transient ischemic attack (TIA), a high-risk setting in which focused preventive efforts can be effective.ObjectiveTo examine the association between black race and early ischemic stroke recurrence.Design, setting, and participantsThis cohort study analyzed data from the Platelet Oriented Inhibition in New TIA and Minor Ischemic Stroke (POINT) trial conducted at 269 sites from May 28, 2010, to December 19, 2017. The trial enrolled 4881 adults within 12 hours of onset of a minor ischemic stroke (National Institutes of Health Stroke Scale score, 0-3) or high-risk TIA (ABCD2 score, ?4). For this analysis, we excluded 598 patients enrolled outside the United States and 239 US patients with missing race/ethnicity data.Main outcomes and measuresThe primary outcome for this analysis was ischemic stroke within 90 days after randomization. Covariates included age, sex, Hispanic ethnicity, study assignment to take clopidogrel vs placebo, index stroke vs TIA, vascular risk factors, statin use, study drug adherence, and index event etiological subtype.ResultsAmong 4044 patients included in the analysis, 918 (22.7%) were black. In an adjusted Cox model, black race was associated with a higher risk of recurrence compared with white race (hazard ratio, 1.6; 95% CI, 1.1-2.3). Findings were similar in subgroup analyses and in analyses limited to sites that enrolled black patients.Conclusions and relevanceAmong US participants in the POINT trial, black individuals faced a higher risk of early stroke recurrence after a minor ischemic stroke or TIA. Our findings support research into black-white racial differences in the underlying mechanisms of recurrent stroke. In the meantime, extra effort should be made to ensure that black patients have access to proven secondary prevention measures.Trial registrationclinicaltrials.gov Identifier: NCT00991029.

Project description:Background and Purpose- While combination aspirin and clopidogrel reduces recurrent stroke compared with aspirin alone in patients with transient ischemic attack (TIA) or minor stroke, the effect on disability is uncertain. Methods- The POINT trial (Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke) randomized patients with TIA or minor stroke (National Institutes of Health Stroke Scale score ≤3) within 12 hours of onset to dual antiplatelet therapy (DAPT) with aspirin plus clopidogrel versus aspirin alone. The primary outcome measure was a composite of stroke, myocardial infarction, or vascular death. We performed a post hoc exploratory analysis to examine the effect of treatment on overall disability (defined as modified Rankin Scale score >1) at 90 days, as well as disability ascribed by the local investigator to index or recurrent stroke. We also evaluated predictors of disability. Results- At 90 days, 188 of 1964 (9.6%) of patients enrolled with TIA and 471 of 2586 (18.2%) of those enrolled with stroke were disabled. Overall disability was similar between patients assigned DAPT versus aspirin alone (14.7% versus 14.3%; odds ratio, 0.97 [95% CI, 0.82-1.14]; P=0.69). However, there were numerically fewer patients with disability in conjunction with a primary outcome event in the DAPT arm (3.0% versus 4.0%; odds ratio, 0.73 [95% CI, 0.53-1.01]; P=0.06) and significantly fewer patients in the DAPT arm with disability attributed by the investigators to either the index event or recurrent stroke (5.9% versus 7.4%; odds ratio, 0.78 [95% CI, 0.62-0.99]; P=0.04). Notably, disability attributed to the index event accounted for the majority of this difference (4.5% versus 6.0%; odds ratio, 0.74 [95% CI, 0.57-0.96]; P=0.02). In multivariate analysis, age, subsequent ischemic stroke, serious adverse events, and major bleeding were significantly associated with disability in TIA; for those with stroke, female sex, hypertension, or diabetes mellitus, National Institutes of Health Stroke Scale score, recurrent ischemic stroke, subsequent myocardial infarction, and serious adverse events were associated with disability. Conclusions- In addition to reducing recurrent stroke in patients with acute minor stroke and TIA, DAPT might reduce stroke-related disability. Registration- URL: https://www.clinicaltrials.gov. Unique identifier: NCT00991029.

Dataset Information

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.

Publications

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.

Similar Datasets

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