Utilization and Reporting of Patient-Reported Outcome Measures in Randomized Clinical Trials of Acute Stroke (2010-2020).

BACKGROUND: Patient-reported outcome measures (PROMs) describe health status from the perspective of the patient. There is growing interest in incorporating PROMs into clinical trials, but the extent that such measures are used in contemporary stroke trials is uncertain. We sought to determine how often acute stroke trials included PROMs as outcome measures and assessed the completeness of methodological reporting. METHODS: We searched MEDLINE for randomized controlled trials published in 9 high-impact journals between 2010 and 2020. Eligible studies were phase 2 or 3 trials that tested therapeutic interventions within 1 month of stroke onset. Using the trial's primary publication and protocol, we abstracted key study characteristics including all primary and secondary outcome measures. We defined PROMs as self-reported measures of quality of life, symptoms, or function collected without interpretation of an external party. RESULTS: Of 116 trials that met eligibility, 57 (49%) included at least 1 PROM. Of these, 41 trials (35%) included a PROM in its primary publication, while 16 (14%) identified a PROM in its protocol. Only 1 trial used a PROM as a primary outcome. Among the 57 total trials, the most commonly used measures were Euro-QOL (n=41, 72%), Stroke Impact Scale (n=10, 18%), and Short-Form 36 (n=6, 11%). Trials were more likely to include a PROM if they were published after 2016, were phase 3, or included only hemorrhagic stroke. Of the 41 trials that included a PROM in the primary publication, 40 (97%) provided PROM results, but only 9 (22%) found statistically significant differences between treatment groups. Quality of methodological reporting was generally poor. CONCLUSIONS: Half of contemporary acute stroke trials published in high-impact journals listed at least 1 PROM as a secondary outcome, but they played a minor role in the presentation of the final trial results. Inclusion of PROMs in acute stroke trials requires greater attention during both the design and reporting phases of the trial. REGISTRATION: URL: https://www.crd.york.ac.uk/PROSPERO/; Unique identifier: CRD42019128727.

Responder analysis confirms results of a stroke transitional care trial but provides more interpretable results.

OBJECTIVES: Interpreting between-group differences in patient-reported outcome measures can be challenging. Responder analyses, which compare the proportions of patients who achieve a meaningful clinical change, represent a more interpretable approach. We conducted a secondary responder analysis of the Michigan Stroke Transitions Trial (MISTT). STUDY DESIGN AND SETTING: The MISTT randomized 265 patients with stroke to three treatment groups: usual care [UC], social work case management [SWCM], or social work case management plus access to a patient-oriented website [SWCM + website]. Two Patient-Reported Outcomes Measurement and Information System (PROMIS) Global-10 subscales (representing physical and mental health) and 5 additional patient-reported outcomes were collected at baseline and 90-days. Responder analyses were conducted using modified Poisson and linear regression using published minimal important differences. Multiple imputation was used to address missing data. RESULTS: For the PROMIS-10 global physical health subscale, responders were 80% more common in the SWCM + website group compared to the UC group (relative risk = 1.8, 95% confidence interval [CI]: 1.0, 3.1), with a number needed to treat of 7 (95% CI: 3, 112). No significant treatment effects were observed for the PROMIS-10 global mental health subscale. CONCLUSION: Results of this responder analysis were largely consistent with the original trial analysis but have the advantage of presenting treatment effects using more clinically interpretable number needed to treat metrics.

Early Termination of Acute Stroke Randomized Controlled Trials Published Between 2013 and 2020: A Systematic Review.

BACKGROUND: Termination of a clinical trial before the maximum planned sample size is accrued can occur for multiple valid reasons but has implications for the interpretation of results. We undertook a systematic review of contemporary acute stroke trials to document the prevalence of and reasons for early termination. METHODS: We searched MEDLINE for randomized controlled trials of acute stroke therapies published between 2013 and 2020 in 9 major clinical journals. Manuscripts describing the primary results of phase 2 and phase 3 trials of acute stroke care were included. Data on study characteristics and adherence to CONSORT reporting guidelines were abstracted and summarized using descriptive statistics. Where feasible, we compared treatment effect sizes between trials terminated early and those not terminated early. RESULTS: Of 96 randomized controlled trials, 39 (41%) were terminated early, 84 (88%) had a data and safety monitoring board, and 57 (59%) reported a prespecified statistical stopping rule. Among the 39 trials terminated early, 10 were discontinued for benefit, 10 due to logistical issues, 8 for futility, 6 because of newly available evidence, 1 for harm, and 4 for other or a combination of reasons. The median percentage of the maximum planned sample size accrued among trials terminated early was 63% (range, 8%-89%). Only 55% of trials (53 of 96) reported whether interim efficacy analyses were conducted, as recommended by the CONSORT guidelines. When 10 endovascular therapy trials were compared according to early termination status, the effect sizes of trials terminated early for benefit were only modestly larger than those not terminated early. CONCLUSIONS: The high prevalence of early termination in combination with the wide variety of reasons underscores the necessity of meticulous trial planning and adherence to methodological and reporting guidelines for early termination. Registration: URL: https://www.crd.york.ac.uk/prospero/; Unique identifier: CRD42019128727.

Changes in PHQ-9 depression scores in acute stroke patients shortly after returning home.

INTRODUCTION: Post-stroke depression is a disabling condition that occurs in approximately one-third of stroke survivors. There is limited information on changes in depressive symptoms shortly after stroke survivors return home. To identify factors associated with changes in post-stroke depressive symptoms during the early recovery period, we conducted a secondary analysis of patients enrolled in a clinical trial conducted during the transition period shortly after patients returned home (MISTT). METHODS: The Michigan Stroke Transitions Trial (MISTT) tested the efficacy of social worker case management and access to online information to improve patient-reported outcomes following an acute stroke. Patient Health Questionnaire-9 (PHQ-9) scores were collected via telephone interviews conducted at 7 and 90 days post-discharge; higher scores indicate more depressive symptoms. Generalized estimating equations were used to identify independent predictors of baseline PHQ-9 score at 7 days and of changes over time to 90 days. RESULTS: Of 265 patients, 193 and 185 completed the PHQ-9 survey at 7 and 90 days, respectively. The mean PHQ-9 score was 5.9 at 7 days and 5.1 at 90 days. Older age, being unmarried, and having moderate stroke severity (versus mild) were significantly associated with lower 7-day PHQ-9 scores (indicating fewer depressive symptoms). However, at 90 days, both unmarried patients and those with moderate or high stroke severity had significant increases in depressive symptoms over time. CONCLUSIONS: In stroke patients who recently returned home, both marital status and stroke severity were associated with depressive symptom scores; however, the relationships were complex. Being unmarried and having higher stroke severity was associated with fewer depressive symptoms at baseline, but both factors were associated with worsening depressive symptoms over time. Identifying risk factors for changes in depressive symptoms may help guide effective management strategies during the early recovery period.

Reporting of Results by Sex in Randomized Controlled Trials of Acute Stroke Therapies (2010-2020).

Background and Purpose: When reporting primary results from randomized controlled trials, recommendations include reporting results by sex. We reviewed the reporting of results by sex in contemporary acute stroke randomized controlled trials. Methods: We searched MEDLINE for articles reporting the primary results of phase 2 or 3 stroke randomized controlled trials published between 2010 and June 2020 in one of nine major clinical journals. Eligible trials were restricted to those with a therapeutic intervention initiated within one month of stroke onset. Of primary interest was the reporting of results by sex for the primary outcome. We performed bivariate analyses using Fisher exact tests to identify study-level factors associated with reporting by sex and investigated temporal trends using an exact test for trend. Results: Of the 115 studies identified, primary results were reported by sex in 37% (n=42). Reporting varied significantly by journal, with the New England Journal of Medicine (61%) and Lancet journals (40%) having the highest rates (P=0.03). Reporting also differed significantly by geographic region (21% Europe versus 48% Americas, P=0.03), trial phase (13% phase 2 versus 40% phase 3, P=0.05), and sample size (24% <250 participants versus 61% >750 participants, P<0.01). Although not statistically significant (P=0.11), there was a temporal trend in favor of greater reporting among later publications (25% 2010­2012 versus 48% 2019­2020). Conclusions: Although reporting of primary trial results by sex improved from 2010 to 2020, the prevalence of reporting in major journals is still low. Further efforts are required to encourage journals and authors to comply with current reporting recommendations.

Benefits and Risks of Dual Versus Single Antiplatelet Therapy for Secondary Stroke Prevention: A Systematic Review for the 2021 Guideline for the Prevention of Stroke in Patients With Stroke and Transient Ischemic Attack.

BACKGROUND: Dual antiplatelet therapy (DAPT) after ischemic stroke or transient ischemic attack may reduce recurrent stroke but also increase severe bleeding compared with single antiplatelet therapy (SAPT). The American Heart Association/American Stroke Association convened an evidence review committee to perform a systematic review and meta-analysis of the benefits and risks of DAPT compared with SAPT for secondary ischemic stroke prevention. METHODS: The Medline, Embase, and Cochrane databases were searched on December 5, 2019, to identify phase III or IV randomized controlled trials (n≥100) from December 1999 to December 2019. We calculated unadjusted relative risks (RRs) and performed meta-analyses of studies based on the duration of treatment (short [≤90 days] versus long [>90 days]). RESULTS: Three short-duration randomized controlled trials were identified that enrolled mostly patients with minor stroke or high risk transient ischemic attack. In these trials, DAPT, compared with SAPT, was associated with a lower 90-day risk of recurrent ischemic stroke (pooled RR, 0.68 [95% CI, 0.55-0.83], I 2=37.1%). There was no significant increase in major bleeding with DAPT in short-duration trials (pooled RR, 1.88 [95% CI, 0.93-3.83], I 2=8.9%). In 2 long-duration treatment randomized controlled trials (mean treatment duration, 18-40 months), DAPT was not associated with a significant reduction in recurrent ischemic stroke (pooled RR, 0.89 [95% CI, 0.79-1.02], I 2=1.4%), but was associated with a higher risk of major bleeding (pooled RR, 2.42 [95% CI, 1.37-4.30], I 2=75.5%). CONCLUSIONS: DAPT was more effective than SAPT for prevention of secondary ischemic stroke when initiated early after the onset of minor stroke/high-risk transient ischemic attack and treatment duration was <90 days. However, when the treatment duration was longer and initiated later after stroke or transient ischemic attack onset, DAPT was not more effective than SAPT for ischemic stroke prevention and it increased the risk of bleeding.

Sex Disparities in Enrollment in Recent Randomized Clinical Trials of Acute Stroke: A Meta-analysis.

Importance: The underenrollment of women in randomized clinical trials represents a threat to the validity of the evidence supporting clinical guidelines and potential disparities in access to novel treatments. Objective: To determine whether women were underenrolled in contemporary randomized clinical trials of acute stroke therapies published in 9 major journals after accounting for their representation in underlying stroke populations. Data Sources: MEDLINE was searched for acute stroke therapeutic trials published between January 1, 2010, and June 11, 2020. Study Selection: Eligible articles reported the results of a phase 2 or 3 randomized clinical trial that enrolled patients with stroke and/or transient ischemic attack and examined a therapeutic intervention initiated within 1 month of onset. Data Extraction: Data extraction was performed by 2 independent authors in duplicate. Individual trials were matched to estimates of the proportion of women in underlying stroke populations using the Global Burden of Disease database. Main Outcomes and Measures: The primary outcome was the enrollment disparity difference (EDD), the absolute difference between the proportion of trial participants who were women and the proportion of strokes in the underlying disease populations that occurred in women. Random-effects meta-analyses of the EDD were performed, and multivariable metaregression was used to explore the associations of trial eligibility criteria with disparity estimates. Results: The search returned 1529 results, and 115 trials (7.5%) met inclusion criteria. Of 121 105 randomized patients for whom sex was reported, 52 522 (43.4%) were women. The random-effects summary EDD was -0.053 (95% CI, -0.065 to -0.040), indicating that women were underenrolled by 5.3 percentage points. This disparity persisted across virtually all geographic regions, intervention types, and stroke types, apart from subarachnoid hemorrhage (0.117 [95% CI, 0.084 to 0.150]). When subarachnoid hemorrhage trials were excluded, the summary EDD was -0.067 (95% CI, -0.078 to -0.057). In the multivariable metaregression analysis, an upper age limit of 80 years as an eligibility criterion was associated with a 6-percentage point decrease in the enrollment of women. Conclusions and Relevance: Further research is needed to understand the causes of the underenrollment of women in acute stroke trials. However, to maximize representation, investigators should avoid imposing age limits on enrollment.

Sex differences in IV thrombolysis treatment for acute ischemic stroke: A systematic review and meta-analysis.

OBJECTIVE: A prior meta-analysis of reports published between 2000 and 2008 found that women were 30% less likely to receive IV recombinant tissue plasminogen activator (rtPA) treatment for stroke than men; we updated this meta-analysis to determine if this sex difference persisted. METHODS: We identified studies that reported sex-specific IV rtPA treatment rates for acute ischemic stroke published between 2008 and 2018. Eligible studies included representative populations of patients with ischemic stroke from hospital-based, registry-based, or administrative data. Random effects odds ratios (ORs) were generated to quantify sex differences. RESULTS: Twenty-four eligible studies were identified during this 10-year period. The summary unadjusted OR based on 17 studies with data on all ischemic stroke patients was 0.87 (95% confidence interval [CI], 0.82-0.93), indicating that women had 13% lower odds of receiving IV rtPA treatment than men. However, substantial between-study variability existed. Lower treatment odds in women were also observed in 7 studies that provided data on the subgroup of patients eligible for IV rtPA treatment, although the summary OR of 0.95 (95% CI, 0.88-1.02) was not statistically significant. Examination of time trends across 33 studies published between 2000 and 2018 found evidence that the sex difference had narrowed in more recent years. CONCLUSIONS: Although there is considerable variability in the findings of individual studies, pooled data from recent studies show that women with acute stroke are less likely to be treated with IV thrombolysis compared with men. However, the size of this difference has narrowed compared to studies published before 2008.