Time-of-Day Could Affect Cognitive Screening Performance in Older Patients with TIA and Stroke.

BACKGROUND AND PURPOSE: The impact of time-of-day on the cognitive performance of older patients with limited cognitive reserve after a transient ischemic attack (TIA) or stroke, and on short cognitive tests, such as the Montreal Cognitive Assessment (MoCA), is unknown. We retrospectively studied whether morning versus afternoon assessment might affect the classification of patients aged 70 or older as severe (SCI), mild (MCI), and no (NCI) cognitive impairment by the MoCA. METHODS: Morning (12 p.m. or earlier) versus afternoon (later than 12 p.m.) proportions of SCI (MoCA score <20), MCI (MoCA score 25-20) and NCI (MoCA score ≥26) were compared in a cohort of patients aged ≥70, attending a rapid-access TIA/stroke clinic. RESULTS: Of 278 patients, 113 (40.6%) were tested in the morning and 165 (59.4%) in the afternoon. The proportion with SCI was greater in the afternoon than in the morning (10.9 vs. 1.8%, respectively, p = 0.004), with no difference in age, education, diagnosis, disability, or vascular risk factors. CONCLUSIONS: Time-of-day appears to affect cognitive performance of older patients after they undergo TIA and minor stroke. If our cross-sectional findings are confirmed in cross-over studies with repeated testing, timing of assessments should be considered in clinical practice and in research studies.

Delirium risk stratification in consecutive unselected admissions to acute medicine: validation of a susceptibility score based on factors identified externally in pooled data for use at entry to the acute care pathway.

Background: recognition of prevalent delirium and prediction of incident delirium may be difficult at first assessment. We therefore aimed to validate a pragmatic delirium susceptibility (for any, prevalent and incident delirium) score for use in front-line clinical practice in a consecutive cohort of older acute medicine patients. Methods: consecutive patients aged ≥65 years over two 8-week periods (2010-12) were screened prospectively for delirium using the Confusion Assessment Method (CAM), and delirium was diagnosed using the DSM IV criteria. The delirium susceptibility score was the sum of weighted risk factors derived using pooled data from UK-NICE guidelines: age >80 = 2, cognitive impairment (cognitive score below cut-off/dementia) = 2, severe illness (systemic inflammatory response syndrome) = 1, infection = 1, visual impairment = 1. Score reliability was determined by the area under the receiver operating curve (AUC). Results: among 308 consecutive patients aged ≥65 years (mean age/SD = 81/8 years, 164 (54%) female), AUC was 0.78 (95% CI 0.71-0.84) for any delirium; 0.71 (0.64-0.79), for prevalent delirium; 0.81 (0.70-0.92), for incident delirium; odds ratios (ORs) for risk score 5-7 versus <2 were 17.9 (5.4-60.0), P < 0.0001 for any delirium, 8.1 (2.2-29.7), P = 0.002 for prevalent delirium, and 25.0 (3.0-208.9) P = 0.003 for incident delirium, with corresponding relative risks of 5.4, 4.7 and 13. Higher risk scores were associated with frailty markers, increased care needs and poor outcomes. Conclusions: the externally derived delirium susceptibility score reliably identified prevalent and incident delirium using clinical data routinely available at initial patient assessment and might therefore aid recognition of vulnerability in acute medical admissions early in the acute care pathway.

Methodological Factors in Determining Risk of Dementia After Transient Ischemic Attack and Stroke: (III) Applicability of Cognitive Tests.

BACKGROUND AND PURPOSE: Cognitive assessment is recommended after stroke but there are few data on the applicability of short cognitive tests to the full spectrum of patients. We therefore determined the rates, causes, and associates of untestability in a population-based study of all transient ischemic attack (TIA) and stroke. METHODS: Patients with TIA or stroke prospectively recruited (2002-2007) into the Oxford Vascular Study had ≥1 short cognitive test (mini-mental state examination, telephone interview of cognitive status, Montreal cognitive assessment, and abbreviated mental test score) at baseline and on follow-up to 5 years. RESULTS: Among 1097 consecutive assessed survivors (mean: age/SD, 74.8/12.1 years; 378 TIA), numbers testable with a short cognitive test at baseline, 1, 6, 12, and 60 months were 835/1097 (76%), 778/947 (82%), 756/857 (88%), 692/792 (87%), and 472/567 (83%). Eighty-eight percent (331/378) of assessed patients with TIA were testable at baseline compared with only 46% (133/290) of major stroke (P<0.001). Untestability was also associated with older age, premorbid dependency, death on follow-up, and with both pre- and postevent dementia (all P<0.01). Untestability (and problems with testing) were commonly caused by acute stroke effects at baseline (153/262 [58%]: dysphasia/anarthria/hemiparesis=84 [32%], drowsiness=58 [22%], and acute confusion=11 [4%]), whereas sensory deficits caused relatively more problems with testing at later time points (24/63 [38%] at 5 years). CONCLUSIONS: Substantial numbers of patients with TIA and stroke are untestable with short cognitive tests. Future studies should report data on untestable patients and those with problems with testing in whom the likelihood of dementia is high.

Methodological Factors in Determining Risk of Dementia After Transient Ischemic Attack and Stroke: (II) Effect of Attrition on Follow-Up.

BACKGROUND AND PURPOSE: Cognitive outcomes in cohorts and trials are often based only on face-to-face clinic assessment. However, cognitive impairment is strongly associated with increased morbidity and mortality, leading to substantial loss to clinic follow-up. In the absence of previous population-based data, we determined the effect of such attrition on measured risk of dementia after transient ischemic attack and stroke. METHODS: Patients with transient ischemic attack or stroke prospectively recruited (2002-2007) into the Oxford Vascular (OXVASC) study had baseline clinical/cognitive assessment and follow-up to 2014. Dementia was diagnosed through face-to-face clinic interview, supplemented by home visits and telephone assessment in patients unable to attend clinic and by hand-searching of primary care records in uncontactable patients. RESULTS: Of 1236 patients (mean age/SD, 75.2/12.1 years; 582 men), 527 (43%) died by 5-year follow-up. Follow-up assessment rates (study clinic, home visit, or telephone) of survivors were 947 in 1026 (92%), 857 in 958 (89%), 792 in 915 (87%), and 567 in 673 (84%) at 1, 6, 12 months and 5 years. Dementia developed in 260 patients, of whom 110 (42%; n=50 primary care records, n=49 home visit, and n=11 telephone follow-up) had not been available for face-to-face clinic follow-up at the time of diagnosis. The 5-year cumulative incidence of postevent dementia was 29% (26%-32%) overall but was only 17% (14% to 19%) in clinic assessed versus 45% (39%-51%) in nonclinic-assessed patients (P difference<0.001). CONCLUSIONS: Exclusion of patients unavailable for clinic follow-up reduces the measured risk of postevent dementia. Use of multiple follow-up methods, including home visits, telephone assessments, and consent, to access primary care records substantially increases ascertainment of longer-term dementia outcomes.

External validation of multivariable prediction models: a systematic review of methodological conduct and reporting.

BACKGROUND: Before considering whether to use a multivariable (diagnostic or prognostic) prediction model, it is essential that its performance be evaluated in data that were not used to develop the model (referred to as external validation). We critically appraised the methodological conduct and reporting of external validation studies of multivariable prediction models. METHODS: We conducted a systematic review of articles describing some form of external validation of one or more multivariable prediction models indexed in PubMed core clinical journals published in 2010. Study data were extracted in duplicate on design, sample size, handling of missing data, reference to the original study developing the prediction models and predictive performance measures. RESULTS: 11,826 articles were identified and 78 were included for full review, which described the evaluation of 120 prediction models. in participant data that were not used to develop the model. Thirty-three articles described both the development of a prediction model and an evaluation of its performance on a separate dataset, and 45 articles described only the evaluation of an existing published prediction model on another dataset. Fifty-seven percent of the prediction models were presented and evaluated as simplified scoring systems. Sixteen percent of articles failed to report the number of outcome events in the validation datasets. Fifty-four percent of studies made no explicit mention of missing data. Sixty-seven percent did not report evaluating model calibration whilst most studies evaluated model discrimination. It was often unclear whether the reported performance measures were for the full regression model or for the simplified models. CONCLUSIONS: The vast majority of studies describing some form of external validation of a multivariable prediction model were poorly reported with key details frequently not presented. The validation studies were characterised by poor design, inappropriate handling and acknowledgement of missing data and one of the most key performance measures of prediction models i.e. calibration often omitted from the publication. It may therefore not be surprising that an overwhelming majority of developed prediction models are not used in practice, when there is a dearth of well-conducted and clearly reported (external validation) studies describing their performance on independent participant data.

Ordinal vs dichotomous analyses of modified Rankin Scale, 5-year outcome, and cost of stroke.

OBJECTIVE: To compare how 3 common representations (ordinal vs dichotomized as 0-1/2-6 or 0-2/3-6) of the modified Rankin Scale (mRS)-a commonly used trial outcome measure-relate to long-term outcomes, and quantify trial ineligibility rates based on premorbid mRS. METHODS: In consecutive patients with ischemic stroke in a population-based, prospective, cohort study (Oxford Vascular Study; 2002-2014), we related 3-month mRS to 1-year and 5-year disability and death (logistic regressions), and health/social care costs (generalized linear model), adjusted for age/sex, and compared goodness-of-fit values (C statistic, mean absolute error). We also calculated the proportion of patients in whom premorbid mRS score >1 or >2 would result in exclusion from trials using dichotomous analysis. RESULTS: Among 1,607 patients, the ordinal mRS was more strongly related to 5-year mortality than both the 0-1/2-6 and 0-2/3-6 dichotomies (all p < 0.0001). Results were similar for 5-year disability, and 5-year care costs were also best captured by the ordinal model (change in mean absolute error vs age/sex: -$3,059 for ordinal, -$2,805 for 0-2/3-6, -$1,647 for 0-1/2-6). Two hundred forty-four (17.1%) 3-month survivors had premorbid mRS score >2 and 434 (30.5%) had mRS score >1; both proportions increased with female sex, socioeconomic deprivation, and age (all p < 0.0001). CONCLUSION: The ordinal form of the 3-month mRS relates better to long-term outcomes and costs in survivors of ischemic stroke than either dichotomy. This finding favors using ordinal approaches in trials analyzing the mRS. Exclusion of patients with higher premorbid disability by use of dichotomous primary outcomes will also result in unrepresentative samples.

Routine screening in the general hospital: what happens after discharge to those identified as at risk of dementia?

Cognitive screening is recommended for older patients with unplanned hospital admission. We determined rates of reassessment/specialist memory referral after routine inclusion of at risk of dementia status in discharge documentation to primary care. Questionnaires were sent to relevant GP practices on consecutive patients aged ≥75 years identified as at risk and discharged 6 months earlier. Among 53 patients (mean age ±SD = 87.3±6.0 years, mean±SD Abbreviated Mental Test Score = 4.4±2.7), 49 (92%) patients had been reviewed since discharge, and 12/43 (28%) without previously known cognitive problem had had a cognitive reassessment. The most common reasons for non-assessment/referral included clinical factors (eg terminal illness/comorbidities) (n=15) and patient/family wishes (n=5) and that confusion was expected in unwell older patients (n=5). Routine cognitive reassessment/specialist referral appears unjustified in patients identified as at risk of dementia during unplanned hospital admission. However, the prognostic value of delirium/confusion in acute illness is under-recognised and could be used to highlight those at risk.

Time Course of Evolution of Disability and Cause-Specific Mortality After Ischemic Stroke: Implications for Trial Design.

BACKGROUND: Outcome in stroke trials is often based on a 3-month modified Rankin scale (mRS). How 3-month mRS relates to longer-term outcomes will depend on late recovery, delayed stroke-related deaths, recurrent strokes, and nonstroke deaths. We evaluated 3-month mRS and death/disability at 1 and 5 years in a population-based cohort study. METHODS AND RESULTS: In 3-month survivors of ischemic stroke (Oxford Vascular Study; 2002-2014), we related 3-month mRS to disability (defined as mRS >2) at 1 and 5 years and/or death rates (age/sex adjusted). Accrual of disability and index-stroke-related and nonstroke deaths in each poststroke year was categorized according to 3-month mRS. Among 1606 patients with acute ischemic stroke, 181 died within 3 months, but 126 index-stroke-related deaths and 320 other deaths occurred during the subsequent 4866 patient-years of follow-up up to 5 years. Although 69/126 (54.8%) post-3-month index-stroke-related deaths occurred after 1 year, mRS>2 at 1 year strongly predicted these deaths (adjusted hazard ratio=21.94, 95%CI 7.88-61.09, P<0.0001). Consequently, a 3-month mRS >2 was a strong independent predictor of death at both 1 year (adjusted hazard ratio=6.67, 95%CI 4.16-10.69, P<0.0001) and 5 years (adjusted hazard ratio=2.93, 95%CI 2.38-3.60, P<0.0001). Although mRS improved by ≥1 point from 3 months to 1 year in 317/1266 (25.0%) patients with 3-month mRS ≥1, improvement in mRS after 1 year was limited (improvement by ≥1 point: 91/858 [10.6%]; improvement to mRS ≤2: 13/353 [3.7%]). CONCLUSIONS: Our results reaffirm use of the 3-month mRS outcome in stroke trials. Although later recovery does occur, extending follow-up to 1 year would capture most long-term stroke-related disability. However, administrative mortality follow-up beyond 1 year has the potential to demonstrate translation of early disability gains into additional reductions in long-term mortality without much erosion by non-stroke-related deaths.

Hemodynamic correlates of transient cognitive impairment after transient ischemic attack and minor stroke: A transcranial Doppler study.

BACKGROUND AND AIMS: Transient cognitive impairment (TCI) on the Mini Mental State Evaluation score is common after transient ischemic attack/minor stroke and might identify patients at increased risk of dementia. We aimed to replicate TCI using the Montreal Cognitive Assessment (MoCA), compare it with persistent Mild Cognitive Impairment (PMCI), and to determine whether global cerebral hemodynamic changes could explain transient impairment. METHODS: Consecutive patients with transient ischemic attack/minor stroke (NIHSS ≤ 3) were assessed with the MoCA and transcranial Doppler ultrasound acutely and at 1 month. We compared patients with TCI (baseline MoCA < 26 with ≥ 2 points increase at 1 month), PMCI (MoCA < 26 with < 2 points increase), and no cognitive impairment (NCI; MoCA ≥ 26). RESULTS: Of 326 patients, 46 (14.1%) had PMCI, 98 (30.1%) TCI, and 182 (55.8%) NCI. At baseline, TCI patients had higher systolic blood pressure (150.95 ± 21.52 vs 144.86 ± 22.44 mmHg, p = 0.02) and lower cerebral blood flow velocities, particularly end-diastolic velocity (30.16 ± 9.63 vs 35.02 ± 9.01 cm/s, p < 0.001) and mean flow velocity (48.95 ± 12.72 vs 54 ± 12.46 cm/s, p = 0.001) than those with NCI, but similar clinical and hemodynamic profiles to those with PMCI. Systolic BP fell between baseline and 1 month (mean reduction = 14.01 ± 21.26 mmHg) and end-diastolic velocity and mean flow velocity increased (mean increase = + 2.42 ± 6.41 and 1.89 ± 8.77 cm/s, respectively), but these changes did not differ between patients with TCI, PMCI, and NCI. CONCLUSIONS: TCI is detectable with the MoCA after transient ischemic attack and minor stroke and has similar clinical and hemodynamic profile to PMCI. However, TCI does not appear to be due to exaggerated acute reversible global hemodynamic changes.

Aberrant P53 expression lacks prognostic or predictive significance in colorectal cancer: results from the VICTOR trial.

AIM: Biomarkers with prognostic and predictive value can help stratify patients with colorectal cancer (CRC) into appropriate treatment groups. We sought to evaluate the clinical utility of P53 protein expression as a biomarker in VICTOR, a large phase III trial of rofecoxib in stage II and III CRC. PATIENTS AND METHODS: Tissue micro arrays were constructed from 884 tumors and the expression of P53 was examined by immunohistochemistry. Tumors were dichotomised as either P53-positive (nuclear expression in >10% of cells or the 'absent' pattern, both representing TP53 mutation) or P53-negative (nuclear expression in <10% of cells). RESULTS: Aberrant P53 expression was found in 65% (482/740) of patients. It was associated with distal location (p<0.001) and stage III disease (p<0.001). No effect was observed on disease-free or overall survival, and there was no interaction with chemotherapy or radiotherapy. CONCLUSION: Analysis of P53 expression in the patients recruited to the VICTOR trial confirmed that P53 expression is associated with site and stage of CRC. However, independently, this biomarker has neither prognostic nor predictive utility in this cohort of patients.

Impact of peer review on reports of randomised trials published in open peer review journals: retrospective before and after study.

OBJECTIVE: To investigate the effectiveness of open peer review as a mechanism to improve the reporting of randomised trials published in biomedical journals. DESIGN: Retrospective before and after study. SETTING: BioMed Central series medical journals. SAMPLE: 93 primary reports of randomised trials published in BMC-series medical journals in 2012. MAIN OUTCOME MEASURES: Changes to the reporting of methodological aspects of randomised trials in manuscripts after peer review, based on the CONSORT checklist, corresponding peer reviewer reports, the type of changes requested, and the extent to which authors adhered to these requests. RESULTS: Of the 93 trial reports, 38% (n=35) did not describe the method of random sequence generation, 54% (n=50) concealment of allocation sequence, 50% (n=46) whether the study was blinded, 34% (n=32) the sample size calculation, 35% (n=33) specification of primary and secondary outcomes, 55% (n=51) results for the primary outcome, and 90% (n=84) details of the trial protocol. The number of changes between manuscript versions was relatively small; most involved adding new information or altering existing information. Most changes requested by peer reviewers had a positive impact on the reporting of the final manuscript--for example, adding or clarifying randomisation and blinding (n=27), sample size (n=15), primary and secondary outcomes (n=16), results for primary or secondary outcomes (n=14), and toning down conclusions to reflect the results (n=27). Some changes requested by peer reviewers, however, had a negative impact, such as adding additional unplanned analyses (n=15). CONCLUSION: Peer reviewers fail to detect important deficiencies in reporting of the methods and results of randomised trials. The number of these changes requested by peer reviewers was relatively small. Although most had a positive impact, some were inappropriate and could have a negative impact on reporting in the final publication.

Modafinil for the treatment of fatigue in lung cancer: results of a placebo-controlled, double-blind, randomized trial.

PURPOSE: Fatigue is a distressing symptom occurring in more than 60% of patients with cancer. The CNS stimulants modafinil and methylphenidate are recommended for the treatment of cancer-related fatigue, despite a limited evidence base. We aimed to evaluate the efficacy and tolerability of modafinil in the management of fatigue in patients with non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Adults with advanced NSCLC and performance status of 0 to 2, who were not treated with chemotherapy or radiotherapy within the last 4 weeks, were randomly assigned to daily modafinil (100 mg on days 1 to 14; 200 mg on days 15 to 28) or matched placebo. The primary outcome was change in Functional Assessment of Chronic Illness Therapy (FACIT) -Fatigue score from baseline to 28 days, adjusted for baseline fatigue and performance status. Secondary outcomes included safety and patient-reported measures of depression, daytime sleepiness, and quality of life. RESULTS: A total of 208 patients were randomly assigned, and 160 patients (modafinil, n = 75; placebo, n = 85) completed questionnaires at both baseline and day 28 and were included in the modified intention-to-treat analysis. FACIT-Fatigue scores improved from baseline to day 28 (mean score change: modafinil, 5.29; 95% CI, 2.57 to 8.02; placebo, 5.09; 95% CI, 2.54 to 7.65), but there was no difference between treatments (0.20; 95% CI, -3.56 to 3.97). There was also no difference between treatments for the secondary outcomes; 47% of the modafinil group and 23% of the placebo group stated that the intervention was not helpful. CONCLUSION: Modafinil had no effect on cancer-related fatigue and should not be prescribed outside a clinical trial setting. Its use was associated with a clinically significant placebo effect.

Multicenter randomized controlled trial of conventional versus laparoscopic surgery for colorectal cancer within an enhanced recovery programme: EnROL.

PURPOSE: Laparoscopic resection and a multimodal approach known as an enhanced recovery program (ERP) have been major changes in colorectal perioperative care that have improved clinical outcomes for colorectal cancer resection. EnROL (Enhanced Recovery Open Versus Laparoscopic) is a multicenter randomized controlled trial examining whether the benefits of laparoscopy still exist when open surgery is optimized within an ERP. PATIENTS AND METHODS: Adults with colorectal cancer suitable for elective resection were randomly assigned at a ratio of 1:1 to laparoscopic or open surgery within an ERP, stratified by center, cancer site (colon v rectum), and age group (<66 v 66-75 v >75 years) using minimization. The primary outcome was physical fatigue at 1 month postsurgery. Secondary outcomes included hospital stay, complications, other patient-reported outcomes (PROs), and physical function. Patients and outcome assessors were blinded until 7 days postsurgery or discharge if earlier. Central independent and blinded pathologic assessment of surgical quality was undertaken. RESULTS: A total of 204 patients (laparoscopy, n=103; open surgery, n=101) were recruited from 12 UK centers from July 2008 to April 2012. One-month physical fatigue scores were similar in both groups (mean: laparoscopy, 12.28; 95% CI, 11.37 to 13.19 v open surgery, 12.05; 95% CI, 11.14 to 12.96; adjusted mean difference, -0.23; 95% CI, -1.52 to 1.07). Median total hospital stay was significantly shorter after laparoscopic surgery (median: laparoscopy, 5; interquartile range [IQR], 4 to 9 v open surgery, 7; IQR, 5 to 11 days; P=.033). There were no differences in other secondary outcomes or in specimen quality after central pathologic review. CONCLUSION: In patients treated by experienced surgeons within an ERP, physical fatigue and other PROs were similar in both groups, but laparoscopic surgery significantly reduced length of hospital stay.