Editor's Choice - Risk of Stroke before Revascularisation in Patients with Symptomatic Carotid Stenosis: A Pooled Analysis of Randomised Controlled Trials.

OBJECTIVE: Current guidelines recommending rapid revascularisation of symptomatic carotid stenosis are largely based on data from clinical trials performed at a time when best medical therapy was potentially less effective than today. The risk of stroke and its predictors among patients with symptomatic carotid stenosis awaiting revascularisation in recent randomised controlled trials (RCTs) and in medical arms of earlier RCTs was assessed. METHODS: The pooled data of individual patients with symptomatic carotid stenosis randomised to stenting (CAS) or endarterectomy (CEA) in four recent RCTs, and of patients randomised to medical therapy in three earlier RCTs comparing CEA vs. medical therapy, were compared. The primary outcome event was any stroke occurring between randomisation and treatment by CAS or CEA, or within 120 days after randomisation. RESULTS: A total of 4 754 patients from recent trials and 1 227 from earlier trials were included. In recent trials, patients were randomised a median of 18 (IQR 7, 50) days after the qualifying event (QE). Twenty-three suffered a stroke while waiting for revascularisation (cumulative 120 day risk 1.97%, 95% confidence interval [CI] 0.75 - 3.17). Shorter time from QE until randomisation increased stroke risk after randomisation (χ2 = 6.58, p = .011). Sixty-one patients had a stroke within 120 days of randomisation in the medical arms of earlier trials (cumulative risk 5%, 95% CI 3.8 - 6.2). Stroke risk was lower in recent than earlier trials when adjusted for time between QE and randomisation, age, severity of QE, and degree of carotid stenosis (HR 0.47, 95% CI 0.25 - 0.88, p = .019). CONCLUSION: Patients with symptomatic carotid stenosis enrolled in recent large RCTs had a lower risk of stroke after randomisation than historical controls. The added benefit of carotid revascularisation to modern medical care needs to be revisited in future studies. Until then, adhering to current recommendations for early revascularisation of patients with symptomatic carotid stenosis considered to require invasive treatment is advisable.

Cost-benefit of outcome adjudication in nine randomised stroke trials.

BACKGROUND: Central adjudication of outcomes is common for randomised trials and should control for differential misclassification. However, few studies have estimated the cost of the adjudication process. METHODS: We estimated the cost of adjudicating the primary outcome in nine randomised stroke trials (25,436 participants). The costs included adjudicators' time, direct payments to adjudicators, and co-ordinating centre costs (e.g. uploading cranial scans and general set-up costs). The number of events corrected after adjudication was our measure of benefit. We calculated cost per corrected event for each trial and in total. RESULTS: The primary outcome in all nine trials was either stroke or a composite that included stroke. In total, the adjudication process associated with this primary outcome cost in excess of £100,000 for a third of the trials (3/9). Mean cost per event corrected by adjudication was £2295.10 (SD: £1482.42). CONCLUSIONS: Central adjudication is a time-consuming and potentially costly process. These costs need to be considered when designing a trial and should be evaluated alongside the potential benefits adjudication brings to determine whether they outweigh this expense.

Outcome Assessment by Central Adjudicators Versus Site Investigators in Stroke Trials: A Systematic Review and Meta-Analysis.

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.

Prospective Randomized Open-label Trial to evaluate risk faCTor management in patients with Unruptured intracranial aneurysms: Study protocol.

RATIONALE: Unruptured intracranial aneurysms are currently left untreated if the presumed complication risk of preventive endovascular or neurosurgical intervention is higher than the risk of rupture. Aneurysm wall inflammation and blood pressure are attractive modifiable risk factors of aneurysm rupture and growth. AIM: To investigate in patients with an unruptured intracranial aneurysm who do not qualify for preventive endovascular or neurosurgical intervention whether a treatment strategy of acetylsalicylic acid 100 mg/day plus intensive blood pressure treatment (targeted systolic blood pressure < 120 mmHg, monitored with a home blood pressure measuring device) reduces the risk of aneurysm rupture or growth compared with care as usual (no acetylsalicylic acid, targeted office systolic blood pressure < 140 mmHg, no home blood pressure measuring device). SAMPLE SIZE: We aim to randomize 776 patients 1:1 to the intervention arm or care as usual. DESIGN: Bi-national (Germany and the Netherlands) multicenter, prospective, randomized, open-label phase III trial with blinded outcome assessment. OUTCOMES: The primary outcome is aneurysm rupture or growth (increase in any aneurysm diameter by ≥ 1 mm) on repeated MR or CT angiography within 36 ± 6 months after randomization. DISCUSSION: The Prospective Randomized Open-label Trial to Evaluate risk faCTor management in patients with Unruptured intracranial aneurysms (PROTECT-U) is the first randomized trial to investigate if a medical strategy reduces the risk of rupture or growth of intracranial aneurysms in patients not undergoing preventive endovascular or neurosurgical aneurysm treatment. Clinical trial Registration: NCT03063541.

Assessment of Migraine History in Patients with a Transient Ischemic Attack or Stroke; Validation of a Migraine Screener for Stroke.

BACKGROUND: To investigate the connection between migraine and stroke, a reliable screening tool to gather information about a person's migraine history is crucial. We studied the test-characteristics of a 5-question Migraine Screener for Stroke (MISS). METHODS: We included a random sample of patients with a transient ischemic attack or stroke who answered the MISS questionnaire when they were admitted to our hospital. After discharge, a semi-structured telephone interview was conducted to validate the migraine diagnosis with the International Classification of Headache Disorders, second-edition criteria as gold standard. RESULTS: Forty-nine (22.2%) of the 221 included patients were diagnosed with life-time migraine (38.5% women, 7.7% men). The sensitivity of all questions combined was 0.47 (95% CI 0.31-0.62), the specificity was 0.97 (95% CI 0.93-0.99), the positive predictive value (PPV) was 0.80 (95% CI 0.59-0.93) and the negative predictive value (NPV) was 0.87 (95% CI 0.82-0.92). One question related to the presence of headache accompanied by hypersensitivity to lights and sounds had a better sensitivity (0.96, 95% CI 0.85-1.00) and NPV (0.99, 95% CI 0.95-1.00) than all questions put together. For assessing migraine with aura, the question about visual disturbances had a good NPV (0.99, 95% CI 0.96-1.00), but a low PPV (0.38, 95% CI 0.24-0.53). CONCLUSIONS: The MISS questionnaire can be used by researchers to rule out migraine history in stroke patients. To prevent misclassification, especially for the aura symptoms, patients with a positive screener should be interviewed more extensively to confirm the migraine diagnosis.

Effects of carotid endarterectomy or stenting on arterial diameters in the circle of Willis.

BACKGROUND: In patients with internal carotid artery (ICA) stenosis, the circle of Willis (CoW) is the primary collateral pathway. We compared luminal diameters in the CoW before and after carotid revascularization and compared the effects of carotid endarterectomy (CEA) and stenting on these diameters. METHODS: At a single center in the International Carotid Stenting Study, 139 patients with symptomatic ICA stenosis of 50% or more were randomized to stenting (n = 81) or CEA (n = 58). The diameters of all segments of the CoW were assessed on computed tomography angiography (CTA), before and 30 days after revascularization. All evaluations were performed blinded to treatment allocation and order of CTA. RESULTS: A .10-mm increase (95% confidence interval [CI], .02-.17; 7%; P = .01) in diameter after revascularization occurred in the ipsilateral precommunicating anterior cerebral artery (A1), whereas both the ipsilateral and contralateral posterior communicating arteries decreased in diameter by .12 mm (95% CI, .04-.21; 14%; P = .01) and .08 mm (95% CI, .00-.17; 10%; P = .05), respectively. The increase in diameter of the A1 was larger after stenting (.15 mm; 95% CI, .07-.24; P = .001) than after CEA (.02 mm; 95% CI, -.11 to .15; P = .79). Only in patients treated with CEA, the diameters of the contralateral A1 and ipsilateral precommunicating posterior cerebral artery were reduced after revascularization. CONCLUSIONS: Carotid revascularization improves anterior collateralization and reduces reliance on posterior collateral pathways via the CoW. Carotid stenting and endarterectomy appear to have different early effects on collateralization.

Cost-effectiveness of surgical decompression for space-occupying hemispheric infarction.

BACKGROUND AND PURPOSE: Surgical decompression reduces mortality and increases the probability of a favorable functional outcome after space-occupying hemispheric infarction. Its cost-effectiveness is uncertain. METHODS: We assessed clinical outcomes, costs, and cost-effectiveness for the first 3 years in patients who were randomized to surgical decompression or best medical treatment within 48 hours after symptom onset in the Hemicraniectomy After Middle Cerebral Artery Infarction With Life-Threatening Edema Trial (HAMLET). Data on medical consumption were derived from case record files, hospital charts, and general practitioners. We calculated costs per quality-adjusted life year (QALY). Uncertainty was assessed with bootstrapping. A Markov model was constructed to estimate costs and health outcomes after 3 years. RESULTS: Of 39 patients enrolled within 48 hours, 21 were randomized to surgical decompression. After 3 years, 5 surgical (24%) and 14 medical patients (78%) had died. In the first 3 years after enrollment, operated patients had more QALYs than medically treated patients (mean difference, 1.0 QALY [95% confidence interval, 0.6-1.4]), but at higher costs (mean difference, €127,000 [95% confidence interval, 73,100-181,000]), indicating incremental costs of €127,000 per QALY gained. Ninety-eight percent of incremental cost-effectiveness ratios replicated by bootstrapping were >€80,000 per QALY gained. Markov modeling suggested costs of ≈€60,000 per QALY gained for a patient's lifetime. CONCLUSIONS: Surgical decompression for space-occupying infarction results in an increase in QALYs, but at very high costs. CLINICAL TRIAL REGISTRATION URL: http://www.controlled-trials.com. Unique identifier: ISRCTN94237756.

Mechanisms of gender-related outcome differences after carotid endarterectomy.

OBJECTIVE: Large randomized trials have confirmed a difference in outcome after carotid endarterectomy (CEA) between men and women. In this review, we aimed to provide an overview of the gender-specific characteristics causing these perioperative and long-term outcome differences between men and women after CEA. METHODS: A systematic search strategy with the synonyms of 'gender' and 'carotid endarterectomy' was conducted from PubMed and EMBASE databases. Only 11 relevant studies specifically discussing gender-specific related characteristics and their influence on outcome after CEA could be identified. RESULTS: Due to the limited number of included studies, pooling of findings was impossible, and results are presented in a descriptive manner. Each included study described only one possible gender-specific factor. Differences in carotid artery diameter, sex hormones, sensitivity for antiplatelet therapy, plaque morphology, occurrence of microembolic signals, and restenosis rate have all been suggested as gender-specific characteristics influencing outcome after CEA. CONCLUSION: Higher embolic potential in women and relatively stable female plaque morphology are the best-described factors influencing the difference in outcomes between men and women. However, the overall evidence for outcome differences by gender-specific characteristics in the literature is limited.

Comparison of telephone and face-to-face assessment of the modified Rankin Scale.

BACKGROUND: A structured interview improves the reliability of the modified Rankin Scale (mRS), a commonly used functional outcome scale in stroke trials. Telephone interview is a fast and convenient way to assess the mRS grade, but its validity is unknown. We assessed the validity of a telephone interview in patients who had had an aneurysmal subarachnoid haemorrhage (SAH) by comparing it with a face-to-face assessment. METHODS: Eighty-three SAH patients were interviewed twice, once face-to-face and once by telephone, by 2 of 5 observers who used a structured interview to assess the mRS grade. Intermodality agreement was measured using weighted kappa statistics. To check for systematic differences between face-to-face and telephone assessment the Wilcoxon test for matched pairs was used. RESULTS: Agreement between telephone and face-to-face assessment was perfect in 47 (57%) patients. A difference of 1 level occurred in 31 (37%) patients and this was almost equally distributed over the grades of the mRS. Weighted kappa was 0.71 (95% CI 0.59-0.82). Telephone assessment did not result in a consistently more or less favourable grade than face-to-face assessment (Wilcoxon test for matched pairs, p = 0.33). CONCLUSIONS: Telephone assessment of the mRS with a structured interview has a good agreement with face-to-face assessment and can thus be used reliably in the setting of a clinical trial.

Cost-effectiveness of preventive treatment of intracranial aneurysms: new data and uncertainties.

BACKGROUND: Previous modeling studies on treatment of unruptured intracranial aneurysms largely disregarded detailed data on treatment risks and omitted several factors that could influence cost-effectiveness. We performed a cost-effectiveness analysis of surgical and endovascular treatment of unruptured aneurysms for different rupture rates and life expectancies, and assessed the influence of excess mortality risks in these persons, de novo development of aneurysms, and utility of awareness of having an untreated aneurysm, and also identified important factors for which data are lacking. METHODS: We used a Markov model to compare surgical, endovascular, and no treatment of unruptured intracranial aneurysms. Inputs for the model were taken mainly from meta-analyses. Direct medical costs were derived from Dutch cost studies and expressed in 2005 Euros. We performed sensitivity analyses to evaluate model robustness. RESULTS: For 50-year-old patients, treatment of unruptured aneurysms is cost-effective for all rupture rate scenarios between 0.3% and 3.5%/year. In 70-year-old patients, treatment is not cost-effective in men with rupture rates < or =1%/year and women with rupture rates < or =0.5%/year. With lower utility of awareness of an untreated aneurysm, the cost-effectiveness of treatment strongly increased. The effect of excess mortality risks on the incremental cost-effectiveness ratios was modest. The risk of formation of new aneurysms had no relevant impact. CONCLUSIONS: Patients' life expectancy, risk of rupture, and utility of awareness of an untreated aneurysm mainly define cost-effectiveness. However, important uncertainties remain on the rupture risk according to size and location of the aneurysm and on the utility of awareness of untreated aneurysm. More data on these factors are needed to define and individualize cost-effectiveness analyses.

Growth rates of intracranial aneurysms: exploring constancy.

OBJECT: The annual rate of rupture of intracranial aneurysms is often assumed to be constant, but it is unknown whether this assumption is true. Recent case reports have suggested that aneurysms grow fast in a short period of time. The authors of the present report investigated the plausibility of a constant growth rate for intracranial aneurysms. METHODS: Assuming a constant aneurysm growth rate within an individual and varying rates between individuals, a hypothetical cohort was simulated. Individuals with high growth rates will display aneurysm formation and rupture at a young age; such persons disappear early from the hypothetical cohort. As a result the mean lesion growth rate varies over time. In hypothetical cohorts with different initial mean growth rates, the authors calculated age-specific incidence rates (per 100,000 person-years) of subarachnoid hemorrhage and compared these rates with population-based data on the incidence of subarachnoid hemorrhage (per 100,000 person-years). RESULTS: A hypothetical cohort with a mean initial growth rate of 0.18 mm/year reproduced most closely the incidence rates observed in the population. However, even for this most plausible hypothetical cohort, age-specific incidence rates in the model differed substantially and statistically significantly from those observed in the population. CONCLUSIONS: Based on the results of this study, it is unlikely that intracranial aneurysms in general grow at a constant time-independent rate. The authors hypothesized that the actual growth process is irregular and discontinuous, which results in periods with and without aneurysm growth and with high and low risks of rupture.

Cost-effectiveness of aspirin treatment in the primary prevention of cardiovascular disease events in subgroups based on age, gender, and varying cardiovascular risk.

BACKGROUND: Aspirin is effective for the primary prevention of cardiovascular events, but it remains unclear for which subgroups of individuals aspirin is beneficial. We assessed the cost-effectiveness of aspirin separately for men and women of different ages with various levels of cardiovascular disease risk. METHODS AND RESULTS: A Markov model was developed to predict the number of cardiovascular events prevented, quality-adjusted life-years, and costs over a 10-year period. Event rates were taken from Dutch population data, and the relative effectiveness of aspirin was taken from a gender-specific meta-analysis. Sensitivity analyses and Monte Carlo simulations were conducted to evaluate the robustness of the results. In 55-year-old persons, aspirin prevented myocardial infarctions in men (127 events per 100,000 person-years) and ischemic strokes in women (17 events per 100,000 person-years). Aspirin implies a net investment and a quality-adjusted life-year gain in men 55 years of age; the incremental cost-effectiveness ratio was 111,949 euros per quality-adjusted life-year (1 euro=$1.27 as of June 2007). Aspirin was cost-effective for 55- and 65-year-old men with moderate cardiovascular risk and men 75 years of age (10-year cardiovascular disease risk >10%). Conversely, aspirin was beneficial for women 65 years of age with high cardiovascular risk and women 75 years of age with moderate cardiovascular risk (10-year cardiovascular disease risk >15%). Results were sensitive to drug treatment costs, effectiveness of aspirin treatment, and utility of taking aspirin. CONCLUSIONS: Aspirin treatment for primary prevention is cost-effective for men with a 10-year cardiovascular disease risk of >10% and for women with a risk of >15%. This occurs much later in life for women than men. Therefore, opportunities for the primary prevention of aspirin seem limited in women, and a differentiated preventive strategy seems warranted.

Underfunding of stroke research: a Europe-wide problem.

BACKGROUND AND PURPOSE: Previous studies in the United States and the United Kingdom have shown that stroke research is underfunded compared with coronary heart disease (CHD) and cancer research despite the high clinical and financial burden of stroke. We aimed to determine whether underfunding of stroke research is a Europe-wide problem. METHODS: Data for the financial year 2000 to 2001 were collected from 9 different European countries. Information on stroke, CHD, and cancer research funding awarded by disease-specific charities and nondisease-specific charity or government- funded organizations was obtained from annual reports, web sites, and by direct communication with organizations. RESULTS: There was marked and consistent underfunding of stroke research in all the countries studied. Stroke funding as a percentage of the total funding for stroke, CHD, and cancer was uniformly low, ranging from 2% to 11%. Funding for stroke was less than funding for cancer, usually by a factor of > or =10. In every country except Turkey, funding for stroke research was less than that for CHD. CONCLUSIONS: This study confirms that stroke research is grossly underfunded, compared with CHD and cancer, throughout Europe. Similar data have been obtained from the United States suggesting that relative underfunding of stroke research is likely to be a worldwide phenomenon.

Prospective cohort study of routine use of risk assessment scales for prediction of pressure ulcers.

OBJECTIVE: To evaluate whether risk assessment scales can be used to identify patients who are likely to get pressure ulcers. DESIGN: Prospective cohort study. SETTING: Two large hospitals in the Netherlands. PARTICIPANTS: 1229 patients admitted to the surgical, internal, neurological, or geriatric wards between January 1999 and June 2000. MAIN OUTCOME MEASURE: Occurrence of a pressure ulcer of grade 2 or worse while in hospital. RESULTS: 135 patients developed pressure ulcers during four weeks after admission. The weekly incidence of patients with pressure ulcers was 6.2% (95% confidence interval 5.2% to 7.2%). The area under the receiver operating characteristic curve was 0.56 (0.51 to 0.61) for the Norton scale, 0.55 (0.49 to 0.60) for the Braden scale, and 0.61 (0.56 to 0.66) for the Waterlow scale; the areas for the subpopulation, excluding patients who received preventive measures without developing pressure ulcers and excluding surgical patients, were 0.71 (0.65 to 0.77), 0.71 (0.64 to 0.78), and 0.68 (0.61 to 0.74), respectively. In this subpopulation, using the recommended cut-off points, the positive predictive value was 7.0% for the Norton, 7.8% for the Braden, and 5.3% for the Waterlow scale. CONCLUSION: Although risk assessment scales predict the occurrence of pressure ulcers to some extent, routine use of these scales leads to inefficient use of preventive measures. An accurate risk assessment scale based on prospectively gathered data should be developed.