Jacoba P. Greving

Development of the PHASES score for prediction of risk of rupture of intracranial aneurysms: a pooled analysis of six prospective cohort studies

BACKGROUND The decision of whether to treat incidental intracranial saccular aneurysms is complicated by limitations in current knowledge of their natural history. We combined individual patient data from prospective cohort studies to determine predictors of aneurysm rupture and to construct a risk prediction chart to estimate 5-year aneurysm rupture risk by risk factor status. METHODS We did a systematic review and pooled analysis of individual patient data from 8382 participants in six prospective cohort studies with subarachnoid haemorrhage as outcome. We analysed cumulative rupture rates with Kaplan-Meier curves and assessed predictors with Cox proportional-hazard regression analysis. FINDINGS Rupture occurred in 230 patients during 29,166 person-years of follow-up. The mean observed 1-year risk of aneurysm rupture was 1·4% (95% CI 1·1-1·6) and the 5-year risk was 3·4% (2·9-4·0). Predictors were age, hypertension, history of subarachnoid haemorrhage, aneurysm size, aneurysm location, and geographical region. In study populations from North America and European countries other than Finland, the estimated 5-year absolute risk of aneurysm rupture ranged from 0·25% in individuals younger than 70 years without vascular risk factors with a small-sized (<7 mm) internal carotid artery aneurysm, to more than 15% in patients aged 70 years or older with hypertension, a history of subarachnoid haemorrhage, and a giant-sized (>20 mm) posterior circulation aneurysm. By comparison with populations from North America and European countries other than Finland, Finnish people had a 3·6-times increased risk of aneurysm rupture and Japanese people a 2·8-times increased risk. INTERPRETATION The PHASES score is an easily applicable aid for prediction of the risk of rupture of incidental intracranial aneurysms. FUNDING Netherlands Organisation for Health Research and Development.

Prevalence of Asymptomatic Carotid Artery Stenosis According to Age and Sex Systematic Review and Metaregression Analysis

Background and Purpose— In the discussion on the value of population-wide screening for asymptomatic carotid artery stenosis (ACAS), reliable prevalence estimates are crucial. We set out to provide reliable age- and sex-specific prevalence estimates of ACAS through a systematic literature review and meta-regression analysis. Methods— We searched PubMed and EmBase until December 2007 for studies that reported the prevalence of ACAS in a population free of symptomatic carotid artery disease. Data were extracted with use of a standardized form on participants’ characteristics, assessment method, study quality, and prevalence estimates for moderate (≥50% stenosis) and severe (≥70% stenosis) ACAS. Metaregression was used to investigate sources of heterogeneity. Results— Forty studies fulfilled the inclusion criteria. There was considerable variation among studies with respect to demographics, methods of grading stenosis, and stenosis cutoff point used. The pooled prevalence of moderate stenosis was 4.2% (95% CI, 3.1% to 5.7%). Prevalence of moderate stenosis among people age <70 years was 4.8% (95% CI, 3.1% to 7.3%) in men and 2.2% (95% CI, 0.9% to 4.9%) in women. Among those ≥70 years, prevalence increased to 12.5% (95% CI, 7.4% to 20.3%) in men and to 6.9% (95% CI, 4.0% to 11.5%) in women. Metaregression showed that both age and sex significantly affected the prevalence of moderate stenosis. No contribution of study size, publication year, geographic region, assessment method, and study quality was found. The pooled prevalence of severe stenosis was 1.7% (95% CI, 0.7% to 3.9%). Conclusions— Prevalence of moderate stenosis increases with age in both men and women, but men at all ages have the higher prevalence estimates. The number of studies that allowed meaningful data synthesis of severe stenosis was limited.

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=

Statin treatment for primary prevention of vascular disease: whom to treat? Cost-effectiveness analysis

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.

CT perfusion and delayed cerebral ischemia in aneurysmal subarachnoid hemorrhage: a systematic review and meta-analysis.

Objective To assess the cost-effectiveness of low dose statins for primary prevention of vascular disease, incorporating current prices, non-adherence (reduced clinical efficacy while maintaining healthcare costs), and the results of the recently published JUPITER trial. Design Cost-effectiveness analysis using a Markov model. Sensitivity analyses and Monte Carlo simulation evaluated the robustness of the results. Setting Primary care in The Netherlands. Participants Hypothetical populations of men and women aged 45 to 75 years without a history of vascular disease at different levels of risk for vascular disease (myocardial infarction and stroke) over 10 years. Interventions Low dose statin treatment daily versus no treatment for 10 years. Main outcome measures Number of fatal and nonfatal vascular events prevented, quality-adjusted life-years (QALYs), costs, and incremental cost-effectiveness ratios over 10 years. Results Over a 10-year period, statin treatment cost €35 000 (£30 000,

PHASES Score for Prediction of Intracranial Aneurysm Growth

49 000) per QALY gained for men aged 55 years with a 10-year vascular risk of 10%. The incremental cost-effectiveness ratio improved as risk for vascular disease increased. The cost per QALY ranged from approximately €5000 to €125 000 when the 10-year vascular risk for men aged 55 years was varied from 25% to 5%. The incremental cost-effectiveness ratio slightly decreased with age after the level of vascular risk was specified. Results were sensitive to the costs of statin treatment, statin effectiveness, non-adherence, disutility of taking medication daily, and the time horizon of the model. Conclusions In daily practice, statin treatment seemed not to be cost-effective for primary prevention in populations at low risk of vascular disease, despite low costs of generic drug pills. Adherence to statin treatment needs to be improved to enhance the cost-effectiveness of the use of statins for primary prevention.

Early Prediction of Delayed Cerebral Ischemia After Subarachnoid Hemorrhage: Development and Validation of a Practical Risk Chart

Delayed cerebral ischemia (DCI) is at presentation a diagnosis per exclusionem, and can only be confirmed with follow-up imaging. For treatment of DCI a diagnostic tool is needed. We performed a systematic review to evaluate the value of CT perfusion (CTP) in the prediction and diagnosis of DCI. We searched PubMed, Embase, and Cochrane databases to identify studies on the relationship between CTP and DCI. Eleven studies totaling 570 patients were included. On admission, cerebral blood flow (CBF), cerebral blood volume (CBV), mean transit time (MTT), and time-to-peak (TTP) did not differ between patients who did and did not develop DCI. In the DCI time-window (4 to 14 days after subarachnoid hemorrhage (SAH)), DCI was associated with a decreased CBF (pooled mean difference −11.9 mL/100 g per minute (95% confidence interval (CI): −15.2 to −8.6)) and an increased MTT (pooled mean difference 1.5 seconds (0.9–2.2)). Cerebral blood volume did not differ and TTP was rarely reported. Perfusion thresholds reported in studies were comparable, although the corresponding test characteristics were moderate and differed between studies. We conclude that CTP can be used in the diagnosis but not in the prediction of DCI. A need exists to standardize the method for measuring perfusion with CTP after SAH, and optimize and validate perfusion thresholds.

Predicting outcome after acute basilar artery occlusion based on admission characteristics.

Background and Purpose— Growth of an intracranial aneurysm occurs in around 10% of patients at 2-year follow-up imaging and may be associated with aneurysm rupture. We investigated whether PHASES, a score providing absolute risks of aneurysm rupture based on 6 easily retrievable risk factors, also predicts aneurysm growth. Methods— In a multicenter cohort of patients with unruptured intracranial aneurysms and follow-up imaging with computed tomography angiography or magnetic resonance angiography, we performed univariable and multivariable Cox regression analyses for the predictors of the PHASES score at baseline, with aneurysm growth as outcome. We calculated hazard ratios and corresponding 95% confidence intervals (CI), with the PHASES score as continuous variable and after division into quartiles. Results— We included 557 patients with 734 unruptured aneurysms. Eighty-nine (12%) aneurysms in 87 patients showed growth during a median follow-up of 2.7 patient-years (range 0.5–10.8). Per point increase in PHASES score, hazard ratio for aneurysm growth was 1.32 (95% CI, 1.22–1.43). With the lowest quartile of the PHASES score (0–1) as reference, hazard ratios were for the second (PHASES 2–3) 1.07 (95% CI, 0.49–2.32), the third (PHASES 4) 2.29 (95% CI, 1.05–4.95), and the fourth quartile (PHASES 5–14) 2.85 (95% CI, 1.43–5.67). Conclusions— Higher PHASES scores were associated with an increased risk of aneurysm growth. Because higher PHASES scores also predict aneurysm rupture, our findings suggest that aneurysm growth can be used as surrogate outcome measure of aneurysm rupture in follow-up studies on risk prediction or interventions aimed to reduce the risk of rupture.

Prediction of Asymptomatic Carotid Artery Stenosis in the General Population Identification of High-Risk Groups

Background and Purpose— To develop and validate a risk chart for prediction of delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage based on admission characteristics. Methods— For derivation of the risk chart, we studied data from 371 prospectively collected consecutive subarachnoid hemorrhage patients with a confirmed aneurysm admitted between 1999 and 2007. For its validation we similarly studied 255 patients admitted between 2007 and 2009. The predictive value of admission characteristics was tested in logistic regression models with delayed cerebral ischemia–related infarction as primary outcome. Procedure-related infarctions were not included. Performance of the models was tested by discrimination and calibration. On the basis of these models, a risk chart was developed for application in clinical practice. Results— The strongest predictors were clinical condition on admission, amount of blood on computed tomography (both cisternal and intraventricular) and age. A model that combined these 4 predictors had an area under the receiver operating characteristic curve of 0.63 (95% confidence interval, 0.57–0.69). This model improved little by including current smoking and hyperglycemia on admission (area under the receiver operating characteristic curve, 0.65; 95% confidence interval, 0.59–0.71). The risk chart predicted risks of delayed cerebral ischemia–related infarction varying from 12% to 61%. Both low risk (<20% risk) and high risk (>40% risk) were predicted in ≈20% of the patients. Validation confirmed that the discriminative ability was adequate (area under the receiver operating characteristic curve, 0.69; 95% confidence interval, 0.61–0.77). Conclusions— Absolute risks of delayed cerebral ischemia–related infarction can be reliably estimated by a simple risk chart that includes clinical condition on admission, amount of blood on computed tomography (both cisternal and intraventricular), and age.

Is centralization of ovarian cancer care warranted?: A cost-effectiveness analysis

Objective: To develop a simple prognostic model to predict outcome at 1 month after acute basilar artery occlusion (BAO) with readily available predictors. Methods: The Basilar Artery International Cooperation Study (BASICS) is a prospective, observational, international registry of consecutive patients who presented with an acute symptomatic and radiologically confirmed BAO. We considered predictors available at hospital admission in multivariable logistic regression models to predict poor outcome (modified Rankin Scale [mRS] score 4–5 or death) at 1 month. We used receiver operator characteristic curves to assess the discriminatory performance of the models. Results: Of the 619 patients, 429 (69%) had a poor outcome at 1 month: 74 (12%) had a mRS score of 4, 115 (19%) had a mRS score of 5, and 240 (39%) had died. The main predictors of poor outcome were older age, absence of hyperlipidemia, presence of prodromal minor stroke, higher NIH Stroke Scale (NIHSS) score, and longer time to treatment. A prognostic model that combined demographic data and stroke risk factors had an area under the receiver operating characteristic curve (AUC) of 0.64. This performance improved by including findings from the neurologic examination (AUC 0.79) and CT imaging (AUC 0.80). A risk chart showed predictions of poor outcome at 1 month varying from 25 to 96%. Conclusion: Poor outcome after BAO can be reliably predicted by a simple model that includes older age, absence of hyperlipidemia, presence of prodromal minor stroke, higher NIHSS score, and longer time to treatment.