Association of glomerular hyperfiltration with mortality in stroke: an analysis using pooled individual patient data

Background and Aims Associations of glomerular hyperfiltration with vascular events and death have been reported, particularly in community populations, but have scarcely been investigated in patients with stroke. Method Centres from the Microbleed International Collaborative Network (MICON) contributed data on estimated glomerular filtration rate (eGFR), recurrent stroke events and death. Using Cox proportional hazards regression modelling, we investigated associations of glomerular hyperfiltration with recurrent ischaemic stroke (IS), symptomatic intracranial haemorrhage (ICrH), death and vascular death. Hyperfiltration was defined as eGFR greater than the age and gender-adjusted 95th percentile. Hypofiltration was defined as eGFR <60 ml/min/1.73 m2. Results 11,175 patients (mean age 70.7, 42% female) were included, 554 with hyperfiltration and 2815 with eGFR<60. Compared to normofiltration, the hyperfiltration group had similar event rates for recurrent IS (37 vs. 35 events per 1000 patient-years) and ICrH (8 vs. 7 events). The rates of death (147 vs. 61) and vascular death (27 vs. 11) were significantly higher in the hyperfiltration group. In multivariable Cox regression models there was no significant association of hyperfiltration with IS (aHR 0.91, 95% CI 0.59 to 1.38) or ICrH (aHR 0.91, 95% CI 0.37 to 2.27). Compared to normofiltration, hyperfiltration was independently associated with the risk of death from any cause (aHR 1.53, 95% CI 1.22 to 1.93) and the risk of vascular death (aHR 1.83, 95% CI 1.09 to 3.08). Conclusion In this large international stroke population, glomerular hyperfiltration was independently associated with 53% increased risk of death, and 83% increased risk of vascular death. Nephrology advisory bodies could recommend screening for hyperfiltration to detect increased vascular risk earlier and in younger age groups.

Current guideline statements for primary and secondary prevention of cardiovascular disease (CVD) rely on estimates of absolute risk of coronary events. For example, the American Heart Association guidelines on primary prevention state that persons with ≥10% risk over 10 years of myocardial infarction (MI) or coronary death should be considered for antiplatelet therapy with aspirin.1 Similarly, the National Cholesterol Education Program Adult Treatment Panel III (ATP III) guidelines2 state that target low-density lipoprotein level should be based on projected absolute risk of future coronary events rather than on presence or absence of specific risk factors. These guidelines state that patients at high risk of MI and coronary death, defined as an absolute 10-year risk of ≥20%, should have a target low-density lipoprotein level <100 mg/dL and should receive statin therapy if needed to achieve this goal. Stroke, however, is not included as one of the outcomes contributing to these absolute risk levels. Included in the group of patients with elevated risk, moreover, are those who already have ischemic heart disease, as well as patients deemed to be “coronary heart disease (CHD) risk equivalents,” indicating those at the same elevated risk as patients with ischemic heart disease. CHD risk equivalents include patients with diabetes mellitus, those with multiple risk factors that put them at elevated risk based on calculation of their Framingham Score, and patients with “other forms of symptomatic atherosclerotic disease.” The latter group is further defined to include those with peripheral arterial disease (PAD), abdominal aortic aneurysm (AAA), and carotid artery disease. The category of “risk equivalents” in the ATP III guidelines, however, does not include the vast majority (≈80%3) of ischemic stroke patients without carotid artery disease as cause of their stroke. Ischemic stroke is therefore notably excluded from the list of outcomes contributing to …

We evaluated data on blacks and whites with acute ST-segment-elevation myocardial infarction treated with either fibrinolysis or primary percutaneous coronary intervention from the National Registry of Myocardial Infarction (NRMI)-4 and -5 participating centers between July 2000 and December 2006 to determine race-related differences in bleeding and outcomes. We found that among patients with ST-segment-elevation myocardial infarction receiving fibrinolysis, the bleeding rates were higher for blacks (n2283) than whites (n42 243; 10.9% versus 10.3%; adjusted odds ratio, 1.21; 95% confidence interval, 1.02-1.43). Similarly, in patients receiving primary percutaneous coronary intervention, the bleeding rates were higher in blacks (n2826) than whites (n46 332; 10.3% versus 7.8%; adjusted odds ratio, 1.33; 95% confidence interval, 1.13-1.56). Bleeding was associated with a higher risk of death in both ethnic groups. However, there was no overall racial difference in in-hospital mortality among those with bleeding or without bleeding treated with either fibrinolysis or primary percutaneous coronary intervention. We concluded that race-related differences existed in bleeding risk among patients with ST-segmentelevation myocardial infarction receiving reperfusion therapy that portend poor prognosis. Thus, the efficacy and safety of many new drugs or treatment strategies for any disease observed in clinical trials that enroll predominantly white patients may not be similar in other ethnic groups that are underrepresented in these trials.

World Kidney Day 2011: Protect Your Kidneys, Save Your Heart

<i>Circulation</i> Editors’ Picks

AHA/ACCF Scientific Statement on the Evaluation of Syncope

Mika Kivimaki initiated the Individual Participant Data (IPD) Meta-Analysis Consortium, which currently has 50 members. The Consortium recently published several research reports on the relationship between job strain (high psychological demands and low decision latitude at work), on the one hand, and cardiovascular disease and its risk factors, on the other hand. Since IPD repre- sents a novel way to conduct epidemiological research collaboration and as some of the findings from the IPD Consortium have been criticized, this commentary aims to address the rationales behind the approach and discuss some of the main criticisms of the Consortium.Researchers must tackle many problems when inter- preting associations between a psychosocial work envi- ronment factor and a health outcome. First of all, work environment factors belong to a "distal" rather than a "proximal" group. In other words, the closer one gets to a biological mechanism relevant for disease development, the more likely it is that a relevant association will be strong. For instance, small samples are needed to establish an individual "brain" factor associated with depression or emotional exhaustion - simply because the brain factor is more or less depression. Factors related to work orga- nization, on the other hand, are more "distal" since there are many factors that influence the relationship between the environment and the body's organs. Accordingly, it is sometimes difficult to obtain sufficient statistical power for the establishment of an undisputable association. For instance, the long "distance" between job strain and the outcome, myocardial infarction (MI), explains why we should expect a weaker association than in the study of "proximal" factors, for instance myocardial metabolism in relation to MI. Nevertheless, on a societal level, job strain is very important since it affects many working people, with a prevalence in the working population (in the IPD Consortium study's operational definition) of around 15%. Accordingly, if an unequivocal association is established, it is of major importance to those respon- sible for work organization and interventions designed to improve working conditions. However, large samples are needed to establish unequivocal proof.Since Karasek introduced his demand-control model (1), there have been many studies of the association between job strain and risk of MI. These studies have become increasingly sophisticated over the years. In addi- tion, there is accumulated indirect evidence from longitu- dinal studies of the relationship between job strain, on the one hand, and blood pressure variations and endocrine, metabolic, and immunological parameters, on the other hand. The results from these studies give us a plausible physiological explanation of the assumed relationship between job strain and MI risk.A reason why this research field has attracted strong attention is that MI is an undisputable illness outcome. The study of MI risk, therefore, serves as a good scientific model for studying the relationship between job strain and adverse health outcomes in general.Establishment of and rationale behind the IPD ConsortiumThere have been divided opinions about the relationship between job strain and risk of MI. The main reason for the controversy has been that, despite the relatively large size of several of the published cohort studies with number of observation years often in the range of 50 000, the statistical power has been too small for an unequivocal establishment of an association. As a result, Mika Kivimaki invited a number researchers, who had included psychosocial job factors in their study protocols and had or had not published results on the relationship between job strain and MI risk, to establish the IPD Consortium. Including unpublished cohorts was important as this provided a possibility to address the problem of publication bias - the tendency of research- ers and journals to publish only positive findings that can lead to inflated associations. …

BACKGROUND AND PURPOSE A low risk of recurrent stroke and death after lacunar infarction has previously been reported, but follow-up has been limited to </=5 years. One hundred eighty patients with pure motor stroke, collected between 1983 and 1986 from a hospital-based stroke registry, were followed up until at least 10 years after the index stroke. Two patients were lost to follow-up. Survival status was determined from the official population registry and compared with survival rates of the Swedish population, matched for age and sex. Cox proportional hazards regression analyses were used to identify independent prognostic predictors. During follow-up 106 (60%) of the 178 patients died, most commonly as a result of coronary heart disease. During the first 5 years after the stroke, survival rates were similar to those of the general population. Beyond this time the risk of death was increased among patients with pure motor stroke, with an excess of 10 to 15 percent units compared with the general population. Independent determinants for death were age (P<0.01), male sex (P<0.01), and nonuse of acetylsalicylic acid (P=0.02). Recurrent stroke occurred in 42 (23.5%) of the patients, corresponding to an annual risk of 2.4%. Hypertension (P=0.025) and diabetes (P=0.024) were independent risk factors for recurrent stroke. For the first few years after lacunar infarct, the risk of death was similar to that of the general population, but later a clear excess of death was observed. The long-term prognosis in lacunar infarction appears less favorable than previously reported.

Association Between Bilirubin and Mode of Death in Severe Systolic Heart Failure

> Among the many useful discoveries which this age has made, there are very few which better deserve the attention of the public that what I am going to lay before your Lordship. > > —Reverend Edward Stone –Chipping-Norton, Oxfordshire –April 25, 1763 These prophetic words, written by Reverend Edward Stone in a 1763 letter to George Parker, the second Earl of Macclesfield, describe the results of the first clinical trial recorded in medical history.1 Stone's report on the rediscovery of the medicinal value of willow bark among subjects suffering from malarial symptoms is considered a significant milestone in the development of aspirin. Although society now takes many of its beneficial effects for granted, aspirin did not suddenly appear for medicinal use after Reverend Stone's discovery. Instead, its tumultuous journey was fueled by individual scientific curiosity, accidental discoveries, and intense business rivalry.1 No other drug is used by a greater number of people worldwide than aspirin, the benefits of which span centuries, beginning with the very first uses of willow bark by Egyptian physicians (Figure 1). Aspirin single-handedly transformed a coal-dye company into a pharmaceutical giant and has emerged as a cornerstone in the present-day therapies available for treating cardiovascular disease (CVD), pain, and inflammation. This article discusses the sentinel historical aspects of the discovery and clinical cardiovascular developments of aspirin, as well as its contemporary use in today's medical arena. Figure 1. Timeline of historical events in the development of aspirin. ### Historical Developments of Salicylates On January 20, 1862, Edwin Smith made one of the most historically important purchases of his life. Well-regarded among his peers for his keen scholarship and intricate knowledge of Egyptology, Smith purchased, for £12, 2 worn papyrus scrolls in a local Luxor street market1 that later turned out to be a formative medical textbook unlocking ancient Egyptian's practice of medicine. Although authorless, the Ebers Papyrus is 110 pages …

Cerebral small vessel disease may be related to vascular and nonvascular pathology. We assessed whether lacunar infarcts and white matter lesions on MRI increased the risk of vascular and nonvascular death and future vascular events in patients with atherosclerotic disease. Brain MRI was performed in 1309 patients with atherosclerotic disease from the Second Manifestations of ARTerial disease-Magnetic Resonance (SMART-MR) study. Infarcts were scored visually and volumetric assessment of white matter lesion was performed. Patients were followed for a median of 4.5 years (range, 0.2 to 7.1 years) for death, ischemic stroke, and ischemic cardiac complications. Cox regression models showed that presence of lacunar infarcts (n=229) increased the risk of vascular (hazard ratio, 2.6; 95% CI, 1.4 to 4.9) and nonvascular death (hazard ratio, 2.7; 95% CI, 1.3 to 5.3), adjusted for age, sex, vascular risk factors, nonlacunar infarcts, and white matter lesion. These risks were similar for patients with silent lacunar infarcts. White matter lesion volume (relative to total intracranial volume) increased the risk of vascular death (hazard ratio per milliliter increase, 1.03; 95% CI, 1.01 to 1.05) and white matter lesions in the upper quintile compared with lower quintiles increased risk of ischemic stroke (hazard ratio, 2.6; 95% CI, 1.3 to 4.9). Cerebral small vessel disease, with or without a history of cerebrovascular disease, is associated with increased risk of death and ischemic stroke in patients with atherosclerotic disease.

Is There a Sex or Race Difference in Stroke Mortality?

BackgroundThe CRASH-3 trial hypothesised that timely tranexamic acid (TXA) treatment might reduce deaths from intracranial bleeding after traumatic brain injury (TBI). To explore the mechanism of action of TXA in TBI, we examined the timing of its effect on death.MethodsThe CRASH-3 trial randomised 9202 patients within 3 h of injury with a GCS score ≤ 12 or intracranial bleeding on CT scan and no significant extracranial bleeding to receive TXA or placebo. We conducted an exploratory analysis of the effects of TXA on all-cause mortality within 24 h of injury and within 28 days, excluding patients with a GCS score of 3 or bilateral unreactive pupils, stratified by severity and country income. We pool data from the CRASH-2 and CRASH-3 trials in a one-step fixed effects individual patient data meta-analysis.ResultsThere were 7637 patients for analysis after excluding patients with a GCS score of 3 or bilateral unreactive pupils. Of 1112 deaths, 23.3% were within 24 h of injury (early deaths). The risk of early death was reduced with TXA (112 (2.9%) TXA group vs 147 (3.9%) placebo group; risk ratio [RR] RR 0.74, 95% CI 0.58–0.94). There was no evidence of heterogeneity by severity (p = 0.64) or country income (p = 0.68). The risk of death beyond 24 h of injury was similar in the TXA and placebo groups (432 (11.5%) TXA group vs 421 (11.7%) placebo group; RR 0.98, 95% CI 0.69–1.12). The risk of death at 28 days was 14.0% in the TXA group versus 15.1% in the placebo group (544 vs 568 events; RR 0.93, 95% CI 0.83–1.03). When the CRASH-2 and CRASH-3 trial data were pooled, TXA reduced early death (RR 0.78, 95% CI 0.70–0.87) and death within 28 days (RR 0.88, 95% CI 0.82–0.94).ConclusionsTranexamic acid reduces early deaths in non-moribund TBI patients regardless of TBI severity or country income. The effect of tranexamic acid in patients with isolated TBI is similar to that in polytrauma. Treatment is safe and even severely injured patients appear to benefit when treated soon after injury.Trial registrationISRCTN15088122, registered on 19 July 2011; NCT01402882, registered on 26 July 2011.

Comorbidities and risk of death in atrial fibrillation: a nationwide cohort study

A B L E 1 Cause-specific risk of death among individuals diagnosed with polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF) between ages 20-84 years,