Stroke patients with prior use of direct oral anticoagulants have a lower risk of in-hospital mortality than stroke patients with prior use of warfarin.

Association of Intracerebral Hemorrhage Among Patients Taking Non–Vitamin K Antagonist vs Vitamin K Antagonist Oral Anticoagulants With In-Hospital Mortality

Importance Although non–vitamin K antagonist oral anticoagulants (NOACs) are increasingly used to prevent thromboembolic disease, there are limited data on NOAC-related intracerebral hemorrhage (ICH). Objective To assess the association between preceding oral anticoagulant use (warfarin, NOACs, and no oral anticoagulants [OACs]) and in-hospital mortality among patients with ICH. Design, Setting, and Participants Retrospective cohort study of 141 311 patients with ICH admitted from October 2013 to December 2016 to 1662 Get With The Guidelines–Stroke hospitals. Exposures Anticoagulation therapy before ICH, defined as any use of OACs within 7 days prior to hospital arrival. Main Outcomes and Measures In-hospital mortality. Results Among 141 311 patients with ICH (mean [SD] age, 68.3 [15.3] years; 48.1% women), 15 036 (10.6%) were taking warfarin and 4918 (3.5%) were taking NOACs preceding ICH, and 39 585 (28.0%) and 5783 (4.1%) were taking concomitant single and dual antiplatelet agents, respectively. Patients with prior use of warfarin or NOACs were older and had higher prevalence of atrial fibrillation and prior stroke. Acute ICH stroke severity (measured by the National Institutes of Health Stroke Scale) was not significantly different across the 3 groups (median, 9 [interquartile range, 2-21] for warfarin, 8 [2-20] for NOACs, and 8 [2-19] for no OACs). The unadjusted in-hospital mortality rates were 32.6% for warfarin, 26.5% for NOACs, and 22.5% for no OACs. Compared with patients without prior use of OACs, the risk of in-hospital mortality was higher among patients with prior use of warfarin (adjusted risk difference [ARD], 9.0% [97.5% CI, 7.9% to 10.1%]; adjusted odds ratio [AOR], 1.62 [97.5% CI, 1.53 to 1.71]) and higher among patients with prior use of NOACs (ARD, 3.3% [97.5% CI, 1.7% to 4.8%]; AOR, 1.21 [97.5% CI, 1.11-1.32]). Compared with patients with prior use of warfarin, patients with prior use of NOACs had a lower risk of in-hospital mortality (ARD, −5.7% [97.5% CI, −7.3% to −4.2%]; AOR, 0.75 [97.5% CI, 0.69 to 0.81]). The difference in mortality between NOAC-treated patients and warfarin-treated patients was numerically greater among patients with prior use of dual antiplatelet agents (32.7% vs 47.1%; ARD, −15.0% [95.5% CI, −26.3% to −3.8%]; AOR, 0.50 [97.5% CI, 0.29 to 0.86]) than among those taking these agents without prior antiplatelet therapy (26.4% vs 31.7%; ARD, −5.0% [97.5% CI, −6.8% to −3.2%]; AOR, 0.77 [97.5% CI, 0.70 to 0.85]), although the interaction P value (.07) was not statistically significant. Conclusions and Relevance Among patients with ICH, prior use of NOACs or warfarin was associated with higher in-hospital mortality compared with no OACs. Prior use of NOACs, compared with prior use of warfarin, was associated with lower risk of in-hospital mortality.

Primary prevention of ischemic stroke: A statement for healthcare professionals from the Stroke Council of the American Heart Association.

Stroke ranks as the third leading cause of death in the United States. It is now estimated that there are more than 700 000 incident strokes annually and 4.4 million stroke survivors.1 2 The economic burden of stroke was estimated by the American Heart Association to be $51 billion (direct and indirect costs) in 1999.3 Despite the advent of treatment of selected patients with acute ischemic stroke with tissue plasminogen activator and the promise of other experimental therapies, the best approach to reducing the burden of stroke remains prevention.4 5 High-risk or stroke-prone individuals can be identified and targeted for specific interventions.6 This is important because epidemiological data suggest a substantial leveling off of prior declines in stroke-related mortality and a possible increase in stroke incidence.7 8   The Stroke Council of the American Heart Association formed an ad hoc writing group to provide a clear and concise overview of the evidence regarding various established and potential stroke risk factors. The writing group was chosen based on expertise in specific subject areas, and it used literature review, reference to previously published guidelines, and expert opinion to summarize existing evidence and formulate recommendations (Table 1⇓). View this table:   Table 1. Levels of Evidence and Grading of Recommendations    As given in Tables 2 through 4⇓⇓⇓, risk factors or risk markers for a first stroke were classified according to potential for modification (nonmodifiable, modifiable, or potentially modifiable) and strength of evidence (well documented, less well documented).5 The tables give the estimated prevalence, population attributable risk, relative risk, and risk reduction with treatment for each factor when known. Population attributable risk reflects the proportion of ischemic strokes in the population that can be attributed to a particular risk factor and is given by the formula 100×[prevalence(relative risk−1)/prevalence(relative risk−1)+1]). …

Low drug levels and thrombotic complications in high‐risk atrial fibrillation patients treated with direct oral anticoagulants

Essentials Direct oral anticoagulants (DOACs) do not require laboratory monitoring currently. DOAC specific measurements were performed at trough in patients with atrial fibrillation. Patients who developed thromboembolic events showed lower DOAC plasma levels. This study supports the concept of measuring DOAC levels at steady state. SUMMARY Background Direct oral anticoagulants (DOACs) are administered at fixed doses without the need for dose adjustment according to laboratory testing. High interindividual variability in drug blood levels has been shown with all DOACs. To evaluate a possible relationship between DOAC C-trough anticoagulant levels and thromboembolic events, 565 consecutive naive patients with atrial fibrillation (AF) were enrolled in this study performed within the START Laboratory Registry. Methods DOAC-specific measurements (diluted thrombin time or anti-activated factor II calibrated for dabigatran; anti-activated FX calibrated for rivaroxaban or apixaban) at C-trough were performed locally at steady state within 15-25 days after the start of treatment. For each DOAC, the interval of C-trough levels, from the limit of quantification to the highest value, was subdivided into four equal classes, and results were attributed to these classes; the median values of results were also calculated. Thromboembolic complications occurring during 1 year of follow-up were recorded. Results Thromboembolic events (1.8%) occurred in 10 patients who had baseline C-trough levels in the lowest class of drug levels. The incidence of thromboembolic events among patients with DOAC C-trough levels in the lowest level class was 2.4%, and that in the remaining groups was 0%. The patients with thrombotic complications also had a higher mean CHA2 DS2 -VASc score than that of the total patient population: 5.3 (95% confidence interval [CI] 4.3-6.3 versus 3.0 (95% CI 2.9-3.1). Conclusion In this study cohort, thrombotic complications occurred only in DOAC-treated AF patients who had very low C-trough levels, with a relatively high CHA2 DS2 -VASc score. Larger studies are warranted to confirm these preliminary observations.

Recurrent venous thromboembolism and bleeding complications during anticoagulant treatment in patients with cancer and venous thrombosis.

A small proportion of patients with deep vein thrombosis develop recurrent venous thromboembolic complications or bleeding during anticoagulant treatment. These complications may occur more frequently if these patients have concomitant cancer. This prospective follow-up study sought to determine whether in thrombosis patients those with cancer have a higher risk for recurrent venous thromboembolism or bleeding during anticoagulant treatment than those without cancer. Of the 842 included patients, 181 had known cancer at entry. The 12-month cumulative incidence of recurrent thromboembolism in cancer patients was 20.7% (95% CI, 15.6%-25.8%) versus 6.8% (95% CI, 3.9%- 9.7%) in patients without cancer, for a hazard ratio of 3.2 (95% CI, 1.9-5.4) The 12-month cumulative incidence of major bleeding was 12.4% (95% CI, 6.5%-18.2%) in patients with cancer and 4.9% (95% CI, 2.5%-7.4%) in patients without cancer, for a hazard ratio of 2.2 (95% CI, 1.2-4.1). Recurrence and bleeding were both related to cancer severity and occurred predominantly during the first month of anticoagulant therapy but could not be explained by sub- or overanticoagulation. Cancer patients with venous thrombosis are more likely to develop recurrent thromboembolic complications and major bleeding during anticoagulant treatment than those without malignancy. These risks correlate with the extent of cancer. Possibilities for improvement using the current paradigms of anticoagulation seem limited and new treatment strategies should be developed.

In-hospital switching of oral P2Y12 inhibitor treatment in patients with acute coronary syndrome undergoing percutaneous coronary intervention: prevalence, predictors and short-term outcome.

BACKGROUND P2Y12 inhibitor switching has appeared in clinical practice as a consequence of prasugrel and ticagrelor availability, apart from clopidogrel, for use in patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI). METHODS In the context of the GReek AntiPlatelet REgistry (GRAPE) we assessed the prevalence, predictive factors and short-term outcome of in-hospital P2Y12 inhibitor switching in 1794 ACS patients undergoing PCI. RESULTS Switching occurred in 636 (35.5%) patients of which in the form of clopidogrel to a novel agent, novel agent to clopidogrel and between prasugrel and ticagrelor in 574 (90.4%), 34 (5.3%) and 27 (4.3%) patients, respectively. Presentation to non PCI-capable hospital, bivalirudin use, age ≥75 years (inverse predictor), and regional trends emerged as predictive factors of switching to a novel agent. At combined in-hospital and one-month follow-up, propensity matched pairs analysis showed no differences in major adverse cardiovascular (MACE) or bleeding events between switching from clopidogrel to a novel agent vs novel agent constant administration. More Bleeding Academic Research Consortium type 1, type 2 and any type events and fewer MACE were seen when switching from clopidogrel to a novel agent vs only clopidogrel administration (23.7%, 3.8%, 30.6%, 1.2% vs 8.9%, 1.2%, 12.0%, 3.8% with P < .001, P = .03, P < .001 and P = .03 respectively). CONCLUSIONS In a real-life experience with contemporary antiplatelet treatment in ACS patients undergoing PCI, in-hospital switching represents common clinical practice. Clinical factors and regional practice differences seem to affect this strategy's choice, while switching to a novel agent may be associated with higher risk of bleeding.

Pharmacokinetic, pharmacodynamic and clinical profile of novel antiplatelet drugs targeting vascular diseases.

Platelet inhibitors are the mainstay treatment for patients with vascular diseases. The current 'gold standard' antiplatelet agent clopidogrel has several pharmacological and clinical limitations that have prompted the search for more effective platelet antagonists. The candidates include various blockers of the purinergic P2Y12 receptor such as prasugrel, an oral irreversible thienopyridine; two adenosine triphosphate analogues that bind reversibly to the P2Y12 receptor: ticagrelor (oral) and cangrelor (intravenous); elinogrel, a direct-acting reversible P2Y12 receptor inhibitor (the only antiplatelet compound that can be administered both intravenously and orally); BX 667, an orally active and reversible small-molecule P2Y12 receptor antagonist; SCH 530348, SCH 205831, SCH 602539 and E5555, highly selective and orally active antagonists on the protease-activated receptor 1. A number of drugs also hit new targets: terutroban, an oral, selective and specific inhibitor of the thromboxane receptor; ARC1779, a second-generation, nuclease resistant aptamer which inhibits von Willebrand factor-dependent platelet aggregation; ALX-0081, a bivalent humanized nanobody targeting the GPIb binding site of von Willebrand factor and AJW200, an IgG4 monoclonal antibody of von Willebrand factor. The pharmacology and clinical profiles of new platelet antagonists indicate that they provide more consistent, more rapid and more potent platelet inhibition than agents currently used. Whether these potential advantages will translate into clinical advantages will require additional comparisons in properly powered, randomized, controlled trials.

Mortality risk in patients with dementia treated with antipsychotics versus other psychiatric medications.

OBJECTIVE Mortality rates in the year following new antipsychotic medication starts for neuropsychiatric symptoms of dementia were compared with rates after starts of other psychiatric medications. METHOD The retrospective, cohort study used national data from the Department of Veterans Affairs (fiscal years 2001-2005) on patients older than 65 years who began outpatient treatment with psychiatric medication following a dementia diagnosis (N=10,615). Twelve-month mortality rates were compared in patients taking antipsychotics and those taking other psychiatric medications. The authors controlled for confounding by using multivariate models and propensity-scoring methods. Secondary analyses included a no-medication group and examination of mortality causes. RESULTS All groups taking antipsychotics had significantly higher mortality rates (22.6%-29.1%) than patients taking nonantipsychotic medications (14.6%). Adjusted mortality risks for atypicals and for combined atypical and conventional antipsychotics were similar to those for conventional antipsychotics. The mortality risk was significantly lower for nonantipsychotic medications than conventional antipsychotics. Except for anticonvulsants, the adjusted risks for all individual classes of nonantipsychotics were significantly lower than the risk for antipsychotics. Mortality risks did not change over 12 months. The proportions of patients taking antipsychotics who died from cerebrovascular, cardiovascular, or infectious causes were not higher than rates for those taking nonantipsychotic psychiatric medications. CONCLUSIONS Antipsychotic medications taken by patients with dementia were associated with higher mortality rates than were most other medications used for neuropsychiatric symptoms. The association between mortality and antipsychotics is not well understood and may be due to a direct medication effect or the pathophysiology underlying neuropsychiatric symptoms that prompt antipsychotic use.

Fingolimod provides long-term protection in rodent models of cerebral ischemia.

OBJECTIVE The sphingosine-1-phosphate (S1P) receptor agonist fingolimod (FTY720), that has shown efficacy in advanced multiple sclerosis clinical trials, decreases reperfusion injury in heart, liver, and kidney. We therefore tested the therapeutic effects of fingolimod in several rodent models of focal cerebral ischemia. To assess the translational significance of these findings, we asked whether fingolimod improved long-term behavioral outcomes, whether delayed treatment was still effective, and whether neuroprotection can be obtained in a second species. METHODS We used rodent models of middle cerebral artery occlusion and cell-culture models of neurotoxicity and inflammation to examine the therapeutic potential and mechanisms of neuroprotection by fingolimod. RESULTS In a transient mouse model, fingolimod reduced infarct size, neurological deficit, edema, and the number of dying cells in the core and periinfarct area. Neuroprotection was accompanied by decreased inflammation, as fingolimod-treated mice had fewer activated neutrophils, microglia/macrophages, and intercellular adhesion molecule-1 (ICAM-1)-positive blood vessels. Fingolimod-treated mice showed a smaller infarct and performed better in behavioral tests up to 15 days after ischemia. Reduced infarct was observed in a permanent model even when mice were treated 4 hours after ischemic onset. Fingolimod also decreased infarct size in a rat model of focal ischemia. Fingolimod did not protect primary neurons against glutamate excitotoxicity or hydrogen peroxide, but decreased ICAM-1 expression in brain endothelial cells stimulated by tumor necrosis factor alpha. INTERPRETATION These findings suggest that anti-inflammatory mechanisms, and possibly vasculoprotection, rather than direct effects on neurons, underlie the beneficial effects of fingolimod after stroke. S1P receptors are a highly promising target in stroke treatment.

Effect of hydroxyethyl starch on bleeding after cardiopulmonary bypass: a meta-analysis of randomized trials.

OBJECTIVE The effects of hydroxyethyl starch on bleeding after cardiopulmonary bypass were determined. METHODS A meta-analysis was performed of postoperative blood loss in randomized clinical trials of hydroxyethyl starch versus albumin for fluid management in adult cardiopulmonary bypass surgery. Impacts of hydroxyethyl starch molecular weight and molar substitution were assessed. Randomized trials directly comparing different hydroxyethyl starch solutions were also included. RESULTS Eighteen trials with 970 total patients were included. Compared with albumin, hydroxyethyl starch increased postoperative blood loss by 33.3% of a pooled SD (95% confidence interval, 18.2%-48.3%; P < .001). Risk of reoperation for bleeding was more than doubled by hydroxyethyl starch (relative risk, 2.24; 95% confidence interval, 1.14-4.40; P = .020). Hydroxyethyl starch increased transfusion of red blood cells by 28.4% of a pooled SD (95% confidence interval, 12.2%-44.6%; P < .001), of fresh-frozen plasma by 30.6% (95% confidence interval, 8.0%-53.1%; P = .008), and of platelets by 29.8% (95% confidence interval, 3.4%-56.2%; P = .027). None of these effects differed significantly between hydroxyethyl starch 450/0.7 and 200/0.5. Insufficient data were available for hydroxyethyl starch 130/0.4 versus albumin; however, no significant differences were detected in head-to-head comparisons of hydroxyethyl starch 130/0.4 with 200/0.5. Albumin improved hemodynamics. There were no differences in fluid balance, ventilator time, intensive care unit stay, or mortality. CONCLUSIONS Hydroxyethyl starch increased blood loss, reoperation for bleeding, and blood product transfusion after cardiopulmonary bypass. There was no evidence that these risks could be mitigated by lower molecular weight and substitution.

Effects of Thiazolidinediones on Stroke Recovery: A Case-Matched Controlled Study

Anti-inflammatory therapy decreases infarct size and enhances stroke recovery. Thiazolidinedione peroxisome proliferator-activated receptor (PPAR)gamma agonists have potent anti-inflammatory and insulin-sensitizing anti-diabetic actions. Thirty stroke patients with type 2 diabetes admitted for acute inpatient stroke rehabilitation receiving pioglitazone or rosiglitazone were matched for age, sex, initial FIMTM score and interval post-stroke with 30 stroke patients with type 2 diabetes not receiving thiazolidinediones. Relevant outcome variables were compared for both groups. The thiazolidinedione treated group showed significantly greater mean improvement in FIMTM score compared to control group (25.6 ± 10.2 SD vs. 19.8 ± 10.5, respectively, P = 0.015). There was no significant difference in length of rehabilitation hospital stay (24.2 ± 7.6 vs. 25.1 ± 7.4 days, P = 0.657) or final discharge destination (home/institution, 19/11 versus 17/13, P = 0.792). Use of thiazolidinediones was associated with enhanced functional recovery in stroke patients with type 2 diabetes.

Predicting mortality of patients hospitalized for acutely exacerbated chronic obstructive pulmonary disease.

PURPOSE To identify factors affecting the short-term prognosis of patients with acutely exacerbated chronic obstructive pulmonary disease (COPD). PATIENTS AND METHODS The 590 patients having COPD as primary disease who were hospitalized in the pneumology unit of a university hospital from 1981 to 1990 were studied. A standardized protocol for the treatment of acutely exacerbated COPD was adopted for all the patients. The patient records were retrospectively analyzed by two observers, and 23 clinical and laboratory variables defining the patient status on admission were collected. Age and arterial gas data were also taken into account, and the outcome mortality was recorded. Interobserver reproducibility was tested by computing the kappa coefficient and Spearman's rho for dichotomous and continuous variables, respectively. The relationship of clinical and laboratory factors to the outcome was assessed first by univariate analysis and then by a logistic regression analysis assessing the independent predictive role of variables previously shown to be univariately correlated with mortality. RESULTS The mortality rate was 14.4%. The logistic regression analysis identified four independent predictors of death: age (odds ratio [OR] 1.07; 95% confidence interval [CI] 1.04 to 1.11), alveolar-arterial oxygen gradient greater than 41 mm Hg (OR 2.33; 95% CI 1.39 to 3.90), ventricular arrhythmias (OR 1.91; 95% CI 1.10 to 3.31), and atrial fibrillation (OR 2.27; 95% CI 1.14 to 4.51). CONCLUSIONS Patients with acutely exacerbated COPD having a high risk of death can be identified at the time of admission. Variables reflecting heart dysfunction are important determinants of this risk. Among pulmonary function data, only alveolar-arterial oxygen gradient contributes to the predictive model.

Ticagrelor vs. clopidogrel in patients with acute coronary syndromes and diabetes: a substudy from the PLATelet inhibition and patient Outcomes (PLATO) trial

AIMS patients with diabetes mellitus (DM) have high platelet reactivity and are at increased risk of ischaemic events and bleeding post-acute coronary syndromes (ACS). In the PLATelet inhibition and patient Outcomes (PLATO) trial, ticagrelor reduced the primary composite endpoint of cardiovascular death, myocardial infarction, or stroke, but with similar rates of major bleeding compared with clopidogrel. We aimed to investigate the outcome with ticagrelor vs. clopidogrel in patients with DM or poor glycaemic control. METHODS AND RESULTS we analysed patients with pre-existing DM (n = 4662), including 1036 patients on insulin, those without DM (n = 13 951), and subgroups based on admission levels of haemoglobin A1c (HbA1c; n = 15 150). In patients with DM, the reduction in the primary composite endpoint (HR: 0.88, 95% CI: 0.76-1.03), all-cause mortality (HR: 0.82, 95% CI: 0.66-1.01), and stent thrombosis (HR: 0.65, 95% CI: 0.36-1.17) with no increase in major bleeding (HR: 0.95, 95% CI: 0.81-1.12) with ticagrelor was consistent with the overall cohort and without significant diabetes status-by-treatment interactions. There was no heterogeneity between patients with or without ongoing insulin treatment. ticagrelor reduced the primary endpoint, all-cause mortality, and stent thrombosis in patients with HbA1c above the median (HR: 0.80, 95% CI: 0.70-0.91; HR: 0.78, 95% CI: 0.65-0.93; and HR: 0.62, 95% CI: 0.39-1.00, respectively) with similar bleeding rates (HR: 0.98, 95% CI: 0.86-1.12). CONCLUSION ticagrelor, when compared with clopidogrel, reduced ischaemic events in ACS patients irrespective of diabetic status and glycaemic control, without an increase in major bleeding events.

In-hospital switching between adenosine diphosphate receptor inhibitors in patients with acute myocardial infarction treated with percutaneous coronary intervention: Insights into contemporary practice from the TRANSLATE-ACS study.

AIMS While randomized clinical trials have compared clopidogrel with higher potency adenosine diphosphate (ADP) receptor inhibitors among patients with acute myocardial infarction, little is known about the frequency, effectiveness and safety of switching between ADP receptor inhibitors in routine clinical practice. METHODS AND RESULTS We studied 11,999 myocardial infarction patients treated with percutaneous coronary intervention at 230 hospitals from April 2010 to October 2012 in the TRANSLATE-ACS study. Multivariable Cox regression was used to compare six-month post-discharge risks of major adverse cardiovascular events (MACE: death, myocardial infarction, stroke, or unplanned revascularization) and Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries (GUSTO)-defined bleeding between in-hospital ADP receptor inhibitor switching versus continuation of the initially selected therapy. Among 8715 patients treated initially with clopidogrel, 994 (11.4%) were switched to prasugrel or ticagrelor; switching occurred primarily after percutaneous coronary intervention (60.9%) and at the time of hospital discharge (26.7%). Among 3284 patients treated initially with prasugrel or ticagrelor, 448 (13.6%) were switched to clopidogrel; 48.2% of switches occurred after percutaneous coronary intervention and 48.0% at hospital discharge. Switching to prasugrel or ticagrelor was not associated with increased bleeding when compared with continuation on clopidogrel (2.7% vs. 3.3%, adjusted hazard ratio 0.96, 95% confidence interval 0.64-1.42, p=0.82). Switching from prasugrel or ticagrelor to clopidogrel was not associated with increased MACE (8.9% vs. 7.7%, adjusted hazard ratio 1.06, 95% confidence interval 0.75-1.49, p=0.76) when compared with continuation on the higher potency agent. CONCLUSIONS In-hospital ADP receptor inhibitor switching occurs in more than one in 10 myocardial infarction patients in contemporary practice. In this observational study, ADP receptor inhibitor switching does not appear to be significantly associated with increased hazard of MACE or bleeding.

Greater clinical benefit of more intensive oral antiplatelet therapy with prasugrel in patients with diabetes mellitus in the trial to assess improvement in therapeutic outcomes by optimizing platelet inhibition with prasugrel-Thrombolysis in Myocardial Infarction 38.

BACKGROUND Patients with diabetes mellitus (DM) are at high risk for recurrent cardiovascular events after acute coronary syndromes, in part because of increased platelet reactivity. The Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel-Thrombolysis in Myocardial Infarction 38 (TRITON-TIMI 38) showed an overall reduction in ischemic events with more intensive antiplatelet therapy with prasugrel than with clopidogrel but with more bleeding. We compared prasugrel with clopidogrel among subjects with DM in TRITON-TIMI 38. METHODS AND RESULTS We classified 13 608 subjects on the basis of preexisting history of DM and further according to insulin use. Prespecified analyses of the primary (cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke) and key secondary end points, including net clinical benefit (death, nonfatal myocardial infarction, nonfatal stroke, and nonfatal TIMI major bleeding) were compared by use of the log-rank test. We found that 3146 subjects had a preexisting history of DM, including 776 receiving insulin. The primary end point was reduced significantly with prasugrel among subjects without DM (9.2% versus 10.6%; hazard ratio [HR], 0.86; P=0.02) and with DM (12.2% versus 17.0%; HR, 0.70; P<0.001, P(interaction)=0.09). A benefit for prasugrel was observed among DM subjects on insulin (14.3% versus 22.2%; HR, 0.63; P=0.009) and those not on insulin (11.5% versus 15.3%; HR, 0.74; P=0.009). Myocardial infarction was reduced with prasugrel by 18% among subjects without DM (7.2% versus 8.7%; HR, 0.82; P=0.006) and by 40% among subjects with DM (8.2% versus 13.2%; HR, 0.60; P<0.001, P(interaction)=0.02). Although TIMI major hemorrhage was increased among subjects without DM on prasugrel (1.6% versus 2.4%; HR, 1.43; P=0.02), the rates were similar among subjects with DM for clopidogrel and prasugrel (2.6% versus 2.5%; HR, 1.06; P=0.81, P(interaction)=0.29). Net clinical benefit with prasugrel was greater for subjects with DM (14.6% versus 19.2%; HR, 0.74; P=0.001) than for subjects without DM (11.5% versus 12.3%; HR, 0.92; P=0.16, P(interaction)=0.05). CONCLUSIONS Subjects with DM tended to have a greater reduction in ischemic events without an observed increase in TIMI major bleeding and therefore a greater net treatment benefit with prasugrel compared with clopidogrel. These data demonstrate that the more intensive oral antiplatelet therapy provided with prasugrel is of particular benefit to patients with DM.

Prevention of central venous catheter-associated thrombosis: a meta-analysis.

PURPOSE Anticoagulant prophylaxis in patients with central venous catheters is controversial. We performed a meta-analysis of randomized controlled trials of anticoagulant prophylaxis in patients with central venous catheters. METHODS MEDLINE and EMBASE were searched up to May 2006, supplemented by manual searches of conference proceedings and bibliographies. RESULTS Fifteen trials were included. Unfractionated heparin infusion, oral fixed low-dose vitamin K antagonist, and subcutaneous low-molecular-weight heparin were evaluated. For all catheter-associated deep vein thrombosis (symptomatic and asymptomatic combined), the summary relative risks ranged from 0.31 to 0.73 (all achieved statistical significance). For symptomatic deep vein thrombosis, the summary relative risks ranged from 0.28 to 0.72, but did not achieve statistical significance for any individual regimen. CONCLUSION Anticoagulant prophylaxis is effective for preventing all catheter-associated deep vein thrombosis in patients with central venous catheters. The effectiveness for preventing symptomatic venous thromboembolism, including pulmonary embolism, remains uncertain.

Cardiovascular risk and events in 17 low-, middle-, and high-income countries.

BACKGROUND More than 80% of deaths from cardiovascular disease are estimated to occur in low-income and middle-income countries, but the reasons are unknown. METHODS We enrolled 156,424 persons from 628 urban and rural communities in 17 countries (3 high-income, 10 middle-income, and 4 low-income countries) and assessed their cardiovascular risk using the INTERHEART Risk Score, a validated score for quantifying risk-factor burden without the use of laboratory testing (with higher scores indicating greater risk-factor burden). Participants were followed for incident cardiovascular disease and death for a mean of 4.1 years. RESULTS The mean INTERHEART Risk Score was highest in high-income countries, intermediate in middle-income countries, and lowest in low-income countries (P<0.001). However, the rates of major cardiovascular events (death from cardiovascular causes, myocardial infarction, stroke, or heart failure) were lower in high-income countries than in middle- and low-income countries (3.99 events per 1000 person-years vs. 5.38 and 6.43 events per 1000 person-years, respectively; P<0.001). Case fatality rates were also lowest in high-income countries (6.5%, 15.9%, and 17.3% in high-, middle-, and low-income countries, respectively; P=0.01). Urban communities had a higher risk-factor burden than rural communities but lower rates of cardiovascular events (4.83 vs. 6.25 events per 1000 person-years, P<0.001) and case fatality rates (13.52% vs. 17.25%, P<0.001). The use of preventive medications and revascularization procedures was significantly more common in high-income countries than in middle- or low-income countries (P<0.001). CONCLUSIONS Although the risk-factor burden was lowest in low-income countries, the rates of major cardiovascular disease and death were substantially higher in low-income countries than in high-income countries. The high burden of risk factors in high-income countries may have been mitigated by better control of risk factors and more frequent use of proven pharmacologic therapies and revascularization. (Funded by the Population Health Research Institute and others.).

Statins in the primary prevention of cardiovascular disease

Statins are widely used in the evidence-based lowering of cardiovascular disease (CVD) risk. The use of these drugs for secondary prevention of CVD is well founded, but their expanding use in primary prevention—in individuals without documented CVD—has raised some concerns. Firstly, evidence suggests that, in primary prevention, statins substantially decrease CVD morbidity, but only moderately reduce CVD mortality. Secondly, long-term statin use might cause adverse effects, such as incident diabetes mellitus. Thirdly, the cost-effectiveness of such a strategy is unclear, and has to be balanced against the risk of 'overmedicating' the general population. Data clearly support the use of statins for primary prevention in high-risk individuals, in whom the strategy is cost-effective and the benefits exceed the risks. Whether primary prevention is beneficial in individuals at low or moderate risk is not certain. Therefore, the prescription of statins for primary prevention should be individualized on the basis of clinical judgment, particularly for low-risk individuals. In appropriately selected individuals, statins should also be used for primary prevention of ischaemic stroke and transient ischaemic attack.

Blockade of adrenoreceptors inhibits the splenic response to stroke.

Recent studies have highlighted the involvement of the peripheral immune system in delayed cellular degeneration after stroke. In the permanent middle cerebral artery occlusion (MCAO) model of stroke, the spleen decreases in size. This reduction occurs through the release of splenic immune cells. Systemic treatment with human umbilical cord blood cells (HUCBC) 24 h post-stroke blocks the reduction in spleen size while significantly reducing infarct volume. Splenectomy 2 weeks prior to MCAO also reduces infarct volume, further demonstrating the detrimental role of this organ in stroke-induced neurodegeneration. Activation of the sympathetic nervous system after MCAO results in elevated catecholamine levels both at the level of the spleen, through direct splenic innervation, and throughout the systemic circulation upon release from the adrenal medulla. These catecholamines bind to splenic alpha and beta adrenoreceptors. This study examines whether catecholamines regulate the splenic response to stroke. Male Sprague-Dawley rats either underwent splenic denervation 2 weeks prior to MCAO or received injections of carvedilol, a pan adrenergic receptor blocker, prazosin, an alpha1 receptor blocker, or propranolol, a beta receptor blocker. Denervation was confirmed by reduced splenic expression of tyrosine hydroxylase. Denervation prior to MCAO did not alter infarct volume or spleen size. Propranolol treatment also had no effects on these outcomes. Treatment with either prazosin or carvedilol prevented the reduction in spleen size, yet only carvedilol significantly reduced infarct volume (p < 0.05). These results demonstrate that circulating blood borne catecholamines regulate the splenic response to stroke through the activation of both alpha and beta adrenergic receptors.

Impact of diabetes on long-term prognosis in patients with unstable angina and non-Q-wave myocardial infarction: results of the OASIS (Organization to Assess Strategies for Ischemic Syndromes) Registry.

BACKGROUND Although unstable coronary artery disease is the most common reason for admission to a coronary care unit, the long-term prognosis of patients with this diagnosis is unknown. This is particularly true for patients with diabetes mellitus, who are known to have a high morbidity and mortality after an acute myocardial infarction. METHODS AND RESULTS Prospectively collected data from 6 different countries in the Organization to Assess Strategies for Ischemic Syndromes (OASIS) registry were analyzed to determine the 2-year prognosis of diabetic and nondiabetic patients who were hospitalized with unstable angina or non-Q-wave myocardial infarction. Overall, 1718 of 8013 registry patients (21%) had diabetes. Diabetic patients had a higher rate of coronary bypass surgery than nondiabetic patients (23% versus 20%, P:<0.001) but had similar rates of catheterization and angioplasty. Diabetes independently predicted mortality (relative risk [RR], 1.57; 95% CI, 1.38 to 1.81; P:<0.001), as well as cardiovascular death, new myocardial infarction, stroke, and new congestive heart failure. Moreover, compared with their nondiabetic counterparts, women had a significantly higher risk than men (RR, 1.98; 95% CI, 1.60 to 2.44; and RR, 1.28; 95% CI, 1.06 to 1.56, respectively). Interestingly, diabetic patients without prior cardiovascular disease had the same event rates for all outcomes as nondiabetic patients with previous vascular disease. CONCLUSIONS Hospitalization for unstable angina or non-Q-wave myocardial infarction predicts a high 2-year morbidity and mortality; this is especially evident for patients with diabetes. Diabetic patients with no previous cardiovascular disease have the same long-term morbidity and mortality as nondiabetic patients with established cardiovascular disease after hospitalization for unstable coronary artery disease.

Relative roles of direct regeneration versus paracrine effects of human cardiosphere-derived cells transplanted into infarcted mice.

RATIONALE Multiple biological mechanisms contribute to the efficacy of cardiac cell therapy. Most prominent among these are direct heart muscle and blood vessel regeneration from transplanted cells, as opposed to paracrine enhancement of tissue preservation and/or recruitment of endogenous repair. OBJECTIVE Human cardiac progenitor cells, cultured as cardiospheres (CSps) or as CSp-derived cells (CDCs), have been shown to be capable of direct cardiac regeneration in vivo. Here we characterized paracrine effects in CDC transplantation and investigated their relative importance versus direct differentiation of surviving transplanted cells. METHODS AND RESULTS In vitro, many growth factors were found in media conditioned by human adult CSps and CDCs; CDC-conditioned media exerted antiapoptotic effects on neonatal rat ventricular myocytes, and proangiogenic effects on human umbilical vein endothelial cells. In vivo, human CDCs secreted vascular endothelial growth factor, hepatocyte growth factor, and insulin-like growth factor 1 when transplanted into the same SCID mouse model of acute myocardial infarction where they were previously shown to improve function and to produce tissue regeneration. Injection of CDCs in the peri-infarct zone increased the expression of Akt, decreased apoptotic rate and caspase 3 level, and increased capillary density, indicating overall higher tissue resilience. Based on the number of human-specific cells relative to overall increases in capillary density and myocardial viability, direct differentiation quantitatively accounted for 20% to 50% of the observed effects. CONCLUSIONS Together with their spontaneous commitment to cardiac and angiogenic differentiation, transplanted CDCs serve as "role models," recruiting endogenous regeneration and improving tissue resistance to ischemic stress. The contribution of the role model effect rivals or exceeds that of direct regeneration.

Markers of myocardial damage and inflammation in relation to long-term mortality in unstable coronary artery disease. FRISC Study Group. Fragmin during Instability in Coronary Artery Disease.

BACKGROUND In patients with unstable coronary artery disease, there is a relation between the short-term risk of death and blood levels of troponin T (a marker of myocardial damage) and C-reactive protein and fibrinogen (markers of inflammation). Using information obtained during an extension of the follow-up period in the Fragmin during Instability in Coronary Artery Disease trial, we evaluated the usefulness of troponin T, C-reactive protein, and fibrinogen levels and other indicators of risk as predictors of the long-term risk of death from cardiac causes. METHODS Levels of C-reactive protein and fibrinogen at enrollment and the maximal level of troponin T during the first 24 hours after enrollment were analyzed in 917 patients included in a clinical trial of low-molecular-weight heparin in unstable coronary artery disease. The patients were followed for a mean of 37.0 months (range, 1.6 to 50.6). RESULTS During follow-up, 1.2 percent of the 173 patients with maximal blood troponin T levels of less than 0.06 microg per liter died of cardiac causes, as compared with 8.7 percent of the 367 patients with levels of 0.06 to 0.59 microg per liter and 15.4 percent of the 377 patients with levels of at least 0.60 microg per liter (P=0.007 and P=0.001, respectively). The rates of death from cardiac causes were 5.7 percent among the 314 patients with blood C-reactive protein levels of less than 2 mg per liter, 7.8 percent among the 294 with levels of 2 to 10 mg per liter, and 16.5 percent among the 309 with levels of more than 10 mg per liter (P=0.29 and P=0.001, respectively). The rates of death from cardiac causes were 5.4 percent among the 314 patients with blood fibrinogen levels of less than 3.4 g per liter, 12.0 percent among the 300 with levels of 3.4 to 3.9 g per liter, and 12.9 percent among the 303 with levels of at least 4.0 g per liter (P=0.004 and P=0.69, respectively). In a multivariate analysis, levels of troponin T and C-reactive protein were independent predictors of the risk of death from cardiac causes. CONCLUSIONS In unstable coronary artery disease, elevated levels of troponin T and C-reactive protein are strongly related to the long-term risk of death from cardiac causes. These markers are independent risk factors, and their effects are additive with respect to each other and other clinical indicators of risk.

Angina with "normal" coronary arteries: sex differences in outcomes.

BACKGROUND Several studies have demonstrated that women with nonobstructive coronary disease have a high rate of subsequent investigations, rehospitalizations for recurrent chest pain, and repeat coronary angiography. The sex specificity of this finding is unclear. We therefore undertook an evaluation of sex differences in rehospitalization for acute coronary syndrome (ACS) or chest pain in patients with "angiographically normal" coronaries. METHODS A retrospective cohort study using prospectively collected angiographic and clinical data on all patients in British Columbia, Canada, presenting for their first cardiac catheterization with suspected ischemic heart disease but angiographically normal coronaries. RESULTS Among 32,856 patients, 7.1% of men versus 23.3% of women were angiographically normal (P < .001). Among angiographically normal patients, women were older and more likely to present with hypertension, prior stroke, chronic obstructive pulmonary disease, and peripheral vascular disease than men, but Canadian Cardiovascular Society class of angina did not vary by sex. Within 1 year, 1.0% died, (19 women, 18 men, P = .27) and 0.6% had a stroke (13 women, 9 men, P = .91). Readmission to hospital for ACS or chest pain requiring catheterization was significantly higher in women compared to men (adjusted OR 4.06; 95% CI 1.15-14.31). CONCLUSIONS In a contemporary, population-based cohort presenting for cardiac catheterization for suspected ischemia, women with angiographically normal coronaries were >4 times more likely to be readmitted to hospital for ACS/chest pain within 180 days compared to men. The observed sex difference has important social and economic implications and suggests that traditional diagnostic methods may not be optimal for women.

Frontal stroke syndromes.

The frontal lobe is the largest lobe of the brain, and it is thus commonly involved in stroke. Moreover, almost one in five strokes is limited to the prerolandic areas. This high frequency of anatomical involvement is in sharp contrast with the apparent rarity of clinical frontal dysfunction in stroke. It is remarkable that frontal behavioral syndromes have been rather uncommonly reported in patients with stroke as compared to patients with other diseases, such as brain tumor. This fact is paradoxical, because an acute process (stroke) is expected to yield more clinical dysfunction than a more chronic disease (tumor). A volume effect may be the main factor leading to this phenomenon. Another interesting aspect of frontal strokes is the contribution of so-called 'silent' strokes, the recurrence of which may nevertheless lead to intellectual decline and compromise recovery from another stroke with more specific neurologic dysfunction. The contribution of stroke to understanding of frontal lobe dysfunction is important, because of the focal nature of this disease, and great opportunity for clinical-topographic classification correlations. One of the first modern attempts to develop a clinical-topographic classification of frontal lobe lesions came from the school of Luria, who tried to delineate three main types of frontal lobe syndromes (premotor syndrome, prefrontal syndrome, medial-frontal syndrome). Recent anatomic correlates using MRI make it possible to improve this classification. We suggest considering six main clinical-anatomic frontal stroke syndromes: (1) prefrontal; (2) premotor; (3) superior medial; (4) orbital-medial; (5) basal forebrain; (6) white matter. Finally, another fascinating topic relates to frontal lobe symptomatology due to stroke sparing the frontal cortex or white matter. This occurs mainly in three instances: lenticulo-capsular stroke, caudate stroke, and thalamic stroke. Studies using blood flow or metabolism measurements suggest that diaschisis (frontal lobe dysfunction from a remote lesion) may play a role. We believe that this is more likely to be related to dynamic interruption of complex circuitry than to static frontal lobe deactivation.

Implementation of contemporary oral antiplatelet treatment guidelines in patients with acute coronary syndrome undergoing percutaneous coronary intervention: a report from the GReek AntiPlatelet rEgistry (GRAPE).

BACKGROUND Few data exist about the implementation of contemporary oral antiplatelet treatment guidelines in patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI). METHODS GReek AntiPlatelet rEgistry (GRAPE), initiated on January 2012, is a prospective, observational, multicenter cohort study focusing on contemporary use of P2Y12 inhibitors. In 1434 patients we evaluated appropriateness of P2Y12 selection initially and at discharge by applying an eligibility-assessing algorithm based on P2Y12 inhibitors' contraindications/specific warnings and precautions. RESULTS Appropriate, less preferable and inappropriate P2Y12 inhibitor selections were made initially in 45.8%, 47.2% and 6.6% and at discharge in 64.1%, 29.2% and 6.6% of patients, respectively. The selection of clopidogrel was most commonly less preferable, both initially (69.7%) and at discharge (75.6%). Appropriate selection of newer agents was high initially (79.2%-82.8%), with further increase as selection at discharge (89.4%-89.8%). Inappropriate selection of the newer agents was 17.2%-20.8% initially, decreasing to 10.2%-10.6% at discharge. Conditions and co-medications related to increased bleeding risk, presentation with ST elevation myocardial infarction and the absence of reperfusion within the first 24h were the most powerful predictors of appropriate P2Y12 selection initially, whereas age ≥75 years, conditions and co-medications related to increased bleeding risk and regional trends mostly affected appropriate P2Y12 selection at discharge. CONCLUSIONS In GRAPE, adherence with the recently released guidelines on oral antiplatelet therapy was satisfactory. Clopidogrel was most commonly used as a less preferable selection, while prasugrel or ticagrelor selection was mostly appropriate. Certain factors may predict initial and at discharge guideline implementation. Clinical Trial Registration-clinicaltrials.gov Identifier: NCT01774955 http://clinicaltrials.gov/.

Impact of aortic stiffness on survival in end-stage renal disease.

BACKGROUND Damage to large arteries is a major factor in the high cardiovascular morbidity and mortality of patients with end-stage renal disease (ESRD). Increased arterial stiffness and intima-media thickness, together with increased pulse pressure, are the principal arterial alterations. Whether increased aortic pulse-wave velocity (PWV), a classic marker of increased arterial stiffness, may predict all-cause and/or cardiovascular mortality has never been investigated. METHODS AND RESULTS A cohort of 241 patients with ESRD undergoing hemodialysis was studied between April 1987 and April 1998. The mean duration of follow-up was 72+/-41 months (mean+/-SD). Mean age at entry was 51.5+/-16.3 years. Seventy-three deaths occurred, including 48 cardiovascular and 25 noncardiovascular fatal events. At entry, together with standard clinical and biochemical analyses, patients underwent echocardiography and aortic PWV measured by Doppler ultrasonography. On the basis of Cox analyses, 2 factors emerged as predictors of all-cause and cardiovascular mortality: age and aortic PWV. Hemoglobin and low diastolic pressure interfered to a smaller extent. After adjustment for all the confounding factors, an OR for PWV >12. 0 versus <9.4 m/s was 5.4 (95% CI, 2.4 to 11.9) for all-cause mortality and 5.9 (95% CI, 2.3 to 15.5) for cardiovascular mortality. For each PWV increase of 1 m/s in our study population, all-cause mortality-adjusted OR was 1.39 (95% CI, 1.19 to 1.62). CONCLUSIONS These results provide the first direct evidence that in patients with ESRD, increased aortic stiffness determined by measurement of aortic PWV is a strong independent predictor of all-cause and mainly cardiovascular mortality.

Sex-related differences in the presentation, treatment and outcomes among patients with acute coronary syndromes: the Global Registry of Acute Coronary Events.

OBJECTIVE To assess whether sex differences exist in the angiographic severity, management and outcomes of acute coronary syndromes (ACS). METHODS The study comprised 7638 women and 19 117 men with ACS who underwent coronary angiography and were included in GRACE (Global Registry of Acute Coronary Events) from 1999-2006. Normal vessels/mild disease was defined as <50% stenosis in all epicardial vessels; advanced disease was defined as >or=one vessel with >or=50% stenosis. RESULTS Women were older than men and had higher rates of cardiovascular risk factors. Men and women presented equally with chest pain; however, jaw pain and nausea were more frequent among women. Women were more likely to have normal/mild disease (12% vs 6%, p<0.001) and less likely to have left-main and three-vessel disease (27% vs 32%, p<0.001) or undergo percutaneous coronary intervention (65% vs 68%, p<0.001). Women and men with normal and mild disease were treated less aggressively than those with advanced disease. Women with advanced disease had a higher risk of death (4% vs 3%, p<0.01). After adjustment for age and extent of disease, women were more likely to have adverse outcomes (death, myocardial infarction, stroke and rehospitalisation) at six months compared to men (odds ratio 1.24, 95% confidence interval 1.14 to 1.34); however, sex differences in mortality were no longer statistically significant. CONCLUSIONS Women with ACS were more likely to have cardiovascular disease risk factors and atypical symptoms such as nausea compared with men, but were more likely to have normal/mild angiographic coronary artery disease. Further study regarding sex differences related to disease severity is warranted.

Platelet glycoprotein IIb/IIIa inhibitors reduce mortality in diabetic patients with non-ST-segment-elevation acute coronary syndromes.

BACKGROUND Diabetes mellitus is a major risk factor for adverse outcomes after acute coronary syndromes (ACS). Because this disease may be associated with increased platelet aggregation, we investigated whether diabetic patients with ACS derive particular benefit from platelet glycoprotein (GP) IIb/IIIa receptor inhibition. METHODS AND RESULTS We performed a meta-analysis of the diabetic populations enrolled in the 6 large-scale platelet GP IIb/IIIa inhibitor ACS trials: PRISM, PRISM-PLUS, PARAGON A, PARAGON B, PURSUIT, and GUSTO IV. Among 6458 diabetic patients, platelet GP IIb/IIIa inhibition was associated with a significant mortality reduction at 30 days, from 6.2% to 4.6% (OR 0.74; 95% CI 0.59 to 0.92; P=0.007). Conversely, 23 072 nondiabetic patients had no survival benefit (3.0% versus 3.0%). The interaction between platelet GP IIb/IIIa inhibition and diabetic status was statistically significant (P=0.036). Among 1279 diabetic patients undergoing percutaneous coronary intervention (PCI) during index hospitalization, the use of these agents was associated with a mortality reduction at 30 days from 4.0% to 1.2% (OR 0.30; 95% CI 0.14 to 0.69; P=0.002). CONCLUSIONS This meta-analysis, including the entire large-scale trial experience of intravenous platelet GP IIb/IIIa inhibitors for the medical management of non-ST-segment-elevation ACS, shows that these agents may significantly reduce mortality at 30 days in diabetic patients. Although not based on a randomized assessment, the survival benefit appears to be of greater magnitude in patients undergoing PCI. Therefore, the use of platelet GP IIb/IIIa inhibitors should be strongly considered in diabetic patients with ACS.

Migraine and cardiovascular disease: systematic review and meta-analysis.

OBJECTIVE To evaluate the association between migraine and cardiovascular disease, including stroke, myocardial infarction, and death due to cardiovascular disease. DESIGN Systematic review and meta-analysis. DATA SOURCES Electronic databases (PubMed, Embase, Cochrane Library) and reference lists of included studies and reviews published until January 2009. Selection criteria Case-control and cohort studies investigating the association between any migraine or specific migraine subtypes and cardiovascular disease. Review methods Two investigators independently assessed eligibility of identified studies in a two step approach. Disagreements were resolved by consensus. Studies were grouped according to a priori categories on migraine and cardiovascular disease. DATA EXTRACTION Two investigators extracted data. Pooled relative risks and 95% confidence intervals were calculated. RESULTS Studies were heterogeneous for participant characteristics and definition of cardiovascular disease. Nine studies investigated the association between any migraine and ischaemic stroke (pooled relative risk 1.73, 95% confidence interval 1.31 to 2.29). Additional analyses indicated a significantly higher risk among people who had migraine with aura (2.16, 1.53 to 3.03) compared with people who had migraine without aura (1.23, 0.90 to 1.69; meta-regression for aura status P=0.02). Furthermore, results suggested a greater risk among women (2.08, 1.13 to 3.84) compared with men (1.37, 0.89 to 2.11). Age less than 45 years, smoking, and oral contraceptive use further increased the risk. Eight studies investigated the association between migraine and myocardial infarction (1.12, 0.95 to 1.32) and five between migraine and death due to cardiovascular disease (1.03, 0.79 to 1.34). Only one study investigated the association between women who had migraine with aura and myocardial infarction and death due to cardiovascular disease, showing a twofold increased risk. CONCLUSION Migraine is associated with a twofold increased risk of ischaemic stroke, which is only apparent among people who have migraine with aura. Our results also suggest a higher risk among women and risk was further magnified for people with migraine who were aged less than 45, smokers, and women who used oral contraceptives. We did not find an overall association between any migraine and myocardial infarction or death due to cardiovascular disease. Too few studies are available to reliably evaluate the impact of modifying factors, such as migraine aura, on these associations.

Acute respiratory failure in patients with severe community-acquired pneumonia: a prospective randomized evaluation of noninvasive ventilation.

In uncontrolled studies, noninvasive positive pressure ventilation (NPPV) was found useful in avoiding endotracheal intubation in patients with acute respiratory failure (ARF) caused by severe community-acquired pneumonia (CAP). We conducted a prospective, randomized study comparing standard treatment plus NPPV delivered through a face mask to standard treatment alone in patients with severe CAP and ARF. Patients fitting the American Thoracic Society criteria for severe CAP were included in presence of ARF (refractory hypoxemia and/or hypercapnia with acidosis). Exclusion criteria were: severe hemodynamic instability, requirement for emergent cardiopulmonary resuscitation, home mechanical ventilation or oxygen long-term supplementation, concomitant severe disease with a low expectation of life, inability to expectorate or contraindications to the use of the mask. Fifty-six consecutive patients (28 in each arm) were enrolled, and the two groups were similar at study entry. The use of NPPV was well tolerated, safe, and associated with a significant reduction in respiratory rate, need for endotracheal intubation (21% versus 50%; p = 0.03), and duration of intensive care unit (ICU) stay (1.8 ± 0.7 d versus 6 ± 1.8 d; p = 0.04). The two groups had a similar intensity of nursing care workload, time interval from study entry to endotracheal intubation, duration of hospitalization, and hospital mortality. Among patients with chronic obstructive pulmonary disease (COPD), those randomized to NPPV had a lower intensity of nursing care workload (p = 0.04) and improved 2-mo survival (88.9% versus 37.5%; p = 0.05). We conclude that in selected patients with ARF caused by severe CAP, NPPV was associated with a significant reduction in the rate of endotracheal intubation and duration of ICU stay. A 2-mo survival advantage was seen in patients with COPD.

Neuronal replacement from endogenous precursors in the adult brain after stroke

In the adult brain, new neurons are continuously generated in the subventricular zone and dentate gyrus, but it is unknown whether these neurons can replace those lost following damage or disease. Here we show that stroke, caused by transient middle cerebral artery occlusion in adult rats, leads to a marked increase of cell proliferation in the subventricular zone. Stroke-generated new neurons, as well as neuroblasts probably already formed before the insult, migrate into the severely damaged area of the striatum, where they express markers of developing and mature, striatal medium-sized spiny neurons. Thus, stroke induces differentiation of new neurons into the phenotype of most of the neurons destroyed by the ischemic lesion. Here we show that the adult brain has the capacity for self-repair after insults causing extensive neuronal death. If the new neurons are functional and their formation can be stimulated, a novel therapeutic strategy might be developed for stroke in humans.

Serum Soluble Corin is Decreased in Stroke.

BACKGROUND AND PURPOSE Soluble corin was decreased in coronary heart disease. Given the connections between cardiac dysfunction and stroke, circulating corin might be a candidate marker of stroke risk. However, the association between circulating corin and stroke has not yet been studied in humans. Here, we aimed to examine the association in patients wtith stroke and community-based healthy controls. METHODS Four hundred eighty-one patients with ischemic stroke, 116 patients with hemorrhagic stroke, and 2498 healthy controls were studied. Serum soluble corin and some conventional risk factors of stroke were examined. Because circulating corin was reported to be varied between men and women, the association between serum soluble corin and stroke was evaluated in men and women, respectively. RESULTS Patients with ischemic and hemorrhagic stroke had a significantly lower level of serum soluble corin than healthy controls in men and women (all P values, <0.05). In multivariate analysis, men in the lowest quartile of serum soluble corin were more likely to have ischemic (odds ratio [OR], 4.90; 95% confidence interval, 2.99-8.03) and hemorrhagic (OR, 17.57; 95% confidence interval, 4.85-63.71) stroke than men in the highest quartile. Women in the lowest quartile of serum soluble corin were also more likely to have ischemic (OR, 3.10; 95% confidence interval, 1.76-5.44) and hemorrhagic (OR, 8.54; 95% confidence interval, 2.35-31.02) stroke than women in the highest quartile. ORs of ischemic and hemorrhagic stroke were significantly increased with the decreasing levels of serum soluble corin in men and women (all P values for trend, <0.001). CONCLUSIONS Serum soluble corin was decreased in patients with stroke compared with healthy controls. Our findings raise the possibility that serum soluble corin may have a pathogenic role in stroke.

Confusion and memory loss from capsular genu infarction: a thalamocortical disconnection syndrome?

We examined six patients with an abrupt change in behavior after infarction involving the inferior genu of the internal capsule. The acute syndrome featured fluctuating alertness, inattention, memory loss, apathy, abulia, and psychomotor retardation, suggesting frontal lobe dysfunction. Contralateral hemiparesis and dysarthria were generally mild, except when the infarct extended into the posterior limb. Neuropsychological testing in five patients with left-sided infarcts revealed severe verbal memory loss. Additional cognitive deficits consistent with dementia occurred in four patients. A right-sided infarct caused transient impairment in visuospatial memory. Functional brain imaging in three patients showed a focal reduction in hemispheric perfusion most prominent in the ipsilateral inferior and medial frontal cortex. We infer that the capsular genu infarct interrupted the inferior and anterior thalamic peduncles, resulting in functional deactivation of the ipsilateral frontal cortex. These observations suggest that one mechanism for cognitive deterioration from a lacunar infarct is thalamocortical disconnection of white-matter tracts, in some instances leading to "strategic-infarct dementia. "

Hospital mortality, length of stay, and preventable complications among critically ill patients before and after tele-ICU reengineering of critical care processes.

CONTEXT The association of an adult tele-intensive care unit (ICU) intervention with hospital mortality, length of stay, best practice adherence, and preventable complications for an academic medical center has not been reported. OBJECTIVE To quantify the association of a tele-ICU intervention with hospital mortality, length of stay, and complications that are preventable by adherence to best practices. DESIGN, SETTING, AND PATIENTS Prospective stepped-wedge clinical practice study of 6290 adults admitted to any of 7 ICUs (3 medical, 3 surgical, and 1 mixed cardiovascular) on 2 campuses of an 834-bed academic medical center that was performed from April 26, 2005, through September 30, 2007. Electronically supported and monitored processes for best practice adherence, care plan creation, and clinician response times to alarms were evaluated. MAIN OUTCOME MEASURES Case-mix and severity-adjusted hospital mortality. Other outcomes included hospital and ICU length of stay, best practice adherence, and complication rates. RESULTS The hospital mortality rate was 13.6% (95% confidence interval [CI], 11.9%-15.4%) during the preintervention period compared with 11.8% (95% CI, 10.9%-12.8%) during the tele-ICU intervention period (adjusted odds ratio [OR], 0.40 [95% CI, 0.31-0.52]). The tele-ICU intervention period compared with the preintervention period was associated with higher rates of best clinical practice adherence for the prevention of deep vein thrombosis (99% vs 85%, respectively; OR, 15.4 [95% CI, 11.3-21.1]) and prevention of stress ulcers (96% vs 83%, respectively; OR, 4.57 [95% CI, 3.91-5.77], best practice adherence for cardiovascular protection (99% vs 80%, respectively; OR, 30.7 [95% CI, 19.3-49.2]), prevention of ventilator-associated pneumonia (52% vs 33%, respectively; OR, 2.20 [95% CI, 1.79-2.70]), lower rates of preventable complications (1.6% vs 13%, respectively, for ventilator-associated pneumonia [OR, 0.15; 95% CI, 0.09-0.23] and 0.6% vs 1.0%, respectively, for catheter-related bloodstream infection [OR, 0.50; 95% CI, 0.27-0.93]), and shorter hospital length of stay (9.8 vs 13.3 days, respectively; hazard ratio for discharge, 1.44 [95% CI, 1.33-1.56]). The results for medical, surgical, and cardiovascular ICUs were similar. CONCLUSION In a single academic medical center study, implementation of a tele-ICU intervention was associated with reduced adjusted odds of mortality and reduced hospital length of stay, as well as with changes in best practice adherence and lower rates of preventable complications.

Stroke and migraine--the spectrum of cause and effect.

The relationship of migraine and stroke is complex. Stroke may be coincidental with migraine but migraine may confer an increased risk of stroke in women under 45 years of age and possibly in men who have migraine with aura. Stroke may mimic migraine but migraine syndromes may be symptomatic of underlying cerebrovascular disorders. True migraine-induced stroke is rare. The mechanisms of stroke induced during a migraine attack remain to be determined but probably involve an interaction between the dynamic shifts in cerebral blood flow and stroke risk factors.

Malignancies, prothrombotic mutations, and the risk of venous thrombosis.

CONTEXT Venous thrombosis is a common complication in patients with cancer, leading to additional morbidity and compromising quality of life. OBJECTIVE To identify individuals with cancer with an increased thrombotic risk, evaluating different tumor sites, the presence of distant metastases, and carrier status of prothrombotic mutations. DESIGN, SETTING, AND PATIENTS A large population-based, case-control (Multiple Environmental and Genetic Assessment [MEGA] of risk factors for venous thrombosis) study of 3220 consecutive patients aged 18 to 70 years, with a first deep venous thrombosis of the leg or pulmonary embolism, between March 1, 1999, and May 31, 2002, at 6 anticoagulation clinics in the Netherlands, and separate 2131 control participants (partners of the patients) reported via a questionnaire on acquired risk factors for venous thrombosis. Three months after discontinuation of the anticoagulant therapy, all patients and controls were interviewed, a blood sample was taken, and DNA was isolated to ascertain the factor V Leiden and prothrombin 20210A mutations. MAIN OUTCOME MEASURE Risk of venous thrombosis. RESULTS The overall risk of venous thrombosis was increased 7-fold in patients with a malignancy (odds ratio [OR], 6.7; 95% confidence interval [CI], 5.2-8.6) vs persons without malignancy. Patients with hematological malignancies had the highest risk of venous thrombosis, adjusted for age and sex (adjusted OR, 28.0; 95% CI, 4.0-199.7), followed by lung cancer and gastrointestinal cancer. The risk of venous thrombosis was highest in the first few months after the diagnosis of malignancy (adjusted OR, 53.5; 95% CI, 8.6-334.3). Patients with cancer with distant metastases had a higher risk vs patients without distant metastases (adjusted OR, 19.8; 95% CI, 2.6-149.1). Carriers of the factor V Leiden mutation who also had cancer had a 12-fold increased risk vs individuals without cancer and factor V Leiden (adjusted OR, 12.1; 95% CI, 1.6-88.1). Similar results were indirectly calculated for the prothrombin 20210A mutation in patients with cancer. CONCLUSIONS Patients with cancer have a highly increased risk of venous thrombosis especially in the first few months after diagnosis and in the presence of distant metastases. Carriers of the factor V Leiden and prothrombin 20210A mutations appear to have an even higher risk.

Extracellular vesicles from human cardiac progenitor cells inhibit cardiomyocyte apoptosis and improve cardiac function after myocardial infarction.

AIMS Recent evidence suggests that cardiac progenitor cells (CPCs) may improve cardiac function after injury. The underlying mechanisms are indirect, but their mediators remain unidentified. Exosomes and other secreted membrane vesicles, hereafter collectively referred to as extracellular vesicles (EVs), act as paracrine signalling mediators. Here, we report that EVs secreted by human CPCs are crucial cardioprotective agents. METHODS AND RESULTS CPCs were derived from atrial appendage explants from patients who underwent heart valve surgery. CPC-conditioned medium (CM) inhibited apoptosis in mouse HL-1 cardiomyocytic cells, while enhancing tube formation in human umbilical vein endothelial cells. These effects were abrogated by depleting CM of EVs. They were reproduced by EVs secreted by CPCs, but not by those secreted by human dermal fibroblasts. Transmission electron microscopy and nanoparticle tracking analysis showed most EVs to be 30-90 nm in diameter, the size of exosomes, although smaller and larger vesicles were also present. MicroRNAs most highly enriched in EVs secreted by CPCs compared with fibroblasts included miR-210, miR-132, and miR-146a-3p. miR-210 down-regulated its known targets, ephrin A3 and PTP1b, inhibiting apoptosis in cardiomyocytic cells. miR-132 down-regulated its target, RasGAP-p120, enhancing tube formation in endothelial cells. Infarcted hearts injected with EVs from CPCs, but not from fibroblasts, exhibited less cardiomyocyte apoptosis, enhanced angiogenesis, and improved LV ejection fraction (0.8 ± 6.8 vs. -21.3 ± 4.5%; P < 0.05) compared with those injected with control medium. CONCLUSION EVs are the active component of the paracrine secretion by human CPCs. As a cell-free approach, EVs could circumvent many of the limitations of cell transplantation.

Simvastatin reduces platelet-endocardium adhesion in atrial fibrillation.

OBJECTIVES To evaluate the relationship between CD40/CD40L system and increased thrombogenesis in AF, and to test the effects of simvastatin treatment. METHODS In vitro study using human tissue, University Hospital (tertiary referral center). Experiments on right atrial segments obtained before the onset of cardiopulmonary bypass were done in either presence or absence of 5 microM simvastatin. Two groups of patients in either chronic atrial fibrillation or sinus rhythm at the time of cardiac surgery. The endocardial expression of CD40, the release of CD40L, and adhesion of platelets to endocardium. Additionally, the thickness of platelet aggregates and the platelet distribution on the endocardium were also evaluated. RESULTS Atrial fibrillation was associated with a significant increase of endocardial CD40 expression (293.1+/-55.1 pg/ml vs. 230.9+/-53.3 pg/ml, p<0.01), and platelet-endocardial adhesion compared with sinus rhythm atria (10.8+/-2.2 vs. 5.2+/-1.3 platelet CD41 AU p<0.01). At immunofluorescence about 62% of fibrillating endocardium was covered by platelets, compared with 12% of not sinus rhythm atria. Addition of simvastatin significantly reduced CD40 expression as well as platelet adhesion to fibrillating atria; its efficacy was not reversed by the addition of mevalonic acid. CONCLUSIONS Chronic atrial fibrillation acutely upregulates CD40 expression as well as platelet adhesion to the endocardium. Simvastatin is effective in modulating this expression, thus it may potentially contribute to reduce the risk of intra-atrial thrombus formation.

Association Between Early Screening for Patent Ductus Arteriosus and In-Hospital Mortality Among Extremely Preterm Infants.

IMPORTANCE There is currently no consensus for the screening and treatment of patent ductus arteriosus (PDA) in extremely preterm infants. Less pharmacological closure and more supportive management have been observed without evidence to support these changes. OBJECTIVE To evaluate the association between early screening echocardiography for PDA and in-hospital mortality. DESIGN, SETTING, AND PARTICIPANTS Comparison of screened and not screened preterm infants enrolled in the EPIPAGE 2 national prospective population-based cohort study that included all preterm infants born at less than 29 weeks of gestation and hospitalized in 68 neonatal intensive care units in France from April through December 2011. Two main analyses were performed to adjust for potential selection bias, one using propensity score matching and one using neonatal unit preference for early screening echocardiography as an instrumental variable. EXPOSURES Early screening echocardiography before day 3 of life. MAIN OUTCOMES AND MEASURES The primary outcome was death between day 3 and discharge. The secondary outcomes were major neonatal morbidities (pulmonary hemorrhage, severe bronchopulmonary dysplasia, severe cerebral lesions, and necrotizing enterocolitis). RESULTS Among the 1513 preterm infants with data available to determine exposure, 847 were screened for PDA and 666 were not; 605 infants from each group could be paired. Exposed infants were treated for PDA more frequently during their hospitalization than nonexposed infants (55.1% vs 43.1%; odds ratio [OR], 1.62 [95% CI, 1.31 to 2.00]; absolute risk reduction [ARR] in events per 100 infants, -12.0 [95% CI, -17.3 to -6.7). Exposed infants had a lower hospital death rate (14.2% vs 18.5% ; OR, 0.73 [95% CI, 0.54 to 0.98]; ARR, 4.3 [95% CI, 0.3 to 8.3]) and a lower rate of pulmonary hemorrhage (5.6% vs 8.9%; OR, 0.60 [95% CI, 0.38 to 0.95]; ARR, 3.3 [95% CI, 0.4 to 6.3]). No differences in rates of necrotizing enterocolitis, severe bronchopulmonary dysplasia, or severe cerebral lesions were observed. In the overall cohort, instrumental variable analysis yielded an adjusted OR for in-hospital mortality of 0.62 [95% CI, 0.37 to 1.04]. CONCLUSIONS AND RELEVANCE In this national population-based cohort of extremely preterm infants, screening echocardiography before day 3 of life was associated with lower in-hospital mortality and likelihood of pulmonary hemorrhage but not with differences in necrotizing enterocolitis, severe bronchopulmonary dysplasia, or severe cerebral lesions. However, results of the instrumental variable analysis leave some ambiguity in the interpretation, and longer-term evaluation is needed to provide clarity.

Sex-based differences in the effect of digoxin for the treatment of heart failure.

BACKGROUND The Digitalis Investigation Group trial reported that treatment with digoxin did not decrease overall mortality among patients with heart failure and depressed left ventricular systolic function, although it did reduce hospitalizations slightly. Even though the epidemiologic features, causes, and prognosis of heart failure vary between men and women, sex-based differences in the effect of digoxin were not evaluated. METHODS We conducted a post hoc subgroup analysis to assess whether there were sex-based differences in the effect of digoxin therapy among the 6800 patients in the Digitalis Investigation Group study. The presence of an interaction between sex and digoxin therapy with respect to the primary end point of death from any cause was evaluated with the use of Mantel-Haenszel tests of heterogeneity and a multivariable Cox proportional-hazards model, adjusted for demographic and clinical variables. RESULTS There was an absolute difference of 5.8 percent (95 percent confidence interval, 0.5 to 11.1) between men and women in the effect of digoxin on the rate of death from any cause (P=0.034 for the interaction). Specifically, women who were randomly assigned to digoxin had a higher rate of death than women who were randomly assigned to placebo (33.1 percent vs. 28.9 percent; absolute difference, 4.2 percent, 95 percent confidence interval, -0.5 to 8.8). In contrast, the rate of death was similar among men randomly assigned to digoxin and men randomly assigned to placebo (35.2 percent vs. 36.9 percent; absolute difference, -1.6 percent; 95 percent confidence interval, -4.2 to 1.0). In the multivariable analysis, digoxin was associated with a significantly higher risk of death among women (adjusted hazard ratio for the comparison with placebo, 1.23; 95 percent confidence interval, 1.02 to 1.47), but it had no significant effect among men (adjusted hazard ratio, 0.93; 95 percent confidence interval, 0.85 to 1.02; P=0.014 for the interaction). CONCLUSIONS The effect of digoxin therapy differs between men and women. Digoxin therapy is associated with an increased risk of death from any cause among women, but not men, with heart failure and depressed left ventricular systolic function.

Pandemic H1N12009 influenza and HIV: a review of natural history, management and vaccine immunogenicity.

PURPOSE OF REVIEW The 2009 pandemic HIN1 influenza strain (H1N12009) produced more severe disease and increased risk for mortality. As an at-risk population for more severe influenza illness, particular concern regarding HIV patients triggered a focused effort to evaluate disease burden and vaccine efficacy in these populations. RECENT FINDINGS As with other immune-compromised individuals, most HIV-infected individuals recovered without major consequence. Although HIV infection was assumed to be a risk factor for more severe disease and death, the published literature does not indicate this to be so. Neuraminadase inhibitors were well tolerated by this population and there was no evidence of clinically significant pharmacokinetic interactions with antiretroviral therapy. Immunogenicity was increased with H1N12009 vaccine compared to the historical results of nonpandemic vaccines and optimized by the use of adjuvants. Booster dosing was also of benefit. H1N12009 vaccine was generally well tolerated without evidence of detrimental effect on HIV status. SUMMARY The worse case scenario was not realized for H1N12009 in the general population or in those with HIV. Immunization with adjuvant represents a key measure to protect this population from H1N12009 and other future novel influenza strains.

Antihypertensive classes, cognitive decline and incidence of dementia: a network meta-analysis.

OBJECTIVES Prevention of cognitive decline and dementia with blood pressure lowering treatments has shown inconsistent results. We compared the effects of different classes of antihypertensive drugs on the incidence of dementia, and on cognitive function. METHODS We conducted a systematic review and included 19 randomized trials (18 515 individuals) and 11 studies (831 674 individuals) analysing the effects of antihypertensive treatment on cognition and on the incidence of dementia, respectively, in hypertensive patients without prior cerebrovascular disorders. Network meta-analysis was used for the comparison of antihypertensive classes. RESULTS Antihypertensive treatment, regardless of the drug class, had benefits on overall cognition [effect size 0.05, 95% confidence interval (CI) 0.02-0.07] and all cognitive functions except language. Antihypertensive treatment reduced the risk of all-cause dementia by 9%, with reference to the control group (hazard ratio 0.91, 95% CI 0.89-0.94), when randomized trials and observationnal studies were combined (n = 15). Result was not significant with randomized trials alone (n = 4). Angiotensin II receptor blockers (ARBs) had larger benefits than placebo on overall cognition (adjusted effect size 0.60 ± 0.18, P = 0.02). ARBs were more effective than β-blockers (0.67 ± 0.18, P = 0.01), diuretics (0.54 ± 0.19, P = 0.04) and angiotensin-converting enzyme inhibitors (0.47 ± 0.17, P = 0.04) in rank. The mean change in blood pressure did not differ significantly between the different antihypertensive drug classes. CONCLUSION Our results support the notion that antihypertensive treatment has beneficial effects on cognitive decline and prevention of dementia, and indicate that these effects may differ between drug classes with ARBs possibly being the most effective.

Obstructive sleep apnea-hypopnea and incident stroke: the sleep heart health study.

RATIONALE Although obstructive sleep apnea is associated with physiological perturbations that increase risk of hypertension and are proatherogenic, it is uncertain whether sleep apnea is associated with increased stroke risk in the general population. OBJECTIVES To quantify the incidence of ischemic stroke with sleep apnea in a community-based sample of men and women across a wide range of sleep apnea. METHODS Baseline polysomnography was performed between 1995 and 1998 in a longitudinal cohort study. The primary exposure was the obstructive apnea-hypopnea index (OAHI) and outcome was incident ischemic stroke. MEASUREMENTS AND MAIN RESULTS A total of 5,422 participants without a history of stroke at the baseline examination and untreated for sleep apnea were followed for a median of 8.7 years. One hundred ninety-three ischemic strokes were observed. In covariate-adjusted Cox proportional hazard models, a significant positive association between ischemic stroke and OAHI was observed in men (P value for linear trend: P = 0.016). Men in the highest OAHI quartile (>19) had an adjusted hazard ratio of 2.86 (95% confidence interval, 1.1-7.4). In the mild to moderate range (OAHI, 5-25), each one-unit increase in OAHI in men was estimated to increase stroke risk by 6% (95% confidence interval, 2-10%). In women, stroke was not significantly associated with OAHI quartiles, but increased risk was observed at an OAHI greater than 25. CONCLUSIONS The strong adjusted association between ischemic stroke and OAHI in community-dwelling men with mild to moderate sleep apnea suggests that this is an appropriate target for future stroke prevention trials.

Antibiotics and risk of subsequent first-time acute myocardial infarction.

CONTEXT Increasing evidence supports the hypothesis of a causal association between certain bacterial infections and increased risk of developing acute myocardial infarction. If such a causal association exists, subjects who used antibiotics active against the bacteria, regardless of indication, might be at lower risk of developing acute myocardial infarction than nonusers. OBJECTIVE To determine whether previous use of antibiotics decreases the risk of developing a first-time acute myocardial infarction. DESIGN Population-based case-control analysis. SETTING The United Kingdom-based General Practice Research Database comprising 350 general practices. PATIENTS A total of 3315 case patients aged 75 years or younger with a diagnosis of first-time acute myocardial infarction between 1992 and 1997 and 13139 controls without myocardial infarction matched to cases for age, sex, general practice attended, and calendar time. MAIN OUTCOME MEASURES Use of antibiotics among those who did or did not have a first-time acute myocardial infarction. RESULTS Cases were significantly less likely to have used tetracycline antibiotics (adjusted odds ratio [OR], 0.70; 95% confidence interval [CI], 0.55-0.90) or quinolones (adjusted OR, 0.45; 95% CI, 0.21-0.95). No effect was found for previous use of macrolides (primarily erythromycin), sulfonamides, penicillins, or cephalosporins. CONCLUSIONS The findings from this large case-control analysis provide further, albeit indirect, evidence for an association between bacterial infections with organisms susceptible to tetracycline or quinolone antibiotics and the risk of acute myocardial infarction. These results of preliminary nature should stimulate more research to further explore the role of infections in the etiology of acute myocardial infarction.

Cardiovascular risk factors and migraine: the GEM population-based study.

BACKGROUND Migraine, particularly with aura, is a risk factor for early-onset ischemic stroke. The underlying mechanisms are unknown, but may in part be due to migraineurs having an increased risk profile for cardiovascular disease. In this study, the authors compare the cardiovascular risk profile of adult migraineurs to that of nonmigraineurs. METHODS Participants (n = 5,755, 48% men, age 20 to 65 years) are from the Genetic Epidemiology of Migraine (GEM) study, a population-based study in the Netherlands. A total of 620 current migraineurs were identified: 31% with aura (MA), 64% without aura (MO), and 5% unclassified. Controls were 5,135 individuals without lifetime migraine. Measured cardiovascular risk factors included blood pressure (BP), serum total and high-density lipoprotein cholesterol (TC, HDL), smoking, oral contraceptive use, and the Framingham risk score for myocardial infarction or coronary heart disease (CHD) death. RESULTS Compared to controls, migraineurs were more likely to smoke (OR = 1.43 [1.1 to 1.8]), less likely to consume alcohol (OR = 0.58 [0.5 to 0.7]), and more likely to report a parental history of early myocardial infarction. Migraineurs with aura were more likely to have an unfavorable cholesterol profile (TC > or = 240 mg/dL [OR = 1.43 (0.97 to 2.1)], TC:HDL ratio > 5.0 [OR = 1.64 (1.1 to 2.4)]), have elevated BP (systolic BP > 140 mm Hg or diastolic BP > 90 mm Hg [OR = 1.76 (1.04 to 3.0)]), and report a history of early onset CHD or stroke (OR = 3.96 [1.1 to 14.3]); female migraineurs with aura were more likely to be using oral contraceptives (OR = 2.06 [1.05 to 4.0]). The odds of having an elevated Framingham risk score for CHD were approximately doubled for the migraineurs with aura. CONCLUSIONS Migraineurs, particularly with aura, have a higher cardiovascular risk profile than individuals without migraine.

Angiogenesis therapy: amidst the hype, the neglected potential for serious side effects.

Although essentially unknown as a therapeutic concept as recently as a decade ago, it is difficult now to open a cardiology journal, attend a cardiology meeting, or scan a newspaper without being caught up in the excitement generated by the thought that angiogenesis therapy may soon have a major impact on the treatment of patients with atherosclerotic lesions obstructing arteries that supply the myocardium or legs. Potent therapeutic interventions, however, are rarely free of at least the potential for causing harmful effects. Angiogenesis therapy is no exception. Despite this and despite the fact that the only reasonably powered, randomized, double-blind clinical studies to date have failed to demonstrate primary end-point efficacy,1 thoughtful consideration of the serious side effects that might accompany any therapeutic benefit has been largely missing from scientific communications. For the lay media, a switch from this unbounded enthusiasm to profound skepticism occurred recently after a report of the tragic death of a young man caused by injection of large amounts of an adenoviral vector into the hepatic artery (unrelated to angiogenesis therapy).2 For the scientific community, however, there has been a general lack of in-depth discussion of the potential dangers inherent in angiogenesis interventions. Such a discussion is appropriate not only because of the event cited above but also because considerable mechanistic data are available that actually permit us to identify specific side effects that we might anticipate as potential complications of angiogenesis therapy. The following therefore is a discussion of potential complications based predominantly on our knowledge of the underlying biological activities of 2 of the most potent angiogenic cytokines, vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF). Angiogenic agents are thought to have the potential to induce neovascularization in many different tissues. This becomes important in that under clinical circumstances it …

Troponin concentrations for stratification of patients with acute coronary syndromes in relation to therapeutic efficacy of tirofiban. PRISM Study Investigators. Platelet Receptor Inhibition in Ischemic Syndrome Management.

BACKGROUND A major challenge for physicians is to identify patients with acute coronary syndromes who may benefit from treatment with glycoprotein-IIb/IIIa-receptor antagonists. We investigated whether troponin concentrations can be used to stratify patients for benefit from treatment with tirofiban. METHODS We enrolled 2222 patients of the Platelet Receptor Inhibition in Ischemic Syndrome Management study with coronary artery disease and who had had chest pain in the previous 24 h. All patients received aspirin and were randomly assigned treatment with tirofiban or heparin. We took baseline measurements of troponin I and troponin T. We recorded death, myocardial infarction, or recurrent ischaemia after 48 h infusion treatment and at 7 days and 30 days. FINDINGS 629 (28.3%) patients had troponin I concentrations higher than the diagnostic threshold of 1.0 microg/L and 644 (29.0%) troponin T concentrations higher than 0.1 microg/L. 30-day event rates (death, myocardial infarction) were 13.0% for troponin-I-positive patients compared with 4.9% for troponin-I-negative patients (p<0.0001), and 13.7% compared wth 3.5% for troponin T (p<0.001). At 30 days, in troponin-I-positive patients, tirofiban had lowered the risk of death (adjusted hazard ratio 0.25 [95% CI 0.09-0.68], p=0.004) and myocardial infarction (0.37 [0.16-0.84], p=0.01). This benefit was seen in medically managed patients (0.30 [0.10-0.84], p=0.004) and those undergoing revascularisation (0.37 [0.15-0.93] p=0.02) after 48 h infusion treatment. By contrast, no treatment effect was seen for troponin-I-negative patients. Similar benefits were seen for troponin-T-positive patients. INTERPRETATION Troponin I and troponin T reliably identified high-risk patients with acute coronary syndromes, managed medically and by revascularisation, who would benefit from tirofiban.

Phenylpropanolamine and the risk of hemorrhagic stroke.

BACKGROUND Phenylpropanolamine is commonly found in appetite suppressants and cough or cold remedies. Case reports have linked the use of products containing phenylpropanolamine to hemorrhagic stroke, often after the first use of these products. To study the association, we designed a case-control study. METHODS Men and women 18 to 49 years of age were recruited from 43 U.S. hospitals. Eligibility criteria included the occurrence of a subarachnoid or intracerebral hemorrhage within 30 days before enrollment and the absence of a previously diagnosed brain lesion. Random-digit dialing identified two matched control subjects per patient. RESULTS There were 702 patients and 1376 control subjects. For women, the adjusted odds ratio was 16.58 (95 percent confidence interval, 1.51 to 182.21; P=0.02) for the association between the use of appetite suppressants containing phenylpropanolamine and the risk of a hemorrhagic stroke and 3.13 (95 percent confidence interval, 0.86 to 11.46; P=0.08) for the association with the first use of a product containing phenylpropanolamine. All first uses of phenylpropanolamine involved cough or cold remedies. For men and women combined, the adjusted odds ratio was 1.49 (95 percent confidence interval, 0.84 to 2.64; P=0.17) for the association between the use of a product containing phenylpropanolamine and the risk of a hemorrhagic stroke, 1.23 (95 percent confidence interval, 0.68 to 2.24; P=0.49) for the association with the use of cough or cold remedies that contained phenylpropanolamine, and 15.92 (95 percent confidence interval, 1.38 to 184.13; P=0.03) for the association with the use of appetite suppressants that contained phenylpropanolamine. An analysis in men showed no increased risk of a hemorrhagic stroke in association with the use of cough or cold remedies containing phenylpropanolamine. No men reported the use of appetite suppressants. CONCLUSIONS The results suggest that phenylpropanolamine in appetite suppressants, and possibly in cough and cold remedies, is an independent risk factor for hemorrhagic stroke in women.

Prevalence and size of directly detected patent foramen ovale in migraine with aura.

BACKGROUND Transcranial contrast Doppler studies have shown an increased prevalence of right-to-left shunts in patients with migraine with aura compared with controls. The anatomy and size of these right-to-left shunts have never been directly assessed. METHODS In a cross-sectional case-control study, the authors performed transesophageal contrast echocardiography in 93 consecutive patients with migraine with aura and 93 healthy controls. RESULTS A patent foramen ovale was present in 44 (47% [95% CI 37 to 58%]) patients with migraine with aura and 16 (17% [95% CI 10 to 26%]) control subjects (OR 4.56 [95% CI 1.97 to 10.57]; p < 0.001). A small shunt was equally prevalent in migraineurs (10% [95% CI 5 to 18%]) and controls (10% [95% CI 5 to 18%]), but a moderate-sized or large shunt was found more often in the migraine group (38% [95% CI 28 to 48%] vs 8% [95% CI 2 to 13%] in controls; p < 0.001). The presence of more than a small shunt increased the odds of having migraine with aura 7.78-fold (95% CI 2.53 to 29.30; p < 0.001). Besides patent foramen ovale prevalence and shunt size, no other echocardiographic differences were found between the study groups. Headache and baseline characteristics did not differ in migraine patients with and without shunt. CONCLUSIONS Nearly half of all patients with migraine with aura have a right-to-left shunt due to a patent foramen ovale. Shunt size is larger in migraineurs than controls. The clinical presentation of migraine is identical in patients with and without a patent foramen ovale.

Effectiveness of thigh-length graduated compression stockings to reduce the risk of deep vein thrombosis after stroke (CLOTS trial 1): a multicentre, randomised controlled trial

BACKGROUND Deep vein thrombosis (DVT) and pulmonary embolism are common after stroke. In small trials of patients undergoing surgery, graduated compression stockings (GCS) reduce the risk of DVT. National stroke guidelines extrapolating from these trials recommend their use in patients with stroke despite insufficient evidence. We assessed the effectiveness of thigh-length GCS to reduce DVT after stroke. METHODS In this outcome-blinded, randomised controlled trial, 2518 patients who were admitted to hospital within 1 week of an acute stroke and who were immobile were enrolled from 64 centres in the UK, Italy, and Australia. Patients were allocated via a central randomisation system to routine care plus thigh-length GCS (n=1256) or to routine care plus avoidance of GCS (n=1262). A technician who was blinded to treatment allocation undertook compression Doppler ultrasound of both legs at about 7-10 days and, when practical, again at 25-30 days after enrolment. The primary outcome was the occurrence of symptomatic or asymptomatic DVT in the popliteal or femoral veins. Analyses were by intention to treat. This study is registered, number ISRCTN28163533. FINDINGS All patients were included in the analyses. The primary outcome occurred in 126 (10.0%) patients allocated to thigh-length GCS and in 133 (10.5%) allocated to avoid GCS, resulting in a non-significant absolute reduction in risk of 0.5% (95% CI -1.9% to 2.9%). Skin breaks, ulcers, blisters, and skin necrosis were significantly more common in patients allocated to GCS than in those allocated to avoid their use (64 [5%] vs 16 [1%]; odds ratio 4.18, 95% CI 2.40-7.27). INTERPRETATION These data do not lend support to the use of thigh-length GCS in patients admitted to hospital with acute stroke. National guidelines for stroke might need to be revised on the basis of these results. FUNDING Medical Research Council (UK), Chief Scientist Office of Scottish Government, Chest Heart and Stroke Scotland, Tyco Healthcare (Covidien) USA, and UK Stroke Research Network.

Venous thrombosis in cancer patients: insights from the FRONTLINE survey.

BACKGROUND Venous thromboembolism (VTE) is a common complication in cancer patients and a significant cause of morbidity and mortality. However, little information is available on oncologists' perceptions of the risk of VTE and its management. The Fundamental Research in Oncology and Thrombosis (FRONTLINE) study is the first comprehensive global survey of thrombosis and cancer. The study was designed to collect data on the perceived risk and patterns of practice with regard to VTE in cancer patients undergoing surgical and medical management of their malignancy and to provide information on international and regional practice patterns, allowing for the design of research studies to answer the concerns of practicing clinicians. METHODS Literature reviews were performed to provide a current evidence base against which to compare the findings, and a survey was developed under the guidance of an advisory board. A paper-based reply-paid questionnaire was distributed globally between July and November 2001 to clinicians involved in cancer care and was made available on a dedicated website. FINDINGS A total of 3,891 completed responses were available for analysis. Brain and pancreatic tumors were considered to carry a high risk for VTE, and 80% of respondents considered the use of central venous lines to be associated with a high risk of VTE. Marked differences were seen in the use of thromboprophylaxis for surgical and medical cancer patients, with over 50% of surgeons reporting that they initiated thromboprophylaxis routinely, while most medical oncologists reported using thromboprophylaxis in less than 5% of medical patients. Low molecular weight heparin (LMWH) was the most popular method of thromboprophylaxis employed in both surgical and medical patients and was more favored by European than U.S. clinicians. Some 20% of respondents reported using aspirin for prophylaxis, despite there being no reliable evidence for this agent as effective in prevention in this population. For the treatment of VTE, LMWH was again the most common initial treatment, although, for the long-term, oral anticoagulation therapy was widely adopted. Many patients were treated for VTE on an outpatient basis, and secondary prevention of VTE was typically continued for 3 to 6 months after an episode of deep vein thrombosis or for longer in the case of pulmonary embolism. INTERPRETATION The results of the FRONTLINE survey demonstrate a need for guidelines to direct clinical practice in line with evidence-based data concerning cancer and VTE. Oncologists need to be educated regarding the true risks of VTE associated with certain cancers and on strategies for prevention and treatment to reduce the morbidity and mortality associated with VTE in all cancer patients. The study has also helped identify areas for future research.

Sphingosine can pre- and post-condition heart and utilizes a different mechanism from sphingosine 1-phosphate.

Consistent with previous reports, sphingosine at a high concentration (5 microM) was cardiotoxic as evidenced by increased infarct size in response to ischemia/reperfusion in an ex vivo rat heart. Sphingosine 1-phosphate (S1P) at 5 microM was cardioprotective. However, at a physiologic concentration (0.4 microM) sphingosine as well as S1P was effective in protecting the heart from ischemia/reperfusion injury both when perfused prior to 40 min of ischemia (preconditioning) or when added to reperfusion media following ischemia (postconditioning). Protection by sphingosine and S1P was evidenced with both pre- and post-conditioning by a >75% recovery of left ventricular developed pressure during reperfusion and a decrease in infarct size from 45% of the risk area to less than 8%. When VPC23019, an S1P(1and3)G-protein coupled receptor antagonist, was added to the preconditioning or postconditioning medium along with S1P, it completely blocked S1P-induced protection. However, VPC 23019 did not affect the ability of 0.4 microM sphingosine to either precondition or postcondition hearts. Studies of preconditioning revealed that inhibition of protein kinase C with GF109203X blocked preconditioning by S1P. However, GF109203X did not affect preconditioning by 0.4 microM sphingosine. Likewise, cotreatment with the PI3 kinase inhibitor wortmanin blocked preconditioning by S1P but not by sphingosine. By contrast, inhibition of protein kinase G with KT5823 had no effect on S1P preconditioning but completely eliminated preconditioning by sphingosine. Also, the protein kinase A inhibitory peptide 14-22 amide blocked preconditioning by sphingosine but not S1P. These data reveal for the first time that sphingosine is not toxic at physiologic concentrations but rather is a potent cardioprotectant that utilizes a completely different mechanism than S1P; one that is independent of G-protein coupled receptors and utilizes cyclic nucleotide-dependent pathways.

Scaffold-based three-dimensional human fibroblast culture provides a structural matrix that supports angiogenesis in infarcted heart tissue.

BACKGROUND We have developed techniques to implant angiogenic patches onto the epicardium over regions of infarcted cardiac tissue to stimulate revascularization of the damaged tissue. These experiments used a scaffold-based 3D human dermal fibroblast culture (3DFC) as an epicardial patch. The 3DFC contains viable cells that secrete angiogenic growth factors and has previously been shown to stimulate angiogenic activity. The hypothesis tested was that a viable 3DFC cardiac patch would stimulate an angiogenic response within an area of infarcted cardiac tissue. METHODS AND RESULTS A coronary occlusion of a branch of the left anterior descending coronary artery was performed by thermal ligation in severe combined immunodeficient mice. 3DFCs with or without viable cells were sized to the damaged area, implanted in replicate mice onto the epicardium at the site of tissue injury, and compared with animals that received infarct surgery but no implant. Fourteen and 30 days after surgery, hearts were exposed and photographed, and tissue samples were prepared for histology and cytochemistry. Fourteen and 30 days after surgery, the damaged myocardium receiving viable 3DFC exhibited a significantly greater angiogenic response (including arterioles, venules, and capillaries) than nonviable and untreated control groups. CONCLUSIONS In this animal model, viable 3DFC stimulates angiogenesis within a region of cardiac infarction and can augment a repair response in damaged tissue. Therefore, a potential use for 3DFC is the repair of myocardial tissue damaged by infarction.

Metformin attenuates blood-brain barrier disruption in mice following middle cerebral artery occlusion

BACKGROUND Metformin, a widely used hypoglycemic drug, reduces stroke incidence and alleviates chronic inflammation in clinical trials. However, the effect of metformin in ischemic stroke is unclear. Here, we investigated the effect of metformin on ischemic stroke in mice and further explored the possible underlying mechanisms. METHODS Ninety-eight adult male CD-1 mice underwent 90-minute transient middle cerebral artery occlusion (tMCAO). Metformin (200 mg/kg) was administrated for up to 14 days. Neurobehavioral outcomes, brain infarct volume, inflammatory factors, blood-brain barrier (BBB) permeability and AMPK signaling pathways were evaluated following tMCAO. Oxygen glucose deprivation was performed on bEND.3 cells to explore the mechanisms of metformin in inhibiting inflammatory signaling pathways. RESULTS Infarct volume was reduced in metformin-treated mice compared to the control group following tMCAO (P < 0.05). Neurobehavioral outcomes were greatly improved in metformin-treated mice (P < 0.05). MPO+ cells, Gr1+ cells, MPO activity and BBB permeability were decreased after metformin administration (P < 0.05). In addition, metformin activated AMPK phosphorylation, inhibited NF-κB activation, down-regulated cytokine (IL-1β, IL-6, TNF-α) and ICAM-1 expression following tMCAO (P < 0.05). Furthermore, metformin activated AMPK signaling pathway and alleviated oxygen-glucose deprivation-induced ICAM-1 expression in bEND.3 cells (P < 0.05). Compound C, a selective AMPK inhibitor, eliminated this promotional effect. CONCLUSIONS Metformin down-regulated ICAM-1 in an AMPK-dependent manner, which could effectively prevent ischemia-induced brain injury by alleviating neutrophil infiltration, suggesting that metformin is a promising therapeutic agent in stroke therapy.

Comparative determinants of 4-year cardiovascular event rates in stable outpatients at risk of or with atherothrombosis.

CONTEXT Clinicians and trialists have difficulty with identifying which patients are highest risk for cardiovascular events. Prior ischemic events, polyvascular disease, and diabetes mellitus have all been identified as predictors of ischemic events, but their comparative contributions to future risk remain unclear. OBJECTIVE To categorize the risk of cardiovascular events in stable outpatients with various initial manifestations of atherothrombosis using simple clinical descriptors. DESIGN, SETTING, AND PATIENTS Outpatients with coronary artery disease, cerebrovascular disease, or peripheral arterial disease or with multiple risk factors for atherothrombosis were enrolled in the global Reduction of Atherothrombosis for Continued Health (REACH) Registry and were followed up for as long as 4 years. Patients from 3647 centers in 29 countries were enrolled between 2003 and 2004 and followed up until 2008. Final database lock was in April 2009. MAIN OUTCOME MEASURES Rates of cardiovascular death, myocardial infarction, and stroke. RESULTS A total of 45,227 patients with baseline data were included in this 4-year analysis. During the follow-up period, a total of 5481 patients experienced at least 1 event, including 2315 with cardiovascular death, 1228 with myocardial infarction, 1898 with stroke, and 40 with both a myocardial infarction and stroke on the same day. Among patients with atherothrombosis, those with a prior history of ischemic events at baseline (n = 21,890) had the highest rate of subsequent ischemic events (18.3%; 95% confidence interval [CI], 17.4%-19.1%); patients with stable coronary, cerebrovascular, or peripheral artery disease (n = 15,264) had a lower risk (12.2%; 95% CI, 11.4%-12.9%); and patients without established atherothrombosis but with risk factors only (n = 8073) had the lowest risk (9.1%; 95% CI, 8.3%-9.9%) (P < .001 for all comparisons). In addition, in multivariable modeling, the presence of diabetes (hazard ratio [HR], 1.44; 95% CI, 1.36-1.53; P < .001), an ischemic event in the previous year (HR, 1.71; 95% CI, 1.57-1.85; P < .001), and polyvascular disease (HR, 1.99; 95% CI, 1.78-2.24; P < .001) each were associated with a significantly higher risk of the primary end point. CONCLUSION Clinical descriptors can assist clinicians in identifying high-risk patients within the broad range of risk for outpatients with atherothrombosis.

Preoperative C-reactive protein predicts long-term mortality and hospital length of stay after primary, nonemergent coronary artery bypass grafting.

BACKGROUND Preoperative C-reactive protein (CRP) levels more than 10 mg/l have been shown to be associated with increased morbidity and mortality after cardiac surgery. We examine the value of preoperative CRP levels less than 10 mg/l for predicting long-term, all-cause mortality and hospital length of stay in surgical patients undergoing primary, nonemergent coronary artery bypass graft-only surgery. METHODS We examined the association between preoperative CRP levels stratified into four categories (< 1, 1-3, 3-10, and > 10 mg/l), and 7-yr all-cause mortality and hospital length of stay in 914 prospectively enrolled primary, nonemergent coronary artery bypass graft-only surgical patients using a proportional hazards regression model. RESULTS Eighty-seven patients (9.5%) died during a mean follow-up period of 4.8 +/- 1.5 yr. After proportional hazards adjustment, the 3-10 and > 10 mg/l preoperative CRP groups were associated with long-term, all-cause mortality (hazards ratios [95% CI]: 2.50 [1.22-5.16], P = 0.01 and 2.66 [1.21-5.80], P = 0.02, respectively) and extended hospital length of stay (1.32 [1.07-1.63], P < 0.001 and 1.27 [1.02-1.62], P = 0.001, respectively). CONCLUSION We demonstrate that preoperative CRP levels as low as 3 mg/l are associated with increased long-term mortality and extended hospital length of stay in relatively lower-acuity patients undergoing primary, nonemergent coronary artery bypass graft-only surgery. These important findings may allow for more objective risk stratification of patients who present for uncomplicated surgical coronary revascularization.

An analysis of age and gender influences on the relative risk for suicide and psychotropic drug self-poisoning.

Psychiatric illness is a significant risk factor for both attempted and completed suicide and psychotropic medications account for 80% of all drug overdoses involving prescription medications. One challenge facing clinicians is to balance the benefit of treatment against the risk of drug overdose. The aim of the present study was to compare the age and gender distribution of patients prescribed psychotropic drugs with patients attempting and completing suicide with these drugs. Data were obtained from the Australian census and studies of general practitioner prescribing, patients who committed suicide or presented with self-poisoning within a defined geographic area. The characteristics of these populations were compared to calculate odds ratios for attempting or completing suicide with psychotropic drugs, before and after correction for rates of prescription, in different age and gender groups. The odds ratios (ORs) for self-poisoning were higher for those aged less than 45 years and yet this group was least likely to be prescribed psychotropic drugs. Men had a much higher rate of completed suicide using more lethal methods. The ORs for self-poisoning and suicide with psychotropic drugs, after correction for prescription rates, for those aged 15 to 24 years were 11.1 and 1.7, respectively. Those aged 25 to 44 years had ORs of 4.9 and 4.3, and, by contrast, those over 75 years had ORs of 0.03 and 0. Women were slightly more likely to poison themselves with psychotropic drugs (OR 1.2). However, the situation reversed after correction for prescription rates (OR 0.69). It is concluded that greater caution should be exercised in prescribing for those under 45 years of age, given their relatively higher risk of drug overdose, and that the least toxic compounds should be used. The risk (of self-poisoning) among the elderly may have been overstated, so that some patients may have been denied the benefit of adequate treatment.

Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group.

BACKGROUND Lowering the blood cholesterol level may reduce the risk of coronary heart disease. This double-blind study was designed to determine whether the administration of pravastatin to men with hypercholesterolemia and no history of myocardial infarction reduced the combined incidence of nonfatal myocardial infarction and death from coronary heart disease. METHODS We randomly assigned 6595 men, 45 to 64 years of age, with a mean (+/- SD) plasma cholesterol level of 272 +/- 23 mg per deciliter (7.0 +/- 0.6 mmol per liter) to receive pravastatin (40 mg each evening) or placebo. The average follow-up period was 4.9 years. Medical records, electrocardiographic recordings, and the national death registry were used to determine the clinical end points. RESULTS Pravastatin lowered plasma cholesterol levels by 20 percent and low-density-lipoprotein cholesterol levels by 26 percent, whereas there was no change with placebo. There were 248 definite coronary events (specified as nonfatal myocardial infarction or death from coronary heart disease) in the placebo group, and 174 in the pravastatin group (relative reduction in risk with pravastatin, 31 percent; 95 percent confidence interval, 17 to 43 percent; P < 0.001). There were similar reductions in the risk of definite nonfatal myocardial infarctions (31 percent reduction, P < 0.001), death from coronary heart disease (definite cases alone: 28 percent reduction, P = 0.13; definite plus suspected cases: 33 percent reduction, P = 0.042), and death from all cardiovascular causes (32 percent reduction, P = 0.033). There was no excess of deaths from noncardiovascular causes in the pravastatin group. We observed a 22 percent reduction in the risk of death from any cause in the pravastatin group (95 percent confidence interval, 0 to 40 percent; P = 0.051). CONCLUSIONS Treatment with pravastatin significantly reduced the incidence of myocardial infarction and death from cardiovascular causes without adversely affecting the risk of death from noncardiovascular causes in men with moderate hypercholesterolemia and no history of myocardial infarction.

How safe are psychiatric medications after a voluntary overdose?

PURPOSE This study assessed psychiatric medications and their potential lethality in a representative sample of suicide attempts. MATERIALS AND METHODS During 1996-98, 563 suicide attempts were studied in a general hospital in Madrid (Spain). Medication overdose was used in 456 suicide attempts (81%). The ratio between dose taken and maximum prescription dose recommended was used to evaluate the medication toxicity. RESULTS Benzodiazepines were the drugs most often used in self-poisoning (65% of overdoses), followed by new antidepressants (11%), tricyclic antidepressants (TCAs) (10%), and antipsychotics (8%). An overdose with any of the three latter psychiatric medications was significantly more frequent in patients prescribed those medications. The overdoses for TCA were potentially lethal in 47% of the cases. However, all patients who overdosed on psychiatric medications recovered well and were discharged without any sequelae. DISCUSSION This study suggests that psychiatric medications, particularly benzodiazepines, new antidepressants and antipsychotics, are relatively safe when they are used for self-poisoning. If patients with mental illnesses are under treated, there is a clear and documented higher risk for suicide. CONCLUSION It is better to prescribe psychiatric medications, particularly the new ones, rather than withhold them due to an exaggerated fear of a lethal overdose

Locations of cerebral infarctions in tuberculous meningitis

The locations of cerebral infarctions were studied in 14 patients with tuberculous meningitis (TBM) and 173 patients with noninflammatory ischemic stroke (IS). In patients with TBM, 75% of infarctions occurred in the “TB zone” supplied by medial striate and thalamoperforating arteries; only 11% occurred in the “IS zone” supplied by lateral striate, anterior choroidal and thalamogeniculate arteries. In patients with IS 29% of infarctions occurred in the IS zone, 29% in the subcortical white matter, and 24% in (or involving) the cerebral cortex. Only 11% occurred in the TB zone. Bilaterally symmetrical infarctions of the TB zone were common with TMB (71%) but rare with IS (5%).

The impact of hydroxyethyl starches in cardiac surgery: a meta-analysis

INTRODUCTION Recent studies in septic patients showed that adverse effects of hydroxyethyl starches (HESs) possibly outweigh their benefits in severely impaired physiological haemostasis. It remains unclear whether this also applies to patient populations that are less vulnerable. In this meta-analysis, we evaluated the impact of various HES generations on safety and efficacy endpoints in patients undergoing cardiac surgery. METHODS We searched the PubMed, Embase and Cochrane Central Register of Controlled Trials databases for randomised controlled trials (RCTs) in the English or German language comparing the use of HES to any other colloid or crystalloid during open heart surgery. RESULTS Blood loss and transfusion requirements were higher for older starches with mean molecular weights more than 200 kDa compared to other volume substitutes. In contrast, this effect was not observed with latest-generation tetrastarches (130/0.4), which performed even better when compared to albumin (blood loss of tetrastarch versus albumin: standardised mean difference (SMD), -0.34; 95% CI, -0.63, -0.05; P = 0.02; versus gelatin: SMD, -0.06; 95% CI, -0.20, 0.08; P = 0.39; versus crystalloids: SMD, -0.05; 95% CI, -0.20, 0.10; P = 0.54). Similar results were found for transfusion needs. Lengths of stay in the intensive care unit or hospital were significantly shorter with tetrastarches compared to gelatin (intensive care unit: SMD, -0.10; 95% CI, -0.15, -0.05; P = 0.0002) and crystalloids (hospital: SMD, -0.52; 95% CI, -0.90, -0.14; P = 0.007). CONCLUSIONS In this meta-analysis of RCTs, we could not identify safety issues with tetrastarches compared with other colloid or crystalloid solutions in terms of blood loss, transfusion requirements or hospital length of stay in patients undergoing cardiac surgery. The safety data on coagulation with older starches raise some issues that need to be addressed in future trials.

Long-term survival, quality of life, and quality-adjusted life-years among critically ill elderly patients.

OBJECTIVES To assess mortality, quality of life (QOL), and quality-adjusted life-years (QALYs) for critically ill elderly patients. DESIGN Cross-sectional survey. SETTING A ten-bed medical-surgical intensive care unit (ICU) in a tertiary care university hospital. PATIENTS The study group included 882 elderly patients (> or =65 yrs of age) and 1,827 controls (<65 yrs of age) treated during the period of 1995 to 2000. INTERVENTION None. MEASUREMENTS AND MAIN RESULTS Mortality was assessed during the ICU and hospital stays, and 12, 24, and 36 months after ICU discharge. The cumulative 3-yr mortality rate among the elderly (57%) was higher (p < .05) than that among the controls (40%). The majority (66%) of the elderly nonsurvivors died within 1 month after intensive care discharge. All elderly patients with day-1 Sequential Organ Failure (SOFA) scores >15 died during the ICU stay. QOL was assessed with EQ-5D and RAND-36 measures from 10 months to 7 yrs after discharge. The majority (88%) of the elderly survivors assessed their present health state as good or satisfactory; 66% found it to be similar or better than 12 months earlier, and 48% similar or better than their preadmission state. QOL measures by RAND-36 revealed that aging decreased their competencies most in physical functioning, physical role limitations, and vitality, but the elderly had better values in mental health than the controls. However, QALYs of the elderly respondents were 21% to 35% lower than the mean QALY minus 2 sd units of the age- and gender-adjusted general population. CONCLUSIONS High age alone is not a valid reason to refuse intensive care, but the benefits perceived by intensive care seem to decrease with aging, if reflected as QALYs. However, 97% of the elderly survivors lived at home and 88% of them considered their QOL satisfactory or good after hospital discharge. Therefore, more reliable information on the outcome for the elderly is clearly needed.

Failure of continuous venovenous hemofiltration to prevent death in paraquat poisoning.

Paraquat poisoning is characterized by multiorgan failure and pulmonary fibrosis with respiratory failure. Multiorgan failure with circulatory collapse is a major cause of early death within 3 days of paraquat ingestion. Recent studies suggested that continuous venovenous hemofiltration (CVVH) had a role in the treatment of multiorgan failure by promoting hemodynamic stability. We therefore evaluated the effect of prophylactic CVVH in 80 patients with paraquat poisoning (August 1996 to February 1999). The amount ingested was 2.1 +/- 1.0 mouthfuls (as 20% concentrate). All patients were treated with hemoperfusion (HP; duration, 6.4 +/- 3.0 hours) within 24 hours of ingestion and then randomly assigned to the HP-alone or HP-CVVH group. Forty-four patients underwent HP only, and 36 patients underwent CVVH (duration, 57.4 +/- 31.3 hours; ultrafiltration volume, 40.2 +/- 4.8 L/d) after HP. Although time to death after ingestion was significantly longer in the HP-CVVH than HP group (5.0 +/- 5.0 versus 2.5 +/- 2.1 days; P < 0.05), there was no difference in mortality rates between the two groups (66.7% versus 63.6%; P = 0.82). In the HP group, early circulatory collapse was a major cause of death compared with the HP-CVVH group, in which late respiratory failure was a major cause of death. In conclusion, prophylactic CVVH after HP prevented early death caused by circulatory collapse and prolonged survival time. However, it could not prevent late death caused by respiratory failure and did not provide a survival benefit in acute paraquat poisoning.

Peroxisome proliferator-activated receptor gamma agonists for the Prevention of Adverse events following percutaneous coronary Revascularization--results of the PPAR study.

BACKGROUND Patients with metabolic syndrome are at increased risk for cardiovascular complications. We sought to determine whether peroxisome proliferator-activated receptor gamma agonists had any beneficial effect on patients with metabolic syndrome undergoing percutaneous coronary intervention (PCI). METHODS A total of 200 patients with metabolic syndrome undergoing PCI were randomized to rosiglitazone or placebo and followed for 1 year. Carotid intima-medial thickness (CIMT), inflammatory markers, lipid levels, brain natriuretic peptide, and clinical events were measured at baseline, 6 months, and 12 months. RESULTS There was no significant difference in CIMT between the 2 groups. There was no difference in the 12-month composite end point of death, myocardial infarction (MI), stroke, or any recurrent ischemia (31.4% vs 30.2%, P = .99). The rate of death, MI, or stroke at 12 months was numerically lower in the rosiglitazone group (11.9% vs 6.4%, P = .19). There was a trend toward a greater decrease over time in high-sensitivity C-reactive protein values compared with baseline in the group randomized to rosiglitazone versus placebo both at 6 months (-35.4% vs -15.8%, P = .059) and 12 months (-40.0% vs -20.9%, P = .089) and higher change in high-density lipoprotein (+15.5% vs +4.1%, P = .05) and lower triglycerides (-13.9% vs +14.9%, P = .004) in the rosiglitazone arm. There was a trend toward less new onset diabetes in the rosiglitazone group (0% vs 3.3%, P = .081) and no episodes of symptomatic hypoglycemia. There was no excess of new onset of clinical heart failure in the rosiglitazone group, nor was there a significant change in brain natriuretic peptide levels. CONCLUSIONS Patients with metabolic syndrome presenting for PCI are at increased risk for subsequent cardiovascular events. Rosiglitazone for 12 months did not appear to affect CIMT in this population, although it did have beneficial effects on high-sensitivity C-reactive protein, high-density lipoprotein, and triglycerides. Further study of peroxisome proliferator-activated receptor agonism in patients with metabolic syndrome undergoing PCI may be warranted.

Influence of smoking and plasma factors on patency of femoropopliteal vein grafts.

OBJECTIVE To determine the effects of smoking, plasma lipids, lipoproteins, apolipoproteins, and fibrinogen on the patency of saphenous vein femoropopliteal bypass grafts at one year. DESIGN Prospective study of patients with saphenous vein femoropopliteal bypass grafts entered into a multicentre trial. SETTING Surgical wards, outpatient clinics, and home visits coordinated by two tertiary referral centres in London and Birmingham. PATIENTS 157 Patients (mean age 66.6 (SD 8.2) years), 113 with patent grafts and 44 with occluded grafts one year after bypass. MAIN OUTCOME MEASURE Cumulative percentage patency at one year. RESULTS Markers for smoking (blood carboxyhaemoglobin concentration (p less than 0.05) and plasma thiocyanate concentration (p less than 0.01) and plasma concentrations of fibrinogen (p less than 0.001) and apolipoproteins AI (p less than 0.04) and (a) (p less than 0.05) were significantly higher in patients with occluded grafts. Serum cholesterol concentrations were significantly higher in patients with grafts that remained patent one year after bypass (p less than 0.005). Analysis of the smoking markers indicated that a quarter of patients (40) were untruthful in their claims to have stopped smoking. Based on smoking markers, patency of grafts in smokers was significantly lower at one year by life table analysis than in non-smokers (63% v 84%, p less than 0.02). Patency was significantly higher by life table analysis in patients with a plasma fibrinogen concentration below the median than in those with a concentration above (90% v 57%, p less than 0.0002). Surprisingly, increased plasma low density lipoprotein cholesterol concentration was significantly associated with improved patency at one year (85%) at values above the median compared with patency (only 68%) at values in the lower half of the range (p less than 0.02). CONCLUSIONS Plasma fibrinogen concentration was the most important variable predicting graft occlusion, followed by smoking markers. A more forceful approach is needed to stop patients smoking; therapeutic measures to improve patency of vein grafts should focus on decreasing plasma fibrinogen concentration rather than serum cholesterol concentration.

Early intermittent noninvasive ventilation for acute chest syndrome in adults with sickle cell disease: a pilot study

Alveolar hypoxia and hypoxic vasoconstriction lead to trapping of sickle cells within the pulmonary vasculature. Improving alveolar ventilation and oxygenation may improve the outcome of acute chest syndrome (ACS). Prospective randomized single-center open study from November 1998 to February 2002 to test whether noninvasive ventilation (NIV) was more effective than oxygen alone in improving oxygenation on day 3 in adults with ACS and to evaluate the effects on pain, transfusion requirements, and length of stay. Seventy-one consecutive ACS episodes in 67 patients were randomly allocated to oxygen (n = 36) or NIV (n = 35) for 3 days in a medical step-down unit. Baseline respiratory rate and pain score were higher in the NIV group. NIV promptly lowered the respiratory rate, raised $$ {\text{Pa}}_{{\text{O}_{2}}} $$ , and decreased alveolar–arterial oxygen gradient $$ (({\text{A}} - {\text{a}})_{{{\text{O}}_{ 2} }} ) $$ , which remained unchanged with oxygen alone. $$ {\text{Pa}}_{{{\text{CO}}_{ 2} }} $$ significantly worsened only in the oxygen group. On day 3, the groups did not differ regarding the proportion of episodes with normal $$ {\text{Pa}}_{{{\text{O}}_{ 2} }} $$ (35% with NIV and 25% with oxygen; P = 0.5) or $$ (({\text{A}} - {\text{a}})_{{{\text{O}}_{ 2} }} ) $$ . Patient satisfaction and compliance were lower with NIV. No differences were noted in pain relief, transfusions, or length of stay. In the subgroup of patients with severe hypoxemia $$ ( {\text{Pa}}_{{{\text{O}}_{ 2} }} \le 6 5\,{\text{mmHg)}} $$ , physiological variables also improved faster with NIV, the differences being slightly more pronounced. Respiratory rate and gas exchange improved faster with NIV. However, NIV failed to significantly reduce the number of patients remaining hypoxemic at day 3, and was associated with greater patient discomfort.

Preoperative statin treatment reduces systemic inflammatory response and myocardial damage in cardiac surgery.

OBJECTIVE To determine if preoperative statin treatment is associated with a reduction in systemic inflammatory response (SIR) and myocardial damage markers following cardiac surgery with cardiopulmonary bypass (CPB). METHODS We study a prospective cohort of 138 patients who underwent coronary and valvular surgery with CPB. We differentiate two study groups: patients with (group A, n=72) or without (group B, n=66) statins. Plasma levels of pro-inflammatory interleukins (tumour necrosis factor-alpha (TNF-alpha), interleukin (IL)-6, IL-8 and IL-2R), creatine phosphokinase (CPK), CPK-MB and troponin I were measured before and 1, 6, 24 and >72 h after surgery. RESULTS The baseline, operative and postoperative morbidity and mortality characteristics were similar for both the groups. Group A had significantly lower postoperative levels of IL-6 than group B at 6h (68.8+/-5 pg ml(-1) vs 108.9+/-108 pg ml(-1), p=0.01), 24h (71.7+/-7 pg ml(-1) vs 110.4+/-106 pg ml(-1), p=0.01) and before hospital discharge (21.6+/-12 pg ml(-1) vs 32.8+/-27 pg ml(-1), p=0.005), as well as significantly lower average IL-6 levels in the first 24h following surgery (71.8+/-5 pgml(-1) vs 112.8+/-82 pg ml(-1), p=0.002). The postoperative CPK-MB at 24h (19.7+/-23 ng ml(-1) vs 33.1+/-32 ng ml(-1), p=0.02) and troponin I levels at the end of the intervention (2.2+/-2.2 ng ml(-1) vs 3.3+/-3.1 ng ml(-1), p=0.03) and at 24h (4.1+/-3.5 ng ml(-1) vs 6.6+/-8 ng ml(-1), p=0.04) were also significantly lower in the group treated with statins prior to surgery. CONCLUSIONS Preoperative treatment with statins is associated with a lower biochemical parameters of SIR and myocardial damage following cardiac surgery with CPB, regardless of it being coronary bypass grafting (CABG) or valvular surgery.

Hospital volume and the outcomes of mechanical ventilation.

BACKGROUND An increased volume of patients is associated with improved survival in numerous high-risk medical and surgical conditions. The relationship between the number of patients admitted (hospital volume) and outcome among patients with critical illnesses is unknown. METHODS We analyzed data from 20,241 nonsurgical patients receiving mechanical ventilation at 37 acute care hospitals in the Acute Physiology and Chronic Health Evaluation clinical information system from 2002 through 2003. Multivariate analyses were performed to adjust for the severity of illness and other differences in the case mix. RESULTS An increase in hospital volume was associated with improved survival among patients receiving mechanical ventilation in the intensive care unit (ICU) and in the hospital. Admission to a hospital in the highest quartile according to volume (i.e., >400 patients receiving mechanical ventilation per year) was associated with a 37 percent reduction in the adjusted odds of death in the ICU as compared with admission to hospitals in the lowest quartile (< or =150 patients receiving mechanical ventilation per year, P<0.001). In-hospital mortality was similarly reduced (adjusted odds ratio, 0.66; 95 percent confidence interval, 0.52 to 0.83; P<0.001). A typical patient in a hospital in a low-volume quartile would have an adjusted in-hospital mortality of 34.2 percent as compared with 25.5 percent in a hospital in a high-volume quartile. Among survivors, there were no significant trends in the length of stay in the ICU or the hospital. CONCLUSIONS Mechanical ventilation of patients in a hospital with a high case volume is associated with reduced mortality. Further research is needed to determine the mechanism of the relationship between volume and outcome among patients with a critical illness.

Direct in vivo assessment of microcirculatory dysfunction in severe falciparum malaria.

BACKGROUND This study sought to describe and quantify microcirculatory changes in the mucosal surfaces of patients with severe malaria, by direct in vivo observation using orthogonal polarization spectral (OPS) imaging. METHODS The microcirculation in the rectal mucosa of adult patients with severe malaria was assessed by use of OPS imaging, at admission and then daily. Comparison groups comprised patients with uncomplicated falciparum malaria, patients with bacterial sepsis, and healthy individuals. RESULTS Erythrocyte velocities were measured directly in 43 adult patients with severe falciparum malaria, of whom 20 died. Microcirculatory blood flow was markedly disturbed, with heterogeneous obstruction that was proportional to severity of disease. Blocked capillaries were found in 29 patients (67%) and were associated with concurrent hyperdynamic blood flow (erythrocyte velocity, >750 mm/s) in adjacent vessels in 27 patients (93%). The proportion of blocked capillaries correlated with the base deficit in plasma and with the concentration of lactate. Abnormalities disappeared when the patients recovered. In healthy individuals and in patients with uncomplicated malaria or sepsis, no stagnant erythrocytes were detected, and, in patients with sepsis, hyperdynamic blood flow was prominent. CONCLUSION Patients with severe falciparum malaria show extensive microvascular obstruction that is proportional to the severity of the disease. This finding underscores the prominent role that microvascular obstruction plays in the pathophysiology of severe malaria and illustrates the fundamental difference between the microvascular pathophysiology of malaria and that of bacterial sepsis.

Statin prophylaxis and inflammatory mediators following cardiopulmonary bypass: a systematic review

INTRODUCTION Induction of an inflammatory response is thought to have a significant role in the complications that follow cardiopulmonary bypass (CPB). The statin drugs are increasingly being recognized as having potent anti-inflammatory effects and hence have potential to influence an important mechanism of injury in CPB, although there is no current confirmation that this is indeed the case. Our objective was to systematically review if pre-operative prophylactic statin therapy, compared with placebo or standard of care, can decrease the inflammatory response in people undergoing heart surgery with CPB. METHODS We performed a systematic and comprehensive literature search for all randomized controlled trials (RCTs) of open heart surgery with CPB in adults or children who received prophylactic statin treatment prior to CPB, with reported outcomes which included markers of inflammation. Two authors independently identified eligible studies, extracted data, and assessed study quality using standardized instruments. Weighted mean difference (WMD) was the primary summary statistic with data pooled using a random effects model. Descriptive analysis was used when data could not be pooled. RESULTS Eight RCTs were included in the review, with the number of trials for each inflammatory outcome being even more limited. Pooled data demonstrated benefit with the use of statin to attenuate the post-CPB increase in interleukins 6 and 8 (IL-6, IL-8), peak high sensitivity C-reactive protein (hsCRP), and tumor necrosis factor-alpha (TNF-alpha) post-CPB (WMD [95% confidence interval (CI)] -23.5 pg/ml [-36.6 to -10.5]; -23.4 pg/ml [-35.8 to -11.0]; -15.3 mg/L [CI -26.9 to -3.7]; -2.10 pg/ml [-3.83 to -0.37] respectively). Very limited RCT evidence suggests that prophylactic statin therapy may also decrease adhesion molecules following CPB including neutrophil CD11b and soluble P (sP)-selectin. CONCLUSIONS Although the RCT evidence may suggest a reduction in post-CPB inflammation by statin therapy, the evidence is not definitive due to significant limitations. Several of the trials were not methodologically rigorous and statin intervention was highly variable in this small number of studies. This systematic review demonstrates that there is a significant gap that exists in the current literature in regards to the potential anti-inflammatory effect of statin therapy prior to CPB.

Pharmacodynamics and pharmacokinetics of eptifibatide in patients with acute coronary syndromes: prospective analysis from PURSUIT.

BACKGROUND Platelet deposition and aggregation are central to the pathogenesis of ischemic complications of acute coronary syndromes (ACS). Pharmacodynamic effects of the platelet glycoprotein IIb/IIIa antagonist eptifibatide have been delineated in healthy subjects but not in patients with ACS. We assessed effects of eptifibatide on ex vivo platelet aggregation in patients enrolled in the Platelet glycoprotein IIb/IIIa in Unstable angina: Receptor Suppression Using Integrilin (eptifibatide) Therapy (PURSUIT) trial of ACS. METHODS AND RESULTS Patients were randomly assigned to an intravenous bolus (180 microgram/kg) and 72-hour infusion of eptifibatide (2.0 microgram/kg per minute, n=48) or placebo (n=50). We assessed correlations of plasma eptifibatide levels with receptor occupancy and inhibition of ex vivo platelet aggregation at 5 minutes and 1, 4, 24, 48, and 72 hours during treatment and 4 and 8 hours after termination of infusion. Blood was collected in buffered citrate and D-phenylalanyl-L-prolyl-L-arginine chloromethylketone anticoagulants. Although eptifibatide produced profound, prolonged inhibition of platelet aggregation during therapy, aggregation appeared to recover partially by 4 hours after the bolus. The aggregation response was greater with thrombin receptor agonist peptide versus ADP stimulation; inhibition of platelet aggregation was greater in blood samples anticoagulated with citrate versus D-phenylalanyl-L-prolyl-L-arginine chloromethylketone (PPACK). Plasma eptifibatide levels correlated significantly with receptor occupancy but not with inhibition of platelet aggregation. CONCLUSIONS A bolus and infusion of eptifibatide inhibits platelet aggregation profoundly in patients with ACS and is followed by brief, partial recovery. These results enhance our understanding of the relation between pharmacodynamic and clinical effects of eptifibatide in such patients and may have important implications for its use in percutaneous interventions.

Heart failure admissions in adults with congenital heart disease; risk factors and prognosis.

BACKGROUND Heart failure (HF) is a serious complication and often the cause of death in adults with congenital heart disease (CHD). Therefore, our aims were to determine the frequency of HF-admissions, and to assess risk factors of first HF-admission and of mortality after first HF-admission in adults with CHD. METHODS The Dutch CONCOR registry was linked to the Hospital Discharge Registry and National Mortality Registry to obtain data on HF-admissions and mortality. Risk factors for both HF-admission and mortality were assessed using Cox regression models. RESULTS Of 10,808 adult patients (49% male), 274 (2.5%) were admitted for HF during a median follow-up period of 21 years. The incidence of first HF-admission was 1.2 per 1000 patient-years, but the incidence of HF itself will be higher. Main defect, multiple defects, and surgical interventions in childhood were identified as independent risk factors of HF-admission. Patients admitted for HF had a five-fold higher risk of mortality than patients not admitted (hazard ratio (HR)=5.3; 95% confidence interval 4.2-6.9). One- and three-year mortality after first HF-admission were 24% and 35% respectively. Independent risk factors for three-year mortality after first HF-admission were male gender, pacemaker implantation, admission duration, non-cardiac medication use and high serum creatinine. CONCLUSIONS The incidence of HF-admission in adults with CHD is 1.2 per 1000 patient-years. Mortality risk is substantially increased after HF-admission, which emphasises the importance to identify patients at high risk of HF-admission. These patients might benefit from closer follow-up and earlier medical interventions. The presented risk factors may facilitate surveillance.

Plasma homocysteine is a risk factor for recurrent vascular events in young patients with an ischaemic stroke or TIA

Young patients with an ischaemic stroke or transient ischaemic attack (TIA) often have no vascular risk factors. Hyperhomocysteinaemia is an established risk factor for stroke in elderly patients but it is uncertain whether it is also important for the prognosis of young ischaemic stroke and TIA patients. We examined the possible effect of the plasma homocysteine level on the risk of recurrent vascular events in patients between 18 and 45 years of age. The study population consisted of 161 consecutive patients with a recent cerebral infarction or TIA. Data on the primary event and the homocysteine level were collected retrospectively from hospital records. General practitioners and patients were contacted by telephone to record vascular events and the type of medication used during the follow–up period. Vascular events included cerebral infarction, TIA, pulmonary embolism, venous thrombosis, myocardial infarction and peripheral arterial disease. A Kaplan- Meier curve showed a dose effect relationship between event-free survival time and tertiles of the homocysteine level (Log rank statistic 5.91; p = 0.05). The Cox hazard ratio, after adjustment for homocysteine lowering treatment, was 1.7 (95 % CI, 1.1 to 2.8) for any vascular outcome event, 1.9 (95% CI, 1.1 to 3.0) for arterial outcome events and 1.8 (95 % CI, 1.1 to 2.9) for cerebral outcome events. In spite of our small number of outcome events we found a significant association at the 95% confidence level between homocysteine level and the risk of recurrent vascular events in young patients with an ischaemic stroke or TIA. The association is of the same magnitude as in elderly people.

Noninvasive ventilation for treatment of acute respiratory failure in patients undergoing solid organ transplantation: a randomized trial.

CONTEXT Noninvasive ventilation (NIV) has been associated with lower rates of endotracheal intubation in populations of patients with acute respiratory failure. OBJECTIVE To compare NIV with standard treatment using supplemental oxygen administration to avoid endotracheal intubation in recipients of solid organ transplantation with acute hypoxemic respiratory failure. DESIGN AND SETTING Prospective randomized study conducted at a 14-bed, general intensive care unit of a university hospital. PATIENTS Of 238 patients who underwent solid organ transplantation from December 1995 to October 1997, 51 were treated for acute respiratory failure. Of these, 40 were eligible and 20 were randomized to each group. INTERVENTION Noninvasive ventilation vs standard treatment with supplemental oxygen administration. MAIN OUTCOME MEASURES The need for endotracheal intubation and mechanical ventilation at any time during the study, complications not present on admission, duration of ventilatory assistance, length of hospital stay, and intensive care unit mortality. RESULTS The 2 groups were similar at study entry. Within the first hour of treatment, 14 patients (70%) in the NIV group, and 5 patients (25%) in the standard treatment group improved their ratio of the PaO2 to the fraction of inspired oxygen (FIO2). Over time, a sustained improvement in PaO2 to FIO2 was noted in 12 patients (60%) in the NIV group, and in 5 patients (25%) randomized to standard treatment (P = .03). The use of NIV was associated with a significant reduction in the rate of endotracheal intubation (20% vs 70%; P = .002), rate of fatal complications (20% vs 50%; P = .05), length of stay in the intensive care unit by survivors (mean [SD] days, 5.5 [3] vs 9 [4]; P = .03), and intensive care unit mortality (20% vs 50%; P = .05). Hospital mortality did not differ. CONCLUSIONS These results indicate that transplantation programs should consider NIV in the treatment of selected recipients of transplantation with acute respiratory failure.

Cost-effectiveness of options for the diagnosis of high blood pressure in primary care: a modelling study.

BACKGROUND The diagnosis of hypertension has traditionally been based on blood-pressure measurements in the clinic, but home and ambulatory measurements better correlate with cardiovascular outcome, and ambulatory monitoring is more accurate than both clinic and home monitoring in diagnosing hypertension. We aimed to compare the cost-effectiveness of different diagnostic strategies for hypertension. METHODS We did a Markov model-based probabilistic cost-effectiveness analysis. We used a hypothetical primary-care population aged 40 years or older with a screening blood-pressure measurement greater than 140/90 mm Hg and risk-factor prevalence equivalent to the general population. We compared three diagnostic strategies-further blood pressure measurement in the clinic, at home, and with an ambulatory monitor-in terms of lifetime costs, quality-adjusted life years, and cost-effectiveness. FINDINGS Ambulatory monitoring was the most cost-effective strategy for the diagnosis of hypertension for men and women of all ages. It was cost-saving for all groups (from -£56 [95% CI -105 to -10] in men aged 75 years to -£323 [-389 to -222] in women aged 40 years) and resulted in more quality-adjusted life years for men and women older than 50 years (from 0·006 [0·000 to 0·015] for women aged 60 years to 0·022 [0·012 to 0·035] for men aged 70 years). This finding was robust when assessed with a wide range of deterministic sensitivity analyses around the base case, but was sensitive if home monitoring was judged to have equal test performance to ambulatory monitoring or if treatment was judged effective irrespective of whether an individual was hypertensive. INTERPRETATION Ambulatory monitoring as a diagnostic strategy for hypertension after an initial raised reading in the clinic would reduce misdiagnosis and save costs. Additional costs from ambulatory monitoring are counterbalanced by cost savings from better targeted treatment. Ambulatory monitoring is recommended for most patients before the start of antihypertensive drugs. FUNDING National Institute for Health Research and the National Institute for Health and Clinical Excellence.

Incidence of adverse drug events and potential adverse drug events. Implications for prevention. ADE Prevention Study Group.

OBJECTIVES To assess incidence and preventability of adverse drug events (ADEs) and potential ADEs. To analyze preventable events to develop prevention strategies. DESIGN Prospective cohort study. PARTICIPANTS All 4031 adult admissions to a stratified random sample of 11 medical and surgical units in two tertiary care hospitals over a 6-month period. Units included two medical and three surgical intensive care units and four medical and two surgical general care units. MAIN OUTCOME MEASURES Adverse drug events and potential ADEs. METHODS Incidents were detected by stimulated self-report by nurses and pharmacists and by daily review of all charts by nurse investigators. Incidents were subsequently classified by two independent reviewers as to whether they represented ADEs or potential ADEs and as to severity and preventability. RESULTS Over 6 months, 247 ADEs and 194 potential ADEs were identified. Extrapolated event rates were 6.5 ADEs and 5.5 potential ADEs per 100 nonobstetrical admissions, for mean numbers per hospital per year of approximately 1900 ADEs and 1600 potential ADEs. Of all ADEs, 1% were fatal (none preventable), 12% life-threatening, 30% serious, and 57% significant. Twenty-eight percent were judged preventable. Of the life-threatening and serious ADEs, 42% were preventable, compared with 18% of significant ADEs. Errors resulting in preventable ADEs occurred most often at the stages of ordering (56%) and administration (34%); transcription (6%) and dispensing errors (4%) were less common. Errors were much more likely to be intercepted if the error occurred earlier in the process: 48% at the ordering stage vs 0% at the administration stage. CONCLUSION Adverse drug events were common and often preventable; serious ADEs were more likely to be preventable. Most resulted from errors at the ordering stage, but many also occurred at the administration stage. Prevention strategies should target both stages of the drug delivery process.

Aspirin in the chemoprevention of colorectal neoplasia: an overview.

Considerable evidence supports the effectiveness of aspirin for chemoprevention of colorectal cancer (CRC) in addition to its well-established benefits in the prevention of vascular disease. Epidemiologic studies have consistently observed an inverse association between aspirin use and risk of CRC. A recent pooled analysis of a long-term posttrial follow-up of nearly 14,000 patients from four randomized, cardiovascular disease prevention trials showed that daily aspirin treatment for about five years was associated with a 34% reduction in 20-year CRC mortality. A separate metaanalysis of nearly 3,000 patients with a history of colorectal adenoma or cancer in four randomized adenoma prevention trials showed that aspirin reduced the occurrence of advanced adenomas by 28% and any adenoma by 17%. Aspirin has also been shown to be beneficial in a clinical trial of patients with Lynch syndrome, a hereditary CRC syndrome; in those treated with aspirin for at least two years, there was a 50% or more reduction in the risk of CRC commencing five years after randomization and after aspirin had been discontinued. A few observational studies have shown an increase in survival among patients with CRC who use aspirin. Taken together, these findings strengthen the case for consideration of long-term aspirin use in CRC prevention. Despite these compelling data, there is a lack of consensus about the balance of risks and benefits associated with long-term aspirin use, particularly in low-risk populations. The optimal dose to use for cancer prevention and the precise mechanism underlying aspirin's anticancer effect require further investigation.

Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinomas (PDAs) are characterized by a robust fibroinflammatory response. We show here that this desmoplastic reaction generates inordinately high interstitial fluid pressures (IFPs), exceeding those previously measured or theorized for solid tumors, and induces vascular collapse, while presenting substantial barriers to perfusion, diffusion, and convection of small molecule therapeutics. We identify hyaluronan, or hyaluronic acid (HA), as the primary matrix determinant of these barriers and show that systemic administration of an enzymatic agent can ablate stromal HA from autochthonous murine PDA, normalize IFP, and re-expand the microvasculature. In combination with the standard chemotherapeutic, gemcitabine, the treatment permanently remodels the tumor microenvironment and consistently achieves objective tumor responses, resulting in a near doubling of overall survival.

Serum Soluble Corin Deficiency Predicts Major Disability within 3 Months after Acute Stroke

OBJECTIVE Serum soluble corin has been associated with stroke. However, whether it is associated with stroke prognosis has not yet been studied. Therefore, we aimed to study the association of serum soluble corin with risk of poor outcomes within 3 months after stroke. METHODS We followed 522 stroke patients for 3 months to identify major disability, death and vascular events. Serum soluble corin was measured at baseline for all participants. Logistic regression was used to examine the associations of baseline serum soluble corin with outcomes of stroke, adjusting for age, sex, baseline NIHSS score, hours from onset to hospitalization, smoking, drinking, hypertension, diabetes, coronary heart disease, atrial fibrillation, family history of stroke, and stroke subtype. RESULTS Patients with high corin had a significantly lower crude risk for the composite outcome of major disability or death (OR = 0.64, 95%CI: 0.43-0.96) than patients with low corin (the lowest tertile). After adjustment for age and baseline NIHSS score, patients with high corin still had a significantly lower risk for the composite outcome of major disability or death (OR = 0.60, 95%CI: 0.36-0.99). This association became bottom line significant after additionally adjusting for other conventional factors (OR = 0.61, P = 0.058). No association was found between serum soluble corin and other composite outcomes. CONCLUSION Serum soluble corin deficiency predicted risk for major disability within 3 months after stroke, independent of baseline neurological deficient. Our results may indicate a probable role of corin in stroke prognosis.

Lipoprotein(a) concentration and the risk of coronary heart disease, stroke, and nonvascular mortality.

CONTEXT Circulating concentration of lipoprotein(a) (Lp[a]), a large glycoprotein attached to a low-density lipoprotein-like particle, may be associated with risk of coronary heart disease (CHD) and stroke. OBJECTIVE To assess the relationship of Lp(a) concentration with risk of major vascular and nonvascular outcomes. STUDY SELECTION Long-term prospective studies that recorded Lp(a) concentration and subsequent major vascular morbidity and/or cause-specific mortality published between January 1970 and March 2009 were identified through electronic searches of MEDLINE and other databases, manual searches of reference lists, and discussion with collaborators. DATA EXTRACTION Individual records were provided for each of 126,634 participants in 36 prospective studies. During 1.3 million person-years of follow-up, 22,076 first-ever fatal or nonfatal vascular disease outcomes or nonvascular deaths were recorded, including 9336 CHD outcomes, 1903 ischemic strokes, 338 hemorrhagic strokes, 751 unclassified strokes, 1091 other vascular deaths, 8114 nonvascular deaths, and 242 deaths of unknown cause. Within-study regression analyses were adjusted for within-person variation and combined using meta-analysis. Analyses excluded participants with known preexisting CHD or stroke at baseline. DATA SYNTHESIS Lipoprotein(a) concentration was weakly correlated with several conventional vascular risk factors and it was highly consistent within individuals over several years. Associations of Lp(a) with CHD risk were broadly continuous in shape. In the 24 cohort studies, the rates of CHD in the top and bottom thirds of baseline Lp(a) distributions, respectively, were 5.6 (95% confidence interval [CI], 5.4-5.9) per 1000 person-years and 4.4 (95% CI, 4.2-4.6) per 1000 person-years. The risk ratio for CHD, adjusted for age and sex only, was 1.16 (95% CI, 1.11-1.22) per 3.5-fold higher usual Lp(a) concentration (ie, per 1 SD), and it was 1.13 (95% CI, 1.09-1.18) following further adjustment for lipids and other conventional risk factors. The corresponding adjusted risk ratios were 1.10 (95% CI, 1.02-1.18) for ischemic stroke, 1.01 (95% CI, 0.98-1.05) for the aggregate of nonvascular mortality, 1.00 (95% CI, 0.97-1.04) for cancer deaths, and 1.00 (95% CI, 0.95-1.06) for nonvascular deaths other than cancer. CONCLUSION Under a wide range of circumstances, there are continuous, independent, and modest associations of Lp(a) concentration with risk of CHD and stroke that appear exclusive to vascular outcomes.

Dose-dependent effect of statins on the incidence of acute kidney injury after cardiac surgery.

BACKGROUND Acute kidney injury (AKI) after cardiac surgery is associated with increased morbidity and mortality. METHODS We assessed whether statin treatment is associated with a lower incidence of postoperative AKI in 2,104 consecutive patients who underwent coronary artery bypass graft or valve surgery at the Minneapolis Veterans Administration Medical Center. Acute kidney injury was defined as absolute increase greater than 0.3 mg/dL or relative increase greater than 50% in serum creatinine from baseline, within 48 hours after surgery or requiring postoperative hemodialysis per AKI network. Propensity scores were utilized to adjust for the differences between the statin and the no-statin treatment groups. All statins were converted to equivalent-dose simvastatin and divided at the median to construct high-dose (≥40 mg) and low-dose (<40 mg) statin groups. RESULTS Of the 2,104 patients, 1,435 (68%) were taking statins (638 high-dose) and 495 (24%) developed AKI (25% high-dose vs 40% low-dose vs 35% no-statin; p = 0.014). Estimated preoperative glomerular filtration rate (p = 0.003), diabetes mellitus (p=0.02), valve surgery with or without coronary artery bypass graft (p = 0.024), cardiopulmonary bypass time (p = 0.001), and intraaortic balloon pump (p = 0.055) were independent predictors of AKI. After propensity adjustment statin treatment was not associated with postoperative AKI (odds ratio 0.79; 95% confidence interval 0.59 to 1.06; p = 0.11 for high-dose v. no-statin). After full adjustment for all independent predictors of AKI, the results did not change. Statins also had no effect on the incidence of postoperative hemodialysis (0.8% high-dose vs 1.9% low-dose vs 1% no-statin; p = 0.15). CONCLUSIONS Statin treatment is not associated with a lower incidence of AKI after cardiac surgery.

The impact of open versus closed format ICU admission practices on the outcome of high risk surgical patients: a cohort analysis

BACKGROUND In the year 2000, the organizational structure of the ICU in the Zaandam Medical Centre (ZMC) changed from an open to a closed format ICU. The objective of this study was to evaluate the effect of this organizational change on outcome in high risk surgical patients. METHODS The medical records of all consecutive high risk surgical patients admitted to the ICU from 1996 to 1998 (open format) and from 2003 to 2005 (closed format), were reviewed. High-risk patients were defined according to the Identification of Risk in Surgical patients (IRIS) score. Parameters studied were: mortality, morbidity, ICU length of stay (LOS) and hospital LOS. RESULTS Mortality of ICU patients was 25.7% in the open format group and 15.8% in the closed format group (p = 0.01). Morbidity decreased from 48.6% to 46.1% (p = 0.6). The average length of hospital stay was 17 days in the open format group, and 21 days in the closed format group (p = 0.03). CONCLUSIONS High risk surgical patients in the ICU are patients that have undergone complex and often extensive surgery. These patients are in need of specialized treatment and careful monitoring for maximum safety and optimal care. Our results suggest that closed format is a more favourable setting than open format to minimize the effects of high risk surgery, and to warrant safe outcome in this patient group.

Nitrite infusions to prevent delayed cerebral vasospasm in a primate model of subarachnoid hemorrhage.

CONTEXT Delayed cerebral vasospasm causes permanent neurological deficits or death in at least 15% of patients following otherwise successful treatment for ruptured intracranial aneurysm. Decreased bioavailability of nitric oxide has been associated with the development of cerebral vasospasm. OBJECTIVE To determine whether infusions of nitrite will prevent delayed cerebral vasospasm. DESIGN, SETTING, AND SUBJECTS A total of 14 anesthetized cynomolgus monkeys had an autologous blood clot placed around the right middle cerebral artery. Cerebral arteriography was performed before clot placement and on days 7 and 14 to assess vasospasm. The study was conducted from August 2003 to February 2004. INTERVENTIONS A 90-mg sodium nitrite intravenous solution infused over 24 hours plus a 45-mg sodium nitrite bolus daily (n = 3); a 180-mg sodium nitrite intravenous solution infused over 24 hours (n = 3); or a control saline solution infusion (n = 8). Each was infused continuously for 14 days. MAIN OUTCOME MEASURES Nitrite, S-nitrosothiol, and methemoglobin levels in blood and cerebrospinal fluid and degree of arteriographic vasospasm. RESULTS In control monkeys, mean (SD) cerebrospinal fluid nitrite levels decreased from 3.1 (1.5) micromol/L to 0.4 (0.1) micromol/L at day 7 and to 0.4 (0.4) micromol/L at day 14 (P = .03). All 8 control monkeys developed significant vasospasm of the right middle cerebral artery, which was complicated by stroke and death in 1 animal. Sodium nitrite infusions increased the nitrite and methemoglobin levels (<2.1% of total hemoglobin) in the blood and cerebrospinal fluid without evoking systemic hypotension. Nitrite infusion prevented development of vasospasm (no animals developed significant vasospasm; mean [SD] reduction in right middle cerebral artery area on day 7 after subarachnoid hemorrhage of 8% [9%] in nitrite-treated monkeys vs 47% [5%] in saline-treated controls; P<.001). There was a negative correlation between the concentration of nitrite in cerebrospinal fluid and the degree of cerebral vasospasm (P<.001). Pharmacological effects of nitrite infusion were also associated with the formation of S-nitrosothiol in cerebrospinal fluid. There was no clinical or pathological evidence of nitrite toxicity. CONCLUSION Subacute sodium nitrite infusions prevented delayed cerebral vasospasm in a primate model of subarachnoid hemorrhage.

Effects of Abciximab on the architecture of platelet-rich clots in patients with acute myocardial infarction undergoing primary coronary intervention.

BACKGROUND Abciximab plus aspirin improves the TIMI 3 flow rate of the infarct-related artery in patients treated with either percutaneous coronary intervention or thrombolysis. The present study investigated whether the reperfusion efficacy of abciximab relates to modifications of clot architecture in patients admitted for acute myocardial infarction (AMI). METHODS AND RESULTS A total of 23 AMI patients in the Abciximab before Direct angioplasty and stenting in Myocardial Infarction Regarding Acute and Long term follow-up (ADMIRAL) trial received, in a double-blind fashion, either abciximab (n=13) or placebo (n=10) before primary stenting. Viscoelastic (G' in dyne/cm(2)) and morphological (mean platelet aggregate surface area [SAG] in micrometer(2)) indexes of ex vivo platelet-rich clots (PRC) were assessed in a double-blind fashion before and after the bolus administration of abciximab or placebo. G' and SAG reflect the mechanical and morphological impact of activated platelets on the PRC fibrin network, respectively. Abciximab administration reduced G' by 63% (P=0.0001) and SAG by 65% (P=0.0007), and no effect was seen in the placebo group. These abciximab-related changes increased fibrin exposure as a consequence of the platelet-aggregate surface reduction and may have improved endogenous fibrinolysis. These effects were identified in all patients, independent of previous heparin administration. CONCLUSIONS Abciximab dramatically reduces platelet aggregate size and increases the fibrin accessibility of ex vivo PRC in AMI patients. These modifications could participate in the better coronary artery patency observed with abciximab.

Costs of the COPD. Differences between intensive care unit and respiratory intermediate care unit.

INTRODUCTION To assess whether respiratory intermediate care units (RICUs) are cost effective alternatives to intensive care units (ICUs) for patients with exacerbation of chronic obstructive pulmonary disease (COPD). PATIENTS AND METHODS Multi-centre, prospective, bottom-up cost study performed in 15 ICUs and 6 RICUs. COPD patients staying longer than 48 h were recruited; those coming from other ICUs/RICUs, with immune-deficiency or stroke, were excluded. After the ICU sample was standardised to the RICU distribution of the reason-for-admission and infusion of a vasoactive drug on admission, 60 ICU patients and 65 RICU patients remained, of the original 164 recruited. For each patient, besides clinical data on admission and discharge, daily information about the resources consumed were recorded and analysed in terms of their costs. RESULTS Total cost per patient was lower in RICUs than in ICUs (754 vs. 1507 Euro; P < 0.0001). In all items, except drugs and nutrition, we found a significant lower cost in RICUs. Dead patients were noticeably different in terms of disease severity between ICUs and RICUs, while surviving ones were not. CONCLUSIONS Our study suggests that some COPD patients, less severe and with pure respiratory failure, could be successfully and less costly treated in RICUs.

Assessment of hemodynamic efficacy and safety of 6% hydroxyethylstarch 130/0.4 vs. 0.9% NaCl fluid replacement in patients with severe sepsis: The CRYSTMAS study

Inadequate initial treatment and delayed hemodynamic stabilization (HDS) may be associated with increased risk of death in severe sepsis patients. In order to compare the hemodynamic efficacy and safety of 6% HES 130/0.4 and NaCl 0.9% for HDS in patients with severe sepsis, we designed a prospective, multicenter, active-controlled, double-blind, randomized study in intensive care units. 174 out of 196 patients reached HDS (88 and 86 patients for HES and NaCl, respectively). Significantly less HES was used to reach HDS vs. NaCl (1,379 ±886 ml in the HES group and 1,709 ±1,164 ml in the NaCl group (mean difference = -331± 1,033, 95% CI -640 to -21, P = 0.0185). Time to reach HDS was 11.8 10.1 hours vs. 14.3 ±11.1 hours for HES and NaCl, respectively. Total quantity of study drug infused over four consecutive days, ICU and hospital LOS, and area under the curve of SOFA score were comparable. Acute renal failure occurred in 24 (24.5%) and 19 (20%) patients for HES and NaCl, respectively (P = 0.454). There was no difference between AKIN and RIFLE criteria among groups and no difference in mortality, coagulation, or pruritus up to 90 days after treatment initiation. Significantly less volume was required to achieve HDS for HES vs. NaCl in the initial phase of fluid resuscitation in severe sepsis patients without any difference for adverse events in both groups. NCT00464204

Human albumin administration in critically ill patients: systematic review of randomised controlled trials.

OBJECTIVE To quantify effect on mortality of administering human albumin or plasma protein fraction during management of critically ill patients. DESIGN Systematic review of randomised controlled trials comparing administration of albumin or plasma protein fraction with no administration or with administration of crystalloid solution in critically ill patients with hypovolaemia, burns, or hypoalbuminaemia. SUBJECTS 30 randomised controlled trials including 1419 randomised patients. MAIN OUTCOME MEASURE Mortality from all causes at end of follow up for each trial. RESULTS For each patient category the risk of death in the albumin treated group was higher than in the comparison group. For hypovolaemia the relative risk of death after albumin administration was 1.46 (95% confidence interval 0.97 to 2.22), for burns the relative risk was 2.40 (1.11 to 5.19), and for hypoalbuminaemia it was 1.69 (1.07 to 2.67). Pooled relative risk of death with albumin administration was 1.68 (1.26 to 2.23). Pooled difference in the risk of death with albumin was 6% (95% confidence interval 3% to 9%) with a fixed effects model. These data suggest that for every 17 critically ill patients treated with albumin there is one additional death. CONCLUSIONS There is no evidence that albumin administration reduces mortality in critically ill patients with hypovolaemia, burns, or hypoalbuminaemia and a strong suggestion that it may increase mortality. These data suggest that use of human albumin in critically ill patients should be urgently reviewed and that it should not be used outside the context of rigorously conducted, randomised controlled trials.

Residual lifetime risk for developing hypertension in middle-aged women and men: The Framingham Heart Study.

CONTEXT The long-term risk for developing hypertension is best described by the lifetime risk statistic. The lifetime risk for hypertension and trends in this risk over time are unknown. OBJECTIVES To estimate the residual lifetime risk for hypertension in older US adults and to evaluate temporal trends in this risk. DESIGN, SETTING, AND PARTICIPANTS Community-based prospective cohort study of 1298 participants from the Framingham Heart Study who were aged 55 to 65 years and free of hypertension at baseline (1976-1998). MAIN OUTCOME MEASURES Residual lifetime risk (lifetime cumulative incidence not adjusted for competing causes of mortality) for hypertension, defined as blood pressure of 140/90 mm Hg or greater or use of antihypertensive medications. RESULTS The residual lifetime risks for developing hypertension and stage 1 high blood pressure or higher (greater-than-or-equal to 140/90 mm Hg regardless of treatment) were 90% in both 55- and 65-year-old participants. The lifetime probability of receiving antihypertensive medication was 60%. The risk for hypertension remained unchanged for women, but it was approximately 60% higher for men in the contemporary 1976-1998 period compared with an earlier 1952-1975 period. In contrast, the residual lifetime risk for stage 2 high blood pressure or higher (greater-than-or-equal to 160/100 mm Hg regardless of treatment) was considerably lower in both sexes in the recent period (35%-57% in 1952-1975 vs 35%-44% in 1976-1998), likely due to a marked increase in treatment of individuals with substantially elevated blood pressure. CONCLUSION The residual lifetime risk for hypertension for middle-aged and elderly individuals is 90%, indicating a huge public health burden. Although the decline in lifetime risk for stage 2 high blood pressure or higher represents a major achievement, efforts should be directed at the primary prevention of hypertension.

Review of the secondary injury theory of acute spinal cord trauma with emphasis on vascular mechanisms.

In patients with spinal cord injury, the primary or mechanical trauma seldom causes total transection, even though the functional loss may be complete. In addition, biochemical and pathological changes in the cord may worsen after injury. To explain these phenomena, the concept of the secondary injury has evolved for which numerous pathophysiological mechanisms have been postulated. This paper reviews the concept of secondary injury with special emphasis on vascular mechanisms. Evidence is presented to support the theory of secondary injury and the hypothesis that a key mechanism is posttraumatic ischemia with resultant infarction of the spinal cord. Evidence for the role of vascular mechanisms has been obtained from a variety of models of acute spinal cord injury in several species. Many different angiographic methods have been used for assessing microcirculation of the cord and for measuring spinal cord blood flow after trauma. With these techniques, the major systemic and local vascular effects of acute spinal cord injury have been identified and implicated in the etiology of secondary injury. The systemic effects of acute spinal cord injury include hypotension and reduced cardiac output. The local effects include loss of autoregulation in the injured segment of the spinal cord and a marked reduction of the microcirculation in both gray and white matter, especially in hemorrhagic regions and in adjacent zones. The microcirculatory loss extends for a considerable distance proximal and distal to the site of injury. Many studies have shown a dose-dependent reduction of spinal cord blood flow varying with the severity of injury, and a reduction of spinal cord blood flow which worsens with time after injury. The functional deficits due to acute spinal cord injury have been measured electrophysiologically with techniques such as motor and somatosensory evoked potentials and have been found proportional to the degree of posttraumatic ischemia. The histological effects include early hemorrhagic necrosis leading to major infarction at the injury site. These posttraumatic vascular effects can be treated. Systemic normotension can be restored with volume expansion or vasopressors, and spinal cord blood flow can be improved with dopamine, steroids, nimodipine, or volume expansion. The combination of nimodipine and volume expansion improves posttraumatic spinal cord blood flow and spinal cord function measured by evoked potentials. These results provide strong evidence that posttraumatic ischemia is an important secondary mechanism of injury, and that it can be counteracted.

Midlife Serum Cholesterol and Increased Risk of Alzheimer’s and Vascular Dementia Three Decades Later

Aims: To investigate midlife cholesterol in relation to Alzheimer’s disease (AD) and vascular dementia (VaD) in a large multiethnic cohort of women and men. Methods: The Kaiser Permanente Northern California Medical Group (healthcare delivery organization) formed the database for this study. The 9,844 participants underwent detailed health evaluations during 1964–1973 at ages 40–45 years; they were still members of the health plan in 1994. AD and VaD were ascertained by medical records between 1 January 1994 and 1 June 2007. Cox proportional hazards models – adjusted for age, education, race/ethnic group, sex, midlife diabetes, hypertension, BMI and late-life stroke – were conducted. Results: In total, 469 participants had AD and 127 had VaD. With desirable cholesterol levels (<200 mg/dl) as a reference, hazard ratios (HR) and 95% CI for AD were 1.23 (0.97–1.55) and 1.57 (1.23–2.01) for borderline (200–239 mg/dl) and high cholesterol (≥240 mg/dl), respectively. HR and 95% CI for VaD were 1.50 (1.01–2.23) for borderline and 1.26 (0.82–1.96) for high cholesterol. Further analyses for AD (cholesterol quartiles, 1st quartile reference) indicated that cholesterol levels >220 mg/dl were a significant risk factor: HR were 1.31 (1.01–1.71; 3rd quartile, 221–248 mg/dl) and 1.58 (1.22–2.06; 4th quartile, 249–500 mg/dl). Conclusion: Midlife serum total cholesterol was associated with an increased risk of AD and VaD. Even moderately elevated cholesterol increased dementia risk. Dementia risk factors need to be addressed as early as midlife, before underlying disease(s) or symptoms appear.

Nitrite protects against morbidity and mortality associated with TNF- or LPS-induced shock in a soluble guanylate cyclase–dependent manner

Nitrite (NO(2)(-)), previously viewed as a physiologically inert metabolite and biomarker of the endogenous vasodilator NO, was recently identified as an important biological NO reservoir in vasculature and tissues, where it contributes to hypoxic signaling, vasodilation, and cytoprotection after ischemia-reperfusion injury. Reduction of nitrite to NO may occur enzymatically at low pH and oxygen tension by deoxyhemoglobin, deoxymyoglobin, xanthine oxidase, mitochondrial complexes, or NO synthase (NOS). We show that nitrite treatment, in sharp contrast with the worsening effect of NOS inhibition, significantly attenuates hypothermia, mitochondrial damage, oxidative stress and dysfunction, tissue infarction, and mortality in a mouse shock model induced by a lethal tumor necrosis factor challenge. Mechanistically, nitrite-dependent protection was not associated with inhibition of mitochondrial complex I activity, as previously demonstrated for ischemia-reperfusion, but was largely abolished in mice deficient for the soluble guanylate cyclase (sGC) alpha1 subunit, one of the principal intracellular NO receptors and signal transducers in the cardiovasculature. Nitrite could also provide protection against toxicity induced by Gram-negative lipopolysaccharide, although higher doses were required. In conclusion, we show that nitrite can protect against toxicity in shock via sGC-dependent signaling, which may include hypoxic vasodilation necessary to maintain microcirculation and organ function, and cardioprotection.

The effect of folate fortification on folic acid-based homocysteine-lowering intervention and stroke risk: a meta-analysis.

OBJECTIVE Folate and vitamin B12 are two vital regulators in the metabolic process of homocysteine, which is a risk factor of atherothrombotic events. Low folate intake or low plasma folate concentration is associated with increased stroke risk. Previous randomized controlled trials presented discordant findings in the effect of folic acid supplementation-based homocysteine lowering on stroke risk. The aim of the present review was to perform a meta-analysis of relevant randomized controlled trials to check the how different folate fortification status might affect the effects of folic acid supplementation in lowering homocysteine and reducing stroke risk. DESIGN Relevant randomized controlled trials were identified through formal literature search. Homocysteine reduction was compared in subgroups stratified by folate fortification status. Relative risks with 95 % confidence intervals were used as a measure to assess the association between folic acid supplementation and stroke risk. SETTING The meta-analysis included fourteen randomized controlled trials,   SUBJECTS A total of 39 420 patients. RESULTS Homocysteine reductions were 26·99 (sd 1·91) %, 18·38 (sd 3·82) % and 21·30 (sd 1·98) %, respectively, in the subgroups without folate fortification, with folate fortification and with partial folate fortification. Significant difference was observed between the subgroups with folate fortification and without folate fortification (P=0·05). The relative risk of stroke was 0·88 (95 % CI 0·77, 1·00, P=0·05) in the subgroup without folate fortification, 0·94 (95 % CI 0·58, 1·54, P=0·82) in the subgroup with folate fortification and 0·91 (95 % CI 0·82, 1·01, P=0·09) in the subgroup with partial folate fortification. CONCLUSIONS Folic acid supplementation might have a modest benefit on stroke prevention in regions without folate fortification.

Vanishing cerebellar infarcts in a migraine patient.

Recent population-based studies have suggested that migraine is a risk factor for the development of infarct-like lesions in the territory of the posterior circulation. These lesions are thought to be true vascular infarcts based on their size, location and magnetic resonance imaging (MRI) characteristics. However, as there are no postmortem studies identifying the pathology of these MRI findings, their true aetiology is unknown. A case patient with migraine is presented, who developed what appeared to be cerebellar infarcts on MRI, but these lesions vanished on repeat imaging 16 days later, questioning their aetiology as vascular ischaemic based infarcts.

Association between serum corin levels and risk of acute myocardial infarction.

BACKGROUND Accumulating evidence has indicated that corin plays critical roles in regulating salt-water balance, blood pressure and cardiac function by activating natriuretic peptides. The present case-control study was designed to evaluate the association of serum soluble corin with acute myocardial infarction (AMI). METHODS We enrolled 856 consecutive AMI patients and 856 control subjects and explored the possible relation between serum corin levels and AMI risk using logistic regression model. RESULTS Patients with AMI had higher BMI, were less physically active, and were more likely to have histories of hypertension, diabetes, hyperlipidemia and smoking compared with the controls. Serum levels of corin were remarkably reduced in AMI patients (825±263pg/ml) compared with those in healthy controls (1246±425pg/ml). Odds ratios of ST elevation (STEMI) and non-ST elevation myocardial infarction (NSTEMI) were significantly decreased with the increasing levels of serum corin in both men and women (P for trend, <0.001) after adjustment for body mass index, hypertension, diabetes, hyperlipidemia, smoking, and physical activity. CONCLUSIONS Our study demonstrates that serum levels of corin are significantly decreased in AMI patients, and it is inversely associated with the incidences of STEMI and NSTEMI in both men and women.

Assessing the cost effectiveness of using prognostic biomarkers with decision models: case study in prioritising patients waiting for coronary artery surgery

OBJECTIVE To determine the effectiveness and cost effectiveness of using information from circulating biomarkers to inform the prioritisation process of patients with stable angina awaiting coronary artery bypass graft surgery. DESIGN Decision analytical model comparing four prioritisation strategies without biomarkers (no formal prioritisation, two urgency scores, and a risk score) and three strategies based on a risk score using biomarkers: a routinely assessed biomarker (estimated glomerular filtration rate), a novel biomarker (C reactive protein), or both. The order in which to perform coronary artery bypass grafting in a cohort of patients was determined by each prioritisation strategy, and mean lifetime costs and quality adjusted life years (QALYs) were compared. DATA SOURCES Swedish Coronary Angiography and Angioplasty Registry (9935 patients with stable angina awaiting coronary artery bypass grafting and then followed up for cardiovascular events after the procedure for 3.8 years), and meta-analyses of prognostic effects (relative risks) of biomarkers. RESULTS The observed risk of cardiovascular events while on the waiting list for coronary artery bypass grafting was 3 per 10,000 patients per day within the first 90 days (184 events in 9935 patients). Using a cost effectiveness threshold of pound20,000- pound30,000 (euro22,000-euro33,000; $32,000-$48,000) per additional QALY, a prioritisation strategy using a risk score with estimated glomerular filtration rate was the most cost effective strategy (cost per additional QALY was < pound410 compared with the Ontario urgency score). The impact on population health of implementing this strategy was 800 QALYs per 100,000 patients at an additional cost of pound 245,000 to the National Health Service. The prioritisation strategy using a risk score with C reactive protein was associated with lower QALYs and higher costs compared with a risk score using estimated glomerular filtration rate. CONCLUSION Evaluating the cost effectiveness of prognostic biomarkers is important even when effects at an individual level are small. Formal prioritisation of patients awaiting coronary artery bypass grafting using a routinely assessed biomarker (estimated glomerular filtration rate) along with simple, routinely collected clinical information was cost effective. Prioritisation strategies based on the prognostic information conferred by C reactive protein, which is not currently measured in this context, or a combination of C reactive protein and estimated glomerular filtration rate, is unlikely to be cost effective. The widespread practice of using only implicit or informal means of clinically ordering the waiting list may be harmful and should be replaced with formal prioritisation approaches.

Large scale replication and meta-analysis of variants on chromosome 4q25 associated with atrial fibrillation.

AIMS A recent genome-wide association study identified a haplotype block on chromosome 4q25 associated with atrial fibrillation (AF). We sought to replicate this association in four independent cohorts. METHODS AND RESULTS The Framingham Heart Study and Rotterdam Study are community-based longitudinal studies. The Vanderbilt AF Registry and German AF Network (AFNet) are case-control studies. Participants with AF (n = 3508) were more likely to be male and were older than referent participants (n = 12 173; Framingham 82 +/- 10 vs. 71 +/- 13 years; Rotterdam 73 +/- 8 vs. 69 +/- 9 years; Vanderbilt 54 +/- 14 vs. 57 +/- 14 years; AFNet 62 +/- 12 vs. 49 +/- 14 years). Single nucleotide polymorphism (SNP) rs2200733 was associated with AF in all four cohorts, with odds ratios (ORs) ranging from 1.37 in Rotterdam [95% confidence interval (CI) 1.18-1.59; P = 3.1 x 10(-5)] to 2.52 in AFNet (95% CI 2.22-2.8; P = 1.8 x 10(-49)). There also was a significant association between AF and rs10033464 in Framingham (OR 1.34; 95% CI 1.03-1.75; P = 0.031) and AFNet (OR 1.30; 95% CI 1.13-1.51; P = 0.0002), but not Vanderbilt (OR 1.16; 95% CI 0.86-1.56; P = 0.33). A meta-analysis of the current and prior AF studies revealed an OR of 1.90 (95% CI 1.60-2.26; P = 3.3 x 10(-13)) for rs2200733 and of 1.36 (95% CI 1.26-1.47; P = 6.7 x 10(-15)) for rs10033464. CONCLUSION The non-coding SNPs rs2200733 and rs10033464 are strongly associated with AF in four cohorts of European descent. These results confirm the significant relations between AF and intergenic variants on chromosome 4.

Preoperative C-reactive protein predicts mid-term outcome after cardiac surgery.

BACKGROUND C-reactive protein (CRP) is a known risk factor for cardiovascular events in the healthy population and in patients with coronary artery disease. High CRP levels before cardiac surgery are associated with worse short-term outcome, but its role after discharge home remains unknown. The study objective was to evaluate the effect of CRP on short-term and mid-term outcome after cardiac surgery. METHODS From August 2000 to May 2004, values for preoperative CRP were available for 597 unselected patients undergoing cardiac operations. CRP was used to divide this cohort in two groups: a low inflammatory status (LHS) group of 354 patients with CRP of less than 0.5 mg/dL, and a high inflammatory status (HIS) group of 243 patients with a CRP of 0.5 mg/dL or more. Follow-up lasted a maximum of 3 years (median, 1.8 +/- 1.5 years) and was 92.6% complete. RESULTS In-hospital mortality was 8.2% in the HIS group and 3.4% in the LIS group (odds ratio [OR], 2.61; p = 0.02). Incidence of postoperative infections was 16.5% in the HIS group and 5.1% in the LIS group (OR, 3.25; p = 0.0001). Sternal wound infections were also more frequent in the HIS group (10.7% versus 2.8%; OR, 3.43; p = 0.002). During follow-up, the HIS group had worse survival (88.5% +/- 2.9% versus 91.9% +/- 2.5%; OR, 1.93; p = 0.05) and a higher need of hospitalization for cardiac-related causes (73.6% +/- 6% versus 86.5% +/- 3.2%; OR, 1.82; p = 0.05). CONCLUSIONS Patients undergoing cardiac surgery with a CRP level of 0.5 mg/dL or more are exposed to a higher risk of in-hospital mortality and postoperative infections. Despite surgical correction of cardiac disease, a high preoperative CRP value is an independent risk factor for mid-term survival and hospitalization for cardiac causes.

A comparison of continuous and bi-level positive airway pressure non-invasive ventilation in patients with acute cardiogenic pulmonary oedema: a meta-analysis

IntroductionWe conducted the present study to investigate the potential beneficial and adverse effects of continuous positive airway pressure (CPAP) compared with bi-level positive airway pressure (BiPAP) noninvasive ventilation in patients with cardiogenic pulmonary oedema. MethodWe included randomized controlled studies comparing CPAP and BiPAP treatment in patients with cardiogenic pulmonary oedema from the Cochrane Controlled Trials Register (2005 issue 3), and EMBASE and MEDLINE databases (1966 to 1 December 2005), without language restriction. Two reviewers reviewed the quality of the studies and independently performed data extraction. ResultsSeven randomized controlled studies, including a total of 290 patients with cardiogenic pulmonary oedema, were considered. The hospital mortality (relative risk [RR] 0.76, 95% confidence interval [CI] 0.32–1.78; P = 0.52; I2 = 0%) and risk for requiring invasive ventilation (RR 0.80, 95% CI 0.33–1.94; P = 0.62; I2 = 0%) were not significantly different between patients treated with CPAP and those treated with BiPAP. Stratifying studies that used either fixed or titrated pressure during BiPAP treatment and studies involving patients with or without hypercapnia did not change the results. The duration of noninvasive ventilation required until the pulmonary oedema resolved (weighted mean difference [WMD] in hours = 3.65, 95% CI -12.12 to +19.43; P = 0.65, I2 = 0%) and length of hospital stay (WMD in days = -0.04, 95% CI -2.57 to +2.48; P = 0.97, I2 = 0%) were also not significantly different between the two groups. Based on the limited data available, there was an insignificant trend toward an increase in new onset acute myocardial infarction in patients treated with BiPAP (RR 2.10, 95% CI 0.91–4.84; P = 0.08; I2 = 25.3%).ConclusionBiPAP does not offer any significant clinical benefits over CPAP in patients with acute cardiogenic pulmonary oedema. Until a large randomized controlled trial shows significant clinical benefit and cost-effectiveness of BiPAP versus CPAP in patients with acute cardiogenic pulmonary oedema, the choice of modality will depend mainly on the equipment available.

Survival analysis: time-dependent effects and time-varying risk factors.

In traditional Kaplan-Meier or Cox regression analysis, usually a risk factor measured at baseline is related to mortality thereafter. During follow-up, however, things may change: either the effect of a fixed baseline risk factor may vary over time, resulting in a weakening or strengthening of associations over time, or the risk factor itself may vary over time. In this paper, short-term versus long-term effects (so-called time-dependent effects) of a fixed baseline risk factor are addressed. An example is presented showing that underweight is a strong risk factor for mortality in dialysis patients, especially in the short run. In contrast, overweight is a risk factor for mortality, which is stronger in the long run than in the short run. In addition, the analysis of how time-varying risk factors (so-called time-dependent risk factors) are related to mortality is demonstrated by paying attention to the pitfall of adjusting for sequelae. The proper analysis of effects over time should be driven by a clear research question. Both kinds of research questions, that is those of time-dependent effects as well those of time-dependent risk factors, can be analyzed with time-dependent Cox regression analysis. It will be shown that using time-dependent risk factors usually implies focusing on short-term effects only.

[Efficacy on post-stroke depression treated with acupuncture at the acupoints based on ziwuliuzhu and prozac].

OBJECTIVE To observe the effects on post-stroke depression treated with acupuncture at the acu points based on ziwuliuzhu (the midnight-noon ebb-flow theory). METHODS Ninety-three patients were randomized into a comprehensive group, a ziwuliuzhu group and a prozac group, 31 cases in each group. In the ziwuliuzhu group, acupuncture was applied to the acupoints based on ziwuliuzhu, once a day, 5 times in a week. In the prozac group, fluoxertine hydrochloride (prozac) was prescribed for oral administration, once a day, 20 mg each time. In the comprehensive group, acupuncture based on ziwuliuzhu combined with the oral administration of prozac were adopted and the treatment frequency was the same as the ziwuliuzhu group and the prozac group. The 4-week treatment was taken as one session in the three groups and 6 sessions were required totally. The clinical efficacy and the Hamilton depression rating scale (HAMD) score and the adverse reaction were compared among the 3 groups. RESULTS The total effective rate was 96.8% (30/31) in the comprehensive group, better than 83.9% (26/31) in the ziwuliuzhu group and 80. 6% (25/31) in the prozac group (both P<0.05). In 4, 12 and 24 weeks of treatment, HAMD score was lower significantly than that before the treatment in the three groups (all P<0.05), and the score in the comprehensive group at each time point after treatment was lower than the other two groups (all P<0.05). In 4 and 12 weeks of treatment, there were not different significantly between the ziwuliuzhu group and the prozac group (both P>0.05). In 24 weeks of treatment, HAMD score in the ziwuliuzhu group was lower than that in the prozac group (P<0.05). For the adverse reaction, there were 2 cases in the comprehensive group, 6 cases in the prozac group and 0 case in the ziwzuliuzhu group. CONCLUSION The comprehensive therapy of acupuncture at the acupoints based on ziwuliuzhu and oral administration of prozac is superior to either the simple oral administration of prozac or the ziwuliuzhu acu-puncture in terms of clinical efficacy and the improvements in depressive state. Regarding the clinical efficacy, the impact of simple ziwuliuzhu acupuncture is not different significantly as compared with the simple oral administration of prozac, but it is better than the simple oral administration of prozac in terms of the long-term HAMD score and safety.

Renal considerations in angiotensin converting enzyme inhibitor therapy: a statement for healthcare professionals from the Council on the Kidney in Cardiovascular Disease and the Council for High Blood Pressure Research of the American Heart Association.

Angiotensin converting enzyme (ACE) inhibitors are now one of the most frequently used classes of antihypertensive drugs. Beyond their utility in the management of hypertension, their use has been extended to the long-term management of patients with congestive heart failure (CHF), as well as diabetic and nondiabetic nephropathies. Although ACE inhibitor therapy usually improves renal blood flow (RBF) and sodium excretion rates in CHF and reduces the rate of progressive renal injury in chronic renal disease, its use can also be associated with a syndrome of “functional renal insufficiency” and/or hyperkalemia. This form of acute renal failure (ARF) most commonly develops shortly after initiation of ACE inhibitor therapy but can be observed after months or years of therapy, even in the absence of prior ill effects. ARF is most likely to occur when renal perfusion pressure cannot be sustained because of substantial decreases in mean arterial pressure (MAP) or when glomerular filtration rate (GFR) is highly angiotensin II (Ang II) dependent. Conditions that predict an adverse hemodynamic effect of ACE inhibitors in patients with CHF are preexisting hypotension and low cardiac filling pressures. The GFR is especially dependent on Ang II during extracellular fluid (ECF) volume depletion, high-grade bilateral renal artery stenosis, or stenosis of a dominant or single kidney, as in a renal transplant recipient. Understanding the pathophysiological mechanisms and the common risk factors for ACE inhibitor–induced functional ARF is critical, because preventive strategies for ARF exist, and if effectively used, they may permit use of these compounds in a less restricted fashion. Under normal physiological conditions, renal autoregulation adjusts renal vascular resistance, so that RBF and GFR remain constant over a wide range of MAPs.1 The intrinsic renal autoregulation mechanism is adjusted by Ang II and the sympathetic nervous system. When renal perfusion pressure falls (as in …