Background There is global interest in the reconfiguration of community mental health services, including primary care, to improve clinical and cost effectiveness. Aims Thisstudyseekstodescribepatternsofserviceuse,continuityof care, health risks, physical healthcare monitoring and the bal- ance between primary and secondary mental healthcare for people with severe mental illness in receipt of secondary mental healthcare in the UK. Method We conducted an epidemiological medical records review in three UK sites. We identified 297 cases randomly selected from the three participating mental health services. Data were manually extracted from electronic patient medical records from both secondary and primary care, for a 2-year period (2012 – 2014). Continuous data were summarised by mean and s.d. or median and interquartile range (IQR). Categorical data were summarised as percentages. The majority of care was from secondary care practitioners: of the 18 210 direct contacts recorded, 76% were from secondary care (median, 36.5; IQR, 14 – 68) and 24% were from primary care (median, 10; IQR, 5 – 20). There was evidence of poor longitudinal continuity: in primary care, 31% of people had poor longitudinal continuity (Modified Modified Continuity Index ≤ 0.5), and 43% had a single named care coordinator in secondary care services over the 2 years. The study indicates scope for improvement in supporting mental health service deliveryinprimary care. Greaterknowledge ofhow care is organised presents an opportunity to ensure some rebal-ancing of the care that all people with severe mental illness receive, when they need it. A future publication will examine differencesbetweenthethree sites that participatedinthis study.

OBJECTIVES The aim of this study was to determine the effect of transient myocardial ischemia on circulating natriuretic peptide levels. BACKGROUND Natriuretic peptides are released by the heart in response to wall stress. We hypothesized that transient myocardial ischemia would cause acute changes in circulating natriuretic peptide levels. METHODS B-type natriuretic peptide (BNP), N-terminal fragment of BNP pro-hormone (NT-proBNP), and N-terminal fragment of atrial natriuretic peptide pro-hormone (NT-pro-ANP) levels were measured in 112 patients before, immediately after, and 4 h after exercise testing with nuclear perfusion imaging. RESULTS Baseline levels of BNP were associated with the subsequent severity of provoked ischemia, with median levels of 43, 62, and 101 pg/ml in patients with none, mild-to-moderate, and severe inducible ischemia, respectively (p 0.03). Immediately after exercise, the median increase in BNP was 14.2 pg/ml in patients with mild-to-moderate ischemia (p 0.0005) and 23.7 pg/ml in those with severe ischemia (p 0.017). In contrast, BNP levels only rose by 2.3 pg/ml in those who did not develop ischemia (p 0.31). A similar relationship was seen between baseline NT-pro-BNP levels and inducible ischemia, but the changes in response to ischemia were less pronounced. NT-pro-ANP levels rose with exercise in both ischemic and non-ischemic patients. When added to traditional clinical predictors of ischemia, a post-stress test BNP 80 pg/ml remained a strong and independent predictor of inducible myocardial ischemia (odds ratio 3.0, p 0.025). CONCLUSIONS Transient myocardial ischemia was associated with an immediate rise in circulating BNP levels, and the magnitude of rise was proportional to the severity of ischemia. These findings demonstrate an important link between the severity of an acute ischemic insult and the circulating levels of BNP. (J Am Coll Cardiol 2004;44:1988–95) © 2004 by the American ublished by Elsevier Inc. doi:10.1016/j.jacc.2004.07.057

Background— Despite the known benefit of intensive statin therapy for reducing future cardiovascular events, its effectiveness in women has been questioned by some. Methods and Results— In the Pravastatin or Atorvastatin Evaluation and Infection Therapy—Thrombolysis in Myocardial Infarction 22 (PROVE IT-TIMI 22) trial, 911 (21.9%) women and 3251 (78.1%) men were randomized to intensive statin (atorvastatin 80 mg) versus standard therapy (pravastatin 40 mg) therapy for a median duration of 2.1 years. The primary end point was death, myocardial infarction, unstable angina; revascularization (occurring after 30 days); or stroke. Safety end points included elevations in liver function tests, creatine kinase, and myalgias/myositis. Women had a reduction in low-density lipoprotein (LDL) of 42.8% from baseline at 30 days (to a median of 60 mg/dL) in the intensive therapy arm, with 88.8% reaching the LDL goal of <100 mg/dL and 65.0% of <70 mg/dL, compared with a 16.8% reduction in LDL (to a median of 88 mg/dL) in the standard therapy arm. Women receiving intensive statin therapy had a significant 25% relative reduction over standard dose (hazard ratio, 0.75; 95% CI, 0.57 to 0.99; P=0.04) for the primary composite end point compared with a 14% reduction for men (hazard ratio, 0.86; 95% CI, 0.75 to 0.99; P=0.04; P-interaction, 0.38). No differences were observed between sexes for safety (all P-interaction ≥0.11). Conclusions— This trial provides evidence that both women and men derived benefit from intensive statin therapy after acute coronary syndrome, and thus, sex should not be a factor in determining who should be treated with intensive statin therapy. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00382460.

It was the objective of this study to determine whether the intrinsic platelet response to adenosine diphosphate (ADP) before thienopyridine exposure contributes to residual platelet reactivity to ADP despite high level P2Y(12) blockade by prasugrel (60 mg loading dose [LD]), 10 mg daily maintenance dose [MD]) or high-dose clopidogrel (600 mg LD, 150 mg daily MD). High residual platelet function during clopidogrel therapy is associated with poor clinical outcomes. It remains unknown whether the relationship between platelet reactivity prior to treatment with clopidogrel (300 mg LD, 75 mg daily MD) and residual on-treatment platelet reactivity is maintained after more potent P2Y(12) inhibition. PRINCIPLE-TIMI 44 was a randomised, double-blind, two-phase crossover study of prasugrel compared with high-dose clopidogrel in 201 patients undergoing cardiac catheterisation for planned per, cutaneous coronary intervention. ADP-stimulated platelet-monocyte aggregates, platelet surface P-selectin and platelet aggregation were measured pre-treatment, during LD (6 h and 18-24 h) and MD (15 d). Correlations of pre-treatment to on-treatment values were determined by Spearman rank order. Prasugrel resulted in greater platelet inhibition than high-dose clopidogrel for each measure. However, for both drugs, pre-treatment reactivity to ADP predicted 6 h, 18-24 h and 15 day reactivity to ADP (correlations 0.24-0.62 for platelet-monocyte aggregates and P-selectin). In conclusion, a patient's intrinsic platelet response to ADP before exposure to thienopyridines contributes to residual platelet reactivity to ADP despite high level P2Y(12) blockade with high-dose. clopidogrel or even higher level P2Y(12) blockade with prasugrel. Patients who are hyper-responsive to ADP pre-treatment are more likely to be hyper-responsive to ADP on-treatment, which may be relevant to therapeutic strategies.

Background-Despite the known benefit of intensive statin therapy for reducing future cardiovascular events, its effectiveness in women has been questioned by some.Methods and Results-In the Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 (PROVE IT-TIMI 22) trial, 911 (21.9%) women and 3251 (78.1%) men were randomized to intensive statin (atorvastatin 80 mg) versus standard therapy (pravastatin 40 mg) therapy for a median duration of 2.1 years. The primary end point was death, myocardial infarction, unstable angina; revascularization (occurring after 30 days); or stroke. Safety end points included elevations in liver function tests, creatine kinase, and myalgias/myositis. Women had a reduction in low-density lipoprotein (LDL) of 42.8% from baseline at 30 days (to a median of 60 mg/dL) in the intensive therapy arm, with 88.8% reaching the LDL goal of <100 mg/dL and 65.0% of <70 mg/dL, compared with a 16.8% reduction in LDL (to a median of 88 mg/dL) in the standard therapy arm. Women receiving intensive statin therapy had a significant 25% relative reduction over standard dose (hazard ratio, 0.75; 95% CI, 0.57 to 0.99; P=0.04) for the primary composite end point compared with a 14% reduction for men (hazard ratio, 0.86; 95% CI, 0.75 to 0.99; P=0.04; P-interaction, 0.38). No differences were observed between sexes for safety (all P-interaction >= 0.11).Conclusions-This trial provides evidence that both women and men derived benefit from intensive statin therapy after acute coronary syndrome, and thus, sex should not be a factor in determining who should be treated with intensive statin therapy.

AIMS:To determine the impact of a strategy using enoxaparin for up to 8 days compared with unfractionated heparin (UFH) for 48 h as an adjunct to fibrinolysis for ST-segment elevation myocardial infarction (STEMI) on 1-year clinical outcomes.METHODS AND RESULTS:Follow-up at 1 year (n = 20 275) was conducted by telephone in the ExTRACT-TIMI 25 trial to ascertain the endpoints of death, MI, and disabling stroke. The primary endpoint of death or non-fatal MI occurred in 1614 (15.8%) and 1732 (17.0%) of patients allocated to enoxaparin and UFH, respectively [hazard ratio (HR) 0.92, 95% confidence interval (CI) 0.86-0.98, P = 0.01]. The enoxaparin strategy significantly reduced non-fatal MI at 1 year (5.7 vs. 6.8%, HR 0.82, 95% CI 0.73-0.92, P < 0.001). The risks of death (10.5 vs. 10.6%, HR 0.98, 95% CI 0.91-1.07) and disabling stroke (1.1 vs. 1.2%, HR 0.97, 95% CI 0.75-1.26) were not reduced. The composite of death, MI, or disabling stroke favoured enoxaparin (HR 0.91, 95% CI 0.85-0.98, P = 0.007).CONCLUSION:Compared with UFH for 48 h, a strategy using enoxaparin as an adjunct to fibrinolysis resulted in a sustained reduction in death or MI at 1 year with no additional benefit after 30 days. Mortality was not reduced at 1 year with the enoxaparin strategy. The study was registered at ClinicalTrials.gov, NCT00077792.

Intensive low-density lipoprotein cholesterol therapy with ezetimibe/simvastatin in IMPROVE-IT (IMProved Reduction of Outcomes: Vytorin Efficacy International Trial) significantly reduced the first primary endpoint (PEP) in patients post-acute coronary syndrome (ACS) compared to placebo/simvastatin.This analysis tested the hypothesis that total events, including those beyond the first event, would also be reduced with ezetimibe/simvastatin therapy.All PEP events (cardiovascular [CV] death, myocardial infarction [MI], stroke, unstable angina [UA] leading to hospitalization, coronary revascularization ≥30 days post-randomization) during a median 6-year follow-up were analyzed in patients randomized to receive ezetimibe/simvastatin or placebo/simvastatin in IMPROVE-IT. Negative binomial regression was used for the primary analysis.Among 18,144 patients, there were 9,545 total PEP events (56% were first events and 44% subsequent events). Total PEP events were significantly reduced by 9% with ezetimibe/simvastatin vs placebo/simvastatin (incidence-rate ratio [RR]: 0.91; 95% confidence interval [CI]: 0.85 to 0.97; p = 0.007), as were the 3 pre-specified secondary composite endpoints and the exploratory composite endpoint of CV death, MI, or stroke (RR: 0.88; 95% CI: 0.81 to 0.96; p = 0.002). The reduction in total events was driven by decreases in total nonfatal MI (RR: 0.87; 95% CI: 0.79 to 0.96; p = 0.004) and total NF stroke (RR: 0.77; 95% CI: 0.65 to 0.93; p = 0.005).Lipid-lowering therapy with ezetimibe plus simvastatin improved clinical outcomes. Reductions in total PEP events, driven by reductions in MI and stroke, more than doubled the number of events prevented compared with examining only the first event. These data support continuation of intensive combination lipid-lowering therapy after an initial CV event. (IMProved Reduction of Outcomes: Vytorin Efficacy International Trial [IMPROVE-IT]; NCT00202878)

AIMS:Elevated natriuretic peptides (NPs) are associated with an increased cardiovascular risk following acute coronary syndromes (ACSs). However, the therapeutic implications are still undefined. We hypothesized that early inhibition of renin-angiotensin-aldosterone system (RAAS) in patients with preserved left ventricular function but elevated NPs but following ACS would reduce haemodynamic stress as reflected by a greater reduction NP compared with placebo.METHODS AND RESULTS:AVANT GARDE-TIMI 43 trial, a multinational, double-blind trial, randomized 1101 patients stabilized after ACS without clinical evidence of heart failure or left ventricular function <or=40% but with an increased level of NP 3-10 days after admission to aliskiren, valsartan, their combination, and placebo. The primary endpoint was the change in NT-proBNP from baseline to Week 8. NT-proBNP declined significantly in each treatment arm, including placebo, by Week 8, though there were no differences in the reduction between treatment strategies (42% in placebo, 44% in aliskiren, 39% in valsartan, and 36% in combination arm). Although several subgroups had higher baseline levels of NP and greater reductions over the study period, there were no differences among treatment groups in any subgroup. There were no differences in clinical outcomes but there were more adverse events, including serious events and adverse events leading to early study drug discontinuation, in patients treated with active therapy.CONCLUSION:In this study of a high-risk population with elevated levels of NPs but relatively preserved systolic function and no evidence of heart failure following ACS, there was no evidence for a benefit of early initiation of inhibition of RAAS with valsartan, aliskiren, or their combination compared with placebo with respect to a reduction in NP over 8 weeks of therapy. Moreover, adverse events were reported more frequently in patients assigned to active therapy.

Current guidelines recommend risk stratification largely based on traditional risk factors such as those in the Framingham Risk Score. We studied the distribution of 12 traditional and non-traditional risk markers (age >= 65 years, male gender, family history of premature coronary heart disease, low-density lipoprotein cholesterol >= 70 mg/di, high-density lipoprotein cholesterol <40 mg/di in men and <50 mg/dl in women, systolic blood pressure > 130 mm Hg, diabetes mellitus, smoking, C-reactive protein >= 2 mg/L, triglycerides >150 mg/di, prediabetes defined as a fasting glucose level 100 to 125 mg/di or hemoglobin Ale >6, and obesity defined as body mass index >= 30 kg/m(2)) in 3,675 patients from the PROVE IT-TIMI 22 trial at 4 months and evaluated the risk of cardiovascular events stratified by the number of risk factors. The median number of risk factors was 5. In individual risk factor subgroups, men, smokers, hypertensives, and patients with increased low-density lipoprotein cholesterol had just that added risk factor compared to their counterparts (median 5 vs 4). In contrast, patients with diabetes, prediabetes, and increased triglycerides, C-reactive protein, or body mass index had not only that, but also another added risk factor (median 6 vs 4). A higher risk factor count was strongly related with increased rate of death, myocardial infarction, unstable angina, stroke, or revascularization, from 0% to 38.6% at 2 years for 0 to >= 9 risk factors (p < 0.0001). In conclusion, with the observed "clustering" of risk factors and the link between increasing risk factor count and adverse outcomes in a patient with 1 diagnosed risk factor, a comprehensive review of traditional and novel risk factors is important to fully assess cardiovascular risk. (C) 2010 Elsevier Inc. All rights reserved. (Am J Cardiol 2010;105:619-623)

AIMS To evaluate the association of bleeding with mortality in ST-elevation myocardial infarction (STEMI). METHODS AND RESULTS We studied 20 323 patients with STEMI receiving fibrinolytic therapy and an antithrombin in ExTRACT-TIMI 25. Relationships between in-hospital bleeding, patient characteristics, treatments, and in-hospital cardiovascular complications with mortality were evaluated using Cox models. Likelihood ratios estimated each variable's model contribution. High 30-day mortality after major bleeding (n = 309, 37.6% mortality) was driven by the poor prognosis of intracranial haemorrhage (ICH; n = 143, 65.4% mortality, model contribution 7.8%). The adjusted hazard ratios (HRs) for 30-day death for any major bleeding and for ICH were 2.9 [2.4-3.6] and 10.3 [8.2-12.8], respectively. Neither non-ICH major nor minor bleeding was associated with 30-day death after adjustment. Cardiogenic shock (HR 13.5, 61% contribution) and age (HR 1.6/decade, 17% contribution) were most strongly correlated with 30-day death. Among 30-day survivors, age (HR 1.6/decade, contribution 43%) and heart rate (HR 1.2 per 10 b.p.m., contribution 18%) were most strongly associated with mortality between Days 31 and 365. CONCLUSION Cardiogenic shock, age, and ICH were important independent correlates of 30-day and 1-year mortality in STEMI patients receiving fibrinolytic therapy. In-hospital non-ICH major and minor bleeding were not independently associated with increased mortality at 30 days or 1 year.

Background Vitamin K antagonists have been the standard oral antithrombotic used for more than a half century for prevention and treatment of thromboembolism. Their limitations include multiple food and drug interactions and need for frequent monitoring and dose adjustments. Edoxaban is a selective and direct factor Xa inhibitor that may provide effective, safe, and more convenient anticoagulation.Study Design ENGAGE AF-TIMI 48 is a phase 3, randomized, double-blind, double-dummy, multinational, noninferiority design megatrial comparing 2 exposure strategies of edoxaban to warfarin. Approximately 20,500 subjects will be randomized to edoxaban high exposure (60 mg daily, adjusted for drug clearance), edoxaban low exposure (30 mg daily, adjusted for drug clearance), or warfarin titrated to an international normalized ratio of 2.0 to 3.0. The edoxaban strategies provide for dynamic dose reductions in subjects with anticipated increased drug exposure. Blinded treatment is maintained through the use of sham international normalized ratios in patients receiving edoxaban. Eligibility criteria include electrical documentation of atrial fibrillation <= 12 months and a CHADS(2) score >= 2. Randomization is stratified by CHADS(2) score and anticipated drug exposure. The primary objective is to determine whether edoxaban is noninferior to warfarin for the prevention of stroke and systemic embolism. The primary safety end point is modified International Society on Thrombosis and Haemostasis major bleeding. Recruitment began in November 2008. The expected median follow-up is 24 months.Conclusions ENGAGE AF-TIMI 48 is a phase 3 comparison of the novel oral factor Xa inhibitor edoxaban to warfarin for the prevention of thromboembolism in patients with atrial fibrillation. (Am Heart J 2010; 160: 635-641.e2.)

Background— The pathobiological basis of ischemic heart disease and thus the manifestations and response to therapy can differ between women and men. In prior studies, sex-based treatment differences have been observed with the antiischemic ranolazine, with a possibly diminished effect in women. Methods and Results— We conducted a prospectively planned analysis of the clinical, biomarker, angiographic, and continuous ECG features and 1-year outcomes of women with unstable ischemic heart disease randomized to ranolazine or placebo in Metabolic Efficiency With Ranolazine for Less Ischemia in Non–ST-Elevation Acute Coronary Syndromes–Thrombolysis in Myocardial Infarction 36 (MERLIN-TIMI 36). Compared with men (n=4269), women (n=2291) were older with more risk factors ( P <0.001). On presentation, women were less likely than men to have significant epicardial coronary artery disease (no stenosis ≥50% on angiography, 19.4% versus 8.6%; P <0.001) or elevated troponin (57.1% versus 68.9%; P <0.001). Yet, women were more likely to have an elevated B-type natriuretic peptide (47.0% versus 40.2%; P <0.001), worse median angina frequency scores (80 versus 100; P <0.001), and an ischemic episode on continuous ECG administered during the first 7 days (22.5% versus 19.3%; P =0.0025). Women and men were at similar adjusted risk for the primary end point of cardiovascular death, myocardial infarction, or recurrent ischemia (adjusted hazard ratio, 1.11; 95% confidence interval, 0.96 to 1.29; P =0.15). Ranolazine was associated with a significant reduction in recurrent ischemia in women (13.0% versus 18.2%; hazard ratio, 0.71; 95% confidence interval, 0.57 to 0.88; P =0.002). Conclusions— Women with a clinical syndrome consistent with unstable ischemic heart disease, despite having less obstructive coronary artery disease, were more likely than men to report anginal episodes and had more recorded ischemic periods on continuous ECG. In this setting, ranolazine may be a particularly useful antiischemic agent in women. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00099788.

OBJECTIVES:We evaluated the efficacy and safety of prasugrel and clopidogrel in the setting of a glycoprotein (GP) IIb/IIIa inhibitor. BACKGROUND:Prasugrel reduced cardiovascular events as compared with clopidogrel in TRITON-TIMI 38 (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial Infarction 38) but with increased bleeding. METHODS:Researchers in the TRITON-TIMI 38 randomized 13,608 subjects with acute coronary syndrome undergoing percutaneous coronary intervention to prasugrel versus clopidogrel. The use of a GP IIb/IIIa inhibitor was at the physician's discretion. For the current analysis, end points were examined at 30 days and were stratified by use of a GP IIb/IIIa inhibitor. RESULTS:A total of 7,414 subjects (54.5%) received a GP IIb/IIIa inhibitor during their index hospitalization. There was a consistent benefit of prasugrel over clopidogrel for reducing cardiovascular death, myocardial infarction, or stroke in patients who did (hazard ratio: 0.76; 95% confidence interval: 0.64 to 0.90) or did not receive a GP IIb/IIIa inhibitor (hazard ratio: 0.78; 95% confidence interval: 0.63 to 0.97, p(interaction) = 0.83). Prasugrel significantly reduced myocardial infarction, urgent revascularization, and stent thrombosis irrespective of GP IIb/IIIa inhibitor use. Although subjects treated with a GP IIb/IIIa inhibitor had greater rates of bleeding, the risk of Thrombolysis in Myocardial Infarction major or minor bleeding with prasugrel versus clopidogrel was not significantly different in patients who were or were not treated with GP IIb/IIIa inhibitor (p(interaction) = 0.19). CONCLUSIONS:Prasugrel significantly reduces the risk of cardiovascular events in patients with acute coronary syndromes after percutaneous coronary intervention regardless of whether or not a GP IIb/IIIa inhibitor is used. The use of a GP IIb/IIIa inhibitor does not accentuate the relative risk of bleeding with prasugrel as compared with clopidogrel.

Background— Prasugrel is a novel thienopyridine that reduces new or recurrent myocardial infarctions (MIs) compared with clopidogrel in patients with acute coronary syndrome undergoing percutaneous coronary intervention. This effect must be balanced against an increased bleeding risk. We aimed to characterize the effect of prasugrel with respect to the type, size, and timing of MI using the universal classification of MI. Methods and Results— We studied 13 608 patients with acute coronary syndrome undergoing percutaneous coronary intervention randomized to prasugrel or clopidogrel and treated for 6 to 15 months in the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel–Thrombolysis in Myocardial Infarction (TRITON-TIMI 38). Each MI underwent supplemental classification as spontaneous, secondary, or sudden cardiac death (types 1, 2, and 3) or procedure related (Types 4 and 5) and examined events occurring early and after 30 days. Prasugrel significantly reduced the overall risk of MI (7.4% versus 9.7%; hazard ratio [HR], 0.76; 95% confidence interval [CI], 0.67 to 0.85; P <0.0001). This benefit was present for procedure-related MIs (4.9% versus 6.4%; HR, 0.76; 95% CI, 0.66 to 0.88; P =0.0002) and nonprocedural (type 1, 2, or 3) MIs (2.8% versus 3.7%; HR, 0.72; 95% CI, 0.59 to 0.88; P =0.0013) and consistently across MI size, including MIs with a biomarker peak ≥5 times the reference limit (HR. 0.74; 95% CI, 0.64 to 0.86; P =0.0001). In landmark analyses starting at 30 days, patients treated with prasugrel had a lower risk of any MI (2.9% versus 3.7%; HR, 0.77; P =0.014), including nonprocedural MI (2.3% versus 3.1%; HR, 0.74; 95% CI, 0.60 to 0.92; P =0.0069). Conclusion— Treatment with prasugrel compared with clopidogrel for up to 15 months in patients with acute coronary syndrome undergoing percutaneous coronary intervention significantly reduces the risk of MIs that are procedure related and spontaneous and those that are small and large, including new MIs occurring during maintenance therapy.