End Point Of Nonfatal Myocardial Infarction Research Articles

Association of epicardial adipose tissue on magnetic resonance imaging with cardiovascular outcomes: Quality over quantity?

Abstract Background Quantity of epicardial adipose tissue (EAT) has been associated with poor cardiovascular outcomes. As suggested by computed tomography (CT) studies the quality of EAT may be of incremental prognostic value. Cardiac magnetic resonance (CMR) is the gold-standard for tissue characterization, however, has never been applied for EAT quality assessment. Objectives To investigate EAT quality measured on CMR T1 mapping as predictor of outcome in an all-comer cohort. Methods We measured EAT area (EATA) and T1 time (EAT-T1) in a four-chamber views (Figure 1) and tested for association with clinical, demographic, and laboratory parameters using linear regression models. We used Cox-regression analyses to test the association between EATA and EAT-T1 with a composite endpoint of non-fatal myocardial infarction, heart failure hospitalization, and all-cause death. Results A total of 966 participants were included (47.2% female, mean age: 58.4years). Mean EATA was 7.3cm2 and mean EAT-T1 was 268ms. On linear regression EAT-T1 was not associated with markers obesity, dyslipidemia or co-morbidities such as diabetes (p>0.05 for all). During a follow-up of 57.7 months, a total of 280 (29.0%) events occurred. EAT-T1 was independently associated (adj. HR: 1.003, 95%-CI: 1.000 – 1.005, p=0.029, Figure 2) with the composite endpoint when adjusted for established clinical risk factors including age, sex, natriuretic peptide levels, left and right ventricular function, arterial hypertension, body mass index, and coronary artery disease. Conclusion In an all-comer CMR cohort, EAT quality, as measured on CMR T1-times, but not EAT quantity is independently associated with a composite endpoint of non-fatal myocardial infarction, heart failure hospitalization, and all-cause death.Figure 1.Regions of interestFigure 2.Kaplan Meier Curves

Treatment patterns in a population of 1.4 million individuals qualifying for initiation of dual-combination blood pressure lowering therapy representing usual clinical practice

Abstract Background Guidelines recommend dual-combination therapy (DCT) in most hypertensive patients requiring initiation of blood pressure (BP)-lowering treatment. This strategy is proven to be more effective as compared to monotherapy in achievement of BP goals, is associated with improved adherence, persistence and reduces risk of cardiovascular (CV) events. Purpose To describe the patterns of treatment with BP-lowering therapies in a large hypertensive population qualifying for initiation of DCT. Methods The study utilized following linked databases in England: Clinical Practice Research Datalink, Hospital Episode Statistics and Office for National Statistics. Adults qualifying for DCT as per the 2018 ESC/ESH guidelines were identified during a 15-year period (2005-2019). The index date is the first date when patient became eligible for initiation of DCT as per the guidelines-based criteria. Patients were followed for 5 years from the index date and were categorized into 4 groups: (1) no treatment, (2) monotherapy, (3) combination therapy with 2 agents, (4) combination therapy with ≥3 agents. For each year during follow-up, the percent of patient-time (Pt) on these categories was summarized for the overall population and two main subgroups i.e., atherosclerotic cardiovascular disease (ASCVD) and diabetes at baseline. In addition, we estimated the 15-year event rate for the composite endpoint of nonfatal myocardial infarction, nonfatal stroke, hospitalization for heart failure, and CV death via the Kaplan Meier method. Results Overall, 1,426,079 individuals met the selection criteria. Mean (SD) age was 62.9 (14.1) years and ∼50% were male. Approximately 15.9% and 13.8% had ASCVD and diabetes at baseline, respectively. In overall population during 5-year follow-up (Table 1), nearly 25% of Pt during follow-up reported non-treatment with any BP-lowering therapy. Monotherapy was most common treatment pattern accounting for nearly 50% of Pt while only 25% of Pt represented DCT. Percent of Pt on monotherapy decreased from 56.7% to 42.6% (year-1 to -5), and the percent of Pt on dual-combination therapy increased from 14.9% to 25.5% (year-1 to -5). Percent of Pt on any combination therapy (≥2 agents) increased from 17.5% to 32.4% (year-1 to -5). Similar pattern was observed in ASCVD and diabetes subgroups. The 15-year event rate for the composite endpoint was 27.1% for the overall population and was 57.5% and 40.1% in ASCVD and diabetes subgroups, respectively (Table 2). Conclusion Our findings indicate an opportunity for substantial improvement in BP control and CV risk reduction in this population, by ensuring appropriate guideline-based initiation, of dual combination BP-lowering therapy.Table 1Table 2

Elevated plasma factor XI is predicts cardiovascular complications in patients with type 2 diabetes mellitus

Abstract Background Atherothrombotic complications are common in patients with type 2 diabetes mellitus (T2DM), reflecting a chronic prothrombotic state. Circulating factor XI (FXI) has been associated with a prothrombotic fibrin clot phenotype and predicted myocardial infarction, stroke and cardiovascular (CV) death in a number of diseases, including CAD. Its role in T2DM is largely unknown. Purpose The purpose of this study was to assess plasma FXI as a predictor of atherothrombotic events in T2DM patients. We also aimed to establish the determinants of elevated plasma FXI in this group of patients. Methods In a cohort of 156 patients aged 43–83 years, 56% male, with T2DM of a median duration time of five years, 64.7% with diagnosed CAD, we measured FXI along with a number of fibrin clot parameters, including turbidity, permeation, compaction, lysability, maximum concentration of D-dimer (D-D max), and rate of D-dimer release during tissue plasminogen activator-induced clot lysis. Patients were followed for a median time of 72 (68-74) months for a composite endpoint of nonfatal myocardial infarction (MI), nonfatal stroke, and cardiovascular (CV) death. Results Follow-up was complete for 133 (85.3%) patients. There were 21 (16%) cases of the composite endpoint, including one nonfatal MI, four nonfatal strokes and 16 cases of CV death. Patients with and without the composite endpoint shared a similar demographic and clinical profile with the exception of age and white blood cell count – patients with the endpoint were older (69.4 [8.4] vs. 65.4 [7.8] years, p=0.03) and had a higher leukocyte count (7.8 [1.9] vs. 7.0 [1.3], p=0.02) as compared with the remainder. FXI was elevated above the upper limit of 120% in 25 (18.8%) patients, including 16 (61.9%) with the composite endpoint vs. 12 (10.7%) without the composite endpoint, p<0.001. Individuals with the composite endpoint had higher baseline FXI concentrations as compared with the remainder (120.1±16.8 vs. 104.9±10.7%. p < 0.001), along with higher D-D max (4.1 [3.8-4.3] vs. 3.8 [3.6-4.1] mg/l, p = 0.006) and slightly longer lysis time (t50% 10.1 [9.8-10.9] vs. 9.8 [8.9-10.4] min, p = 0.03). On multivariable analysis, co-existing CAD, LDL cholesterol, and thrombin activatable fibrinolysis inhibitor activity were independent predictors of elevated FXI in T2DM patients. Conclusion Elevated plasma FXI in T2DM patients is associated with CAD, LDL cholesterol and TAFI, and predicts myocardial infarction, stroke, and CV death in long term follow-up. Our finding may have implications for risk stratification and suggests a role for FXI inhibitors in T2DM patients with a high risk of atherothrombotic complications.

Atorvastatin

Atorvastatin

Hepatic T1-time predicts cardiovascular risk in all-comers referred for cardiovascular magnetic resonance

Abstract Background Liver damage is frequently observed in patients with cardiovascular disease (CVD) but infrequently quantified. We hypothesized that in patients with CVD undergoing cardiac magnetic resonance (CMR), liver T1-times indicate liver damage and are associated with cardiovascular outcome. Methods We measured hepatic T1-times, displayed on standard cardiac T1-maps, in an all-comer CMR-cohort. At the time of CMR, we assessed validated general liver fibrosis scores. Kaplan-Meier estimates and Cox-regression models were used to investigate the association between hepatic T1-times and a composite endpoint of non-fatal myocardial infarction, heart failure hospitalization, and death. Results 1022 participants (58±18 y/o, 47% female) were included (972 patients, 50 controls). Hepatic T1-times were 590±89ms in patients and 574±45ms in controls (p=0.052). They were significantly correlated with cardiac size and function, presence of atrial fibrillation, NT-pro-BNP levels, and gamma-glutamyl-transferase levels (p<0.001 for all). During follow-up (58±31 months), a total of 280 (29%) events occurred. On Cox-regression, high hepatic T1-times yielded a significantly higher risk for events (adj.HR 1.66 [95% CI: 1.45–1.89] per 100ms increase, p<0.001), even when adjusted for age, sex, left and right ventricular ejection fraction, NT-proBNP, and myocardial T1-time. On restricted cubic splines, we found that a hepatic T1-time exceeding 610ms was associated with excessive risk. Conclusion Hepatic T1-times on standard CMR scans were significantly associated with cardiac size and function, comorbidities, natriuretic peptides, and independently predicted cardiovascular mortality and morbidity. A hepatic T1-time >610ms seems to indicate excessive risk. Funding Acknowledgement Type of funding sources: None.

Allopurinol versus usual care in UK patients with ischaemic heart disease (ALL-HEART): a multicentre, prospective, randomised, open-label, blinded-endpoint trial

Allopurinol is a urate-lowering therapy used to treat patients with gout. Previous studies have shown that allopurinol has positive effects on several cardiovascular parameters. The ALL-HEART study aimed to determine whether allopurinol therapy improves major cardiovascular outcomes in patients with ischaemic heart disease. ALL-HEART was a multicentre, prospective, randomised, open-label, blinded-endpoint trial done in 18 regional centres in England and Scotland, with patients recruited from 424 primary care practices. Eligible patients were aged 60 years or older, with ischaemic heart disease but no history of gout. Participants were randomly assigned (1:1), using a central web-based randomisation system accessed via a web-based application or an interactive voice response system, to receive oral allopurinol up-titrated to a dose of 600 mg daily (300 mg daily in participants with moderate renal impairment at baseline) or to continue usual care. The primary outcome was the composite cardiovascular endpoint of non-fatal myocardial infarction, non-fatal stroke, or cardiovascular death. The hazard ratio (allopurinol vs usual care) in a Cox proportional hazards model was assessed for superiority in a modified intention-to-treat analysis (excluding randomly assigned patients later found to have met one of the exclusion criteria). The safety analysis population included all patients in the modified intention-to-treat usual care group and those who took at least one dose of randomised medication in the allopurinol group. This study is registered with the EU Clinical Trials Register, EudraCT 2013-003559-39, and ISRCTN, ISRCTN32017426. Between Feb 7, 2014, and Oct 2, 2017, 5937 participants were enrolled and then randomly assigned to receive allopurinol or usual care. After exclusion of 216 patients after randomisation, 5721 participants (mean age 72·0 years [SD 6·8], 4321 [75·5%] males, and 5676 [99·2%] white) were included in the modified intention-to-treat population, with 2853 in the allopurinol group and 2868 in the usual care group. Mean follow-up time in the study was 4·8 years (1·5). There was no evidence of a difference between the randomised treatment groups in the rates of the primary endpoint. 314 (11·0%) participants in the allopurinol group (2·47 events per 100 patient-years) and 325 (11·3%) in the usual care group (2·37 events per 100 patient-years) had a primary endpoint (hazard ratio [HR] 1·04 [95% CI 0·89-1·21], p=0·65). 288 (10·1%) participants in the allopurinol group and 303 (10·6%) participants in the usual care group died from any cause (HR 1·02 [95% CI 0·87-1·20], p=0·77). In this large, randomised clinical trial in patients aged 60 years or older with ischaemic heart disease but no history of gout, there was no difference in the primary outcome of non-fatal myocardial infarction, non-fatal stroke, or cardiovascular death between participants randomised to allopurinol therapy and those randomised to usual care. UK National Institute for Health and Care Research.

862-P: Interleukin-6 and Cardiovascular Outcomes in Patients with Type 2 Diabetes: A Post Hoc Analysis of CANVAS Trial

Introduction: The sodium glucose co-transporter 2 inhibitor (SGLT2i) canagliflozin (CANA) reduced cardiovascular (CV) outcomes in patients with type 2 diabetes (T2D) at high CV risk in the CANVAS Program. CANA has been shown to reduce markers of inflammation in small clinical studies. Higher interleukin-6 (IL-6) levels, a key inflammatory mediator, are associated with increased CV risk. We assessed the association between IL-6 and CV outcomes in patients with T2D and determined the effects of CANA on IL-6 levels over time. Methods: Patients were randomly assigned to CANA (100 or 300 mg/day) or placebo. Plasma IL-6 was measured at baseline and 1, 3, and 6 years after randomization. Outcomes were a composite CV endpoint of non-fatal myocardial infarction, non-fatal stroke, or CV death; a composite of CV death or heart failure hospitalization (hHF) ; or hHF alone. Multivariable adjusted Cox proportional hazard regression model was used to estimate the associations between baseline IL-6 and CV outcomes. The effect of CANA versus placebo on IL-6 levels over time was assessed with a repeated measures mixed effect model. Results: Of 4,330 CANVAS trial participants, 3,503 (80.9%) had available IL-6 measurements at baseline. In multivariable adjusted models, each doubling of baseline IL-6 was associated with 14% (95% CI 4-24%) , 24% (13-37%) , or 35% (16-57%) increased risk for the composite CV endpoint, CV death or hHF, or hHF alone, respectively (all p<0.01) . Compared with placebo, CANA reduced IL-6 levels by 4.4% (95% CI 1.3-9.9%; p=0.01) during follow-up. The proportion of the effect of CANA on the composite CV, CV death or hHF, and hHF endpoints explained by the change in IL-6 was 16.5% (p=0.02) , 28.5% (p=0.34) , and 11.4% (p=0.05) , respectively. Conclusion: In patients with T2D at high CV risk, increased IL-6 is associated with a higher risk of CV outcomes. CANA reduced IL-6 levels over time which may partly explain its protective effect. Disclosure A.Koshino: None. M.Schechter: None. T.Sen: None. B.Neuen: Advisory Panel; AstraZeneca, Boehringer Ingelheim International GmbH, Consultant; Bayer AG, Other Relationship; Janssen Research & Development, LLC. C.Arnott: Other Relationship; Amgen Inc. V.Perkovic: Advisory Panel; Astellas Pharma Inc., Baxter, DURECT Corporation, Merck & Co., Inc., Metavant Sciences, Mundipharma, Relypsa Inc., Other Relationship; AbbVie Inc., AstraZeneca, Bayer AG, Bristol-Myers Squibb Company, Dimerix, Eli Lilly and Company, Eli Lilly and Company, Gilead Sciences, Inc., GlaxoSmithKline plc., Janssen Research & Development, LLC, Mitsubishi Tanabe Pharma Corporation, Novartis Pharma K.K., Novo Nordisk, Novo Nordisk, Otsuka America Pharmaceutical, Inc., Pfizer Inc., Sanofi, Servier Laboratories, Tricida, Inc., UpToDate. M.K.Hansen: Employee; Janssen Research & Development, LLC. H.L.Heerspink: Consultant; AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Chinook Therapeutics Inc., CSL Behring, Gilead Sciences, Inc., Goldfinch Bio, Inc., Janssen Research & Development, LLC, Mitsubishi Tanabe Pharma Corporation, Mundipharma, Traveere Pharmaceuticals, Research Support; AstraZeneca, Boehringer Ingelheim International GmbH, Novo Nordisk A/S.

Abstract 16233: Systemic Arterial Pulsatility Index is a Potential Metric for Microvascular Dysfunction

Introduction: Coronary microvascular dysfunction is associated with both atherosclerosis and heart failure (HF). We aimed to evaluate the prognostic value of global coronary flow reserve (CFR) and systemic arterial pulsatility index, a metric of ventricular-arterial coupling, (SAPi = [systemic systolic pressure-systemic diastolic pressure]/pulmonary capillary wedge pressure) in patients with known or suspected coronary artery disease. Methods: This was a retrospective analysis at an academic tertiary care center for patients who underwent right heart catheterization (RHC) and positron emission tomography (PET) imaging within a 6 month period. Global CFR was evaluated with PET imaging and SAPi was calculated using cardiac hemodynamics from RHC. Patients were evaluated for endpoints of non-fatal myocardial infarction, revascularization, and death. Cox proportional hazards regression modeling was used to examine the associations between CFR & SAPi with death and other adverse cardiovascular events. Results: Among 74 patients with complete imaging and hemodynamic data (mean age 64.23 ± 11.18 years, 54.67% female) the mean SAPi was 4.87 ± 3.09 and CFR was 52.95 ± 16.17. Increased SAPi as a continuous variable trended towards decreased mortality [HR: 0.814 (95% CI 0.663-1.016, chi square 3.31, p=.07).] Increased CFR as a continuous variable was significantly associated with decreased mortality [HR: 0.964 (95% CI 0.936-0.993, chi square 6.03, p<0.05). Neither were associated with non-fatal myocardial infarction or early revascularization. There was a weak trend toward correlation between SAPi and CFR (r=0.19, p=0.11). Conclusions: SAPi a hemodynamic marker of ventricular arterial coupling was weakly associated with CFR. On the other hand, CFR was significantly associated with death in patients with known or suspected coronary artery disease. Future work is needed to assess the correlation between SAPi and coronary microvascular dysfunction.

P0782PROGNOSTIC IMPACT OF NECK CIRCUMFERENCE ON CARDIVASCULAR OUTCOMES AND MORTALITY IN PATIENTS WITH MODERATE CHRONIC KIDNEY DISEASE: AN ANALYSIS FROM THE GERMAN CHRONIC KIDNEY DISEASE (GCKD) STUDY

Abstract Background and Aims Neck circumference (NC) is an approximator of upper body subcutaneous fat tissue and a marker of obesity. It has been shown to be associated with cardiovascular risk factors and incident chronic kidney disease (CKD). In CKD patients, the impact on cardiovascular events and all cause death has not been fully elucidated yet. The prognostic impact on these outcomes in a representative cohort of adult patients with moderate CKD of Caucasian origin was investigated here. Method We used data from the GCKD study, a German multi-centric prospective observational cohort study of 5217 adults with moderate chronic kidney disease, defined as eGFR 30–60 mL/min/1.73 m2 or eGFR >60 mL/min/1.73 m2 and significant proteinuria (albuminuria >300 mg/g creatinine or proteinuria >500 mg/g creatinine). Exclusion criteria were active malignancy, heart failure NYHA class IV, organ transplantation, and non-Caucasian origin. NC was measured repeatedly (annually, except at first year of follow-up) during the study, therefore, the mean value was analyzed. We report data from the 4-year follow-up visit regarding 1) a combined endpoint of non-fatal myocardial infarction, non-fatal stroke, cardiovascular death, and peripheral artery disease event (amputation or revascularization) and 2) all-cause death as another endpoint. Cox proportional hazard regression was used to calculate hazard ratios (HR) with 95% CIs. In univariate analysis, ordinal regression with quintiles of NC was applied. Results NC was accrued in 4453 participants and analyzed. NC overall was 40±5 cm (43±4 cm in men and 37±4 cm in women, p<0.001), mean age 60±12 years, 41% were female, 96% had hypertension, 35% were diabetic, 58% had ever smoked, eGFR was 50±18 ml/min/1.73 m (CKD-EPI), BMI 28±6 kg/m, LDL-cholesterol 119±43 mg/dl. Higher quintiles of NC were associated increased risk of the cardiovascular outcome in univariate analysis: highest (44 cm) vs. lowest (36.5 cm), HR 2.34 (1.63–3.36; p<0.001). In multivariable analysis adjusted for age, sex, and BMI, this effect was reduced but still apparent: HR 1.04 (1.01–1.08, p=0.025). Age (HR per year 1.05, 1.04–1.07, p<0.001), and female sex (HR 0.69, 0.50–0.95, p=0.023), showed also significant effects, whereas BMI did not (p=0.831). The effect of higher quintiles of NC on the risk of all-cause death in univariate analysis was even stronger: highest vs. lowest, HR 3.2 (1.72–5.81, p=0.006). However, after adjustment this effect was abolished: HR 0.99 (0.95–1.04; p=0.85). Only age (HR 1.07, 1.04–1.09, p<0.001), and female sex (HR 0.45, 0.27-0.74, p=0.002), remained significant predictors of all-cause death in this model. Conclusion In patients with chronic kidney disease, we found higher NC to be associated with increased cardiovascular event risk, but not all-cause death, after adjustment for age, sex and BMI. The risk of cardiovascular outcomes and overall mortality was consistently lower in women. Our analysis supports evidence, that upper body subcutaneous adipose tissue might be an independent contributor to cardiovascular event risk.

Dulaglutide and renal outcomes in type 2 diabetes: an exploratory analysis of the REWIND randomised, placebo-controlled trial

Two glucagon-like peptide-1 (GLP-1) receptor agonists reduced renal outcomes in people with type 2 diabetes at risk for cardiovascular disease. We assessed the long-term effect of the GLP-1 receptor agonist dulaglutide on renal outcomes in an exploratory analysis of the REWIND trial of the effect of dulaglutide on cardiovascular disease. REWIND was a multicentre, randomised, double-blind, placebo-controlled trial at 371 sites in 24 countries. Men and women aged at least 50 years with type 2 diabetes who had either a previous cardiovascular event or cardiovascular risk factors were randomly assigned (1:1) to either weekly subcutaneous injection of dulaglutide (1·5 mg) or placebo and followed up at least every 6 months for outcomes. Urinary albumin-to-creatinine ratios (UACRs) and estimated glomerular filtration rates (eGFRs) were estimated from urine and serum values measured in local laboratories every 12 months. The primary outcome (first occurrence of the composite endpoint of non-fatal myocardial infarction, non-fatal stroke, or death from cardiovascular causes), secondary outcomes (including a composite microvascular outcome), and safety outcomes of this trial have been reported elsewhere. In this exploratory analysis, we investigate the renal component of the composite microvascular outcome, defined as the first occurrence of new macroalbuminuria (UACR >33·9 mg/mmol), a sustained decline in eGFR of 30% or more from baseline, or chronic renal replacement therapy. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01394952. Between Aug 18, 2011, and Aug 14, 2013, 9901 participants were enrolled and randomly assigned to receive dulaglutide (n=4949) or placebo (n=4952). At baseline, 791 (7·9%) had macroalbuminuria and mean eGFR was 76·9 mL/min per 1·73 m2 (SD 22·7). During a median follow-up of 5·4 years (IQR 5·1-5·9) comprising 51 820 person-years, the renal outcome developed in 848 (17·1%) participants at an incidence rate of 3·5 per 100 person-years in the dulaglutide group and in 970 (19·6%) participants at an incidence rate of 4·1 per 100 person-years in the placebo group (hazard ratio [HR] 0·85, 95% CI 0·77-0·93; p=0·0004). The clearest effect was for new macroalbuminuria (HR 0·77, 95% CI 0·68-0·87; p<0·0001), with HRs of 0·89 (0·78-1·01; p=0·066) for sustained decline in eGFR of 30% or more and 0·75 (0·39-1·44; p=0·39) for chronic renal replacement therapy. Long-term use of dulaglutide was associated with reduced composite renal outcomes in people with type 2 diabetes. Eli Lilly and Company.

Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial

Three different glucagon-like peptide-1 (GLP-1) receptor agonists reduce cardiovascular outcomes in people with type 2 diabetes at high cardiovascular risk with high glycated haemoglobin A1c (HbA1c) concentrations. We assessed the effect of the GLP-1 receptor agonist dulaglutide on major adverse cardiovascular events when added to the existing antihyperglycaemic regimens of individuals with type 2 diabetes with and without previous cardiovascular disease and a wide range of glycaemic control. This multicentre, randomised, double-blind, placebo-controlled trial was done at 371 sites in 24 countries. Men and women aged at least 50 years with type 2 diabetes who had either a previous cardiovascular event or cardiovascular risk factors were randomly assigned (1:1) to either weekly subcutaneous injection of dulaglutide (1·5 mg) or placebo. Randomisation was done by a computer-generated random code with stratification by site. All investigators and participants were masked to treatment assignment. Participants were followed up at least every 6 months for incident cardiovascular and other serious clinical outcomes. The primary outcome was the first occurrence of the composite endpoint of non-fatal myocardial infarction, non-fatal stroke, or death from cardiovascular causes (including unknown causes), which was assessed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01394952. Between Aug 18, 2011, and Aug 14, 2013, 9901 participants (mean age 66·2 years [SD 6·5], median HbA1c 7·2% [IQR 6·6-8·1], 4589 [46·3%] women) were enrolled and randomly assigned to receive dulaglutide (n=4949) or placebo (n=4952). During a median follow-up of 5·4 years (IQR 5·1-5·9), the primary composite outcome occurred in 594 (12·0%) participants at an incidence rate of 2·4 per 100 person-years in the dulaglutide group and in 663 (13·4%) participants at an incidence rate of 2·7 per 100 person-years in the placebo group (hazard ratio [HR] 0·88, 95% CI 0·79-0·99; p=0·026). All-cause mortality did not differ between groups (536 [10·8%] in the dulaglutide group vs 592 [12·0%] in the placebo group; HR 0·90, 95% CI 0·80-1·01; p=0·067). 2347 (47·4%) participants assigned to dulaglutide reported a gastrointestinal adverse event during follow-up compared with 1687 (34·1%) participants assigned to placebo (p<0·0001). Dulaglutide could be considered for the management of glycaemic control in middle-aged and older people with type 2 diabetes with either previous cardiovascular disease or cardiovascular risk factors. Eli Lilly and Company.

The beneficial effects of iron supplementation other than improvement of anemia

Previous randomized controlled trials (RCTs) have shown beneficial effects of iron supplementation other than anemia improvement including treatment of restless leg syndrome and general fatigue, even in non-anemic subjects with iron deficiency. Recently, some RCTs in congestive heart failure (CHF) demonstrated that intravenous administration of ferric carboxymaltose improves patient symptoms and reduces incidence of hospitalization for worsening heart failure. Consequently, the European Society of Cardiology recommends that iron deficient patients with CHF are administered ferric carboxymaltose (evidence level A). Moreover, the PIVOTAL study for hemodialysis patients proved that proactive administration of iron sucrose decreases the dose of erythropoiesis-stimulating agents and frequency of transfusion compared with its sole administration in reaction to iron deficiency. Notably, this proactive treatment is superior to a low-dose regimen in preventing the primary composite endpoints of nonfatal myocardial infarction, stroke, hospitalization for CHF, and death. These clinical findings are supported by basic research on cardiomyocyte-specific transferrin receptor knock-out mice showing heart failure with impaired mitochondrial respiratory function. In this model, cardiac iron deficiency impairs the mitochondrial electron transport chain, thus leading to low adenosine triphosphate production, and it subsequently prevents mitophagy resulting in damaged mitochondrial accumulation in the heart.

Prevalence, management, and outcomes of familial hypercholesterolemia in patients with acute coronary syndromes in the Arabian Gulf

Information on the epidemiology of familial hypercholesterolemia (FH) in the Arabian Gulf region, which has an elevated rate of consanguinity and type II diabetes, is scarce. To assess the prevalence of FH, its management, and impact on atherosclerotic cardiovascular disease (ASCVD) outcomes in a multicenter cohort of Arabian Gulf patients with acute coronary syndrome (ACS). Patients (N=3224) hospitalized with ACS were studied. FH was diagnosed using the Dutch Lipid Clinic Network criteria. A composite endpoint of nonfatal myocardial infarction, stroke, transient ischemic attack, and mortality between the "probable/definite" and the "unlikely" FH patients was assessed after 1year. Analyses were performed using univariate and multivariate statistical techniques. At admission, the proportion of "probable/definite", "possible", and "unlikely" FH in ACS patients was 3.7% (n=119), 28% (n=911), and 68% (n=2194), respectively. Overall, 54% (n=1730) of patients had diabetes, whereas 24% (n=783) were current smokers. The "probable/definite" FH group was younger (50 vs 63years; P<.001), had a greater prevalence of early coronary disease (38% vs 8.8%; P<.001), and previous statin use (87% vs 57%; P<.001) when compared with the "unlikely" FH group. After 1year, the "probable/definite" FH cohort had worse lipid control (13% vs 23%; P<.001) and presented with a greater association with the composite ASCVD endpoint when compared with the "unlikely" FH group (odds ratio: 1.85; 95% confidence interval: 1.01-3.38; P=.047) after multivariable adjustment. In Arabian Gulf citizens, FH was common in ACS patients, was undertreated, and was associated with a worse 1-year prognosis.

Status Epilepticus and Subsequent Epilepsy

Two glucagon-like peptide-1 (GLP-1) receptor agonists reduced renal outcomes in people with type 2 diabetes at risk for cardiovascular disease. We assessed the long-term effect of the GLP-1 receptor agonist dulaglutide on renal outcomes in an exploratory analysis of the REWIND trial of the effect of dulaglutide on cardiovascular disease.REWIND was a multicentre, randomised, double-blind, placebo-controlled trial at 371 sites in 24 countries. Men and women aged at least 50 years with type 2 diabetes who had either a previous cardiovascular event or cardiovascular risk factors were randomly assigned (1:1) to either weekly subcutaneous injection of dulaglutide (1·5 mg) or placebo and followed up at least every 6 months for outcomes. Urinary albumin-to-creatinine ratios (UACRs) and estimated glomerular filtration rates (eGFRs) were estimated from urine and serum values measured in local laboratories every 12 months. The primary outcome (first occurrence of the composite endpoint of non-fatal myocardial infarction, non-fatal stroke, or death from cardiovascular causes), secondary outcomes (including a composite microvascular outcome), and safety outcomes of this trial have been reported elsewhere. In this exploratory analysis, we investigate the renal component of the composite microvascular outcome, defined as the first occurrence of new macroalbuminuria (UACR >33·9 mg/mmol), a sustained decline in eGFR of 30% or more from baseline, or chronic renal replacement therapy. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01394952.Between Aug 18, 2011, and Aug 14, 2013, 9901 participants were enrolled and randomly assigned to receive dulaglutide (n=4949) or placebo (n=4952). At baseline, 791 (7·9%) had macroalbuminuria and mean eGFR was 76·9 mL/min per 1·73 m2 (SD 22·7). During a median follow-up of 5·4 years (IQR 5·1–5·9) comprising 51 820 person-years, the renal outcome developed in 848 (17·1%) participants at an incidence rate of 3·5 per 100 person-years in the dulaglutide group and in 970 (19·6%) participants at an incidence rate of 4·1 per 100 person-years in the placebo group (hazard ratio [HR] 0·85, 95% CI 0·77–0·93; p=0·0004). The clearest effect was for new macroalbuminuria (HR 0·77, 95% CI 0·68–0·87; p<0·0001), with HRs of 0·89 (0·78–1·01; p=0·066) for sustained decline in eGFR of 30% or more and 0·75 (0·39–1·44; p=0·39) for chronic renal replacement therapy.Long-term use of dulaglutide was associated with reduced composite renal outcomes in people with type 2 diabetes.Eli Lilly and Company.

Protocol of the Febuxostat versus Allopurinol Streamlined Trial (FAST): a large prospective, randomised, open, blinded endpoint study comparing the cardiovascular safety of allopurinol and febuxostat in the management of symptomatic hyperuricaemia

IntroductionGout affects 2.5% of the UK's adult population and is now the most common type of inflammatory arthritis. The long-term management of gout requires reduction of serum urate levels and...

Methodology of a large prospective, randomised, open, blinded endpoint streamlined safety study of celecoxib versus traditional non-steroidal anti-inflammatory drugs in patients with osteoarthritis or rheumatoid arthritis: protocol of the standard care versus celecoxib outcome trial (SCOT)

IntroductionCyclooxygenase 2 (COX-2) inhibitors have less upper gastrointestinal toxicity than traditional non-steroidal anti-inflammatory drugs (NSAIDs). However, both COX-2 inhibitors and traditional NSAIDs may be associated with adverse cardiovascular side effects....

No accord for the ACCORD-Lipid trial results

No accord for the ACCORD-Lipid trial results

Effects of oral glucose-lowering drugs on long term outcomes in patients with diabetes mellitus following myocardial infarction not treated with emergent percutaneous coronary intervention - a retrospective nationwide cohort study

BackgroundThe optimum oral pharmacological treatment of diabetes mellitus to reduce cardiovascular disease and mortality following myocardial infarction has not been established. We therefore set out to investigate the association between individual oral glucose-lowering drugs and cardiovascular outcomes following myocardial infarction in patients with diabetes mellitus not treated with emergent percutaneous coronary intervention.Materials and methodsAll patients aged 30 years or older receiving glucose-lowering drugs (GLDs) and admitted with myocardial infarction (MI) not treated with emergent percutaneous coronary intervention in Denmark during 1997-2006 were identified by individual-level linkage of nationwide registries of hospitalizations and drug dispensing from pharmacies. Multivariable Cox regression models adjusted for age, sex, calendar year, comorbidity, and concomitant pharmacotherapy were used to assess differences in the composite endpoint of non-fatal MI and cardiovascular mortality between individual GLDs, using metformin monotherapy as reference.ResultsThe study comprised 9876 users of GLDs admitted with MI. The mean age was 72.3 years and 56.5% of patients were men. A total of 3649 received sulfonylureas and 711 received metformin at admission. The average length of follow-up was 2.2 (SD 2.6) years. A total of 6,171 patients experienced the composite study endpoint. The sulfonylureas glibenclamide, glimepiride, glipizide, and tolbutamide were associated with increased risk of cardiovascular mortality and/or nonfatal MI with hazard ratios [HRs] of 1.31 (95% confidence interval [CI] 1.17-1.46), 1.19 (1.06-1.32), 1.25 (1.11-1.42), and 1.18 (1.03-1.34), respectively, compared with metformin. Gliclazide was the only sulfonylurea not associated with increased risk compared with metformin (HR 1.03 [0.88-1.22]).ConclusionsIn patients with diabetes mellitus admitted with MI not treated with emergent percutaneous coronary intervention, monotherapy treatment with the sulfonylureas glibenclamide, glimepiride, glipizide, and tolbutamide was associated with increased cardiovascular risk compared with metformin monotherapy.

The Jupiter study, CRP screening, and aggressive statin therapy-implications for the primary prevention of cardiovascular disease

CRP levels are strong, independent predictors of cardiovascular risk and can enhance risk stratification. Jupiter enrolled 17 802 apparently healthy middle-aged men and women with CRP levels over 2.0 mg/l, and LDL less than 130 mg/dl. They were randomized to receive rosuvastatin 20 mg daily or placebo, and followed for a primary endpoint of nonfatal myocardial infarction, stroke, arterial revascularization, hospitalization for unstable angina, or cardiovascular death for 1.9 years. Rosuvastatin lowered CRP (37%), LDL (50%), nonfatal myocardial infarction (55%), nonfatal stroke (48%), hospitalization and revascularization (47%), all-cause mortality (20%), and benefited women and minority subgroups. Rosuvastatin was tolerated relatively well, with a small rise in physician-reported diabetes. Jupiter data suggest that patients with high levels of CRP should receive statins. Approximately 4.3% of the population satisfies Jupiter inclusion criteria. A review of the assessment of cardiovascular risk is under way at the National Institutes of Health to guide practitioners.

The Effect of Pioglitazone on Recurrent Myocardial Infarction in 2,445 Patients With Type 2 Diabetes and Previous Myocardial Infarction: Results From the PROactive (PROactive 05) Study

This analysis from the PROactive (PROspective pioglitAzone Clinical Trial In macroVascular Events) study assesses the effects of pioglitazone on mortality and macrovascular morbidity in patients with type 2 diabetes and a previous myocardial infarction (MI). People with type 2 diabetes have an increased incidence of MI compared with the general population. Those with diabetes and MI have a worse prognosis than nondiabetic patients with cardiovascular disease. The PROactive study was a prospective, multicenter, double-blind, placebo-controlled trial of 5,238 patients with type 2 diabetes and macrovascular disease. Patients were randomized to either pioglitazone or placebo in addition to their other glucose-lowering and cardiovascular medication. Treatment of diabetes, dyslipidemia, and hypertension was encouraged according to the International Diabetes Federation guidelines. Patients were followed for a mean of 2.85 years. The primary end point was the time to first occurrence of macrovascular events or death. Of the total cohort, the subgroup of patients who had a previous MI (n = 2,445 [46.7%]; n = 1,230 in the pioglitazone group and n = 1,215 in the placebo group) was evaluated using prespecified and post-hoc analyses. Pioglitazone had a statistically significant beneficial effect on the prespecified end point of fatal and nonfatal MI (28% risk reduction [RR]; p = 0.045) and acute coronary syndrome (ACS) (37% RR; p = 0.035). There was a 19% RR in the cardiac composite end point of nonfatal MI (excluding silent MI), coronary revascularization, ACS, and cardiac death (p = 0.033). The difference in the primary end point defined in the main PROactive study did not reach significance in the MI population (12% RR; p = 0.135). The rates of heart failure requiring hospitalization were 7.5% (92 of 1,230) with pioglitazone and 5.2% (63 of 1,215) with placebo. Fatal heart failure rates were similar (1.4% [17 of the 92] with pioglitazone versus 0.9% [11 of the 63] with placebo). In high-risk patients with type 2 diabetes and previous MI, pioglitazone significantly reduced the occurrence of fatal and nonfatal MI and ACS. (PROspective pioglitAzone Clinical Trial In macroVascular Events; http://www.clinicaltrials.gov/ct/show/NCT00174993?order = 1; ISRCTN NCT00174993).