Characteristics and outcomes in patients with a prior myocardial infarction treated with extended dual antiplatelet therapy with ticagrelor 60 mg: findings from ALETHEIA, a multi-country observational study.

BACKGROUND: Guidelines recommend extended dual antiplatelet therapy, including ticagrelor 60 mg twice daily, in high-risk post-myocardial infarction (MI) patients who have tolerated 12 months and are not at high bleeding risk. The real-world utilization and bleeding and ischaemic outcomes associated with long-term ticagrelor 60 mg in routine clinical practice have not been well described. METHODS: Register and claims data from the USA (Optum Clinformatics, IBM MarketScan, and Medicare) and Europe (Sweden, Italy, UK, and Germany) were extracted. Patients initiating ticagrelor 60 mg ≥12 months after MI, meeting eligibility criteria for the PEGASUS-TIMI (Prevention of Cardiovascular Events in Patients with Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin - Thrombolysis in Myocardial Infarction 45) 54 trial, were included. The cumulative incidence of the composite of MI, stroke, or all-cause mortality and that of bleeding requiring hospitalization were calculated. Meta-analyses were performed to combine estimates from each source. RESULTS: A total of 7035 patients treated with ticagrelor 60 mg met eligibility criteria. Median age was 67 years and 29% were females; 12% had a history of multiple MIs. The majority (95%) had been treated with ticagrelor 90 mg prior to initiating ticagrelor 60 mg. At 12 months from initiation of ticagrelor 60 mg, the cumulative incidence [95% confidence interval (CI)] of MI, stroke, or mortality was 3.33% (2.73-4.04) and was approximately three-fold the risk of bleeding (0.96%; 0.69-1.33). CONCLUSIONS: This study provides insights into the use of ticagrelor 60 mg in patients with prior MI in clinical practice. Observed event rates for ischaemic events and bleeding generally align with those in the pivotal trials, support the established safety profile of ticagrelor, and highlight the significant residual ischaemic risk in this population.Clinical Trials.gov Registration NCT04568083.

Arterial hypertension in patients with atrial fibrillation in Europe: A report from the EURObservational Research Programme pilot survey on atrial fibrillation.

BACKGROUND: Hypertension (HTN) is the most prevalent co-morbidity among atrial fibrillation (AF) patients; the relationship between the two is bidirectional, with an incremental effect on adverse outcomes. PURPOSE: To study clinical features, treatment patterns and 1year outcomes amongst AF patients with HTN in the EURObservational Research Programme Atrial Fibrillation (EORP-AF) Pilot Registry, a prospective multi-national survey conducted by the European Society of Cardiology in 9 European countries. METHODS: Of 3119 enrolled AF patients, 2194 were diagnosed with HTN (AF-HTN) and 909 were normotensive (AF-NT) (16 patients had unknown HTN status). We compared baseline clinical features, management strategy and 1-year outcomes in terms of all-cause death, cardiovascular (CV) death, and any thrombosis-related event (TE: stroke, transient ischemic attack, acute coronary syndrome, coronary intervention, cardiac arrest, peripheral/pulmonary embolism) in AF-HTN vs AF-NT patients. RESULTS: The AF-HTN patients had more prevalent CV risk factors and comorbidities (median CHA2DS2-VASc score (IQR) 4 (3, 5) in AF-HTN, versus 2 (1, 3) in AF-NT; p<0.01). Crude rate of all-cause death and any TE event was higher in AF-HTN (194 (11.2%) versus 60 (8.2%), p=0.02). Kaplan-Meier analysis curves for death by hypertensive status showed no significant differences between the subgroups (log rank test, p=0.22). On logistic regression analysis, HTN did not emerge as an independent risk factor for outcomes (OR 1.08, 95% CI 0.76-1.54). CONCLUSION: AF-HTN patients have a higher prevalence of comorbidities and this conferred a higher risk for a composite endpoint of all-cause death and thromboembolic events. In this cohort HTN did not independently predict all-cause mortality at 1-year.

Adherence to alendronic or risedronic acid treatment, combined or not to calcium and vitamin D, and related determinants in Italian patients with osteoporosis.

PURPOSE: Osteoporosis is a chronic disease and an important health and social burden due to its worldwide prevalence. Literature and clinical experience report incomplete adherence to the therapy. This retrospective observational study aimed at assessing the adherence to first-line antiosteoporosis drugs (AODs; reimbursed by the National Health System, according to the Italian Medicine Agency recommendation number 79), alendronate or risedronate, with or without calcium and/or vitamin D supplements, in a real, Italian clinical setting. PATIENTS AND METHODS: Analyses were carried out on data present in the ARNO Observatory, a population-based patient-centric Italian database. From a population of 5,808,832 inhabitants with available data, a cohort of 3.3 million of patients aged ≥40 years was selected. New users of first-line AODs as monotherapy (accrual period, 2007-2009) were followed up over 3 years to assess adherence at 6, 12, and 36 months to AODs and to supplements and related determinants. RESULTS: Approximately 40,000 new users were identified: mostly women, aged on average (standard deviation) 71±10 years. Alendronate was the most prescribed (38.2% of patients), followed by risedronate (34.9%) and alendronate with colecalciferol as a fixed-dose combination (25.8%). Adherence at the 6-month follow-up was 54%, and this constantly and significantly decreased after 1 year to 46%, and after 3 years to 33% (P<0.01). Adherence to the fixed-dose combination was higher than to plain alendronate throughout the follow-up period. Similarly, adherence to supplements constantly decreased with the duration of treatment. Women and patients aged >50 years were more likely to adhere to treatment regimen (P<0.001). The use of drugs for peptic ulcer and gastroesophageal reflux disease and of corticosteroids for systemic use were significantly associated with high adherence at different times. Polytherapy (>5 drugs), cardiovascular, and neurological therapies were significantly associated with low adherence throughout the follow-up period. CONCLUSION: In a huge clinical practice sample, this study highlights suboptimal adherence to first-line AODs and to supplements and important determinants, such as concomitant therapies.

Prognostic significance of anaemia in patients with heart failure with preserved and reduced ejection fraction: results from the MAGGIC individual patient data meta-analysis.

BACKGROUND: Anaemia is common among patients with heart failure (HF) and is an important prognostic marker. AIM: We sought to determine the prognostic importance of anaemia in a large multinational pooled dataset of prospectively enrolled HF patients, with the specific aim to determine the prognostic role of anaemia in HF with preserved and reduced ejection fraction (HF-PEF and HF-REF, respectively). DESIGN: Individual person data meta-analysis. METHODS: Patients with haemoglobin (Hb) data from the MAGGIC dataset were used. Anaemia was defined as Hb < 120 g/l in women and <130 g/l in men. HF-PEF was defined as EF ≥ 50%; HF-REF was EF < 50%. Cox proportional hazard modelling, with adjustment for clinically relevant variables, was undertaken to investigate factors associated with 3-year all-cause mortality. RESULTS: Thirteen thousand two hundred and ninety-five patients with HF from 19 studies (9887 with HF-REF and 3408 with HF-PEF). The prevalence of anaemia was similar among those with HF-REF and HF-PEF (42.8 and 41.6% respectively). Compared with patients with normal Hb values, those with anaemia were older, were more likely to have diabetes, ischaemic aetiology, New York Heart Association class IV symptoms, lower estimated glomerular filtration rate and were more likely to be taking diuretic and less likely to be taking a beta-blocker. Patients with anaemia had higher all-cause mortality (adjusted hazard ratio [aHR] 1.38, 95% confidence interval [CI] 1.25-1.51), independent of EF group: aHR 1.67 (1.39-1.99) in HF-PEF and aHR 2.49 (2.13-2.90) in HF-REF. CONCLUSIONS: Anaemia is an adverse prognostic factor in HF irrespective of EF. The prognostic importance of anaemia was greatest in patients with HF-REF.

Changes in body weight and pulse: outcome events in overweight and obese subjects with cardiovascular disease in the SCOUT trial.

BACKGROUND/OBJECTIVES: The Sibutramine Cardiovascular OUTcomes (SCOUT) trial showed a significantly increased relative risk of nonfatal cardiovascular events, but not mortality, in overweight and obese subjects receiving long-term sibutramine treatment with diet and exercise. We examined the relationship between early changes (both increases and decreases) in pulse rate, and the impact of these changes on subsequent cardiovascular outcome events in both the placebo and sibutramine groups. SUBJECTS/METHODS: 9804 males and females, aged ⩾55 years, with a body mass index of 27-45 kg m(-)(2) were included in this current subanalysis of the SCOUT trial. Subjects were required to have a history of cardiovascular disease and/or type 2 diabetes mellitus with at least one cardiovascular risk factor, to assess cardiovascular outcomes. The primary outcome event (POE) was a composite of nonfatal myocardial infarction, nonfatal stroke, resuscitated cardiac arrest or cardiovascular death. Time-to-event analyses of the POE were performed using Cox regression models. RESULTS: During the initial 6-week sibutramine treatment period, the induced pulse rate increase was related to weight change (1.9±7.7 beats per minute (bpm) with weight increase; 1.4±7.3 bpm, 0-5 kg weight loss; 0.6±7.4 bpm, ⩾5 kg weight loss). Throughout the subsequent treatment period, those continuing on sibutramine showed a consistently higher mean pulse rate than the placebo group. There was no difference in POE rates with either an increase or decrease in pulse rate over the lead-in period, or during lead-in baseline to 12 months post randomization. There was also no relationship between pulse rate at lead-in baseline and subsequent cardiovascular events in subjects with or without a cardiac arrhythmia. CONCLUSION: Baseline pulse rate and changes in pulse rate may not be an important modifier nor a clinically useful predictor of outcome in an individual elderly cardiovascular obese subject exposed to weight management.

Addition of either pioglitazone or a sulfonylurea in type 2 diabetic patients inadequately controlled with metformin alone: impact on cardiovascular events. A randomized controlled trial.

BACKGROUND AND AIMS: Metformin is the first-line therapy in type 2 diabetes. In patients inadequately controlled with metformin, the addition of a sulfonylurea or pioglitazone are equally plausible options to improve glycemic control. However, these drugs have profound differences in their mechanism of action, side effects, and impact on cardiovascular risk factors. A formal comparison of these two therapies in terms of cardiovascular morbidity and mortality is lacking. The TOSCA.IT study was designed to explore the effects of adding pioglitazone or a sulfonylurea on cardiovascular events in type 2 diabetic patients inadequately controlled with metformin. METHODS: Multicentre, randomized, open label, parallel group trial of 48 month duration. Type 2 diabetic subjects, 50-75 years, BMI 20-45 Kg/m(2), on secondary failure to metformin monotherapy will be randomized to add-on a sulfonylurea or pioglitazone. The primary efficacy outcome is a composite endpoint of all-cause mortality, nonfatal myocardial infarction, nonfatal stroke, and unplanned coronary revascularization. Principal secondary outcome is a composite ischemic endpoint of sudden death, fatal and non-fatal myocardial infarction and stroke, endovascular or surgical intervention on the coronary, leg or carotid arteries, major amputations. Side effects, quality of life and economic costs will also be evaluated. Efficacy, safety, tolerability, and study conduct will be monitored by an independent Data Safety Monitoring Board. End points will be adjudicated by an independent external committee. CONCLUSIONS: TOSCA.IT is the first on-going study investigating the head-to-head comparison of adding a sulfonylurea or pioglitazone to existing metformin treatment in terms of hard cardiovascular outcomes. REGISTRATION: Clinicaltrials.gov ID NCT00700856.

Relationship between HbA1c levels and risk of cardiovascular adverse outcomes and all-cause mortality in overweight and obese cardiovascular high-risk women and men with type 2 diabetes.

AIMS/HYPOTHESIS: The optimal HbA(1c) concentration for prevention of macrovascular complications and deaths in obese cardiovascular high-risk patients with type 2 diabetes remains to be established and was therefore studied in this post hoc analysis of the Sibutramine Cardiovascular OUTcomes (SCOUT) trial, which enrolled overweight and obese patients with type 2 diabetes and/or cardiovascular disease. METHODS: HRs for meeting the primary endpoint (nonfatal myocardial infarction, nonfatal stroke, resuscitated cardiac arrest or cardiovascular death) and all-cause mortality were analysed using Cox regression models. RESULTS: Of 8,252 patients with type 2 diabetes included in SCOUT, 7,479 had measurements of HbA(1c) available at baseline (i.e. study randomisation). Median age was 62 years (range 51-86 years), median BMI was 34.0 kg/m(2) (24.8-65.1 kg/m(2)) and 44% were women. The median HbA(1c) concentration was 7.2% (3.8-15.9%) (55 mmol/l [18-150 mmol/l]) and median diabetes duration was 7 years (0-57 years). For each 1 percentage point HbA(1c) increase, the adjusted HR for the primary endpoint was 1.17 (95% CI 1.11, 1.23); no differential sex effect was observed (p = 0.12 for interaction). In contrast, the risk of all-cause mortality was found to be greater in women than in men: HR 1.22 (1.10, 1.34) vs 1.12 (1.04, 1.20) for each 1 percentage point HbA(1c) increase (p = 0.02 for interaction). There was no evidence of increased risk associated with HbA(1c) ≤ 6.4% (≤ 46 mmol/l). Glucose-lowering treatment regimens, diabetes duration or a history of cardiovascular disease did not modify the associations. CONCLUSIONS/INTERPRETATION: In overweight, cardiovascular high-risk patients with type 2 diabetes, increasing HbA(1c) concentrations were associated with increasing risks of cardiovascular adverse outcomes and all-cause mortality.

Prognostic significance of serum uric acid in outpatients with chronic heart failure is complex and related to body mass index: data from the IN-CHF Registry.

BACKGROUND AND AIMS: In the field of cardiovascular diseases, elevated levels of serum uric acid (UA) reflect a marked activation of the xanthine oxidase pathway with increase in free radicals production; it is often associated with an inflammatory state, oxygen consumption and endothelial dysfunction. All these associations have been also confirmed in heart failure (HF) but the pathophysiological role of UA in this setting is not well understood. The aim of this study was to evaluate the prognostic role of UA in outpatients enrolled in the Italian Registry of Congestive Heart Failure (IN-CHF). METHODS AND RESULTS: All patients met the European Society of Cardiology (ESC) criteria for diagnosis of HF. We considered patients with complete clinical data and UA level available at the baseline and at 1-year follow-up. The study population was composed of 877 patients aged 63 ± 12 years. One-year mortality was 10.8% and dead patients had a higher level of UA than survivors (7.1 mg dl⁻¹ vs 6.6 mg dl⁻¹, p < 0.0207). In multivariable full model of analysis, UA did not result in an independent predictor of death in overall population, but only in patients with low body mass index (BMI) (≤22 kg m⁻²) (hazard ratio (HR): 2.38, 95% confidence interval (CI) 1.36-4.18). In this subgroup, a statistically significant gradual relationship between UA and survival was detected starting from values higher than 8 mg dl⁻¹. CONCLUSION: Elevated level of UA is not an independent predictor of mortality in chronic HF, but it markedly worsens outcome if associated with low level of BMI. This association is likely an indicator of chronic inflammatory and catabolic state.

Maintained intentional weight loss reduces cardiovascular outcomes: results from the Sibutramine Cardiovascular OUTcomes (SCOUT) trial.

AIM: The Sibutramine Cardiovascular OUTcomes trial showed that sibutramine produced greater mean weight loss than placebo but increased cardiovascular morbidity but not mortality. The relationship between 12-month weight loss and subsequent cardiovascular outcomes is explored. METHODS: Overweight/obese subjects (N = 10 744), ≥55 years with cardiovascular disease and/or type 2 diabetes mellitus, received sibutramine plus weight management during a 6-week Lead-in Period before randomization to continue sibutramine (N = 4906) or to receive placebo (N = 4898). The primary endpoint was the time from randomization to first occurrence of a primary outcome event (non-fatal myocardial infarction, non-fatal stroke, resuscitated cardiac arrest or cardiovascular death). RESULTS: For the total population, mean weight change during Lead-in Period (sibutramine) was -2.54 kg. Post-randomization, mean total weight change to Month 12 was -4.18 kg (sibutramine) or -1.87 kg (placebo). Degree of weight loss during Lead-in Period or through Month 12 was associated with a progressive reduction in risk for the total population in primary outcome events and cardiovascular mortality over the 5-year assessment. Although more events occurred in the randomized sibutramine group, on an average, a modest weight loss of approximately 3 kg achieved in the Lead-in Period appeared to offset this increased event rate. Moderate weight loss (3-10 kg) reduced cardiovascular deaths in those with severe, moderate or mild cardiovascular disease. CONCLUSIONS: Modest weight loss over short-term (6 weeks) and longer-term (6-12 months) periods is associated with reduction in subsequent cardiovascular mortality for the following 4-5 years even in those with pre-existing cardiovascular disease. While the sibutramine group experienced more primary outcome events than the placebo group, greater weight loss reduced overall risk of these occurring in both groups.

Effect of canrenone on left ventricular mechanics in patients with mild systolic heart failure and metabolic syndrome: the AREA-in-CHF study.

BACKGROUND AND AIM: We analyzed the effect of the mineralocorticoid receptor antagonist canrenone on LV mechanics in patients with or without metabolic syndrome (MetS) and compensated (Class II NYHA) heart failure (HF) with reduced ejection fraction (EF≤45%) on optimal therapy (including ACE-i or ARB, and ß-blockers). METHODS AND RESULTS: From a randomized, double-blind placebo-controlled trial (AREA-in-CHF), patients with (73 on canrenone [Can] and 77 on placebo [Pla]), based on modified ATPIII definition (BMI≥30kg/m(2) instead of waist girth) or without MetS (146 by arm). In addition to traditional echocardiographic parameters, we also evaluated myocardial mechano-energetic efficiency (MME) based on a previously reported method. At baseline, Can and Pla did not differ in age, BMI, blood pressure (BP), metabolic profile, BNP, and PIIINP. Compared with MetS-Pla, and controlling for age, sex and diabetes, at the final control MetS-Can exhibited increased MME, preserved E/A ratio, and decreased atrial dimensions (0.04

Circulating cardiovascular biomarkers in recurrent atrial fibrillation: data from the GISSI-atrial fibrillation trial.

OBJECTIVE: we evaluated the prognostic role of circulating cardiovascular biomarkers in patients with a history of recent atrial fibrillation (AF). BACKGROUND: predicting long-term maintenance of sinus rhythm in patients with AF is difficult. METHODS: plasma concentrations of three specific cardiac markers [high-sensitivity troponin T (hsTnT), N-terminal probrain natriuretic peptide (NT-proBNP) and mid-regional proatrial natriuretic peptide (MR-proANP)] and three stable fragments of vasoactive peptides [mid-regional proadrenomedullin (MR-proADM), copeptin (CT-proAVP) and CT-proendothelin-1 (CT-proET-1)] were measured at baseline and after 6 and 12 months in 382 patients enrolled in the GISSI-AF study, a prospective randomized trial to determine the effect of valsartan to reduce the recurrence of AF. The association between these markers, clinical characteristics and recurrence of AF was tested by univariate and multivariate Cox models. RESULTS: mean patient age was 68 ± 9 years (37.2% females). A total of 84.8% of patients had a history of hypertension. In total, 59.7% qualified for history of AF because of successful cardioversion, 11.8% because of two or more episodes of AF in the 6 months preceding randomization and 28.5% because of both. Patients in AF at 6 or 12 months (203 (53.1%) with first recurrence) had significantly higher concentrations of most biomarkers. Despite low baseline levels, higher concentrations of hsTnT {adjusted hazard ratio (HR) [95% confidence intervals (CIs) for 1 SD increment] (1.15 [1.04-1.28], P = 0.007), MR-proANP (1.15 [1.01-1.30], P = 0.04), NT-proBNP (1.24 [1.11-1.39], P = 0.0001) and CT-proET-1 (1.16 [1.01-1.33], P = 0.03) independently predicted higher risk of a first recurrence of AF. Changes over time of MR-proANP tended to predict subsequent recurrence (adjusted HR [95%CI]) (1.53 [0.98-2.37], P = 0.06). CONCLUSION: circulating markers of cardiomyocyte injury/strain and endothelin are related to recurrence of AF in patients in sinus rhythm with a history of recent AF.

Weight and blood pressure response to weight management and sibutramine in diabetic and non-diabetic high-risk patients: an analysis from the 6-week lead-in period of the sibutramine cardiovascular outcomes (SCOUT) trial.

OBJECTIVE: To assess treatment responses to sibutramine and weight management in diabetic patients during the lead-in period of the Sibutramine Cardiovascular OUTcomes (SCOUT) trial. METHODS: SCOUT is an ongoing, prospective, randomized, double-blind, placebo-controlled outcome trial in cardiovascular high-risk overweight/obese patients. A total of 10 742 patients received single-blind sibutramine and individualized weight management during the 6-week lead-in period; 84% had a history of type 2 diabetes mellitus and additional co-morbidities. Post-hoc analyses assessed anthropomorphic and vital sign responses between patients with and without diabetes. RESULTS: Concomitant antidiabetic medication use was reported by 86% of the diabetic patients (approximately 30% required insulin-alone or in combination). Body weight and waist circumference decreased in diabetic patients: median 2.1 kg; 2.0 cm (both men and women); for those on insulin: 1.9 kg; 1.5/2.0 cm (men/women); without insulin: 2.3 kg; 2.0 cm (both men and women); blood pressure (BP) was also reduced (median systolic/diastolic 3.5/1.0 mmHg) with larger reductions in diabetic patients who were hypertensive and/or lost the most weight (>5%). In diabetic patients who entered with BP at target (<130/<85 mmHg) but did not lose weight (N = 245), increases of 3.5/2.0 mmHg were observed. Non-diabetic patients had greater weight losses (2.5 kg) but smaller reductions in BP (systolic/diastolic -2.5/-0.5 mmHg). Pulse rate increases were less in diabetic vs. non-diabetic patients (1.5 vs. 2.0 bpm). CONCLUSION: In these high-risk diabetic patients, sibutramine and lifestyle modifications for 6 weeks resulted in small, but clinically relevant, median reductions in body weight, waist circumference and BP. A small median increase in pulse rate was recorded.

Aldosterone status associated with insulin resistance in patients with heart failure--data from the ALOFT study.

BACKGROUND: Aldosterone has a key role in the pathophysiology of heart failure. In around 50% of such patients, aldosterone "escapes" from inhibition by drugs that interrupt the renin-angiotensin axis; such patients have a worse clinical outcome. Insulin resistance is a risk factor in heart failure and cardiovascular disease. The relation between aldosterone status and insulin sensitivity was investigated in a cohort of heart failure patients. METHODS: 302 patients with New York Heart Association (NYHA) class II-IV heart failure on conventional therapy were randomised in the ALiskiren Observation of heart Failure Treatment study (ALOFT), designed to test the safety of a directly acting renin inhibitor. Plasma aldosterone and 24-hour urinary aldosterone excretion, as well as fasting insulin and homeostasis model assessment of insulin resistance (HOMA-IR) were measured. Subjects with aldosterone escape and high urinary aldosterone were identified according to previously accepted definitions. RESULTS: 20% of subjects demonstrated aldosterone escape and 34% had high urinary aldosterone levels. At baseline, there was a positive correlation between fasting insulin and plasma (r = 0.22 p<0.01) and urinary aldosterone(r = 0.19 p<0.03). Aldosterone escape and high urinary aldosterone subjects both demonstrated higher levels of fasting insulin (p<0.008, p<0.03), HOMA-IR (p<0.06, p<0.03) and insulin-glucose ratios (p<0.006, p<0.06) when compared to low aldosterone counterparts. All associations remained significant when adjusted for potential confounders. CONCLUSIONS: This study demonstrates a novel direct relation between aldosterone status and insulin resistance in heart failure. This observation merits further study and may identify an additional mechanism that contributes to the adverse clinical outcome associated with aldosterone escape.

Blood pressure changes associated with sibutramine and weight management - an analysis from the 6-week lead-in period of the sibutramine cardiovascular outcomes trial (SCOUT).

OBJECTIVE: To explore vital sign changes among patient subgroups during the 6-week lead-in period of the sibutramine cardiovascular outcomes (SCOUT) trial. METHODS: SCOUT is an ongoing, double-blind, randomized, placebo-controlled outcome trial in overweight/obese patients at high risk of a cardiovascular event. During the 6-week lead-in period, 10,742 patients received sibutramine and weight management. Vital sign changes were assessed post hoc by initial blood pressure (mmHg) categorized as normal (<130/<85), high-normal (130 to <140/85 to <90) or hypertensive (>or=140/>or=90); weight change categories (weight gain/no weight change, >0 to 2.5% weight loss, >2.5 to 5% weight loss and >5% weight loss) and current antihypertensive medication class use (none, one, or two or more). To assess the impact of sibutramine on blood pressure and pulse rate, only patients (N = 10,025) who reported no change in the class of antihypertensive medication used and who did not report an increase in antihypertensive medication use were analysed. RESULTS: At entry, approximately 50% of patients were hypertensive and 26% were high-normal. In hypertensive patients, blood pressure changes (mmHg) decreased by median [5th, 95th percentile] of -6.5 systolic [-27.0, 8.0] and -2.0 diastolic [-15.0, 8.0] (p < 0.001). Hypertensive patients with no weight loss or with weight gain had median decreases of -3.5 systolic [-26.0, 10.0] and -1.5 diastolic [-16.0, 9.0] (p < 0.001). Normotensive patients had median increases of 1.5 systolic [-15.0, 19.5] and 1.0 diastolic [-10.5, 13.0] (p < 0.001) attenuated with increasing weight loss. Approximately 43% of patients initially categorized as hypertensive had a lower blood pressure category at end-point. Concomitant antihypertensive medication classes did not affect blood pressure reductions. Pulse rates were uniformly elevated (median 1-4 bpm, p < 0.001) across blood pressure and weight change categories. CONCLUSIONS: In hypertensive patients (>or=140/>or=90), blood pressure decreases were observed during 6-week treatment with sibutramine even when body weight was unchanged. In patients with normal blood pressure (<130/<85), weight loss of >5% induced decreases in systolic blood pressure; otherwise, small increases were observed. Small pulse rate increases were observed regardless of blood pressure or weight change status.

Right ventricular functional recovery after acute myocardial infarction: relation with left ventricular function and interventricular septum motion. GISSI-3 echo substudy.

OBJECTIVE: To evaluate the pattern of right ventricular (RV) functional recovery and its relation with left ventricular (LV) function and interventricular septal (IVS) motion in low risk patients after acute myocardial infarction (AMI). DESIGN AND SETTING: Multicentre clinical trial carried out in 47 Italian coronary care units. PATIENTS: 500 patients from the GISSI (Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico) -3 echo substudy, who underwent serial echocardiograms 24-48 hours after symptom onset and at discharge, six weeks, and six months after AMI. RESULTS: Tricuspid annular plane systolic excursion (TAPSE) increased significantly during follow up (mean (SD) 1.79 (0.46) cm at 24-48 hours to 1.92 (0.46) cm at six months, p < 0.001) and the increase was already significant at discharge (1.88 (0.47) cm, p < 0.001). LV ejection fraction (LVEF) was the best correlate of TAPSE at 24-48 hours (r = 0.15, p = 0.001). TAPSE increased significantly in patients both with reduced (< 45%) and with preserved (> or = 45%) LVEF, but the magnitude of increase was higher in patients with lower initial LVEF (p = 0.001). Improvement in IVS wall motion score index (IVS-WMSI) was the only independent predictor of TAPSE changes during follow up (r = -0.12, p = 0.007). CONCLUSIONS: In low risk patients after AMI, RV function recovered throughout six months of follow up and was already significant at discharge. TAPSE was significantly related to LVEF at 24-48 hours. The magnitude of RV functional recovery was higher in patients with lower initial LVEF. RV functional recovery is best related to IVS-WMSI improvement, suggesting that IVS motion has an important role in RV functional improvement in this setting.

Starc II, a multicenter randomized placebo-controlled double-blind clinical trial of trapidil for 1-year clinical events and angiographic restenosis reduction after coronary angioplasty and stenting.

The objective of this study was to investigate the effect of trapidil 200 mg t.i.d. in preventing the occurrence of death, of myocardial infarction and the need for repeat revascularization at 12 months after balloon PTCA with or without stenting. Coronary restenosis after stenting is still a major drawback of percutaneous coronary interventions (PCI) for 30-40% of patients. Trapidil has been shown to prevent restenosis after PTCA. Eligible patients were randomized to placebo or oral trapidil 200 mg t.i.d. at least 48 hr before PCI and continuing 6 months after a successful balloon angioplasty or stent implantation. Aspirin was given to all patients, and ticlopidine 250 mg b.i.d. to those who received a stent for 4 weeks. In a randomized subgroup of 216 patients, quantitative coronary angiography was performed also at 6-month follow-up. Out of the 933 patients enrolled, primary endpoint incidence was 20.3% in trapidil and 18.0% in placebo (P = 0.37). When recurrence or deterioration of angina was added to the combined endpoint, incidence was 27.4% in trapidil and 23.0% in placebo (P = 0.12). Restenosis rate in patients with 6-month angiography was 25.0% in trapidil arm vs. 30.1% in placebo (P = 0.43). Stent restenosis rate was similar in patients randomized to trapidil or placebo (30.2% vs. 23.8%, respectively; P = 0.44), while in patients treated with balloon angioplasty, it was lower in trapidil (17.1%) than in placebo (40.0%; P = 0.03). Oral trapidil 200 mg t.i.d. for 6 months in addition to aspirin did not influence the occurrence of major cardiac events after coronary angioplasty with or without stenting. In a prespecified subgroup of 191 patients treated with balloon angioplasty only, trapidil reduced angiographic restenosis.

Antiarrhythmic mechanisms of n-3 PUFA and the results of the GISSI-Prevenzione trial.

The purpose of this paper is twofold: on the one hand, to confirm the positive results on n-3 PUFA from the overall results Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico (GlSSI)-Prevenzione trial; on the other, to summarize and describe how the results of an important trial can help generate hypotheses either on mechanisms of action or on differential results in particular subgroups of patients, as well as test the pathophysiological hypotheses that have accompanied in the years the story of the hypothesized mechanisms of action of a drug. GISSI-Prevenzione was conceived as a pragmatic population trial on patients with recent myocardial infarction and it was conducted in the framework of the Italian public health system. In GISSI-Prevenzione, 11,323 patients were enrolled in a clinical trial aimed at testing the effectiveness of n-3 polyunsaturated fatty acids (PUFA) and vitamin E. Patients were invited to follow Mediterranean dietary habits, and were treated with up-to-date preventive pharmacological interventions. Long-term n-3 PUFA at 1 g daily, but not vitamin E at 300 mg daily, was beneficial for death and for combined death, non-fatal myocardial infarction, and stroke. All the benefit, however, was attributable to the decrease in risk for overall (-20%), cardiovascular (-30%), and sudden death (-45%). At variance from the orientation of a scientific scenario largely dominated by the "cholesterol-heart hypothesis", GISSI-Prevenzione results indicate n-3 PUFA (virtually devoid of any cholesterol-lowering effect) as a relevant pharmacological treatment for secondary prevention after myocardial infarction.

Treatment of chronic heart failure with beta adrenergic blockade beyond controlled clinical trials: the BRING-UP experience.

BACKGROUND: Several large controlled trials have shown that beta blockers given to patients with heart failure (New York Heart Association functional class II-IV) reduce morbidity and mortality. Despite these impressive results, implementing the use of beta blockade in clinical practice appears slow and difficult. The BRING-UP study was designed to tackle this problem. OBJECTIVES: To accelerate the adoption of beta blockade in clinical practice; to provide an epidemiological estimate of the proportion of patients with heart failure suitable for this treatment in general cardiology care; and to assess effectiveness of these drugs outside the setting of clinical trials. METHODS: The design of the study and recommendations derived from available evidence on the use of beta blockers were discussed with cardiologists during regional meetings. All consecutive heart failure patients in a one month period, whether treated or not with beta blockers, were eligible for the study. In each patient, the decision to prescribe a beta blocker was a free choice for the participating physicians. All centres were provided with carvedilol, metoprolol, and bisoprolol at appropriate doses; the choice of the drug and dosage was left to the responsible clinician. All patients were followed for one year. RESULTS: 197 cardiological centres enrolled 3091 patients, 24.9% of whom were already on beta blocker treatment at baseline. beta Blockers were newly prescribed in 32.7% of cases, more often in younger and less severely ill patients. The mean daily dose of the drugs used at one year corresponded to about 70% of the maximum dose used in clinical trials. Starting treatment with beta blockers did not affect the prescription or dosage of other recommended drugs. The overall rate of beta blocker treatment increased over the year of the study from 24.9% to 49.7%. During the 12 month period, 351 deaths occurred (11.8%). In multivariate analysis, the use of beta blockers was independently associated with a better prognosis, with a relative risk of 0.60 and a lower incidence of hospital admissions for worsening heart failure. CONCLUSIONS: The implementation of beta blockers in clinical practice is feasible and could be accelerated. These drugs are associated with a lower mortality and reduced hospital admission rates, not only in clinical trials but also in the normal clinical setting.