Efficacy and Safety of Ticagrelor Monotherapy by Clinical Presentation: Pre-Specified Analysis of the GLOBAL LEADERS Trial.

Background The optimal duration of dual antiplatelet therapy after coronary drug-eluting stent placement in adults with stable coronary artery disease (SCAD) versus acute coronary syndromes (ACS) remains uncertain. Methods and Results This was a prespecified subgroup analysis of the GLOBAL LEADERS trial. Participants were randomly assigned 1:1 to the experimental or reference strategy, stratified by ACS (experimental, n=3750; reference, n=3737) versus SCAD (experimental, n=4230; reference, n=4251). The experimental strategy was 75 to 100 mg aspirin daily plus 90 mg ticagrelor twice daily for 1 month, followed by 23 months of ticagrelor monotherapy. The reference strategy was 75 to 100 mg aspirin daily plus either 75 mg clopidogrel daily (for SCAD) or 90 mg ticagrelor twice daily (for ACS) for 12 months, followed by aspirin monotherapy for 12 months. The primary end point at 2 years was a composite of all-cause mortality or non-fatal centrally adjudicated new Q-wave myocardial infarction. The key secondary safety end point was site-reported Bleeding Academic Research Consortium grade 3 or 5 bleeding. The primary end point occurred in 147 (3.92%) versus 169 (4.52%) patients with ACS (rate ratio [RR], 0.86; 95% CI, 0.69-1.08; P=0.189), and in 157 (3.71%) versus 180 (4.23%) patients with SCAD (RR, 0.87; 95% CI, 0.71-1.08; P=0.221) with experimental and reference strategy, respectively (P-interaction=0.926). Bleeding Academic Research Consortium grade 3 or 5 bleeding occurred in 73 (1.95%) versus 100 (2.68%) patients with ACS (RR, 0.73; 95% CI, 0.54-0.98; P=0.037), and in 90 (2.13%) versus 69 (1.62%) patients with SCAD (RR, 1.32; 95% CI, 0.97-1.81; P=0.081; P-interaction=0.007). Conclusions While there was no evidence for differences in efficacy between treatment strategies by subgroup, the experimental strategy appeared to reduce bleeding risk in patients with ACS but not in patients with SCAD. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01813435.

The impact of beta-adrenoreceptor gene polymorphisms on survival in patients with congestive heart failure.

OBJECTIVE: Discordant results have been published regarding a possible association between beta-adrenoreceptor (betaAR) gene polymorphisms and survival in patients with congestive heart failure (CHF). The aim of the study was to analyze the impact of five functional betaAR gene polymorphisms in patients with stable CHF. METHODS: We prospectively studied 444 consecutive patients with CHF related to left ventricular systolic dysfunction. The beta1ARSer49Gly, beta1ARGly389Arg, beta2AR Arg16Gly, beta2AR Gln27Glu and beta2AR Thr164Ile polymorphisms were determined. Patients underwent echocardiography, radionuclide angiography and a cardiopulmonary exercise test. RESULTS: Mean age was 56.6+/-11.9 years old, left ventricular ejection fraction (LVEF) was 32+/-12%, and peak VO2 was 15.5+/-4.9 ml/min/kg or 63+/-18% of maximal predicted VO2. Most of the patients (95%) were receiving angiotensin converting enzyme inhibitors and 91% beta-blockers. There was no statistically significant differences between baseline characteristics among beta1AR and beta2AR genotypes. During a median follow-up period of 1232 days, there were 110 cardiac-related deaths and five urgent transplantations. Independent predictors of survival were percent (%) of maximal predicted VO2 (p<0.0001), age (p<0.0001), LVEF (p=0.004), creatinine (p=0.02) and atrial fibrillation (p=0.04). No betaAR polymorphisms were associated with survival. However, patients with the combined beta2ARGly16Gly/beta2ARGln27Gln genotype, who express receptors highly sensitive to down-regulation, had a significantly lower survival rate than patients with other genotypes but only in univariate analysis. CONCLUSIONS: In this prospective study, we found no association between five functional betaAR polymorphisms and survival in patients with stable CHF. However, we demonstrated, only in univariate analysis, a possible association between the combined beta2ARGly16Gly/beta2ARGln27Gln genotype and survival.

Is hormonal activation during exercise useful for risk stratification in patients with moderate congestive heart failure?

BACKGROUND: We previously demonstrated that A-type natriuretic peptide (ANP) at peak exercise was an independent predictor of cardiac survival. No data are available concerning the predictive value of B-type natriuretic peptide (BNP) at peak exercise. METHODS: One hundred and fifty consecutive stable patients with moderate congestive heart failure (CHF) underwent echocardiography and a cardiopulmonary exercise test. Blood samples were drawn at rest and at peak exercise for the determination of plasma levels of ANP, BNP, and norepinephrine. RESULTS: Exercise significantly increased plasma values of ANP, BNP, and norepinephrine. After a median follow-up period of 1171 days, there were 35 cardiac related deaths. Mortality rates at 1 and 2 years were 4% and 8%, respectively. Independent predictors of cardiac survival were percent of maximal predicted oxygen consumption (RR = 4.8 [2.1-11], P =.002), BNP at rest (RR = 2.5 [1.2-5.6], P =.01), and left atrial diameter (RR = 2.8 [1.2-6.5], P =.02). CONCLUSIONS: In patients with stable, moderate CHF, plasma levels of ANP, BNP, and norepinephrine measured at peak exercise did not improve risk stratification. However, in addition to percent of maximal predicted oxygen consumption and left atrial diameter, plasma level of BNP at rest was an independent predictor of survival in CHF patients with low risk of cardiac events.

Influence of diabetes mellitus on heart failure risk and outcome.

Our aim is to summarize and discuss the recent literature linking diabetes mellitus with heart failure, and to address the issue of the optimal treatment for diabetic patients with heart failure. THE STUDIES LINKING DIABETES MELLITUS (DM) WITH HEART FAILURE (HF) : The prevalence of diabetes mellitus in heart failure populations is close to 20% compared with 4 to 6% in control populations. Epidemiological studies have demonstrated an increased risk of heart failure in diabetics; moreover, in diabetic populations, poor glycemic control has been associated with an increased risk of heart failure. Various mechanisms may link diabetes mellitus to heart failure: firstly, associated comorbidities such as hypertension may play a role; secondly, diabetes accelerates the development of coronary atherosclerosis; thirdly, experimental and clinical studies support the existence of a specific diabetic cardiomyopathy related to microangiopathy, metabolic factors or myocardial fibrosis. Subgroup analyses of randomized trials demonstrate that diabetes is also an important prognostic factor in heart failure. In addition, it has been suggested that the deleterious impact of diabetes may be especially marked in patients with ischemic cardiomyopathy. TREATMENT OF HEART FAILURE IN DIABETIC PATIENTS : The knowledge of the diabetic status may help to define the optimal therapeutic strategy for heart failure patients. Cornerstone treatments such as ACE inhibitors or beta-blockers appear to be uniformly beneficial in diabetic and non diabetic populations. However, in ischemic cardiomyopathy, the choice of the revascularization technique may differ according to diabetic status. Finally, clinical studies are needed to determine whether improved metabolic control might favorably influence the outcome of diabetic heart failure patients.

Aspirin does not adversely affect survival in patients with stable congestive heart failure treated with Angiotensin-converting enzyme inhibitors.

BACKGROUND: Experimental studies and retrospective analyses of mortality trials with angiotensin-converting enzyme inhibitors (ACE-Is) have suggested that aspirin may reduce the beneficial effect of these drugs. The aim of this study was to assess a possible detrimental effect of aspirin on survival in stable patients with left ventricular systolic dysfunction who had congestive heart failure and had been treated with ACE-Is. METHODS AND RESULTS: We performed a retrospective analysis in 755 consecutive stable patients with left ventricular systolic dysfunction. A Cox regression model was used to select independent predictors of survival and to test for a possible interaction between aspirin and ACE-Is with an adjustment to differences in clinical characteristics in subgroups of patients. Of the 755 patients, 328 (43.4%) had proven ischemic cardiomyopathy, 693 patients (91.8%) were receiving ACE-Is, and 317 patients were receiving aspirin (mean [+/- SD] dose, 183 +/- 65 mg/d; 74% of the patients receiving < or = 200 mg/d). During a median follow-up period of 1,996 days, there were 273 cardiac-related deaths, 14 urgent transplantations, 71 nonurgent transplantations, and 46 noncardiac-related deaths, and 3 patients were lost to follow-up. The cardiovascular mortality rates were 11.5% and 19.0%, respectively, at 1 and 2 years. There were no interactions among aspirin, ACE-Is, and survival in the overall population (p = 0.21), or in subgroups of patients with ischemic cardiomyopathy (p = 0.41) or with nonischemic cardiomyopathy (p = 0.74). CONCLUSIONS: In this population of stable patients with left ventricular systolic dysfunction, our retrospective analysis did not demonstrate any interaction between the use of aspirin and survival in patients receiving ACE-Is.

Geometrical validation of intravascular ultrasound radiofrequency data analysis (Virtual Histology) acquired with a 30 MHz boston scientific corporation imaging catheter.

Recently, the plaque characterization field was explored with the use of the substrate (frequency domain analysis) rather than the envelope (amplitude or gray-scale imaging) of the intravascular ultrasound (IVUS) radiofrequency data. However, there is no data about the agreement of quantitative outcome between the two methods. The aim of this study was to assess the correlation and agreement between quantitative coronary ultrasound and the geometrical measurements provided by the spectral analysis of ultrasound radiofrequency data [IVUS-Virtual Histology (IVUS-VH), Volcano Therapeutics). Twenty-five patients were included in this study. The IVUS catheter used was a commercially available mechanical sector scanner (Ultracross 2.9 Fr 30 MHz catheter, Boston Scientific) covered with an outer sheath. IVUS-VH significantly underestimated lumen [relative difference (RD)=14.8+/-5.6; P<0.001], vessel (RD=14.1+/-4.8; P<0.001), and plaque (RD=11.5+/-10.8; P<0.001) cross-sectional areas (CSAs). Nevertheless, when adjusted for the ultrasound propagation delay caused by the sheath, relative differences of measurements were remarkably low (0.49%+/-6.3%, P=0.64 for lumen; 2.33%+/-4.6%, P=0.007 for vessel; and 4.2%+/-10.4%, P=0.005 for plaque CSA). These data suggest that the volumetric output of the IVUS-VH software underestimates measurements when acquired with a 30 MHz catheter. However, after applying a mathematical adjustment method for the ultrasound propagation delay caused by the outer sheath of the 30 MHz catheter, relative differences of direct measurements were negligible. These results suggest that ultrasound radiofrequency data analysis could provide, aside from precise compositional data, an accurate geometrical output.

In vivo intravascular ultrasound-derived thin-cap fibroatheroma detection using ultrasound radiofrequency data analysis.

OBJECTIVES: The purpose of this study was to assess the prevalence of intravascular ultrasound (IVUS)-derived thin-cap fibroatheroma (IDTCFA) and its relationship with the clinical presentation using spectral analysis of IVUS radiofrequency data (IVUS-Virtual Histology [IVUS-VH]). BACKGROUND: Thin-cap fibroatheroma lesions are the most prevalent substrate of plaque rupture. METHODS: In 55 patients, a non-culprit, non-obstructive (<50%) lesion was investigated with IVUS-VH. We classified IDTCFA lesions as focal, necrotic core-rich (> or =10% of the cross-sectional area) plaques being in contact with the lumen; IDTCFA definition required a percent atheroma volume (PAV) > or =40%. RESULTS: Acute coronary syndrome (ACS) (n = 23) patients presented a significantly higher prevalence of IDTCFA than stable (n = 32) patients (3.0 [interquartile range (IQR) 0.0 to 5.0] vs. 1.0 [IQR 0.0 to 2.8], p = 0.018). No relation was found between patient's characteristics such as gender (p = 0.917), diabetes (p = 0.217), smoking (p = 0.904), hypercholesterolemia (p = 0.663), hypertension (p = 0.251), or family history of coronary heart disease (p = 0.136) and the presence of IDTCFA. A clear clustering pattern was seen along the coronaries, with 35 (35.4%), 31 (31.3%), 19 (19.2%), and 14 (14.1%) IDTCFAs in the first 10 mm, 11 to 20 mm, 21 to 30 mm, and > or =31 mm segments, respectively, p = 0.008. Finally, we compared the severity (mean PAV 56.9 +/- 7.4 vs. 54.8 +/- 6.0, p = 0.343) and the composition (mean percent necrotic core 19.7 +/- 4.1 vs. 18.1 +/- 3.0, p = 0.205) of IDTCFAs between stable and ACS patients, and no significant differences were found. CONCLUSIONS: In this in vivo study, IVUS-VH identified IDTCFA as a more prevalent finding in ACS than in stable angina patients.

Association between beta-1 and beta-2 adrenergic receptor gene polymorphisms and the response to beta-blockade in patients with stable congestive heart failure.

Previous studies have clearly demonstrated the beneficial effect of beta-blockers in patients with stable congestive heart failure (CHF). beta-blockers improve left ventricular ejection fraction (LVEF) and reduce cardiac mortality. However, there is an interindividual variability in the response to these agents. Two studies have suggested a possible impact of some functional betaAR gene polymorphisms on the effects of beta-blockade. The objective of the study is to analyse the association between genetic variations in the beta1 or the beta2 adrenoreceptor (AR) gene and the effects of beta-blockade in patients with stable CHF. We studied 199 consecutive patients with stable CHF not treated with beta-blockers. Before introduction of beta-blockers and 3 months after the maximal tolerated dose was reached, patients underwent an echocardiography and a radionuclide angiography. The beta1ARGly389Arg, beta1ARSer49Gly, beta2ARGly16Arg, beta2ARGln27Glu and beta2ARThr164Ile polymorphisms were determined: beta-blockade resulted in a significant decrease in heart rate, a significant increase in LVEF (from 30+/-10% to 40+/-13%, P<0.0001). There was no association between the five polymorphisms and heart rate or LVEF, either before or after beta-blockade. Heart rate and LVEF responses to beta-blockade were not associated with the beta1AR or the beta2AR polymorphisms. betaAR polymorphisms did not explain the interindividual variability in the response to beta-blockers.