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In this trial, over 19,000 patients with stable coronary artery disease were assigned to ivabradine (adjusted to achieve a target heart rate) or placebo. At 27 months, there was no between-group difference in the rate of death from cardiovascular causes or nonfatal MI. An elevated heart rate is established as a marker of cardiovascular risk in the general population and among patients with cardiovascular disease. 1 – 5 Ivabradine inhibits the I f (pacemaker) current in the sinoatrial node 6 and reduces the heart rate without affecting blood pressure or left ventricular systolic function. It has been shown to lessen symptoms and reduce ischemia in patients with stable angina pectoris. 7 , 8 Ivabradine is known to improve outcomes in patients with systolic heart failure. 9 A trial of ivabradine involving patients with coronary artery disease and left ventricular systolic dysfunction did not show clinical benefit, 10 but post hoc . . .

The optimum blood pressure target in hypertension remains debated, especially in coronary artery disease, given concerns for reduced myocardial perfusion if diastolic blood pressure is too low. We aimed to study the association between achieved blood pressure and cardiovascular outcomes in patients with coronary artery disease and hypertension. We analysed data from 22 672 patients with stable coronary artery disease enrolled (from Nov 26, 2009, to June 30, 2010) in the CLARIFY registry (including patients from 45 countries) and treated for hypertension. Systolic and diastolic blood pressures before each event were averaged and categorised into 10 mm Hg increments. The primary outcome was the composite of cardiovascular death, myocardial infarction, or stroke. Hazard ratios (HRs) were estimated with multivariable adjusted Cox proportional hazards models, using the 120–129 mm Hg systolic blood pressure and 70–79 mm Hg diastolic blood pressure subgroups as reference. After a median follow-up of 5·0 years, increased systolic blood pressure of 140 mm Hg or more and diastolic blood pressure of 80 mm Hg or more were each associated with increased risk of cardiovascular events. Systolic blood pressure of less than 120 mm Hg was also associated with increased risk for the primary outcome (adjusted HR 1·56, 95% CI 1·36–1·81). Likewise, diastolic blood pressure of less than 70 mm Hg was associated with an increase in the primary outcome (adjusted HR 1·41 [1·24–1·61] for diastolic blood pressure of 60–69 mm Hg and 2·01 [1·50–2·70] for diastolic blood pressure of less than 60 mm Hg). In patients with hypertension and coronary artery disease from routine clinical practice, systolic blood pressure of less than 120 mm Hg and diastolic blood pressure of less than 70 mm Hg were each associated with adverse cardiovascular outcomes, including mortality, supporting the existence of a J-curve phenomenon. This finding suggests that caution should be taken in the use of blood pressure-lowering treatment in patients with coronary artery disease. Servier.

The BEAUTIFUL study assessed the morbidity and mortality benefits of the heart rate-lowering agent ivabradine. The placebo arm of the BEAUTIFUL trial was a large cohort of patients with stable coronary artery disease and left-ventricular dysfunction. We did a subanalysis of this placebo group to test the hypothesis that elevated resting heart rate at baseline is a marker for subsequent cardiovascular death and morbidity. The association of baseline resting heart rate with cardiovascular outcomes was analysed using Cox proportional hazard models for groups with a heart rate of 70 beats per min (bpm) or greater (2693 patients) versus less than 70 bpm (2745 patients). Additional analyses were done with finer categorisation of heart rate, and with heart rate as a continuous variable. After adjustment for baseline characteristics, patients with heart rates of 70 bpm or greater had increased risk for cardiovascular death (34%, p=0·0041), admission to hospital for heart failure (53%, p<0·0001), admission to hospital for myocardial infarction (46%, p=0·0066), and coronary revascularisation (38%, p=0·037). For every increase of 5 bpm, there were increases in cardiovascular death (8%, p=0·0005), admission to hospital for heart failure (16%, p<0·0001), admission to hospital for myocardial infarction (7%, p=0·052), and coronary revascularisation (8%, p=0·034). The analysis of fine-groupings of heart rate suggests that the increase in mortality and heart failure outcomes rises continuously above 70 bpm, whereas the relation is less pronounced for coronary outcomes. For heart failure outcomes, the predictive value of resting heart rate was stronger for earlier events than for later events. In patients with coronary artery disease and left-ventricular systolic dysfunction, elevated heart rate (70 bpm or greater) identifies those at increased risk of cardiovascular outcomes, with a differential effect on outcomes associated with heart failure and outcomes associated with coronary events. Servier, France.

In this trial, patients with systolic heart failure and anemia were assigned to receive either darbepoetin alfa or placebo. At 28 months, there was no significant difference in the rate of death from any cause or hospitalization for worsening heart failure. Anemia is common in patients with heart failure, and patients with both heart failure and anemia have a lower functional capacity, worse quality of life, and higher rates of hospitalization and death 1 – 3 than those without anemia. 4 , 5 The cause of anemia in patients with heart failure is often unknown but may be related to an absolute or relative deficiency of, or resistance to, erythropoietin. Anemia in such patients is associated with impaired renal function, inflammation, and use of renin–angiotensin system blockers. 6 , 7 Small studies have suggested that increasing the hemoglobin level with the use of an erythropoiesis-stimulating agent (ESA) . . .

Dual antiplatelet therapy (DAPT), aspirin plus a P2Y12 inhibitor, is the standard antithrombotic treatment following acute coronary syndromes. The factor Xa inhibitor rivaroxaban reduced mortality and ischaemic events when added to DAPT, but caused increased bleeding. The safety of a dual pathway antithrombotic therapy approach combining low-dose rivaroxaban (in place of aspirin) with a P2Y12 inhibitor has not been assesssed in acute coronary syndromes. We aimed to assess rivaroxaban 2·5 mg twice daily versus aspirin 100 mg daily, in addition to clopidogrel or ticagrelor (chosen at investigator discretion before randomisation), for patients with acute coronary syndromes started within 10 days after presentation and continued for 6–12 months. In this double-blind, multicentre, randomised trial (GEMINI-ACS-1) done at 371 clinical centres in 21 countries, eligible patients were older than 18 years with unstable angina, non-ST segment elevation myocardial infarction (NSTEMI) or ST segment elevation myocardial infarction (STEMI), with positive cardiac biomarkers and either ischaemic electrocardiographic changes or an atherosclerotic culprit lesion identified during angiography. Participants were randomly assigned (1:1) within 10 days after admission for the index acute coronary syndromes event to either aspirin or rivaroxaban based on a computer-generated randomisation schedule. Randomisation was balanced by using randomly permuted blocks with size of four and was stratified based on the background P2Y12 inhibitor (clopidogrel or ticagrelor) intended to be used at the time of randomisation. Investigators and patients were masked to treatment assignment. Patients received a minimum of 180 days of double-blind treatment with rivaroxaban 2·5 mg twice daily or aspirin 100 mg daily. The choice of clopidogrel or ticagrelor during trial conduct was not randomised and was based on investigator preference. The primary endpoint was thrombolysis in myocardial infarction (TIMI) clinically significant bleeding not related to coronary artery bypass grafting (CABG; major, minor, or requiring medical attention) up to day 390. Primary analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT02293395. Between April 22, 2015, and Oct 14, 2016, 3037 patients with acute coronary syndromes were randomly assigned; 1518 to receive aspirin and 1519 to receive rivaroxaban. 1704 patients (56%) were in the ticagrelor and 1333 (44%) in the clopidogrel strata. Median duration of treatment was 291 days (IQR 239–354). TIMI non-CABG clinically significant bleeding was similar with rivaroxaban versus aspirin therapy (total 154 patients [5%]; 80 participants [5%] of 1519 vs 74 participants [5%] of 1518; HR 1·09 [95% CI 0·80–1·50]; p=0·5840). A dual pathway antithrombotic therapy approach combining low-dose rivaroxaban with a P2Y12 inhibitor for the treatment of patients with acute coronary syndromes had similar risk of clinically significant bleeding as aspirin and a P2Y12 inhibitor. A larger, adequately powered trial would be required to definitively assess the efficacy and safety of this approach. Janssen Research & Development and Bayer AG.

Vorapaxar inhibits platelet activation by antagonising thrombin-mediated activation of the protease-activated receptor 1 on human platelets. The effect of adding other antiplatelet drugs to aspirin for long-term secondary prevention of thrombotic events in stable patients with previous myocardial infarction is uncertain. We tested this effect in a subgroup of patients from the Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events (TRA 2°P)-TIMI 50 trial. In TRA 2°P-TIMI 50—a randomised, placebo-controlled, parallel trial—we randomly assigned patients with a history of atherothrombosis to receive vorapaxar (2·5 mg daily) or matching placebo in a 1:1 ratio. Patients, and those giving treatment, assessing outcomes, and analysing results were masked to treatment allocation. Patients with a qualifying myocardial infarction within the previous 2 weeks to 12 months were analysed as a pre-defined subgroup. The primary efficacy endpoint was cardiovascular death, myocardial infarction, or stroke, analysed by intention to treat. We analysed events by Kaplan-Meier analysis and compared groups with a Cox proportional hazard model. TRA 2°P-TIMI 50 is registered at ClinicalTrials.gov (NCT00526474). 17 779 of 26 449 patients had a qualifying myocardial infarction and were assigned treatment (8898 to vorapaxar and 8881 to placebo). Median follow-up was 2·5 years (IQR 2·0–2·9). Cardiovascular death, myocardial infarction, or stroke occurred in 610 of 8898 patients in the vorapaxar group and 750 of 8881 in the placebo group (3-year Kaplan-Meier estimates 8·1%vs 9·7%, HR 0·80, 95% CI 0·72–0·89; p<0·0001). Moderate or severe bleeding was more common in the vorapaxar group versus the placebo group (241/8880 [3·4%, 3-year Kaplan-Meier estimate] vs 151/8849 [2·1%, 3-year Kaplan-Meier estimate], HR 1·61, 95% CI 1·31–1·97; p<0·0001). Intracranial haemorrhage occurred in 43 of 8880 patients (0·6%, 3-year Kaplan-Meier estimate) with vorapaxar versus 28 of 8849 (0·4%, 3-year Kaplan-Meier estimate) with placebo (p=0·076). Other serious adverse events were equally distributed between groups. For patients with a history of myocardial infarction, inhibition of protease-activated receptor 1 with vorapaxar reduces the risk of cardiovascular death or ischaemic events when added to standard antiplatelet treatment, including aspirin, and increases the risk of moderate or severe bleeding. Merck.

Acute myocardial infarction (MI) patients remain at high risk for recurrent events. Cholesterol efflux, mediated by apolipoprotein A-I, removes excess cholesterol from atherosclerotic plaque and transports it to the liver for excretion. Impaired cholesterol efflux is associated with higher cardiovascular (CV) event rates among both patients with stable coronary artery disease and recent MI. CSL112, a novel intravenous formulation of apolipoprotein A-I (human) derived from human plasma, increases cholesterol efflux capacity. AEGIS-II is a phase 3, multicenter, double-blind, randomized, placebo-controlled, parallel-group trial investigating the efficacy and safety of CSL112 compared to placebo among high-risk acute MI participants. Eligibility criteria include age ≥ 18 years with type 1 (spontaneous) MI, evidence of multivessel stable coronary artery disease, and presence of diabetes requiring pharmacotherapy, or ≥2 of the following: age ≥ 65 years, prior MI, or peripheral artery disease. A target sample of 17,400 participants will be randomized 1:1 to receive 4 weekly infusions of CSL112 6 g or placebo, initiated prior to or on the day of discharge and within 5 days of first medical contact. The primary outcome is the time to first occurrence of the composite of CV death, MI, or stroke through 90 days. Key secondary outcomes include the total number of hospitalizations for coronary, cerebral, or peripheral ischemia through 90 days and time to first occurrence of the composite primary outcome through 180 and 365 days. AEGIS-II will be the first trial to formally test whether enhancing cholesterol efflux can reduce the rate of recurrent major adverse CV events.

Ivabradine specifically inhibits the I f current in the sinoatrial node to lower heart rate, without affecting other aspects of cardiac function. We aimed to test whether lowering the heart rate with ivabradine reduces cardiovascular death and morbidity in patients with coronary artery disease and left-ventricular systolic dysfunction. Between December, 2004, and December, 2006, we screened 12 473 patients at 781 centres in 33 countries. We enrolled 10 917 eligible patients who had coronary artery disease and a left-ventricular ejection fraction of less than 40% in a randomised, double-blind, placebo-controlled, parallel-group trial. 5479 patients received 5 mg ivabradine, with the intention of increasing to the target dose of 7·5 mg twice a day, and 5438 received matched placebo in addition to appropriate cardiovascular medication. The primary endpoint was a composite of cardiovascular death, admission to hospital for acute myocardial infarction, and admission to hospital for new onset or worsening heart failure. We analysed patients by intention to treat. The study is registered with ClinicalTrials.gov, number NCT00143507. Mean heart rate at baseline was 71·6 (SD 9·9) beats per minute (bpm). Median follow-up was 19 months (IQR 16–24). Ivabradine reduced heart rate by 6 bpm (SE 0·2) at 12 months, corrected for placebo. Most (87%) patients were receiving β blockers in addition to study drugs, and no safety concerns were identified. Ivabradine did not affect the primary composite endpoint (hazard ratio 1·00, 95% CI 0·91–1·1, p=0·94). 1233 (22·5%) patients in the ivabradine group had serious adverse events, compared with 1239 (22·8%) controls (p=0·70). In a prespecified subgroup of patients with heart rate of 70 bpm or greater, ivabradine treatment did not affect the primary composite outcome (hazard ratio 0·91, 95% CI 0·81–1·04, p=0·17), cardiovascular death, or admission to hospital for new-onset or worsening heart failure. However, it did reduce secondary endpoints: admission to hospital for fatal and non-fatal myocardial infarction (0·64, 95% CI 0·49–0·84, p=0·001) and coronary revascularisation (0·70, 95% CI 0·52–0·93, p=0·016). Reduction in heart rate with ivabradine does not improve cardiac outcomes in all patients with stable coronary artery disease and left-ventricular systolic dysfunction, but could be used to reduce the incidence of coronary artery disease outcomes in a subgroup of patients who have heart rates of 70 bpm or greater. Servier, France.

ObjectiveTo evaluate cardiovascular (CV) outcomes in outpatients with coronary artery disease (CAD) living alone compared with those living with others.MethodsThe prospeCtive observational LongitudinAl RegIstry oF patients with stable coronarY artery disease (CLARIFY) included outpatients with stable CAD. CLARIFY enrolled participants in 45 countries from November 2009 to July 2010, with 5 years of follow-up. Living arrangement was documented at baseline. The primary outcome was a composite of major adverse cardiovascular events (MACEs) defined as CV death, myocardial infarction (MI) and stroke.ResultsAmong 32 367 patients, 3648 patients were living alone (11.3%). After multivariate adjustment, there were no residual differences in MACE among patients living alone compared with those living with others (HR 1.04, 95% CI 0.92 to 1.18, p=0.52); however, there was significant heterogeneity in the exposure effect by sex (Pinteraction<0.01). Specifically, men living alone were at higher risk for MACE (HR 1.17, 95% CI 1.002 to 1.36, p=0.047) as opposed to women living alone (HR 0.82, 95% CI 0.65 to 1.04, p=0.1), predominantly driven by a heterogeneous effect by sex on MI (Pinteraction=0.006). There was no effect modification for MACE by age group (Pinteraction=0.3), although potential varying effects by age for MI (Pinteraction=0.046) and stroke (Pinteraction=0.05).ConclusionsLiving alone was not associated with an independent increase in MACE, although significant sex-based differences were apparent. Men living alone may have a worse prognosis from CV disease than women; further analyses are needed to elucidate the mechanisms underlying this difference.Trial registration numberISRCTN43070564.

Heart rate (HR) is an emerging risk factor in coronary artery disease (CAD). However, there is little contemporary data regarding HR and the use of HR-lowering medications, particularly beta-blockers, among patients with stable CAD in routine clinical practice. The goal of the present analysis was to describe HR in such patients, overall and in relation to beta-blocker use, and to describe the determinants of HR. CLARIFY is an international, prospective, observational, longitudinal registry of outpatients with stable CAD, defined as prior myocardial infarction or revascularization procedure, evidence of coronary stenosis of >50%, or chest pain associated with proven myocardial ischemia. A total of 33,438 patients from 45 countries in Europe, the Americas, Africa, Middle East, and Asia/Pacific were enrolled between November 2009 and July 2010. Most of the 33,177 patients included in this analysis were men (77.5%). Mean (SD) age was 64.2 (10.5) years, HR by pulse was 68.3 (10.6) bpm, and by electrocardiogram was 67.2 (11.4) bpm. Overall, 44.0% had HR ≥ 70 bpm. Beta-blockers were used in 75.1% of patients and another 14.4% had intolerance or contraindications to beta-blocker therapy. Among 24,910 patients on beta-blockers, 41.1% had HR ≥ 70 bpm. HR ≥ 70 bpm was independently associated with higher prevalence and severity of angina, more frequent evidence of myocardial ischemia, and lack of use of HR-lowering agents. Despite a high rate of use of beta-blockers, stable CAD patients often have resting HR ≥ 70 bpm, which was associated with an overall worse health status, more frequent angina and ischemia. Further HR lowering is possible in many patients with CAD. Whether it will improve symptoms and outcomes is being tested.