The management of chronic heart failure (HF) with low ejection fraction (EF) has changed considerably over the past 30 years: the introduction of angiotensin-converting enzyme inhibitors (ACEIs), ...β-blockers, angiotensin-receptor blockers, mineralocorticoid-receptor antagonists and recently, the Ifblocker, ivabradine, has led to a significant reduction in overall mortality and HF mortality. Recently, a trial testing a dual inhibitor blocking the angiotensin-II receptor and neprylisin, the enzyme responsible for B-type natriuretic peptide degradation, showed that this complex molecule improved clinical outcomes compared with the ACEI enalapril. However, challenges remain in the management of HF, with suboptimal implementation of guideline-recommended therapies, a changing profile of patients who are older and have multiple comorbidities and a high rate of early rehospitalization for HF. Use of devices such as implantable cardiac defibrillators and cardiac resynchronization therapy are also associated with an improvement in outcomes in this condition. HF with preserved EF (HFpEF), a growing fraction of the HF population, remains a clinical dilemma: no pharmacological intervention has so far demonstrated any convincing benefit on outcome. Heterogeneity of the populations tested, role of comorbidities, difficulties in identifying patients with HFpEF, as well as a mismatch between the clinical phenotypes and the treatments tested, can explain the failure to find beneficial interventions. Overall, the management of HF after discharge remains fragmented and concerted action by all professionals concerned is needed. (Circ J 2015; 79: 948–953)
Patients with diabetes and recent worsening heart failure that had led to hospitalization were randomly assigned to receive sotagliflozin or placebo. At a median of 9 months, the total number of ...deaths from cardiovascular causes and hospitalizations and urgent visits for heart failure was significantly lower with sotagliflozin than with placebo.
Summary Background Chronic heart failure is associated with high mortality and morbidity. Raised resting heart rate is a risk factor for adverse outcomes. We aimed to assess the effect of heart-rate ...reduction by the selective sinus-node inhibitor ivabradine on outcomes in heart failure. Methods Patients were eligible for participation in this randomised, double-blind, placebo-controlled, parallel-group study if they had symptomatic heart failure and a left-ventricular ejection fraction of 35% or lower, were in sinus rhythm with heart rate 70 beats per min or higher, had been admitted to hospital for heart failure within the previous year, and were on stable background treatment including a β blocker if tolerated. Patients were randomly assigned by computer-generated allocation schedule to ivabradine titrated to a maximum of 7·5 mg twice daily or matching placebo. Patients and investigators were masked to treatment allocation. The primary endpoint was the composite of cardiovascular death or hospital admission for worsening heart failure. Analysis was by intention to treat. This trial is registered, number ISRCTN70429960. Findings 6558 patients were randomly assigned to treatment groups (3268 ivabradine, 3290 placebo). Data were available for analysis for 3241 patients in the ivabradine group and 3264 patients allocated placebo. Median follow-up was 22·9 (IQR 18–28) months. 793 (24%) patients in the ivabradine group and 937 (29%) of those taking placebo had a primary endpoint event (HR 0·82, 95% CI 0·75–0·90, p<0·0001). The effects were driven mainly by hospital admissions for worsening heart failure (672 21% placebo vs 514 16% ivabradine; HR 0·74, 0·66–0·83; p<0·0001) and deaths due to heart failure (151 5% vs 113 3%; HR 0·74, 0·58–0·94, p=0·014). Fewer serious adverse events occurred in the ivabradine group (3388 events) than in the placebo group (3847; p=0·025). 150 (5%) of ivabradine patients had symptomatic bradycardia compared with 32 (1%) of the placebo group (p<0·0001). Visual side-effects (phosphenes) were reported by 89 (3%) of patients on ivabradine and 17 (1%) on placebo (p<0·0001). Interpretation Our results support the importance of heart-rate reduction with ivabradine for improvement of clinical outcomes in heart failure and confirm the important role of heart rate in the pathophysiology of this disorder. Funding Servier, France.
In this paper the Working Group on Myocardial and Pericardial Disease proposes a revised definition of dilated cardiomyopathy (DCM) in an attempt to bridge the gap between our recent understanding of ...the disease spectrum and its clinical presentation in relatives, which is key for early diagnosis and the institution of potential preventative measures. We also provide practical hints to identify subsets of the DCM syndrome where aetiology directed management has great clinical relevance.
Summary Background Raised resting heart rate is a marker of cardiovascular risk. We postulated that heart rate is also a risk factor for cardiovascular events in heart failure. In the SHIFT trial, ...patients with chronic heart failure were treated with the selective heart-rate-lowering agent ivabradine. We aimed to test our hypothesis by investigating the association between heart rate and events in this patient population. Methods We analysed cardiovascular outcomes in the placebo (n=3264) and ivabradine groups (n=3241) of this randomised trial, divided by quintiles of baseline heart rate in the placebo group. The primary composite endpoint was cardiovascular death or hospital admission for worsening heart failure. In the ivabradine group, heart rate achieved at 28 days was also analysed in relation to subsequent outcomes. Analysis adjusted to change in heart rate was used to study heart-rate reduction as mechanism for risk reduction by ivabradine directly. Findings In the placebo group, patients with the highest heart rates (≥87 beats per min bpm, n=682, 286 events) were at more than two-fold higher risk for the primary composite endpoint than were patients with the lowest heart rates (70 to <72 bpm, n=461, 92 events; hazard ratio HR 2·34, 95% CI 1·84–2·98, p<0·0001). Risk of primary composite endpoint events increased by 3% with every beat increase from baseline heart rate and 16% for every 5-bpm increase. In the ivabradine group, there was a direct association between heart rate achieved at 28 days and subsequent cardiac outcomes. Patients with heart rates lower than 60 bpm at 28 days on treatment had fewer primary composite endpoint events during the study (n=1192; event rate 17·4%, 95% CI 15·3–19·6) than did patients with higher heart rates. The effect of ivabradine is accounted for by heart-rate reduction, as shown by the neutralisation of the treatment effect after adjustment for change of heart rate at 28 days (HR 0·95, 0·85–1·06, p=0·352). Interpretation Our analysis confirms that high heart rate is a risk factor in heart failure. Selective lowering of heart rates with ivabradine improves cardiovascular outcomes. Heart rate is an important target for treatment of heart failure. Funding Servier, France.
Summary Background Rosiglitazone is an insulin sensitiser used in combination with metformin, a sulfonylurea, or both, for lowering blood glucose in people with type 2 diabetes. We assessed ...cardiovascular outcomes after addition of rosiglitazone to either metformin or sulfonylurea compared with the combination of the two over 5–7 years of follow-up. We also assessed comparative safety. Methods In a multicentre, open-label trial, 4447 patients with type 2 diabetes on metformin or sulfonylurea monotherapy with mean haemoglobin A1c (HbA1c ) of 7·9% were randomly assigned to addition of rosiglitazone (n=2220) or to a combination of metformin and sulfonylurea (active control group, n=2227). The primary endpoint was cardiovascular hospitalisation or cardiovascular death, with a hazard ratio (HR) non-inferiority margin of 1·20. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov , number NCT00379769. Findings 321 people in the rosiglitazone group and 323 in the active control group experienced the primary outcome during a mean 5·5-year follow-up, meeting the criterion of non-inferiority (HR 0·99, 95% CI 0·85–1·16). HR was 0·84 (0·59–1·18) for cardiovascular death, 1·14 (0·80–1·63) for myocardial infarction, and 0·72 (0·49–1·06) for stroke. Heart failure causing admission to hospital or death occurred in 61 people in the rosiglitazone group and 29 in the active control group (HR 2·10, 1·35–3·27, risk difference per 1000 person-years 2·6, 1·1–4·1). Upper and distal lower limb fracture rates were increased mainly in women randomly assigned to rosiglitazone. Mean HbA1c was lower in the rosiglitazone group than in the control group at 5 years. Interpretation Addition of rosiglitazone to glucose-lowering therapy in people with type 2 diabetes is confirmed to increase the risk of heart failure and of some fractures, mainly in women. Although the data are inconclusive about any possible effect on myocardial infarction, rosiglitazone does not increase the risk of overall cardiovascular morbidity or mortality compared with standard glucose-lowering drugs. Funding GlaxoSmithKline plc, UK.
This open-label, randomized, and multicentre trial tested the hypothesis that, on a background of aspirin, continuing clopidogrel would be superior to stopping clopidogrel at 12 months following ...drug-eluting stent (DES) implantation.
Patients (N = 1799) who had undergone placement of ≥1 DES for stable coronary artery disease or acute coronary syndrome were included in 58 French sites (January 2009-January 2013). Patients (N = 1385) free of major cardiovascular/cerebrovascular events or major bleeding and on aspirin and clopidogrel 12 months after stenting were eligible for randomization (1:1) between continuing clopidogrel 75 mg daily (extended-dual antiplatelet therapy, DAPT, group) or discontinuing clopidogrel (aspirin group). The primary outcome was net adverse clinical events defined as the composite of death, myocardial infarction, stroke, or major bleeding. Follow-up was planned from a minimum of 6 to a maximum of 36 months after randomization. Owing to slow recruitment, the study was stopped after enrolment of 1385 of a planned 1966 patients. Median follow-up after stenting was 33.4 months. The primary outcome occurred in 40 patients (5.8%) in the extended-DAPT group and 52 in the aspirin group (7.5%; hazard ratio 0.75, 95% confidence interval 0.50-1.28; P = 0.17). Rates of death were 2.3% in the extended-DAPT group and 3.5% in the aspirin group (HR 0.65, 95% CI 0.34-1.22; P = 0.18). Rates of major bleeding were identical (2.0%, P = 0.95).
Extended DAPT did not achieve superiority in reducing net adverse clinical events compared to 12 months of DAPT after DES placement. The power of the OPTIDUAL trial was however low and reduced by premature termination of enrolment.
NCT00822536.
Torcetrapib, a cholesteryl ester transfer protein inhibitor, markedly raises levels of high-density lipoprotein cholesterol. Unexpectedly, in the ILLUMINATE trial, torcetrapib therapy in combination ...with atorvastatin, as compared with atorvastatin alone, increased the risk of death from both cardiovascular and noncardiovascular causes. The drug also raised blood pressure.
Torcetrapib therapy in combination with atorvastatin, as compared with atorvastatin alone, increased the risk of death from both cardiovascular and noncardiovascular causes.
Evidence supporting the proposition that high-density lipoprotein (HDL) cholesterol should be considered as a therapeutic target includes experimental models of atherosclerosis,
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an inverse relationship to the risk of cardiovascular disease in humans,
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clinical trials of drugs for which raising HDL cholesterol levels is a primary pharmacologic effect,
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and the residual risk of cardiovascular disease associated with a low HDL cholesterol level after effective statin therapy.
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Cholesteryl ester transfer protein (CETP) promotes the transfer of cholesteryl esters from HDL to other lipoproteins; the inhibition of this protein raises HDL cholesterol levels and decreases low-density lipoprotein (LDL) cholesterol levels. There is evidence . . .
Objectives The study aimed to determine whether isolated heart rate (HR) reduction with ivabradine reduces afterload of patients with systolic heart failure. Background The effective arterial ...elastance (Ea) represents resistive and pulsatile afterload of the heart derived from the pressure volume relation. HR modulates Ea, and, therefore, afterload burden. Methods Among the patients with systolic heart failure (ejection fraction ≤35%) randomized to either placebo or ivabradine in the SHIFT (Systolic Heart Failure Treatment With the If Inhibitor Ivabradine Trial), 275 patients (n = 132, placebo; n = 143, ivabradine 7.5 mg twice a day) were included in the echocardiographic substudy. Ea, total arterial compliance (TAC), and end-systolic elastance (Ees) were calculated at baseline and after 8 months of treatment. Blood pressure was measured by arm cuff; stroke volume (SV), ejection fraction, and end-diastolic volume were assessed by echocardiography. Results At baseline Ea, TAC, HR, and Ees did not differ significantly between ivabradine- and placebo-treated patients. After 8 months of treatment, HR was significantly reduced in the ivabradine group (p < 0.0001) and was accompanied by marked reduction in Ea (p < 0.0001) and improved TAC (p = 0.004) compared with placebo. Although contractility remained unchanged, ventricular-arterial coupling was markedly improved (p = 0.002), resulting in a higher SV (p < 0.0001) in the ivabradine-treated patients. Conclusions Isolated HR reduction by ivabradine improves TAC, thus reducing Ea. Because Ees is unaltered, improved ventricular-arterial coupling is responsible for increased SV. Therefore, unloading of the heart may contribute to the beneficial effect of isolated HR reduction in patients with systolic heart failure. (Systolic Heart Failure Treatment With the If Inhibitor Ivabradine Trial SHIFT; ISRCTN70429960 )
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