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Swedberg K.,Gothenburg University | Komajda M.,University Pierre and Marie Curie | Bohm M.,Universitatskliniken des Saarlandes | Borer J.S.,New York University | And 4 more authors.
The Lancet | Year: 2010

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. © 2010 Elsevier Ltd. Source


Yatham L.N.,University of British Columbia | Vieta E.,University of Barcelona | Goodwin G.M.,University of Oxford | Bourin M.,University of Nantes | And 3 more authors.
British Journal of Psychiatry | Year: 2016

Background Adjunctive antidepressant therapy is commonly used to treat acute bipolar depression but few studies have examined this strategy. Aims To examine the efficacy of agomelatine v. placebo as adjuncts to lithium or valproate in bipolar depression. Method Patients who were currently depressed despite taking lithium or valproate for at least 6 weeks were randomised to treatment with agomelatine (n = 172) or placebo (n = 172) for 8 weeks of acute therapy and 44 weeks of continuation therapy (trial registration: ISRCTN28588282). Results No significant differences in improvement of depressive symptoms were observed between the two groups either at 8 weeks or 52 weeks on the primary efficacy measure of change in Montgomery-Aes sberg Depression Rating Scale scores from baseline to end-point. Adverse events including switches into mania/hypomania were low and similar in both groups. Conclusions Agomelatine adjunctive therapy was not superior to placebo adjunctive therapy for acute bipolar depression. © The Royal College of Psychiatrists 2016. Source


Bohm M.,Universitatsklinikum des Saarlandes | Swedberg K.,Gothenburg University | Komajda M.,University Pierre and Marie Curie | Borer J.S.,New York University | And 4 more authors.
The Lancet | Year: 2010

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. © 2010 Elsevier Ltd. Source


Canet E.,Institute Of Recherches Internationales Servier Iris | Lerebours G.,Institute Of Recherches Internationales Servier Iris | Vilaine J.-P.,Institute Of Recherches Servier Idrs
Annals of the New York Academy of Sciences | Year: 2011

The link between elevated heart rate and cardiovascular events is established in healthy individuals and in patients with cardiovascular disease. The new agent, ivabradine, specifically and selectively inhibits the I f current, with the sole action of heart rate reduction, with no impact on any other cardiac parameters. The benefits of "pure" heart rate reduction with ivabradine have been the focus of one of the largest clinical development programs ever performed, involving >20,000 individuals. Ivabradine has anti-ischemic and antianginal efficacy in monotherapy, as well as in combination with other antianginals, such as beta-blockers, and is safe and well tolerated. Two major morbidity-mortality trials, BEAUTIFUL and SHIFT, showed that heart rate reduction with ivabradine dramatically improves prognosis in patients with coronary artery disease and left ventricular dysfunction, symptomatic angina, or chronic heart failure. The development of ivabradine represents a clear innovation in the management of cardiovascular disease. © 2011 New York Academy of Sciences. Source


Corruble E.,University Paris - Sud | De Bodinat C.,Institute Of Recherches Internationales Servier Iris | Belaidi C.,Institute Of Recherches Internationales Servier Iris | Goodwin G.M.,University of Oxford
International Journal of Neuropsychopharmacology | Year: 2013

Abstract In the present randomized, controlled, double-blind trial (12 wk treatment plus double-blind extension for 12 wk), 25-50 mg/d agomelatine (n = 164) and 10-20 mg/d escitalopram (n = 160) were compared for short- and long-term efficacy, subjective sleep and tolerability. The effects of these drugs on emotional experiences were also compared in patients having completed the Oxford Questionnaire on the Emotional Side-Effects of Antidepressants (agomelatine: n = 25; escitalopram: n = 20). Agomelatine and escitalopram similarly improved depressive symptoms, with clinically relevant score changes over 12 and 24 wk and notable percentage of remitters (week 12: 60.9 and 54.4%; week 24: 69.6 and 63.1% respectively). Over the 12 and 24-wk treatment periods, the 'global satisfaction on sleep' scores increased in both treatment groups and did not differ between groups. Satisfaction with sleep-wake quality was high in both groups; the 'wellness feeling on waking' was more improved with agomelatine than with escitalopram (p = 0.02). In patients with pronounced sleep complaints, quality of sleep and feeling on waking were significantly more improved with agomelatine than with escitalopram (p = 0.016 and p = 0.009, respectively). Emotional blunting was less frequent on agomelatine than on escitalopram. Indeed, 28% of patients on agomelatine vs. 60% on escitalopram felt that their emotions lacked intensity and 16% of patients on agomelatine vs. 53% on escitalopram felt that things that they cared about before illness did not seem important any more (p = 0.024). The tolerability profile of agomelatine was found to be superior to that of escitalopram and the incidence of patients with at least one emergent adverse event leading to treatment discontinuation was lower in the agomelatine group than in the escitalopram group (5.5 vs. 10.6%). The findings suggest that agomelatine displays additional long-term clinical benefits on sleep-wake quality and emotional experiences over escitalopram in the management of depression. © CINP 2013. Source

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