1. Background/Introduction 2. Primary Objective: 3. Secondary Objective: 4. Study Design: 5. Inclusion (Pros and Cons) 6. Exclusion (Pros and Cons) 7. Intervention and Comparation (Pros and Cons) 8. Primary Outcomes (Pros and Cons) 9. Secondary Outcomes (Pros and Cons) 10. Statistic Analysis (most important here) - (Pros and Cons) 11. Baseline Characteristics (Pros and Cons) 12. Primary endpoints (Pros and Cons) 13. Secondary endpoints (Pros and Cons) 14. Article's limitation (Pros and Cons) 15. Author's conclusion (Pros and Cons) 16. Discussion for study subject (Pros and Cons) 17. Discussion for methodology/design (Pros and Cons) 18. Statistic methods use (Pros and Cons) 19. Statistical vs. clinical significance (Pros and Cons) Articles Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study Karl Swedberg, Michel Komajda, Michael Bhm, Jerey S Borer, Ian Ford, Ariane Dubost-Brama, Guy Lerebours, Luigi Tavazzi, on behalf of the SHIFT Investigators* 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 eect 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 blocker if tolerated. Patients were randomly assigned by computer-generated allocation schedule to ivabradine titrated to a maximum of 75 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 229 (IQR 18-28) months. 793 (24%) patients in the ivabradine group and 937 (29%) of those taking placebo had a primary endpoint event (HR 082, 95% CI 075-090, p<00001). The eects were driven mainly by hospital admissions for worsening heart failure (672 [21%] placebo vs 514 [16%] ivabradine; HR 074, 066-083; p<00001) and deaths due to heart failure (151 [5%] vs 113 [3%]; HR 074, 058-094, p=0014). Fewer serious adverse events occurred in the ivabradine group (3388 events) than in the placebo group (3847; p=0025). 150 (5%) of ivabradine patients had symptomatic bradycardia compared with 32 (1%) of the placebo group (p<00001). Visual side-eects (phosphenes) were reported by 89 (3%) of patients on ivabradine and 17 (1%) on placebo (p<00001). Interpretation Our results support the importance of heart-rate reduction with ivabradine for improvement of clinical outcomes in heart failure and conrm the important role of heart rate in the pathophysiology of this disorder. Funding Servier, France. Introduction Chronic heart failure is common, disabling, and serious. It aects roughly 2-3% of the population in many industrialised countries.1 Even with existing treatment, which has substantially improved outcomes in the past two decades,2,3 prognosis is fairly poor. Development of novel therapeutic approaches for the treatment of this disorder is crucial. Standard pharmacological treatment includes blockers and renin-angiotensinaldosterone system (RAAS) antagonists.1 blockers have reduced morbidity and mortality beyond what is achieved with RAAS antagonists alone.4 Additional benets of these drugs in the management of chronic heart failure include improved left-ventricular remodelling5 and reduction in sudden deaths.6 These benets seem to be linked, at least in part, to their heart-rate-lowering properties.7,8 Heart-rate reduction could be particularly important in chronic heart failureeg, by attenuating the eect of energy starvation of the myocardium.9 However, in addition to their attenuating eect on heart rate, blockers have www.thelancet.com Vol 376 September 11, 2010 other undesired actions on the heart, including an eect on myocardial contractility. Raised resting heart rate is a risk factor for mortality and cardiovascular outcomes in epidemiological and observational studies.10,11 In patients with coronary artery disease and left-ventricular dysfunction, a heart rate of 70 beats per minute (bpm) or higher was associated with a 34% increased risk of cardiovascular death and a 53% increase in admission to hospital for heart failure compared with heart rate lower than 70 bpm.12 Heart rate is also directly related to risk of death, cardiovascular death, or admission to hospital in patients with heart failure,13 and heart-rate reduction is associated with improved outcomes.14 However, heart rate remains increased in most patients treated with blockers,15 which constitutes a further reason to seek new therapeutic strategies. Ivabradine is a specic inhibitor of the If current in the sinoatrial node.16 Results of studies in healthy hearts suggest that, at concentrations achieved during therapeutic use, ivabradine has no action on other Lancet 2010; 376: 875-85 Published Online August 29, 2010 DOI:10.1016/S01406736(10)61198-1 This online publication has been corrected. The corrected version rst appeared at thelancet.com on December 10, 2010. See Comment page 847 See Articles page 886 *Investigators listed at end of paper Department of Emergency and Cardiovascular Medicine, Sahlgrenska Academy, University of Gothenburg, Gteborg, Sweden (Prof K Swedberg MD); Department of Cardiology, University Pierre et Marie Curie Paris VI, La Piti-Salptrire Hospital, Paris, France (Prof M Komajda MD); Universittskliniken des Saarlandes, Klinik fr Innere Medizin III, Homburg/Saar, Germany (Prof M Bhm MD); Division of Cardiovascular Medicine and the Howard Gilman Institute for Heart Valve Disease, State University of New York Downstate Medical Center, Brooklyn and New York, NY, USA (Prof J S Borer MD); Robertson Centre for Biostatistics, University of Glasgow, Glasgow, UK (Prof I Ford PhD); Institut de Recherches Internationales Servier (IRIS), Courbevoie, France (A Dubost-Brama MD, G Lerebours MD); and Maria Cecilia HospitalGVM Care and Research, Ettore Sansavini Health Science Foundation, Cotignola, Italy (Prof L Tavazzi MD) Correspondence to: Prof Karl Swedberg, Department of Medicine, Sahlgrenska University Hospital/Ostra, SE-416 85 Gteborg, Sweden karl.swedberg@gu.se 875 Articles channels in the heart or vascular system. Unlike blockers, ivabradine does not modify myocardial contractility and intracardiac conduction, even in patients with impaired systolic function.17 We designed the Systolic Heart failure treatment with the If inhibitor ivabradine Trial (SHIFT) with the aim of evaluating the eect of ivabradine in addition to guidelines-based treatment on cardiovascular outcomes, symptoms, and quality of life in patients with chronic heart failure and systolic dysfunction. Methods Study design and patients SHIFT was an event-driven, multinational, randomised, double-blind, placebo-controlled, parallel-group clinical trial in patients with moderate-to-severe heart failure and left-ventricular systolic dysfunction. The study was undertaken in 677 centres in 37 countries. Eligible patients were men or women aged 18 years and older who were in sinus rhythm and had a resting heart rate of 70 bpm or higher, as measured on 12-lead electrocardiography (ECG) after at least 5-min rest on two consecutive visits before randomisation, with stable symptomatic chronic heart failure of 4 or more weeks' duration, a previous admission to hospital for worsening heart failure within the previous 12 months, and a left-ventricular ejection fraction of 35% or lower. Any cause of heart failure was allowed apart from congenital heart disease or primary severe valvular disease. 7411 patients assessed 305 excluded because of non-compliance with study criteria 7106 selected* 548 excluded 349 non-compliance with study criteria 125 withdrew consent 68 adverse event 5 missing 1 no randomisation call 6558 randomised 3268 assigned ivabradine 3290 assigned placebo 26 excluded 5 study drug not dispensed 21 patients from removed centres 3264 analysed (including 1 lost to follow-up and 58 who withdrew consent for study participation) Figure 1: Trial prole *Selected patients entered the 7-30-day run-in period without study treatment for conrmation of inclusion or exclusion criteria. 876 Randomisation and masking After a run-in of 14 days without study treatment to enable conrmation of inclusion and exclusion criteria, patients were randomly allocated to treatment groups by computergenerated assignment through a telephone interactive voice response system. The allocation sequence was generated at the sponsor level through validated in-house application software; access was restricted to people responsible for study therapeutic units production until database lock. These people had no involvement in the rest of the trial. Eligible patients were allocated to receive ivabradine or placebo in addition to treatments appropriate to their heart failure, with particular emphasis on background treatment with a blocker. Patients and investigators were masked to treatment allocation. The study drugs (ivabradine or placebo) were identical in appearance. Stratication was done by centre and treatment with or without a blocker at inclusion. The rst patient was randomly assigned on Oct 3, 2006, and the last patient on June 1, 2009. Study closure occurred between Feb 1, and March 31, 2010. The nal visit was regarded as the end of the study for every patient. Procedures 27 excluded 2 study drug not dispensed 25 patients from removed centres 3241 analysed (including 2 lost to follow-up and 73 who withdrew consent for study participation) Main exclusion criteria were recent (<2 885