Discussant Inder Anand, MD, FRCP, D Phil (Oxon.) Professor of Medicine, University of Minnesota, Director Heart Failure Program, VA Medical Center 111C Minneapolis, USA

DISCLOSURES Research grants: NLHBI, Corventis, Novartis Consultant / Advisory Board: Amgen, ARCA, Boston Scientific, Corventis, CVRx, Medtronic, Paracor, Sanofi-avantis

Rationale of the SHIFT Study High heart rate is strongly related with mortality in the general population and in patients with CAD and Heart Failure. In the Beautiful Trial, patients in the placebo group with HR >70 bpm compared with HR <70 bpm: 34%  53 %  Lowering HR to reduce CV outcomes is an attractive hypothesis to test Fox et al Lancet 2008;372:817-21.

Major Findings of SHIFT A Study In patients with HF, EF < 35% in SR, and baseline resting HR >70 bpm, 90% on BB, 90% ACEi, >60% aldosterone blockers, use of Ivabradine was associated with: ~ 9 bpm  in HR compared to placebo 18%  in the risk of PEP - CV mortality and Hospitalization for HF 26%  in the risk of Hospitalization for HF 9%  in the risk of CV mortality (p=ns) 10%  in the risk of all-cause mortality (p=0.09) Greater benefit was seen in patients HR >77 bpm, independent of BB dose

Was the background dose of beta-blocker used in SHIFT optimal? Only 26% patients were prescribed target dose of BB by the investigators. 55% received at least 50% target dose In BB HF trials, higher % patients reached target dose: 38% in CIBIS, 43% in CIBIS II; 64% in MERIT-HF and 65% in COPERNICUS BB doses used in recent drug and device trials are not published In clinical practice lower doses of BB are used & fewer patients reach target dose: -

Could use of higher BB dose have changed the outcomes? Meta-regression of 23 beta-blocker HF trials involving 19,209 patients Mortality benefit was related to magnitude of HR reduction and not to the dose of BB. Pooled Mortality Hazard Ratio was 0.76 for an average HR Reduction 12 bpm O -20 -10 -15 -5 1 -1 -2 -3 Death Log Risk Ratio Heart Rate Reduction (beats/min) McAlister et al Ann Intern Med 2009;150:784-794

Could use of higher BB dose changed the outcomes? The reduction in mortality hazard with Ivabradine for an average 9-bpm decrease in HR is consistent with the prediction from the meta-analysis. In clinical trials higher doses of BB have not been shown reduce HR further. In SHIFT also higher dose of BB did not cause greater  HR: 15.4 bpm in entire cohort vs  15.5 bpm those on > 50% target dose. Unlikely that use of higher BB doses in SHIFT would have caused a further HR or altered the outcomes In real world, clinicians are unable to doses of BB to target levels because of actual or perceived side effects. Previous drug or device HF trials that led to the approval of specific therapies were done in patients receiving background therapy as prescribed by the investigators and no force titration was attempted. Hence, SHIFT should be judged on the merits of its findings in the population studied

Which patients are likely to be candidates for Ivabradine? Patients with A Fib unlikely to benefit: Exclude ~ 25% HF patients Patients with resting HR > 70 bpm: Data from recent HF trials and HF registries suggest that over 50% patients have HR >70 bpm and ~ 40% have HR >77 bpm where most of the benefits of ivabradine were seen Use of devices was low in SHIFT because of inclusion criteria and geography. These patients need not be excluded if they meet the other inclusion criteria and pacing rate are set appropriately low. Approximately 40% of all HF patients with LV systolic dysfunction receiving standard of care HF therapies might benefit from the addition of ivabradine

CONCLUSIONS SHIFT confirms the importance of heart rate in the pathophysiology of HF and supports the concept that reduction in HR contributes significantly to beneficial outcomes in patients with HF. HR is not only a risk factor but may well be a mediator of progression of HF In patients with systolic HF in sinus rhythm with HR >70 bpm, receiving usual clinical care and are unable to tolerate higher doses of BB, the addition of the pure HR reducing agent ivabradine is likely to improve HF outcomes