Download USC Journal club April 28, 2009

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:
Target dose
reached (%)
% > 50%
target dose
COHERE (USA, 2004)
44
-
VA NATIONAL (USA, 2009)
25
-
Euro Heart Survey (2005)
10
-
Impact Reco II (France, 2009)
23
54
IMPROVE HF (USA, 2010)
17
-
HF Registeries
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
1
Death Log Risk Ratio
O
0
O
-1
O
-2
O
-3
-20
-15
-10
Heart Rate Reduction (beats/min)
McAlister et al Ann Intern Med 2009;150:784-794
-5
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