Ivabradine and Outcomes in Chronic Heart Failure (SHIFT)
Swedberg K, et al. Lancet. 2010;376:875-885
Presentation Date: August 27, 2015
Presenter: Ellen Yin, PharmD
Mentor: Toni Ripley, PharmD, FCCP, BCPS-AQ Cardiology
Background:
Beta-blocker therapy is a cornerstone of systolic heart failure
treatment and has been shown to reduce morbidity and
mortality. Benefits of beta-blocker therapy are likely linked to
its HR lowering properties. However, beta-blockers also have
other undesirable actions on the heart including an effect on
myocardial contractility. Ivabradine is a specific inhibitor of
the If current in the sinoatrial node. It delays phase four
depolarization lowering the HR. In the BEAUTIFUL trial,
studying ivabradine vs. placebo in patients with CAD and leftventricular dysfunction, HR reduction with ivabradine in
patients with a baseline HR greater than 70 bpm was shown
to improve coronary endpoints. All other endpoints were not
significantly different.
26% actually reaching the target dose. The main reasons for
not titrating the beta-blocker dose higher were hypotension
and fatigue.
Objective:
To assess the effect of HR reduction by selective sinus-node
inhibitor ivabradine on outcomes in heart failure.
Study design:
International, multicenter, randomized, double-blind,
placebo-controlled, parallel group.
Study population:
Inclusion Criteria
Exclusion Criteria
-Age ≥ 18 years
-Sinus rhythm with resting HR ≥
70 bpm
-NYHA Class II, III, IV for ≥ 4 weeks
-Previous admission for
worsening heart failure within
previous 12 months
-LVEF ≤ 35%, documented within
previous 3 months
-Recent (<2 months) myocardial
infarction
-Pacemaker with atrial or ventricular
pacing > 40% of the time,
-Atrial fibrillation or flutter
-On non-dihydropyridine calcium
channel blockers, class I
antiarrhythmics, strong inhibitors of
CYP3A4 , selected QT prolonging agents
Treatment:
Ivabradine titrated to a maximum of 7.5 mg twice daily or
matching placebo on top of standard heart failure treatment.
Patients were followed up every 4 months and treated for 1248 months.
Results:
Results were available for 3241 patients in the ivabradine
group and 3264 patients in the placebo group. Median
follow-up was 22.9 months. Groups were well balanced with
an average age of 60.4 years (11% of patients were aged > 75
years). Patients were mainly white (89%) males (76%).
Patients had a baseline HR of 80 bpm with a blood pressure
of 120/75 and LVEF about 30%. Fifty-six percent of patients
reached at least 50% of the target dose of beta-blocker with
The primary composite endpoint of cardiovascular death or
hospital admission for worsening heart failure was
significantly different between the two groups with a number
needed to treat of 26 favoring ivabradine (HR 0.82, 95% CI
0.75-0.90, p<0.001). The effects were mainly driven by
hospital admission for worsening heart failure and deaths due
to heart failure. There was no difference in mortality
outcomes when looking at cardiovascular mortality or allcause mortality. Bradycardia, atrial fibrillation, and visual
side-effects were reported more frequently in the ivabradine
group.
Conclusion:
Ivabradine significantly reduced major risks associated with
heart failure and the results show the importance of HR
reduction for improvement of clinical outcomes.
Discussion:
Strengths of this study include that it was a well-designed
study. Limitations include generalizability (limited NYHA class
IV patients, limited number of elderly patients, and did not
include any patients from the US – limited minority patients
included) and baseline heart failure medication therapy not
being fully maximized (seen by a primary event rate of 18% in
the placebo group compared with 14% assumed for power
analysis). Beta-blocker therapy may not have been titrated to
maximally tolerated doses and non-recommended betablocker therapy was used.
Practical Implications:
It’s important to first make sure the patient is on all the
appropriate guideline recommended heart failure treatment
medications to avoid pre-mature initiation of ivabradine.
Ivabradine should not be a substitute for beta-blocker
therapy. Previous studies have shown all-cause mortality
benefits with beta-blocker therapy but this has not been seen
with ivabradine. Beta-blocker therapy should be titrated up
to maximally tolerated doses; as seen in SHIFT and
BEAUTIFUL, patients with lower heart rates tended to do
better. Ivabradine may be beneficial in a niche patient
population that truly cannot tolerate higher doses of betablockers and still have a HR ≥ 70 bpm. Monitor for adverse
events such as bradycardia, visual disturbances, and atrial
fibrillation.
Ivabradine and Outcomes in Chronic Heart Failure (SHIFT)
Swedberg K, et al. Lancet. 2010;376:875-885
Presentation Date: August 27, 2015
Questions:
1. Do you agree with the FDA approval using the heart rate
of 70 versus 77 as seen in the sub-group analysis? 1
Sub-group analyses are usually not powered for the primary
outcome. Therefore, I believe it was appropriate for the FDA
to approve ivabradine for patients with a HR ≥ 70 bpm based
off the inclusion criteria. From a practicality standpoint, it
also makes sense to use 70 bpm as the threshold. However,
clinicians should also use clinical judgement to determine if
adding ivabradine would be beneficial if a patient’s HR is
between 70-77 bpm.
2. Given the bradycardia concern, should this agent be
started inpatient or would you feel comfortable starting on
an outpatient basis? 1
Patients should only be started on ivabradine if the baseline
HR is ≥ 70 bpm. For patients in SHIFT, on average at 28 days
after ivabradine initiation, the HR fell by about 10 bpm. Most
patients should not experience bradycardia. Symptomatic
bradycardia happened in about 5% of patients, while
asymptomatic bradycardia happened in about 6% of patients
with only 2% withdrawing from the study due to symptomatic
or asymptomatic bradycardia. Therefore, I would feel
comfortable starting the agent as an outpatient with frequent
follow-up in patients with concern for bradycardia.
3. Would you start a patient on digoxin or this to reduce
readmission for a patient with HFrEF? 1,2
When comparing SHIFT to DIG, digoxin led to a significant 15
(9-21)% relative risk reduction in the primary endpoint
compared with a 18 (10-25)% relative risk reduction with
ivabradine, both P<0.001. In both trials, the primary effect
was on heart failure hospitalization without any significant
effect on CV death. Heart failure hospitalization was reduced
by 26 (17–34)% with ivabradine and by 28 (21–34)% with
digoxin, both P< 0.001. The results of both trials are very
similar although patients were not on beta-blocker therapy in
the DIG trial (beta-blocker use not reported). Considering
this, the decision to put patients on digoxin vs ivabradine
should be patient specific. It depends on a patient’s comorbidities and insurance coverage. For example, if a patient
has atrial fibrillation, digoxin would be a better choice for the
patient. If a patient has renal dysfunction, ivabradine may be
a better choice as it does not need to be renally adjusted.
Cost, patient compliance, and drug/drug interactions should
also be taken into account. It should also be noted that of the
patients in SHIFT, 22% were already on cardiac glycosides.
Presenter: Ellen Yin, PharmD
Mentor: Toni Ripley, PharmD, FCCP, BCPS-AQ Cardiology
4. What is the perceived mechanism behind the increased
risk of atrial fibrillation with ivabradine? 3,4
The molecular subunits of the If channel are the
hyperpolarization-activated cyclic-nucleotide gated (HCN)
channels. Several genetic alterations of the HCN channel gene
have been reported to be associated with asymptomatic
sinus bradycardia, sinus arrhythmia, and atrial fibrillation.
Ruairidh et al. proposed that polymorphisms in the HCN4
locus, or other HR related loci, may affect the risk of atrial
fibrillation on ivabradine treatment by changing the electrical
activity in pulmonary vein myocytes. However, this is
postulated using data extrapolated from rabbit studies. Atrial
fibrillation is also common in patients with CAD and cardiac
failure so incident atrial fibrillation cannot be completely
pinpointed to drug administration.
5. How much weight do you give to the ‘death from heart
failure’ outcome? 5
The validity of cause-specific mortality as an endpoint rests
on the fundamental assumption that the cause of death can
be determined accurately. The mode of death in patients
with heart failure is frequently difficult to determine. An
endpoint validation committee reviewed and adjudicated all
pre-specified events according to definitions included in a
charter. These definitions were not included in the main
SHIFT article. When considering cause-specific mortality, the
number of events is reduced, and this reduces the statistical
power of the analysis to detect any difference between the
treatment groups. When a difference is significant, the
comparison can only be considered informative. A significant
difference in a specific mode of death does not offset the lack
of difference in all-cause mortality.
6. Regarding insurance coverage, what have people been
required to prove in order to get coverage? 6
Ivabradine is a tier 3 drug on most insurance plans requiring
prior authorization. According to Anthem Blue Cross Blue
Shield, requests for ivabradine may be approved if the
following criteria are met: ≥ 18 years AND NYHA class II, III, or
IV heart failure symptoms AND LVEF ≤ 35% AND will be
utilizing in combination with a beta-blocker OR has a
contraindication or intolerance to beta-blocker therapy AND
is in normal sinus rhythm AND has a resting HR ≥ 70 bpm. It
may not be approved for any of the following: HR is
maintained exclusively by a pacemaker OR severe
hypotension (BP < 90/50 mmHg) OR severe hepatic
impairment.
Ivabradine and Outcomes in Chronic Heart Failure (SHIFT)
Swedberg K, et al. Lancet. 2010;376:875-885
Presentation Date: August 27, 2015
Presenter: Ellen Yin, PharmD
Mentor: Toni Ripley, PharmD, FCCP, BCPS-AQ Cardiology
7. Can you give examples of the ideal candidates for this
medication? 1,7
The ideal candidate is a patient on all appropriate guideline
recommended heart failure treatment medications at the
target dose of beta-blocker but still has a resting HR ≥ 70 bpm
with frequent hospital admissions for heart failure. Patients
who cannot tolerate higher doses of beta-blocker therapy or
have a contraindication to beta-blocker therapy such as
severe asthma or COPD may also be a candidate for therapy.
Also, based on results from the BEAUTIFUL and SIGNIFY trial,
patients with non-ischemic cardiomyopathy may also benefit
more from therapy. The hypothesis is that ischemic
cardiomyopathy is characterized by loss of substantial
quantities of myocardium through infarction which lead to
irreversible scaring and limited potential for recovery
whereas some or much of non-ischemic cardiomyopathy may
be reversible.
References:
8. Are there any sub-group analysis according to betablocker dose? 8
There was a subgroup analysis published in the Journal of the
American College of Cardiology. The primary endpoint and
heart failure hospitalization were significantly reduced in all
subgroups with <50% of target beta-blocker dose, including
no beta-blocker (p=0.012). There was an apparent trend to
reduction in treatment-effect magnitude with increasing
beta-blocker dose. Across beta-blocker subgroups, treatment
effect was borderline non-significant only for the primary
endpoint and significance was further lost after adjusting for
interaction between baseline heart rate and ivabradine
effect. The authors concluded that the magnitude of heart
rate reduction by beta-blocker plus ivabradine, rather than
beta-blocker dose, primarily determines subsequent effect on
outcomes.
1. Swedberg K, Komajda M, Bohm M, et al.; SHIFT Investigators. Ivabradine
and outcomes in chronic heart failure (SHIFT): a randomized placebocontrolled study. Lancet 2010;376:875-885.
2. The Digitalist Investigation Group. The effect of digoxin on mortality and
morbidity in patients with heart failure. N Engl J Med 1997;336:525-533.
3. Cowie M. Ivabradine and atrial fibrillation: what should we tell our
patients? Heart 2014; 100:1487-1488.
4. Ruairidh M, Oksana P, Mauro S, et al. Atrial fibrillation associated with
ivabradine treatment: meta-analysis of randomized controlled trials. Heart
2014; doi: 10.1136/heartjnl-2014-305482.
5. Zanolla L, Zardini P. Selection of endpoints for heart failure clinical trials.
Eur J Heart Fail 2003; 5:717-723.
6. Anthem Blue Cross Blue Shield. Rx prior authorization. Available at:
https://www.anthem.com/pharmacyinformation /priorauth.html.
Accessed Sept 13, 2015.
7. McMurray J. It is BEAUTIFUL we should be concerned about, not SIGNIFY:
is ivabradine less effective in ischeaemic compared with non-ischaemic
LVSD? Eur Heart J 2015: dio:10.1093/eurheartj/ehv190.
8. Swedberg K, Komajda M, Bohm M, et al. Effects on outcome of heart rate
reduction by ivabradine in patients with congestive heart failure: is there
an influence of beta-blocker dose? J Am Coll Cardiol 2012; 59:1938-45.