Ivabradine in HF

1. IvabradineIvabradine
Role in the Chronic HF ArmamentariumRole in the Chronic HF Armamentarium
Dr.Vinod SharmaDr.Vinod Sharma
11
National Heart InstituteNational Heart Institute

2. Significance of heart rate in patients with HFSignificance of heart rate in patients with HF
Elevated resting heart rate is an independent predictor of CV morbidity andElevated resting heart rate is an independent predictor of CV morbidity and
mortality in both general population and in patients with HF, irrespective ofmortality in both general population and in patients with HF, irrespective of
underlying EF.underlying EF.
Patients with HF in particular are prone to higher resting heart rates due toPatients with HF in particular are prone to higher resting heart rates due to
compensatory neurohumeral activation resulting in increased sympatheticcompensatory neurohumeral activation resulting in increased sympathetic
activity. This drives an increase in oxygen demand, reduced ventricularactivity. This drives an increase in oxygen demand, reduced ventricular
efficiency and consequently worsens HF.efficiency and consequently worsens HF.
Multicentre studies have demonstrated an association between higherMulticentre studies have demonstrated an association between higher
admission heart rates with worse outcomes, including mortality, in patientsadmission heart rates with worse outcomes, including mortality, in patients
admitted to hospital with HF.admitted to hospital with HF.
Higher discharge heart rates in patients with HF are associated with increasedHigher discharge heart rates in patients with HF are associated with increased
mortality and hospital readmission.mortality and hospital readmission.
A meta analysis of patients with HF indicated that for every 5 bpm reduction inA meta analysis of patients with HF indicated that for every 5 bpm reduction in
heart rate achieved, an 18% reduction in all cause mortality is observed.heart rate achieved, an 18% reduction in all cause mortality is observed.
McAlister FA et al: Ann Int Med 2009McAlister FA et al: Ann Int Med 200922

3. Association of HR and outcome in a broadAssociation of HR and outcome in a broad
spectrum of patients with chronic HF: results fromspectrum of patients with chronic HF: results from
the CHARM (Candesartan in HF: Assessment ofthe CHARM (Candesartan in HF: Assessment of
Reduction in Mortality & Morbidity) ProgramReduction in Mortality & Morbidity) Program
33
Castagno D et al, J Am Coll Cardiol 2012:59(20) 1785-
95
““In CHF patients, baseline resting HR in thoseIn CHF patients, baseline resting HR in those
with sinus rhythm is associated with increasedwith sinus rhythm is associated with increased
Mortality, with every 10 bpm increaseMortality, with every 10 bpm increase
associated with respective increases of 8% inassociated with respective increases of 8% in
an cause mortality, in both HFrEF & HFpEF”.an cause mortality, in both HFrEF & HFpEF”.

4. Prognostic relevance of resting heart rate inPrognostic relevance of resting heart rate in
chronic systolic heart failure in sinus rhythmchronic systolic heart failure in sinus rhythm
44
Vasc Health & Risk Mgmt 2016Vasc Health & Risk Mgmt 2016

5. HR Management in HFHR Management in HF
The beneficial effects of B-blockers on both morbidityThe beneficial effects of B-blockers on both morbidity
and mortality in HFrEF suggest that HR can be aand mortality in HFrEF suggest that HR can be a
therapeutic targettherapeutic target..
There is disagreement as to whether these effectsThere is disagreement as to whether these effects
derive from HR reduction or from other results ofderive from HR reduction or from other results of
adrenergic receptor inhibition.adrenergic receptor inhibition.
Flannery G et al: AJC 2008Flannery G et al: AJC 2008
Analyses of individual trials have demonstrated noAnalyses of individual trials have demonstrated no
relationship between improved outcomes & HR change, arelationship between improved outcomes & HR change, a
trend to dose-dependent reduction in all cause mortality, andtrend to dose-dependent reduction in all cause mortality, and
an association of target B-blockers dosing with improvedan association of target B-blockers dosing with improved
outcomes.outcomes.
COMET 2005COMET 2005
MERIT – HF 2005MERIT – HF 2005 55

6. HR Management in HFHR Management in HF
(contd..)(contd..)
Analysis of the HF: A Controlled Trial InvestigatingAnalysis of the HF: A Controlled Trial Investigating
Outcomes of Exercise Training (HF-ACTION) found thatOutcomes of Exercise Training (HF-ACTION) found that
after multivariable adjustmentafter multivariable adjustment only B-blocker dose, notonly B-blocker dose, not
HR, remained associated with improved mortality andHR, remained associated with improved mortality and
hospitalizationshospitalizations..
JACC Heart Fail 2016JACC Heart Fail 2016
Meta-analyses of > 19000 B-blocker treated patientsMeta-analyses of > 19000 B-blocker treated patients
with HFrEF found that the magnitude of HR loweringwith HFrEF found that the magnitude of HR lowering
directly correlated with improved all cause mortalitydirectly correlated with improved all cause mortality
and LVEF with no significant relationship between B-and LVEF with no significant relationship between B-
blocker dose and HR or all cause mortalityblocker dose and HR or all cause mortality..
McAlister et al: Ann Int Med 2009McAlister et al: Ann Int Med 200966

7. Heart rate achieved or Beta-blocker dose inHeart rate achieved or Beta-blocker dose in
patients with chronic Heart Failure:patients with chronic Heart Failure:
Which is better target?Which is better target?
Eur J Heart Fail 2012: 14: 737-47Eur J Heart Fail 2012: 14: 737-47
““Use of Beta-blockers & resting HR wereUse of Beta-blockers & resting HR were
independent predictors of prognosis but beta-independent predictors of prognosis but beta-
blocker dose was not”.blocker dose was not”.
----------------------------------------------------------------------------------------------------------------------
It may be hypothesized that achieving a HRIt may be hypothesized that achieving a HR
within the target range may be a morewithin the target range may be a more
appropriate therapeutic goal than optimizingappropriate therapeutic goal than optimizing
beta-blocker dose in patient with CHF.beta-blocker dose in patient with CHF.
77

8. Optimized B-blocker therapy in HF:Optimized B-blocker therapy in HF:
Is there space for additional HR control?Is there space for additional HR control?
Russell SJ et al, Br J Cardiol 2012; 19:21-3Russell SJ et al, Br J Cardiol 2012; 19:21-3
More than half of patients with CHF, whoMore than half of patients with CHF, who
are on beta-blockers have inadequatelyare on beta-blockers have inadequately
controlled HR.controlled HR.
Substantial proportion of patients do notSubstantial proportion of patients do not
tolerate the target doses of beta-blockerstolerate the target doses of beta-blockers
used in the large clinical trials.used in the large clinical trials.
88

9. Safety & tolerability of B-Blockers:Safety & tolerability of B-Blockers:
Prejudices & RealityPrejudices & Reality
Erdmann E, Eur Heart J 2009;11 (Suppl) A21-5Erdmann E, Eur Heart J 2009;11 (Suppl) A21-5
Further up titration of Beta-Further up titration of Beta-
blockers is not achievable inblockers is not achievable in
many patients.many patients.
99

10. Ivabradine and IIvabradine and Iff
Ivabradine directly blocks HCN channels in a use dependentIvabradine directly blocks HCN channels in a use dependent
manner, which decreases Imanner, which decreases Iff and reduces the sinus rate in bothand reduces the sinus rate in both
healthy and diseased hearts at rest and with exertion.healthy and diseased hearts at rest and with exertion.
Primary cardiac effect of Ivabradine appears to result from this HRPrimary cardiac effect of Ivabradine appears to result from this HR
reduction, and ivabradine does not directly change inotropy,reduction, and ivabradine does not directly change inotropy,
diastolic function, cardiac output, vascular resistance or BP.diastolic function, cardiac output, vascular resistance or BP.
Ivabradine has not activity at the atrioventricular node and doesIvabradine has not activity at the atrioventricular node and does
not alter the ventricular rate in AF.not alter the ventricular rate in AF.
Although HCN channels are not expressed in normal ventricularAlthough HCN channels are not expressed in normal ventricular
myocardium, expression is increased in the ventricularmyocardium, expression is increased in the ventricular
myocardium of patients with HFrEF, raising the possibility that themyocardium of patients with HFrEF, raising the possibility that the
mechanism of action of ivabradine may be multifaceted in thesemechanism of action of ivabradine may be multifaceted in these
patients, perhaps by reducing ventricular ectopy.patients, perhaps by reducing ventricular ectopy. 1010

11. Ivabradine & outcomes in chronic HF (SHIFT):Ivabradine & outcomes in chronic HF (SHIFT):
a randomized placebo-controlled studya randomized placebo-controlled study
N = 6558 patient with CHF on stable background therapy includingN = 6558 patient with CHF on stable background therapy including
beta-blocker & HRbeta-blocker & HR >> 70 bpm with sinus rhythm, randomized to70 bpm with sinus rhythm, randomized to
Ivabradine (up to 75 mg BD) or placebo.Ivabradine (up to 75 mg BD) or placebo.
Median follow up 22.9 monthsMedian follow up 22.9 months
Results:Results:
-- Improved clinical outcomesImproved clinical outcomes
-- 18% primary composite end point of CV death or18% primary composite end point of CV death or
hospitalization for worsening HF.hospitalization for worsening HF.
-- 26% Hospitalization for worsening HF.26% Hospitalization for worsening HF.
-- 26% pump failure death in Ivabradine group.26% pump failure death in Ivabradine group.
1111
“Since the majority of patients
in SHIFT were taking Beta-
blockers, it was hypothesised
that the combination of beta-
blocker plus Ivabradine rather
than dose of BB was relevant
to this finding”.
Swedberg K et al, Lancet 2010: 376: 875-85

12. Effects on outcomes of heart rate reduction byEffects on outcomes of heart rate reduction by
Ivabradine in patients with congestive heartIvabradine in patients with congestive heart
failure: is there an influence of beta-blockerfailure: is there an influence of beta-blocker
dose? : findings from the SHIFTdose? : findings from the SHIFT
(Systolic Heart Failure Treatment with the I(f)(Systolic Heart Failure Treatment with the I(f)
inhibitor IvabradineTrial) Studyinhibitor IvabradineTrial) Study
1212
Combination of drugs rather than
the dose of beta-blocker was
important in improving the
primary end points of CV death &
hospitalization
Swedberg K et al, J Am Coll Cardiol 2012:59: 1938-45

13. Effects of combining Ivabradine andEffects of combining Ivabradine and
Beta-blockers: focus on the use ofBeta-blockers: focus on the use of
Carvedilol in the SHIFT populationCarvedilol in the SHIFT population
1313
Combination of beta-blockers
plus Ivabradine resulted in
improved outcomes regardless
of the individual beta-blocker
prescribed.
Bocchi EA et al, Cardiology 2015:131; 218-24

14. Ivabradine fills the Beta-blocker GapIvabradine fills the Beta-blocker Gap
To achieve therapeutic HR reduction in HF patients, aTo achieve therapeutic HR reduction in HF patients, a
synergistic approach of BB & Ivabradine is necessary.synergistic approach of BB & Ivabradine is necessary.
Many patients do tolerate only sub-optimal but not theMany patients do tolerate only sub-optimal but not the
recommended full dose of BB due to objective orrecommended full dose of BB due to objective or
subjective SE / AE.subjective SE / AE.
SHIFT, 89% of patient had BB but only 26% were inSHIFT, 89% of patient had BB but only 26% were in
target dose, and only 56% had at leasttarget dose, and only 56% had at least >> 50% of target50% of target
dose irrespective of specific BB used.dose irrespective of specific BB used.
1414

15. Hemodynamic B-Blockers Vs IvabradineHemodynamic B-Blockers Vs Ivabradine
Beta Blocker Ivabradine
HR &
Diastole duration
+
Impairs Isovolumic relaxation
offsetting benefit in terms of the
diastolic pressure – time integral
+
Protects IVR & does
not offset DPT
integral
Alpha – Adrenergic
coronary vaso-
constriction
Increase No
1515
For the same level of HR reduction, the increase in
diastolic time & perfusion duration and volumes are
greater with Ivabradine than BB

16. Hemodynamic B-Blockers Vs IvabradineHemodynamic B-Blockers Vs Ivabradine
Beta Blocker Ivabradine
Stroke
Volume
Reduce SV during
initiation first month of
treatment and uptitration
Significant
increase in SV
with Ivabradine
1616
This effect of BB could be compensated for
prescribing Ivabradine with lower initial doses of
Betablockers
LVEDP
This effect being still present when Ivabradine is Co-prescribed
with a BB, resulting in increased SV & maintenance of Cop

17. When to start IVABRADINE?When to start IVABRADINE?
1717

18. Early Therapy with B-blockers Plus IvabradineEarly Therapy with B-blockers Plus Ivabradine
Versus B-blockers alone in patientsVersus B-blockers alone in patients
hospitalized with HF and Reduced EFhospitalized with HF and Reduced EF (ETHIC-(ETHIC-
AHF Study)AHF Study): Results at One-year Follow up: Results at One-year Follow up
Hidalgo et al. Int J Clin Cardiol 2017Hidalgo et al. Int J Clin Cardiol 2017
A prospective, comparative and randomized trial with aA prospective, comparative and randomized trial with a
simple randomization strategy.simple randomization strategy.
To use B-blockers in increasing doses and to addTo use B-blockers in increasing doses and to add
Ivabradine only in those patients who after reaching theIvabradine only in those patients who after reaching the
optimal dose or the maximum tolerated dose of B-optimal dose or the maximum tolerated dose of B-
blockers, persisted with heart rate > 70 bpm (controlblockers, persisted with heart rate > 70 bpm (control
group), versus the strategy of simultaneous and earlygroup), versus the strategy of simultaneous and early
start, 24-48 hrs after HF admission, of B-blockers andstart, 24-48 hrs after HF admission, of B-blockers and
Ivabradine, with simultaneous and progressive up-Ivabradine, with simultaneous and progressive up-
titration of both (intervention group).titration of both (intervention group).
1818

19. Heart rate in both groups duringHeart rate in both groups during
follow upfollow up
1919

20. LVEF in both groups duringLVEF in both groups during
follow upfollow up
2020

21. Exercise Tolerance: The CARVIVA TrialExercise Tolerance: The CARVIVA Trial
Not only prognosis, but also exercise tolerance can be improved by theNot only prognosis, but also exercise tolerance can be improved by the
combination of BB & Ivabradine in comparison to BB alone.combination of BB & Ivabradine in comparison to BB alone.
CARVIVA (n = 131 HF), NYHA II / III, LVEF 27CARVIVA (n = 131 HF), NYHA II / III, LVEF 27 ++ 4.9%4.9%
Ivabradine as well as combination of Carvedilol plus Ivabradine after 12Ivabradine as well as combination of Carvedilol plus Ivabradine after 12
weeks of treatment improved exercise tolerance & QoL, but Carvedilolweeks of treatment improved exercise tolerance & QoL, but Carvedilol
alone did not.alone did not.
Dominant negative effects of an increasing blockade of BetaDominant negative effects of an increasing blockade of Beta11 adreno-adreno-
receptor with higher doses of B1 selective BB. It prevents up regulation ofreceptor with higher doses of B1 selective BB. It prevents up regulation of
HR & Cop during physical exercise and results in reduced exerciseHR & Cop during physical exercise and results in reduced exercise
capacity, which is additionally impaired by negative Ionotrophy of BB.capacity, which is additionally impaired by negative Ionotrophy of BB.
Treatment with Ivabradine alone or combination of IVA with low or mediumTreatment with Ivabradine alone or combination of IVA with low or medium
dose of BB allows adequate rise in HR with increasing sympatheticdose of BB allows adequate rise in HR with increasing sympathetic
activation (induced by physical exercise) as Ivabradine lacks an inhibitoryactivation (induced by physical exercise) as Ivabradine lacks an inhibitory
effects on B1 adreno-receptors and maintains cardiac conduction &effects on B1 adreno-receptors and maintains cardiac conduction &
contractility.contractility. 2121

22. Evidence based medical therapyEvidence based medical therapy
2222

23. Role in Chronic HF TherapyRole in Chronic HF Therapy
Patients with stable HFrEF in sinus rhythm with LVEFPatients with stable HFrEF in sinus rhythm with LVEF << 35%35%
taking a B-blocker at the maximum tolerated dosing.taking a B-blocker at the maximum tolerated dosing.
US Food & Drug Administration used the SHIFT entry criteria,US Food & Drug Administration used the SHIFT entry criteria,
specifically HRspecifically HR >> 70 bpm.70 bpm.
European Medicines Agency approved Ivabradine only forEuropean Medicines Agency approved Ivabradine only for
those with HR > 75 bpm.those with HR > 75 bpm.
Critical prerequisite for Ivabradine initiation in HFrEF is theCritical prerequisite for Ivabradine initiation in HFrEF is the
use of guideline-directed medical therapy including ause of guideline-directed medical therapy including a
maximally titrated B-blocker or true B-blocker intolerance,maximally titrated B-blocker or true B-blocker intolerance,
because Ivabradine appears inferior to evidenced-based B-because Ivabradine appears inferior to evidenced-based B-
blocker therapy with respect to mortality.blocker therapy with respect to mortality.
2323

24. Dosing approach for IvabradineDosing approach for Ivabradine
2424
JACC Vol 70, No.14, 2017JACC Vol 70, No.14, 2017

25. Dosage & Safety of IvabradineDosage & Safety of Ivabradine
Most common adverse effect of Ivabradine (Most common adverse effect of Ivabradine (>>1/10 )1/10 )
reported is luminous phenomena also known asreported is luminous phenomena also known as
phosphenes. 75% of the reported phosphenes resolvedphosphenes. 75% of the reported phosphenes resolved
during treatment, and 100% resolved after treatment.during treatment, and 100% resolved after treatment.
Common (Common (>> 1/100 to < 1/10) side effects include1/100 to < 1/10) side effects include
bradycardia (reported in 3.3% of patients, usually withinbradycardia (reported in 3.3% of patients, usually within
the first 3 months of initiation), headache and atrialthe first 3 months of initiation), headache and atrial
fibrillation.fibrillation.
BEAUTIFUL and SHIFT trials, found an increasedBEAUTIFUL and SHIFT trials, found an increased
relative risk of AF with Ivabradine of approximately 15%relative risk of AF with Ivabradine of approximately 15%
compared with placebo (95% CI 1.07 – 1.24, p = 0.0027).compared with placebo (95% CI 1.07 – 1.24, p = 0.0027).
The ESC HF guidelines include a warning thatThe ESC HF guidelines include a warning that
Ivabradine may increase the risk of AF.Ivabradine may increase the risk of AF. 2525

26. Current Region-Specific Approved IndicationsCurrent Region-Specific Approved Indications
for use of Ivabradinefor use of Ivabradine
2626
JACC Vol 70, No.14, 2017JACC Vol 70, No.14, 2017

27. Therapeutic effects of heart rate reduction byTherapeutic effects of heart rate reduction by
Ivabradine in HF patients with systolic dysfunction andIvabradine in HF patients with systolic dysfunction and
sinus rhythmsinus rhythm >> 75 /min75 /min
2727
Data from SHIFTData from SHIFT
The EMA Decision for a Cutoff of > 75 bpm
“When analyzing the benefit of Ivabradine
medication in SHIFT in patients with an initial HR >
bpm, it becomes evident that those patients had not
only a reduced rate of HF hospitalization (30%) &
deaths from HF (39%) but also a significant
reduction of CV death rate by 17%. In contrast, the
SHIFT patients with an initial HR < 75 bpm did not
benefit significantly regarding outcomes”.