HEART RATE MANAGEMENT

1. Clinical Pearls
in Heart Rate
Management

2. Ivabradine: Pure HR lowering If current inhibitor
1
Has HR-lowering
properties without
other direct
cardiovascular effects
2
First in class of agents
that act specifically on
the sino-atrial node
3
Inhibits the If current
of cardiac pacemaker
cells without affecting
other cardiac ionic
currents
4
Has a unique
pharmacodynamic
profile as HR reduction
is not associated with
negative inotropic
effects or vasodilation
Koruth JS, et al. J Am Coll Cardiol. 2017;70(14):1777–84.

3. Benefits of Heart
Rate reduction
with Ivabradine
Reduces oxygen
demand in myocyte
Improves perfusion
in coronary arteries
Reduces energy
requirements
Reduces load on
heart muscle
Reduces ischemia
and angina
Improves heart
muscle functioning
and prevents
worsening of HF
CAD Heart Failure
Koruth JS, et al. J Am Coll Cardiol. 2017;70(14):1777–84.

4. Guideline recommendations for Ivabradine
based therapy in CCS and HFrEF

5. Knuuti J, et al. Eur Heart J. 2020 Jan 14;41(3):407-477.

6. 2021 ESC Heart Failure Guideline Recommendations
In patients with CCS and HFrEF
• Ivabradine should be
considered as an alternative
to beta-blockers (when
contraindicated) or as
additional anti-anginal
therapy in patients in SR
whose heart rate is ≥70
b.p.m.
McDonagh TA, et al. Eur Heart J. 2021 Sep 21;42(36):3599-3726.

7. 2021 ESC Heart Failure Guideline Recommendations
• Ivabradine should be considered in symptomatic
patients with LVEF ≤35%, in SR and a resting
heart rate ≥70 b.p.m. to reduce the risk of HF
hospitalization and CV death
• Despite treatment with an evidence-based dose of
beta-blocker (or maximum tolerated dose below
that), ACE-I/(or ARNI), and an MRA
• Who are unable to tolerate or have
contraindications for a beta-blocker
McDonagh TA, et al. Eur Heart J. 2021 Sep 21;42(36):3599-3726.

8. 2022 AHA/ACC/HFSA Guidelines
Management of Stage C HF: Ivabradine
Recommendation for the Management of Stage C HF: Ivabradine
Referenced studies that support the recommendation are
summarized in the Online Data Supplements.
COR LOE Recommendation
2a B-R
1. For patients with symptomatic (NYHA class II
to III) stable chronic HFrEF (LVEF ≤35%) who
are receiving GDMT, including a beta blocker at
maximum tolerated dose, and who are in sinus
rhythm with a heart rate of ≥70 bpm at rest,
ivabradine can be beneficial to reduce HF
hospitalizations and cardiovascular death.
Heidenreich PA, et al. Circulation. 2022 May 3;145(18):e895-e1032. doi: 10.1161/CIR.0000000000001063. Epub 2022 Apr 1.

9. ACC 2021
Expert
Consensus
Decision
Pathway for
HFrEF
J Am Coll Cardiol. 2021 Feb 16;77(6):772-810.

10. 2021 HFA of ESC Consensus HFrEF: Patient Profiles for
Ivabradine and other GDMT
Rosano GMC, et al. Eur J Heart Fail. 2021 May 1. doi:
10.1002/ejhf.2206. Online ahead of print.
Patient profiles suitable for
Ivabradine
• CAD and angina – with BB to
control symptoms
• Patients with low BP and high
heart rate >70 bpm
• Patients with low BP and
heart rate 60-70 bpm
• Patients with normal BP and
high heart rate >70 bpm

11. Case
Scenarios
CCS with Recurrent
Angina unresponsive to
β-blocker
HFrEF with high HR
despite β-blocker

12. Case 1: CCS with Recurrent Angina unresponsive to β-blocker
54-year-old man with recurrent angina, long standing T2DM,
hypertension and dyslipidemia
2012 – STEMI, treated with PCI
2018 – underwent CABG for worsening angina and multivessel
disease
2020 – Limiting, progressive angina in the previous 3 months
seeking treatment for the same

13. Case history
HR – 76 bpm
BP – 118/76 mmHg
Physical examination – unremarkable
ECG – Sinus rhythm
LVEF: 52%
• Metformin 1000 mg BD
• Empagliflozin 25 mg OD
• Aspirin 75 mg OD
• Rosuvastatin 20 mg OD
• Metoprolol XL 25 mg OD

14. Diagnosis and
Treatment
modifications
• Recurrent angina with long-
standing CCS
• Dose of Metoprolol XL was
increased to 50 mg

15. Follow up 1
HR – 72 bpm
BP – 112/72 mmHg
Angina symptoms not relieved
Patient complained of fatigue, dizziness, and
lightheadedness upon standing
Metoprolol XL dose was reduced to 25 mg
Amlodipine 5 mg OD was added

16. Follow up 2
HR – 75 bpm
BP – 110/68 mmHg
CCS II - Modest improvement in angina
CAG: patient ineligible for another revascularization -
LIMA-LAD patent but distal portion of the native
vessel severely disease, CTO of RCA
Since the patient was still symptomatic with high HR
and low BP on Metoprolol, Ivabradine 5 mg BID was
added

17. Management and follow up
Significant clinical
improvement, although he still
experienced chest pain during
more vigorous exercise
HR: 66 bpm BP: 118/72 mmHg
Ivabradine was up-titrated to
7.5 mg bid
After 1 month: Patient was
angina free with no side
effects and was pleased with
the treatment
• HR: 60 bpm
• BP 122/76 mmHg

18. Stable CAD patients often have resting HR ≥70 bpm despite high
usage of beta-blockers
The Euro Heart Survey - Patients (%) in different HR
according to HR lowering treatment at baseline
35
0
5
10
15
20
25
30
≤62 63-70 71-76 77-82
BBs
Resting HR (bpm)
≥83
CCBs
39% of patients receiving β-blockers
had a heart rate above 70 bpm
Daly CA, et al. Postgrad Med J. 2010 Apr;86(1014):212-7.
41% of patients receiving β-blockers
had a heart rate above 70 bpm
HR ≥70 bpm
41%
HR <70 bpm
59%
CLARIFY worldwide: Among 24,910
patients on Beta-blockers

19. CAD and HR management: India vs Rest of the World
CLARIFY: ProspeCtive observational LongitudinAl RegIstry oF patients with stable coronary arterY disease
Parameter India Rest of the World
Angina prevalence 27.8% 21.9%
Mean Heart Rate 76.1 bpm 68 bpm
Prevalence of HR >70 bpm 82.2% 48.5%
Achievement of HR goal
≤60 bpm
2.5% 22.9%
Kaul U, et al. Indian Heart J. Jul-Aug 2017;69(4):447-452.

20. CONTROL-2: Ivabradine + Beta-blocker combination effectively
reduces HR and improves clinical outcomes vs BB uptitration in CAD
Significantly greater reduction in HR
(61 ± 6 vs. 63 ± 8 bpm; p = 0.001)
• Significantly more patients were in CCS class I angina (37.1% vs. 28%; p = 0.017)
Significantly more patients were angina-
free (50.6% vs. 34.2%; p < 0.001)
Glezer M, et al. Adv Ther. 2018 Mar;35(3):341-352.

21. CONTROL-2: Ivabradine + Beta-blocker combination had significantly
better acceptance and tolerability vs BB uptitration in CAD
In patients with stable angina, combination therapy with Ivabradine + BB demonstrated
good tolerability, safety, and more pronounced clinical improvement, vs BB uptitration
Glezer M, et al. Adv Ther. 2018 Mar;35(3):341-352.

22. ADDITIONS: Efficacy & tolerability of Ivabradine + Metoprolol
combination
• Ivabradine +
Metoprolol safely and
effectively reduces
heart rate, angina
attacks and nitrate use,
and improves QoL in
stable-angina patients
• The effect of ivabradine
was greater in patients
with a baseline heart
rate ≥ 70 bpm
Werdan K, et al. Cardiology. 2016;133(2):83-90.

23. Take Home
Summary
• Many CCS patients do not achieve the
desired HR targets despite treatment
with β-blocker and some may also
have β-blocker intolerance
• High HR is an important contributor to
recurrent angina in CCS and can
significantly affect quality of life
• Ivabradine can be a useful add on
especially when HR is not controlled
despite β-blocker or in patients not
tolerating β-blockers

24. Case 2:
HFrEF with
high HR
despite β-
blocker
• 62-year-old lady with HFrEF and history of
hypertension and CKD
• 2014 – treated for triple vessel disease,
stented in LAD, RCA proximally and in the
middle segment
• 2016 – Presented with HFrEF
• Dyspnea on exertion - NYHA II
• HR: 82 bpm SR
• BP: 102/66
• BNP: 526
• LVEF 28%
• QRSd 122ms

25. Treatment
administered
Telmisartan 40 mg OD
Bisoprolol 2.5 mg OD
Furosemide 40 mg OD
Aspirin 75 mg OD
Atorvastatin 40 mg OD
Pantoprazole 40 mg OD

26. Plan of
Treatment
Uptitrate Telmisartan and
Bisoprolol
Add Eplerenone
ICD – patient not keen
Follow up after 3 months

27. Follow up 1
• Still symptomatic with DOE
• Telmisartan 80 mg OD, Bisoprolol 10 mg OD,
Eplerenone 25 mg OD
• NYHA III
• BP: 104/62 mmHg
Reassessment
• Holter ECG: Min HR – 63 bpm, Max HR – 95
bpm, Mean HR – 74 bpm
• Echocardiography: LVEF – 34%

28. Management
and
subsequent
follow up
Ivabradine initiated at 5 mg BD,
uptitrated to 7.5 mg BD
HR 62 bpm SR
NYHA I
LVEF after 6 months – 42%
Stable between 2016 – 2020

29. Management
and
subsequent
follow up
OPD visit in 2020
• NYHA II
• LVEF 38%
• HR: 58 bpm
• 6 years since presentation
with post MI HF
• No ICD
• No CRT
• Telmisartan 40 mg OD
• Bisoprolol 10 mg OD
• Furosemide 40 mg OD
• Eplerenone 25 mg OD
• Ivabradine 5 mg BD
• Aspirin 75 mg OD
• Atorvastatin 40 mg
OD

30. Ivabradine and Beta-blockers are complementary to each other
Katsi V, et al. Pharmacol Res. 2019 Aug;146:104279.

31. Tardif JC, et al. Eur Heart J. 2011 Oct;32(20):2507-15.
Sub-group analysis from SHIFT Echo substudy
Ivabradine as an add on to GDMT including β-blocker can
help to improve LVEF

32. Ivabradine can also help in symptomatic relief and
improve quality of life on top of GDMT
Zugck C, et al. Adv Ther. 2014 Sep;31(9):961-74.
9.6
51.1
37.2
2.1
24.1
60.5
14.8
0.7
0
10
20
30
40
50
60
70
NYHA I NYHA II NYHA III NYHA IV
Patients
(%)
Proportion of patients in different NYHA
classes from baseline to study end (month 4)
Baseline
At 4 months
% of patients with LVEF ≤35% or >35% and with/without signs
of decompensation from baseline to study end (month 4)

33. Ivabradine OD
formulation can
also improve
ventricular
remodeling,
cardiac function,
and QOL in
patients with
HFrEF
Ye F, et al. J Am Coll Cardiol. 2022;80(6):584–594

34. SHIFT: Ivabradine + Carvedilol combination improved
Cardiovascular outcomes
Bocchi EA, et al. Cardiology. 2015;131(4):218-24.

35. CARVIVA-HF: Impact of Ivabradine + Carvedilol on HR
and exercise capacity
• Ivabradine in combination with carvedilol was more effective than carvedilol
alone at improving exercise tolerance and quality of life in HF patients
76.7
57.2
0
10
20
30
40
50
60
70
80
90
Baseline After 12 weeks
HR
(bpm)
Volterrani M, et al. Int J Cardiol. 2011 Sep 1;151(2):218-24.

36. Take Home
Summary
• Suboptimal use of GDMT is an important
contributor in worsening HFrEF
• Optimization of GDMT including the addition
of Ivabradine in HFrEF patients with high HR
despite maximum tolerated β-blocker can
• Improve LVEF
• Improve QOL
• Prevent progression of HF