1) A study evaluated the addition of ivabradine to metoprolol in patients with stable angina pectoris and found that it significantly reduced mean resting heart rate, weekly angina attacks, and use of short-acting nitrates over 4 months compared to baseline. 2) The mean heart rate fell by 19.7 bpm, weekly angina attacks decreased 8-fold, and quality of life scores increased with the combination therapy. 3) Heart rate reductions and clinical benefits were greater in patients who had higher baseline heart rates of 70 bpm or more.

1. Newer Approach in
management of Angina &
CHF: Heart rate
modulation and beyond..
Dr. Arindam Pande
MBBS (Hons), MD, DM, FSCAI(USA), FESC, FACC (USA), FRCP (Glasg)
Consultant Interventional Cardiologist,
Medica SuperSpeciality Hospital, Kolkata
www.drarindampande.com
https://www.facebook.com/DrPandeCardiologist/

3. Blue Whale

6. Content
 Heart rate and cardiovascular outcomes
 Treatment options
 Limitations of Beta blockers
 Is heart rate adequately addressed with the
beta blockers?
 What is the additive effect of Ivabradine to
beta blockers therapy?
 Clinical evidences for Ivabradine and
metoprolol combination
 Take home message

7. Real life Case: 1
 62 years male, HTN, T2DM, Ex-smoker
 ASMI 2 years back, S/P PCI to LAD
 Currently NYHA Class 2
 Pulse 84/min, BP 128/80 mmHg, Chest/CVS – NAD
 ECG – Sinus Rhythm, q-s in anterior chest leads
 Echo – LVEF 44%
 Current medications
Aspirin 75 mg
Atorvastatin 40 mg
Valsartan 160 mg BD
Metoprolol XL 75 mg
Metformin XL 1g BD
 What’s next??

8. Atherosclerosis
Endothelial dysfunction↑
Oxidative stress↑
Plaque stability↓
Arterial stiffness↑
Ischemia
Oxygen consumption↑
Duration of diastole↓
Coronary perfusion↓
Remodeling
Cardiac hypertrophy↑
Chronic heart failure
Oxygen demand↑
Ventricular efficiency ↓
Ventricular relaxation↑
Elevated heart rate
+
+ +
+
The pivotal role of heart rate in cardiovascular
disease

9.  Positive association with total and/or cardiovascular mortality
 Association independent of other cardiovascular risk factors
 Association valid in both genders, in the elderly, in different
ethnicities
 A strong predictor of mortality in patients with coronary artery
disease
 Relation to known pathophysiologic mechanisms of
coronary artery disease
 Clinical outcome benefit associated with heart rate reduction
The prognostic validity of resting heart rate

10. Resting heart rate independently predicts
mortality in Western and Asian populations
Okamura T et al., Am Heart J. 2004;147:1024-1032. Benetos A et al., Hypertension.1999;33:44-52.
HR<60 60≤HR≤80 80<HR≤100 HR>100 bpm
Survival probability curves for CV
mortality in French men (n=12 123)
7 10 15 21
Follow-up (years)
1.00
0.95
0.85
0.80
1 17 1913131353
0.90
P (Cox)=0.0001
Survival probability
Cumulative survival rates due to cardiac
events in Japanese men (n=3856)
Q1
Q2
Q3
Q4
<60 bpm
60-65 bpm
66-73 bpm
78 bpm
1.00
0.99
0.98
0.97
Cumulativesurvivalrate
0 5 10 15 20
Person-years
1.00
0.99
0.98
0.97
0

11. Long-term Cardiovascular Risks Associated With an
Elevated Heart Rate: The Framingham Heart Study
J Am Heart Assoc. 2014;3:e000668
Baseline Characteristics of
FHS Participants by Heart
Rate Quartile

12. In multivariable adjusted analyses, each 1-SD (11 bpm) increase in baseline
heart rate was associated with a 15% increased risk of cardiovascular
disease
This association (Cardiovascular disease) appeared most pronounced for
incident heart failure events, with each 1-SD increase in baseline heart rate
associated with a 32% increased risk of future heart failure
Association of Baseline
Resting Heart Rate and
Cardiovascular Outcomes
J Am Heart Assoc. 2014;3:e000668

13. Association of Baseline
Resting Heart Rate and
Cardiovascular Outcomes
When examined across sex-specific quartiles of heart rate, individuals in the top
quartile had a 2-fold increased risk of heart failure
Resting heart rate predicted increased risk of all-cause mortality, with each 1-
SD increase in heart rate associated with a 17% increased risk of all-cause
death (multivariable adjusted hazard ratio 1.17, 95% CI 1.11 to 1.24, P<0.0001)
J Am Heart Assoc. 2014;3:e000668

14. 1807 patients within 24 h of onset of symptoms of acute myocardial infarction
Mortality versus admission heart rate
with acute myocardial infarction
Hjalmarson A, et al., Am J Cardiol.1990;65:547-553.
0
10
20
30
40
50
Mortality(%)
<50 50-59 60-69 70-79 80-89 90-99 100-109 110-119 120
Total
In-hospital
Post-discharge
Resting heart rate (bpm)

15. Resting heart rate as a predictor of prognosis
in patients with stable CAD
JE. Ho et al. Presented at ACC 2009
Post hoc analysis in 9580 patients from the TNT study, median follow-up was 4.9 years
JE. Ho et al. Presented at ACC 2009

16. Heart rate as a predictor of
cardiovascular death
% with cardiovascular death
Heart rate < 70 bpm
Heart rate ≥ 70 bpmP = 0.0041
Hazard ratio = 1.34 (1.10 – 1.63)
Years
0 0.5 1 1.5 2
0
5
10
15
Fox K, et al. Lancet. 2008;372:817-821
Prospective data from the BEAUTIFUL placebo arm; 5438 patients with stable CAD and LVSD

17. Heart rate as a predictor of
hospitalization for heart failure
% with hospitalization for heart failure
0
5
10
15
Years
0 0.5 1 1.5 2
P < 0.0001
Hazard ratio = 1.53 (1.25 – 1.88)
Heart rate < 70 bpm
Heart rate ≥ 70 bpm
Fox K, et al. Lancet. 2008;372:817-821
Prospective data from the BEAUTIFUL placebo arm; 5438 patients with stable CAD and LVSD

18. Heart rate as a predictor of
hospitalization for myocardial infarction
P = 0.0066
Hazard ratio = 1.46 (1.11 – 1.91)
Years
0 0.5 1 1.5 2
0
Heart rate < 70 bpm
Heart rate ≥ 70 bpm
8
% with hospitalization for fatal and nonfatal MI
0
4
6
2
Fox K, et al. Lancet. 2008;372:817-821
Prospective data from the BEAUTIFUL placebo arm; 5438 patients with stable CAD and LVSD

19. The cardiovascular risk factor
“resting heart rate”
 Resting heart rate as a risk factor of
HF
In CHARM study, increased
mortality, with every 10-b.p.m.
increase associated with respective
increases of 8% in all-cause
mortality, in both HFrEF and HFpEF
J Am Coll Cardiol. 2012 May 15;59(20):1785-95

20. Treatment options for elevated HR
Angiotensin-converting enzyme (ACE)
inhibitors
Beta-blockers
Mineralocorticoid receptor antagonists

21. Limitations of beta blockers
Patients with CHF (Chronic Heart
Failure) who are on beta-blockers have
inadequately controlled heart rate (HR) 1
Patients do not tolerate the target doses
of beta-blockers used in the large clinical
trials 2
1. Clin Res Cardiol 2013;102:23–31
2. Br J Cardiol 2012;19:21–3.

22. Is heart rate adequately
addressed with the beta
blockers?

23.  Objective:
 To evaluate the use of beta-blockers in chronic
heart failure (CHF) and the extent of heart rate
reduction achieved in clinical practice and to
determine differences in outcome of patients who
fulfilled select inclusion criteria of the SHIFT study
according to resting heart rate modulated by beta-
blocker therapy
 Primary out come:
 All-cause death or hospital admission for worsening
heart failure after 1 year follow up
Clin Res Cardiol (2013) 102:23–31

24. Baseline
demographic and
clinical
characteristics,
and
pharmacotherapy
Clin Res Cardiol (2013) 102:23–31

25. 3,181 patients assessed to treatment dosages
of beta-blockers, and clinical profiles including
resting heart rate
622 (20 %) fulfilled select criteria adopted from
the randomized SHIFT trial (LVEF ≤ 35 %, sinus
rhythm, NYHA II–IV)
Of these patients, 443 patients entered
outcome analyses with complete follow up of
at least 1 year
Clin Res Cardiol (2013) 102:23–31

26. Distribution of resting heart rate of patients
fulfilling inclusion criteria for outcome analysis
Clin Res Cardiol (2013) 102:23–31

27. Heart
Rate
<70 bpm
(n = 160) (%)
Heart
rate
≥70 bpm
(n = 283) (%)
p value* Heart
Rate <75
bpm
(n = 210) (%)
Heart
rate ≥75
bpm
(n = 233) (%)
p value‡
Primary endpoint
All-cause death or
hospital
admission for worsening
heart
failure
14 (9) 59 (21) <0.01 23 (12) 50 (27) <0.01
Secondary endpoints
All-cause death 3 (2) 22 (8) <0.05 4 (2) 21 (9) <0.05
All-cause death or heart
transplantation
6 (4) 41 (15) <0.001 10 (5) 37 (16)
<0.001
Data are presented as number of first events and percentages
*Resting heart rates ≥70 bpm as compared to those<70 bpm
‡Resting heart rates ≥75 bpm as compared to those<75 bpm
1-year outcome of patients fulfilling select SHIFT criteria
The primary endpoint was significantly increased in the
group of patients with heart rates ≥70 and ≥75 bpm
Clin Res Cardiol (2013) 102:23–31

28. Kaplan–Meier 5-year event-free survival curves
according to resting heart rate
5-year event free survival was
significantly lower among
patients with heart rates ≥ 70
bpm
5-year event free survival was
significantly lower among
patients with heart rates ≥ 75
bpm
Clin Res Cardiol (2013) 102:23–31

29. Out come of the study
 In clinical practice, 53 % of CHF patients
have inadequate heart rate control (heart
rates ≥ 75 bpm) despite concomitant beta-
blocker therapy
 Further up titration of beta-blockers is not
achievable in many patients
 The administration of a selective heart rate
lowering agent, such as IVABRADINE
adjuvant to beta-blockers may pose an
opportunity to further modulate outcome
Clin Res Cardiol (2013) 102:23–31

30. Ivabradine/Metoprolol
5/25 and 5/50 XL

31. What is the adding effect of
IVABRADINE to beta
blockers therapy?

32. Study 1: Effect of early treatment with
ivabradine combined with beta-blockers
versus beta-blockers alone
 Objective:
 To analyse the effect of the early coadministration
of ivabradine and beta-blockers (intervention
group) versus beta-blockers alone (control group)
in patients hospitalised with heart failure and
reduced left ventricular ejection fraction (HFrEF)
 Primary outcome:
 HR at 28 days after discharge
 Secondary outcome
 HR at four months, drug safety
Int J Cardiol. 2016 Aug 15;217:7-11

33. Study flowchart. ACS: acute
coronary syndrome
71 patients
38
control
group
(Beta blocker)
33
Intervention
group
(Beta blocker +
Ivabradine)
Int J Cardiol. 2016 Aug 15;217:7-11

34. Int J Cardiol. 2016 Aug 15;217:7-11
Percentage of patients with heart rate values < 70 bpm
HR values (HR < 70 bpm) was significantly higher in the
intervention group
P=0.05
P=0.01
P=0.1

35.  Statistically significant differences between the two
groups with respect to the ejection fraction as well
as for the values of BNP (Brain Natriuretic Peptide)
at four months of follow-up
 No severe side effects attributable to drugs were
observed in any group
 Only 7 (21%) patients in the intervention group and
6 (15%) in the control group had bradycardia with
heart rate < 60 bpm
 The early coadministration of ivabradine and
beta-blockers during hospital admission for
acute HFrEF is feasible and safe
Int J Cardiol. 2016 Aug 15;217:7-11

36. Study 2

37. Study 2: Ivabradine in Combination with Metoprolol in
Patients with Stable Angina Pectoris: A post hoc
Analysis from the ADDITIONS Trial
ADDITIONS Trial
 To evaluate
adding
ivabradine to the
therapy of
patients on
metoprolol in
patients with
stable angina
pectoris
 Multicenter, 4-month,
non interventional,
prospective, open-
label,
 Along with metoprolol,
received ivabradine (5
or 7.5 mg, b.i.d.)
 Heart rate,
 Angina attacks,
 Nitrate
consumption,
 Quality of life (QoL)
and Tolerability
 The influence of
baseline heart rate
Objective Method Investigated
Cardiology 2016;133:83–90

38. p < 0.0001 for all differences
1.7
0.5
0.2
0
0.2
0.4
0.6
0.8
1
1.2
1.4
1.6
1.8
Base line 1 month 4 month
Meanweeklynumberof
anginaattach
Weekly number of angina attacks
p < 0.0001 for all differences
2.4
0.7
0.3
0
0.5
1
1.5
2
2.5
3
Base line 1 month 4 month
Meanweeklyuseofshort-acting
nitrates
Use of short acting nitrates
p < 0.0001 for all differences
p < 0.0001 for all differences
84.9
70.9
65.3
0
10
20
30
40
50
60
70
80
90
Base line 1 month 4 month
Meanheartrate(bpm)
Reduction in mean resting heart rate with
ivabradine in combination with metoprolol
Mean heart
rate fell by
19.7 ± 11.2
bpm
between
baseline
and month 4
Weekly
angina
attacks
decreased
8-fold
0
0.2
0.4
0.6
0.8
1
Base line 1 month 4 month
EQ-5Dindex
EQ-5D index (QoL)
The EQ-5D
index score
increased
from base
line
Cardiology 2016;133:83–90

39. Relative reduction in the number of angina attacks ( a ) and use of short-
acting nitrates per week ( b ) and the heart rate ( c ) in stable-angina
patients on metoprolol and ivabradine, compared to baseline values and
stratified by baseline heart rate <70 and ≥70 bpm
Heart reduction
more ≥70 bpm
Heart rate reductions were associated with larger
relative reductions in angina attacks and short-acting
nitrate consumption
Cardiology 2016;133:83–90

40. Safety
 Of the 989 patients in the safety set, <1% (7
patients) reported 14 adverse drug reactions
 Bradycardia was reported in only 1 patient
 The tolerability of the metoprolol and ivabradine
association was rated as ‘very good’ or ‘good’ by
>99% of physicians
 No deaths or MIs were reported
Cardiology 2016;133:83–90
Study concluded that Ivabradine combined with
metoprolol safely and effectively reduces heart rate,
angina attacks and nitrate use, and improves QoL in
stable-angina patients

41. Study 3: Ivabradine/Metoprolol combination in
patients with stable angina
 Objective:
 To assess the effect of
ivabradine administration on top
of metoprolol over 4 months, in
patients with CAD and stable
angina
 Method:
 N= 636 CAD patients
 Post hoc analysis
 Duration: 4 months
 Data recorded at baseline, 1
and 4 months
 Ivabradine dose is 5 mg twice
daily
 Evaluation parameters:
 To record the effect of
ivabradine on:
 Resting heart rate (HR),
 Angina attacks,
 Use of nitroglycerin,
 Angina classification
 QoL
Clinical Cardiology 2016; 39(12):697–702

42. -7.7
-13.7
-22.8
-25 -20 -15 -10 -5 0
<70
70-80
>80
Heartrate(bpm)/1stvisit
Heart rate at rest; difference between the first and third
study visits
Patients with a baseline HR >80 bpm, 70 to 80 bpm, and <70 bpm
presented an average HR decrease of 22.8 bpm, 13.7 bpm, and
7.7 bpm, respectively
Clinical Cardiology 2016; 39(12):697–702
Study 3: Ivabradine/Metoprolol combination in patients with
stable angina

43. 2
0.5
0.2
-1
-0.5
0
0.5
1
1.5
2
2.5
3
Visit 1 Visit 2 Visit 3
No. of angina attacks
1.4
0.3
0.1
-0.5
0
0.5
1
1.5
2
Visit 1 Visit 2 Visit 3
No. of consumption of short acting
nitrates
The combination of
ivabradine with metoprolol
significantly
reduced angina events and
use of nitroglycerin, this
leads to improved
QoL
Clinical Cardiology 2016; 39(12):697–702
Study 3: Ivabradine/Metoprolol combination in patients with stable angina

44. 41.7
84.6
42.9
13.513.8
0.951.6 0.95
0
20
40
60
80
100
120
Visit 1 Visit 3
Angina classification according to the Canadian
Cardiovascular Society (% of patients) at first and third visit
Stage IV
Stage III
Stage II
Stage I
The percentage of patients with angina CCS (Canadian Cardiovascular
Society) classes III or IV decreased from 15.4% at the first visit to 1.9%
at the third
Clinical Cardiology 2016; 39(12):697–702
Study 3: Ivabradine/Metoprolol combination in patients with
stable angina

45. Study 3: Ivabradine/Metoprolol
combination in patients with stable
angina
 The improvement of symptoms and angina class led to
a significant 14.7-point increase in EQ-5D
questionnaire score (P < 0.001)
 Adherence to treatment during the entire trial was high
(98%)
Clinical Cardiology 2016; 39(12):697–702

46. Real life Case: 2
 22 years female, no other risk factors
 Complains of palpitation
 Pulse 112/min, BP 110/70 mmHg, Chest/CVS – NAD
 ECG – Sinus Tachycardia
 Echo – LVEF 64%, no other abnormalities
 Current medications
Sustained release Propranolol 40 mg BD
 What’s next??

47. Study 4: Ivabradine in combination with
metoprolol succinate in the treatment of
inappropriate sinus tachycardia (IST)
Objective:
 To assess the efficacy and safety of combining ivabradine with
metoprolol succinate in patients with refractory highly
symptomatic IST
Methods:
 N= 20 (36±10 years; 16 women) with IST
 All received metoprolol succinate 95 mg single dose during
first month
 After 1 month of treatment with metoprolol, ivabradine added
up to 7.5 mg twice daily
 Holter monitoring and treadmill stress test performed at
baseline, after 4, and 8 weeks of the study
J Cardiovasc Pharmacol Ther. 2013 Jul;18(4):338-44

48. Significantly lower resting HR
on each step of the treatment
(114.4 ±7.5 vs 97.3 ± 14.4 vs
90.5 ± 13.3 bpm; P < .001)
Mean HR significantly lower in
patients treated with both drugs
in comparison to baseline and
monotherapy (103.3 ± 3.9 vs 84.1
± 5.9 vs 77.6 ± 5.2 bpm; P < .001)
J Cardiovasc Pharmacol Ther. 2013 Jul;18(4):338-44
Resting heart rate
Mean heart rate (HR) during 24-hour Holter
monitoring

49. The mean HR on ivabradine
and metoprolol was
significantly lower than for
metoprolol monotherapy
Daytime mean heart rate (HR)
Correlation between heart rate (HR) reduction and
mean HR on 24-hours Holter monitoring in patients
treated with combined
Data analysis revealed correlations
between HR reduction on
combined treatment and baseline
HR for mean 24 hours HR,
daytime HR, and maximum HR
J Cardiovasc Pharmacol Ther. 2013 Jul;18(4):338-44

50. Representative examples of heart rate (HR) trends recorded during 24-hour
Holter monitoring in patients with inappropriate sinus tachycardia (IST)
J Cardiovasc Pharmacol Ther. 2013 Jul;18(4):338-44

51.  The maximal duration of exercise was longer in combined
therapy compared to baseline and metoprolol therapy
 Reduction of events was significant during combined drug
therapy (mean events 5 ± 1 vs 16 ± 4; P < .05)
 A significant reduction of symptoms, evaluated by means of
EHRA (European Heart Rhythm Association) score, after 30
days with ivabradine combination compared to metoprolol
 Combination is well tolerated
 Did not observe side effects such as severe bradycardia or
hypotension
 Well option for IST
J Cardiovasc Pharmacol Ther. 2013 Jul;18(4):338-44

52. Take Home Message..
 Heart rate is an independent and modifiable risk factor in
patients with chronic systolic HF and a powerful risk marker in
patients with IHD
 Reduction of HR appears to reduce morbidity and mortality and
is likely to reduce the costs of rehospitalization in patients with
systolic HF
 Clinical data is very clear regarding the benefit from heart rate
reduction with Ivabradine in patients with coronary artery
disease and heart rate above 70 bpm
 When added to existing standard therapies including
maximized β-blockers, ivabradine reduced HR, decreased
hospitalizations or cardiovascular deaths, and improved quality
of life and LV size and function with relatively limited adverse
events

53.  Combination favors lower beta-blocker doses, facilitate up-
titration for the achievement of target HR, and avoid the possible
dose-dependent adverse events related to their use
 Significantly decreased angina symptoms as well as use of
nitroglycerin in patients with stable angina and CAD, leading to
improved quality of life
 Significant reduction in Inappropriate Sinus Tachycardia (IST)-
related symptoms
 Thus combining ivabradine with metoprolol is an effective and
well-tolerated treatment option for HF, stable angina and IST
Take Home Message

54. THANK YOU