1. Ivabradine
Dr.Rajesh Rajan M.D.,D.Card,FACC,FAHA,FESC PRESIDENT – IACC 1

2. Elevated Resting Heart Rate
Accelerates production of atherosclerosis (Int J Cardiol 2008;126:302-12)
Associated with coronary plaque disruption (Circulation 2001;126: )
Framingham Study
progressive increase in all cause and cardiovascular mortality in relation
to antecedent HR (Am Heart J 1987; 113: )
Continuous increase in death rates in survivors of Acute MI
starting at HR > 70 (J Am Coll Cardiol 2007;50:823-30)
Circ journal: Heart rates greater than 80. 2

3. Beta-Adrenoceptors Endogenous catecholamines activate B-receptors
(Adenylate Cyclase)
Increased cAMP
Increased Ca++ influx
B-receptors, located on cardiac nodal tissue, the conducting system, and contracting myocytes
Inotropic effects due to several methods including increased calcium availability to Troponin-C in cardiac myocytes
Chronotropic, in part at least, to activation of L-type calcium channels, and their effect on the action potential.
Inotropic
Chronotropic 3

4. Beta Blockers (BB) B1negative chronotropy and inotropy
AV conduction delay
Reduced atrial and ventricular arrythmias
B2Bronchoconstriction
Peripheral unopposed alpha constriction
Decrease glycogenolysis
(contribute to hypoglycemic events)
Other antagonize release of renin
reduces intraocular pressures
Alpha constriction, which at least initially increases peripheral resistance, but also of potential concern in cocaine users.
Glycogenolysis, particularly in Type I diabetics
Renin, thereby altering the renin-angiotensin pathway 4

5. Impact of BB Acute MI CHF Norwegian Multicenter Study Group Timolol *
CAPRICORN †
ISIS-1 ‡
CHF
COPERNICUS £
MERIT-HF €
Norwegion: AMI, given Timilol for up to 33 months, showing reduced mortality in the Timolol group.
CAPRICORN, AMI and EF lower than 40% BB reduced all cause mortality
ISIS-1, Atenolol vs placebo during hospitalization for AMI (16,000 patients). Showed reduced in-hospital mortality.
COPPERNICUS, Carvedilol in patients with EF less than 25%, reduced severity of HF and hospitalizations
MERIT-HF: Metoprolol XL vs placebo, 4000 patients with Class II-IV HF, EF of less than 40%, stopped early due to mortality benefit with Metoprolol 5

6. Intolerence of BB Side effects
Bronchoconstriction, AV delay, hypoglycemia
Weight gain, depression, fatigue
BB may not be tolerated in high enough doses to attain
heart rates below 70bpm
Acute setting (Acute MI, or CHF), the negative inotropic
effect could be deleterious
This has been shown in dogs (Eur Heart J (2004) 25 (7):
Target doses for many studies are between 150 to 200mg of metoprolol daily. 6

7. If Current
The funny current is highly expressed in spontaneously active cardiac regions, such as the sinoatrial node (SAN, the natural pacemaker region), the atrio-ventricular node (AVN) and the Purkinje fibres of conduction tissue.
Particularly unusual, the funny current is a mixed sodium-potassium current, inward and slowly activating on hyperpolarization at voltages in the diastolic range (normally from -60/-70 mV to -40 mV).
When at the end of a sinoatrial action potential the membrane repolarizes below the If threshold (about -40/-50 mV), the funny current is activated and supplies inward current, which is responsible for starting the diastolic depolarization phase (DD);
By this mechanism, the funny current controls the rate of spontaneous activity of sinoatrial myocytes, hence the cardiac rate.

8. If Current
Another unusual feature of If is its dual activation by voltage and by cyclic nucleotides. Cyclic adenosine monophosphate (cAMP) molecules bind directly to f-channels and increase their open probability. cAMP dependence is a particularly relevant physiological property,
Since it underlies the If –dependent autonomic regulation of heart rate. Sympathetic stimulation raises the level of cAMP molecules which bind to f-channels and shift the If activation range to more positive voltages;
This mechanism leads to an increase of the current at diastolic voltages and therefore to an increase of the steepness of DD and heart rate acceleration.
Parasympathetic stimulation (which acts to increase probability of potassium channels opening but decreases the probability of calcium channel opening) decreases the heart rate by the opposite action, that is by shifting the If activation curve towards more negative voltages.

9. Ivabradine Does not alter… Specifically binds the Funny channel
Reduces the slope for diastolic depolarization
Prolongs diastolic duration
Does not alter…
Ventricular repolarization
Myocardial contractility
Blood pressure
Because it binds to the F channel in the open position, it has greatest activity when there is greater open-close cycling of the F channel.
Hence it exhibits is greatest effect when heart rates are highest.
In that sense it has a partial self limiting capability. 9

10. Ivabradine Trials Reduces atherosclerosis (Circ 2008;117:2377-87)
Decreases vascular oxidative stress
Improves endothelial function
Increases exertional tolerance and time to ischemia in
patients with > 3 months angina (Circ 2003;107:817-23)
Non-inferior to Atenolol (Eur Heart J 2005;26: )
Exercise tolerance, time to angina or ischemia
Non-inferior to Amlodipine (Drugs 2007;67(3): )
Atherosclerosis, Male apolipoprotein E-deficient mice fed a high-cholesterol diet, Ivabradine decreased atherosclerotic plaque size in the ascending aorta by >70% in 6 weeks.
Exertional tolerance: Using bicycle Exercise Tolerence test, there was an increased time to ST depression and time to exercise limiting angina. NOTE, this was after a 2-7 day washout of all anti-anginals, including betablockers.
Compared to atenolol for 12 weeks of administration 10

11. MorBidity-mortality EvAlUation of The I f inhibitor Ivabradine in patients with coronary disease and left ventricULar dysfunction
BEAUTIFUL Trial

12. RATIONALE
In CAD patients, high heart rate is associated with higher mortality1
CAD patients with associated LVD are at higher risk of mortality2
Heart rate reduction could reduce mortality in CAD patients3
Ivabradine is a pure heart rate reducing agent with proven antianginal and anti-ischemic efficacy 4,5,6
1- Diaz A,et al. Eur Heart J. 2005;26: Emond M. Circulation. 1994;90:2645– Cucherat Ml. Eur Heart J. 2007;28: Borer JS et al. Circulation. 2003;107: Tardif JC,et al. Eur Heart J. 2009;30: Tardif JC et al. Eur Heart J. 2005;26:

13. Pathophysiological objective
MorBidity-mortality EvAlUation of The I f inhibitor Ivabradine in patients with coronary disease and left ventricULar dysfunction
Clinical objective
To examine the effects of ivabradine on cardiovascular events in coronary patients with left ventricular dysfunction
Pathophysiological objective
To examine the effects of elevated HR (>70 bpm) on cardiovascular events in these coronary patients

14. 781 sites in 33 countries across 4 continents
Worldwide study
participants with documented coronary artery disease and left ventricular dysfunction
781 sites in 33 countries across 4 continents

15. Inclusion criteria Male or female
Nondiabetic 55 years, diabetic 18 years
Documented coronary artery disease
Sinus rhythm and resting heart rate 60 bpm
Documented left ventricular systolic dysfunction (<40%)
Clinically stable for 3 months with regards to angina or heart failure symptoms or both
Therapeutically stable for 1 month (appropriate or stable doses of conventional medications)
K. Fox et al. Am Heart J. 2006;152:

16. Follow-up for 12 to 35 months–median 19 months
Design of the study
Ivabradine 5 mg  7.5 mg bid
Multicenter (781 centers / 33 countries) randomized trial
patients with stable CAD and left ventricular dysfunction (EF <40%)
Already receiving appropriate conventional cardiovascular medical therapy
Placebo bid
Visits
Follow-up for 12 to 35 months–median 19 months
Fox K et al. Lancet. 2008;372:

17. 12 138 screened 10 917 randomized 5479 to ivabradine 5438 to placebo
Patients and follow-up
screened
randomized
5479 to ivabradine
5438 to placebo
5479 analyzed
5438 analyzed
Median study duration: 19 months Maximum: 35 months
Fox K et al. Lancet. 2008;372:

18. Baseline characteristics
Placebo
Ivabradine
All
Time since CAD diagnosis (years)
8.2 (7.1)
8.1 (7.0)
8.2 (7.0)
Previous MI (%) 89 88 88
Time since last MI (years)
6.2 (6.0)
5.9 (5.7)
6.0 (5.9)
History of diabetes (%) 37 37 37
History of hypertension (%) 71 71 71
Previous coronary revascularization (%) 52 51 52
Values in parentheses are standard deviations
Fox K et al. Lancet. 2008;372:

19. Concomitant treatment
-blockers (%)
Statins (%)
Antithrombotic agents (%)
Renin-angiotensin blockers (%) 87 74 94 90
Placebo
Ivabradine
All
Fox K et al. Lancet. 2008;372:

20. Results

21. Heart rate above 70 bpm increases risk of myocardial infarction by 46%
Prospective data from the BEAUTIFUL placebo arm 8
Hazard ratio = 1.46 (1.11 – 1.91)
P=0.0066
Heart rate ≥70 bpm 6
% with hospitalization for
fatal and nonfatal MI 4
Heart rate <70 bpm 2
0.5 1
1.5 2
Years
Fox K et al. Lancet. 2008;372:

22. Heart rate above 70 bpm increases
risk of coronary revascularization by 38%
% with coronary revascularization 6
P=0.037
Hazard ratio = 1.38 (1.02 – 1.86)
Heart rate ≥70 bpm 4 2
Heart rate <70 bpm
0.5 1
1.5 2
Years
Fox K et al. Lancet. 2008;372:

23. Effect of ivabradine on primary endpoint (Overall population)
% with primary composite end point of CV death, hospitalization for acute MI, or for new-onset or worsening heart failure
Ivabradine
Placebo
P=0.94
Hazard ratio = 1.00 (0.91 – 1.10) 5 10 15 20 25
Years
0.5 1
1.5 2
Fox K et al. Lancet. 2008;372:

24. fatal or nonfatal MI (%)
Ivabradine reduces fatal and nonfatal myocardial infarction (HR ≥70 bpm) 8
P=0.001
Hazard ratio = 0.64 (0.49 – 0.84)
Placebo
(HR >70 bpm)
RRR 36%
fatal or nonfatal MI (%)
Hospitalization for 4
Ivabradine
0.5 1
1.5 2
Years
RRR: relative risk reduction
Fox K et al. Lancet. 2008;372:

25. Ivabradine shifts the patients from high risk to low risk8
HR >70 bpm in placebo
(mean HR = 79 bpm)
-36%* 4
HR <70 bpm in placebo (mean HR = 64 bpm)
fatal or nonfatal MI (%)
Hospitalization for
HR > 70 bpm with Procoralan (mean HR = 66 bpm after treatment)
Procoralan eliminate the excess risk of MI in CAD patioents with HR above 7à who are at higher risk of CV events, and restore that risk to a low level by reducing specifically HR below 70 bpm.
*P=0.001
**P=0.0066
0.5 1
1.5 2
Years
Fox K et al. Lancet. 2008;372:

26. Ivabradine reduces the need for revascularization (HR ≥70 bpm)8
Hazard ratio = 0.70 (0.52 – 0.93)
P=0.016
Placebo
(HR >70 bpm)
RRR 30%
Coronary revascularization (%) 4
Ivabradine
0.5 1
1.5 2
Years
RRR: relative risk reduction
Fox K et al. Lancet. 2008;372:

27. Ivabradine reduces all coronary events in coronary patients with HR ≥70 bpm
Predefined end point
Hazard ratio
Risk reduction
P value
0.114
31%
0.69
Fatal MI
0.001
36%
0.64
Fatal and nonfatal MI
0.023
22%
0.78
Fatal and nonfatal MI or unstable angina
0.009
23%
0.77
Fatal and nonfatal MI, unstable angina, or revascularization
0.016
30%
0.70
Coronary revascularization
Fox K et al. Lancet. 2008;372: 27 27

28. Optimal reduction in heart rate in coronary patients with HR ≥70 bpm90 80
Placebo 70
Heart rate (bpm) 60
Ivabradine 50 15 30 90
180
360
540
720
Follow-up (days)
Fox K, et al. Lancet. 2008;372:

29. New Results
In angina patients

30. New results in angina patients
Rationale
Angina is the most common clinical manifestation of coronary artery disease (CAD).
Ivabradine has established anti-ischemic and antianginal efficacy.
In the large BEAUTIFUL trial, Ivabradine demonstrates that it reduces coronary events in CAD patients.
Objective
To explore the effects of Ivabradine on cardiovascular outcomes
in BEAUTIFUL patients with limiting angina at baseline.

31. 12 138 patients with CAD and LVD screened
Design and methodology
New results in angina patients
patients with CAD and LVD screened
randomized
1507 randomized
with angina
773 to placebo
734 to Ivabradine
734 analyzed
773 analyzed
Fox K, Ford I, et al; BEAUTIFUL Investigators. Effect of ivabradine on cardiovascular outcomes in patients with stable coronary artery diseaseand left-ventricular systolic dysfunction with limiting angina: a subgroup analysis of the randomized, controlled BEAUTIFUL trial. Data on file.

32. New results in angina patients Total BEAUTIFUL population
Baseline treatment
New results in angina patients
Patients with angina
Total BEAUTIFUL population
Ivabradine (n=734)
Placebo (n=773)
Ivabradine
Placebo
Aspirin or antithrombotic agent
92%
92%
94%
94%
Statin
67%
64%
74%
74%
ACE inhibitor and/or ARB
88%
86%
90%
90%
β-Blocker
89%
90%
87%
87%
Fox K, Ford I, et al; BEAUTIFUL Investigators. Effect of ivabradine on cardiovascular outcomes in patients with stable coronary artery diseaseand left-ventricular systolic dysfunction with limiting angina: a subgroup analysis of the randomized, controlled BEAUTIFUL trial. Eur heart Jour On line.

33. -24% Ivabradine reduces primary end point in angina patients
New results in angina patients
Primary end point(PEP) : CV death + hospitalization for HF or MI
n=1507
P=0.05
Years 5 10 15 20
0.5 1
1.5 2
Cumulative incidence
for PEP* (%)
-24%
Placebo
Ivabradine
Fox K, Ford I, et al; BEAUTIFUL Investigators. Effect of ivabradine on cardiovascular outcomes in patients with stable coronary artery diseaseand left-ventricular systolic dysfunction with limiting angina: a subgroup analysis of the randomized, controlled BEAUTIFUL trial. Eur heart Jour On line.

34. Ivabradine reduces myocardial infarction in patients with angina
New results in angina patients
All patients with angina
Patients with angina and
heart rate >70 bpm
Placebo
Ivabradine
Hospitalization for fatal and nonfatal MI
HR (95% CI), 0.58 (0.37–0.92); P=0.021
Years 5 10 15
0.5 1
1.5 2
Event rate (%)
42%
Placebo
Ivabradine
Hospitalization for fatal and nonfatal MI
HR (95% CI), 0.27 (0.11–0.66); P=0.002
Years 5 10 15
0.5 1
1.5 2
Event rate (%)
73%
Fox K, Ford I, et al; BEAUTIFUL Investigators. Effect of ivabradine on cardiovascular outcomes in patients with stable coronary artery diseaseand left-ventricular systolic dysfunction with limiting angina: a subgroup analysis of the randomized, controlled BEAUTIFUL trial. Eur heart Jour On line.

35. Summary of observed cardiovascular risk reduction in angina patients
New results in angina patients
24%
0.76
Primary composite end point
12%
0.88
CV death
42%
0.58
16%
0.84
Hospitalization for HF
13%
0.87
All-cause mortality
Risk reduction
Hazard ratio
Predefined end point
30%
0.70
Coronary revascularization
Hospitalization for MI
(n=1507)
Fox K, Ford I, et al; BEAUTIFUL Investigators. Effect of ivabradine on cardiovascular outcomes in patients with stable coronary artery diseaseand left-ventricular systolic dysfunction with limiting angina: a subgroup analysis of the randomized, controlled BEAUTIFUL trial. Eur heart Jour On line.

36. In brief
Ivabradine, the first selective and specific If inhibitor, has already demonstrated antianginal and anti-ischemic efficacy and improvement of cardiac performance
BEAUTIFUL, the first morbidity-mortality trial with ivabradine, includes patients with documented stable coronary artery disease and left ventricular dysfunction receiving optimal guidelines-based therapy.
In patients with coronary artery disease and left ventricular dysfunction, those with a heart rate >70 bpm have a higher risk of cardiovascular mortality, hospitalization for myocardial infarction, and heart failure.
In patients with heart rate >70 bpm, ivabradine reduces the composite of fatal and nonfatal myocardial infarction and reduces the need for revascularisation.
In angina patients, ivabradine reduces the primary end point of cardiovascular death, hospitalization for heart failure, or for myocardial infarction.

37. Systolic Heart failure treatment with the If inhibitor ivabradine Trial
SHIFT Trial
published online August 29, 2010 DOI: /S (10)

38. Background
Elevated heart rate is associated with poor outcome in a number of cardiovascular conditions including heart failure
Heart rate remains elevated in many heart failure patients despite treatment by beta-blockers
Ivabradine is a novel heart rate-lowering agent acting by inhibiting the If current in the sino-atrial node
We hypothesized that the addition of ivabradine to recommended therapy would be beneficial in heart failure patients with elevated heart rate

39. Primary objective
To evaluate whether the If inhibitor ivabradine
improves cardiovascular outcomes
in patients with
1. Moderate to severe chronic heart failure
2. Left ventricular ejection fraction 35%
3. Heart rate 70 bpm and
4. Recommended therapy

40. 6505 patients, 37 countries, 677 centres
Multinational study
Bulgaria
Czech Republic
Estonia
Hungary
Europe
Germany Portugal
Belgium Greece Spain
Denmark Ireland Sweden
Finland Italy Turkey
France The Netherlands UK
Latvia
Lithuania
Norway
Poland
Romania
Russia
Slovakia
Slovenia
Ukraine
North America
Canada
Asia
China
Hong Kong
India
South Korea
Malaysia
South America
Argentina
Brazil
Chili
Australia
6505 patients, 37 countries, 677 centres

41. Class II to IV NYHA heart failure Ischaemic/non-ischaemic aetiology
Inclusion criteria
18 years
Class II to IV NYHA heart failure
Ischaemic/non-ischaemic aetiology
LV systolic dysfunction (EF 35%)
Heart rate 70 bpm
Sinus rhythm
Documented hospital admission for worsening heart failure 12 months
Swedberg K, et al. Eur J Heart Fail. 2010;12:75-81. 41

42. Ivabradine 7.5/5/2.5 mg bid according to
Study design
Ivabradine 5 mg bid
Ivabradine 7.5/5/2.5 mg bid according to
HR and tolerability
Screening
7 to 30 days
Matching placebo, bid
D D D M4
Every 4 months
3.5 years
Swedberg K, et al. Eur J Heart Fail. 2010;12:75-81. 42

43. Primary composite endpoint
Study endpoints
Primary composite endpoint
Cardiovascular death
Hospitalization for worsening heart failure
Other endpoints
All-cause / CV / HF death
All-cause / CV / HF hospitalization
Composite of CV death, hospitalization for HF or non-fatal MI
NYHA class / Patient & Physician Global Assessment
In total population and in patients with at least 50% target dose of beta-blockers
Swedberg K, et al. Eur J Heart Fail. 2010;12:75-81. 43

44. 7411 screened 6558 randomized 3268 to ivabradine 3290 to placebo
Patients and follow-up
7411 screened
6558 randomized
3268 to ivabradine
3290 to placebo
Excluded: 27
Excluded: 26
3241 analysed
2 lost to follow-up
3264 analysed
1 lost to follow-up
Median study duration: 22.9 months; maximum: 41.7 months

45. Baseline characteristics
Ivabradine
3241
Placebo
3264
Mean age, y
60.7
60.1
Male, % 76 77
Ischaemic aetiology, % 68 67
NYHA II, % 49
NYHA III/IV, % 51
Previous MI, % 56
Diabetes, % 30 31
Hypertension, % 66

46. Baseline characteristics
Ivabradine
3241
Placebo
3264
Mean heart rate, bpm 80
Mean LVEF, % 29
Mean SBP, mm Hg
122
121
Mean DBP, mm Hg 76
eGFR, mL/min/1.73 m2 75

47. Chronic HF background treatment
Patients (%)
100 91 91 89 90 90 84 83
Ivabradine 80
Placebo 70 61 59 60 50 40 30 22 22 20 10 3 4
Beta-blockers
ACEIs and/or
Diuretics
Aldosterone
Digitalis
ICD/CRT
ARBs
antagonists

48. Background beta-blocker treatment
Patients (%)
100
Ivabradine 10 20 30 40 50 60 70 80 90 89 89
Placebo 56 56 26 26
BB at randomization
At least 50% target daily dose
Target daily dose

49. Mean heart rate reduction
Mean ivabradine dose: 6.4 mg bid at 1 month
6.5 mg bid at 1 year
Heart rate (bpm) 90
Ivabradine
Placebo 80 80 75 75 70 67 64 60 50
2 weeks 1 4 8 12 16 20 24 28 32
Months

50. Primary composite endpoint
Ivabradine n=793 (14.5%PY) Placebo n=937 (17.7%PY)
HR = 0.82 [95% CI ] p<0.0001
Cumulative frequency (%) 40
Ivabradine
Placebo
- 18% 30 20 10 6 12 18 24 30
Months

51. Hospitalization for heart failure
Ivabradine n=514 (9.4%PY) Placebo n=672 (12.7%PY)
HR = 0.74 [95% CI ] p<0.0001
Cumulative frequency (%) 30
Ivabradine
Placebo
- 26% 20 10 6 12 18 24 30
Months

52. Cardiovascular death HR = 0.91 p=0.128
Ivabradine n=449 (7.5%PY) Placebo n=491 (8.3%PY)
HR = p=0.128
Cumulative frequency (%) 30
Ivabradine
Placebo 20 10 6 12 18 24 30
Months

53. Effect of ivabradine on outcomes
Endpoints
Hazard ratio
95% CI
p value
Primary composite endpoint
0.82
[0.75;0.90]
p<0.0001
All-cause death
0.90
[0.80;1.02]
p=0.092
Death from HF
0.74
[0.58;0.94]
p=0.014
Hospitalisation for any cause
0.89
[0.82;0.96]
p=0.003
Hospitalisation for CV reason
0.85
[0.78;0.92]
p=0.0002
CV death/hospitalisation for HF or non-fatal MI
[0.74;0.89]

54. Effect of ivabradine in prespecified subgroups
Test for interaction
Age <65 years ≥65 years
Sex Male Female
Beta-blockers No Yes
Aetiology of heart failure Non-ischaemic
Ischaemic
NYHA class NYHA class II
NYHA class III or IV
Diabetes No Yes
Hypertension No Yes
Baseline heart rate <77 bpm
≥77 bpm
p=0.029
0.5
1.0
1.5
Hazard ratio
Favours ivabradine
Favours placebo

55. Patients with at least 50% BB target dose (n=3181)
p value
Ivabradine
Placebo
Hazard ratio
Primary composite endpoint ns
330
(11.9 PY)
362
(13.3 PY)
0.90
Cardiovascular death ns
176
(5.9 PY)
175
(5.9 PY)
1.00
Hospitalisation for worsening HF
213
(7.7 PY)
260
(9.6 PY)
0.81
p=0.021
0.5
1.0
1.5
Hazard ratio
Favours ivabradine
Favours placebo

56. NYHA class changes p=0.0003 Ivabradine Placebo 70 68 28 24 6 5
Patients (%) 70 68
p=0.0003 70 60
Ivabradine 50
Placebo 40 28 30 24 20 10 5 6
Improvement
Stability
Worsening

57. Incidence of selected adverse events (N = 6492)
Patients with an event
Ivabradine
N=3232, % (n)
Placebo
N=3260, % (n)
p value
All serious adverse events
45% (1450)
48% (1553)
0.025
All adverse events
75% (2439)
74% (2423)
0.303
Heart failure
25% (804)
29% (937)
0.0005
Symptomatic bradycardia
5% (150)
1% (32)
<0.0001
Asymptomatic bradycardia
6% (184)
1% (48)
Atrial fibrillation
9% (306)
8% (251)
0.012
Phosphenes
3% (89)
1% (17)
Blurred vision
<1% (7)
0.042

58. Conclusion
Heart failure with systolic dysfunction and elevated heart rate is associated with poor outcomes (primary composite endpoint in the placebo group is 18%/year)
Ivabradine reduced CV mortality or heart failure hospitalization by 18% (p<0.0001). The absolute risk reduction was 4.2%
This beneficial effect was mainly driven by a favourable effect on heart failure death/hospital admission (RRR 26%)
Overall, treatment with ivabradine was safe and well tolerated

59. ESC
Should be considered to reduce the risk of HF hospitalization in
patients in sinus rhythm with an EF ≤35%, a heart rate remaining ≥70
b.p.m., and persisting symptoms (NYHA class II–IV) despite treatment
with an evidence-based dose of beta-blocker (or maximum tolerated dose
below that), ACE inhibitor (or ARB), and an MRA (or ARB).
- IIa B
May be considered to reduce the risk of HF hospitalization in patients in
sinus rhythm with an EF ≤35% and a heart rate ≥70 b.p.m. who are unable to
tolerate a beta-blocker. Patients should also receive an ACE inhibitor (or ARB)
and an MRA (or ARB) ]
- IIb C

60. Autonomic Nervous System
ACh = acetylcholine; AC = adenylate cyclase; β-AR = β-adrenoceptor receptor;
Gi = inhibitory G-protein (inhibits AC); Gs = stimulatory G-protein (stimulates AC);
M2-R= type-2 muscarinic receptor; NA = noradrenaline (norepinephrine). 60

61. 61

62. Autonomic Nervous System
ACh = acetylcholine; AC = adenylate cyclase; β-AR = β-adrenoceptor receptor;
Gi = inhibitory G-protein (inhibits AC); Gs = stimulatory G-protein (stimulates AC);
M2-R= type-2 muscarinic receptor; NA = noradrenaline (norepinephrine). 62