Coralan

Ivabradine
Adding more life to years in angina and heart
failure patients
CORALAN: Dual indication in angina and heart failure

Available in 100 countries worldwide

Despite contemporary therapy, 1/3 of chronic stable angina
outpatients are still symptomatic

Pharmacological treatments
+ revascularization

1/3 of chronic stable angina outpatients

are still symptomatic (weekly episodes)1

1. Beltrame JF et al. Arch Intern Med. 2009;169(16):1491-1499.

 IVABRADINE in Angina
• 2005 -EMA,approved ivabradine) for chronic,
stable angina patients, who remain
inadequately controlled despite an optimal
dose of BB,whose HR is above 60 BPM
OR
• unable to tolerate or with a contraindication
to the use of BB.
 Ivabradine in angina
based on results of
• ASSOCIATE trial(coralan in 889pts.given on top
of atenolol 50 mg o.d, showed additional
efficacy on all ETT parameters at trough of
drug activity) and
• The BEAUTIFUL trial( large outcome study done in 10,917
patients with CAD and LV-dysfunction (EF< 42%) on top of optimal
background therapy with 86.9%patients receiving beta-blockers.in
patients with limiting angina,on coralan had a lesser risk of having a heart
attack, of getting admitted to hospital for heart failure or cardiovascular
death (coralan 12% vs placebo 15.5%).
 Reduces myocardial infarction

Angina
patients
with LVSD
(Left Ventricular
Systolic Dysfunction)

Fox K et al. Eur Heart J. 2009;30:2337-2345.

 is a well-recognized antianginal for patients

ANGINA RELIEF EVENT PREVENTION

 First-line
 Lifestyle management (diet,
Short-acting nitrate + beta-blockers
regular physical exercise)
or CCB-heart rate lowering
-Consider CCB-DHP if low heart rate or
intolerance/contraindications  Control of risk factors
-Consider beta-blockers + CCB-DHP if CCS angina > 2

 Second-line  Treatments
Ivabradine Aspirin
Long-acting nitrates Statins
Nicorandil Consider ACE inhibitors or ARBs
Ranolazine
Trimetazidine

Montalescot G. et al. European Heart Journal.2013;34:2949–3003.

 Ivabradine

Adding More Life to Years in Angina

a. Mode of action

16PA1056SA - For internal circulation only

b. Improving myocardial perfusion
c. Clinical benefits
d. Patient profiles
e. In practice
 AnginaPactoris
Angina Pectoris

Unique mechanism of action

If Channel

Control RR
Coralan 0.3 µM

0 mV

-40 mV

-70 mV
Delay of diastolic depolarization
in the sinus node

DiFrancesco D, Camm JA. Drugs. 2004;64:1757-1765.

 AnginaPactoris
Angina Pectoris

Unique pharmacological properties

• Negative chronotropic effect

• No impact on the inotropism and dromotropism of the heart

• No coronary constriction

• Increases stroke volume

• Preserves cardiac output

 The MOST tested antianginal agent

Coralan1-3

1. Werdan K. et al. Clin Res Cardiol. 2012;101:365-373. 2. Amosova E et al. Cardiovasc Drugs Ther. 2011;25:531-537. 3. Fox K et al. Eur Heart J. 2009;30:2337-
2345. 4. Wei J et al. Int J Cardiol. 2011;146(1):4-12. 5. Ezekowitz MD, Hossack K, Mehta JL, et al. Amlodipine in chronic stable angina: results of a multicenter
double-blind crossover trial. Am Heart J. 1995;129:527-535. 6. Nissen SE et al. JAMA. 2004;292:2217-2225. 7. Poole-Wilson PA et al. Lancet. 2004;364:849-857.
8. Stone PH et al. J Am Coll Cardiol. 2006;48(3):566-575. 9. Chaitman BR et al. JAMA. 2004;291(3):309-316. 10. Morrow DA et al. JAMA. 2007;297:1775-1783.
11. Di Somma S et al. Cardiovasc Drugs Ther. 1993;7(1):119-123. 12. IONA Study Group. Lancet. 2002;359:1269-1275.
An Appraisal in the Management of

16PA1067SA - For internal circulation only

Heart Failure
 Coralan is recommended in the
2012 ESC guidelines on the
management of stable heart failure 1

ACE inhibitor

-Blocker Ivabradine
MR antagonist NYHA class II-IV
Systolic dysfunction (EF ≤35%)
Heart rate ≥70 bpm (sinus rhythm)

1. McMurray J et al. European Society of Cardiology Guidelines for the diagnosis and treatment of acute and chronic
heart failure 2012. Eur Heart J. 2012;33:1787-1847.
 IVABRADINE

Adding More Life and Years in HF

a. Improving systolic function
b. Clinical benefits
c. Patient profiles
d. In practice
ivabradine improves systolic function
 Heart Failure

Rapidly improves symptoms

(when added early to beta-blockers)
P<0.003
Number of patients improving by at
least one NYHA class

Coralan + carvedilol* Carvedilol**

(n=42) (n=38)
*up to 5mg/12.5 mg bid **up to 25 mg bid Duration of therapy: 3 months

Adapted from Volterrani M et al. Effect of carvedilol, ivabradine or their combination on exercise capacity in patients with heart failure (the
Systolic Heart failure treatment with
the If inhibitor ivabradine Trial
 Patients and follow-up

7 411 screened
6 558 randomised

3268 to Procoralan 3290 to placebo

Excluded patients: 27 Excluded patients: 26
Patients from removed centres: 25 Patients from removed centres : 21
Study drug not dispensed: 2 Study drug not dispensed: 5

3241 analysed 3264 analysed

2 lost to follow up 1 lost to follow up
73 consent withdrawals 58 consent withdrawals

Median study duration: 22.9 months; Maximum: 41.7 months

 Heart Failure

Reduces repeated rehospitalizations

due to worsening HF
Coralan Placebo Hazard P-value
(n=3241) (n=3264) ratio
First 25%
514 (16%) 672 (21%) 0.75 P<0.001
hospitalization

Second
hospitalization 189 (6%) 283 (9%) 0.66 34% P<0.001

Third
hospitalization 90 (3%) 128 (4%) 0.71 29% P<0.012

0.4 0.6 0.8 1.0 1.2

Favors Coralan Favors
placebo

Borer JS et al. Effect of ivabradine on recurrent hospitalization for worsening heart failure in patients with chronic systolic heart failure: the
SHIFT Study. Eur Heart J. 2012;33(22):2813-2820.
 Heart Failure

Reduces the risk of death from heart failure

Heart rate 75 bpm
n=4150
Patients with death from heart failure (%)

P<0.006

Placebo
39%
Coralan

Time (months)
Böhm M et al. Heart rate at baseline influences the effect of ivabradine on cardiovascular outcomes in chronic heart failure: analysis from
the SHIFT study. Clin Res Cardiol. 2012;102(1):11-22.
 Heart Failure

Reduces the risk of death and rehospitalization

in whatever the aetiology of heart failure
HF of whatever
Ischemic HF
hospitalization for worsening heart failure (primary

origin
(n=6505) (n=4418)
Patients with cardiovascular death and

composite end point in %)

(95% CI 0·78–0·97)

(95% CI 0·75–0·90)

1. Swedberg K et al; SHIFT Investigators. Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-
controlled study. Lancet. 2010;376(9744):875-885.
The common profiles of patients with heart failure
 Heart Failure

Patients remain stable longer

With less decompensation

1. Zugck C et al. Ivabradine treatment in a chronic heart failure patient cohort: symptom reduction and improvement in quality of life in clinical practice. Adv Ther. 2014;31(9):961-974.
 Heart Failure

Effective and safe

for patients with associated conditions
RIGHT PATIENT ACEi / ARB β-Blocker MRA Ivabradine
&
RIGHT TREATMENT1-2

Renal dysfunction

Hypotension

Asthma/COPD

Hyperkalemia

Bradycardia
1. Maggioni AP et al. Are hospitalized or ambulatory patients with heart failure treated in accordance with ESC guidelines? Evidence from
ESC Heart Failure Long-Term Registry.
Eur J Heart Fail. 2013;15(7):1173-1184. 2. Coralan Summary of Product Characteristics (European Medicines Agency - latest update of
 Contraindications
• Ac.MI,USA,C.shock,
• congenital LQT,HR<70,ac.CVA,
• PPM depend,AVB blocks,SSS,severe
• hypotension,unstable or acute HF.
• Avoid in A.Fib.pregnancy
• if no improvement in sympotoms In
3-months--discontinue.severe renal failure,
 For angina and heart failure patients

INITIATE UPTITRATE

*2.5 mg bid for patients over 75 years old

1. Coralan Summary of Product Characteristics (European Medicines Agency - latest update of December 2013)
 Heart Failure
Dose titrations

>60 bpm
Ivabradine 7.5 mg bid

If elderly (≥75 years old),

start with 2.5 mg bid, then
uptitrate based on the heart rate
Check
resting 50-60 bpm
Ivabradine 5 mg bid 2 weeks heart rate Ivabradine 5 mg bid
If renal impairment,
no dose adjustment if creatinine
clearance above 15 mL/min

<50 bpm
Ivabradine 2.5 mg bid
Symptoms related to If mild hepatic insufficiency,
bradycardia
no dose adjustment
Treatment must be discontinued if heart rate remains
below 50 bpm or symptoms of bradycardia persist

1. Coralan Summary of Product Characteristics (European Medicines Agency - latest update of December 2013)
2. Images are taken from SERVIER medical art available on http://smart.servier.fr/servier-medical-art.