Management of the coronary patient in 2011 Roberto Ferrari
What is new in treatment of stable CAD? In the era of interventional cardiology, is chronic stable angina a rare disease?
Stable angina pectoris Prevalence in Europe Prevalence in community studies (Rose questionnaire) Age (yrs) Males Females 45-54 2-5% 0.1-1% 65-74 10-20% 10-15% 20.000-40.000 individuals per million population (2-4%) ESC Guidelines Eur Heart J 2006
Stable angina pectoris Incidence in Europe Annual incidence ~0.5% in Western populations, with large geographic variations (twice as high in Scotland compared to France) ESC Guidelines Eur Heart J 2006
Shift in stable CAD epidemiology Decline incidence in younger Increased incidence in elderly Prevalence expected to increase
Despite interventional cardiology stable CAD remains a public health problem 2.6% of total health expenditure in the EU (45.000.000 )
Pharmacological treatment of stable angina Anti-anginal (improves symptoms/exercise capacity, quality of life) Cardioprotective (prevention of cardiovascular outcomes)
Outcome improvement Anti-platelet agents Aspirin Clopidogrel (if aspirin not tolerated) Lipid-lowering drugs Statins ACE-inhibitors Ramipril and perindopril β-blockers Only in post MI and HF patients
Ivabradine Inhibits the If current of the sinus node cells Is a prototype of a new class of drugs and the first and only pure HR reducing agent
If current in the sinus node: the determinant of HR Sinus node Sinus node action potential and currents mv 0 500 ms -50 pa -50 50 I f Sinus node channels I K I CaL -50 I CaT Ca channel T- type f-channel -50-50 I NaCa Ca channel L- type K channel Robinson RB, DiFrancesco D. Fundamental and Clinical Cardiology; NY; Marcel Decker; 2001:151-170.
Suppression of I f Current RR 0 mv Heart rate reduction exclusively -40 mv -70 mv Ivabradine 30% reduction of diastolic slope other currents maintain pacemaker activity safety factor of ivabradine
Ivabradine interacts internaly with the I f channel: a safety valve Closed Open Inihibited Extracellular side Intracellular side Na K Ivabradine When the channel is in closed state (bradycardia) ivabradine is inactive. Bucchi A, Baruscotti M, DiFrancesco D. J Gen Physiol. 2002;120:1-13
HR dependent effect of ivabradine The higher the rate, the higher the penetration, the greater the effect and vice versa Camm J et al. JACC. 2007;49 (Suppl1).Abstract.
Heart rate bpm HR: the determinant of ischaemia 100 95 ** ** n = 19 * p<0.05 ** p<0.01 90 85 80 ** ** * * 75 70 * ST depression 65 60 20 10 4 2 2 10 20 60 Time (min) Change in HR one hour surrounding an ischaemic event Adapted from Kop WJ et al J. Am Coll C Cardiol 2001;38:742-749
Ivabradine and angina Against placebo Against atenolol Against amlodipine On top of atenolol
Effects on HR in patients already receiving β-blockers 889 stable angina patients, 20 countries 68 67 66 64 62 60 Ivabradine 5 mg bid Placebo atenolol Ivabradine atenolol 58 60 (-7 bpm) 58 (-9 bpm) 56 Ivabradine 7.5 mg bid (90% of pts) or 5 mg bid (10%) 54 Tardif JC et al. Eur Heart J. 2008;29:386 Baseline M2 M4
Tardif JC et al. Eur Heart J. 2008;29:386. Anti-ischaemic efficacy of ivabradine in combination with -blockers 60 50 889 patients with stable angina, 4 months of treatment ivabradine atenolol P<0.001 P<0.001 placebo atenolol 40 30 P<0.001 P<0.001 20 10 0 Total exercise duration Time to limiting angina Time to angina onset Time to 1mm ST depression Ivabradine on top of usual dose of β-blockers improves all parameters of exercise capacity without safety concerns
(%) Ivabradine, contrary to β-blockers, maintains cardiac contractility Saline Ivabradine (0.5 mg/kg) Propranolol (1 mg/kg) 200 Heart rate 125 100 100 0 * * * * * P <0.05 * * 75 50 25 * ** ** -100 Baseline Rest Ex 5 Ex 10 Ex 12 (km/h) 0 * * * - 20 Baseline Rest Ex 5 Ex 10 Ex 12 (km/h) No negative inotropic effect Simon L et al. J Pharmacol Exp Ther. 275:659-666, 1995
Ivabradine, contrary to β-blockers, Change from baseline (%) allows coronary dilatation 8 Simon L, et al. J Pharmacol Exp Ther. 1995;275:659-666. 6 4 2 0-2 -4-6 -8 * Saline 0.5 mg/kg Ivabradine 1.0 mg/kg Propranolol * * p<0.05 vs. Baseline p<0.05 vs. Saline p<0.05 vs. Propranolol EXERCISE Baseline Exercise 5 min 10 min 12 min -blockade unmasking a-adrenergic vasoconstriction
NORADRENALINE β α Coronary dilatation Coronary constriction
Intrinsic more efficiency of Ivabradine vs atenolol Increase in TED related to 1 beat of heart rate reduction (after 4-month treatment) 12 10 10.1 8 6 4 5.6 2 0 Atenolol 100 mg Ivabradine 7.5mg Ivabradine allows coronary dilatation Tardif JC, et al. Eur Heart J. 2005;26:2529-2536.
Pure HR reduction with Ivabradine does not cause the side-effects of the -blockers and calcium-channel-blockers BB CCB Ivabradine Bradycardia Hypotension Negative inotropic effect Peripheral vasoconstriction Increase coronary resistance Bronchospasm Decrease to insuline response Fatigue Depression Sleep disturbancies Erectile dysfunction Lower limbs oedema Constipation Visual effects x x x x x x x x x x x x /- x x x x x x x x
New EMEA indications "Symptomatic treatment of chronic stable angina pectoris in coronary artery disease patients with normal sinus rhythm. Ivabradine is indicated : in patients unable to tolerate or with a contra-indication to the use of -blockers or in combination with -blockers in patients inadequately controlled with an optimal -blocker dose and whose heart rate is > 60 bpm."
Ivabradine programme Symptoms release in angina (12.000 P) Prognostic improvement in CAD with or without LV dysfunction (BEAUTifUL and SIGNifY 24.000 P) Prognostic improvement in HF (SHifT 6.500 P)
HR as a predictor of CARDIOVASCULAR DEATH HOSPITALISATION FOR HF HOSPITALISATION FOR MI REVASCULARISATION
Effect of ivabradine on the primary endpoint (overall population) Effect of ivabradine on the primary composite endpoint (HR 70 bpm) Effect of ivabradine on hospitalisation for MI (HR 70 bpm) Effect of ivabradine on coronary revascularisation (HR 70 bpm)
Event rate (%) Effect of ivabradine on primary composite end point Event rate (%) All angina patients HR >70 bpm 30 25 HR (95% CI), 0.76 (0.58 1.00), P=0.05 30 25 HR (95% CI), 0.69 (0.47 1.01), P=0.06 20 15 Placebo 20 24% 15 Placebo 31% 10 5 Ivabradine 10 5 Ivabradine 0 0 0.5 1 1.5 2 Years 0 0 0.5 1 1.5 2 Years * Composite of cardiovascular mortality or hospitalization for fatal and nonfatal myocardial infarction or heart failure Fox et al. Eur Heart J. In press.
Event rate (%) Event rate (%) Effect of ivabradine on hospitalisation for MI All angina patients HR >70 bpm 15 HR (95% CI), 0.58 (0.37 0.92), P=0.021 15 HR (95% CI), 0.27 (0.11 0.66), P=0.002 10 10 5 Placebo 42% Placebo 73% 5 Ivabradine 0 0 0.5 1 1.5 2 Years Ivabradine 0 0 0.5 1 1.5 2 Years * Fatal and nonfatal events Fox et al. Eur Heart J. In press.
Treatment Placebo Angina Substudy n=773 Ivabradine Angina Substudy n=734 BEAUTifUL All n=10 917 Antithrombotics, % 92 92 94 Statin, % 64 67 74 Beta-blockers, % 90 89 87 Anti-RAS, % 86 88 90 Organic Nitrates, % 75 72 43
Ivabradine - The first anti-anginal agent with demonstrated reduction of MI in stable CAD Improved total exercise duration Improved time to onset of ST segment depression Decrease in anginal episodes Reduced Prevention revascularisation of MI Improved survival -Blockers Calcium antag. Nitrates Trimetazidine NA NA NA Ranolazine NA NA NA Nicorandil Ivabradine NA Adapted from: Guidelines on the management of stable angina pectoris. Eur Heart J. 2006;27:1341-1381. Fox K et al. Lancet Online August 31, 2008.
FROM TO
Why?
HR and the CV system HR is a determinant of the energy needs of the heart HR controls energy delivery to the heart High HR impairs endothelial function and facilitates atherosclerosis
HR and the heart: its cost For each beat 1.35x10-19 Ca 2 ions mobilised 300 mg ATP used for contraction 89 ml blood ejected but in a day? 93 600 beats 13.5 millions of billions of Ca 2 mobilised almost 30 kg ATP immediately used 9000 lt blood ejected! 132.000 km in 27 seconds!
HR and the heart: a reduction of 10 bpm/day saves 5 kg ATP Essential to maintain vitality
Coronary flow HR and the coronary arteries SYSTOLE DIASTOLE Coronary flow occurs mainly in diastole
HR and atherosclerosis: plaque development Diameter stenosis (%) Atherosclerotic crosssectional area (mm 2 ) Sinoatrial node ablation 136 (22) 103 (20) Heart rate Bradycardia reduces progression of atherosclerosis Beere et al. Science. 1984;226:180-2.
HR and atherosclerosis Custodis et al. Circ. 2008:117. HR reduction by ivabradine delays atherosclerosis in apolipoprotein E deficient mice
HR and coronary plaque rupture Bradycardia prevents acute coronary syndromes Heidland and Strauer. Circulation. 2001;104:1477-81.
Ivabradine: consideration Well defined mechanism of action HR of anginal patients must be reduced to 60 bpm Ivabradine alone or on top of ß-blockers improves symptoms of angina
REDUCTION: Reduction of ischaemic Events by reduction of heart rate In the treatment Of stable angina with Procoralan Multicenter, prospective, open label, study (Germany); 4,954 angina pts; 4 months follow up 100 90 80 70 60 Starting dose: 9.0 mg bid (80.3% - 5 mg bid) Average dose: 10.2 mg bid (14% - 7.5 mg bid) Averag e dose: 10.5 mg bid (19% - 7.5 mg bid) Baseline 1 month 4 months Cardiovascular therapy before Procoralan ASS 82% Statin 66% ACEI 53% ARA 19% β-blocker 54%* LA nitrates 25% CCB 25% * During the Procoralan therapy, 6.9% patients were treated concomitantly using a B-blocker. Koster R, Kaehler J, Meinertz T, for the REDUCTION Study Group. Am Heart J 2009;158:e51-e57
REDUCTION: proof of anti-anginal efficacy of Procoralan under routine practice conditions Multicenter, prospective, open study in 4 954 angina patients in germany; 4 months follow up 3 Angina attacks 4 Acute nitrate consumption 2 1 2.4-80 % 3 2 3.3-82 % 0.4 1 P<0.0001 0 0 Baseline After 4 months Baseline After 4 months Efficacy was graded by physicians as being excellent/very good for 97% of the patients Koster R, Kaehler J, Meinertz T, for the REDUCTION Study Group. Am Heart J 2009;158:e51-e57 0.6
Study objective To assess the efficacy of ivabradine vs placebo in prevention of CV events in patients with stable CAD without clinical HF
Population Outpatients with stable CAD Age > 55 years With at least one other CV risk factor Without LVSD (LVEF > 40%) or clinical signs of HF
Population With resting HR>70 bpm (two consecutive ECG recordings at 5 min apart, at selection and inclusion visits) and in sinus rhythm Receiving appropriate guidelines driven CV medication
Ivabradine programme Symptoms release in angina (12.000 P) Prognostic improvement in CAD with or without LV dysfunction (BEAUTifUL and SIGNifY 24.000 P) Prognostic improvement in HF (SHifT, 6.500 P)
Angina Rationale Angina is preceded by HR HR reduction by Ivabradine - reduces O 2 demand - improves O 2 delivery