Ελληνική Καρδιολογική Εταιρία Σεμινάριο Ειδικευομένων 21-22/6/2013. Σταθερή στηθάγχη Σύγχρονη αντι - ισχαιμική αγωγή

Ελληνική Καρδιολογική Εταιρία Σεμινάριο Ειδικευομένων 21-22/6/2013 Σταθερή στηθάγχη Σύγχρονη αντι - ισχαιμική αγωγή Κακκάβας Θ. Απόστολος Επιμελητής Β Καρδιολογίας, ΠΓΝ Πατρών

Ερώτηση 1 Ποια από τις παρακάτω κατηγορίες φαρμάκων δεν έχει φανεί από τις μελέτες ότι αυξάνει την επιβίωση στους ασθενείς με χρόνια στεφανιαία νόσο; Α) τα αντι-αιμοπεταλιακά Β) οι β-αναστολείς Γ) οι ACEIs / ARBs Δ) τα νιτρώδη

Medical Therapy to Prevent MI and Death: Antiplatelet Therapy Class I 1. Treatment with aspirin 75 to 162 mg daily should be continued indefinitely in the absence of contraindications in patients with SIHD (LOE : A) 2. Treatment with clopidogrel is reasonable when aspirin is contraindicated in patients with SIHD (LOE: B) Class IIb 1. Treatment with aspirin 75 to 162 mg daily and clopidogrel 75 mg daily might be reasonable in certain high-risk patients with SIHD (LOE: B) Class III: No Benefit 1. Dipyridamole is not recommended as antiplatelet therapy for patients with SIHD (LOE: B)

CURE Major Bleeding at 1 year by ASA Dose ASA (N=6303) Clopidogrel + ASA (N=6259) P-Value ASA Dose: 75-100 mg (N=1927) 1.9% 3.0% 0.53 100-200 mg (N=7428) 2.8% 3.4% 200-325 mg (N=2301) 3.7% 4.9% Peters RJG, et al. Circulation 2003

CAPRIE: Long-Term Efficacy of Clopidogrel versus ASA 384 centers in 16 countries - 19,185 pts with ischemic stroke, MI or PAD Follow up 1-3 years Cumulative Event Rate (MI, Ischemic Stroke or Vascular Death) Cumulative event rate (%) 16 12 8 4 ASA Clopidogrel p = 0.043, n = 19,185 8.7% * Overall relative risk reduction 0 0 3 6 9 12 15 18 21 24 27 30 33 36 Months of follow-up ASA = acetylsalicylic acid MI = myocardial infarction *Intention to treat analysis 1.CAPRIE Steering Committee. Lancet 1996; 348: 1329 1339. 2. Antiplatelet Trialists' Collaboration. BMJ 2002; 324: 71 86.

CURE: Early and Long-Term Efficacy of Clopidogrel clopidogrel (300/75 mg) on top of standard therapy (including ASA) 12,562 pts with NSTE-ACS Cumulative events (MI, stroke, or cardiovascular death) Cumulative hazard rate 0.14 0.12 0.10 0.08 0.06 0.04 0.02 Placebo (+ASA) * (n =6,303) Clopidogrel * (+ ASA) (n = 6,259) 20% RRR p = 0.00009 0.00 0 3 6 9 12 Months of follow-up *On top of standard therapy (including ASA) The CURE Trial Investigators. N Engl J Med 2001

CREDO: Long-term Efficacy of Clopidogrel clopidogrel (1yr vs 1m) on top of standard therapy (including ASA) 2,116 pts undergoing urgent or elective PCI - followed for 1 year Combined endpoint occurrence (%) 15 10 5 0 n = 2,116 1-year results (Stroke, MI or death) Placebo (+ ASA) * Clopidogrel (+ ASA)* 0 3 6 9 12 Months from randomization Steinhubl S et al, JAMA 2002 11.5% 8.5% 27% RRR p = 0.02 * On top of standard therapy including acetylsalicylic acid All patients received clopidogrel post-pci up to Day 28 MI = myocardial infarction PCI = percutaneous coronary intervention

CHARISMA Trial Design Patients age 45 years at high risk Low dose ASA 75 162 mg/day of atherothrombotic events (n=15603) R Double-blind treatment up to 1040 primary efficacy events* Clopidogrel 75 mg/day (n=7802) 1-month visit Low dose ASA 75 162 mg/day 3-month visit Visits every 6 months Final visit (Fixed study end date) Placebo 1 tablet/day (n=7801) * MI (fatal or non-fatal), stroke (fatal or non-fatal), or cardiovascular death; event-driven trial Bhatt DL et al. Am Heart J 2004; 148: 263 268.

Overall Population: Primary Efficacy Outcome (MI, Stroke, or CV Death) Cumulative event rate (%) 8 6 4 2 Placebo + ASA* 7.3% Clopidogrel + ASA* 6.8% RRR: 7.1% [95% CI: -4.5%, 17.5%] p=0.22 0 0 6 12 18 24 30 Months since randomization First Occurrence of MI (fatal or non-fatal), stroke (fatal or non-fatal), or cardiovascular death *All patients received ASA 75-162 mg/day The number of patients followed beyond 30 months decreases rapidly to zero and there are only 21 primary efficacy events that occurred beyond this time (13 clopidogrel and 8 placebo) Bhatt DL, Fox KA, Hacke W, et al. NEJM 2006

Overall Population: Safety Results Clopidogrel Placebo + ASA + ASA Safety Outcome* - N (%) (n=7802) (n=7801) RR (95% CI) p value GUSTO Severe Bleeding 130 (1.7) 104 (1.3) 1.25 (0.97, 1.61) 0.09 Fatal Bleeding 26 (0.3) 17 (0.2) 1.53 (0.83, 2.82) 0.17 Primary ICH 26 (0.3) 27 (0.3) 0.96 (0.56, 1.65) 0.89 GUSTO Moderate Bleeding 164 (2.1) 101 (1.3) 1.62 (1.27, 2.08) <0.001 *Adjudicated outcomes by intention to treat analysis ICH= Intracranial Hemorrhage Bhatt DL, Fox KA, Hacke W, et al. NEJM 2006.

Primary Efficacy Results (MI/Stroke/CV Death) by pre-specified entry category Population RR (95% CI) p value Qualifying CAD, CVD or PAD * 0.88 (0.77, 0.998) 0.046 (n=12,153) Multiple Risk Factors * 1.20 (0.91, 1.59) 0.20 (n=3,284) Overall Population 0.93 (0.83, 1.05) 0.22 (n=15,603) 0.4 0.6 0.8 1.2 1.4 Clopidogrel + ASA Better Placebo + ASA Better * A statistical test for interaction showed marginally significant heterogeneity (p=0.045) in treatment response for these pre-specified subgroups of patients 166 patients did not meet any of the main inclusion criteria but were followed (intent-to-treat analysis) Bhatt DL, Fox KA, Hacke W, et al. NEJM 2006 1.6

CHD Event Rates in Secondary Prevention and ACS Statin Trials CHD Events (%) 30 25 20 15 10 5 y = 0.1629x 4.6776 R² = 0.9029 p < 0.0001 HPS-P 4S-S LIPID-P HPS-S A2Z 20 CARE-P A2Z 80 TNT 10 LIPID-S PROVE-IT-AT TNT 80 IDEAL S20/40 IDEAL CARE-S A80 PROVE-IT-PR 4S-P 0 30 50 70 90 110 130 150 170 190 210 LDL Cholesterol (mg/dl) Updated from - O Keefe, J. et al., J Am Coll Cardiol 2004;43:2142-6.

Ερώτηση 2 Ποιο από τα παρακάτω είναι σωστό όσον αφορά τη θεραπεία της χρόνιας στεφανιαίας νόσου: Α) Οι β-αναστολείς έχουν απόλυτη ένδειξη χορήγησης, ανεξάρτητα της παρουσίας ή μη συστολικής δυσλειτουργίας της LV Β) Οι β-αναστολείς αντενδείκνυνται σε ασθενείς με περιφερική αρτηριακή νόσο Γ) Οι ACEIs / ARBs έχουν ένδειξη ακόμα και σε ασθενείς χωρίς συστολική δυσλειτουργία της LV Δ) κανένα από τα παραπάνω

Beta-Blocker Therapy Class I 1. Beta-blocker therapy should be started and continued for 3 years in all patients with normal LV function after MI or ACS (LOE: B) 2. Beta-blocker therapy should be used in all patients with LV systolic dysfunction (EF <40%) with heart failure or prior MI, unless contraindicated. (Use should be limited to carvedilol, metoprolol succinate, or bisoprolol, which have been shown to reduce risk of death) (LOE: A) Class IIb 1. Beta blockers may be considered as chronic therapy for all other patients with coronary or other vascular disease (LOE: C)

Systematic review of randomised controlled trials Patients with acute or past MI BBs vs placebo Main outcome: all cause mortality and non fatal reinfarction 23% reduction in the odds of death in long term Most evidence is available for propranolol, timolol, and metoprolol NNT for 2 years to avoid 1 death is 42, which compares favourably with other treatments for pts with acute or past MI Conclusions: BBs are effective in long term secondary prevention after MI, but they are underused in such cases BMJ 1999

Renin-Angiotensin-Aldosterone Blocker Therapy Class I 1. ACE inhibitors should be prescribed in all patients with SIHD who also have HTN, DM, LVEF 40%, or CKD, unless contraindicated (LOE: A) 2. ARBs are recommended for patients with SIHD who have HTN, DM, LV systolic dysfunction, or CKD and have indications for, but are intolerant of ACE inhibitors (LOE: A) Class IIa 1. Treatment with an ACE inhibitor is reasonable in patients with both SIHD and other vascular disease (LOE: B) 2. It is reasonable to use ARBs in other patients who are ACE inhibitor intolerant (LOE: C)

ACEIs Trials

All cause death (%) 40 35 30 25 20 15 10 5 0 CHARM Trial One year HR 0.67 p<0.001 Two year HR 0.80 p=0.001 Placebo 708 (31.0%) 0 1 2 3 Number at risk Candesartan 2289 2105 1894 1382 580 Placebo 2287 2023 1811 1333 548 Candesartan 642 (28.0%) Hazard ratio 0.88 (95% CI 0.79 0.98), p=0.018 3.5 yrs Young et al, Circulation 2004

ELITE II Primary Endpoint: All-Cause Mortality 1.0 Probability of Survival 0.8 0.6 0.4 0.2 Captopril Losartan Hazard Ratio (95-7% C.I.) = 1.13 (0.95-1.35) P = 0.16 0.0 0 100 200 300 400 500 600 700 Lancet 2000;355:1582-87 87 Days of Follow-up

VALIANT Trial N Engl J Med 2003 30% All-cause Mortality* Valsartan vs captopril HR 1.00, 97.5% CI 0.90-1.11, p=0.98 Combo vs captopril HR 0.98, 97.5% CI 0.89-1.09, p=0.73 40% CV Death, re-mi, or hospitalization for HF* Valsartan vs captopril HR 0.95, p=0.20 Combo vs captopril HR 0.97, p=0.37 20% 19,9% 19,3% 19,5% 30% 31,1% 31,9% 31,1% 20% 10% 10% 0% Valsartan Combo Captopril 0% Valsartan Combo Captopril www. Clinical trial results.org * Met criteria for non-inferiority of valsartan vs captopril

HOPE Trial 9,297 high-risk pts, > 55 years old, with evidence of CVD or DM plus 1 other CV risk factor, not known to have low EF or HF randomly assigned to ramipril (10 mg /day) or placebo, for a mean of 5 yrs % of Patients 0,2 0,15 0,1 0,05 Ramipril Placebo P<0.001 CV Death, MI or Stroke 0 0 500 1000 15000 Days of Follow-up NEJM 2000

Primary endpoint % CV death, MI or cardiac arrest 14 12 10 8 Placebo Perindopril 6 4 2 0 0 1 2 3 4 5 RRR: 20% p = 0.0003 Years

PEACE Trial 8,290 patients with stable CAD without HF 25 20 15 21,9 22,5 Primary Composite of CV, nonfatal MI, and coronary revascularization p = 0.43 10 5 0 Trandolapril Placebo www. Clinical trial results.org Presented at AHA 2004

Use of ACEIs was associated with a decrease in CV mortality (RR 0.83), nonfatal MI (RR 0.84), all-cause mortality (RR 0.87), and revascularization rates (RR 0.93) Tx of 100 pts for an average duration of 4.4 yrs prevents either of the adverse outcomes CONCLUSIONS: The cumulative evidence provided by this meta-analysis shows a modest favorable effect of ACEIs on the outcome of pts with CAD and preserved LV systolic function

Ερώτηση 3 Ποιο από τα παρακάτω είναι σωστό όσον αφορά τη χορήγηση αντιστηθαγχικής αγωγής; Α) Οι β αναστολείς και οι αναστολείς Ca αποτελούν τη θεραπεία εκλογής ως αρχική αντι ισχαιμική αγωγή Β) Τα νιτρώδη παρατεταμένης δράσης, η ρανολαζίνη και η ιβαμπραδίνη μπορούν να χορηγηθούν επιπλέον των BBs / CCBs ή ως πρώτη γραμμή αντι στηθαγχκής θεραπείας (επί αντένδειξης ή δυσανεξίας στους BBs / CCBs) Γ) Επί εμμονής της στηθάγχης υπό τη χορήγηση διπλής αντιστηθαγχικής αγωγής πρέπει να επανεξετάζεται η ανάγκη επαναιμάτωσης του ασθενή Δ) Όλα τα παραπάνω

Medical Therapy for Relief of Symptoms Class I 1. B-blockers should be prescribed as initial therapy for relief of symptoms in patients with SIHD (LOE: B) 2. Ca channel blockers or long-acting nitrates should be prescribed for relief of symptoms when BBs are contraindicated or cause unacceptable side effects in patients with SIHD (LOE: B) 3. Ca channel blockers or long-acting nitrates, in combination with BBs, should be prescribed for relief of symptoms when initial treatment with BBs is unsuccessful in patients with SIHD (LOE: B) 4. Sublingual nitroglycerin or nitroglycerin spray is recommended for immediate relief of angina in patients with SIHD (LOE: B)

Class IIa 1. Treatment with a long-acting nondihydropyridine CCB (verapamil or diltiazem) instead of a BB as initial therapy for relief of symptoms is reasonable in patients with SIHD (LOE: B) 2. Ranolazine can be useful when prescribed as a substitute for BBs for relief of symptoms in patients with SIHD if initial Tx with BBs leads to unacceptable side effects, or is ineffective or if initial Tx with BBs is contraindicated (LOE: B) 3. Ranolazine in combination with BBs can be useful when prescribed for relief of symptoms when initial Tx with BBs is not successful in pts with SIHD (LOE: A)

Η Καρδιακή Συχνότητα ως μείζων παράγων εμφάνισης ισχαιμίας στη σταθερή ΣΝ Andrews TC, et al. Circulation.1993

Ιβαμπραδίνη Το Procoralan είναι ο πρώτος εκλεκτικός, ειδικός αναστολέας του ρεύματος I f του φλεβόκομβου Μειώνει αποκλειστικά την καρδιακή συχνότητα (δεν επηρεάζει την κολποκοιλιακή αγωγιμότητα, τη συσταλτικότητα του μυοκαρδίου, καθώς και την αρτηριακή πίεση) Σπάνιες ανεπιθύμητες ενέργειες (φωταψίες)

Design of the study Ivabradine 5 mg 7.5 mg bid Multicenter (781 centers / 33 countries) randomized trial 10 917 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;372:807-816.

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 25 20 Hazard ratio = 1.00 (0.91 1.10) P=0.94 Ivabradine 15 Placebo 10 5 Fox K et al. Lancet. 2008;372:807-816. 0 0 0.5 1 1.5 2 Years

Ivabradine reduces fatal and nonfatal myocardial infarction (HR 70 bpm) Hospitalization for fatal or nonfatal MI (%) 8 4 Hazard ratio = 0.64 (0.49 0.84) P=0.001 RRR 36% Placebo (HR >70 bpm) Ivabradine 0 0 0.5 1 1.5 2 Years Fox K et al. Lancet. 2008;372:807-816. RRR: relative risk reduction

Ivabradine reduces the need for revascularization (HR( 70 bpm) Coronary revascularization (%) 8 4 Hazard ratio = 0.70 (0.52 0.93) P=0.016 RRR 30% Placebo (HR >70 bpm) Ivabradine 0 0 0.5 1 1.5 2 Years Fox K et al. Lancet. 2008;372:807-816. RRR: relative risk reduction

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

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.

Study design Screening 7 to 30 days Ivabradine 5 mg bid Matching placebo, bid Ivabradine 7.5/5/2.5 mg bid according to HR and tolerability D0 D14 D28 M4 Every 4 months 3.5 years Swedberg K, et al. Eur J Heart Fail. 2010;12:75-81.

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 e of beta-blockers blockers Swedberg K, et al. Eur J Heart Fail. 2010;12:75-81.

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

Chronic HF background treatment Patients (%) 100 90 89 90 91 91 84 83 Ivabradine 80 70 60 61 59 Placebo 50 40 30 20 22 22 10 0 Beta-blockers ACEIs and/or ARBs Diuretics Aldosterone antagonists Digitalis 3 4 ICD/CRT

Background beta-blocker treatment Patients (%) 100 90 80 89 89 Ivabradine Placebo 70 60 50 40 56 56 30 20 10 0 26 26 BB at randomization At least 50% target daily dose Target daily dose

Mean heart rate reduction Heart rate (bpm) 90 Mean ivabradine dose: 6.4 mg bid at 1 month Ivabradine Placebo 6.5 mg bid at 1 year 80 80 75 75 70 67 60 64 50 0 2 weeks 1 4 8 12 16 20 24 28 32 Months

Primary composite endpoint Cumulative frequency (%) 40 30 Ivabradine n=793 (14.5%PY) Placebo n=937 (17.7%PY) Ivabradine Placebo HR = 0.82 [95% CI 0.75-0.90 0.90] p<0.0001 CV death Hospitalization for worsening HF - 18% 20 10 0 0 6 12 18 24 30 Months

Ρανολαζίνη Ο πρώτος εκλεκτικός αναστολέας του παρατεταμένου, όψιμου ρεύματος ιόντων Νατρίου (I Na ) στο μυοκάρδιο (I Na Συνιστώμενη αρχική δόση της ρανολαζίνης 375mg x 2 ημερησίως, Μετά από 2-4 εβδομάδες, η δόση 500mg x 2 ημερησίως (μέγιστη συνιστώμενη δόση των 750mg δις ημερησίως) Πιο συχνά ανεπιθύμητα συμβάματα: Δυσκοιλιότητα Ναυτία Ζάλη

Αντενδείξεις Υπερευαισθησία στη δραστική ουσία ή σε κάποιο από τα έκδοχα Σοβαρή νεφρική ανεπάρκεια (κάθαρση κρεατινίνης <30ml/min) Μέτρια ή σοβαρή ηπατική ανεπάρκεια Συγχορήγηση ισχυρών αναστολέων του κυτοχρώματος (CYP) 3A4 (π.χ. ιτρακοναζόλη, κετοκοναζόλη, βορικοναζόλη, ποσακοναζόλη, αναστολείς της HIV πρωτεάσης, κλαριθρομυκίνη, τελιθρομυκίνη, νεφαζοδόνη) Ταυτόχρονη χορήγηση με χυμό του γκρέιπφρουτ Συγχορήγηση αντιαρρυθμικών τάξης Ιa (π.χ. κινιδίνη) ή τάξης ΙΙΙ (π.χ. δοφετιλίδη, σοταλόλη) εκτός της αμιοδαρόνης

Monotherapy With Ranolazine Increases Exercise Performance (MARISA) Trough Peak 560 ** *** *** *** *** *** Time, sec 520 480 440 ** *** *** *** *** *** *** *** *** *** *** *** 400 Exercise duration Time to angina Time to 1-mm ST depression Exercise duration Time to angina Time to 1-mm ST depression N = 175, All/Near Completers population; LS means ± SE. **p < 0.01 vs placebo; ***p < 0.001 vs. placebo Placebo 500 mg bid 1000 mg bid 1500 mg bid

Ranolazine With a Beta- or Calcium Blocker Increases Exercise Times (CARISA) Trough Peak Change from baseline, sec 150 100 * * * * *** * ** ** *** ** 50 Exercise duration Time to angina Time to 1-mm ST depression Exercise duration Time to angina Time to 1-mm ST depression N = 791, ITT/LOCF; LS mean ± SE. *p < 0.05; **p 0.01; ***p 0.001 vs placebo. Placebo 750 mg bid 1000 mg bid

Ranolazine Decreases Weekly Angina Attacks and Nitroglycerin Consumption (CARISA) 6 5 Placebo Ranolazine 750 mg bid Ranolazine 1000 mg bid Number per wk 4 3 2 ** *** * *** 1 0 Baseline Double-blind Baseline Double-blind Angina attacks N = 791, ITT/LOCF; LS mean ± SE. *p < 0.05, **p 0.01, ***p 0.001 vs placebo Nitroglycerin consumption

N = 6560 UA/NSTEMI (Moderate-High Risk) Standard Therapy Ranolazine IV to PO RANDOMIZE (1:1) Double-blind blind Holter Placebo Matched IV/PO Long-term Follow-up (Median 348 Days) Morrow DA et al. JAMA 2007; 297: 1775-83

Primary Endpoint Results CV Death, MI, or Recurrent Ischemia (%) 30 Placebo 23.5%* (N=3,281) 20 10 0 Ranolazine 21.8%* (N=3,279) HR 0.92 (95% CI 0.83 to 1.02) P = 0.11 0 180 360 540 Days from Randomization *KM cumulative incidence (%) at 12 months Morrow DA et al. JAMA 2007; 297: 1775-83

Components of Primary Endpoint Results CV Death or MI (%) Recurrent Ischemia (%) 20 20 Placebo 16.1%* (N=3,281) 15 10 Placebo 10.5%* Ranolazine 10.4%* 15 10 Ranolazine 13.9%* (N=3,279) 5 0 HR 0.99 (95% CI 0.85 to 1.15) P =0.87 0 180 360 540 5 0 HR 0.87 (95% CI 0.76 to 0.99) P =0.030 0 180 360 540 Days from Randomization Days from Randomization *KM Cumulative Incidence (%) at 12 months Morrow DA et al. JAMA 2007; 297: 1775-83

Major Safety Endpoints Results PLACEBO (N=3,273*) RANOLAZINE (N=3,268*) HR P-value Death - any cause (N) Sudden cardiac death 175 65 172 56 0.99 p = 0.91 0.87 p = 0.43 Symptomatic Documented arrhythmia 102 99 0.97 p = 0.84 Clinically significant arrhythmia on Holter 83.1% 73.7% 0.89 p<0.001 *safety analysis cohort (received at least one dose) VT 3 beats, SVT >120bpm, new AF, brady<45 bpm, CHB or pause >2.5s Morrow DA et al. JAMA 2007; 297: 1775-83

AHA SIHD 2012

NICE clinical guideline 2012

Μείωση Καρδιακής Συχνότητας ηρεμίας έναντι β-αποκλειστή Αρχική ΚΣ: 80 bpm n=939 90 INITIATIVE study 80 ΚΣ (bpm) 70 60 50 40 30 20 Κατά την ένταξη -14,3 bpm -15,6 bpm Κατά την ένταξη 10 0 Ivabradine 7,5mg Ατενολόλη 100mg Tardif JC, Ford I, Tendera M et al. European Heart Journal 2005; 26: 2529 2536 2536

Aντι-ισχαιμικήισχαιμική αποτελεσματικότητα Συνολική διάρκεια άσκησης κατά την ύφεση n=939 n ατενολόλη Procoralan Procoralan 5 mg bid 595 vs ατενολόλης 50 mg od 286 M1 Procoralan 7.5 mg bid 300 vs ατενολόλης 100 mg od 286 M4 INITIATIVE study 6.7 [-7.4;[ 20.8] P<0.0001 10.3 [-8.3;[ 28.8] P<0.0001 Procoralan 10 mg bid 298 vs ατενολόλης 100 mg od 286 M4 Tardif JC, Ford I, Tendera M et al. European Heart Journal 2005; 26: 2529 2536 2536-35 sec 0 + 35 sec Όρια ισοδυναμίας 15.7 [-2.9;[ 34.3] P<0.0001 P for non-inferiority

n=939 Aντι-ισχαιμικήισχαιμική αποτελεσματικότητα Αύξηση στη συνολική διάρκεια άσκησης (4 μήνες αγωγή) INITIATIVE study Atenolol 100mg 78,8 Ivabradine 7.5mg 86,8 * Χρόνος (sec) *p<0.0001 P for non-inferiority Tardif JC, Ford I, Tendera M et al. European Heart Journal 2005; 26: 2529 2536 2536

Aντι-ισχαιμικήισχαιμική αποτελεσματικότητα επιπλέον του β-αναστολέα Αύξηση του Χρόνου μέχρι την κατάσπαση του διαστήματος ST κατά 1mm (4 μήνες αγωγή) n=889 Ιβαμπραδίνη 7,5mg + Ατενολόλη 50mg +46 * Placebo + Ατενολόλη 50mg +15 Χρόνος (sec) *p<0.001 Tardif JC, et al. Eur Heart J. 2009; 29 (suppl( suppl) ) 386.

Aντι-ισχαιμικήισχαιμική αποτελεσματικότητα επιπλέον του β-αναστολέα n=889 Μεταβολή των παραμέτρων της δοκιμασίας κόπωσης (4 μήνες αγωγή) 60 50 40 30 20 10 Ιβαμπραδίνη 7,5mg + ατενολόλη 50mg Placebo + ατενολόλη 50mg p<0.001 p<0.001 p<0.001 0 Συνολική Διάρκεια Άσκησης Χρόνος μέχρι την εμφάνιση περιοριστικής στηθάγχης Χρόνος μέχρι την εμφάνιση στηθάγχης Tardif JC, et al. Eur Heart J. 2009; 29 (suppl( suppl) ) 386.

Aντι-ισχαιμικήισχαιμική αποτελεσματικότητα επιπλέον του β-αναστολέα n=440 Mεταβολή στη Συνολική Διάρκεια Άσκησης (sec) 30 20 10 0 Ιβαμπραδίνη 7,5mg + ατενολόλη 50mg Placebo + ατενολόλη 50mg P<0.001 P=0.02 Συνολικός πληθυσμός Πληθυσμός με ΚΣ< 65bpm Tardif JC et al. Eur Heart J. 2008;29(suppl). 386

Αντι-στηθαγχική αποτελεσματικότητα επιπλέον του β-αναστολέα Μετά από 4 µήνες αγωγής Αριθμός στηθαγχικών επεισοδίων ανά εβδομάδα 2,0 1,6 1,2 0,8 0,4 0,0 Ατενολόλη 50mg Ιβαμπραδίνη 7,5mg + ατενολόλη 50mg Tardif JC, et al. Eur Heart J. 2009; 29 (suppl( suppl) ) 386.

Aντι-ισχαιμικήισχαιμική αποτελεσματικότητα επιπλέον του β-αναστολέα 450 446 410 р=0.001 400 370 388 386 330 Βισοπρολό λη 5 mg Βισοπρολόλη 5 mg+ Procoralan 7.5 mg Βισοπρολόλη 5 mg Βισοπρολόλη 5 mg + Βισοπρολόλη 5 mg Amosova E, et al. Cardiovasc Drug Ther 2011, DOI10.1007/s10557-011 011-6327- 3

Βελτίωση της πρόγνωσης σε ασθενείς με Καρδιακή Ανεπάρκεια Πρωτεύον σύνθετο τελικό σημείο (ΚΑ θάνατος ή νοσηλεία λόγω ΚΑ) 40 30 20 HR = 0.82 (0.75 0.90) P < 0.0001 Placebo Ivabradine -18% 10 0 0 6 12 18 24 30 Months Swedberg K, et al. Lancet. 2010;376:875-885.

Η επίδραση του Procoralan 7,5mg στο Θάνατο λόγω καρδιακής ανεπάρκειας Αθροιστική συχνότητα (%) 10 5 0 HR = 0.74 [95% CI=0.58;0.94] P=0.014 0 6 12 18 24 30 3 μήνες Placebo + AMEA + β-αναστολείς Μήνες Procoralan 7,5mg + AMEA + β-αναστολείς -26% Swedberg K, et al. Lancet. 2010;376:875-885. 885.

Η επίδραση του Procoralan 7,5mg στη Νοσηλεία λόγω καρδιακής ανεπάρκειας Αθροιστική συχνότητα (%) 30 20 10 0 HR = 0.74 [95% CI 0.66-0.83] 0.83] P<0.0001 Placebo + AMEA + β-αναστολείς 0 6 12 18 24 30 3 μήνες Μήνες Ιβαμπραδίνη + AMEA + β-αναστολείς -26% Swedberg K, et al. Lancet. 2010;376:875-885.

Μείωση της εκ νέου νοσηλείας λόγω Καρδιακής Ανεπάρκειας 40 30 20 IRR (95% CI), 0.75 (0.65;0.87) P=0.0002 Placebo Procoralan -25% 10 0 0 6 12 18 24 30 Borer JS et al. Eur Heart J Online, 27 August 2012 Χρόνος (μήνες)

Εκ νέου νοσηλεία λόγω ΚΑ Προσέγγιση συνολικού χρόνου Ιβαμπραδίνη (n=3241) Placebo (n=3264) Σχετικός κίνδυνος Τιμήp Πρώτη νοσηλεία 514 (16%) 672 (21%) 0.75 p<0.001 Δεύτερη νοσηλεία 189 (6%) 283 (9%) 0.66 p<0.001 Τρίτη νοσηλεία 90 (3%) 128 (4%) 0.71 p=0.012 0.4 0.6 0.8 1.0 Υπέρ ιβαμπραδίνης 1.2 Υπέρ placebo Borer JS et al. Eur Heart J Online, 27 August 2012

Μειώνει τον Δείκτη τελο-συστολικού όγκου αριστερής κοιλίας E -5.8; p<0.001 LVESVI [ml/m2] 75 70 65 60 55 50 45 40 35 30 25 20 15 10 5 0-7.0 ml/m 2-0.9 ml/m 2 Αρχική M 8 Αρχικ ή M 8 echo Iβαμπραδίνη (N=208) Placebo (N=203) Tardif JC et al. Eur Heart J 2011; Online August 29. LVESVI = Δείκτης Τελοσυστολικού Όγκου Αριστερής Κοιλ

Clopidogrel 75 mg has been compared with aspirin 325 mg in patients with previous MI, stroke, or symptomatic PAD in the prospective, randomized CAPRIE (Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events) study.718 Although clopidogrel demonstrated superiority over aspirin in the secondary prevention of MI and death in this group of patients, the magnitude of difference was small. Because no additional trials comparing aspirin and clopidogrel in patients with SIHD have been conducted, clopidogrel remains an acceptable alternative agent to aspirin. In certain high-risk patients, combined treatment with aspirin and clopidogrel has been shown to be beneficial. In the CURE (Clopidogrel in Unstable Angina to Prevent Recurrent Events) study, patients with a recent NSTEMI were randomized to clopidogrel plus aspirin (300 mg/d and 75mg/d) for an average of 9 months. These patients experienced fewer deaths from cardiovascular causes, nonfatal MIs, and strokes than did patients receiving placebo plus aspirin (75 to 325 mg/d).724 Similar results were found in the CREDO (Clopidogrel for Reduction of Events During Observation) study. Combined therapy for an average of 1 year significantly reduced the risk of death, MI, or stroke.

In contradistinction to these positive results among high-risk patients, a comparison of aspirin alone versus aspirin combined with clopidogrel in 15 603 patients with multiple cardiovascular risk factors (most of whom were without a prior cardiovascular event) in the CHARISMA (Clopidogrel for High Atherothrombotic Risk Ischemic Stabilization, Management, and Avoidance) trial demonstrated no differences in the rates of MI, stroke, or death.393 A post hoc analysis of this study suggested that a subgroup of patients with documented prior MI, ischemic stroke, or symptomatic PAD might have had better outcomes from dual antiplatelet therapy (DAPT) with clopidogrel plus aspirin.719 In a meta-analysis of 5 RCTs comparing clopidogrel plus aspirin to aspirin alone in patients with IHD, the incidence of all-cause mortality, MI, and stroke was found to be reduced in the clopidogrel-plus-aspirin group, whereas the risk of major bleeding increased significantly. 726 Overall, it appears that the addition of clopidogrel to aspirin could be beneficial in certain high-risk groups of patients with SIHD, but data on specific subgroups are lacking,727 and further research will be required to identify the ideal target population.

A systematic review of randomized trials of oral anticoagulants with and without antiplatelet therapy among 20 000 patients with IHD, however, failed to provide evidence of benefit from anticoagulation, and it is not recommended.753 Similarly, there is no evidence that individuals with defects in the coagulation system, such as G1691A factor V Leiden, G20201A prothrombin, G455A fibrinogen chain, G10976A factor VII, or the plasminogen activator inhibitor-1 4G/5G polymorphisms, are at higher risk of cardiac events, and they should not receive anticoagulation therapy solely to prevent such events

Two large long-term follow-up studies investigating the prognostic importance of heart rate showed that all-cause mortality rate progressively increases with higher resting heart rate after adjustment for exercise capacity, age, diabetes mellitus, systolic arterial pressure, BMI, and level of physical activity.772,773 Therefore, it is recommended that beta-blocker dosing be adjusted to limit the heart rate to 55 to 60 beats per minute at rest.

In large prospective studies, bisoprolol, carvedilol, and metoprolol, when administered on a background of ACE inhibitors and diuretics with or without digoxin, have been shown to reduce the risk of death and to improve symptoms, clinical status, and quality of life in patients with chronic systolic heart failure. Importantly, these benefits were seen in patients with and without IHD.571,760,761

Beta blockers have been compared with and combined with dihydropyridine calcium channel blockers in controlled clinical trials. The results of the APSIS (Angina Prognosis Study in Stockholm), TIBBS (Total Ischemic Burden Bisoprolol Study), and IMAGE (International Multicenter Angina Exercise) studies showed that a beta blocker was more effective than a calcium channel blocker in control of angina, reduction of cardiovascular events, and need for revascularization.786 788 A rationale for combining these agents is a reduction of dihydropyridineinduced tachycardia by betablockade. When combined, beta blockers and dihydropyridine calcium channel blockers have increased exercise time and shown a trend toward a lower rate of cardiovascular outcomes.788,789 Caution is warranted when a beta blocker is combined with verapamil or diltiazem because of the potential for development of bradycardia, AV block, or excessive fatigue.

The combination of a beta blocker with a nitrate could be an additive combination in patients with SIHD. Nitrates increase sympathetic tone, which can lead to reflex tachycardia, which is attenuated by the beta blocker. Beta blockers can increase LV wall tension associated with decreased heart rate, which is counteracted by the concomitant use of nitroglycerin combination is more effective in controlling angina than is either monotherapy alone.790,791

Absolute contraindications to beta blockers are severe bradycardia, preexisting high-degree AV block, sick sinus syndrome (without a pacemaker in place), and refractory heart failure. Relative contraindications include bronchospastic disease or active PAD (beta blockers without vasodilating properties or selective agents at low doses may be used). Because they can mask symptoms of hypoglycemia, beta blockers should be used with caution in patients with insulindependent diabetes mellitus. Abrupt beta-blocker withdrawal should be avoided because heightened betareceptor density and sensitivity can result in a rebound phenomenon associated with an increased risk for AMI and sudden death. If withdrawal is necessary, beta blockers should be tapered over a 1- to 3-week period, with consideration given to use of sublingual nitroglycerin or substitution with a nondihydropyridine calcium channel blocker during the withdrawal period. The principle adverse effects of beta blockers are fatigue, exercise intolerance, lethargy, insomnia, nightmares, and impotence

Renin-Angiotensin-Aldosterone Blocker Therapy Class I 1. ACE inhibitors should be prescribed in all patients with SIHD who also have hypertension, diabetes mellitus, LVEF 40% or less, or CKD, unless contraindicated. 295 298,301 (Level of Evidence: A) 2. ARBs are recommended for patients with SIHD who have hypertension, diabetes mellitus, LV systolic dysfunction, or CKD and have indications for, but are intolerant of, ACE inhibitors.792 794 (Level of vidence: A) Class IIa 1. Treatment with an ACE inhibitor is reasonable in patients with both SIHD and other vascular disease795,796 (Level of Evidence: B) 2. It is reasonable to use ARBs in other patients who are ACE inhibitor intolerant.797 (Level of Evidence: C) (Table 15)

patients with atherosclerotic vascular disease or diabetes mellitus and at least 1 other IHD risk factor, the HOPE (Heart Outcomes Prevention Evaluation) study301 showed that compared with placebo, ramipril significantly decreased the primary composite endpoint of cardiovascular death, AMI, and stroke by 22%.301 MICRO-HOPE (Microalbuminuria, Cardiovascular, and Renal Outcomes), a substudy of HOPE, additionally showed, in middle-aged patients with diabetes mellitus who were at high risk for cardiovascular events, significant reductions in MI by 22%, stroke by 33%, cardiovascular death by 37%, and the combined primary event outcome by 25%.802 Furthermore, the need for revascularization and incidence of worsening angina also were significantly reduced.

The EUROPA (European trial on Reduction Of cardiac events with Perindopril in stable coronary Artery disease) trial provided added support to the HOPE trial results in patients with SIHD without clinical evidence of heart failure.296 In 12 218 patients followed up for a mean of 4.2 years, there was a 20% relative increase in the time to the primary composite endpoint of cardiovascular death, nonfatal MI, or cardiac arrest with perindopril compared with placebo.296 Perindopril was further tested in the PEACE (Prevention of Events with Angiotensin-Converting Enzyme Inhibitor) trial, which enrolled 4158 patients with SIHD and normal or slightly reduced LV function (ie, absence of LV wallmotion abnormalities).295 The incidence of the primary endpoint of death from cardiovascular causes, MI, or coronary revascularization was equivalent between perindopril and placebo, but the overall rate of cardiovascular events was lower than in the HOPE and EUROPA trials.

In QUIET (Quinapril Ischemic Event Trial), there was also no significant reduction with quinapril in ischemic events and progression of CAD in coronary angioplasty patients without systolic LV dysfunction (RR: 13%; P0.49), although this finding has been attributed to study design limitations.797 Similarly, the IMAGINE (Ischemia Management With Accupril Post-Bypass Graft via Inhibition of the Converting Enzyme) study demonstrated no reduction in clinical outcomes in low-risk patients (LVEF 40%) with quinapril after surgical revascularization.803 In a meta-analysis of ACE-inhibitor therapy versus placebo in 31 555 patients from HOPE, EUROPA, PEACE, and QUIET, ACE-inhibitor therapy produced 14% reductions in all-cause mortality and MI (bothp0.0004), a 23% reduction in stroke (P0.0004), and a 7% reduction in revascularization procedures (P0.025) compared with placebo.796

A meta-regression analysis of 26 trials compared the effects of ACE inhibitors and ARBs on major vascular events by BP effects.804 Treatment with ACE inhibitor based regimens was associated with a reduction in the risk for stroke (by 19%), IHD (by 16%), and heart failure (by 27%) for each 5 mm Hg reduction in BP; Corresponding figures for the reduction in risk for ARBs were 26%, 17%, and 12%, respectively. There were no significant differences between ARB- and ACE inhibitor based regimens in the risk of stroke, IHD, and heart failure for each 5 mm Hg reduction in BP. When these outcomes were assessed at zero BP reduction, the risk reduction for IHD was significantly greater for ACE inhibitors than for ARBs (P0.002). Furthermore, unlike ARBs, ACE inhibitors were associated with a significant additional risk reduction for IHD of 9% (P0.004), without differences seen for stroke or heart failure versus ARBs. It is therefore recommended that ARBs be substituted for ACE inhibitors in patients with SIHD and hypertension who are intolerant of ACE inhibitors.563,565,792,804,805

Ελάττωση της ΚΣ συνεπάγεται μείωση της ισχαιμίας 63 ασθενείς με σταθερή στηθάγχη και υψηλή συχνότητα ασυμπτωματικής ισχαιμίας Μεγαλύτερη μείωση της ΚΣ συνεπάγεται μεγαλύτερη μείωση των επεισοδίων μυοκαρδιακής ισχαιμίας Stone PH. Circulation. 1990;82:1962-1972. 1972.

Absolute contraindications to beta blockers are severe bradycardia, preexisting high-degree AV block, sick sinus syndrome (without a pacemaker in place), and refractory heart failure. Relative contraindications include bronchospastic disease or active PAD (beta blockers without vasodilating properties or selective agents at low doses may be used). Because they can mask symptoms of hypoglycemia, beta blockers should be used with caution in patients with insulindependent diabetes mellitus. Abrupt beta-blocker withdrawal should be avoided because heightened betareceptor density and sensitivity can result in a rebound phenomenon associated with an increased risk for AMI and sudden death. If withdrawal is necessary, beta blockers should be tapered over a 1- to 3-week period, with consideration given to use of sublingual nitroglycerin or substitution with a nondihydropyridine calcium channel blocker during the withdrawal period. The principle adverse effects of beta blockers are fatigue, exercise intolerance, lethargy, insomnia, nightmares, and impotence