Νεόηεξα θάξκαθα γηα ηελ αληηκεηώπηζε ηεο ζηεζάγρεο

14ν πλέδξην New Trends in Cardiology 11-12 Απξηιίνπ 2014 Νεόηεξα θάξκαθα γηα ηελ αληηκεηώπηζε ηεο ζηεζάγρεο Γεώξγηνο Γηαλλαθνύιαο Λέθηνξαο Καξδηνινγίαο ΑΠΘ A Καξδηνινγηθή Κιηληθή, Ννζνθνκείν ΑΥΕΠΑ

Per 1000 patient years Incidence of Angina Framingham Study : 1980/2002-2003 Men Women 12 10 8 6 4 4.0 5.6 3.1 10.1 5.3 10.5 5.0 7.6 4.2 2 0.9 0 45-54 55-64 65-74 75-84 85-94 Age AHA, Heart Disease and Stroke Statistics, 2008 Update. NHLBI Rosamond W, et al. Heart Disease and Stroke Statistics 2008 Update. Circulation 2008;117:e59.

Prognostic implications of angina Mozaffarian D, et al. Am Heart J 2003;146:1015-22.

Chronic nitrate use causes endothelial dysfunction and oxidative stress Oelze et al. Eur Heart J 2013

Stable Angina Current Pharmacotherapy Beta-blockers Calcium channel blockers Nitrates Aspirin Statins? ACE inhibitors New therapies (ranolazine, nicorandil, ivabradine, trimatazidine?)

Nicorandil

Nicorandil Agonist Nitrate effect EXTRACELLULAR PLC + PLD PKC CYTOSOL mediates protection Nicorandil Free Oxygen Radicals TK unknown effector K ATP CHANNEL MITOCHONDRION

Lancet 2002;359:1269

CONCLUSION: Nicorandil is beneficial as treatment for angina pectoris Zhu et al. Circ J. 2007

Ivabradine

Cumulative survival Heart rate is strongly related to CV mortality The Coronary Artery Surgery Study (CASS) registry; 24 913 CAD patients; 14.1-year follow-up Adjusted survival curves for overall mortality Adjusted survival curves for cardiovascular mortality 1.0 1.0 0.9 0.9 0.8 0.7 P<0.0001 0.8 0.7 P<0.0001 0.6 0.6 0.5 0.5 0 5 10 15 20 Years after enrollment 0 5 10 15 20 62 63-70 71-76 77-82 83 bpm Diaz A, et al Eur Heart J. 2005;26:967-974.

Τρόποσ δράςησ Απνθιεηζηηθή κείωζε ηεο Καξδηαθήο πρλόηεηαο Το ρεφμα f ςτη μεμβράνη του φλεβοκομβικοφ κυττάρου. Η ιβαμπραδίνη προςδζνεται ειδικά ςτο κανάλι f των φλεβοκομβικών κυττάρων, και αναςτζλλει εκλεκτικά το ρεφμα I f 1. Bois P, et al. Br J Pharmacol. 1996;118:1051-1057 2. Bucchi A, et al. J Gen Physiol. 2002;120:1-13, 3. Thollon C, et al. Br J Pharmacol. 1994;112:37-42 Δυναμικό ενζργειασ ενόσ φλεβοκομβικοφ κυττάρου: μζςω τησ αναςτολήσ του ρεφματοσ I f, η ιβαμπραδίνη μειώνει την κλίςη τησ καμπφλησ τησ Αυτόματησ Διαςτολικήσ Εκπόλωςησ (SDD), μειώνοντασ αποκλειςτικά την Καρδιακή Συχνότητα.

vs BEAUTI f UL SIGNI f Y Primary diagnosis CAD CAD LVEF at inclusion < 40% > 40% HR at inclusion 60 bpm 70 bpm Study treatment regimen Fixed treatment regimen (5-7.5 mg bid) Flexible treatment regimen to reach target heart rate of 60 bpm (7.5 mg up to 10 mg bid) Follow-up Up to 36 months Up to 48 months Primary end points CV death & MI or HF hospitalization CV death & nonfatal MI

Ranolazine

Angina pathophysiology Oxygen supply and demand mismatch Chaitman BR. Circulation 2006;113:2462-2472 Belardinelli L, et al. Eur Heart J 2004;6(suppl I):I3-I7

Selective inhibitor of the late sodium channel current (late I Na+ ) ranolazine 0 Sodium Current Late Ischemia 0 Sodium Current Late Peak Na + Peak Na + Impaired Inactivation Απνηπρία Αδξαλνπνίεζεο ηωλ δηαύιωλ Na + Belardinelli L, et al. Eur Heart J Suppl 2006; (8 suppl A): A10-13 Belardinelli L, et al. Eur Heart J Suppl 2004; 6(suppl I): I3-7

Beats/min mm Hg Αληηζηεζαγρηθή δξάζε ηεο Ραλνιαδίλεο αλεμάξηεηα από ηελ Καξδηαθή πρλόηεηα θαη ηελ Αξηεξηαθή Πίεζε 100 A. Heart Rate 160 B. Arterial Blood Pressure Systolic Diastolic 80 140 120 60 100 80 40 60 20 40 20 0 Placebo 2.7 ± 0.1 5.9 ± 0.3 9.4 ± 0.4 0 Placebo 2.7 ± 0.1 5.9 ± 0.3 9.4 ± 0.4 Ranolazine Concentration (µm) Therapeutic Levels = 2 to 8 µm Ranolazine Concentration (µm)

H Ραλνιαδίλε βειηηώλεη ηελ αηκάηωζε ηνπ κπνθαξδίνπ ζην ζπηλζεξνγξάθεκα Ζξεκία Κόπωζε Baseline Peak HR = 142 bpm After RAN 1.000mg bid (3-4 wks) Peak HR = 142 bpm 25% 11% 56% κείωζε ζην έιιείκκα αηκάηωζεο Μειέηε ζε 20 αζζελείο κε Ν θαη ηεζάγρε πνπ ιάκβαλαλ 1.000mg Ραλνιαδίλεο bid επηπξνζζέηωο ζηε ζπλήζε αγωγή Βειηίωζε ηεο αηκάηωζεο ηνπ κπνθαξδίνπ θαη κείωζε ηεο βαξύηεηαο ηεο ηζραηκίαο ζην 70% ηωλ αζζελώλ Αύμεζε ηεο δηάξθεηαο ηεο άζθεζεο ζην Stress Test θαηά 32 sec Βειηίωζε ηεο ζηεζάγρεο ζην 75% ηωλ αζζελώλ Venkataraman R, et al. JACC Cardiovascular imaging 2009;2:1301-9

Rate-Pressure Product (mmhg min -1 ± SE) Ranolazine vs Atenolol N = 154 Δηάξθεηα άζθεζεο 40,000 ranolazine p < 0.001 p = 0.006 p < 0.04 30,000 20,000 10,000 * * placebo atenolol (100mg) * * * * p <0.001 vs placebo 0 3 6 9 12 15 18 Minutes on treadmill Placebo Ranolazine IR 400 mg tid (1741 ± 1026 ng base/ml) Atenolol 100 mg qd Rousseau MF, et al. Am J Cardiol 2005;95(3):311-6

MERLIN: ρεδηαζκόο ηεο κειέηεο Ραλνιαδίλε 1.000mg bid: Αξρηθά ελδνθιεβίωο & ζηε ζπλέρεηα από ηνπ ζηόκαηνο UA: αζηαζήο ζηεζάγρε, NSTEMI: έκθξαγκα ηνπ κπνθαξδίνπ ρωξίο αλάζπαζε ηνπ ST δηαζηήκαηνο, Sx symptoms: ζπκπηώκαηα εκθξάγκαηνο ηνπ κπνθαξδίνπ ζε θαηάζηαζε εξεκίαο, St-Dep: θαηάζπαζε ηνπ δηαζηήκαηνο ST 0.1mV, ctn: θαξδηαθή ηξνπνλίλε, έλαο δείθηεο λέθξωζεο, DM: ζαθραξώδεο δηαβήηεο, TRS: Κιίκαθα επηθηλδπλόηεηαο θαηά ΣΙΜΙ Morrow D, et al. JAMA 2007;297:1775-83

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

Ποσοστό ασθενών (%) Primary composite endpoint (CV death, MI or Recurrent Ischemia) 30 Placebo (n = 1.776) Ranolazine (n = 1.789) i.v. 1,000 mg b.i.d. p.o. 29 28 27 26 29.4 RR 14% P = 0,017 25 24 23 25.2 Patients with a history of stable angina Wilson SR, et al. J Am Coll Cardiol 2009; 53 (17): 1510-1516

(%) Secondary endpoints 25 20 15 10 5 RR 23% p=0.048 8.1 5.6 RR 22% p=0.005 16.4 12.5 RR 22% 21.1 p=0.002 16.5 Placebo (n = 1.776) Ranolazine (n = 1.789) i.v. 1,000 mg b.i.d. p.o. 0 worsening angina New antianginal therapy Recurrent ischemia Wilson SR, et al. J Am Coll Cardiol 2009; 53 (17): 1510-1516

Πνζνζηό αζζελώλ (%) Δπίπηωζε Τπεξθνηιηαθώλ Αξξπζκηώλ Αζζελείο κε ηζηνξηθό ζηεζάγρεο 52.5 50 47.5 45 1752 (53.5%) RR 19% P < 0,001 42.5 40 1413 (43.2%) Placebo (n = 1.776) Ranolazine (n = 1.789) Wilson SR, et al. J Am Coll Cardiol 2009;53:1510-1516

Percent (%) MERLIN-TIMI 36: Effect of Ranolazine on HbA 1c in Patients with Diabetes A. Worsening Hyperglycemia 1 B. Failure to Achieve HbA1c < 7% 2 P < 0.001, RR 0.63 % Placebo Ranolazine P <0.001, RR 0.80 % 1. KM Cumulative Incidence of 1% in HbA1c at 12 months 2. At 4 months

Trimetazidine

Trimetazidine use in angina Add-on to existing treatments in patients who are not adequately controlled by or who are intolerant to other medicines To address the lack of long-term data, a study investigating the long-term effects of trimetazidine will be carried out.

Many thanks giannak@med.auth.gr

Ranolazine for Angina with Non-obstructive CAD in Women Pilot randomized, double-blind, placebo-controlled, crossover trial 20 women with angina, no obstructive CAD, and 10% ischemic myocardium Ranolazine 1000 mg bid or placebo for 4 weeks separated by a 2-week washout The Seattle Angina Questionnaire and CMR were evaluated after each treatment SAQ scores on ranolazine versus placebo Mehta PK, et al. JACC Cardiovasc Imaging 2011;4:514-22a

Σειεπηαίεο Μειέηεο Πνην ην κέιινλ;

Pretreatment with ranolazine 1,000 mg twice daily for 7 days significantly reduced procedural myocardial injury (CK-MB, CTnI) in elective PCI. Am Heart J 2012;163:1019-23

AF in 26.5% pts. with amiodarone vs. 17.5% with ranolazine (p=0.035). Νo difference in the incidence of adverse events. Am J Cardiol. 2011;108:673-676

Amiodarone alone 65% success for conversion Ranolazine + amiodarone: 88% success AND faster (9.8 vs. 14.6 hours) Equally safe therapies Am J Cardiol. 2012;110:673-677

Investigated if ranolazine improves diastolic function in patients with HFpEF. Inclusion criteria: EF 45%, E/E >15 or NT-proBNP>220 pg/ml, LVEDP 18 mmhg. Patients received i.v. ranolazine (n=12) or placebo (n=8) during catheterization and for 24 h, followed by oral treatment with ranolazine 1000 mg twice daily or placebo for 14 days. Results: After 30 min of infusion LVEDP, PCWP, and mean PAP decreased significantly in the ranolazine group but not in the placebo group. After 14 days of treatment, during cardiopulmonary exercise test the VE/VCO 2 slope decreased in the ranolazine group. Conclusions: The results of this exploratory, proof-of-concept study revealed improvement with ranolazine in some important measures of diastolic function.

The initial combination of BB and CCB is generally supported by good evidence of symptomatic benefit. Ranolazine added to either BB offers consistently significant gains, while LAN and trimetazidine may also be effective, although the evidence for these is somewhat more heterogeneous. Ivabradine, although associated with an improvement in ETT, has failed to demonstrate clinical benefits, there are no data for nicorandil in this role Presentation Abstract AHA Los Angeles 2012

Έλαξμε - Σηηινπνίεζε Γόζεο Η ζπληζηώκελε αξρηθή δόζε ηεο Ραλνιαδίλεο, είλαη 375mg δηο εκεξεζίωο. Μεηά από 2-4 εβδνκάδεο, ε δόζε ζα κπνξνύζε λα ηηηινπνηεζεί ζηα 500mg δηο εκεξεζίωο, θαη ζύκθωλα κε ηελ αληαπόθξηζε ηνπ αζζελνύο, λα ηηηινπνηεζεί πεξαηηέξω ζηε κέγηζηε ζπληζηώκελε δόζε ηωλ 750mg δηο εκεξεζίωο. 375mg 500mg 750mg

Αληελδείμεηο Τπεξεπαηζζεζία ζηε δξαζηηθή νπζία ή ζε έθδνρα. νβαξή λεθξηθή αλεπάξθεηα (ΡΔ <30 ml/min). νβαξή επαηηθή αλεπάξθεηα. πγρνξήγεζε ηζρπξώλ αλαζηνιέωλ ηνπ θπηνρξώκαηνο CYP3A4 (π.ρ. ηηξαθνλαδόιε, θεηνθνλαδόιε, αλαζηνιείο ηεο HIV πξωηεάζεο, θιαξηζξνκπθίλε, ηειηζξνκπθίλε). πγρνξήγεζε αληηαξξπζκηθώλ ηάμεο Ιa (π.ρ. θηληδίλε) ή ηάμεο ΙΙΙ (π.ρ. δνθεηηιίδε, ζνηαιόιε) εθηόο ακηωδαξόλεο. Σαπηόρξνλε ρνξήγεζε κε ρπκό ηνπ γθξέηπθξνπη.

Αζθάιεηα θαη Αλεθηηθόηεηα Πην ζπρλά αλαθεξόκελα αλεπηζύκεηα ζπκβάκαηα: Γπζθνηιηόηεηα Ναπηία Εάιε ( < 10%) Γελ παξαηεξήζεθε νξγαλνηνμηθόηεηα Κακία έλδεημε γηα ζνβαξά αλεπηζύκεηα ζπκβάληα (π.ρ. Αηθλίδηνο θαξδηαθόο ζάλαηνο) Ασφάλεια

N = 4545 patients with chronic stable angina Phelps, et al. Clin Therapeut 2012; 34(6):1395-1407

6 months post treatment Phelps, et al. Clin Therapeut 2012; 34(6):1395-1407

Event rates, % Impact of Ranolazine Hospitalization and Healthcare Costs Retrospective case-control study based on a national health insurance database Follow-up 6 months Ranolazine (n = 881), nitrates (n = 1788), BB/CCB (n = 1876) Ranolazine vs BB/CCB or nitrates OR 95% CI Revascularisation 0.42 0.33-0.55 Hospitalisation 0.60 0.46-0.77 Healthcare costs Ranolazine BB/CCB Nitrates $13,961 $17,612 $18,166 - +21% +23% 35 30 25 20 15 10 5 0 8.3 Ranolazine BB/CCB Nitrates * p <0.01 vs BB/CCB and nitrates * 14.1 11.9 * 2 4 6.5 27.4 Phelps CE, et al. ACC 2010 33.8 33.2 PCI CABG Hospitalisation *

Change in QTc (msec) [Ranolazine] (ng/ml) Effect of Ranolazine on QTc interval in LQT3 LQT3 due to KPQ mutation leading to increased SCN5A activation of Late Na current 3000 2000 1000 On Ranolazine, IV Off 45 mg/hr 90 mg/hr Therefore Ranolazine inhibits the Late Sodium Current -10-20 -30-40 * * * * * * p < 0.05 p < 0.01 p < 0.001 p < 0.0001-50 repeated measures ANOVA Values are mean 0 4 8 12 16 20 24 ± SE from 5 patients QTc (Fridericia) change from baseline Time (hrs) Moss A, et al. J Cardiovasc Electrophysiol 2008;19:1289-93 QTc vs. [RAN] plasma r = 0.7 ± 0.22 slope = 24.1 msec/1,000 ng/ml (P = 0.008)

Effect of Ranolazine on QTc interval in LQT3 Moss A, et al. J Cardiovasc Electrophysiol 2008;19:1289-93

Baseline BNP and Clinical Outcomes Results CV Death, MI, or Recurrent Ischemia (%) 35 30 BNP >80 pg/ml (n = 1935) 26.4% 25 20 15 10 5 0 P < 0.001 BNP 80 pg/ml (n = 2608) 20.4% 0 180 360 540 Days from Randomization Morrow et al JACC 10

Baseline BNP and Effect of Ranolazine on Primary Endpoint CV Death, MI, or Recurrent Ischemia (%) 30 Results BNP POS Placebo 25 20 p = 0.009 BNP POS Ranolazine BNP NEG 15 10 5 0 P-interaction = 0.05 0 180 360 Days from Randomization *KM cumulative incidence (%) at 12 months Morrow et al. JACC. 2010 23; 55:1189

EFFECTS OF RANOLAZINE ON LV DIASTOLIC FUNCTION 125 Moss AJ et al. J Cardiovasc Electrophysiol 2008;19:1289 100 75 50 25 0 BL Ran BL Ran ISOVOLUMIC RELAXATION (msec) p < 0.05 MITRAL E-WAVE VEL. (cm/s) p < 0.05

Dose Titration The recommended initial dose of Ranexa is 375 mg twice daily After 2 4 weeks, the dose should be titrated to 500 mg twice daily and, according to the patient s response, further titrated to a recommended maximum dose of 750 mg twice daily 375mg 500mg 750mg If a patient experiences treatment-related adverse events (e.g. dizziness, nausea, or constipation), down titration of Ranexa to 500 mg or 375 mg twice daily may be required. If symptoms do not resolve after dose reduction, treatment should be discontinued Ranexa Summary of Product Characteristics, July 2008

Pharmacology Ranolazine is rapidly metabolized in the liver, primarily through the cytochrome P-450 3A enzyme (CYP3A) pathway, and in the intestine More than 70% of the drug is excreted in the urine Careful dosage adjustments in elderly BW< 60 kg mild-to-moderate renal insufficiency mild hepatic impairment In NYHA functional class III IV

Drug Interactions potent CYP3A inhibitors ketoconazole contraindicated moderate CYP3A inhibitors diltiazem and verapamil should be used with caution Macrolide antibiotics and grapefruit juice -all of which inhibit CYP3A to varying degrees-should be used with caution Ranolazine increases the concentration of serum digoxin and verapamil

Summary Sodium Current 0 Late I Na Peak INa Ranolazine is a selective late sodium channel blocker, which improves myocardial blood flow and electrical stability Ranolazine is an effective anti-anginal agent which has no effect on systemic haemodynamic function (PR and BP) Ranolazine improves exercise tolerance, and can be used in combination with beta blockers and calcium channel antagonists Ranolazine may have additional antiarrhythmic and anti-diabetic properties

Ραλνιαδίλε: Γεληθέο αξρέο ζηε ρξήζε

Δλδείμεηο ρνξήγεζεο ξαλνιαδίλεο Ωο ζπκπιεξωκαηηθή ζεξαπεία γηα ηνλ αζζελή κε ρξόληα ζηαζεξή ζηεζάγρε, όηαλ ε ζπκπηωκαηνινγία δελ ειέγρεηαη κε ή δελ είλαη δπλαηή ε αλνρή ηεο αληηζηεζαγρηθήο αγωγήο πξώηεο γξακκήο (β-αλαζηνιέα ή/θαη αληαγωληζηήο αζβεζηίνπ)

Stable Angina NICE Guidelines β-blocker or calcium antagonist Depending on comorbidity, contraindications and patient preference Change to alternative If treatment unsuccessful or not tolerated Combine β-blocker or calcium antagonist If treatment unsuccessful Monotherapy with: A long-acting nitrate or Ivabradine or Nicorandil or Ranolazine If treatment unsuccessful Choice depends on comorbidities, contraindications, patient preference and drug costs Combination of β-blocker or calcium antagonist with: A long-acting nitrate or Ivabradine or Nicorandil or Ranolazine When β-blocker or calcium antagonist not tolerated or combination unsuccessful Choice reasons as above NICE Guidance GL 126 July 2011 Add third anti-anginal Symptoms not controlled and awaiting revasc, or revasc not considered appropriate or acceptable

Food for discussion

COURAGE Trial New stents? New drugs? Weintraub WS, et al. N Eng J Med 2008;359:677-87