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New Therapeutic Options for Chronic Stable Angina

New Therapeutic Options for Chronic Stable Angina. New mechanistic approaches to chronic stable angina. CH 3. N. CH 3. O. O. H. O. N. CH 3. SO 2. N. N. NH. H. CH 3. OH. OCH 3. H. N. N. N. O. O. CH 3. Rho kinase inhibition (fasudil). Metabolic modulation (trimetazidine).

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New Therapeutic Options for Chronic Stable Angina

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  1. New Therapeutic Options for Chronic Stable Angina

  2. New mechanistic approaches to chronic stable angina CH3 N CH3 O O H O N CH3 SO2 N N NH H CH3 OH OCH3 H N N N O O CH3 Rho kinase inhibition (fasudil) Metabolic modulation (trimetazidine) Sinus node inhibition (ivabradine) Preconditioning (nicorandil) O NO2 O H H3C O O CH3 N N N H3C O N CH3 O CH3 O Late INa inhibition (ranolazine)

  3. Evaluation of fasudil in stable angina: Trial design N = 84 80 mg tid 2 weeks ET* 60 mg tid 2 weeks 40 mg tid ET* Fasudil20 mg tid(n = 41) 2 weeks ET* Run-in(Class II or III angina) 2 weeks ET* 3 weeks Placebo (n = 43) ET ET = exercise test (treadmill) *ET at trough and 1 and 4 hours post-dose Vicari RM et al. J Am Coll Cardiol. 2005;46:1803-11.

  4. Results: Fasudil improves exercise duration N = 84 Weeks 2 4 6 8 (20 mg) (40 mg) (60 mg) (80 mg) Placebo Fasudil Visit (fasudil dose tid) Vicari RM et al. J Am Coll Cardiol. 2005;46:1803-11.

  5. Results: Fasudil improves exercise time to ≥1 mm ST depression N = 84 * Weeks 2 4 6 8 (20 mg) (40 mg) (60 mg) (80 mg) Placebo Fasudil Visit (fasudil dose tid) *P = 0.001 Vicari RM et al. J Am Coll Cardiol. 2005;46:1803-11.

  6. TACT: Study design Trimetazidine in Angina Combination Therapy Trimetazidine 20 mg tid (n = 90) Primary outcomes • ET duration • Time to 1 mm ST  • Time to angina onset • Mean no. angina attacks • Mean short-acting nitrate use • Change in rate-pressure product • Change in CCS angina class Run-in(CCS class I–III) ≥2 weeks 2 x ET (weeks -1, 0) Placebo (n = 87) 12 weeks ET ET N = 166 menET = exercise test (treadmill/bicycle) Chazov EI et al. Am J Ther. 2005;12:35-42.

  7. TACT: Trimetazidine reduces angina episodes N = 166 men with CCS class I–III angina P < 0.05 Months Placebo Trimetazidine 20 mg tid Chazov EI et al. Am J Ther. 2005;12:35-42.

  8. IONA: Study design Impact Of Nicorandil in Angina Stable angina on optimum antianginal therapyN = 5126 Nicorandil 20 mg bidn = 2565 Placebon = 2561 RandomizedDouble-blind 1.6 years mean follow-up Primary outcome:CHD death, nonfatal MI, hospitalization for chest pain IONA Study Group. Lancet. 2002;359:1269-75.

  9. IONA: Reduction in primary outcome CHD death, nonfatal MI, hospitalization for chest pain 1.0 0.9 Nicorandil RRR 17% HR 0.83 (0.72–0.97)P = 0.014 Proportionevent-free 0.8 Placebo 0.7 0 0 0.5 1.0 1.5 2.0 2.5 3.0 Follow-up (years) IONA Study Group. Lancet. 2002;359:1269-75.

  10. INITIATIVE: Study design Ivabradine5 mg bid(n = 317) 10 mg bid Placebo Ivabradine5 mg bid(n = 315) 7.5 mg bid Placebo Placebo 4 weeks 12 weeks 2 weeks 7 days 2–7 days Run-in Washout Atenolol50 mg(n = 307) 100 mg 50 mg 25 mg Selection ET ET* ET* Inclusion ET International Trial on the Treatment of Angina with Ivabradine vs. Atenolol ET = exercise test (treadmill) *ET at trough and 4 hours post-dose Tardif J-C et al. Eur Heart J. 2005;26:2529-36.

  11. INITIATIVE: Effects of ivabradine vs β-blockade on primary outcome P < 0.001 for noninferiority vs atenolol (both ivabradine doses) 100 mg(n = 286) 7.5 mg bid(n = 300) 10 mg bid(n = 298) Tardif J-C et al. Eur Heart J. 2005;26:2529-36. Patients completing trial

  12. INITIATIVE: Summary • Ivabradine 7.5 mg bid and 10 mg bid were noninferior to atenolol 100 mg as measured by • Total exercise duration • Time to limiting angina, angina onset, and 1 mm ST • Most common adverse events were transient visual symptoms, mainly increased brightness in limited areas • Sinus bradycardia occurred in 2.2% (ivabradine 7.5 mg),5.4% (ivabradine 10 mg), and 4.3% (atenolol) of patients If current inhibition may be as effective as β-blockade in treatment of stable angina Tardif J-C et al. Eur Heart J. 2005;26:2529-36.

  13. Ranolazine: Late Na+ current inhibitor • First new class of antianginals to be approved in the US since 1960s • Antianginal and anti-ischemic effects with no change in HR or BP • May be used in patients with slow HR, low BP, prolonged AV conduction, CHF, diabetes, or asthma • Modest prolongation of QTc interval with no known clinical sequelae

  14. Ranolazine: Pathophysiologic effects vs older antianginals O2 Supply O2 Demand Coronary blood flow Heart rate Arterial pressure Venous return Myocardial contractility Drug class β-blockers —   —  DHP CCBs  *  —  Non-DHP CCBs    —  Long-acting nitrates   / —   — Late Na+ current inhibitors(ranolazine) — — — — —† Boden WE et al. Clin Cardiol. 2001;24:73-9.Gibbons RJ et al. ACC/AHA 2002 guidelines. www.acc.org/clinical/guidelines/stable/stable.pdf Kerins DM et al. In: Goodman and Gilman’s The Pharmacological Basis of Therapeutics. 10th ed. *Except amlodipine†Ranolazine: No direct effect butmay prevent ischemia-related decline

  15. MARISA: Study overview Monotherapy Assessment of Ranolazine In Stable Angina Objective: Assess the antianginal effects of ranolazine as monotherapy in stable angina Design: Randomized, double-blind, placebo-controlled, crossover Population: N = 191 with stable angina Treatment: Ranolazine SR 500 mg, 1000 mg, or 1500 mg bid Placebo Primary outcome: Total exercise duration at trough Follow-up: 3 active treatment periods, each lasting 1 week; 1-week placebo period 1-year open-label follow-up Chaitman BR et al. J Am Coll Cardiol. 2004;43:1375-82.

  16. MARISA: Study design Single-blind placebo qualifying phase Double-blind phase Post-study follow-up 1 week 4 weeks 2 weeks Visit 1 Pre-visit 1 Visit 7 Randomized, 1-week periods, crossover, placebo, ranolazine SR 500–1500 mg bid Qualifying ET ET each week at trough and 4 hours post-dose ET = exercise test (treadmill) Chaitman BR et al. J Am Coll Cardiol. 2004;43:1375-82.

  17. MARISA: Dose-related increase in exercise duration with ranolazine N = 175 evaluable patients with stable angina † † * Ranolazine SR bid *P = 0.003 vs placebo; †P < 0.001 vs placebo Chaitman BR et al. J Am Coll Cardiol. 2004;43:1375-82.

  18. MARISA: Tolerability of treatments Dose-related adverse events* *Occurring in ≥3% of patients†Exceeds recommended dose Chaitman BR et al. J Am Coll Cardiol. 2004;43:1375-82.

  19. MARISA: Summary • Compared with placebo, ranolazine SR 500–1500 mg bid significantly improved: • Total exercise duration • Time to angina onset • Time to 1 mm ST  • No clinically significant  in HR or BP at rest or during exercise • 7% (13/191) of ranolazine patients discontinued due to adverse events, mostly (11/13) at the highest dose • No effect on QT dispersion • No patient discontinued because of QTc prolongation* Ranolazine monotherapy is associated with increased exercise performance in the absence of any clinically meaningful pathophysiologic effects * >30% from baseline Chaitman BR et al. J Am Coll Cardiol. 2004;43:1375-82.

  20. Antianginals: Effects on exercise duration 1. Chaitman BR et al. J Am Coll Cardiol. 2004;43:1375-82. 2. Davies RF et al. J Am Coll Cardiol. 1995;25:619-25. 3. Go M et al. Am J Cardiol. 1984;53:669-73. 4. Stone PH et al. Circulation. 1990;82:1962-72. *bid

  21. CARISA: Study overview Combination Assessment of Ranolazine In Stable Angina Objective: Assess the antianginal effects of ranolazine when added to standard antianginal therapy Design: Randomized, double-blind, placebo-controlled, parallel-group Population: N = 823 with angina/ischemia despite standard qd doses of amlodipine 5 mg, atenolol 50 mg, or diltiazem 180 mg Treatment: Ranolazine SR 750 mg or 1000 mg bid Placebo Primary outcome: Total exercise duration at trough Follow up: 12 weeks Chaitman BR et al. JAMA. 2004;291:309-16.

  22. CARISA: Study design Background CCB or -blocker plus nitrates prn Ranolazine SR 1000 mg bid (n = 275) Single-blind placeboqualifying phase Ranolazine SR 750 mg bid (n = 279) 1 week ET Placebo (n = 269) 2 weeks 4 weeks 6 weeks ET ET* ET* ET* ET = Exercise test (treadmill)*ET at trough and 4 hours post-dose Chaitman BR et al. JAMA. 2004;291:309-16.

  23. CARISA: Ranolazine increases exercise duration Background CCB or -blocker plus nitrates prn * * (n = 258) (n = 272) (n = 261) Ranolazine SR bid *P = 0.03 vs placebo Chaitman BR et al. JAMA. 2004;291:309-16.

  24. CARISA: Ranolazine reduces angina frequency Background CCB or -blocker plus nitrates prn P < 0.001 P = 0.006 Anginal episodes per week Placebo Ranolazine SR750 mg bid Ranolazine SR1000 mg bid Chaitman BR et al. JAMA. 2004;291:309-16.

  25. CARISA: Ranolazine reduces nitrate consumption P = 0.02 Background CCB or -blocker plus nitrates prn P < 0.001 Number per week Nitroglycerin use Placebo Ranolazine SR750 mg bid Ranolazine SR1000 mg bid Chaitman BR et al. JAMA. 2004;291:309-16.

  26. CARISA: Summary • Ranolazine SR added to standard therapy significantly improved: • Total exercise duration, time to angina onset, time to 1 mm ST  • Anginal frequency and nitroglycerin consumption • No clinically significant changes in HR or BP at rest or during exercise • Small QTc increases with no effect on QT dispersion Ranolazine provides additional antianginal and anti-ischemic efficacy in patients who remain symptomatic on standard therapies Chaitman BR et al. JAMA. 2004;291:309-16.

  27. ERICA: Study design Evaluation of Ranolazine in Chronic Angina Stable angina on amlodipine 10 mgN = 565 Ranolazine SR 1000 mg bid RandomizedDouble-blind Placebo 7 weeks Primary outcome:Angina frequency Stone PH et al. Circulation. 2005;112(suppl II):II-748-9.

  28. ERICA: Ranolazine reduces angina frequency and nitrate consumption N = 565 6 5 P = 0.028 4 Mean P = 0.014 number 3 per week 2 1 0 Baseline Week 7 Baseline Week 7 Anginal attacks Nitroglycerin use Placebo Ranolazine SR 1000 mg bid Stone PH et al. Circulation. 2005;112(suppl II):II-748-9.

  29. ERICA: Summary • Added to maximum-dose amlodipine, ranolazine SR 1000 mg bid significantly reduced anginal frequency and nitroglycerin use • No change in HR or BP • Early withdrawal rate due to adverse events was comparably low in both groups • 1.1% ranolazine • 1.4% placebo Ranolazine provides additional, well-tolerated antianginal efficacy in patients who remain symptomatic despite maximal CCB therapy Stone PH et al. Circulation. 2005;112(suppl II):II-748-9.

  30. Ranolazine: Long-term use Exercise-induced chronic angina Successfully completed 1 of 2 treadmill studiesN = 746 Open label Ranolazine titrated to 1000 mg bid 2.96 years mean follow-up Results: Overall mortality: 2.8% per patient year (PPY) SCD mortality: 0.6% PPY QTc >500msec: 10 patients; Torsade de Pointes: 0 patients Ranolazine discontinuation due to AEs: 9.7% in first 2 years Age >64 years and prior Hx of HF were significant predictors of AE-associated discontinuation Koren MJ et al. J Am Coll Cardiol. 2006;47(suppl A):Abstract 999-253. SCD = sudden cardiac death

  31. Ranolazine extended-release tablets:Approved Jan 31, 2006 • Ranolazine is indicated for the treatment of chronic angina • Because ranolazine prolongs the QT interval, it should be reserved for patients who have not achieved an adequate response with other antianginal drugs • Ranolazine should be used in combination with amlodipine, β-blockers or nitrates • Effects on angina rate and exercise tolerance appear to be smaller in women FDA. http://www.fda.gov/bbs/topics/news/2006/NEW01306.html.Ranolazine extended-release tablets prescribing information.

  32. Ranolazine: Drug interactions Inhibitors of CYP3A increase ranolazine plasma levels and QTc prolongation and should not be coadministered with ranolazine: • Ketoconazole and other azole antifungals • Diltiazem • Verapamil • Macrolide antibiotics • HIV protease inhibitors • Grapefruit juice or grapefruit-containing products Ranolazine extended-release tablets prescribing information.

  33. Ranolazine extended-release tablets: Dosing • Dosing should be initiated at 500 mg bid and increased to 1000 mg bid, as needed, based on clinical symptoms • The maximum recommended daily dose of ranolazine is 1000 mg bid Ranolazine extended-release tablets prescribing information.

  34. Electrophysiologic effects of ranolazine

  35. Late INa effect mitigates IKr effect Antzelevitch C et al. J Cardiovasc Pharmacol Therapeut. 2004;9(suppl 1):S65-83.Antzelevitch C et al. Circulation. 2004;110:904-10.Cobbe S. Eur Heart J Suppl. 2004;6(suppl I):I9-11. *At 500–1000 mg bid,mean concentration range ~2–6 µM

  36. Overview of torsade de pointes  Net repolarizing current (IKr or INa) Action potential duration and QT interval Early afterdepolarizations (EADs)  Dispersion of ventricular repolarization (ΔAPD) Trigger Substrate Torsade de pointes Antzelevitch C et al. J Cardiovasc Pharmacol Therapeut. 2004;9(suppl 1):S65-83. APD = action potential duration

  37. Ranolazine: No apparent proarrhythmic characteristics • No potential for early afterdepolarizations (EADs) • Did not cause EADs • Suppressed EADs induced by proarrhythmic agents • Does not cause  dispersion of ventricular repolarization • Concentration-dependent  transmural dispersion of APD (cardiomyocytes) • No effect on QT dispersion in humans • No torsade de pointes reported in clinical trials Antzelevitch C et al. Circulation. 2004;110:904-10. Cobbe S. Eur Heart J Suppl. 2004;6(suppl I):I9-11. Chaitman BR et al. J Am Coll Cardiol. 2004;43:1375-82.

  38. Exercise Training Enhanced external counterpulsation (EECP)  Endothelial function Promotes coronary collateral formation  Peripheral vascular resistance  Ventricular function Placebo effect Transmyocardial revascularization (TMR) Sympathetic denervation Angiogenesis Spinal cord stimulation (SCS)  Neurotransmission of painful stimuli  Release of endogenous opiates Redistributes myocardial blood flow to ischemic areas Current nonpharmacologic antianginal strategies Allen KB et al. N Engl J Med. 1999;341:1029-36. Bonetti PO et al. J Am Coll Cardiol. 2003;41:1918-25.Murray S et al. Heart. 2000;83:217-20.

  39. Potential cardioprotective benefits of exercise NO production ROS generation ROS scavenging Other mechanisms Vasculature Myocardium Thrombosis Domenech R. Circulation. 2006;113:e1-3. Kojda G et al. Cardiovasc Res. 2005;67:187-97. Shephard RJ et al. Circulation. 1999;99:963-72.

  40. Exercise vs PCI in low-risk CAD N = 101 men with CCS class I–III angina* PCI 20 min bicycle ergometry daily Assessed at 12 months Exercise vs PCI Fewer rehospitalizations Lower cost Lower resting HR (P < 0.01) Greater improvement in maximal O2 uptake (P < 0.001) *>80% had 1- or 2-vessel disease Hambrecht R et al. Circulation. 2004;109:1371-8.

  41. EECP improves angina class N = 2289 consecutive EECP Clinical Consortium patients EECP = enhanced external counterpulsation Lawson WE et al. Cardiology. 2000;94:31-5.

  42. Surgical laser TMR improves angina class N = 275 with CCS class IV angina P < 0.001 TMR vs medical (both time points) † *Reduction of ≥2 CCS classes †Due to treatment failure TMR = transmyocardial revascularization Allen KB et al. N Engl J Med. 1999;341:1029-36.

  43. SCS vs CABG: Equivalent symptom relief in high-risk patients N = 104 with CCS class III or IV angina 18 16 14 12 Mean 10 70% 73% 68% 77% number * per 8 * * week * 6 4 2 0 Anginal attacks Nitrate consumption Anginal attacks Nitrate consumption SCS CABG Baseline 6 months SCS = spinal cord stimulation*P < 0.0001 Mannheimer C et al. Circulation. 1998;97:1157-63.

  44. Summary • Many patients continue to experience angina despite medical therapy and/or revascularization • Late Na+ blockade is a potentially effective new antianginal option with a mechanism of action complementary to traditional agents • Potential clinical application in broad range of patients unresponsive to current treatment options • Elderly • Diabetes • LV dysfunction or heart failure

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