The Role Of Ranolazine in Angina Pectoris.pptx

PPT Mengenai Peran Ranolazine dalam Tata laksana Angina Pectoris

1. The Role of RANOLAZINE in ANGINA PECTORIS ID-RAN-072020-006

2. Coronary Artery Disease The most frequent (and often the first) manifestation of stable CAD is chronic stable angina 1 1. Camm J, et al. International Journal of Cardiology 201 (2015) 200–207 2. Knuuti J et al. European Heart Journal (2020) 41, 407477. doi:10.1093/ eurheartj /ehz425

3. Angina arises from a mismatch between myocardial oxygen demand and the ability of the coronary arteries to deliver sufficient blood . However, it is now increasingly appreciated that stable angina symptoms may also develop as a consequence of impaired vasodilation of the distal coronary microcirculation 1 Chronic stable angina

4. Angina: how big is the problem? 1. Beltrame JF et al. Arch Intern Med 2009;169:1491–9. 2. Ferrari R et al. Nat Rev Cardiol  2018;15:120–32. Prevalence / incidence of chronic stable angina is expected to increase in the coming decade due to: 2 Ageing population Epidemic of obesity and other risk factors Increasing use of life-prolonging therapies Improved management of acute coronary syndromes 1 in 3 patients with stable angina in primary care experience ≥ 1 episodes of angina per week (Australian study*), indicating: 1 Greater physical limitation Worse quality of life

5. Despite the use of beta blockers in 78% of patients, long-acting nitrates in 53%, calcium antagonists in 40%, ivabradine in 11% and trimetazidine in 7%: 1 Angina patients still experience symptoms and impaired quality of life despite treatment Borras X et al. Rev Esp Cardiol 2012;65:734–41. Wiest FC et al. Am J Med 2004;117:234–41 A cross-sectional, multicenter, observational study of 2039 patients with stable angina attending outpatient clinics in Spain. Half of patients remained symptomatic and had impaired quality of life 1 39% reported 1–3 attacks per week over the previous 4 weeks 1 11% reported >3 attacks per week over the previous 4 weeks 1 The remaining 50% had fewer than one attack per week and were regarded as asymptomatic 1 Inadequate antianginal medication use is an issue in chronic stable angina Among >7,000 US Department of Veterans Affairs patients, 30% of patients were considered to be inadequately treated 2 Of those with frequent symptoms: 22% were receiving no anti anginal medication 2 33% were receiving only one class of anti anginal drugs (many of which were being taken at lower than the recommended dose) 2

6. Aim of pharmacological management of chronic coronary syndromes 1 Relief angina symptom Reduce exercise-induced ischemia Prevent cardiovascular events 1. Knuuti J et al. European Heart Journal (2020) 41, 407477. doi:10.1093/ eurheartj /ehz425

7. ESC suggested stepwise strategy Suggested stepwise strategy for long-term anti-ischaemic drug therapy in patients with chronic coronary syndromes and specific baseline characteristics. BB = beta-blocker; b.p.m . = beats per minute; CCB = [any class of] calcium channel blocker; DHP-CCB = dihydropyridine calcium channel blocker; HF = heart failure; LAN = long-acting nitrate; LV = left ventricular; NDHP-CCB: non- dihydropyridine calcium channel blocker. a Combination of a BB with a DHP-CCB should be considered as a first step; combination of a BB or a CCB with a second-line drugmay be considered as a first step.s The strategy must be adapted to each patient’s characteristics and preferences, and does not necessarily follow the steps indicated in the figure 1 1. Adapted from Knuuti J et al. European Heart Journal (2020) 41, 407477. doi:10.1093/ eurheartj /ehz425 (from figure 8)

8. Practical situations in which some of the second-line drugs might be useful as first line Head‑to‑head comparisons between first- and second-line treatments demonstrating superiority of one over any other in terms of anti- anginal effects are lacking 1 However, the literature shows that some agents have specific properties (in addition to their anti- anginal effect) that allow the selection of the best treatment for the specific physiopathology or for the comorbidities and/or risk factors 1 This provides a possible framework for individualized therapy using the established anti- anginal drugs , which could help clinicians to make the best selection of medications for their patients 1 1. Adapted from Ferrari R et al. Nat Rev Cardiol  2018;15:120–32

9. 1 st line Short-acting nitrate plus Beta-blockers or CCB-heart rate ↓ Consider CCB-DHP if low heart rate or intolerance/contraindications Consider Beta-blockers + CCB-DHP if CCS Angina > 2 2 nd line May add or switch 1 st line for some cases Ivabradine Long-acting nitrates Nicorandil Ranolazine Trimetazidine Montalescot G, et al. Eur Heart J 2013;34:2949-3003

10. Mortality 1 Symptom relief Symptoms 1 ESC 2 ACC/AHA 3 β-blockers No Yes IA IB DHPs No Yes IA IB Non-DHPs No Yes IA IIaB LANs No Yes IIaB IB Ivabradine No Yes IIaB – Ranolazine No Yes IIaB IIaA or IIaB Nicorandil No Yes IIaB – Trimetazidine No Yes IIaB First vs second line OMT options: older vs. newer options – clinical evidence ACC, American College of Cardiology; AHA, American Heart Association; DHP, dihydropyridine ; ESC, European Society of Cardiology; LAN, long acting nitrate. 1. Modified from Manolis AJ et al. Int J Cardiol  2016;220:445–53 (table 1) . 2. Knuuti J et al. Eur Heart J 2020;41:407–77. 3. Fihn SD et al. Circulation 2012;126:e354–e471.

11. Factors influencing choice of therapy include: 1 Individualising treatment to optimise outcomes in angina CCS, chronic coronary syndrome; CV, cardiovascular. Drug availability Potential drug interactions The person's preference Expected tolerance related to the individual person’s profile and comorbidities Severity of symptoms/impact on patient Risk of CV event “ … there is no universal definition of an optimal treatment in patients with CCS, and drug therapies must be adapted to each patient’s characteristics and preferences.” 1 ESC 2019 guidelines 1. Knuuti J et al. European Heart Journal (2020) 41, 407477. doi:10.1093/ eurheartj /ehz425

12. Ischaemia ↑ Late I Na Na + overload Ca ++ overload NCX NCX: sodium-calcium exchanger Mechanical dysfunction ↑ Diastolic tension ↓ Contractility Electrical dysfunction Arrhythmias O 2 supply & demand ↑ ATP consumption ↓ ATP formation RANOLAZINE Pathophysiology of myocardial ischaemia and Ranolazine mechanism of action 1. Modified from figure 2 of Hasenfuss G, Maier LS. Clin Res Cardiol 2008;97:222-26.

13. Ranolazine Metanalysis - Chronic Stable Angina

14. Cochrane Database Analysis

15. Comorbidity or risk factor Preferred treatment Intolerance first step Ranolazine, ivabradine , trimetazidine Significant AV conduction abnormalities Ranolazine, ivabradine , trimetazidine Low HR Ranolazine, trimetazidine Low BP Ranolazine, ivabradine , trimetazidine AF Ranolazine CHF Ivabradine Diabetes mellitus Ranolazine, ivabradine Suggested use of ranolazine , ivabradine and trimetazidine according to comorbidities or risk factors 1. Modified from Manolis AJ et al. Int J Cardiol  2016;220:445–53 (from table 2 & 3) Drugs are listed in alphabetical order. AF, atrial fibrillation; AV, atrioventricular ; BP, blood pressure; CHF, chronic heart failure; HR, heart rate; Disclaimer: in Indonesia ranolazine is indicated, at a maximum dose of 750 mg bid, as add-on therapy for patients with stable angina

16. Anti-angina effect of Ranolazine do not depend upon changes on heart rate, blood pressure or vasodilation Ranolazine Haemodynamic Effect Ranolazine Product Summary Characteristic. BPOM approval 2019

17. Ranolazine 750 mg bid + background therapy* for 12 weeks (n=279) Trough Peak Standing SBP NS NS Standing HR NS NS End-exercise SBP NS NS End-exercise HR -3.1 ‡ -2.3 ** 1. Chaitman BR, et al. JAMA 2004;291:309-16. ‡ p=0.01; **p=0.05; # p=0.02; § = p=0.04 Ranolazine 1,000 mg bid + background therapy* for 12 weeks (n=275) Trough Peak -2.8 # -2.8 # NS NS -3.3 § NS -2.8 # -2.0 SBP: systolic blood pressure; HR: heart rate CARISA : no clinically meaningful changes in blood pressures or heart rates with Ranolazine Disclaimer: in Indonesia ranolazine is indicated, at a maximum dose of 750 mg bid, as add-on therapy for patients with stable angina Double-blind, 3-group parallel trial. Patients (n=823) with symptomatic chronic angina were randomly assigned to receive twice-daily placebo (n=269) or 750 mg (n=279) or 1,000 mg (n=275) of sustained-release ranolazine for 12 weeks. * As add-on to background therapy with atenolol 50 mg/d or amlodipine 5mg/d or diltiazem 180mg/d

18. Mean change in vital signs from baseline at the end of the 6-week double-blind treatment phase 1. Adapted from Stone P, et al. J Am Coll Cardiol 2006;48(3):566-75 (from table 5). * Analysis of variance with effects for treatment and pooled site ERICA : no haemodynamic changes with ranolazine Disclaimer: in Indonesia ranolazine is indicated, at a maximum dose of 750 mg bid, as add-on therapy for patients with stable angina Double-blind, randomised, placebo-controlled parallel group study. Patients (n=565) with stable angina receiving amlodipine 10 mg were randomised to ranolazine (500 mg bid increased to 1,000 mg bid, n=281) or placebo (n=284) for 7 weeks totally. Primary end point was the frequency of angina episodes per week during the double-blind treatment phase. Efficacy was also assessed by nitroglycerin consumption per week and the Seattle Angina Questionnaire (SAQ)

19. Individualized OMT according to heart rate as suggested by experts *Normal ejection fraction; ** heart rate N 70 bpm . BB, beta blocker; BP, blood pressure; bpm, beats per minute; CCB, calcium channel blocker; DHP, dihydropyridine; LA, long-acting; OMT, optimal medical therapy; SBP, systolic blood pressure. 2 Disclaimer: in Indonesia ranolazine is indicated, at a maximum dose of 750 mg bid, as add-on therapy for patients with stable angina 1. Modified from Manolis AJ et al. Int J Cardiol  2016;220:445–53 (from figure 1)

20. Comorbidity or risk factor Preferred treatment Intolerance first step Ranolazine, ivabradine , trimetazidine Significant AV conduction abnormalities Ranolazine, ivabradine , trimetazidine Low HR Ranolazine, trimetazidine Low BP Ranolazine, ivabradine , trimetazidine AF Ranolazine CHF Ivabradine Diabetes mellitus Ranolazine, ivabradine Suggested use of ranolazine , ivabradine and trimetazidine according to comorbidities or risk factors 1. Modified from Manolis AJ et al. Int J Cardiol  2016;220:445–53 (from table 2 & 3) Drugs are listed in alphabetical order. AF, atrial fibrillation; AV, atrioventricular ; BP, blood pressure; CHF, chronic heart failure; HR, heart rate; Disclaimer: in Indonesia ranolazine is indicated, at a maximum dose of 750 mg bid, as add-on therapy for patients with stable angina

21. Disclaimer: in Indonesia ranolazine is indicated, at a maximum dose of 750 mg bid, as add-on therapy for patients with stable angina 1. Adapted from Arnold, S V, et al. Circulation. 2020;141:00–00. DOI: 10.1161/CIR.0000000000000766 (from table 3)

22. A second consideration of pharmacological treatment of angina in patients with T2DM is the impact of ranolazine on both angina and blood glucose. Ranolazine reduces myocardial ischemia at the cellular level and is the only anti- anginal medication to be tested and found effective specifically in patients with T2DM . In addition to its anti- anginal effects, ranolazine appears to reduce HbA1c by ≈0.5% to 0.7% via a reduction in glucagon secretion. Both the antianginal effect and the glucose-lowering effect of ranolazine appear to be enhanced in patients with poorly controlled T2DM. Disclaimer: in Indonesia ranolazine is indicated, at a maximum dose of 750 mg bid, as add-on therapy for patients with stable angina 1. Adapted from Arnold, S V, et al. Circulation. 2020;141:00–00. DOI: 10.1161/CIR.0000000000000766

23. 1. Adapted from Timmis AD, et al. Eur Heart J 2006;27:42-8 (from figure 2) *Background therapy: atenolol 50 mg od or amlodipine 5 mg od or diltiazem 180 mg od. Angina episodes/week NTG consumption/week Normalised (A) weekly angina episodes and (B) nitroglycerin use in diabetic vs. non- diabetic patients A B Placebo + backgroung therapy* 1 2 3 4 5 Ranolazine 750 mg + backgroung therapy* Ranolazine 1,000 mg + background therapy* 2.99±0.56 3.39±0.35 2.08±0.37 2.59±0.28 1.03±0.19 2.46±0.31 Placebo 1 2 3 4 6 Ranolazine 750 mg + background therapy* Ranolazine 1,000 mg + background therapy* 4.35±1.27 2.80±0.34 2.03±0.54 2.14±0.31 0.56±0.09 2.11±0.35 5 Diabetic patients (n=189) Non-diabetic patients (n=634) CARISA : Anti- anginal efficacy of ranolazine in patients with diabetes Statistical tests for interactions found no evidence that the effect of ranolazine differed between diabetic and non-diabetic patients 1 . Disclaimer: in Indonesia ranolazine is indicated, at a maximum dose of 750 mg bid, as add-on therapy for patients with stable angina This analysis compared the effects of ranolazine in diabetic and nondiabetic patients (taking insulin or not taking insulin) enrolled in CARISA. in the CARISA trial, 823 patients with chronic angina on background once daily atenolol (50 mg), diltiazem (180 mg), or amlodipine (5 mg) were randomized to 12 weeks of therapy in a three-arm parallel study to placebo, ranolazine 750 mg twice daily or ranolazine 1000 mg twice daily.

24. * Background therapy: atenolol 50 mg od or amlodipine 5 mg od or diltiazem 180 mg od. Placebo + background therapy* for 12 weeks (n=37) Ranolazine 750 mg bid + background therapy* for 12 weeks (n=47) At baseline mean HbA 1c in patients treated with placebo or ranolazine 750 mg bid or ranolazine 1,000 mg bid were 7.5, 7.7 and 7.9, respectively. a significant placebo-corrected reduction in HbA 1c ( p =0.008) in diabetic patients 2 Ranolazine 1,000 mg bid + background therapy* for 12 weeks (n=47) Change from baseline to week 12 in HbA 1c 1. Modified from Timmis AD, et al. Eur Heart J 2006;27:42-8 (from table 2) p=0.008 - 0.02% - 0.50% -0.5 -1 p=0.0002 - 0.70 vs. placebo -0.48 vs. placebo - 0.72% Change from baseline CARISA : Effect of ranolazine on HbA 1c in patients with chronic angina and diabetes Note: in Indonesia ranolazine is indicated, at a maximum dose of 750 mg bid, as add-on therapy for patients with stable angina. This analysis compared the effects of ranolazine in diabetic and nondiabetic patients (taking insulin or not taking insulin) enrolled in CARISA. In the CARISA trial, 823 patients with chronic angina on background once daily atenolol (50 mg), diltiazem (180 mg), or amlodipine (5 mg) were randomized to 12 weeks of therapy in a three-arm parallel study to placebo, ranolazine 750 mg twice daily or ranolazine 1000 mg twice daily.

25. 1. Kosiborod M, et al. J Am Coll Cardiol . 2013;61:2038-45 . 8 weeks Double-blind treatment period: Design: Average weekly number of anginal episodes over the last 6 weeks of the study. After a single-blind, 4-week placebo run-in, patients were randomised to ranolazine (target dose 1,000 mg bid) or placebo. n=949 subjects with type 2 diabetes, coronary artery disease , and chronic stable angina who were symptomatic despite treatment with up to 2 antianginal agents. Randomised , double-blind, placebo-controlled clinical trial To examine the efficacy of ranolazine vs. placebo on weekly angina frequency in subjects with stable angina and type 2 diabetes Objective: Primary outcome: Treatment: Population: TERISA : overview Disclaimer: in Indonesia ranolazine is indicated, at a maximum dose of 750 mg bid, as add-on therapy for patients with stable angina

26. Run in Phase Placebo (n=465) Ranolazine (n=462) Weekly Angina Frequency Study Week 2 4 6 8 2 4 6 -2 Treatment Phase p=0.008 Randomised, double-blind, placebo-controlled study. Patients (n= 927) with type 2 diabetes, coronary artery disease, and chronic stable angina already on up to 2 antianginal agents were randomised to ranolazine 1,000 mg bid (n=462) or placebo (n=465) for 8 weeks TERISA : Weekly Angina Frequency Disclaimer: in Indonesia ranolazine is indicated, at a maximum dose of 750 mg bid, as add-on therapy for patients with stable angina 1. Adapted from Kosiborod M, et al. J Am Coll Cardiol. 2013;61:2038-45 (from figure 2)

27. Run in Phase Treatment Phase Placebo (n=465) Ranolazine (n=462) Weekly Nitroglycerin consumption Study Week 2 3 4 8 2 4 6 -2 p=0.003 1 Randomised, double-blind, placebo-controlled study. Patients (n= 927) with type 2 diabetes, coronary artery disease, and chronic stable angina already on up to 2 antianginal agents were randomised to ranolazine 1,000 mg bid (n=462) or placebo (n=465) for 8 weeks TERISA: Weekly Nitroglycerin Consumption Disclaimer: in Indonesia ranolazine is indicated, at a maximum dose of 750 mg bid, as add-on therapy for patients with stable angina 1. Adapted from Kosiborod M, et al. J Am Coll Cardiol. 2013;61:2038-45 (from figure 2)

28. 1. Adapted from Kosiborod M, et al. J Am Coll Cardiol. 2013;61:2038-45 (from figure 3) * Relative difference in the incidence rates Randomised, double-blind, placebo-controlled study. Patients (n= 949) with type 2 diabetes, coronary artery disease, and chronic stable angina already on up to 2 antianginal agents were randomised to ranolazine 1,000 mg bid (n=462) or placebo (n=465) for 8 weeks HbA 1c >6 HbA 1c ≤ 6 HbA 1c >6.5 HbA 1c ≤ 6.5 HbA 1c >7 HbA 1c ≤ 7 HbA 1c >7.5 HbA 1c ≤ 7.5 HbA 1c >8 HbA 1c ≤ 8 Incidence Density Ratio* p for interaction Ranolazine better Placebo better 0.7 0.8 0.9 1 1.1 1.2 0.046 0.047 0.022 0.041 0.038 TERISA : Exploratory Analysis-HbA 1c Note: in Indonesia ranolazine is indicated, at a maximum dose of 750 mg bid, as add-on therapy for patients with stable angina.

29. 1. Adapted from Arnold, S V, et al. Circulation. 2020;141:00–00. DOI: 10.1161/CIR.0000000000000766 (from table 3) Disclaimer: in Indonesia ranolazine is indicated, at a maximum dose of 750 mg bid, as add-on therapy for patients with stable angina

30. In patients with CAD, optimal medical therapy is key for reducing symptoms, halting the progression of atherosclerosis, and preventing atherothrombotic events 1 Myocardial revascularization plays a central role in the management of CCS on top of medical treatment, but always as an adjunct to medical therapy without supplanting it 1 Both PCI and OMT have a role to play in angina management OMT, optimized medical therapy; PCI, percutaneous coronary intervention; CAD, stable coronary artery disease. 1. Knuuti J et al. European Heart Journal (2020) 41, 407477. doi:10.1093/ eurheartj /ehz425

31. ESC management pathway in symptomatic patients with suspected obstructive CAD CAD, coronary artery disease; CTA, computed tomography angiography; CVD, cardiovascular disease; ECG, electrocardiogram; LV, left ventricular. a Consider microvascular angina. b Antianginal medications and/or risk-factor modification. . 1. Adapted from Knuuti J et al. European Heart Journal (2020) 41, 407477. doi:10.1093/ eurheartj /ehz425 (from figure 4)

32. Stable CAD is a progressive disease and is not generally resolved with revascularization CAD, coronary artery disease. 1. Borras X et al. Rev Esp Cardiol 2012;65:734–41 66% of patients had previously undergone revascularization 1 In a cross-sectional, multicenter, observational study of 2039 patients with stable angina attending outpatient clinics in Spain: 1 59% of these developed recurrent angina 1

33. COURAGE: freedom from angina over time according to treatment After 3 years, up to 41% of patients who undergo PCI + OMT for angina continue to experience symptoms OMT, optimal medical therapy; PCI, percutaneous coronary intervention. 1. Adapted from Weintraub WS et al. N Engl J Med 2008;359:677–87.(from figure 1) Baseline Months Angina-free (%) p =0.35 p <0.001 p <0.001 p <0.001 p =0.005 p =0.010 p =0.30 Study design COURAGE: randomized clinical trial in 2,287 patients with stable coronary disease assigned to PCI plus OMT (n=1,149) or to OMT alone (n=1,138). Angina- specific health status (Seattle Angina Questionnaire) and overall physical and mental function ( RAND-36) were assessed. 1