Curriculum Vitae Name : Prof. DR. Dr. Idrus Alwi SpPD, K-KV, FACC, FESC, FAPSIC, FINASIM, FACP. Current Position : Professor of Internal Medicine,

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1 Curriculum Vitae Name : Prof. DR. Dr. Idrus Alwi SpPD, K-KV, FACC, FESC, FAPSIC, FINASIM, FACP. Current Position : Professor of Internal Medicine, Faculty of Medicine, UI Medical Student : Faculty of Medicine University of Indonesia 1986 Internist : Faculty of Medicine University of Indonesia 1996 Cardiovascular Consultant : The Indonesian Society of Internal Medicine, 2001 PhD : Faculty of Medicine University of Indonesia, 2006 FACC : American College of Cardiology, 2006 FESC : European Society of Cardiology, 2008 FAPSIC : Asia Pacific Society of Interventional Cardiology, 2009 FINASIM : Indonesian Society of Internal Medicine, 2009 FACP : American Colleague of Physician, 2013 Advanced Course in Cardiology, Melbourne 1997 Advanced Course on Echocardiography and Others Non Invasive Cardiology, Melbourne Stem cell NOGA course, Cincinnatti, Ohio, 2009 ASAN Interventional Cardiology Course, Seoul, 2011

2 Statin Reduce Cardiovascular Events in Stable CAD Patients: The Role of Pitavastatin Prof. Idrus Alwi MD, PhD, FINASIM, FACP, FACC, FESC, FAPSIC Division of Cardiology, Department of Internal Medicine, Faculty of Medicine, University of Indonesia, Jakarta, Indonesia

3 10-year CHD Death Rate (Deaths per 1000) CHD Incidence per 1000 Individuals with elevated Cholesterol are at increased risk of CHD 50 Multiple Risk Factor Intervention Trial (MRFIT) (n=361,662) 150 Framingham Study (n=5209) Serum cholesterol (mg/dl) Serum cholesterol (mg/dl) Each 1% reduction in total cholesterol level resulted in a 2% decrease in CHD risk Each 1% increase in total cholesterol level was associated with a 2% increase in CHD risk Gotto AM Jr et al. Circulation. 1990;81: Castelli WP. Am J Med. 1984;76:4-12.

4 Nonfatal MI and CHD death relative risk reduction, % Multiple Studies Showed a Relationship Between LDL-C Reduction & CHD Relative Risk London Oslo MRC Los Angeles Upjohn LRC NHLBI POSCH 4S WOSCOPS CARE LIPID AF/TexCAPS HPS ALERT PROSPER ASCOT-LLA CARDS MI = myocardial infarction LDL-C reduction, % Robinson JG et al. J Am Coll Cardiol. 2005;46:

5 Statins Have Revolutionised CVD Risk Management 4S WOSCOPS CARE LIPID AF/TEXCAPS HPS PROSPER ASCOT CARDS TNT simvapravapravapravalovasimvapravaatorvaatorvaatorva- All drugs in class 20 50% Relative Risk Reduction In primary and secondary prevention In men and women years of age In diabetics, hypertensives, smokers Lower LDL-C is better

6 Cholesterol Treatment Trialists Collaboration: Statin Benefits Across a Range of Baseline Levels All Evaluated Trials Combined: LDL-C 90 to 130 mg/dl shows same benefit as LDL-C 50 to 90 mg/dl; 1 mmol/l = 38.6 mg/dl Events (% per annum) RR(CI) per 1 mmol/l reduction in LDL-CC Statin Control <2mmol/l (<77 mg/dl) 910 (4.1%) 1,012 (4.6%) 0.78 ( ) 2 to <2.5 mmol/l (77-96 mg/dl) 1,528 (3.6%) 1,729 (4.2%) 0.77 ( ) 2.5 to <3.0 mmol/l ( mg/dl) 1,866 (3.3%) 2,225 (4.0%) 0.77 ( ) (P=0.3) 3.0 to <3.5 mmol/l ( mg/dl) 2,007 (3.2%) 2,454 (4.0%) 0.76 ( ) 3.5 mmol/l (>136 mg/dl) 4,508 (3.0%) 5,736 (3.9%) 0.80 ( ) Total 10,973 13,350 (4.0%) 0.78 ( ) (3.2%) Abbreviation: LDL-C, low-density lipoprotein cholesterol. Baigent C, et al. Lancet. 2010;376:

7 The Progression from CV Risk Factors to Endothelial Injury and Clinical Events LDL-C BP Risk factors Diabetes Smoking Heart failure Oxidative stress Endothelial dysfunction NO Local mediators Tissue ACE-Ang II PAI-1 VCAM ICAM cytokines Endothelium Growth factors matrix Proteolysis Thrombosis Inflammation Vasoconstriction Vascular lesion and remodelling Plaque rupture NO Nitric oxide Clinical endpoints Atherothrombotic Manifestation (AMI, Stroke) Modified from Gibbons GH, Dzau VJ. N Engl J Med 1994;330;

8 Atherosclerosis Endothelial dysfunction Inflammation Oxidation Plaque instability and thrombus Plaque rupture Monocyte LDL-C Adhesion Macrophage Oxidized molecule LDL-C Foam cell CRP Smooth muscle cells Libby P. Circulation. 2001;104: ; Ross R. N Engl J Med. 1999;340:

9 9

10 Risk categories (ESC Guideline 2016) 10

11 Risk categories 11 ESC Guideline 2016

12 Intervention strategies as a function of total cardiovascular risk and low-density lipoprotein cholesterol level 12 ESC Guideline 2016

13 ASCVD Risk Categories and LDL-C Treatment Goals Risk category Extreme risk Very high risk High risk Risk factors/10-year risk Progressive ASCVD including unstable angina in individuals after achieving an LDL-C <70 mg/dl Established clinical cardiovascular disease in individuals with DM, stage 3 or 4 CKD, or HeFH History of premature ASCVD (<55 male, <65 female) Established or recent hospitalization for ACS, coronary, carotid or peripheral vascular disease, 10-year risk >20% DM or stage 3 or 4 CKD with 1 or more risk factor(s) HeFH 2 risk factors and 10-year risk 10%-20% DM or stage 3 or 4 CKD with no other risk factors LDL-C (mg/dl) Treatment goals Non-HDL-C (mg/dl) Apo B (mg/dl) <55 <80 <70 <70 <100 <80 <100 <130 <90 Moderate risk 2 risk factors and 10-year risk <10% <100 <130 <90 Low risk 0 risk factors <130 <160 NR Abbreviations: ACS, acute coronary syndrome; apo, apolipoprotein; ASCVD, atherosclerotic cardiovascular disease; CKD, chronic kidney disease; DM, diabetes mellitus; HeFH, heterozygous familial hypercholesterolemia; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; NR, not recommended. Barter PJ, et al. J Intern Med. 2006;259: ; Boekholdt SM, et al. J Am Coll Cardiol. 2014;64(5): ; Brunzell JD, et al. Diabetes Care. 2008;31: ; Cannon CP, et al. N Engl J Med. 2015;372(25): ; Grundy SM, et al. Circulation. 2004;110: ; Heart Protection Study Collaborative Group. Lancet. 2002;360:7-22; Jellinger P, Handelsman Y, Rosenblit P, et al. Endocr Practice. 2017;23(4): ; Lloyd-Jones DM, et al. Am J Cardiol. 2004;94:20-24; McClelland RL, et al. J Am Coll Cardiol. 2015;66(15): ; NHLBI. NIH Publication No ; Ridker PM, J Am Coll Cardiol. 2005;45: ; Ridker PM, et al. JAMA. 2007;297(6): ; Sever PS, et al. Lancet. 2003;361: ; Shepherd J, et al. Lancet. 2002;360: ; Smith SC Jr, et al. Circulation. 2006;113: ; Stevens RJ, et al. Clin Sci. 2001;101(6): ; Stone NJ. Am J Med. 1996;101:4A40S-48S; Weiner DE, et al. J Am Soc Nephrol. 2004;15(5):

14 The guidelines: ACC/AHA, November ACC, American College of Cardiology AHA, American Heart Association

15 Guidelines identify four statin benefit groups Group 1 Clinical ASCVD CHD, stroke, and peripheral arterial disease, all of presumed atherosclerotic origin Group 2 LDL-C 190 mg/dl (~5 mmol/l) Group 3 Diabetes mellitus + age of years + LDL-C mg/dl ( mmol/l) Group 4 ASCVD risk 7.5% No diabetes + age of years + LDL-C mg/dl ( mmol/l) ASCVD, atherosclerotic cardiovascular disease CHD, coronary 15 heart disease LDL-C, low-density lipoprotein-cholesterol Stone NJ, et al. J Am Coll Cardiol 2013 Nov 7. Epub ahead of print

16 Guidelines Specify Statin Doses High-intensity LDL-C by 50% Moderate-intensity LDL-C by 30 50% Atorvastatin (40) 80 mg mg Rosuvastatin mg 5 10 mg Simvastatin mg 10 mg Pravastatin mg mg Lovastatin 40 mg 20 mg Fluvastatin XL 80 mg Fluvastatin 40 mg bid mg Pitvastatin 2 4 mg 1 mg Low-intensity LDL-C by <30%* Bold: Statins and doses evaluated in RCTs Italics: Statins and doses approved by US FDA but not tested in RCTs reviewed *Should be used in patients unable to tolerate moderate-to high-intensity therapy Stone NJ, et al. J Am Coll Cardiol 2013 Nov 7. Epub ahead of print Asian 16 ancestry may modify the statin dose prescribed Reproduced with kind permission from American College of Cardiology Jan 2014

17 Does High-Intensity Pitavastatin Therapy Further Improve Clinical Outcomes? The REAL-CAD Study in 13,054 Patients With Stable Coronary Artery Disease Takeshi Kimura, Teruo Inoue, Isao Taguchi, Hiroshi Iwata, Satoshi Iimuro, Takafumi Hiro, Yoshihisa Nakagawa, Yukio Ozaki, Yasuo Ohashi, Hiroyuki Daida, Hiroaki Shimokawa, Ryozo Nagai, on behalf of the REAL-CAD Study Investigators Disclosure: Public Health Research Foundation, Kowa Pharmaceutical Co. Ltd.

18 Backgrounds Recommendations for Lipid-lowering Therapy in Patients with Established CAD ACC/AHA guideline: High-intensity statin therapy atorvastatin 40/80 mg, rosuvastatin 20/40 mg, or simvastatin 80 mg Previous More versus Less Statins Trials More vs less statin PROVE IT TNT IDEAL SEARCH A to Z Subtotal (5 trials) LDL-C Reduction (mmol/l) Events (% per annum) Statin/more Control/less 406 (11.3%) 889 (4.0%) 938 (5.2%) 1,347 (3.6%) 257 (7.2%) 3,837/19,829 (4.5%) 458 (13.1%) 1,164 (5.4%) 1,106 (6.3%) 1,406 (3.8%) 282 (8.1%) 4,416/19,783 (5.3%) Unweighted RR (CI) Trend: χ 2 1=12.4 (p=0.0004) 0.85 ( ) p< Cholesterol Treatment Trialists (CTT) Collaboration. Lancet 2010; 376:

19 Backgrounds and Objectives The high-intensity statins are not widely used in daily clinical practice, particularly in Asia. No clear evidence regarding more versus less statins has been established in Asian population. Most of the doses of high-intensity statin therapy defined in the ACC/AHA guideline are not approved in Japan. Furthermore, maximum approved doses of statins are prescribed only very infrequently in Japan. Therefore, we sought to determine whether higher-dose statin therapy would be beneficial in Japanese patients in the largest-ever trial comparing the efficacy of high-dose versus low-dose statin therapy in patients with established stable CAD.

20 REAL-CAD ( Randomized Evaluation of Aggressive or Moderate Lipid Lowering Therapy with Pitavastatin in Coronary Artery Disease ) A prospective, multi-center, randomized, open-label, blinded endpoint, physician-initiated trial to determine whether high-dose as compared with low-dose pitavastatin therapy within the approved dose range could reduce CV events in Japanese patients with stable CAD. Eligibility: Consent for enrollment Men and women, years of age Stable CAD: ACS or PCI/CABG >3 months Clinical diagnosis of CAD with coronary stenosis 50 % diameter stenosis LDL-C <120 mg/dl on pitavastatin 1 mg/day during the run-in period Pitavastatin 1 mg/day Randomization Pitavastatin 1 mg/day Pitavastatin 4 mg/day Jan LDL-C <120 mg/dl ~ Mar Jan. ~ Mar Run-in Period (>1 month) Follow-up (36-60 months) Pitavastatin 1 mg and 4 mg have LDL-C lowering effect comparable to atorvastatin 5 mg and 20 mg, respectively.

21 Study Design Primary Endpoint a composite of CV death, non-fatal MI, non-fatal ischemic stroke, or unstable angina requiring emergency hospitalization Sample size calculation Hypothesis: 16% relative risk reduction with the high-dose pitavastatin Tx Assumptions: Annual primary endpoint event rate of 2.5%, Drop-out rate of 10% Sample size: 12,600 patients were to be enrolled with anticipated 1,033 events during the planned 3 years of enrollment and at least 3 years of follow-up. Power: 80%, Alpha: 0.05 The actual event rate was lower than anticipated. On October 27, 2015, the steering committee decided not to extend the study further despite the original event-driven trial design, because substantial number of centers were reluctant to extend the study further.

22 Study Patient Flow Jan Mar Japanese centers Enrolled N=14,774 Randomized N=13,054 Excluded N=1,720 Withdrawal/Missing consent N=790 Other reasons N=930 Pitavastatin 1 mg N=6,528 Pitavastatin 4 mg N=6,526 Withdrawal/Missing consent N=100 Withdrawal/Missing consent N=136 Safety analysis set (SAS) N=6,428 Not meeting the eligibility N=214 ACS within 3 months N=35 LDL-C <100 mg/dl without statins N=76 LDL-C 120 mg/dl at randomization N=105 Full analysis set (FAS) N=6,214 Follow-up period [ median]: 3.9 ( ) years 1 year FU completed: 96.9% Final FU completed beyond Jan. 2016: 83.2% Safety analysis set (SAS) N=6,390 Not meeting the eligibility N=191 ACS within 3 months N=16 LDL-C <100 mg/dl without statins N=76 LDL-C 120 mg/dl at randomization N=101 Full analysis set (FAS) N=6,199 Follow-up period [ median]: 3.9 ( ) years 1 year FU completed: 97.0% Final FU completed beyond Jan. 2016: 83.4%

23 Baseline Characteristics Variables Pitavastatin 1 mg (N=6,214) Pitavastatin 4 mg (N=6,199) Age years 68.1± ±8.3 Male sex 83% 83% BMI kg/m ± ±3.3 Hypertension 75% 76% Diabetes mellitus 40% 40% Current smoking 16% 17% History of ACS 72% 72% ACS within 1 year before randomization 24% 24% Coronary revascularization 91% 90% Revascularization within 1 year before randomization 28% 28% Ischemic stroke 7% 7% Peripheral vascular disease 7% 7% CKD (egfr <60 ml/min/1.73m 2 ) 36% 35% Aspirin 93% 92% DAPT 45% 44% Statins before enrollment 91% 91%

24 TG (mg/dl) hs-crp (mg/l) LDL-C (mg/dl) HDL-C (mg/dl) Serial Changes in Lipid Parameters and hs-crp LDL-C 100 Pitavastatin 1mg 55 Pitavastatin 4mg Main effect p< Interaction p< Baseline No. of Patients 1mg 6,214 6,031 4mg 6,199 5,890 5,615 5,518 Years 5,252 5,203 4,509 4,405 No. of Patients 1mg 4mg ,212 6, ,028 5, ,596 5,482 HDL-C Years Main effect p< Interaction p= ,238 5, Baseline ,498 4, No. of Patients 1mg 6,208 6,032 4mg 6,195 5, ,606 5,498 TG Years ,245 5, ,507 4,402 1mg 4mg hs-crp Main effect p< Interaction p= 0.77 Main effect p< Baseline Baseline No. of Patients ,032 5,994 Months ,734 5,585

25 Cumulative incidence(%) Primary Endpoint (CV death/ MI/ Ischemic stroke/ UA) No. at risk 1mg 4mg 6,214 6,199 HR 0.81 (95% CI, ), Cox P=0.01 No. of patients with event: 4mg 266 (4.3%), 1mg 334 (5.4%) NNT for 5 years=63 Pitavastatin 1 mg Pitavastatin 4 mg log-rank P= Years ,743 5,631 5,321 5,256 4,501 4,427 2,760 2,

26 Cumulative incidence(%) Secondary Endpoint Primary Endpoint plus Coronary Revascularization* HR 0.83 (95% CI, ), Cox P=0.002 No. of patients with event: 4mg 489 (7.9%), 1mg 600 (9.7%) NNT for 5 years=41 Pitavastatin 1 mg Pitavastatin 4 mg log-rank P= : Excluding TLR for lesions treated at prior PCI * No. at risk Years mg 4mg 6,214 6,199 5,660 5,556 5,166 5,131 4,327 4,277 2,627 2,

27 What we learned from this trial In an Asian CAD population, pitavastatin 4 mg daily reduced the composite primary outcome (cardiovascular death, myocardial infarction, ischemic stroke, and unstable angina) more than pitavastatin 1 mg daily At 3 years, ARR = 1.1%; RRR = 19%; NNT = 63 Pitavastatin 4 mg daily also reduced total mortality At 3 years, ARR = 0.9%; RRR = 27%; NNT =111 Both doses reduced LDL-c Pitavastatin 4 mg daily final LDL-c was 76.6 mg/dl Pitavastatin 1 mg final LDL-c was 91 mg/dl

28 Other Secondary Endpoints Outcomes No. of patients with event (%) 1 mg (n=6,214) 4 mg (n=6,199) HR(95% CI) P Value Death from any cause 260 (4.2) 207 (3.3) 0.81 ( ) 0.03 CV death 112 (1.8) 86 (1.4) 0.78 ( ) 0.09 MI 72 (1.2) 40 (0.6) 0.57 ( ) Ischemic stroke 83 (1.3) 84 (1.4) 1.03 ( ) 0.84 Hemorrhagic stroke 30 (0.5) 43 (0.7) 1.46 ( ) 0.11 Unstable angina requiring emergency hospitalization 90 (1.4) 76 (1.2) 0.86 ( ) 0.34 Coronary revascularization (All) 626 (10.1) 529 (8.5) 0.86 ( ) Coronary revascularization (non-tlr) 356 (5.7) 277 (4.5) 0.79 ( ) Coronary revascularization (TLR) 319 (5.1) 276 (4.5) 0.88 ( ) mg Better 1 mg Better

29 Subgroup Analyses Primary Endpoint (CV death/ MI/ Ischemic stroke/ UA) Subgroup Overall Age Sex Diabetes LDL-C hs-crp HDL-C TG BMI < Male Female Yes No < 95 mg/dl 95 mg/dl < 1 mg/l 1 mg/l 40 mg/dl > 40 mg/dl < 150 mg/dl 150 mg/dl < No. of patients 12,413 4,009 8,404 10,253 2,160 4,978 7,435 7,865 4,548 8,510 3,516 2,607 9,803 8,045 4,358 6,693 4,788 Event rate (%) 1 mg 4 mg HR (95% CI) mg Better 1 1 mg Better 0.81 ( ) 0.67 ( ) 0.87 ( ) 0.81 ( ) 0.81 ( ) 0.75 ( ) 0.86 ( ) 0.81 ( ) 0.81 ( ) 0.75 ( ) 0.89 ( ) 0.78 ( ) 0.82 ( ) 0.86 ( ) 0.73 ( ) 0.87 ( ) 0.78 ( ) P value for interaction

30 Safety Outcomes Event Pitavastatin 1 mg (N=6,428) Pitavastatin 4 mg (N=6,390) P value Adverse events N (%) Rhabdomyolysis 1 (0.0) 2 (0.0) 0.62 Muscle-complaints 45 (0.7) 121 (1.9) <0.001 New onset of diabetes mellitus 279 (4.3) 285 (4.5) 0.76 Laboratory test abnormalities N (%) Elevation of ALT, AST, or both 3ULN 174 (2.7) 187(2.9) 0.46 Elevation of CK 5ULN 40 (0.6) 42 (0.7) 0.83 Study drug discontinuation N (%) 503 (8.1) 610 (9.8) <0.001

31 Study Limitations 1. The present study was conducted as an open-label trial with its inherent limitations. However, considering the limitations of the open-label trial design, the primary endpoint was defined as not including coronary revascularization procedures. 2. The present study was prematurely terminated despite the original eventdriven trial design, although we observed significant risk reduction for the primary endpoint. 3. Final follow-up was not completed in a substantial proportion of patients, reflecting a limitation of physician-initiated study relying upon voluntary efforts of the site investigators.

32 Conclusions and Implications High-dose (4 mg/day) as compared with low-dose (1 mg/day) pitavastatin therapy significantly reduced CV events in Japanese patients with stable CAD. The present study suggests that the administration of maximum tolerable doses of statins within the range of local approval would be the preferred statins therapy in Japanese patients with established CAD regardless of the baseline LDL-C levels.

33 Take Home Points High dose pitavastatin therapy (4 mg daily) improves cardiovascular outcomes more than low dose pitavastatin (1 mg daily), and is also associated with a total mortality reduction. High dose pitavastatin therapy is well tolerated. Tolerability of higher statin doses in Asian populations had been questioned. There has been substantial reluctance to use higher dose statins in Asian patients. This trial should give comfort that this strategy is safe, well tolerated, and beneficial. This trial further supports intensive LDL-c lowering with high dose statins, including in Asian populations.

34 Thank You For Your Kind Attention