Is it an era for statin for life?

Is it an era for statin for life? Mohamed Abdel Ghany Professor of Cardiology Cairo University Cardiovascular Disease (CVD) is the leading global cause of death 1

Dyslipidemia as a main Risk Factor for Cardiovascular Disease INTERHEART: Impact of multiple risk factors on CV risk Design Participants Objective Large international case-control study 12,461 cases; 14,637 controls; 52 countries To determine association of first MI with: Smoking Lipids Hypertension Diabetes Obesity Diet Physical Alcohol Psychosocial activity consumption factors* Follow-up 4 years, February 1999 March 2003 512 2.9 2.4 1.9 3.3 13.0 42.3 68.5 182.9 333.7 256 Odds ratio for 1st MI (99% CI) 128 64 32 16 8 4 2 1 Smk = smoking DM = diabetes Smk HTN = hypertension (1) Obes = obesity Ps = psychosocial factors Note: odds ratio plotted on a doubling scale DM (2) HTN (3) 1+2+3 ApoB- All 4 All 4 ApoA1 + Obes (4) All 4 + Ps All risk factors Yusuf S et al. Lancet. 2004;364:937-52. 2

Total Cholesterol Distribution: CHD vs Non-CHD Population Framingham Heart Study 26-Year Follow-up No CHD 35% of CHD Occurs in People with TC<200 mg/dl CHD 150 200 250 300 Total Cholesterol (mg/dl) Castelli WP. Atherosclerosis. 1996;124(suppl):S1-S9. 1996 Reprinted with permission from Elsevier Science. On-Treatment LDL-C is Closely Related to CHD Events in Statin Trials Lower is Better 30 25 20 JUPITER study included for reference only; event rate at 4.5 years, lipid changes at 2 years Rx - Statin therapy PRA - pravastatin ATV - atorvastatin 4S Rx Secondary Prevention 4S Placebo LIPID Placebo 15 LIPID Rx CARE - Placebo 10 CARE Rx CORONA - Placebo CORONA Rx HPS Placebo Primary Prevention HPS - Rx TNT ATV10 TNT ATV80 PROVE-IT PRA WOSCOPS Placebo JUPITER Placebo PROVE-IT ATV AFCAPS Placebo 6 5 AFCAPS Rx WOSCOPS Rx JUPITER Rx ASCOT Rx ASCOT Placebo 0 40 (1.0) 60 (1.6) 80 100 120 140 (2.1) (2.6) (3.1) (3.6) LDL-C achieved mg/dl (mmol/l) 160 (4.1) 180 (4.7) 200 (5.2) Adapted from Rosensen RS. Exp Opin Emerg Drugs 2004; 9(2): 269 279 LaRosa JC et al. N Engl J Med 2005; 352: 1425 1435 Ridker PM et al. NEJM 2008; 359: 2195 2207 Rosuvastatin Slide Kit Feb 2012 [6] 3

Proportional reduction in event rate (% SE) Proportional reduction in event rate (% SE) 22/01/2017 Relationship Between Proportional Reduction in Events and Mean LDL-C Reduction at 1 Year A prospective meta-analysis of data from 90,056 individuals from 14 statin trials A 1 mmol/l (39 mg/dl) reduction in LDL-C was associated with a 50 23% reduction in major coronary events 50 21% reduction in major vascular events 40 40 30 30 20 20 10 10 0 0.5 (19) 1.0 (38) 1.5 (58) 2.0 (77) -10 Reduction in LDL-C mmol/l (mg/dl) 0-10 0.5 (19) 1.0 (38) 1.5 (58) 2.0 (77) Reduction in LDL-C mmol/l (mg/dl) CTT Collaborators. Lancet 2005; 366: 1267 1278 Rosuvastatin Slide Kit Feb 2012 [7] More versus Less Intensive Statin Treatment is Associated with Further Reductions in Major Vascular Events 0.51 mmol/l further reduction in LDL-C with more intensive statin therapy 2-3 mmol/l further reduction in LDL-C with more intensive statin therapy 15% additional reduction in major vascular events (p<0.0001) 40-50% additional reduction in major vascular events (p<0.0001) CTT Collaborators. Lancet 2010; 376: 1670 1681 Rosuvastatin Slide Kit Feb 2012 [8] 4

9 Overview on Dyslipidemia Management in Egypt Rosuvastatin Slide Kit Dec Feb 2011 2012 [9] Centralized Pan-Middle East Survey on the Under-Treatment of Hypercholesterolemia: Results from the CEPHEUS Study in Egypt Primary Objectives: To establish the proportion of patients on lipid-lowering pharmacological treatment reaching the LDL-C goals according to the NCEP ATP III / updated 2004 NCEP ATP III. Study Design: This was a multi-centre, observational study of 1043 patients (18 years old or above) receiving lipid-lowering pharmacological treatment for at least 3 months and with no dose change for a minimum of 6 weeks. Reda A, Abdel-Rehim AA, Etman A, Afifi OS. Cardiol Ther. 2014 Nov 18 Rosuvastatin Slide Kit Feb 2012 [10] 5

% of patients Achieving LDL Goals 22/01/2017 Only 32.5% of Treated Patients Achieved Treatment Goals* 80.0% 70.0% 66.5% 71.1% 60.0% 72.4% of CEPHEUS Population 50.0% 40.0% 30.0% 34.3% 20.0% 10.0% 10.7% 7.9% 0.0% Very high High but not very high *2004 updated NCEP ATP III Reda A, Abdel-Rehim AA, Etman A, Afifi OS. Cardiol Ther. 2014 Nov 18 Medium high Medium low Low Risk Level Rosuvastatin Slide Kit Feb 2012 [11] How can we manage dyslipidemia in according to LATEST Guidelines? 6

2013 ACC/AHA Cholesterol Treatment Guideline Recommendations Focus on ASCVD Risk Reduction: 4 statin benefit groups* Clinical ASCVD LDL-level 190 mg/dl Diabetes, aged 40-75 years, with LDL-C 70-189 mg/dl Estimated 10-year risk of ASCVD of 7.5%, 40-75 years of age, and with LDL-C 70-189 mg/dl * Moderate- or high-intensity statin therapy recommended for these 4 groups Clinical ASCVD defined as acute coronary syndromes, history of MI, stable or unstable angina, coronary or arterial revascularization, stroke, transient ischemic attacks, or peripheral artery disease Estimated using Pooled Cohort Risk Assessment Equations Stone NJ, et al. J Am Coll Cardiol. 2013: doi:10.1016/j.jacc.2013.11.002. Available at: http://content.onlinejacc.org/article.aspx?articleid=1770217. Accessed November 13, 2013. 7

Intensity of Statin Therapy High-Intensity Statin Therapy Moderate-Intensity Stain Therapy Low-Intensity Statin Therapy LDL C 50% LDL C 30% to <50% LDL C <30% Atorvastatin (40 ) 80 mg Rosuvastatin 20 (40) mg Atorvastatin 10 (20) mg Rosuvastatin (5) 10 mg Simvastatin 20 40 mg Pravastatin 40 (80) mg Lovastatin 40 mg Fluvastatin XL 80 mg Fluvastatin 40 mg bid Pitavastatin 2 4 mg Simvastatin 10 mg Pravastatin 10 20 mg Lovastatin 20 mg Fluvastatin 20 40 mg Pitavastatin 1 mg Lifestyle modification remains a critical component of ASCVD risk reduction, both prior to and in concert with the use of cholesterol lowering drug therapies. Statins/doses that were not tested in randomized controlled trials (RCTs) reviewed are listed in italics Evidence from 1 RCT only: down-titration if unable to tolerate atorvastatin 80 mg in IDEAL Initiation of or titration to simvastatin 80 mg not recommended by the FDA due to the increased risk of myopathy, including rhabdomyolysis. Stone NJ, et al. J Am Coll Cardiol. 2013: doi:10.1016/j.jacc.2013.11.002. Available at: http://content.onlinejacc.org/article.aspx?articleid=1770217. Accessed November 13, 2013. 2016 ACC Expert consensus decision updates Patients 21 Years of Age with Stable Clinical ASCVD without Comorbidities, on Statin for Secondary Prevention Patients 21 Years of Age with Clinical ASCVD with Comorbidities, on Statin for Secondary Prevention Patient has 50% LDL- C reduction (may consider LDL-C <100 mg/dl) on maximally tolerated statin J Am Coll Cardiol. 2016 Jul 5;68(1):92-125. doi: 10.1016/j.jacc.2016.03.519. Epub 2016 Apr 1. Patient has 50% LDL-C reduction (may consider LDL-C <70 mg/dl or may consider non-hdl-c <100 mg/dl in patients with diabetes) on maximally tolerated statin 8

2016 ESC/EAS Guidelines for the management of dyslipidaemias The Task Force of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS) Developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR) Task Force Members: A L. Catapano* (Chairperson) (Italy), I Graham* (Chairperson) (Ireland), G De Backer (Belgium), O Wiklund (Sweden), M. J Chapman (France), H Drexel (Austria), A W. Hoes (The Netherlands), C S. Jennings (UK), U Landmesser (Germany), T R. Pedersen (Norway), Ž Reiner (Croatia), G Riccardi (Italy), M-R Taskinen (Finland), L Tokgozoglu (Turkey), W. M. M Verschuren (The Netherlands), Ch Vlachopoulos (Greece), D A. Wood (UK), J L Zamorano (Spain). Additional Contributor: M T Cooney (Ireland) Alberico L. Catapano et al. Eur Heart J 2016;eurheartj.ehw272 Very high-risk High-risk: Moderate-risk: Low-risk: Risk Categories Subjects with any of the following: Documented CVD*. DM with target organ damage or with a major risk factor Severe CKD (GFR <30 ml/min/1.73 m2). A calculated SCORE 10% for 10-year risk of fatal CVD. Subjects with: Markedly elevated single risk factors Most other people with DM Moderate CKD (GFR 30 59 ml/min/1.73 m2). A calculated SCORE 5% and <10% for 10- year risk of fatal CVD. SCORE is 1% and <5% for 10-year risk of fatal CVD. SCORE <1% for 10-year risk of fatal CVD. Adapted from Alberico L. Catapano et al. Eur Heart J 2016;eurheartj.ehw272 9

Alberico L. Catapano et al. Eur Heart J 2016;eurheartj.ehw272 Crestor Role in Dyslipidemia from Efficacy to Cardio Protection Greatest effects on the atherogenic lipid profile and beneficial changes on inflammatory markers Profound benefits on atherosclerosis Greatest reductions in cardiovascular morbidity and mortality Schuster H. Expert Rev Cardiovasc Ther 2007;5(2):177 193. 10

Studies Atherogenic lipid profile +/ inflammatory markers Atherosclerosis Cardiovascular morbidity & mortality Stellar METEOR JUPITER STELLAR: Study Design 6-week dietary lead-in period LDL-C 160 mg/dl and <250 mg/dl TG <400 mg/dl 18 years 6-week active treatment CRESTOR (rosuvastatin calcium) (480 patients) Atorvastatin (641 patients) 10 mg 20 mg 40 mg 10 mg 20 mg 40 mg 80 mg The primary endpoint was the percent change in LDL-C from baseline to 6 weeks Simvastatin (655 patients) 10 mg 20 mg 40 mg 80 mg CRESTOR 40 mg should be used only for those patients not achieving their LDL-C goal with 20 mg. Pravastatin (492 patients) 10 mg 20 mg 40 mg Adapted from Jones PH, et al. Am J Cardiol. 2003;92:152-160. 11

LDL-C ( SE) Reduction (%) HDL-C Increase (%) 22/01/2017 STELLAR Percentage Change in LDL-C 0 CRESTOR (mg) 10 20 40 Atorvastatin (mg) 10 20 40 80 Simvastatin (mg) 10 20 40 80 Pravastatin (mg) 10 20 40 10 20-20.1 30 40 50 60-45.8 * -52.4-55.0-36.8-42.6-47.8-51.1-28.3-35.0-38.8-45.8-24.4-29.7 STELLAR Percentage Change from Baseline in HDL-C at Week 6 12 10 8 6 4 * 7.7 9.5 9.6 5.7 4.8 4.4 6.8 6.0 5.3 5.2 3.2 4.4 5.6 2 2.1 0 10 20 40 CRESTOR (mg) 10 20 40 80 Atorvastatin (mg) 10 20 40 80 Simvastatin (mg) 10 20 40 Pravastatin (mg) Jones PH, et al. Am J Cardiol. 2003;92:152-160. 12

Patients reaching LDL-C <100 mg/dl (%) 22/01/2017 STELLAR: Percentage of Patients Achieving an LDL-C of <100 mg/dl * 90 80 70 60 50 40 30 20 10 0 53 53 80 76 76 80 70 60 53 44 28 18 18 8 8 3 10 20 40 10 20 40 80 10 20 40 80 1 40 80 CRESTOR (rosuvastatin calcium) Atorvastatin Simvastatin Pravastatin (n=473) (n=633) (n=648) (n=485) 8 14 Adapted from: McKenney JM, et al. Curr Med Res Opin. 2003;19:689-698. Impact on atherosclerosis progression 13

Change in IMT of 12 carotid sites (mm) +0.0131 mm/yr 22/01/2017 Effects of Rosuvastatin on Carotid IMT Measured using B-mode Ultrasound METEOR Study Design Patients (n=984) Asymptomatic for CHD Rosuvastatin 40 mg (n=702) Maximum IMT 1.2 <3.5 mm Modest hypercholesterolaemia Placebo (n=282) Men (aged 45 70) Women (aged 55 70) Visit: Week: 1 6 2 4 3 2 4 0 5 6 6 13 7 26 8 39 9 52 10 65 11 78 12 91 13 104 Run-in/eligibility Lipids Safety Lipids Safety CIMT Safety CIMT Safety Lipids Safety CIMT Safety randomised, double-blind, placebo-controlled, parallel-group, multicentre phase III study to determine whether rosuvastatin 40 mg could slow the progression of atherosclerosis among asymptomatic patients assessed as being at low risk of CHD. 1 CIMT Lipids Safety Crouse JR et al. JAMA 2007; 297: 1344 1353 CIMT=carotid intima media thickness TREATING DYSLIPIDAEMIA WITH CRESTOR SHOWN TO SLOW THE PROGRESSION OF ATHEROSCLEROSIS 1 METEOR Study suggests that development of atherosclerosis can be slowed, even in lowrisk asymptomatic patients PROGRESSION +0.03 +0.02 Change in carotid intima media thickness (CIMT) at 2 years 1 Placebo -48% LDL-C +8% HDL-C CRESTOR 40 mg 2 YEARS +0.01 0.00 CRESTOR Time (years) 1-0.0014 mm/yr 2 * -0.01 Change in CIMT (95% CI) Placebo n=252 CRESTOR 40 mg n=624 REGRESSION Adapted from Crouse JR, et al. JAMA 2007 297:1344-1353. REFERENCE: 1. Crouse JR, et al. JAMA 2007 297:1344-1353. 14

Crestor is approved to slow the progression of atherosclerosis a thickening of the artery wall due to the buildup of cholesterol and other fatty materials. http://www.fda.gov/newsevents/newsroom/pressannou ncements/ucm200128.htm JUPITER Justification for the Use of statins in Primary prevention: an Intervention Trial Evaluating Rosuvastatin Please see slide 28 for Summary of Product Characteristics Ridker P et al. N Eng J Med 2008;359: 2195-2207 15

Change from baseline (%) 22/01/2017 JUPITER study design No history of CAD men 50 yrs women 60 yrs LDL-C <130 mg/dl CRP 2.0 mg/l Placebo run-in Rosuvastatin 20 mg (n=8901) Placebo (n=8901) Visit: Week: 1 6 2 4 3 0 4 13 6-monthly Final Lead-in/ eligibility Randomisation Lipids CRP Tolerability Lipids CRP Tolerability Median follow-up 1.9 years Lipids CRP Tolerability HbA 1C CAD=coronary artery disease; LDL-C=low-density lipoprotein cholesterol; CRP=C-reactive protein; HbA 1c=glycated haemoglobin Ridker P et al. N Eng J Med 2008;359: 2195-2207 JUPITER Effects on LDL-C, HDL-C, TG and hscrp at 12 months; Percentage change between rosuvastatin and placebo 10 LDL-C HDL-C TG hscrp 0-10 -20 4% p<0.001* 17% p<0.001-30 -40 37% p<0.001-50 -60 50% p<0.001 *P-value at study completion (48 months) = 0.34 Ridker P et al. N Eng J Med 2008;359: 2195-2207 16

Cumulative Incidence Cumulative Incidence 22/01/2017 Time to First Major Cardiovascular Event with Rosuvstatin versus Placebo 0.08 Results from JUPITER 0.06 0.04 Hazard ratio 0.56 (95% CI 0.46-0.69) p<0.00001 Placebo RRR 44% Rosuvastatin 20 mg 0.02 NNT for 2 y=95 4 y=31 5 y*=25 *Extrapolated figure based on Altman and Andersen method 0.00 0 1 2 3 4 Number at Risk Follow-up (years) Rosuvastatin Placebo 8901 8901 8631 8621 8412 8353 6540 6508 3893 3872 1958 1963 1353 1333 983 955 544 534 157 174 Ridker PM et al. NEJM 2008; 359: 2195 2207 JUPITER: Fatal or Nonfatal Myocardial Infarction 3 2.5 Rosuvastatin Placebo Number of events 31 68 2 1.5 HR 0.46 (95% CI 0.30-0.70) P<0.0002 RRR 54% 1 0.5 0 1 2 3 4 Follow-up Years 17

Cumulative Incidence, % Cumulative Incidence, % 22/01/2017 JUPITER: Bypass Surgery or PTCA / Hospitalization for UA 6 Rosuvastatin Placebo Number of events 76 143 5 4 3 HR 0.53 (95% CI 0.40-0.70) P<0.00001 RRR 47% 2 1 0 1 2 3 4 Follow-up Years Number at Risk Rosuvastatin8,901 8,640 8,426 6,550 3,905 1,966 1,359 989 547 158 Placebo 8,901 8,641 8,390 6,542 3,895 1,977 1,346 963 538 176 JUPITER: Fatal or Nonfatal Stroke 3 Rosuvastatin Placebo Number of events 33 64 2.5 2 1.5 HR 0.52 (95% CI 0.34-0.79) P=0.002 RRR 48% 1 0.5 0 1 2 3 4 Follow-up Years 18

Cumulative Incidence, % 22/01/2017 JUPITER: Death from Any Cause 7 Rosuvastatin Placebo 6 5 4 3 Number of events 198 247 HR 0.80 (95% CI 0.67 0.97) P=0.021 RRR 20% 2 1 0 0 1 2 3 4 6 Number at risk Years Rosuvastatin 8901 8787 4313 1601 682 Placebo 8901 8782 4323 1613 683 Post hoc analyses of JUPITER in High Risk Patients Reduction in major CV events with rosuvastatin 20 mg compared to placebo Relative Risk Reduction in event rate RRR 50% 2 RRR 43% 2 Framingham score >20% 2 Absolute risk reduction in event rate: 8.8 per 1000 patient years 1 CV death, stroke and MI P=0.028 (vs placebo) EU score 5% 2 Absolute risk reduction in event rate: 5.1 per 1000 patient years 1 CV death, stroke and MI P=0.0003 (vs placebo) combined end-point of cardiovascular death, stroke and myocardial infarction 1. CRESTOR, Summary of Product Characteristics. 2. Koenig W, Ridker PM. Eur Heart J (2011) 32, 75 83; doi:10.1093/eurheartj/ehq370. Reproduced by permission of Oxford University Press 19

JUPITER: Number Needed to Treat (5 year) Endpoint All FRS 10 FRS>10 Primary Endpoint 25 47 17 Primary Endpoint, Mortality 20 34 14 MI, Stroke, CABG/PTCA, Death 20 37 14 MI, Stroke, Death 29 60 20 Benchmarks: Statins for hyperlipidemia 5-year NNT 40-60 Diuretics 5-year NNT 80-100 Beta-blockers 5-year NNT 120-160 Aspirin Men 5-year NNT 220-270 Aspirin Women 5-year NNT 280-330 Ridker et al. Circulation CV Qual Outcomes 2009;2: 616-23. Consider Statins a lifelong commitment You may think that once your cholesterol goes down, you can stop taking medication. But, if your cholesterol levels have decreased after you take a Statin, you'll likely need to stay on it indefinitely. If you stop taking it, your cholesterol levels will probably go back up. http://www.mayoclinic.org/diseases-conditions/high-blood-cholesterol/in-depth/statins/art- 20045772-last accessed 25/2/2015 20

Summary Ischemic heart disease is the leading cause of death globally Dyslipidemia is a major risk factor for ISH. CEPHEUS showed a big gap in Dyslipidemia management in Egypt. Crestor provides high efficacy on Lipid parameters Crestor shown to slow progression of atherosclerosis and provides the optimum cardio protection. Crestor For Life Thank you 21