IMPROVE-IT : Are we back to the lower the better? Further LDL-Cholesterol lowering on top of statins: backgrounds and the results of the study

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1 IMPROVE-IT : Are we back to the lower the better? Further LDL-Cholesterol lowering on top of statins: backgrounds and the results of the study Fundación Fernández-Cruz Clinico San Carlos, Madrid Spain, 26 oct 2015 Prof. Dr. J.W. Jukema Dept Cardiology, Leiden University Medical Center The Netherlands

2 DISCLOSURE: JW Jukema has received research grants from and/or was speaker (with or without lecture fees) on (CME accredited) meetings sponsored by Amgen, Astellas, Anthera, Astra-Zeneca, Bayer, Biotronik, Boston Scientific,Correvio, Daiichi Sankyo, Lilly, Genzyme, Medtronic, Merck-Schering-Plough, Pfizer, Orbus Neich, Novartis, Roche, Servier, Sanofi Aventis, The Medicine Company, the Netherlands Heart Foundation, the Interuniversity Cardiology Institute of the Netherlands and the European Community Framework KP7 Programme

3 Old

4 New

5 Further LDL-C lowering: Go / Hold/ Stop?

6 Nicolai Anitschkow ( ) Identified cell types involved in atherosclerosis Smooth muscle cells Macrophages Lymphocytes There is no atherosclerosis without cholesterol Anitschkow NN, Chatalov S (1913). "Über experimentelle Cholesterinsteatose und ihre Bedeutung für die Entstehung einiger pathologischer Prozesse". Zentralbl Allg Pathol 24: 1-9. Anitschkow NN (1913). "Über die Veränderungen der Kaninchenaorta bei experimenteller Cholesterinsteatose". Beitr Pathol Anat 56:

7 CTT: more intensive LDL lowering can decrease CV events by 40-50% Event (% per annum) Statin/more Control/less RR (CI) per 1 mmol/l reduction in LDL-C Trend test More vs less statin <2 mmol/l 2 to <2.5 mmol/l 2.5 to <3.0 mmol/l 3 to <3.5 mmol/l 3.5 mmol/l Total 704 (4.6%) 1189 (4.2%) 1065 (4.5%) 517 (4.5%) 303 (5.7%) 3837 (4.5%) 795 (5.2%) 1317 (4.8%) 1203 (5.0%) 633 (5.8%) 398 (7.8%) 4416 (5.3%) 0.71 ( ) 0.77 ( ) 0.81 ( ) 0.61 ( ) 0.64 ( ) 0.72 ( ) 1 X2 =2.04 (p=0.2) Statin vs contol <2 mmol/l 2 to <2.5 mmol/l 2.5 to <3.0 mmol/l 3 to <3.5 mmol/l 3.5 mmol/l Total All trials combined 206 (2.9%) 339 (2.4%) 801 (2.5%) 1490 (2.9%) 4205 (2.9%) 7136 (2.8%) 217 (3.2%) 412 (2.9%) 1022 (3.2%) 1821 (3.6%) 5338 (3.7%) 8934 (3.6%) 0.87 ( ) 0.77 ( ) 0.76 ( ) 0.77 ( ) 0.80 ( ) 0.79 ( ) 1 X2 =0.80 (p=0.4) <2 mmol/l 2 to <2.5 mmol/l 2.5 to <3.0 mmol/l 3 to <3.5 mmol/l 3.5 mmol/l Total 910 (4.1%) 1528 (3.6%) 1866 (3.3%) 2007 (3.2%) 4508 (3.0%) (3.2%) 1012 (4.6%) 1729 (4.2%) 2225 (4.0%) 2454 (4.0%) 5736 (3.9%) (4.0%) 0.78 ( ) 0.77 ( ) 0.77 ( ) 0.76 ( ) 0.80 ( ) 0.78 ( ) 1 X2 =1.08 (p=0.3) 99% or 95% CI Statin/more better Control/less better Cholesterol Treatment Trialists (CTT) Collaboration. Lancet. 2010;376:

8 Propotional reduction of coronary events Effect of LDL-C Lowering with Statins CTT prospective meta-analysis, 14 randomised studies, n = % relative risk reduction per 1 mm/l (38.7mg/dl) LDL- C lowering LDL-C lowering [mmol/l] Cholesterol Treatment Trialists (CTT), Lancet 2005; 366:

9 Statin landmark trials

10 STATINS Safety: In general good safety profile!

11 How (Low) Should We Go? How low is normal? Where does less progression change into induced regression? How can we go that low?

12 IVUS Allows for Determination of Atherosclerosis Burden by Total Plaque Volume 3.1 mm 3.1 mm

13 Change in TAV (%) Reversal Primary end point: Percent change in total atheroma volume P= * Pravastatin -0.4 Atorvastatin Significant atherosclerotic progression from baseline *Progression vs baseline (P=0.001); No change vs baseline (P=0.98) No significant change from baseline; atherosclerotic progression was stopped Nissen SE et al. JAMA Mar 3;291(9):

14 Comparison of LDL-C reduction and change in atheroma volume Change in Atheroma Volume, mm Both Treatment Groups (n=502) % Change in Low-Density Lipoprotein Cholesterol Regardless of the agent used, an LDL-C reduction of at least 50% was required to halt progression. The dashed lines indicate upper and lower 95% CIs for the mean values

15 How (Low) Should We Go? How low is normal? Where does less progression change into induced regression? How can we go that low?

16 reduction of LDL (%) Statins: Rule of six mg +20 mg +40 mg % - 6% -50-6% mg Statin

17 LDL-C Reduction across separate studies (no direct comparisons) Rosuvastatin 10 mg (-46%) mg 20 mg 40 mg 10 mg 20 mg 40 mg 80 mg rosuvastatin atorvastatin simvastatin 10 mg 20 mg 40 mg 80 mg pravastatin Ezetimibe /simvastatin 10 mg 20 mg 40 mg 10/20 10/40 10/80 Ezetimibe/simvastatin 10/20mg (-51%) Adapted from Goldberg AC et al Mayo Clin Proc 2004;79: ; Jones PH et al Am J Cardiol 2003;92:

18 Therapy for atherosclerosis Do we need a new drug to expand our therapeutic alternatives? Many statin patients are treated unsatisfactorily and do not reach their therapeutic goals, even with higher doses Doubling the dose of statin decreases LDL cholesterol by only another 6 % Increasing doses of statins are connected with higher risk of adverse events Non-statin additives/alternatives?

19 Non-fatal myocardial infarction or CHD death Relative Risk reduction (%) Estimated change in the five-year relative risk. LDL-C reduction (%) Robinson, J Am Coll Cardiol 2005;46: )

20 Dual Inhibition: Ezetimibe and Statin Statin Synthesis of Cholesterol Bile Cholesterol absorption Intestine DAR Ezetimibe Dietary cholesterol Excretion

21 LDL-C Reduction 3 steps of titration with statins or 1 step with Ezetimibe co-administration? Statin 10 mg 20 mg 40 mg 80 mg 3-fold TITRATION Statin10 mg +Ezetimibe 10 mg SIMPLE CO- ADMINISTRATION % reduction of LDL-cholesterol

22 Ezetimibe: Background Ezetimibe inhibits Niemann-Pick C1-like 1 (NPC1L1) protein located primarily on the epithelial brush border of the GI tract resulting in reduced cholesterol absorption When added to statin, produces ~20% further reduction in LDL-C Two recent human genetic analyses have correlated polymorphisms in NPC1L1 with lower levels of LDL-C and lower risk of CV events* *MI Genetics Consortium Investigators NEJM 2014; online Nov 12; Ference BA et al

23 The proof of the pudding is the long term eating Evidence from Trials!

24 Theory, Hypothesis, Test! Wrong Conclusion! You Need Clinical Trials to Adequately Test Your Hypothesis!!

25 Ezetimibe Reduces Carotid Artery Atherosclerosis in apoe Knockout Mice* Control Ezetimibe 5 mg/kg/d * Mice fed 0.15% cholesterol diet for 6 months Davis et al. Atherosclerosis. 2000; 151:133 (Abs).

26 IMProved Reduction of Outcomes: Vytorin Efficacy International Trial A Multicenter, Double-Blind, Randomized Study to Establish the Clinical Benefit and Safety of Vytorin (Ezetimibe/Simvastatin Tablet) vs Simvastatin Monotherapy in High-Risk Subjects Presenting With Acute Coronary Syndrome

27 Goals IMPROVE-IT: First large trial evaluating clinical efficacy of combination EZ/Simva vs. simvastatin (i.e., the addition of ezetimibe to statin therapy): Does lowering LDL-C with the non-statin agent ezetimibe reduce cardiac events? Is (Even) Lower (Even) Better? (estimated mean LDL-C ~50 vs. 65mg/dL) Safety of ezetimibe Cannon CP AHJ 2008;156:826-32; Califf RM NEJM 2009;361:712-7; Blazing MA AHJ 2014;168:205-12

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29 Major worries regarding the design of the IMPROVE-IT trial 1) Low absolute event rates 2) High drop-out/loss to follow-up 3) Very low baseline LDL-c levels law of diminishing returns

30 Absolute CV Risk [%] Diminishing absolute risk reduction for lower absolute LDL-C reduction with lower baseline LDL-C Relative Risk reduction -20% -15% -11% -4% mmol mmol mmol - 1 mmol 4 LDL-C [mg/dl] % -25% -25% -25%

31 Are you still there?

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33 Inclusion Criteria: Patient Population Hospitalization for STEMI, NSTEMI/UA < 10 days Age 50 years, and 1 high-risk feature: New ST chg, + troponin, DM, prior MI, PAD, cerebrovasc, prior CABG > 3 years, multivessel CAD LDL-C mg/dl ( mg/dl if prior lipid-lowering Rx) Major Exclusion Criteria: CABG for treatment of qualifying ACS Current statin Rx more potent than simva 40mg Creat Cl < 30mL/min, active liver disease

34 Patients stabilized post ACS 10 days: LDL-C *mg/dL (or **mg/dL if prior lipid-lowering Rx) N=18,144 Standard Medical & Interventional Therapy Simvastatin 40 mg Study Design Uptitrated to Simva 80 mg if LDL-C > 79 (adapted per FDA label 2011) *3.2m M **2.6m M Ezetimibe / Simvastatin 10 / 40 mg Follow-up Visit Day 30, every 4 months 90% power to detect ~9% difference Duration: Minimum 2 ½-year follow-up (at least 5250 events) Primary Endpoint: CV death, MI, hospital admission for UA, coronary revascularization ( 30 days after randomization), or stroke Cannon CP AHJ 2008;156:826-32; Califf RM NEJM 2009;361:712-7; Blazing MA AHJ 2014;168:205-12

35 Baseline Characteristics Simvastatin (N=9077) % EZ/Simva (N=9067) % Age (years) Female Diabetes MI prior to index ACS STEMI / NSTEMI / UA 29 / 47 / / 47 / 24 Days post ACS to rand (IQR) 5 (3, 8) 5 (3, 8) Cath / PCI for ACS event 88 / / 70 Prior lipid Rx LDL-C (mg/dl) (IQR) 95 (79, 110) 95 (79,110)

36 Study Metrics Simva (N=9077) EZ/Simva (N=9067) Uptitration to Simva 80mg, % 27 6 Premature study drug D/C, % Median follow-up, yrs WDC without vital status, %/yr Lost to follow-up, %/yr Follow up for primary endpoint, % Follow up for survival, % Total primary endpoint events = 5314 Total patient-years clinical follow-up = 97,822 Total patient-years follow-up for survival = 104,135

37 LDL-C and Lipid Changes 1 Yr Mean LDL-C TC TG HDL hscrp Simva EZ/Simva Δ in mg/dl Median Time avg 69.5 vs mg/dl

38 Primary and 3 Prespecified Secondary Endpoints ITT Simva* EZ/Simva*p-value Primary CVD/MI/UA/Cor Revasc/CVA Secondary # All D/MI/UA/Cor Revasc/CVA Secondary # CHD/MI/Urgent Cor Revasc Secondary # CVD/MI/UA/All Revasc/CVA Ezetimibe/Simva Better Simva Better *7-year event rates (%) UA, documented unstable angina requiring rehospitalization; Cor Revasc, coronary revascularization ( 30 days after randomization); All D, all-cause death; CHD, coronary heart disease death; All Revasc, coronary and non-coronary revascularization ( 30 days)

39 Individual Cardiovascular Endpoints and CVD/MI/Stroke HR Simva* EZ/Simva* p-value All-cause death CVD CHD MI Stroke Ischemic stroke Cor revasc 30d UA CVD/MI/stroke Ezetimibe/Simva Better Simva Better *7-year event rates (%)

40 CV Death, Non-fatal MI, or Non-fatal Stroke HR 0.90 CI (0.84, 0.97) p=0.003 NNT= 56 Simva 22.2% 1704 events EZ/Simva 20.4% 1544 events 7-year event rates

41 For which situation the parachute will protect best?

42 Major Pre-specified Subgroups Simva EZ/Simva Male Female Age < 65 years Age 65 years No diabetes Diabetes * Prior LLT No prior LLT LDL-C > LDL-C Ezetimibe/Simva Better Simva Better 7-year event rates *p-interaction = 0.023, otherwise > 0.05

43 IMPROVE-IT vs. CTT: Ezetimibe vs. Statin Benefit CTT Collaboration. Lancet 2005; 366: ; Lancet 2010;376: NEJM 2015;372:

44 Safety: Again no problem!

45 Safety ITT No statistically significant differences in cancer or muscle- or gallbladder-related events Simva n=9077 % EZ/Simva n=9067 % p ALT and/or AST 3x ULN Cholecystectomy Gallbladder-related AEs Rhabdomyolysis* Myopathy* Rhabdo, myopathy, myalgia with CK elevation* Cancer* (7-yr KM %) * Adjudicated by Clinical Events Committee % = n/n for the trial duration

46 Primary outcome - NODM HR 1.04 (95% CI ) p = , Decreased risk with Ez/Simva Increased risk with Ez/Simva NODM = antihypergycemic med and/or 2 fasting glucoses > 7 mmol/l

47 Conclusions IMPROVE-IT: First trial demonstrating incremental clinical benefit when adding a non-statin agent (ezetimibe) to statin therapy: YES: Non-statin lowering LDL-C with ezetimibe reduces cardiovascular events YES: Even Lower is Even Better (achieved mean LDL-C 53 vs. 70 mg/dl at 1 year) YES: Confirms ezetimibe safety profile Reaffirms the LDL hypothesis, that reducing LDL-C prevents cardiovascular events Results could be considered for future guidelines

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49 Statin Therapy and Incident Diabetes Statin Placebo or Control n Events Rate Events Rate OR (95% CI) Weight (%) ASCOT-LLA ( ) 7.07% HPS 14, ( ) 13.91% JUPITER 17, ( ) 11.32% WOSCOPS ( ) 4.24% LIPID ( ) 6.53% CORONA ( ) 4.65% PROSPER ( ) 6.94% MEGA ( ) 8.03% AFCAPS/TEXCAPS ( ) 3.76% 4S ( ) 8.88% ALLHAT ( ) 10.23% GISSI HF ( ) 9.50% GISSI PREV ( ) 4.94% Overall (I 2 = 11.2% [95% CI %] 1.09 ( ) 100% Sattar N et al. Lancet 2010;375:735-42

50 Meta-Analysis of New-Onset Diabetes and First Major Cardiovascular Events in Trials Comparing Intensive- to Moderate-Dose Statin Therapy Preiss D et al. JAMA 2011;305:

51 Achievement of Dual LDL-C (<70 mg/dl) and hs- CRP (<2 mg/l) Targets More Frequent with Addition of Ezetimibe to Simvastatin and Associated with Better Outcomes in IMPROVE IT From the data presentation at ESC 2015 (London, UK) by Erin A. Bohula May, Robert P. Giugliano, Christopher P. Cannon, Jing Zhou, Amy McCagg, Michael A. Blazing, Jennifer A. White, Andrew M. Tershakovec, & Eugene Braunwald Published in Circulation Aug : Circulation. 2015;132: DOI: /CIRCULATIONAHA Circulation. 2015;132: DOI: /CIRCULATIONAHA

52 Pre-specified LDL-C and hs-crp Target Achievement at 1 month by randomized Treatment The addition of ezetimibe to simvastatin resulted in significant reductions in LDL-C and hs-crp compared to simva monotherapy (p<0.001), translating to significantly more patients meeting both of the targets: 50% versus 29%, p<0.001 Circulation. 2015;132: DOI: /CIRCULATIONAHA

53 Primary Endpoint by 1 month Pre-specified LDL- C and/or hs-crp Target Achievement After adjustment, achieving both targets at 1 month was associated with a 27% lower relative risk in the primary composite endpoint compared to meeting neither LDL-C nor hs-crp target at 1 month. An analysis of the secondary and individual endpoints suggested that relative to achieving neither target, meeting both targets was associated with a significant improvement in outcomes, with the exceptionof stroke. Circulation. 2015;132: DOI: /CIRCULATIONAHA

54 Conclusion In this pre-specified analysis of the IMPROVE-IT trial, patients were significantly more likely to achieve LDL-C and hs-crp targets with EZ/simva vs simva monotherapy. There was a graded association of improved outcomes with target achievement for the primary endpoint. The specific therapy used to attain target levels did not differentially impact outcomes, suggesting that in this analysis target achievement is more important than the specific choice of agent used to achieve the target Circulation. 2015;132: DOI: /CIRCULATIONAHA

55 Questions? 1. One of the excl. criteria was use of statin therapy that had LDL cholesterol lowering potency greater than 40 mg of simvastatin. Based on the IMPROVE-IT results which secondary prevention therapy, if needed, would you recommend when patients are already on simvastatin 40 mg and well tolerated? 2. Knowing that for a period (till June 2011) 80 mg simvastatin was allowed in a blinded manner. Between October 26, 2005, and July 8, 2010, a total of 18,144 patients underwent randomization at 1147 sites in 39 countries, therefore all patients could receive 80 mg? The simvastatin dose was increased to 80 mg for elevated LDL cholesterol levels in 27% of the patients in the simvastatin-monotherapy group and in 6% of the patients in the simvastatin ezetimibe group. What is your opinion on the allowance of 80 mg simvastatin in both groups on the prim. Endpoint? 3. What is your opinion on the fact that the benefit appeared to be particularly pronounced in patients with diabetes mellitus and in patients 75 years of age or older. Moreover we see in other ACS studies a particularly pronounced effect within the diabetes population? 4. Could you explain the significant differences in Urgent coronary revascularization 30 days after randomization? 5. Is the Improve-IT trial a secondary prevention trial or a chronic phase trial if we take into account the benefit only after one year?