Statins ARE Enough For The Prevention of CVD! Professor Kausik Ray Imperial College London, UK

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1 1 Disclosures Advisory boards PCSK9- Sanofi/ Regeneron, Amgen, Pfizer, Roche, MSD NLI/ SC member for Odyssey- (Sanofi/ Regeneron), Roche Investigator initiated research grant support (Sanofi/Regeneron/ Pfizer/ Amgen/ MSD) CME lectures at Symposia (Sanofi/ Regeneron, Amgen, Pfizer, AZ, MSD)

2 Statins ARE Enough For The Prevention of CVD! Professor Kausik Ray Imperial College London, UK

3 Before Considering Whether a Treatment is Enough Consider The Following Is there a problem? Where is the problem/ who is affected? Is there a proven treatment in the majority? Is the treatment easy to administer and take for the patient? Is the treatment safe when you give it to the masses? Is the treatment affordable?

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8 Statins are the current standard of care in treating dyslipidaemia Statins have been the cornerstone of drug therapy since their introduction in the late 1980s due to their effectiveness in reducing LDL-C by 63% 1 Lowering LDL-C with statin regimens can reduce the 5-year event rate of first major coronary events, revascularisations, and strokes by ~1/4 per 1.0 mmol/l reduction in LDL-C 2 Serious adverse side effects are rare 3,4 A variety of statins with well-established efficacy and safety profiles are available to tailor treatment 1 New formulations may ensure better adherence and more extensive dosing regimens LDL-C, low-density lipoprotein cholesterol 1. Jeger R & Dieterle T. Swiss Med Wkly 2012;142:w13515; 2. Heart Protection Study Collaborative Group. Lancet 2002;360:7 22; 3. Semple SJ. Lipids in Health and Disease 2012;11:40; 4. Naci H et al. Circ Cardiovasc Qual Outcomes 2013;6:

9 Reduction of LDL-C leads to the reduction of major vascular events 50% Major vascular events Proportional reduction in event rate (SE) 40% 30% 20% 10% 0% % Reduction in LDL cholesterol (mmol/l) SE, standard error Baigent C et al. Lancet 2005;366:

10 Effect on major coronary events is independent of baseline prognostic factors Events (%) Groups Treatment Control Rate Ratio (CI) Prior disease Post-MI 1681 (11 7) 2207 (15 4) 0.78 ( ) Other CHD 568 (8 7) 744 (11 4) 0.77 ( ) None 1088 (4 5) 1469 (6 1) 0.72 ( ) Age (years) (6 1) 2344 (8 5) 0.74 ( ) > (9 5) 2076 (11 9) 0.81 ( ) Gender Male 2686 (7 8) 3630 (10 6) 0.76 ( ) Female 651 (6 1) 790 (7 3) 0.82 ( ) Treated hypertension Yes 2038 (8 2) 2596 (10 4) 0.79 ( ) No 1299 (6 4) 1824 (9 1) 0.75 ( ) History of diabetes Yes 776 (8 3) 979 (10 5) 0.78 ( ) No 2561 (7 2) 3441 (9 6) 0.77 ( ) Diastolic blood pressure (mmhg) (7 8) 3590 (10 3) 0.77 ( ) > (6 1) 827 (8 2) 0.76 ( ) Overall 3337 (7 4) 4420 (7 4) 0.77 ( ) MI, myocardial infarction; CHD, coronary heart disease; CI, confidence interval Baigent C et al. Lancet 2005;366: Effect p<0.0001

11 Effect on major coronary events is independent of baseline lipid values Groups (mmol/l) Events (%) Treatment Control Total cholesterol: (6 9) 940 (8 6) > (7 0) 2246 (9 4) > (8 8) 1220 (12 1) LDL cholesterol: (6 8) 1443 (8 7) > (7 3) 1814 (9 6) > (9 3) 1120 (12 9) HDL cholesterol: (9 3) 1538 (12 1) > (7 4) 1270 (10 2) > (6 2) 1595 (8 1) Triglycerides: (7 3) 1521 (9 6) > (7 1) 1304 (9 8) > (7 9) 1564 (10 2) Overall 3337 (7 4) 4420 (9 8) RR & CI (Treatment:Control) Heterogeneity/trend p-value p=0 7 p=0 5 p=0 8 p= ( ) RR, rate ratio, HDL, high-density lipoprotein Baigent C et al. Lancet 2005;366: Treatment Control better better Effect p<0.0001

12 No threshold of baseline LDL-C for benefit from intensive statin therapy Events (% per annum) RR (CI) per 1 mmol/l reduction in LDL-C Trend test Statin/more Control/less More vs less statin <2 mmol/l 704 (4.6%) 795 (5.2%) 0.71 ( ) 2 to <2.5 mmol/l 1189 (4.2%) 1317 (4.8%) 0.77 ( ) 2.5 to <3.0 mmol/l 1065 (4.5%) 1203 (5.0%) 0.81 ( ) χ 2 = to <3.5 mmol/l 517 (4.5%) 633 (5.8%) 0.61 ( ) (p = 0.2) 3.5 mmol/l 303 (5.7%) 398 (7.8%) 0.64 ( ) Total 3837 (4.5%) 4416 (5.3%) 0.72 ( ) 99%; or 95% CI Statin/more better Control/less better Cholesterol Treatment Trialists (CTT) Collaboration. Lancet 2010;376:

13 Guidelines recommend LDL-C targets and the prescription of highest recommended statin doses to reach targets Maximum doses of statins are infrequently prescribed 1 there is room for improvement CVD, cardiovascular disease; a, class of recommendation; b, level of evidence; c, references Tables taken from ESC/EAS Guidelines for the management of dyslipidaemias 2 1. Hermans MP et al. Curr Med Res Opin 2010;26: ; 2. Eur Heart J 2011;32:

14 4 Statin Benefit Groups IA IA IB IA IIaB

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16 Side effects are not more frequent with high-dose statins Trial ALN 3xULN (%) Higher dose Lower dose CK 10xULN or myopathy (%) Higher dose *Reported as persistent elevation in alanine or aspartate transaminase ALN, alanine transaminase; ULN, upper limit of normal; CK, creatine kinase Armitage J. Lancet 2007;370: Lower dose Rhabdomyolysis (%) Higher dose Lower dose PROVE-IT Phase Z of A to Z trial* TNT* IDEAL SPARCL*

17 No evidence that statins increase the risk of cancer Relative risk of onset of cancer from the Cholesterol Treatment Trialists' (CTT) meta-analysis of statin trials, according to year of onset Year of onset No. with cancer onset in trials Statin (N = 45,054) Control (N = 45,002) Risk Ratio for statin vs control (CI) > > > > All 2810/199,063 person-year (1.4% per year) 2804/197,680 person-year (1.4% per year) Statin better Control better Peto R et al. N Engl J Med 2008;359:

18 From: Statin Intolerance: Reconciling Clinical Trials and Clinical Experience JAMA. 2015;313(10): doi: /jama Table Title: Muscle Adverse Events Reported in Randomized, Double-Blind, Placebo-Controlled Cardiovascular Outcome Trials of Statins a Date of download: 5/18/2015 Copyright 2015 American Medical Association. All rights reserved.

19 Patients intolerant to a particular statin are able to tolerate an alternative statin without side effects Due to the different PKs and metabolism of individual statins, patients intolerant to a statin may tolerate another 1 Nearly two-thirds of the statin-intolerant patients were able to tolerate an alternative statin without side effects 1 No evidence so far that add-on LDL-lowering therapies decrease the residual CV risk 2,3 PK pharmacokinetic 1. Nair RK et al. The British Journal of Cardiology. Managing patients with statin intolerance : a retrospective study available at: accessed July 2013; 2. Cimminielo C. Intern Emerg Med 2011;6(suppl 1):53 60; 3. Michos ED et al. J Am Coll Cardiol 2012;59:

20 How well are we doing with statins?

21 Overall rates of secondary prevention medication use for CVD is low worldwide PURE study, 17 countries 100 Antiplatelet Beta-blockers ACEi or ARBs Diuretics % of patients with treatment BP-lowering Ca-channel blockers Statins CHD Stroke CHD or stroke PURE, Prospective Urban Rural Epidemiology; ACEi, angiotensin-converting-enzyme inhibitor; ARB, angiotensin receptor blocker; BP, blood pressure Yusuf S et al. Lancet 2011;378:

22 % of patients at LDL-C goal CEPHEUS: about half of patients achieved LDL-C goals 65 Patients on lipid-lowering drugs for >3 months (stable medication >6 weeks) 41 Europe 1 JETF guidelines Asia 2 NCEP ATP III guidelines* *Patients with 2 cardiovascular risk factors according to NCEP ATP III guidelines; CEPHEUS, CEntralized Pan-European survey on the Under-treatment of hypercholesterolaemia, NCEP ATP, National Cholesterol Educational Program Adult Treatment Panel; JETF, Joint European Task Force 1. Hermans MP et al. Curr Med Res Opin 2010;26: ; 2. Park JE et al. Eur J Prev Cardiol 2012;19:

23 Physicians don t like to switch treatment regimens; patients don t like to be switched Europe (N=15,199) Asia (N=8,064) % of patients Same tablet, same dose Same tablet, dose increased Switched 2 times Switched 3 times About 60% of patients still on same lipid-lowering drug since first prescribed 1,2 Statins could be used better (up-titration, switching) 1. Hermans MP et al. Curr Med Res Opin 2010;26: ; 2. Park JE et al. Eur J Prev Cardiol 2012;19:

24 Nearly half of patients sometimes forget to take their tablets % of patients forgetting to take their tablets Europe (N=15,199) Sometimes Once every 2 weeks 26 Asia (N=8,064) 16 Once every week Europe (N=15,199) Thought that missing their daily tablets at least once a week would not jeopardise their cholesterol levels 32 44% of patients sometimes forgot to take their tablets, up to a quarter forgot once a week 1,2 Up to 40% of the patients thought missing a tablet at least once a week would not affect their cholesterol levels 1,2 % of patients 1. Hermans MP et al. Curr Med Res Opin 2010;26: ; 2. Park JE et al. Eur J Prev Cardiol 2012;19: Asia (N=8,064)

25 Before considering other treatments, increasing persistence may do the job Primary prevention (goal: <130 mg/dl N=87,219) Secondary prevention (goal: <100 mg/dl N=15,139) % of patients reaching LDL-C goal High persistence (PDC 80%) PDC, proportion of days covered Shalev V et al. Pharmacotherapy 2013 doi: /phar.1326 Poor persistence (PDC 33%) Persistence with statins was strongly associated with drug effect of LDL level reduction

26 Screen early, treat early, think about lifetime risk 54.5% relative risk reduction per 1 mm/l (38.7mg/dL) LDL-C lowering 22% relative risk reduction per 1 mmol/l (38.7mg/dL) LDL-C lowering 50% Major vascular events Proportional Risk Reduction (SE) 30% 20% 10% rs rs rs rs rs rs12916 rs rs rs Lower LDL-C (mg/dl) Proportional reduction in event rate (SE) 40% 30% 20% 10% 0% -10% Reduction in LDL cholesterol (mmol/l) Ference BA et al. J Am Coll Cardiol 2012;60: ; Baigent C et al. Lancet 2005;366:

27 Global access to healthcare is something that needs to be considered Current global population ~7 billion 1 Access to health care ~2 billion 2 No access to health care ~5 billion 2 Worldwide use of statins as secondary preventative medication (PURE study): 9 15% 3 Statins are affordable and available. An increase in global statin exposure will have a greater reduction in population rates of CVD than any new, expensive treatment: 5 billion new patients large ARR vs 2 billion new patients small ARR ARR, absolute risk reduction; WHO, World Health Organisation 1.United States Consensus Bureau. U.S. and World Population Clock. Available at: accessed August 2013; 2. George Institute for Global Health. Available at: accessed August 2013; 3. Yusuf S et al. Lancet 2011;378:

28 What is the real extent of unmet medical need with statins Better access to health care and evidence-based treatment such as statins will have a far greater impact on the global population Further research into optimising the use of statins in the patient population should be undertaken to maximise the benefit of these treatments

29 Why might additional therapies offer very little on top of statins?

30 The lower the baseline LDL-C the less benefit from further LDL-C reduction 1.0 Logit of the Primary Endpoint Atorvastatin 80 mg Pravastatin 40 mg Baseline LDL-C (mg/dl) Giraldez RR et al. J Am Coll Cardiol 2008;52:

31 Increase in NNT as levels of LDL- C fall Low/moderate risk: High risk: Very high risk: <~115 mg/dl <~100 mg/dl <~70 mg/dl (or 50%) LDL cholesterol (mmol/l): Events (%) Treatment Control RR & CI (Treatment:Control) NNT (6.8) 1443 (8.7) 52.6 > (7.3) 1814 (9.6) 43.5 Absolute benefit diminishes at lower baseline LDL-C levels > (9.3) 1120 (12.9) Treatment better Control better NNT, number needed to treat; Guidelines taken from European Guidelines on CVD prevention in clinical practice: Perk J et al. Eur Heart J 2012;33: ; Baigent C et al. Lancet 2005;366:

32 Weighing up the benefit of any treatment to society Statin Absolute Benefit Treatment X Absolute Harm CVD Risk Absolute cost of statins Absolute cost of Treatment X

33 Black hole in your budget with a lot of unknowns!

34 Conclusions Statins are affordable, well-tolerated and effective and have proven effects on outcomes Statins should be used more efficiently Higher dose More potent molecules Biggest population attributable benefit will come from better utilisation of statins and not more expensive, unknown treatments with small absolute gains

35 You might think statins aren t enough and you might think that you are stuck! STATINS

36 But when you find yourself stuck in a situation there is one thing that you should always remember..

37 Not everyone who shows up. PCSK9 CETP inhibitors STATINS Is there to help