The case for intensive lipid management: The opportunities and issues for cardiologists

1. MasterClass: Advanced CV Risk management in cardiology June 17-18, 2011, London Presentation topic The case for intensive lipid management: The opportunities and issues for cardiologists Slide lecture prepared and held by: • Prof. John Betteridge • University College London

2. A Survey of 246 Suggested Coronary Risk Factors Paul N. Hopkins and Roger R. Williams Department of Internal Medicine, Cardiology Division, University of Utah Medical Center, Salt Lake City, UT 84132 (USA) Atherosclerosis 1981

3. BMJ 1975, 4 500-502

4. The Fate of LDL LDLR PCSK9 prevents LDLR recycling Down regulate HMGCoA reductase Reduce LDL receptor synthesis Esterified by ACAT (storage)

5. FH3: mutations in PCSK9Proproteinconvertasesubtilisin/kexin type 9 • PCSK9 is a protease which binds to LDL-R and directs them to lysosomes for degradation, rather than recycling to cell surface • Loss of function (non-sense and some mis-sense) mutations lead to LDL levels • 2.6% of US blacks, LDL 28%, CHD 88% • 3.2% of US whites, LDL 15%, CHD 47% • (Cohen et al. NEJM 2006;354:1264) • Rare gain of function (other mis-sense) mutations described which lead to severe FH • D374Y accounts for 2% of FH in UK • phenotype generally more severe than HeFH due to LDLR mutations • true homozygotes not described? • Statins increase PCSK9 as well as LDLR activity – counterproductive • Potential therapeutic target Tall, NEJM 2006;354:1310Horton et al. Trends BiochemSci2006;32:71Zhang et al. PNAS 2008;105:13045

6. Familial Hypercholesterolaemia Autosomal dominant inheritance Xanthomata Premature vascular disease Elevated low density lipoprotein levels Genetic defect at the LDL receptor

7. LDL-C Distribution and CAD Incidence Presence or Absence of PCSK9 46L Allele No PCSK946L Allele ( n=9223 ) Dallas Heart Study 30 20 10 0 50th Percentile 12 8 4 0 P=0.003 Frequency ( % ) 0 50 100 150 200 250 300 Coronary Heart Disease ( % ) PCSK946L Allele ( n=301 ) 30 20 10 0 No Yes 0 50 100 150 200 250 300 PCSK946L Plasma LDL Cholesterol in White Subjects ( mg/dL) COHEN et al. New Engl J Med 354:1264, 2006

8. LDL and Atherogenesis LDL Readily Enter the Artery Wall Where They May be Modified Vessel Lumen LDL Endothelium LDL Oxidation of Lipidsand ApoB Hydrolysis of Phosphatidylcholineto Lysophosphatidylcholine Aggregation Other Chemical Modifications Modified LDL Intima Modified LDL are Pro inflammatory Steinberg D et al. N Engl J Med 1989;320:915-924.

9. Macrophages and Foam Cells Express Growth Factors and Proteinases Vessel Lumen Monocyte LDL AdhesionMolecules Endothelium MCP-1 LDL Intima Modified LDL Cytokines Growth FactorsMetalloproteinases Cell ProliferationMatrix Degradation Macrophage Foam Cell Ross R. N Engl J Med 1999;340:115-126.

10. From Association to Cause Cholesterol and CHD strength dose response independent consistent plausible mechanism predictive reversible

11. Problems with Early Trials • Available drugs of limited efficacy, poorly tolerated or both. small differences between control and treated groups • Clinical trial science poorly developed. low end-point numbers poor data collection Lack of definitive outcomes: small reduction in CHD events (mainly non-fatal MI) no effect on overall mortality

12. Effects of Statins Plasma LDL LDL receptors Synthesis Statins Hepatic cholesterol Biliary cholesterol Intestinal pool Dietary cholesterol

13. Statins:The Evidence Base. Continuum of risk High-risk CHD patients (high cholesterol) 4S (simvastatin) Secondaryprevention 22.6 Majority of CHD patients (broad range of cholesterol levels) CARE (pravastatin) LIPID(pravastatin) HPS 12.9 Placebo MI rate per 100 subjects per 5 years 8.44 Patients at high risk of CHD (high cholesterol) 7.9 WOSCOPS (pravastatin) Primaryprevention Patients at low risk of CHD (low HDL-C) 2.8 AFCAPS/TexCAPS (lovastatin)

14. CHD Risk Despite Statin Therapy *Nonfatal myocardial infarction and coronary death; **Primary prevention trial; ***Secondary prevention trial

15. Early Primary and Secondary CVD Prevention Trials 4S-PI Secondary prevention 25 Primary prevention Lipid-PI 20 4S-Rx With CHD Event (%) 15 CARE-PI CARE-Rx Lipid-Rx 10 WOS-PI WOS-Rx ? ? AFCAPS-Rx 5 AFCAPS-PI 0 50 70 90 110 130 150 170 190 210 LDL-cholesterol (mg/dl)

16. PROVE-IT TrialIntensive and Moderate Lipid-Lowering after Acute Coronary Syndromes Population: 4162 patients within 10 days of acute coronary syndrome Treatment: Standard: Pravastatin 40mg/day mean LDL 2.46mmol/l Intensive:Atorvastatin 80mg/day mean LDL 1.6mmol/l Primary endpoint: Death , MI, unstable angina requiring hospitalisation, revascularisation and stroke Follow-up: 18-36 months (mean 24 months) Pravastatin 40mg 26.3% CVD Endpoints Atorvastatin 80mg 22.4% 16% reduction p=0.005 6 12 18 24 30 Months Cannon et al N Engl J Med April 8th 2004

17. Intensive Lipid Lowering with Atorvastatin in Patients with Stable Coronary DiseaseTreat to New Targets Trial (TNT) Population:10,001 patients with CHD: previous MI, angina with objective evidence of atherosclerotic CHD, coronary revascularization. Protocol:15464 CHD patients, LDL-C 130-250mg/dl (3.4-6.5mmol/l) 8 week run-in treatment with atorvastatin 10 mg/day. 5461 excluded. If LDL -C <130mg/dl randomised to either atorvastatin 10mg/dl or 80mg/day. Median follow-up 4.9yrs. Primary end point:Occurrence of first CVD event; CHD death, non-fatal, non procedure - related MI, resuscitation after cardiac arrest, fatal or non fatal stroke. . La Rosa et al NEJM March 2005

18. Treat to New Targets: Lipid Effects La Rosa et al NEJM March 2005

19. 0 1 2 3 4 5 6 Time (years) Primary Efficacy Outcome Measure: First Major Cardiovascular Event*TNT 0.15 HR = 0.78 (95% CI 0.69, 0.89) P=0.0002 HR 0.78 (95%CI 0.69, 0.89) p=0.0002 Atorvastatin 10 mg Atorvastatin 10mg Atorvastatin 80mg Atorvastatin 80 mg 0.10 Proportion of patients experiencing major cardiovascular event 0.05 Relative risk reduction 22% Relative risk reduction = 22% 0 *CHD death, nonfatal non-procedure-related MI, resuscitated cardiac arrest, fatal or nonfatal stroke

20. Statin Therapy in Secondary Prevention Trials Event Rates Against LDL-CNew Insights from TNT Statin trials show highly significant reductions in CHD events and stroke. The lower the LDL the better. Despite these dramatic effects there remains a significant residual risk. TNT has demonstrated that more intensive LDL lowering results in increased benefit      Events (%)        LDL cholesterol (mg/dl) La Rosa et al NEJM March 2005

21. Odds Ratio (95% CI) PROVE IT-TIMI 22 A-TO-Z TNT IDEAL OR, 0.84 95% CI, 0.77-0.91 p=0.00003 Total .66 1 1.34 INTENSIVE MODERATE Meta-AnalysisCardiovascular Outcomes Intensive vs Moderate Statin Therapy Population: 27,548 patients with stable CVD in TNT and IDEAL or acute coronary syndrome, PROVE-IT-TIMI-22, and A-to-Z Results: 16% odds reduction in coronary death or myocardial infarction, p<0.0001. No difference in total or non-cardiovascular mortality. Cannon et al J Am Coll Cardiol, 2006; 48: 438-445

22. Implications of Recent Trials Adult Treatment Panel III Guidelines High Risk CVD: Initiate statin therapy regardless of baseline LDL-C; LDL goal <70mg/dl (1.8mmol/L) Circulation 2004;110 227

23. Statins and Stroke Reduction A Meta-Analysis Across 26 trials, statins reduced stroke by 21% (P<.0001), with no evidence of heterogeneity between trials Odds Ratios (95% CI) Trials ASCOT-LLA ALLHAT-LLT PROSPER HPS GREACE MIRACL GISSI LIPID AFCAPS/TexCAPS Post-CABG CARE WOSCOPS 4S SMALL TRIALS OVERALL (95% confidence interval) 0.79 (0.73-0.85) 0.2 0.4 0.6 0.8 1.0 1.2 1.4 Statin better Control better Amarenco et al. Stroke. 2004;35:2902-2909.

24. Heart Protection StudyStroke Outcomes Simvastatin Placebo 12 10.4 10.3 10 * P<.05. 8 169 170 Incidence of stroke (%) 6 * 4.8 4 3.2 275 415 2 0 Prior cerebrovascular diseasen=3280 No prior cerebrovascular diseasen=17,256 HPS Collaborative Group. Lancet. 2004;363:757-767.

25. SPARCL: Does Robust Lipid Lowering Reduce the Occurrence of Stroke in Patients without CHD? Patient population Atorvastatin 80 mg 4200patients • Stroke/TIA 1-6 months prior • LDL 100-190 mg/dL (2.6-4.9 mmol/L) • Exclusions: • Age <18 years • Hx of CAD • Endarterectomy in prior month • Subarachnoid hemorrhage Double-blind placebo 5 years Primary endpoint: Time to first fatal or non fatal stroke Welch KMA, et al. 26th International Stroke Conference; February 14-16, 2001, Ft Lauderdale, Fl, USA.

26. High-Dose Atorvastatin after Stroke or Transient Ischaemic Attack The SPARCL Trial Population: 4731 patients with stroke or TIA one to six months before study entry. LDL-C 2.6-4.9mmol/l and no known CHD Design: Randomised, double-blind, placebo-controlled trial comparing atorvastatin 80mg/day to placebo. Median follow-up 4.9years. Primary endpoint: Time to first nonfatal or fatal stroke Results: 11.2% patients (265) on drug and 13.1% (311) on placebo had an event HR, 0.84 (95%CI 0.71-0.99) p=0.03. 5 year absolute risk reduction 2.2% % Patients Years SPARCL Investigators NEJM 2006; 355: 549-559