Case Presentation. Rafael Bitzur The Bert W Strassburger Lipid Center Sheba Medical Center Tel Hashomer

Case Presentation Rafael Bitzur The Bert W Strassburger Lipid Center Sheba Medical Center Tel Hashomer

Case Presentation 50 YO man NSTEMI treated with PCI 1 month ago Medical History: Obesity: BMI 32, waist circumference 110 cm HTN: well controlled with ACE-I and β-blocker IFG (fasting glucose 108 mg/dl, HbA1c 6.3%) Dyslipidemia treated with simvastatin 20 mg

Case Presentation Lipid profile TC 188 mg/dl LDL 90 mg/dl HDL 34 mg/dl TG 320 mg/dl CK, GOT, GPT normal. No myalgia.

Case Presentation Treatment options (+TLC) Atorvastatin 80 mg instead of simva Add fibrate o` l e dyrz dn?jlz Add niacin ER Add Omega 3

Risk of death in patients with CHD is greatest early after an ACS Deaths/100 patients/month 25 20 15 10 Acute MI Unstable angina Stable angina 5 0 0 1 2 3 4 5 6 Time (months after hospital admission) Braunwald (1996)

MIRACL: Primary efficacy measure Cumulative incidence (%) 15 Placebo Atorvastatin 17.4% 14.8% 10 5 0 Time to first occurrence of composite endpoint of: Death (any cause) Non-fatal MI Resuscitated cardiac arrest Worsening angina with new objective evidence and urgent rehospitalisation RRR = 16% p=0.048 95% CI = 0.701 0.999 0.999 NNT = 38 0 4 8 12 16 Time since randomisation (weeks) JAMA. 2001;285:1711

PROVE IT-TIMI TIMI 22: Early benefit with intensive lipid lowering N = 4162 with ACS 16% RRR at 2 years 30 (p = 0.005) Death or major CV event (%) 20 10 40 mg Pravastatin P = 0.03 at 4 mos 80 mg Atorvastatin NNT = 25 0 0 3 6 9 12 15 18 21 24 27 30 Follow-up (months) Ray KK and Cannon CP Am J Cardiol. 2005;96(suppl):54F-60F. Adapted from Cannon CP et al. N Engl J Med. 2004;350:1495-504.

A to Z: Primary Endpoint Composite CV Death, MI, ACS or Stroke KM Rate (%) 20 15 10 5 HR 0.89 CI 0.76 1.04 652 primary events p = 0.14 P/S20 Rate = 16.7% S40/80 Rate = 14.4% 0 0 1 4 8 12 16 20 24 Month from Randomization JAMA. 2004;292:1307

CRP - EFFECT ONLY IN ACS? LDL-C, CRP, and Early Clinical Benefit in A to Z, MIRACL, and PROVE IT TIMI TIMI 22 A-to-Z MIRACL PROVE IT Number of patients randomized 4497 3086 4162 Early* LDL achieved on treatment, mg/dl 62 72 62 Early* LDL cholesterol differential, mg/dl 62 63 33 CRP differential, % 0/17 34 38 Early event reduction, % 0* 16* 18 * Measured 120 days after randomization. Measured 90 days after randomization. Adapted from Nissen. JAMA. 2004;292:1365, with permission.

High-Dose Statin Treatment Rreduces Ox-LDL Markers MIRACL study subgroup analysis, N = 2341 with ACS, atorvastatin 80 mg for 16 weeks ApoB-100 Atorvastatin Placebo Total apob-oxpl Atorvastatin Placebo Total apob-ic IgG Atorvastatin Placebo Total apob-ic IgM Atorvastatin Placebo Mean 95% CI 33.0 34.2, 31.8 5.8 4.6, 7.0 29.7 31.5, 28.0 0.2 2.3, 1.9 29.5 31.9, 27.0 2.1 1.1, 5.4 25.7 28.1, 23.3 13.2 9.3, 17.3 OxPL = oxidized phospholipids IC-IgG, -IgM = immune complexes with IgG and IgM, respectively Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering 40 20 0 20 40 % change Tsimikas S et al. Circulation. 2004;110:1406-12.

Case Presentation Treatment options Atorvastatin 80 mg instead of simva Add fibrate Add niacin ER Omega 3

TG Level Is Significant CVD Risk Factor: Meta-Analysis of 29 Studies Groups CHD Cases Duration of follow-up 10 years 5902 <10 years 4256 Sex Male 7728 Female 1994 Fasting status Fasting 7484 Nonfasting 2674 Adjusted for HDL Yes 4469 No 5689 *Individuals in top vs. bottom third of usual log-tg values; adjusted for at least age, sex, smoking status, and lipid concentrations; also adjusted for BP (in most studies). 1 N = 262,525 1.72 (1.56-1.90) 2 CHD Risk Ratio* (95% CI) Circulation. 2007;115:450-458

TG Level Remains CVD Risk Factor in Patients On Statins: TNT Adjusted HRs of death, MI, and recurrent ACS between 30 days and 2 years of follow-up* 1.2 1 0.8 0.6 0.4 TG<150 mg/dl TG>150 mg/dl 0.2 0 LDL<70 mg/dl LDL>70 mg/dl *Adjusted for age, gender, low HDL-C, smoking, HTN, obesity, DM, prior statin therapy, prior ACS, PVD, treatment effect JACC 2008;51:724 30

Diet for Metabolic Dyslipidemia NEJM 2008;359:229-41

Outcomes in Fibrate Trials: Diabetes / Metabolic Syndrome Trial N Control Drug Primary Prevention Rel. RR HHS* 292 13.0% 3.9% 71%.005 Secondary Prevention Major CVD Event Rate BIP 1470 18.4% 14.1% 25%.03 VA-HIT 769 29.4% 21.2% 32%.004 Rel. RR indicates relative risk reduction *Patients with triglycerides >204 mg/dl and an LDL/HDL >5 Patients with the metabolic syndrome; baseline HDL-C, 33 mg/dl; triglycerides, 170 mg/dl Patients with diabetes; baseline HDL-C, 31 mg/dl; triglycerides, 164 mg/dl * Circulation. 1992;85:37-45. Arch Intern Med. 2005;165:1154-1160. Arch Intern Med. 2002;162:2597-2604. P

Fibrate Trials: Diabetic or Metabolic Syndrome Subanalyses % 0-10 -20-30 -40-50 -60-70 -80 HHS* -71 BIP** -25 RRR in MACE VA- HIT*** -32 *Patients with triglycerides >204 mg/dl and an LDL/HDL >5 * * Patients with the metabolic syndrome; baseline HDL-C, 33 mg/dl; triglycerides, 170 mg/dl * * * Patients with diabetes; baseline HDL-C, 31 mg/dl; triglycerides, 164 mg/dl

FIELD: Primary End Point Nonfatal MI, or CHD Death 8 11% Reduction P=.16 Event Rate, % 7 6 5 4 3 2 1 0 6% Placebo 5% Fenofibrate Lancet. 2005;366:1849-1861

ACCORD: Fibrates: What s s in Store? Fenofibrate+statin vs. statin in 9750 patients with DM2 Due 2011

Case Presentation Treatment options Atorvastatin 80 mg instead of simva Add fibrate Add niacin ER Omega 3

Change from Baseline (%) Lipid Effects of Niacin Extended- Release 30 20 10 0-10 -20-30 -40-50 -5 10-3 16-14 -8-12 Most potent agent for HDL: 20%+; nonlinear Favorable effects on LDL-particle density LDL (linear), TG, and Lp(a) 21-21 -13-17 24-16 -32 30 29-22 -21 500 1000 1500 2000 2500 3000 mg -25-39 -30-44 -26 HDL-C LDL-C Lp(a) TG Am J Cardiol 1998;82:74U-81U.

Coronary Drug Project Long-Term Mortality Benefit of Niacin in Post-MI Patients Survival (%) 100 90 80 70 60 50 40 30 20 10 15 years: 4% absolute reduction in mortality NNT = 25 Placebo Niacin P = 0.0012 0 2 4 6 8 10 12 14 16 Years of follow-up J Am Coll Cardiol 1986;8:1245 1255

NIACIN: Clinical Events ARBITER 2 HATS Patients with Event (%) 12 10 8 6 4 2 0 9.6 Statin + Placebo RR = 0.4 P =.20 3.8 Statin + Niacin ER % Free of Event 100 90 80 70 0 Simvastatin Niacin All placebos RR = 0.10 P =.03 97% 0 1 2 3 76% YEARS Composite End Point (MI, UAP, CVA, Sudden Death, Coronary or peripheral revascularization) Circulation 2004;110:3512-3517. Composite End Point (Death from Coronary Causes, Nonfatal MI, Stroke, or Revascularization for Worsening Ischemia) NEJM 2001;345:1583-1592

ARBITER-HALTS 6 Study 363 CHD/equivalent patients with low HDL-C (<50 mg/dl men, <55 mg/dl women) All on statin with LDL-C<100 mg/dl Primary end point: change in cimt after 14 months The trial was terminated early, on the basis of efficacy N Engl J Med 2009;361.

ARBITER-HALTS 6 study Lipids with niacin (mg/dl) LDL-C 83 73 HDL-C 43 50 N Engl J Med 2009;361.

ARBITER-HALTS 6 Study N Engl J Med 2009;361.

Oxford Niaspan Study 71 statin-treated patients with HDL-C<40 mg/dl and DM2 + CHD or carotid/peripheral atherosclerosis. 2 g daily modified-release NA vs. placebo Primary end point: change in carotid artery wall area quantified by MRI, after 1 year. J Am Coll Cardiol 2009;54:1787 94

Oxford Niaspan Study Lipids in niacin group LDL-C 85 69 mg/dl (-19%) HDL-C 39 48 mg/dl (+23%) J Am Coll Cardiol 2009;54:1787 94

Oxford Niaspan Study Inverse relationship between the HDL-C and wall area, and no relationship between the LDL-C and wall area. Increases in HDL-C may be beneficial Flow-mediated dilation of the brachial artery showed a favorable trend with niacin. Aortic distensibility and glyceryl-trinitrate-mediated brachial reactivity did not change significantly with niacin. J Am Coll Cardiol 2009;54:1787 94

NIA Plaque study 145 patients with clinically evident atherosclerosis, treated with a statin to ATP III LDL-C targets. Randomized to 1500 mg extended-release niacin or placebo. Both arms improved No significant difference between the two treatment arms in MRI outcomes, including carotid arterial wall volume and measurements of the lipid core. Sibley et al. AHA 2009

NIA Plaque: Change in lipid parameters Lipid measure (mg/dl) Statin + placebo, baseline Statin + placebo, 18 mo Statin+ER niacin, baseline Statin+ER niacin, 18 mo p (between groups) LDL-C 86 77 88 67 0.03 HDL-C 55 49 55 58 <0.001 TG 123 93 115 84 0.02 Sibley et al. AHA 2009

Niacin: What s in Store? HPS2-THRIVE: Niacin and a blocker of PG D2 on top of statin therapy in 20,000 patients AIM-HIGH: Simvastatin+Niaspan vs. Simvastatin in 3300 patients with CVD, low HDL and high TG Due 2012

Case Presentation Treatment options Atorvastatin 80 mg instead of simva Add fibrate Add niacin ER Omega 3

Omega-3 3 and Lipids in Patients with TG >500 mg/dl Baseline (mg/dl) 60% 40% 20% 0% -20% TG 816 P<0.0001 6.7 HDL-C 22 P=0.0002 0.0 9.1 Non- HDL-C 27 P=0.0015-3.6-13.8 Chol 296 P=0.0059-1.7-0.9-9.7 VLDL-C 175 P<0.0001 LDL-C 89 P<0.0001 45.0-4.8-40% -60% -45.0 Placebo -42.0 Omega-3 Acid Ethyl Esters (4 g/day) Pooled analysis: Harris WS et al. J Cardiovasc Risk 1997;4:385-391. Pownall HJ et al. Atherosclerosis 1999;143:285-297.

Omega-3 3 and Lipids in Patients with TG >500 mg/dl Baseline (mg/dl) 60% 40% 20% 0% -20% TG 816 P<0.0001 6.7 HDL-C 22 P=0.0002 0.0 9.1 Non- HDL-C 27 P=0.0015-3.6-13.8 Chol 296 P=0.0059-1.7-0.9-9.7 VLDL-C 175 P<0.0001 LDL-C 89 P<0.0001 45.0-4.8-40% -60% -45.0 Placebo -42.0 Omega-3 Acid Ethyl Esters (4 g/day) Pooled analysis: Harris WS et al. J Cardiovasc Risk 1997;4:385-391. Pownall HJ et al. Atherosclerosis 1999;143:285-297.

Dietary Supplementation With Omega-3 3 Fatty Acids After MI GISSI-Prevenzione Event Rate (%) 20 15 10 5 15% Reduction P =.023 20% Reduction P =.008 Placebo (n = 2828) Omega-3 fatty acids 1 g (n = 2836) 0 Death/ Nonfatal MI/ Nonfatal Stroke CVD Death/ Nonfatal MI/ Nonfatal Stroke Lancet. 1999;354:447-455.

GISSI-Prevenzione: Effects of EPA+DHA on Serum Lipids No Difference 5% Difference mg/dl 50 48 46 44 42 40 38 HDL Cholesterol n-3 Control 1 2 3 4 5 6 Months mg/dl 170 165 160 155 150 145 140 Triglycerides n-3 Control 1 2 3 4 5 6 Months Circulation 2002;105:1897-1903.

Case Presentation Treatment options Atorvastatin 80 mg instead of simva Add fibrate Add niacin ER Omega 3