10/15/2012. Lessons Learned from Tim Russert: Investigating Residual Risk. Tim Russert: Residual CV Risk?

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1 Lessons Learned from Tim Russert: Investigating Residual Risk Peter H. Jones, MD, FACP Associate Professor Methodist DeBakey Heart and Vascular Center Baylor College of Medicine Houston, Texas Tim Russert: Residual CV Risk? April 28 Preclinical CAD at age 58, started on a statin LDL-C 67mg/dL, Triglycerides 3mg/dL, HDL 32mg/dL Performed well on stress test June 28 AMI at work, attempts to resuscitate fail Too little, too late? Grady D. A Search for Answers in Russert s Death. The New York Times. June 17, 28. Johnson A. NBC s Tim Russert Dies of a Heart Attack at 58. NBC News and msnbc.com. June 14, 28. So, What s New in Lipids since the ATP III Update in 24? AHA endorsed LDL-C < 7 mg/dl as a reasonable target in secondary prevention Defining level for HDL-C as a risk is based on gender (< 4 men, < 5 women) Primary prevention with statin (JUPITER) is beneficial, especially in women and age > 7 More data about CVD risk of MeS No data from statins in ESRD (dialysis), class 3/4 HF, dementia and aortic stenosis; some benefit in CKD Incremental benefit of fibrates combined with statin in high TG/low HDL subgroup (ACCORD Lipid) but no incremental benefit with niacin + statin (AIM HIGH) 1

2 What will the NCEP ATP IV look like in 211? More emphasis on the identification of primary CVD prevention patients for treatment? How to do this biomarkers? Subclinical atherosclerosis? Do apo B, nonhdl-c and/or particle number become targets along with LDL-C? Incremental benefit with optimal statin treatment (to LDL-C goal): Niacin (probably not) Fenofibrate (low HDL/high TG) Omega 3? What is the driver of incremental benefit? HDL-C Apo B or LDL-P Both? Peri-procedural statins? Emphasis on Stage 3 and 4 CKD for risk reduction with statins? The Reality of ATP IV: No expert opinion Evidence-based data only Determine risk level: Highest (CHD, PAD, Stroke) High risk primary prevention Highest risk: Post ACS AT 8 mg (PROVE IT) Stable CHD - SM 4 (HPS) PRA 4 (LIPID, CARE) AT 8 (TNT, IDEAL, SPARCL) The Reality of ATP IV: No expert opinion Evidence-based data only High risk primary prevention: PRA 4 (WOSCOPS) SM 4 (HPS) RSV 2 (JUPITER) LOV 2-4 (AFCAPS/TexCAPS) AT 1 (ASCOT LLA, CARDS) 2

3 CTTC Group Meta-analysis of 17, Subjects: Event Reduction per 4 mg/dl LDL-C Decrease Lancet 21: 376:167 Patient Populations of Primary Prevention Statin Trials CVD=cardiovascular disease; CHD=coronary heart disease; Total C=total cholesterol; LDL C=low density lipoprotein cholesterol; HDL C=high density lipoprotein cholesterol; hscrp=high sensitivity C reactive protein; RSV=rosuvastatin; PRA=pravastatin; LOV=lovastatin n=5742 Shepherd J et al. N Engl J Med. 1995;333; Ridker PM et al. N Engl J Med. 21;344: Ridker PM et al. Am J Cardiol. 27;1:

4 JUPITER Primary Trial Endpoint: MI, Stroke, UA/Revascularization, CV Death Incidence.6.8 HR.56 P <.1 Number Needed to Treat (NNT 5 ) = 25 Placebo 251 / % Cumulative Rosuvastatin 2 mg 142 / 891 Number at Risk Follow-up (years) Rosuvastatin 8,91 8,631 8,412 6,54 3,893 1,958 1, Placebo 8,91 8,621 8,353 6,58 3,872 1,963 1, JUPITER: Primary End Point in Prespecified Subgroups HR (95% CI) Rosuvastatin Superior Rosuvastatin Inferior 11 Primary and other composite end points as exploratory analysis of 5695 subjects > 7 yr in JUPITER Ann Intern Med 21;152:

5 Time to Occurrence of MACE in JUPITER According to Achieved LDL-C JACC 211;57:1666 ASCOT LLA incidence of all-cause mortality and non-cardiovascular mortality over 11 year follow up Eur Heart J 211; online Aug 28 Residual Cardiovascular Risk in Placebo-Controlled Statin Trials 4 Patients Experiencing Major CH HD Events, % Placebo Statin S 1 LIPID 2 CARE 3 HPS 4 WOSCOPS 5 AFCAPS/ TexCAPS 6 N , LDL -35% -25% -28% -29% -26% -25% Secondary High Risk Primary 1 4S Group. Lancet. 1994;344(8934): LIPID Study Group. N Engl J Med. 1998;339(19): Sacks FM, et al. N Engl J Med. 1996;335(14): HPS Collaborative Group. Lancet. 22;36(9326): Shepherd J, et al. N Engl J Med. 1995;333(2): Downs JR, et al. JAMA. 1998;279(2):

6 Residual Cardiovascular Disease Risk in Patients With Intensive Statin Therapy 4 Patients Experiencing Major CV VD Events, % Standard statin therapy High-dose statin therapy PROVE IT-TIMI 22 1 IDEAL 2 TNT 3 N ,1 LDL-C,* mg/dl *Mean or median LDL-C after treatment 1 Cannon CP, et al. N Engl J Med. 24;35(15): Pedersen TR, et al. JAMA. 25;294(19): LaRosa JC, et al. N Engl J Med. 25;352(14): CVD Events Across On-Treatment HDL-C Quintiles: Treating to New Targets (TNT) Study Patients With LDL-C 7 mg/dl on Statin a,b ence of Major vents, % 5-Year Incide CVD Ev HDL-C Quintiles, a mg/dl Hazard Ratio vs Q1* Q1 <37 Q2 Q3 Q4 Q5 37 to <42 42 to <47 47 to < a On-treatment level (3 months statin therapy); n=2661 b Mean LDL-C=58 mg/dl; mean TG=126 mg/dl *P=.3 for differences among quintiles of HDL-C Barter P, et al. New Engl J Med. 27;357(13): Copyright 27 Massachusetts Medical Society. Incidence per 1 per son-years Primary Endpoint Incidence Rates in JUPITER According to On-Treatment HDL-C and apoa-i Quartiles A B Placebo Rosuvastatin 2 mg Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Quartile of on-treatment HDL cholesterol Quartile of on-treatment apoa-i Ridker PM, et al. Lancet. 21;376(9738): Copyright 21 Elsevier Ltd. 6

7 Associations between HDL-C levels and cardiovascular outcomes: Statin treatment does not alter inverse relationship Black circles indicate patients who are receiving statin interventions, and green circles indicate patients who are receiving a nonstatin control. Jafri H et al. Ann Intern Med 21;153:8-88 Triglyceride Level Is Significant CVD Risk Factor: Meta-analysis of 29 Studies Groups CHD Cases Duration of follow-up 1 years 592 <1 years 4256 Gender Male 7728 Female 1994 Fasting status Fasting 7484 Nonfasting 2674 Adjusted for HDL Yes 4469 No 5689 Overall CHD Risk Ratio a Decreased Risk 1 CHD Risk Ratio (95% CI) Increased Risk N=262, ( ) a Individuals in top vs bottom third of usual log-triglyceride values, adjusted for at least age, sex, smoking status, lipid concentrations, and blood pressure (most) 2 Adapted from Sarwar N, et al. Circulation. 27;115(4): What Is Non HDL-C? Triglyceride Cholesterol All atherogenic lipoproteins HDL LDL IDL VLDL Chylomicron remnant APO A-1 APO B APO B APO B APO B 48 non-hdl non HDL-C = Total cholesterol HDL-C 7

8 Elevated Triglycerides Are Metabolically Related to Small LDL and HDL Particles Visceral adiposopathy TG Renal Small, clearance dense HDL HDL Cholesterol FFA TG CETP ester VLDL Lipases TG Fatty liver Cholesterol ester CETP LDL TG Lipases TG Small, dense LDL CETP=cholesteryl ester transfer protein; FFA=free fatty acid Adapted from Bays H, et al. Expert Opin Pharmacother. 23;4(11): Non HDL-C Is Superior to LDL-C in Predicting CHD Risk The Framingham Study A strong positive and graded association between non HDL-C and risk for CHD occurred within every level of LDL-C Non HDL-C is a stronger predictor of CHD risk than LDL-C Risk Relative CHD Liu J, et al. Am J Cardiol. 26;98(1): Copyright 26 Elsevier Inc < LDL-C, mg/dl <16 Non HDL-C, mg/dl Elevated Triglycerides Are Associated With Increased Small LDL Particle Number ApoB Cholesterol ester Fewer Particles More Particles LDL= 13 mg/dl More ApoB Correlates with: TC 198 mg/dl LDL-C 13 mg/dl TG 9 mg/dl HDL-C 5 mg/dl Non HDL-C 148 mg/dl Correlates with: TC 21 mg/dl LDL-C 13 mg/dl TG 25 mg/dl HDL-C 3 mg/dl Non HDL-C 18 mg/dl Data from Otvos JD, et al. Am J Cardiol. 22;9(8A):22i-29i. 8

9 LDL-C, LDL-P and Apoprotein B in Metabolic Syndrome: Framingham Heart Study Am J Cardiol 28:12(suppl); 1K-34K LDL Particle Number Distribution in T2DM Subjects Percent of Subjects th 2 th 5 th 8 th percentile 1% 24% 43% 21% 11% (n=19) (n=364) (n=631) (n=37) (n=163) LDL-C 7-99 mg/dl (n=1484) (nmol/l) 16% 43% 3% 9% 2% (n=147) (n=377) (n=26) (n=76) (n=15) 15 Percent of Subjects 1 5 4% LDL-C <7 mg/dl (n=871) (nmol/l) Cromwell WC, Otvos JD. Am J Cardiol. 26;98(12): Copyright 26 Elsevier Inc. ADA/ACC 28 Consensus Statement: Treatment Goals in Patients With Cardiometabolic Risk and Lipoprotein Abnormalities Highest-risk patient Known CVD Diabetes plus 1 additional major CVD risk factor a High-risk patients No diabetes or known CVD but 2 major CVD risk factors a Diabetes but no other major CVD risk factors a Goals LDL-C Non-HDL-C ApoB <7 mg/dl <1 mg/dl <8 mg/dl <1 mg/dl <13 mg/dl <9 mg/dl In individuals on statin therapy who continue to have low HDL-C or elevated non HDL-C, especially if ApoB levels remain elevated, combination therapy is recommended. The preferred agent to use in combination with a statin is nicotinic acid a Major risk factors beyond dyslipidemia include smoking, hypertension, and family history of premature CHD. Brunzell JD, et al. Diabetes Care. 28;31(4): Copyright 28 American Diabetes Association. 9

10 Effects of Statins on LDL-C and LDL-P Sniderman. J Clin Lipidol 28;2:36-42 Treatments that Alter Cholesterol Content of LDL Change LDL-C and LDL-P Differentially 1 Cholesterol per particle decreases with: Statins Statin + Ezetimibe or Bile Acid Sequestrates Estrogen Replacement Therapy Anti-retrovirals (some) Low fat, High carb diet Therapy LDL-C More Than LDL-P Cholesterol per particle increases with: Fibrates Niacin Pioglitazone Omega 3 FAs Exercise Mediterranean and low carb diet Therapy LDL-P More Than LDL-C Little Change in Cholesterol per Particle with: Bile Acid Sequestrate or Ezetimibe Monotherapy Similar Change in LDL-C and LDL-P Cromwell WC. In: Clinical Challenges in Lipid Disorders.Toth PP, Sica DA, editors. Oxford: Clinical Publishing; 28.p What is the Evidence that adding a drug to statins can provide incremental outcomes benefit? 1

11 ACCORD: Baseline Characteristics Characteristic Mean or % Characteristic Mean or % Age (yrs) 62 Total Cholesterol (mg/dl) 175 Women % 31 LDL-C (mg/dl) 11 Race / Ethnicity HDL-C (mg/dl) 38 White % 68 Triglyceride (mg/dl)* 162 Black % 15 Blood pressure (mm Hg) 134/74 Hispanic % 7 Serum creatinine (mg/dl).9 Secondary prevent % 37 Current smoking % 15 DM duration (yrs) * 9 On a statin % 6 A1c (%) * 8.3 On another LLA % 8 BMI (kg/m 2 ) 32 On Insulin % 33 Ginsberg, H N, et al. New Engl J Med. Epub ahead of print. March 14, 21. * Median values ACCORD Outcomes Ginsberg, H N, et al. New Engl J Med. Epub ahead of print. March 14, 21. ACCORD: Primary Outcome By Treatment Group and Baseline Subgroups Subgroup Fenofibrate Placebo Hazard ratio (95% CI) P value for interaction % of events (no. in group) (2,765) 11.3 (2,753) Overall 1.5 LDL cholesterol 84 mg/dl 9.4 (938) 12.2 (891) mg/dl 112 mg/dl 9.9 (934) 12.4 (877) 11.2 (922) 1.6 (927).12 HDL cholesterol 34 mg/dl 12.2 (964) 15.6 (96) 35-4 mg/dl 41 mg/dl 1.1 (86) 9.1 (925) 9.5 (866) 9. (968).24 Triglycerides 128 mg/dl 9.9 (891) 11.3 (939) mg/dl 24 mg/dl 1.5 (924) 11.1 (934) 9.9 (913) 12.8 (888).64 Triglyceride-HDL cholesterol combination TG 24 mg/dl + HDL-C 34 mg/dl 12.4 (485) 17.3 (456) All others 1.1 (2264) 1.1 (2284).6 Glycated hemoglobin 8.% 8.7 (1,324) 1.6 (1,335) 8.1% 12.2 (1,435) 11.9 (1,415) Adapted from Ginsberg HN, et al. N Engl J Med. 21;362(17): Copyright 21 Massachusetts Medical Society. Fenofibrate better Placebo better 11

12 Atherothrombosis Intervention in Metabolic Syndrome with low HDL/high trigylcerides: Impact on Global Health (AIM HIGH) Results 3414 subjects with CVD; age 64; 34% with T2DM and 71% with MeS; 94% had prior statin use Randomized to simvastatin to reduce LDL-C < 8 mg/dl, and then to niacin ER 2 gm in 1718 or PBO in 1696 Baseline lipids: LDL-C 71 TG 161 HDL 35 nonhdl-c 16 apo B 81 AIM HIGH: HDL-C at Baseline & Follow-up 55 5 Combination Therapy Monotherapy L mg/dl P <.1 * * * 3 25 Baseline Year 1 Year 2 Year 3 AIM HIGH: LDL-C at Baseline & Follow-up 8 75 Combination Therapy Monotherapy 7 L mg/dl 65 6 * P < Baseline Year 1 Year 2 Year 3 12

13 AIM HIGH: Primary Outcome Cumulative % with Primary Outcome Monotherapy 1696 Combination Therapy 1718 HR 1.2, 95% CI.87, 1,21 Log-rank P value=.79 Combination Therapy Monotherapy 16.4% N at risk Time (years) % Trials with Niacin and Statin Combination Trial Therapy AIM-HIGH 1 Simvastatin + Niacin ER End Point N Patients Dates CVD o prevention HDL and TG No benefit HPS 2- Simvastatin + THRIVE 2,3 Niacin ER + laropiprant CVD 25 2 o prevention 7 DM 7-12 (5 yr) Devine PJ, et al. Cardiovasc Drugs Ther. 27;21: So, What did the EAS/ESC do with their guidelines in 211? 13

14 ESC/EAS Guidelines for Managing Dyslipidemia Risk based approach (risk factors and SCORE) A. Very high risk: Documented CVD (invasive and noninvasive) MI, stroke, CABG, ACS, PAD, carotid plaque (US) Type 2 DM (CHD, CKD) Type 1 DM with microalbumin, end organ damage CKD SCORE 1% 1 yr risk for fatal CVD (3 X higher for fatal and nonfatal events) B. High risk: A. markedly elevated single RF (severe HTN, HeFH) B. Type DM at any age C. SCORE 5 and < 1% C. Moderate risk: SCORE 1 to < 5%; risk can be modified by FHx, HDL-C, Lp(a), apo B and MeS Atherosclerosis 211: 217: S1-S44 Eur Heart J 211: 32: ESC/EAS Guidelines for Managing Dyslipidemia Lipid targets: Primary - LDL-C NonHDL-C and apo B as alternative targets in mixed dyslipidemia, T2 DM, MeS, CKD No targets for HDL-C and TG Lp(a) in premature CHD or FHx of premature CHD Very high risk: LDL-C < 7 mg/dl (< 1.8 mmol/l) or 5% reduction from baseline: apo B < 8 mg/dl, nonhdl-c < 1 mg/dl High risk: LDL-C < 1 mg/dl (< 2.5 mmol/l), apo B < 1 mg/dl, nonhdl-c < 13 mg/dl Moderate risk: LDL-C < 115 mg/dl (< 3 mmol/l) Atherosclerosis 211: 217: S1-S44 Eur Heart J 211: 32: ESC/EAS Guidelines for Managing Dyslipidemias Tests not recommended for routine use: Lipoprotein particle size Lp(a), except in premature CHD or FHx Genotyping hs-crp as a target of treatment Special populations: 1. Autoimmune chronic inflammatory conditions (RA, SLE, psoriaisis) are at high risk 2. Genetic dyslipidemias: FCHL (1:1) : apo B > 12 mg/dl + TG > 135 mg/dl HeFH (1:5) 3. PCI: load with high dose statin before procedure 4. Elderly (> 7 yr): consider for primary prevention 14

15 Summary CTTC meta-analysis confirms an approx 2% reduction in MACE and 1% reduction in total mortality for 1 mmol/l in LDL-C, with no lower limit. Residual CVD risk remains after treatment with statins (including intensive statin therapy) to reduce LDL-C Low HDL-C probably contributes to residual risk for CVD, even if LDL-C is at goal Elevated triglycerides are a marker for increased remnant lipoproteins that can be atherogenic as well as for increased particle numbers, especially in individuals with insulin resistance Non HDL-C captures these remnant particles and is a better predictor of CVD risk than LDL-C, and is equal to apo B Summary (Continued) After LDL-C, guidelines recommend targeting non HDL-C (possibly Apo B) to optimize risk reduction and suggest niacin, fibrates and/or intestinally-acting drugs (colesevelam, ezetimibe) added to statins Identification of appropriate primary prevention candidates for statin Rx is important because therapy will benefit women and age > 7 15