Current Cholesterol Guidelines and Treatment of Residual Risk J. Peter Oettgen, MD Associate Professor of Medicine Harvard Medical School Director, Preventive Cardiology Beth Israel Deaconess Medical Center Boston, MA
NONE Disclosures
Learning Objectives Review the epidemiology and pathogenesis of atherosclerotic cardiovascular disease Review the management of hypercholesterolemia based on the 2013 guidelines, new clinical trial results, new cholesterol lowering agents Assess cardiovascular risk using the 2013 guidelines
Epidemiology of Cardiovascular Disease Prevalence of Coronary Heart Disease - 13,000,000 Myocardial Infarction - 7,100,000 Congestive Heart Failure - 4,900,000 Stroke - 5,400,000 Mortality CHD (2002) Total - 494,382 Males - 252,760 Females - 241,622 Cost of CHD (2002) - $142.1 Billion dollars AHA. 2010 Heart and Stroke Statistical Update
The Anatomy of the Vulnerable Atherosclerotic Plaque Lumen Plaque
Which Coronary Lesions Lead to Myocardial Infarctions? < 50% 68% > 70% 14% 50%-70% 18% > 70% 50% -70% < 50% Falk et al. Circulation. 1992:657-671.
Angiographically Inapparent Atheroma Nissen SE et al. In: Topol EJ, ed. Textbook of Interventional Cardiology. WB Saunders, 1994:207.
C P O G I R Y T H
Histology of Plaque
Characteristics of Plaques Prone to Rupture VULNERABLE STABLE
Early* TC Levels Predict Later CHD CHD Events/1000 Men 40 30 20 10 Results After 40 Years 6.9 11.5 17.5 35.2 *Avg. age 22 0 118-172 173-189 190-208 209-315 TC (mg/dl) Klag MJ et al. N Engl J Med. 1993;328:313-318.
Lowering Serum Cholesterol: A Primary Goal of Risk Reduction 96 million Americans: TC>200 mg/dl 38 million Americans: TC>240 mg/dl Multiple trials demonstrating benefit of cholesterol lowering for both primary and secondary prevention
Framingham: Many CHD Patients Have TC Below or Near Average Proportion of Group (%) 40 30 20 10 Non-CHD (n = 1378) CHD (n = 193) 0 150 200 250 300 350 TC (mg/dl) Castelli WP. Am J Med. 1984;76:4-12.
NCEP ATP III: Modifying the CHD Risk Continuum Primary Prevention Identify High Risk Patients Secondary Prevention, CHD Risk Equivalents Diabetes Noncoronary atherosclerosis Peripheral arterial disease Abdominal aortic aneurysm Carotid artery disease Multiple risk factors that confer > 20% 10-year risk of CHD NCEP ATP III. JAMA. 2001;285:2486-2497.
2013 Cholesterol Treatment Guidelines NJ Stone et al., Circulation Nov 12, 2013
What s new in the 2013 guidelines? Focus on ASCVD Risk reduction: 4 statin benefit groups A new perspective on LDL/ non-hdl targets Global risk assessment for primary prevention Safety recommendations Role of biomarkers and noninvasive tests NJ Stone et al., Circulation Nov 12, 2013
4 Major statin benefit groups Patients with clinical ASCVD Patients with LDL cholesterol 190 mg/dl Diabetes, age 40-75, no ASCVD, LDL > 70mg/dl 10-year ASCVD risk 7.5% NJ Stone et al., Circulation Nov 12, 2013
ASCVD
A new perspective on LDL/ non-hdl targets More focus on high versus moderate intensity therapy and not a particular target LDL More emphasis on identifying patients likely to benefit most Less focus on other lipid lowering agents because clinical benefit less clear NJ Stone et al., Circulation Nov 12, 2013
High Intensity Intensity of Statin Therapy Moderate Intensity Daily dose lowers LDL Daily dose lowers LDL by 50% by 30-50% Atorvastatin 40-80mg Crestor 20-40 mg A variety of statins and doses NJ Stone et al., Circulation Nov 12, 2013
LDL 190 mg/dl
Diabetes Mellitus
Risk Assessment
Pooled Cohort Equations Based on data pooled from 4 NHLBI-sponsored cohort studies including: Atherosclerosis Risk in Communities (ARIC) Cardiovascular Health Study (CHS) Coronary artery risk development in young adults (CARDIA) Framingham Heart Study (FHS) At least 10-year follow-up in each study More ethnically diverse
Risk Calculation NJ Stone et al., Circulation Nov 12, 2013
Risk Calculation NJ Stone et al., Circulation Nov 12, 2013
Periodic Reassessment of Risk
Risk Calculation NJ Stone et al., Circulation Nov 12, 2013
Risk Calculation NJ Stone et al., Circulation Nov 12, 2013
Risk Calculation NJ Stone et al., Circulation Nov 12, 2013
Potential benefits of calculation Gives you 10-year risk and what it would be with optimal risk factors Gives you lifetime risk with current risks and optimal risks.
Potential Limitations of Risk Calculation Lifetime risk may be high and 10 year risk low; does this mean not to treat? Family history is not accounted for LDL not calculated or measured Overestimation of risk in low-risk populations NJ Stone et al., Circulation Nov 12, 2013
Adverse events estimates 0.1 excess cases of diabetes per 100 statin-treated individuals treated per year 0.3 excess cases of diabetes per 100 high dose statin-treated individuals treated per year Myopathy 0.01 cases per 100, and 0.01 excess cases of hemorhagic stroke.
Statins and Vitamin D Low serum vitamin D levels (<32 ng/ml) are associated with reversible myositis myalgias in statin-treated patients Myalgias resolved in 92% of vitamin D deficient patients with statin associated symptoms Ahmed W, et al. Transl Res. 2009;153(1):11-16.
Evidence Gaps and Future Studies Adults > 75 years old Randomized trials comparing fixed dose approach to LDL target Does addition of non-statin to reach lower LDL targets add additional benefit that is greater than any added risk A better understanding of the diabetes associated with statin use
Recommendations for Optimizing, and Addressing Insufficient Response to Statin Therapy.
Recommendations for Optimizing, and Addressing Insufficient Response to Statin Therapy.
Ezetimibe
IMPROVE-IT
IMPROVE-IT
IMPROVE-IT
IMPROVE-IT
Use of ezetimibe based on the guidelines Use high intensity statin and lifestyle to achieve lowest LDL level that a safe and tolerated regimen can provide. If high intensity statin not tolerated or response to therapy not adequate, the data support using a moderate intensity statin to which a non-statin such as ezetemibe can be added These data do not address to use of ezetemibe in patients with low risk primary prevention
PCSK9 INHIBITION
PCSK9 Regulates the levels of LDLRs by Targeting of Lysosomal Degradation 1. Qian YW, et al. J Lipid Res. 2007;48(7):1488-1498; 2. Horton JD, et al. J Lipid Res. 2009;50:S172-S177; 3. Zhang DW, et al. J Biol Chem. 2007;282(55):18602-18612.
Recycling of LDLRs Enables Efficient Clearance of LDL-C Particles 1. Brown MS, Goldstein JL. Proc Natl Acad Sci U S A. 1979;76(7):3330-3337; 2. Steinberg D, Witztum JL. Proc Natl Acad Sci U S A. 2009;106(24):9546-9547; 3. Goldstein JL, Brown MS. Arterioscler Thromb Vasc Biol. 2009;29(4):431-438.
Results: Single-dose SQ Stein EA, et al. N Engl J Med. 2012;366(12):1108-1118.
Potential roles for PCSK9 inhibitors Treatment of statin-intolerant patients Myalgias, myositis Diabetes mellitus LFT abnormalities Add-on therapy for patients failing to reach target
Summary Focus of new guidelines on risk assessment and intensity of treatment. High intensity treatment for those with ACVD, Diabetes Mellitus, high LDL (> 190 mg/dl), or 10 year risk > 7.5%
Future directions New Therapeutic Approaches Toward Raising HDL; Promote reverse cholesterol transport; CETP inhibitors Lowering Cholesterol without Myositis/Hepatitis PCSK9 (Promotes breakdown of LDL receptors in the liver through proteosomal degradation; inhibitors being developed) Antisense oligonucleotides directed against ApoB Microsomal triglyceride transfer protein inhibitors Pharmacology & Therapeutics 139 (2013) 301 312
Assessment of Cardiovascular Risk
Critical Question #1 What is the evidence regarding reclassification or contribution to risk assessment when hs- CRP, ApoB, GFR, microalbuminuria, family history, cardiorespiratory fitness, ABI, CAC, or CIMT are considered in addition to the variables that are in the traditional risk scores?
Recommendation #1 If, after quantitative risk assessment, a risk-based treatment decision is uncertain, assessment of 1 or more of the following: Family history, hs-crp, CAC score, or ABI may be considered to inform treatment decision making.
Recommendation #2 CIMT is not recommended for routine measurement in clinical practice for risk assessment for a first ASCVD event
Recommendation #3 The contribution to risk assessment for a first ASCVD event using ApoB, chronic kidney disease, microalbuminuria, or cardiorespiratory fitness is uncertain at present.
Measure Family Hx CRP CAC score Specific Measures for Risk Assessment (RA) Cutoff for increased RA Male <55 years of age 2 mg/l 300 Agastson units or 75 th percentile ABI < 0.9
Predictive value of CRP 52 prospective studies (246,669 participants) Measuring CRP resulted in the reclassification of 1.5% of patients from lowrisk to moderate or from moderate to high. Starting a statin based on and elevated CRP and intermediate risk, would reduce 1 cardiovascular event for every 440 patients over 10 years NEJM (2012) 367;14: 1312-20
Critical question #2 Are models constructed to assess the long-term ( 15 years or lifetime) risk for a first CVD event in adults effective in assessing variation in long-term risk among adults at low and/or intermediate short-term risk, whether analyzed separately or combined?
Recommendation #1 It is reasonable to assess traditional ASCVD risk factors every 4 to 6 years in adults 20 to 79 year of age who are free from ASCVD and estimate 10-year ASCVD risk every 4 to 6 years in adults 40 to 79 years of age who are free from ASCVD.
Recommendation #2 Assessing 30-year or lifetime ASCVD risk based on traditional risk factors may be considered in adults 20 to 59 years of age who are free from ASCVD and who are not at high short-term risk.
Risk Calculation NJ Stone et al., Circulation Nov 12, 2013
Risk Calculation NJ Stone et al., Circulation Nov 12, 2013
Risk Calculation NJ Stone et al., Circulation Nov 12, 2013
Summary Selective use of additional risk markers in patients at borderline risk Further evaluation of risk calculator with possible adjustments in future for specific populations Continued focus on high intensity therapy for high risk groups Use of lifetime risk in younger patients