ACC/AHA GUIDELINES ON LIPIDS AND PCSK9 INHIBITORS

ACC/AHA GUIDELINES ON LIPIDS AND PCSK9 INHIBITORS Ziyad Ghazzal MD, FACC, FSCAI Professor of Medicine Deputy Vice President/Dean Associate Dean for Clinical Affairs American University of Beirut Adjunct Professor Emory University School of Medicine Atlanta GA

45 yo gentleman, presents for a cardiac check up. Negative past medical history. No family history of cardiac disease Asymptomatic from the cardiac standpoint. Good exercise tolerance. Exercises five times per week Chronic smoker Physical examination unremarkable. BP 130/80 mmhg Lipid profile: TC = 193mg/dL LDL = 124mg/dL HDL = 28mg/dL TG = 253mg/dL

2013 ACC/AHA GUIDELINE ON THE TREATMENT OF BLOOD CHOLESTEROL TO REDUCE ATHEROSCLEROTIC CARDIOVASCULAR RISK IN ADULTS

4 STATIN BENEFIT GROUPS Clinical ASCVD* LDL-C 190 mg/dl, Age 21 years Acute coronary syndromes, or a history of MI, Primary stable prevention or unstable angina, Diabetes: coronary Age or other 40-75 arterial years, LDL-C 70-189 mg/dl revascularization, stroke, TIA, or peripheral arterial disease presumed to be of atherosclerotic origin Primary prevention - No Diabetes: 7.5% 10-year ASCVD risk, Age 40-75 years, LDL-C 70-189 mg/dl (without NYHA class II-IV heart failure or receiving hemodialysis)

WHY NOT CONTINUE TO TREAT TO TARGET? Major difficulties: Current RCT data do not indicate what the target should be Unknown magnitude of additional ASCVD risk reduction with one target compared to another Unknown rate of additional adverse effects from multidrug therapy used to achieve a specific goal Therefore, unknown net benefit from treat-to-target approach

SUMMARY OF STATIN INITIATION RECOMMENDATIONS TO REDUCE ASCVD RISK Heart-healthy lifestyle habits are the foundation of ASCVD prevention (See 2013 AHA/ACC Lifestyle Management Guideline) Age >21 y and a candidate for statin therapy Yes Clinical ASCVD Yes Age 75 y High-intensity statin (Moderate-intensity statin if not candidate for high-intensity statin) No Yes Age >75 y OR if not candidate for high-intensity statin Moderate-intensity statin Definitions of High- and Moderate-Intensity Statin Therapy (See Table 5) High Daily dose lowers LDL-C by approx. 50% Moderate Daily dose lowers LDL-C by approx. 30% to <50% LDL-C 190 mg/dl No Yes High-intensity statin (Moderate-intensity statin if not candidate for high-intensity statin) Regularly monitor adherence to lifestyle and drug therapy with lipid and safety assessments (See Fig 5) Diabetes Type 1 or 2 Age 40-75 y Yes Yes Moderate-intensity statin Estimated 10-y ASCVD risk 7.5%* High-intensity statin No

SUMMARY OF STATIN INITIATION RECOMMENDATIONS TO REDUCE ASCVD RISK No DM age <40 or >75 y Primary prevention (No diabetes, LDL-C 70-189 mg/dl, and not receiving statin therapy) Estimate 10-y ASCVD Risk every 4-6 years Pooled Cohort Equations* <5% 10-y ASCVD risk Age <40 or >75 y and LDL-C <190 mg/dl 7.5% 10-y ASCVD risk (Moderate- or highintensity statin) 5%-<7.5% 10-y ASCVD risk (Moderate-intensity statin) In selected individuals, additional factors may be considered to inform treatment decision making Clinician-Patient Discussion Prior to initiating statin therapy, discuss: 1. Potential for ASCVD risk reduction benefit 2. If decision is unclear, consider primary LDL-C >160 mg/dl, family history of premature ASCVD, lifetime ASCVD risk, abnormal CAC score or ABI, or hs-crp >2 mg/l 3. Potential for adverse effects and drug drug interactions 4. Healthy lifestyle 5. Management of other risk factors 6. Patient preferences Emphasize adherence to lifestyle Manage other risk factors Monitor adherence No to statin Yes to statin Encourage adherence to lifestyle Initiate statin at appropriate intensity Manage other risk factors Monitor adherence (See Fig 5)

45 yo gentleman, presenting for a cardiac check up Asymptomatic from the cardiac standpoint. Good exercise tolerance Chronic smoker Physical examination unremarkable. BP 130/80 mmhg Lipid profile: TC = 193mg/dL LDL = 124mg/dL HDL = 28mg/dL TG = 253mg/dL

Some worry that a person aged 70 years without other risk factors will receive statin treatment on the basis of age alone. The estimated 10-year risk is still 7.5%, a risk threshold for which a reduction in ASCVD risk events has been demonstrated in RCTs. Most ASCVD events occur after age 70 years, giving individuals >70 years of age the greatest potential for absolute risk reduction.

Algorithm development was conducted in the MESA (Multi-Ethnic Study of Atherosclerosis), a prospective community-based cohort study of 6,814 participants age 45 to 84 years who were free of clinical heart disease at baseline The MESA risk score was calculated: an estimate of 10-year CHD risk using traditional risk factors and CAC

The absence of CAC reclassifies approximately one-half of candidates as not eligible for statin therapy

proprotein convertase substilisin-kexin type 9 PCSK9 INHIBITORS

THE EVOLUTION OF PCSK9 INHIBITION DIRECTED THERAPIES Lee Joseph, Jennifer G. Robinson Progress in Cardiovascular Diseases, Volume 58, Issue 1, 2015, 19 31

LOW-DENSITY LIPOPROTEIN (LDL) CHOLESTEROL LEVELS. SABAT INE MS ET AL. N ENGL J M ED 2015;372:1500-1509.

CUMULATIVE INCIDENCE OF CARDIOVASCULAR EVENTS Most adverse events occurred with similar frequency in the two groups, although neurocognitive events were reported more frequently in the evolocumab group SABAT INE MS ET AL. N ENGL J M ED 2015;372:1500-1509.

CALCULATED LDL CHOLESTEROL LEVELS OVER TIME (INTENTION-TO-TREAT ANALYSIS) RO BI NSON JG ET AL. N ENG L J M ED 2015;372:1489-1499.

The alirocumab group, as compared with the placebo group, had higher rates of injection-site reactions (5.9% vs. 4.2%), myalgia (5.4% vs. 2.9%), neurocognitive events (1.2% vs. 0.5%), and ophthalmologic events (2.9% vs. 1.9%)