Young high risk patients the role of statins Dr. Mohamed Jeilan

Young high risk patients the role of statins Dr. Mohamed Jeilan KCS Congress: Impact through collaboration CONTACT: Tel. +254 735 833 803 Email: kcardiacs@gmail.com Web: www.kenyacardiacs.org

Disclosures Conflict of Interests Astra Zeneca Honoraria

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A 60 yr. old man is referred because of hypercholesterolaemia (total cholesterol 240mg/dL). His HDL is 45mg/dL and his systolic blood pressure is 135. He is a smoker who cannot quit and he has a family history of coronary artery disease. He has no other risk factors.

How should he be treated? 10 yr. risk (ASCVD calculator) 19%

A 30 yr. old man is referred because of hypercholesterolaemia (total cholesterol 240mg/dL). His HDL risk is 45mg/dL and his systolic blood pressure is 135. He is a smoker who cannot quit and he has a family history of coronary artery disease. He has no other risk factors.

Should he receive a statin? 10 yr. risk 6% (Framingham) Lifetime risk 67% (Framingham)

Most MI s in Africa occur in young patients 01 Most Africans are young true 02 But when did they get the disease?

A 27 yr. old male patient presents with chest pain and ST depression.

The fatty streak is the father of atherosclerosis JAMA 1999 Pathological Determinants of Atherosclerosis in the Young is seen in 30% of Korean war veterans in (mean age 22) is seen in 37% of organ donors age 20-29 has the same risk factor profile as those that predict INFARCTION in adults (cholesterol, HTN, cigarettes)

Bogalusa Heart Study NEJM 1998 50% of children and 85% of adults have fatty streaks Fibrous plaques increase from 8% to 69% as you progress from childhood to third decade Strong correlation with cholesterol (LDL) concentration Rise in obesity, T2DM and hypertension in young adults and children

CV Risk factors in children Rise in obesity, T2DM and hypertension in young adults and children

Continuous, graded, strong relationship between serum cholesterol and sixyear age-adjusted CHD death rate JAMA. 1986 Nov 28;256(20):2823-8.

Childhood dyslipidaemia is on the rise and is increasingly understood as a risk factor for atherosclerotic disease American Academy of Paediatrics recommend screening for this condition (2008) NHLBI updated this guidance in 2011 When (at what age)?

Age 2 to 8 Age 12 to 20 Positive FHx of premature ASCVD BMI > 95 th percentile, hypertension (>95th percentile), smoking, diabetes

Screening what are the guidelines? Issuing Organization Year Populations to be Screened Screening Measurement Screening Interval USPSTF [23] 2008 (update in progress) Men 35 years: Universal screening Men 20-34 years: if at increased risk for coronary heart disease (CHD) Women 20 years: if at increased risk for CHD Fasting or non-fasting lipid panel Uncertain; every 5 years, with shorter intervals for individuals with elevated lipid levels and longer intervals for those not at increased risk with normal lipid levels ACC/AHA [24] 2013 Adults 20-78 years None given Every 4-6 years if free of ASCVD ESC/EAS [28] 2011 Adults with any of the following risk factors: Type 2 diabetes Obesity Hypertension Smoker Chronic inflammatory disease Chronic kidney disease Family history of premature cardiovascular disease (CVD) or familial dyslipidemia Men 40 years and Women 50 years or post-menopausal: Consider screening Fasting lipid panel with calculation of non-hdl-c and TC/HDL-C ratio; apob or apob/apoa1 ratio considered alternate risk factors None given

Screening what are the guidelines? Issuing Organization Year Populations to be Screened Screening Measurement Screening Interval USPSTF [23] 2008 (update in progress) Men 35 years: Universal screening Men 20-34 years: if at increased risk for coronary heart disease (CHD) Women 20 years: if at increased risk for CHD Fasting or non-fasting lipid panel Uncertain; every 5 years, with shorter intervals for individuals with elevated lipid levels and longer intervals for those not at increased risk with normal lipid levels ACC/AHA [24] 2013 Adults >21 years None given Every 4-6 years if free of ASCVD ESC/EAS [28] 2011 Adults with any of the following risk factors: Type 2 diabetes Obesity Hypertension Smoker Chronic inflammatory disease Chronic kidney disease Family history of premature cardiovascular disease (CVD) or familial dyslipidemia Men 40 years and Women 50 years or post-menopausal: Consider screening Fasting lipid panel with calculation of non-hdl-c and TC/HDL-C ratio; apob or apob/apoa1 ratio considered alternate risk factors None given

The interventions Diet Lifestyle modifications including activity and exercise Smoking cessation Statin Aspirin

The interventions Diet how effective is it? Lifestyle modifications including activity and exercise Smoking cessation Statin Aspirin

The interventions Diet how effective is it? Lifestyle modifications including activity and exercise Smoking cessation Statin Aspirin

Cox proportional-hazards regression showed that for men who consumed 35 g or more of fish daily as compared with those who consumed none, the relative risks of death from coronary heart disease and from sudden or nonsudden myocardial infarction were 0.62 (95 percent confidence interval, 0.40 to 0.94) and 0.56 (95 percent confidence interval, 0.33 to 0.93), respectively

Mediterranean Diet PREDIMED Study

PREDIMED Study The traditional Mediterranean diet is characterized by a high intake of olive oil, fruit, nuts, vegetables, and cereals; a moderate intake of fish and poultry; a low intake of dairy products, red meat, processed meats, and sweets; and wine in moderation, consumed with meals parallel-group, multicenter, randomized trial men (55 to 80 years of age) and women (60 to 80 years of age) with no cardiovascular disease at enrollment, who had either type 2 diabetes mellitus or at least three major risk factors Ramdomize to one of three diets: a Mediterranean diet supplemented with extra-virgin olive oil, a Mediterranean diet supplemented with mixed nuts, or a control diet (advice to reduce dietary fat)

PREDIMED Study The multivariable-adjusted hazard ratios were 0.70 (95% confidence interval [CI], 0.54 to 0.92) and 0.72 (95% CI, 0.54 to 0.96) for the group assigned to a Mediterranean diet with extra-virgin olive oil Conclusion: Among persons at high cardiovascular risk, a Mediterranean diet supplemented with extra-virgin olive oil or nuts reduced the incidence of major cardiovascular events

Lifestyle modification Critical component of ASCVD risk reduction Prior to, and in concert with cholesterol lowering drugs adhering to a heart healthy diet limiting intake of dietary trans-fats, carbohydrates. Increase intake of fruits, vegetables, nuts and legumes reduce excessive body weight regular exercise habits avoidance of tobacco products

Lifestyle Modification A summary

So who to treat with Statin? Children < 8 years LDL >500mg/dL

Familial hypercholesterolaemia Heterozygous most studied 1 in 500 worldwide LDL > 240mg/DL Tendon xanthomas, TC >600mg/dL associated with MI in childhood Homozygous most powerful Case series of 7 patients

Familial Hypercholesterolemia

ACC / AHA http://www.cvriskcalculator.com/

JUPITER TRIAL

The Evidence: Risk reduction with LDL-C lowering

2,884,260 patients with a qualifying lipid analysis 3.8% with LDL-C level > 190 mg/dl. Statins - 32% of patients in their 30s. LDL-C >250 mg/dl 25% not prescribed a statin

Discussion

Therapeutic Equivalence of Statins

What about safety and tolerability? Short term studies. Myalgia, arthritis, arthralgia, rhabdomyolysis, liver dysfunction, myositis Diabetes?

3270175-45

Conclusions We have a serious epidemic of cardiovascular disease on our hands The disease process starts in the very young Risk calculating models are reasonable for predicting risk in older patients but may underestimate the risk and benefit of early intervention A dearth of data on efficacy of interventions at the younger age groups. Lifestyle interventions provide a powerful tool Statins should be considered in the highest risk populations

It s never too late OBESITY AFRICA The next big thing November 2017

Thank you

Primary prevention using statin therapy (when should we start?)

What do the guidelines tell us?

ASCVD Risk

The Profile: Components and Numbers

Dyslipidemia Guidelines American College of Cardiology (ACC)/American Heart Association(AHA) American Association of Clinical Endocrinologists (AACE) National Lipid Association (NLA) Department of Veteran s Affairs (VA)/Department of Defense (DOD) International Atherosclerosis Society (IAS) European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS)

Risk reduction seems independent of method used

Lets take a look at the guidelines

ACC/AHA 2013 Risk Algorithm Intervention Population Treatment Goal Intervention ACC/AHA- ASCVD Adults 21 years old in any of the following risk groups: 1.Known ASCVD 2.LDL-C >190 mg/dl 3.40-75 years old, with diabetes and LDL-C levels 70-189 mg/dl and no ASCVD 4. 7.5% 10 year ASCVD risk with LDL-C levels 70-189 mg/dl By Risk Group Counsel on healthy lifestyle habits 1.: 50% reduction in LDL-C High-intensity statin therapy for most patients in groups 1 and 2, 2. 50% reduction in LDL-C and for group 3 patients if 7.5% 10- year ASCVD risk; consider for group 4 3.30-50% reduction in LDL- C 4.30-50% reduction in LDL- C Moderate-intensity statins for group 1-2 patients >75 years or with statin-associated adverse events, and for most group 3-4 patients

ESC 2016

ESC Treatment Targets

International Atherosclerosis Society (IAS) 2014 Risk Algorithm Intervention Population Treatment Goal Intervention Lifestyle changes(first line): Lifetime-FRS (preferred) or QRISK2 Non-HDL-C 130 mg/dl LDL-C 100 mg/dl LDL-C <100 mg/dl Non-HDL-C <130 mg/dl is an alternative target Nutrition counseling, physical activity, smoking cessation and weight loss. Pharmacologic Therapy in addition to lifestyle changes: Moderate to high intensity statin adjusted to absolute risk

Components of treatment

Drugs for reducing LDL-C Statins Non Statin lipid modifying drugs Ezetimibe Bile Acid Sequestrants: Cholestyramine, colestipol Cholesterol absorption Inhibitors: Ezetimibe Fibrates Niacin Novel drugs PCSK9 inhibitors

Statins Moderate-intensity Lovastatin 40 mg Pravastatin 40 mg Simvastatin 40 mg Atorvastatin 10 to 20 mg Rosuvastatin 5 to 10 mg High-intensity Atorvastatin 40 to 80 mg Rosuvastatin 20 to 40 mg

Jupiter Trial 17,802 healthy men and women LDL < 130 mg per deciliter (3.4 mmol per liter) and hscrp levels of 2.0 mg per liter or higher Rosuvastatin 20 mg daily or placebo combined primary end point of MI, stroke, arterial revascularization, hospitalization for unstable angina, or death from cardiovascular causes.

Jupiter Trial - Results Stopped after a median follow-up of 1.9 years (maximum, 5.0). Rosuvastatin reduced LDL cholesterol levels by 50% and highsensitivity C-reactive protein levels by 37% The rates of the primary end point were 0.77 and 1.36 per 100 person-years of follow-up in the rosuvastatin and placebo groups, respectively (HR 0.56; 95% confidence interval [CI], 0.46 to 0.69; P<0.00001)

JUPITER TRIAL

Cumulative incidence (%) Group 4: Primary prevention ASCOT-LLA: Atorvastatin 10 mg provided a 36% RRR of the primary endpoint of non-fatal MI and fatal CHD (p=0.0005) compared with placebo 1 Diabetes subgroup analysis: 20% RRR in total CV events and procedures in nondiabetic patients was similar to the 23% RRR seen in the diabetic group 2 Incidence of non-fatal MI and fatal CHD 1 4 3 2 1 Placebo (n=5137); final LDL-C=126 mg/dl Atorvastatin 10 mg (n=5168); final LDL-C=90 mg/dl 36% RRR HR=0.64 95% CI 0.50 0.83) (p=0.0005) ARR=1.1% 0 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.3 Time (years) 1. Reprinted from The Lancet, 361, Sever et al, Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial, 1149 1158, Copyright (2003), with permission from Elsevier 2. Sever PS, et al. Diabetes Care 2005;28:1151 1157 5.0

Therapeutic Equivalence of Statins

Non-Statins

Thank you

AAP AHA No CVD risk factors. Treat when LDL > 190mg/dL after 6 months of diet therapy Diabetes Consider treating when LDL > 130mg/dL after 6 months of diet therapy FHx of CAD or >2 addition risk factors present? Treat when LDL > 160mg/dL after 6 months of diet therapy Treat when LDL > 190mg/dL Treat when LDL > 190mg/dL after 6 months of diet therapy

Use of Risk prediction models United States Framingham Risk Score (FRS; multiple adaptations) Reynolds Risk Score (RRS) American College of Cardiology/American Heart Association (AC/AHA- ASCVD) European population cohorts Systematic Coronary Risk Evaluation (SCORE) QRisk2 WHO risk charts

Novel drugs: PCSK9 Inhibitors

Proprotein convertase subtilisin kexin 9 (PCSK9) inhibitors Not been adequately evaluated in primary prevention in patients without familial hypercholesterolemia Their effects in secondary prevention suggest that they could be expected to reduce cardiovascular outcomes to a similar degree, as is seen with statin therapy However, their cost, the requirement for injections, and the lack of long-term safety data would make them an option only in the highestrisk primary prevention patients who are unable to tolerate statin therapy

Conclusions The processes leading to atherosclerosis begin early in life The rationale for activities focused on LDL-C reduction is based upon epidemiologic data documenting a continuous, positive, graded relationship between LDL-C concentration and CVD events and mortality Lowering LDL-C with statin therapy for primary prevention is effective at reducing CVD events (mostly myocardial infarction) over a wide range of baseline LDL-C levels and lipid profiles Lifestyle modification is a critical component of ASCVD risk reduction