Global Causes of Death 2011 The inescapable conclusion is that an - PowerPoint PPT Presentation

Global Causes of Death 2011 “ The inescapable conclusion is that an epidemic of • NCDs cause 64% (35 million) of global deaths premature CV disease is developing, the brunt of • 80% (28 million) are in LMICs • NCDs will cost the world $47 trillion over the next 20 years which will be borne by low and middle income • CVD is responsible for around one third of all deaths worldwide countries ” .

CVD Prevention: Challenge! “ The human race has had long experience and a fine tradition in surviving adversity; we now face a task for which we have little experience, the task of surviving prosperity ” Alan Gregg (1890-1957) Rockefeller Foundation

CVD Prevention Opportunity! Genetic Environmental Clinical Events Age (yrs) Fetus 0 20 40 60

Coronary Heart Disease Mortality in Beijing 1984-1999 2500 1822 Extra deaths Attributable to Risk Factor Changes 2000 Cholesterol 77% 1000 Diabetes 19% BMI 4% 500 Smoking 1% 0 642 fewer deaths by treatments AMI treatments 41% -500 Hypertension treatment 24% Secondary prevetion 11% -1000 Heart failure 10% Aspirin for Angina 10% 1999 1984 Angina: CABG & PTCA 2% Critchley J. Circulation, 2004;110:1236-1244

Forecasting Future CVD Costs in USA 900 800 Billions 2008 $ 700 600 500 400 300 200 >20% of cost of car from Indirect Direct 100 0 staff health insurance 2026 2024 2010 2012 2013 2014 2015 2016 2017 2018 2019 2020 2021 2022 2023 2025 2027 2029 2030 2011 2028 Heidenreich Circ 2011; 123: 933-944

Modifiable Risk Factors: Prevention Opportunity Age 15152 MI patients in 52 countries 3 Gender Odds Ratio 2 Smoking 1 BP 0 Diabetes Cholesterol 9 RFs accounted for 90% of MI in men and 94% in women INTERHEART Lancet 2004

Lifetime Atherosclerosis Management  Treat to Lower Levels  Treat multiple Risk Factors  Start Earlier

New Lancet Statin Efficacy and Safety Study 5 trials with LDL 30 Proportional reduction in major CV event rate (95% CI) reduction at 1year >1.1 mmol/L (average: 1.4 mmol/L) 17 trials with LDL reduction at 1year <1.1 mmol/L (average: 0.9 mmol/L) 20 10 5 trials with further LDl reduction (average: 0.5 mmol/L) 0 0 0.5 1.0 1.5 Mean 1-year LDLC difference Between treatment groups (mmol/L) Lancet September 2016

Very Low Levels of Atherogenic Lipoproteins and the Risk for CV Events A Meta-Analysis of Statin Trials Matthijs Boekholdt J Am Coll Cardiol 2014; 64: 485 – 94

Evolocumab in Hyperlipidemia as Add-On Therapy (DESCARTES Study) Blom NEJM 2014; 370: 1809-1819

Residual Risk in TNT Study Increased Risk RR Range Older age 1.13 1.04-1.23 Increased BMI 1.09 1.02-1.17 Male Sex 1.33 1.07-1.65 Increased BP 1.38 1.17-1.63 DM 1.33 1.11-1.60 Baseline ApoB 1.19 1.11-1.28 BUN 1.10 1.03-1.17 + Current smoking, CVD and CCB use Decreased Risk RR Range High dose statin 0.82 0.70-0.94 Aspirin 0.67 0.56-0.81 Baseline ApoA-1 0.91 0.84-0.99 Mora Circ 2012; 125: 1979-1987

Coexistence of Multiple CV Risk Factors 800 million people (1 in 8) have a BP ≥140/90 mmHg 80% 640M also have other uncontrolled CV risk factors

Pathophysiology: Additive Effect of Cholesterol and BP on CHD Risk 34 Deaths /10,000 N=316,099 Patient-years 23 21 18 17 17 12 13 11 14 12 10 9 8 8 6 6 5 6 6 6 245+ 142+ 4 3 221-244 132-141 3 203-220 125-131 182-202 118-124 <182 <118 Neaton et al. Arch Intern Med. 1992;152:56-64.

ASCOT-LLA: non-fatal MI and fatal CHD Sever PS, et al. Lancet 2003;361:1149 – 58

Most of us have Arterial Disease! 100 85% Atherosclerosis (%) 80 71% 60% 60 37% 40 17% 20 0 <20 20-29 30-39 40-49 ≥50 Age (years) 32 Year Old Female Tuzcu Circ 2001 103:2075-10

Framingham Heart Study :Lifetime Risk Men Women 0.7 69% 0.7 ≥2 Major RFs Adjusted Cumulative Incidence 1 Major RF 0.6 0.6 ≥ Elevated RF ≥ Not Elevated RF All Optimal RFs 50% 50% 0.5 0.5 46% 0.4 0.4 39% 36% 0.3 0.3 27% 0.2 0.2 0.1 0.1 8% 5% 0 0 50 60 70 80 90 60 70 90 50 80 Attained Age Lloyd-Jones Circ. 2006; 113: 791-798

LDL Cholesterol and Coronary Heart Disease among Black Subjects by PCSK9 142X or PCSK9 679X Allele No Nonsense 12 Mutation Coronary Heart Disease (%) 50 th Percentile (n=3278) 30 P=0.008 Frequency (%) 20 8 88% 10 0 0 50 100 150 200 250 300 PCSK9 142X 4 or PCSK9 679X 28% (N=85) 30 20 0 No Yes 10  Exposure to CV RFs over time is key PCSK9 142X or PCSK9 679X 0 0  Compound interest from early management 50 100 150 200 250 300 Cohen NEJM 2006; 354:1264-72 LDL Cholesterol in Black Subjects (mg/dl )

Benefit from Lifetime Lower LDLc Ference J Am Coll Cardiol. 2015; 65: 1552 – 61

LDL EXposure is Key! Effect of Lower LDL-C Mediated by Polymorphisms in NPC1L1, HMGCR, or Both Ference J Am Coll Cardiol 2015; 65: 1552 – 61

Trial Support for Lower LDLc Irrespective of Approach Silverman JAMA 2016; 316: 1289-1297

HOPE-3 Studies: NEJM April 2016 “ Because of the short follow up of trial the probable life time benefit of continuous treatment is much larger than the benefit observed during trials ” “ The size of the intermediate risk population eligible for primary prevention is enormous. Three quarters of Salim Yusuf men over 55 and women over 60 would be eligible based on HOPE-3 criteria ”

HPS: Effects on 11-year Mortality and Morbidity Of Lowering LDL Cholesterol With Simvastatin for About 5 Years in 20,536 High-risk Individuals: A Randomised Controlled Trial Heart Protection Study Collaborative Group Lancet 2011; 378: 2013 – 20

Long Term Benefits From LDLc Lowering Past Trial Duration Ford Circ 2016; 133: 1073-1080

Hazards of Smoking and Benefits of Smoking Cessation 113,752 w and 88,496 m aged ≥25y in US NHIS Jha N Engl J Med 2013; 368: 341-50

Study Population and Exposures  Study sample: 102,773 persons (age 27 - 100 years)  enrolled in one of 14 prospective cohort or case-control studies  LDL-C genetic score: 46 polymorphisms associated primarily with lower LDL-C at genome-wide level of significance  SBP genetic score: 33 polymorphisms associated with lower SBP at genome-wide level of significance  Genetic scores used as both the instrument of randomization and the instrument of exposure B. Ference (Plymouth, US), FP 3163 ESC 2016

Combined Effect of LDL-C and SBP on Cardiovascular Events N = 14,368 Major Vascular Events B. Ference (Plymouth, US), FP 3163

Effect of 1 mmol/L lower LDL-C & 10 mmHg lower SBP on Major Cardiovascular Events 0 0.25 0.75 0.50 1.00 SBP and LDL-C have independent, multiplicative and cumulative effects on CVD risk B. Ference (Plymouth, US), FP 3163

Conclusions  LDL-C and SBP have independent, multiplicative and cumulative causal effects on risk of CV events  Because their effects are multiplicative and cumulative over time, long-term exposure to combination of modestly lower LDL-C and SBP has the potential to dramatically reduce the lifetime risk of CVD  CV events are largely preventable and CVD prevention can be substantially improved and simplified by designing programs that promote long-term exposure to combination of lower LDL-C and lower SBP beginning in early adulthood

CV disease is preventable “ Life-long Rx likely to be cost-effective and often cost saving ” Circulation 2011;124:967-990

CVD Prediction and Prevention Knowledge Communication Empowerment

JBS3 Lifetime Risk Calculator Heart March 2014 and www.jbs3risk.com

Impact of Heart Age Tool on Modifiable CVRFs 3153 subjects (47% male), Mean Age 46yrs, 12m FU 2 1.0 4 8 2.0 2.0 P<0.001 P<0.001 P<0.001 P<0.001 P<0.001 P<0.001 0.8 1 3 6 1.5 1.5 Systolic Blood Pressure (mmHg) 0.6 Total cholesterol (mg/dl) 4 2 1.0 1.0 0 Current smoking (%^) 0.4 Glucose (mg/dl) Heart Age (yrs) 1 2 0.5 0.5 Weight (kg) 0.2 -1 0.0 0 0 0.0 0.0 -2 -0.2 -2 -1 -0.5 -0.5 -0.4 -3 -2 -4 -1.0 -1.0 -0.6 -4 -0.8 -3 -6 -1.5 -1.5 -1.0 -5 -8 -4 -2.0 -2.0 Control FR Lopez-Gonzalez European Journal of Preventive Cardiology 2015: 22; 389 – 396 HA

Familial Hypercholesterolaemia IMT difference between FH and sibs against age 0.08 Δ IMT (mm) FH v. siblings 0.06 0.04 0.02 0 -0.02 -0.04 8 10 16 18 12 14 Age (years)

Statins and IMT in FH Children 208 FH children (8-18 yrs) 2 yrs with Pravastatin 20-40mg Placebo (n=104) Pravastatin (n=104) 15 Mean D IMT (mm) 10 5 0 -5 -10 -15 CCA Bulb CA Mean carotid P=0.06 P=0.3 P=0.2 P=0.019 Weigman JACC 2004

AdDIT: Intervention in Adolescent Diabetes Statin Arm atorvastatin placebo ACE Inhibitor Arm quinapril quinapril 125 125 atorvastatin placebo placebo placebo 125 125

Independent and graded association between GFR and CVD from any cause (per 100 person-yr) 40 14.14 Age-standardized rate of death 36.60 14 Age-standardized rate of CV events (per 100 person-yr) 35 11.36 12 35 10 25 21.80 8 20 6 15 4.76 11.29 4 10 2 3.65 5 1.08 2.11 0.76 0 0 ≥60 ≥60 45-59 30-44 15-29 <15 45-59 30-44 15-29 <15 Estimated GFR (ml/min/1.73m 2 ) Estimated GFR (ml/min/1.73m 2 ) Go et al; NEJM 2004