AXIS CONCLAVE 2018 . DECEMBER 2018 Uday M Jadhav

1. AXIS CONCLAVE 2018 . DECEMBER 2018 UdayM Jadhav MD.FACC(USA). FAHA(USA).FSCCT(USA) FESC(Eur) FASH (USA).FACP.FICC.FCSI.FIAE.FISE.FICP Cardiology and CV Imaging Department M.G.M New Bombay Hospital. India

3. Vallejo-Vaz AJ, Robertson M, Catapano AL, Watts GF, Kastelein JJ, Packard CJ, Ford I, Ray KK. Circulation 2017;136(20):1878-1891

4. WOSCOPS Present analysis WOSCOPS participants n = 6595 Pravastatin40 mg/d vs. Placebo Evidence of angina, intermittent claudication, stroke, transient ischemic attack, and ECG abnormalities other than those already excluded in the main WOSCOPS trial. Any evidence of vascular disease n = 1066 Current WOSCOPS analyses n = 5529 Primary prevention free of any evidence of vascular disease Participants with LDL-C <190 mg/dL n = 2969 Participants with LDL-C ≥190 mg/dL n = 2560 Primary severe hypercholesterolaemia ECG, electrocardiogram;LDL-C, low-density lipoprotein cholesterol Vallejo-Vaz AJ, et al. Circulation 2017;136:1878–91

5. 20-year Long-term Follow-up  15 years observational long-term FU 5-year RCT 5 years post-RCT Randomisation Pravastatin vs Placebo RCT ended – Treatment according to patients’ physicians Approx. 1/3 of individuals originally allocated to pravastatin or placebo were on statins Effect of initial randomisation to Pravastatin or Placebo on mortality endpoints at 20 years of follow-up  Effect of 5 years of treatment with statin (vs placebo) in the long-term (at 20 years) FU, follow-up; RCT, randomised controlled trial Vallejo-Vaz AJ, et al. Circulation 2017;136:1878–91

6. Randomised trial phase (5-year Follow-up) Risk Reduction with pravastatin vs. placebo ARR 1.9% RRR 27% ARR 2.2% ARR 1.9% RRR 25% ARR 2.3% LDL-C, low-density lipoprotein cholesterol; MACE, major adverse cardiovascular events Vallejo-Vaz AJ, et al. Circulation 2017;136:1878–91

7. Long-term mortality endpoints at 20 years of follow-up Risk Reduction with pravastatin vs. placebo ARR 1.2% RRR 28% ARR 2.3% ARR 0.95% RRR 25% ARR 3.2% ARR 2.0% RRR 18% ARR 5.4% CHD, coronary heart disease; LDL-C, low-density lipoprotein cholesterol Vallejo-Vaz AJ, et al. Circulation 2017;136:1878–91

8. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: Executive Summary

9. Table 9. Normal and Abnormal Lipid Values in Childhood*†

10. ACC 2018 : Top 10 Take Home Messages • In adults 40 to 75 years of age evaluated for primary ASCVD prevention, have a clinician–patient risk discussion before starting statin therapy. Risk discussion should include a review of major risk factors (e.g., cigarette smoking, elevated blood pressure, (LDL-C), hemoglobin A1C [if indicated], and calculated 10-year risk of ASCVD); • the presence of risk-enhancing factors (see No. 8); • the potential benefits of lifestyle and statin therapies; • the potential for adverse effects and drug–drug interactions; • the consideration of costs of statin therapy; and • the patient preferences & values in shared decision-making.

11. 2013 - Risk Calculator

12. PRACTICAL IMPLICATIONS OF ASCVD CALCULATOR A systematic examination of the 2013 ACC/AHA Pooled Cohort risk assessment tool for atherosclerosis cardiovascular disease. Kamali KN. J Am CollCardiol October 2014; 64:959-68  Young individuals 40 to 50 years of age may not reach a 10year predicted ASCVD risk of 7.5% or even the moderately recommended risk threshold of 5% to <7.5% 10year ASCVD risk in spite of significant risk factor burden  Importance of the recommendation to assess longer term risk in younger individuals (age <50 years of age) who many have substantial risk factor burden but low short term risk, primarily because of their age

13. Editorial comment Primary Prevention of Atherosclerotic Cardiovascular disease Bringing Clinicians and Patients to the Starting Line Michael E. Farkouh JACC. Oct 2014, Vol 64; No. 10  7.5% 10-year threshold, was chosen arbitrarily  In some healthcare systems, a 10year risk of 10% may be more appropriate  For others who are younger and whose cardiovascular health is at greater because of a positive family history, for example, a 5% threshold may be more suitable

14. Cardiovascular Risk Prediction Basic Concepts, Current Status, and Future Directions Circulation. 2010; 121: 1768-1777 Even younger adults with substantial risk factor burden may still have 10-year risk estimates well below 10%, although their remaining lifetime risks may exceed 50% on the basis of these risk factors. This is not a problem of the 10-year risk score per se nor incorrect risk prediction but rather a function of the decision thresholds that are imposed on the risk estimates and the short time horizon imposed by 10-year risk estimation. For almost all combinations of risk factors, even with extreme values, nonsmoking men <45 years of age and essentially all women <65 years of age have 10-year predicted risks below 10%.

15. ACC 2018: Top 10 Take Home Messages • In adults 40 to 75 years of age without diabetes mellitus and with LDL-C levels ≥70 mg/dL (≥1.8 mmol/L), at a 10-year ASCVD risk of ≥7.5%, start a moderate-intensity statin if a discussion of treatment options favors statin therapy. Risk-enhancing factors favor statin therapy (see No. 8).If risk status is uncertain, consider using coronary artery calcium (CAC) to improve specificity (see No. 9).If statins are indicated, reduce LDL-C levels by ≥30%, and if 10-year risk is ≥20%, reduce LDL-C levels by ≥50%.

16. ACC 2018 :Top 10 Take Home Messages • In adults 40 to 75 years of age without diabetes mellitus and 10-year risk of 7.5% to 19.9% (intermediate risk), risk-enhancing factors favor initiation of statin therapy (see No. 7).Risk-enhancing factors include • family history of premature ASCVD; • persistently elevated LDL-C levels ≥160 mg/dL (≥4.1 mmol/L); • metabolic syndrome; • chronic kidney disease; • history of preeclampsia or premature menopause (age <40 yrs) • chronic inflammatory disorders (e.g., rheumatoid arthritis, psoriasis, or chronic HIV);• high-risk ethnic groups (e.g., South Asian); • persistent elevations of triglycerides ≥ 175 mg/dL(≥1.97 mmol/L);

17. ACC 2018: Top 10 Take Home Messages • In adults 40 to 75 years of age without diabetes mellitus and 10-year risk of 7.5% to 19.9% (intermediate risk), risk-enhancing factors favor initiation of statin therapy (see No. 7).Risk-enhancing factors include and, if measured in selected individuals • apolipoprotein B ≥130 mg/dL • high-sensitivity C-reactive protein ≥2.0 mg/L • ankle-brachial index <0.9 and l • lipoprotein (a) ≥50 mg/dL or 125 nmol/L, especially at higher values of lipoprotein (a). Risk-enhancing factors may favor statin therapy in patients at 10-year risk of 5-7.5% (borderline risk)

18. ACC 2018: Top 10 Take Home Messages • In adults 40 to 75 years of age without diabetes mellitus and with LDL-C levels ≥70 mg/dL- 189 mg/dL (≥1.8-4.9 mmol/L), at a 10-year ASCVD risk of ≥7.5% to 19.9%, if a decision about statin therapy is uncertain, consider measuring CAC.• If CAC is zero, treatment with statin therapy may be withheld or delayed, except in cigarette smokers, those with diabetes mellitus, and those with a strong family history of premature ASCVD. • A CAC score of 1 to 99 favors statin therapy, especially in those ≥55 years of age. • For any patient, if the CAC score is ≥100 Agatston units or ≥75th percentile, statin therapy is indicated unless otherwise deferred by the outcome of clinician–patient risk discussion.

21. Redefining Normal Lipids in 2015 There are no “normal cholesterol” values that apply to the individual patients in a given population based on the studies from which they were derived “Normal”: cholesterol values are one where there isno subclinical atherosclerosis “Abnormal”: cholesterol values are ones where thereis subclinical atherosclerosis

22. Secondary Prevention

23. Which is more likely to be a better predictor of the risk of atherosclerotic heart disease? Risk factors for atherosclerosis or the presence of atherosclerosis itself ?

24. Other Populations at Risk (Ethnicity)

25. Role of Coronary Artery Calcium Score of Zero and Other Negative Risk Markers for Cardiovascular Disease: • The Multi-Ethnic Study Of Atherosclerosis (MESA) • BlahaM J. Circulation.Jan 22, 2016 • CAC =0. CIMT (JAPI 2000, CAD 2017) • Absence of carotid plaque (JAPI 2001) • Brachial flow-mediated dilation >5% change ( IHJ 2003) • (ABI) >0.9 and <1.3 (JAPI 2000) • HS-CRP) <2 mg/L ( IHJ 2004) • Homocysteine <10 µmol/L • NTpro-BNP <100 pg/mL • No microalbuminuria(JAPI 2004) • No family history of Coronary heart disease (any/premature) (JAPI 2008) • Absence of metabolic syndrome (RSSDI 2003, JAPI 2007) • Healthy lifestyle

32. ACC 2018 : Table 10. Racial/Ethnic Issues in Evaluation, Risk Decisions, and Treatment of ASCVD Risk

33. ACC LIPID GUIDELINES 2018 Table 10

34. Table 8. Selected Examples of Candidates for CAC Measurement Who Might Benefit From Knowing Their CAC Score Is Zero

35. Progression of coronary artery calcification seems to be inevitable, but predictable - results of the Heinz Nixdorf Recall (HNR) study† R.Erbel, Nils Lehmann. Eur Heart J, Nov. 2014 Progression of CAC seems to follow a sustained, apparently inevitable and partly genetically determined heritable pathway which can be predicted over time

36. EFFECT OF STATINS ON ATHEROMA PROGRESSSION 8 CLINICAL TRIALS WITH IVUS PLAQUE MORPHOLOGY JACC APRIL 2015; R.Puri, Steven Nissen et al. REVERSAL SATURN AQUSRIUS NORMALIZE ACTIVATE ILUSTRATE  STRADIVARIUS  PERISCOPE

37. Impact of Statins on Serial Coronary Calcification During Atheroma Progression and Regression J Am Coll Cardiol. 2015;65(13):1273-1282. Plaque Calcification in the Setting of No-Statin Therapy or High-Intensity Statin Therapy Natural plaque progression likely involves lipid-pool expansion coupled with microcalcifications within lipid pools. Following long-term high-intensity statin therapy, plaque regression manifests as delipidation and probable vascular smooth muscle cell calcification, promoting plaque stability. .

38. CT Calcium Score vs. Stress Testing Michael Crawford Clinical Cardiology Jan 1, 2018  Stress testing detects the functional consequences of atherosclerosis but does not diagnose atherosclerosis because myocardial ischemia can be caused by other conditions such as microvascular disease or left ventricular hypertrophy  Stress testing cannot detect non-flow-limiting plaques  Stress testing is superior for detecting those at the highest risk and those who may benefit from revascularization  CAC scores > 400 are associated with a yearly MACE rate of 6% vs. 10% with a markedly positive stress test  CAC may represent an ideal first screening test, which then could be followed by a second test if CAC crosses some threshold

39. A 15-year warranty period for asymptomatic individuals without coronary artery calcium: A prospective follow-up of 9,715 individuals ValentiV, B OH, Heo R, et al. JACC Cardiovasc Imaging. 2015;8:900-909  Represents an opportune time to intervene with lifestyle changes, statins, aspirin  CAC score of 0 confers a 15-year warranty period against mortality in individuals at low to intermediate risk, unaffected by age or sex

40. Abstract From: Lipoprotein(a): the perpetual supporting actor Eur Heart J. July 2018;39(27):2597-2599.

41. Lipoprotein(a): the perpetual supporting actor European Heart Journal, Volume 39(27), 14 July 2018: 2597–2599,   Lp(a) might yet receive a leading actor Oscar nomination after all. Antisense oligonucleotides targeting Apo(a) in persons with elevated Lp(a) has shown very impressive results in lowering Lp(a) levels (≥ 70–80% decrease) Phase 2B trial will start to recruit patients with Lp(a) ≥ 60 mg/dL, and established CVD to test the efficacy and safety of ISIS 681257 administered subcutaneously with a target sample size of 270 participants (ClinicalTrials.gov identifier NCT03070782)

42. LIPOPROTEIN (a) AND CAD : LURIC STUDY Relations between lipoprotein(a) concentrations, LPA genetic variants, and the risk of mortality in patients with established coronary heart disease: a molecular and genetic association study Lancet Diabetes Endocrinol May 26, 2017 3313 patients with established coronary heart disease in the Ludwigshafen Risk and Cardiovascular Health (LURIC) study Median follow-up was 9·9 years  Lipoprotein(a) concentrations in plasma are associated with cardiovascular risk in the general population  Whether lipoprotein(a) concentrations or LPA genetic variants predict long-term mortality in patients with established coronary heart disease remains less clear

43. LIPOPROTEIN (a) AND CAD : LURIC STUDY • Lancet Diabetes Endocrinol May 26, 2017 •  Increased severity of coronary heart disease was associated with lipoprotein(a) concentrations in plasma in the highest tertile - HR 1·44 • In patients with prevalent coronary heart disease, lipoprotein(a) concentrations and genetic variants showed no associations with mortality • Lp(a) not useful risk factors to measure to predict progression to death after coronary heart disease

44. LIPOPROTEIN (a) AND CAD : LURIC STUDY  Lowering of lipoprotein(a) concentrations by drugs such as PCSK9 inhibitors has an added effect on cardiovascular outcomes beyond that mediated by their substantial reductions of LDL-cholesterol concentrations needs to be determined  Patients with established coronary heart disease who carry SNPs associated with increased concentrations of lipoprotein(a) are more likely to have earlier onset of disease and be more susceptible to atherosclerotic manifestations outside of the coronary tree  Integration of lipoprotein(a) into risk stratification in primary rather than in secondary prevention might be more useful

47. Hypertriglyceridemia

48. Hypertriglyceridemia

50. Postprandial TG determination supported by large clinical studies:  Women's Health Study  Copenhagen City Heart Study  Physicians Health Study  Apolipoprotein-related Mortality Risk Study  Second Northwick Park Heart Study  Norwegian Study  EARS II study  ARIC study