Beyond LDL-Cholesterol

Transcription

1 Biomarkers for Risk Stratification Beyond LDL-Cholesterol Athanasios J.Manolis Director Cardioilogy Dep, Asklepeion Hospital, Athens, Greece Adj. Professor of Medicine, Emory University Atlanta, USA Adj. Professor of Hypertension, Boston University, Boston, USA

2 Disclosures Research Grants, Honoraria, Advisory Boards SERVIER MENARINI NOVARTIS PFIZER GSK BAYER ASTRA ZENECA WIN ABBOTT RECORDATI FERRER AMGEN BOERINGHER INGHELHEIM ALGORITHM ELPEN SANOFI

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4 Cardiovascular Desease in 2011

5 Residual Risk Large-scale, randomized, clinical trials of LDL-lowerin therapies have demonstrated significant reduction in CVD events over a wide range of baseline LDL-C levels. However, even with LDL-C levels lowered substantially or at treatment goals with statin therapy, CVD risks are not eliminated and there remains significant residual risk. Intensifying statin therapy may provide additional benefits; this approach, however, has limited potential, owing to tolerability, side effects, and finite efficacy. Further LDL-C lowering may also be achieved with the use of nonstatin agents, such as cholesterol absorption inhibitors and PCSK9 inhibitors, added to statin therapy.

6 Integral Strategy of CV Prevention Secondary Prevention Healthy lifestyle Medication Primary Prevention Opportunistic screening Risk assessment Healthy lifestyle Medication CVD High Risk patients > 55 years Patients with established CVD: at very high risk of recurrence in absence of prevention. Low risk/ Standard population The recurrence rate or revascularization need in the first year after a CVD event is 50% Annual rate of mortality after AMI is 5-6 times higher than in patients without established CHD. Underlying risk of death in candidate patients who have not received proper secondary prevention : 5% per year, after first AMI 10% per year, after a subsequent AMI The risk of death persists lifelong

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8 Prevalence of Co-morbidities in Patients with Stable Ischaemic Heart Disease Br Med J 2012 Volume 19 Suppl 2

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13 Biomarkers Beyond LDL-Cholesterol Risk Factors Non-HDL-C Remnant Cholesterol Apo B TG/PPL Lp(a) PCSK9 Inflammation Uric Acid

14 Major Atherosclerotic CVD Risk factors AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS AND AMERICAN COLLEGE OF ENDOCRINOLOGY GUIDELINES FOR MANAGEMENT OF DYSLIPIDEMIA AND PREVENTION OF CARDIOVASCULAR DISEASE Paul S. Jellinger, et al. 2017

15 Biomarkers Beyond LDL-Cholesterol Risk Factors Non-HDL-C Remnant Cholesterol Apo B TG/PPL Lp(a) PCSK9 Inflammation Uric Acid

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17 Non HDL-C: When to Calculate? Non-HDL-C = TC HDL-C Normal LDL-C, TG and HDL-C Individuals with TG 200mg/dL ( VLDL-C) and ASCVD risk cannot be adequately assessed using LDL-C alone TC = 180 mg/dl TG = 250 mg/dl HDL-C = 30 mg/dl LDL-C = 100 mg/dl Non-HDL = =150 mg/dl

18 Non HDL-C as a Risk Factor Compared with LDL-C, non-hdl-c predictor of risk in pts with TG mg/dL, DM, insulin resistance, and/or established ASCVD In high-risk individuals, non-hdl-c may be a secondary treatment target Non-HDL-C may be a goal in persistently apo B Non-HDL-C targets when >30 mg/dl than established LDL-C risk levels

19 Biomarkers Beyond LDL-Cholesterol Risk Factors Non-HDL-C Remnant Cholesterol Apo B TG/PPL Lp(a) PCSK9 Inflammation Uric Acid

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21 Apo B Apo B-100 is the major apolipoprotein of the atherogenic lipoprotein families (VLDL,IDL,LDL) AMORIS (Apolipoprotein-Related Mortality Risk) and Nurses studies, showed that apo B predicting risk to LDL-C, non-hdl- C, or other cholesterol ratios Apo B is more closely associated with the insulin resistance than LDL-C or non-hdl-c IRAS (Insulin Resistance Atherosclerosis Study) revealed that apo B was more closely associated than non-hdl-c with markers such as central adiposity, insulin resistance, thrombosis, and inflammation Apo B can be used as secondary target as non-hdl-c

22 INTERHEART: Association of risk factors with acute MI in women and men VBWG Risk factor Current smoking Diabetes Hypertension Abdominal obesity Psychosocial index Fruits/Vegetables Exercise Alcohol ApoB-ApoA1 ratio Gender F M F M F M F M F M F M F M F M F M Adjusted for age, sex, geographic region Note: odds ratio plotted on a doubling scale Odds ratio (99% CI) Yusuf S et al. Lancet. 2004;364:

23 Biomarkers Beyond LDL-Cholesterol Risk Factors Non-HDL-C Remnant Cholesterol Apo B TG/PPL Lp(a) PCSK9 Inflammation Uric Acid

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26 Biomarkers Beyond LDL-Cholesterol Risk Factors Non-HDL-C Remnant Cholesterol Apo B TG/PPL Lp(a) PCSK9 Inflammation Uric Acid

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29 Biomarkers Beyond LDL-Cholesterol Risk Factors Non-HDL-C Remnant Cholesterol Apo B TG/PPL Lp(a) PCSK9 Inflammation Uric Acid

30 PCSK9 Inhibitors: Mechanisms of Action, Metabolic Effects, and Clinical Outcomes PCSK9 drugs represent a novel approach to achieving substantial reductions in LDL-C concentrations in a variety of patient populations at high CV risk even on a background of maximally tolerated statin therapy. To date, the primary clinical benefit of evolocumab is a reduction in MI, ischemic stroke, and coronary revascularization but not CV or all-cause mortality. Hess C et al Annu Rev Med 2017, Oct 24

31 Biomarkers Beyond LDL-Cholesterol Risk Factors Non-HDL-C Remnant Cholesterol Apo B TG/PPL Lp(a) PCSK9 Inflammation Uric Acid

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33 Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS) Stable CAD (post MI) On Statin, ACE/ARB, BB, ASA Persistent Elevation of hscrp (> 2 mg/l) N = 10, Countries April June Primary Events Randomized Canakinumab 50 mg SC q 3 months Randomized Canakinumab 150 mg SC q 3 months Randomized Canakinumab 300 mg SC q 3 months* Randomized Placebo SC q 3 months Primary CV Endpoint: Nonfatal MI, Nonfatal Stroke, Cardiovascular Death (MACE) Key Secondary CV Endpoint: MACE + Unstable Angina Requiring Unplanned Revascularization (MACE+) Critical Non-Cardiovascular Safety Endpoints: Cancer and Cancer Mortality, Infection and Infection Mortality Ridker ESC 2017

34 TG Percent Change from Baseline (median) HDLC LDLC hscrp CANTOS: Dose-Dependent Effects on Inflammatory Biomarkers and Lipids (48Months) Placebo SC q 3 mth Canakinumab 50mg SC q 3 mth Canakinumab 150mg SC q 3 mth Canakinumab 300mg SC q 3 mth Months Placebo Canakinumab 50 Canakinumab 150 Canakinumab 300 Ridker ESC 2017

35 Endpoint CANTOS: Consistency of HRs Across All Cardiovascular Endpoints Placebo (N=3347) Canakinumab SC q 3 months 50 mg (N=2170) 150 mg (N=2284) 300 mg (N=2263) P-trend Primary Secondary Myocardial Infarction Urgent Revascularization Any Coronary <0.001 Revascularization Stroke Cardiac Arrest CV Death All Cause Mortality Ridker ESC 2017

36 Biomarkers Beyond LDL-Cholesterol Risk Factors Non-HDL-C Remnant Cholesterol Apo B TG/PPL Lp(a) PCSK9 Inflammation Uric Acid

37 CV Conditions and RF Associated with Elevated UA Hypertension and prehypertension Renal disease Metabolic syndrome Obstructive sleep apnea Vascular disease (carotid, peripheral, coronary artery) Stroke and vascular dementia Preeclampsia Inflammation markers Endothelial dysfunction Oxidative stress Sex and race (postmenopausal women, blacks) Feig D. et al. N Engl J Med 2008; 359:

38 Zhao et Al, Atherosclerosis 2013;231:61 Baseline Serum Uric Acid Level as a Predictor of CV Disease Related Mortality and All-cause Mortality: A Meta-analysis of Prospective Studies 9 prospective studies partecipants 6048 CV deaths

39 Biomarkers Beyond LDL-Cholesterol The Role of Treatment Life Style Changes Drug Treatment

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41 Biomarkers Beyond LDL-Cholesterol The Role of Treatment Life Style Changes Drug Treatment

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43 Adherence Drops After First Six Months Treatment area 3 months 6 months 12 months Cholesterol 60% Diabetes (type 2) Obesity Hypertension 53% 48% 47% 52% 43% 41% 34% 41% 38% 35% By the end of the first year of treatment, 50-90% of patients stopped taking their prescribed medications 8% Castellano JM, et al., Global Heart ;8:263

44 Characteristics of Treatment Adherence Decreases with time and complexity. Slightly higher in secondary prevention, but still insufficient. Related with medication cost. The reduction of adherence is directly related to increased cardiovascular events. Combination therapy enhances adherence.

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47 First and Second Line Treatment for SCHD Mortality Symptoms Relief b-blockers No Yes DHP s No Yes Non-DHP s No Yes LAN No Yes Ivabradine No Yes Ranolazine No Yes Nicorandil No Yes Trimetazidine No Yes

48 Secondary CV Prevention in South America in a Community Setting Objective: To assess the use of effective secondary prevention therapies in individuals with a history of coronary heart disease or stroke PIB Avezum A. et al. GLOBAL HEART, 2016

49 Importance of Treatment Adherence Metanalysis of 44 prospective studies comprising 1,978,919 non-overlapping participants with CVD: 135,627 CVD events 94,126 cases of all-cause mortality. Study promoted by ESC with almost patients included Only 60% of the included patients were good adherents* The good adherence to CV medication led to: 20% reduction of CVD risk 35% reduction of all-cause mortality 9,1% of all events that occur are due to poor adherence in patients with prescribed cardiovascular medications. *Good adherence: 80% taking medication. Chowdhury et al. Eur Heart J 2013

50 Darapladib for Preventing Ischemic Events in SCHD: the STABILITY Study Optimal medical treatment Optimal Medical Target??? % Statin Antiplatelets B-blocker RAS LDL >2.5 mmol/l BP >140/90 mmhg BMI >30 kg/m 2 WC Smoking >102 cm White H, Manolis AJ et al N Engl J Med 2014

51 Therapeutic Control of Blood Pressure, LDL-C and Diabetes EUROASPIRE II EUROASPIRE III EUROASPIRE IV p=0.01 P< p=0.69 *In patients on BP lowering drugs; **In patients on lipid-lowering drugs; *** In patients with known diabetes

52 Characteristics of the CNIC-FS-FERRER polypill (Trinomia ) Hard gelatin 0 size capsule containing 5 coated inmediate release pills: Aspirin (100 mg (2x50mg)) Statin (atorvastatin 20 mg (2 x 10 mg)) ACE inhibitor (ramipril 2,5mg; 5mg or 10 mg) New technology that allows avoiding chemicophysical incompatibilities between components. 3 Trinomia presentations: Trinomia 100/20/2,5 Trinomia 100/20/5 Trinomia 100/20/10 Aspirin Ramirpil 2*505/10 mg mg Atorvastatin 2*10 mg Ramipril 2.5/5/10 mg Trinomia should be taken orally as a single capsule per day, preferably after a meal.

53 J Hypertens 2017

54 Communication Matters Physicians usually don t see adherence as an issue they can address White coat adherence Average time spent on outpatient visit: How much time do we spend discussing new prescriptions? Analysis 181 patients receiving 234 new medication Rx. from16 family physicians, 18 internists, and 11 cardiologists: Average time spent by MD explaining role of new medications: 49 seconds. More than 60 percent of patients misunderstood prescription directions immediately after doctor visits. Forty to 60 percent of patients could not correctly report medication expectations 10 to 80 minutes after physicians provided information Healthy Adherer Effect

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