Educational Objectives Evaluate current data on hypertension management

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Educational Objectives • Evaluate current data on hypertension management and review current guidelines •

Educational Objectives • Evaluate current data on hypertension management and review current guidelines • Review current ACC recommendations for the addition of nonstatin medications to statin therapy • Discuss the role of PCSK 9 inhibitors and other nonstatin lipid lowering agents in the management of dyslipidemia and cardiac risk

High Blood Pressure Remains one of the most important Multipliers of CV risk •

High Blood Pressure Remains one of the most important Multipliers of CV risk • BP > 140/90 mm Hg is associated with – ~ 70% of first myocardial infarctions – ~ 75% of first strokes • Hypertension is associated with at least a 2 -3 fold increase in the risk of developing heart failure • The estimated direct and indirect costs of hypertension in 2007 was 64 billion dollars Rosamond et al. Circulation 2007 115; e 69 -171

Even if you make it to age 65 without HTN, you’ll likely develop it

Even if you make it to age 65 without HTN, you’ll likely develop it 100 Men 80 60 Risk of hypertension (%) Women 40 20 0 65 67 69 71 73 75 77 79 81 83 85 age Vasan RS et al. JAMA. 2002; 287: 1003 -1010.

Blood Pressure Distribution in the Population According to Age 150 Men BP trajectory accelerates

Blood Pressure Distribution in the Population According to Age 150 Men BP trajectory accelerates about the time of Women menopause 150 130 PP 110 80 80 70 70 30 -39 40 -49 50 -59 60 -69 70 -79 80 Age PP 110 30 -39 40 -49 50 -59 60 -69 70 -79 80 PP=Pulse Pressure. Age Adapted from : Third National Health and Nutrition. Examination Survey, Hypertension 1995; 25: 305 -13

Reducing SBP Reduces CV Mortality MIDAS/NICS/VHAS 1. 50 Odds Ratio 1. 25 1. 00

Reducing SBP Reduces CV Mortality MIDAS/NICS/VHAS 1. 50 Odds Ratio 1. 25 1. 00 P = 0. 003 UKPDS C vs A NORDIL STOP ACEIs INSIGHT HOT L vs H HOT M vs H MRC 1 STOP CCBs 0. 75 HOPE CAPPP STONE UKPDS L vs H Syst-China MRC 2 SHEP EWPHE Syst-Eur RCT 70 -80 0. 50 PART 2/SCAT 0. 25 - 5 0 ATMH STOP-1 5 10 15 20 Difference in SBP (mm. Hg) 25 Staessen JA, et al. Lancet. 2001; 358: 1305 -15.

Long-Term Antihypertensive Therapy Significantly Reduces CV Events Myocardial 0 Stroke infarction Heart failure –

Long-Term Antihypertensive Therapy Significantly Reduces CV Events Myocardial 0 Stroke infarction Heart failure – 10 Average reduction in events (%) – 20 – 30 20%-25% – 40 – 50 – 60 35%-40% >50% Blood Pressure Lowering Treatment Trialists’ Collaboration. Lancet. 2000; 355: 1955 -1964.

JAMA. Published online December 18, 2013. doi: 10. 1001/jama. 2013. 284427

JAMA. Published online December 18, 2013. doi: 10. 1001/jama. 2013. 284427

2014 JNC 8 Algorithm Lifestyle Modification Age > 60 Age < 60 All Ages

2014 JNC 8 Algorithm Lifestyle Modification Age > 60 Age < 60 All Ages Diabetes All Ages CKD < 150 / 90 < 140 / 90 Non Black Thiazide, ACE-I, ARB or CCB Alone or in combination Black Thiazide or CCB Alone or in combination ACE-I or ARB Alone or in combination JAMA. Published online December 18, 2013. doi: 10. 1001/jama. 2013. 284427

JNC 8 It’s not JNC 7; nor was it ever meant to be. No

JNC 8 It’s not JNC 7; nor was it ever meant to be. No discussion of prevention or evaluation. Just management. And only informed by RCT data

JNC – 8: What’s different? • Broadening of options for initial antihypertensive – ACE

JNC – 8: What’s different? • Broadening of options for initial antihypertensive – ACE – I, ARBs, Thiazide diuretics, CCB in general population – Thiazide diuretics, CCB in Black population – Beta blockers excluded – ACE – I and ARBs mandated for CKD – ACE – I and ARBs NOT mandated for DM – BP goal for general population not changed • Loosening of BP goals for elderly: > 150 / 90 • Labeling patients > 60 years of age as elderly

BP goals in general populations: Comparison of guidelines ESH/ESC: ASH/ISH: CHEP: ADA: ACP AAFP:

BP goals in general populations: Comparison of guidelines ESH/ESC: ASH/ISH: CHEP: ADA: ACP AAFP: JNC 8: < 140/85 < 140/90 < 130/80 < 140/90 And virtually every other worldwide guideline

JNC – 8: What’s different? • Broadening of options for initial antihypertensive – ACE

JNC – 8: What’s different? • Broadening of options for initial antihypertensive – ACE – I, ARBs, Thiazide diuretics, CCB in general population – Thiazide diuretics, CCB in Black population – Beta blockers excluded – ACE – I and ARBs mandated for CKD – ACE – I and ARBs NOT mandated for DM – BP goal for general population not changed • Loosening of BP goals for elderly: > 150 / 90 • Labeling patients > 60 years of age as elderly

BP goal in the Elderly: A comparison of guidelines ACP and AAFP – JNC

BP goal in the Elderly: A comparison of guidelines ACP and AAFP – JNC 8: < 150/90 > 60 years – ESH/ESC: < 150/90 > 80 years – CHEP: < 150/90 > 80 years – NICE: < 150/90 > 80 years

We, the panel minority, believed that evidence was Not even all JNC 8 Authors

We, the panel minority, believed that evidence was Not even all JNC 8 Authors Agreed insufficient to increase the SBP goal from its current 14 January 2014 level of less than 140 mm Hg…partially undoing the Evidence Supporting a Systolic Blood Pressure Goal of remarkable progress in reducing cardiovascular Less Than 150 mm Hg in Patients Aged 60 Years or mortality in Americans older than 60 years. Older: The Minority View (6/17 JNC 8 panel members) Wright et al. Ann Intern Med. 2014; 160(7): 499 -503.

HYVET Trial: Study Design 3, 845 patients > 80 years with SBP ≥ 160

HYVET Trial: Study Design 3, 845 patients > 80 years with SBP ≥ 160 mm Hg Exclusion Criteria: Standing SBP < 140 mm. Hg Stroke in last 6 months Dementia; Need for daily nursing care R Active Treatment 1. 5 mg Indapamide (thiazide diuretic) ± perindopri (ACE-l) Placebo Matching Tablets Target blood pressure 150/80 mm. Hg g g Primary Endpoint: fatal and non-fatal strokes Secondary Endpoints: death from: stroke, cardiovascular causes, cardiac causes and any cause N Engl J Med 2008; 358/ACC 2008

Baseline BP 173 / 91 mm Hg Achieved BP 146 / 78 mm Hg

Baseline BP 173 / 91 mm Hg Achieved BP 146 / 78 mm Hg N Engl J Med 2008; 358/ACC 2008

All stroke (30% reduction) Placebo P=0. 055 Indapamide ±perindopril Placebo Indapamide. SR ±perindopril N

All stroke (30% reduction) Placebo P=0. 055 Indapamide ±perindopril Placebo Indapamide. SR ±perindopril N Engl J Med 2008; 358/ACC 2008

Total Mortality (21% reduction) Placebo P=0. 019 Indapamide ±perindopril Placebo Indapamide. SR ±perindopril N

Total Mortality (21% reduction) Placebo P=0. 019 Indapamide ±perindopril Placebo Indapamide. SR ±perindopril N Engl J Med 2008; 358/ACC 2008

Fatal Stroke (39% reduction) Placebo P=0. 046 Indapamide ±perindopril Placebo Indapamide. SR ±perindopril N

Fatal Stroke (39% reduction) Placebo P=0. 046 Indapamide ±perindopril Placebo Indapamide. SR ±perindopril N Engl J Med 2008; 358/ACC 2008

Heart Failure (64% reduction) Placebo P<0. 0001 Indapamide ±perindopril Placebo Indapamide. SR ±perindopril N

Heart Failure (64% reduction) Placebo P<0. 0001 Indapamide ±perindopril Placebo Indapamide. SR ±perindopril N Engl J Med 2008; 358/ACC 2008

Hypertension in the Very Elderly Trial (HYVET) CVD events HR 95% CI P value

Hypertension in the Very Elderly Trial (HYVET) CVD events HR 95% CI P value All stroke - 34% 0. 46 - 0. 95 0. 025 Total mortality - 28% 0. 59 - 0. 88 0. 001 Fatal stroke - 45% 0. 33 - 0. 93 0. 021 Cardiovascular mortality - 27% 0. 55 -0. 97 0. 029 Heart failure - 72% 0. 17 -0. 48 <0. 001 Cardiovascular events - 37% 0. 51 -0. 71 <0. 001 (3845 Participants) N Engl J Med 2008; 358/ACC 2008

 • RCT comparing SBP goal of <140 vs. < 120 mm Hg •

• RCT comparing SBP goal of <140 vs. < 120 mm Hg • Men and women > 50 years old • SBP 130 – 180 mm Hg (Treated or untreated) • High Risk – – Clinical or subclinical CVD CKD (GFR 20 – 59) Framingham Risk Score ≥ 15% Age ≥ 75 years • Exclusions: prior stroke, severe CKD, CHF, diabetes SPRINT. N Engl J Med 2015 November 9

SPRINT Outcomes Primary Outcome (MI, Stroke, Heart failure, ACS, CV death) 25% RRR Total

SPRINT Outcomes Primary Outcome (MI, Stroke, Heart failure, ACS, CV death) 25% RRR Total Mortality 27% RRR Standard (319 events) Intensive (243 events) SPRINT. N Engl J Med 2015 November 9

SPRINT: Pre-specified Subgroups The elderly cohort had the same benefit as seen in the

SPRINT: Pre-specified Subgroups The elderly cohort had the same benefit as seen in the overall study population SPRINT. N Engl J Med 2015 November 9

SPRINT Serious Adverse Events Number (%) of Participants Intensive Standard HR (p value) 1793

SPRINT Serious Adverse Events Number (%) of Participants Intensive Standard HR (p value) 1793 (38. 3) 1736 (37. 1) 1. 04 (0. 25) Hypotension 110 (2. 4) 66 (1. 4) 1. 67 (0. 001) Syncope 107 (2. 3) 80 (1. 7) 1. 33 (0. 05) Injurious fall 105 (2. 2) 110 (2. 3) 0. 95 (0. 71) Bradycardia 87 (1. 9) 73 (1. 6) 1. 19 (0. 28) Electrolyte abnormality 144 (3. 1) 107 (2. 3) 1. 35 (0. 020) Acute kidney injury or renal failure 193 (4. 1) 117 (2. 5) 1. 66 (<0. 001) SAE reports SPRINT. N Engl J Med 2015 November 9

SPRINT Outcomes Primary Outcome (MI, Stroke, Heart failure, ACS, CV death) 25% RRR Total

SPRINT Outcomes Primary Outcome (MI, Stroke, Heart failure, ACS, CV death) 25% RRR Total Mortality 27% RRR Standard (319 events) Intensive (243 events) Standard (319 events) In SPRINT: BP readings were obtained Intensive automatically without the presence of a (243 events) healthcare professional. SPRINT. N Engl J Med 2015 November 9

Comparison of office, home and ambulatory BP measurements Mean Systolic BP Study N Kleinert

Comparison of office, home and ambulatory BP measurements Mean Systolic BP Study N Kleinert 1984 93 148 131 Flapan 1987 24 167 151 126 Kenny 1987 19 156 147 139 Marolf 1987 31 147 134 130 Bialy 1988 15 129 131 130 James 1988 13 155 141 133 O’brien 1988 18 160 153 148 Mengden 1992 51 153 147 149 1438 128 119 118 1702 131. 6 122. 5 120. 7 Mancia 1995 Average Office Self ABPM Appel LJ, et. al. . Ann Intern Med, 118(11): 867 -82.

2013 ESH / ESC Guidelines for the Management of Hypertension: ELDERLY Clinical scenario Recommendations

2013 ESH / ESC Guidelines for the Management of Hypertension: ELDERLY Clinical scenario Recommendations Fit elderly patients aged <80 years • Target SBP: <140 mm. Hg Elderly >80 years with initial SBP ≥ 160 mm. Hg • Reduce SBP to 140 -150 mm. Hg providing in good physical and mental condition Frail elderly • Hypertension treatment decision at discretion of treating clinician Continuation of well- tolerated hypertension treatment • Consider when patients become octogenarians All hypertension treatment agents are recommended and may be used in elderly • Diuretics, CCBs, preferred for isolated systolic hypertension Adapted from: The Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC) - J Hypertension 2013; 31: 1281 -1357

Educational Objectives • Evaluate current data on hypertension management and review current guidelines •

Educational Objectives • Evaluate current data on hypertension management and review current guidelines • Review current ACC recommendations for the addition of nonstatin medications to statin therapy • Discuss the role of PCSK 9 inhibitors and other nonstatin lipid lowering agents in the management of dyslipidemia and cardiac risk

68 year old man with recurrent atherosclerotic events • 68 year old man with

68 year old man with recurrent atherosclerotic events • 68 year old man with history of recurrent atherosclerotic events (NSTEMI, TIA, UA) • Currently on 80 mg atorvastatin daily with an LDL-c of 98 mg/d. L • While on this therapy, he suffers another NSTEMI • What else can we do?

We haven’t yet seen the floor of LDL-c lowering benefit J Am Coll Cardiol

We haven’t yet seen the floor of LDL-c lowering benefit J Am Coll Cardiol 2014; 64: 485– 94)

 2016 ACC Expert Consensus Lloyd-Jones D et. al. J Am Coll Cardiol. 2016;

2016 ACC Expert Consensus Lloyd-Jones D et. al. J Am Coll Cardiol. 2016; 67(5): 558 -587.

 2016 ACC Expert Consensus • The 2013 ACC-AHA cholesterol guidelines were intentionally vague

2016 ACC Expert Consensus • The 2013 ACC-AHA cholesterol guidelines were intentionally vague on the use of non-statin therapy • To offer clinicians more guidance, the American College of Cardiology convened an Expert Panel to offer guidance: – In what patients should non-statin therapy be considered? – In what situations should non-statin therapy be considered? – If non-statins are used, which agents and in what order? Lloyd-Jones D et. al. J Am Coll Cardiol. 2016; 67(5): 558 -587.

2016 ACC Expert Consensus: “Thresholds” at which to consider adding a non-statin • Familial

2016 ACC Expert Consensus: “Thresholds” at which to consider adding a non-statin • Familial Hypercholesterolemia (or LDL > 190 mg/d. L) • If LDL-c >100 mg/d. L or < 30 -50% LDL-c reduction • Diabetes • If LDL-c >100 mg/d. L (or Non-HDL-c >130 mg/d. L) OR if < 3050% LDL-c reduction • Uncomplicated ASCVD • If LDL-c >100 mg/d. L • Complicated ASCVD (ASCVD + DM or FH, recent ACS or stroke, ASCVD event while on a statin) • If LDL-c >70 mg/d. L or < 50% LDL-c reduction Lloyd-Jones D et. al. J Am Coll Cardiol. 2016; 67(5): 558 -587.

2016 ACC Expert Consensus: Which Agents to use • Ezetimibe is the first choice

2016 ACC Expert Consensus: Which Agents to use • Ezetimibe is the first choice • Bile acid sequestration may be considered if Ezetimibe is not tolerated • PCSK 9 inhibitors may be considered if the goals of therapy have not been achieved on maximally tolerated statin plus ezetimibe Lloyd-Jones D et. al. J Am Coll Cardiol. 2016; 67(5): 558 -587.

IMPROVE-IT Study Design Patients < 10 days post ACS; LDL < 125 mg/d. L

IMPROVE-IT Study Design Patients < 10 days post ACS; LDL < 125 mg/d. L N=18, 144 ASA plus standard medical therapy Simvastatin 40 mg Eze/Simva 10/40 mg Duration: Minimum 2 ½ year follow up (5250 events) Primary Endpoint: CV death, MI, Hopital Admission for Unstable angina, revascularization, or stroke Cannon CP AHJ 2008; 156: 826 -32

Primary Endpoint CV death, MI, unstable angina requiring rehospitalization, coronary revascularization (≥ 30 days),

Primary Endpoint CV death, MI, unstable angina requiring rehospitalization, coronary revascularization (≥ 30 days), or stroke 6 % RRR HR 0. 936 CI (0. 887, 0. 988) p=0. 016 Simva — 34. 7% 2742 events EZ/Simva — 32. 7% 2572 events Cannon et al. N Engl J Med 2015; 372: 2387 -2397

CV Death, Non-fatal MI, or Non-fatal Stroke HR 0. 90 CI (0. 84, 0.

CV Death, Non-fatal MI, or Non-fatal Stroke HR 0. 90 CI (0. 84, 0. 97) p=0. 003 NNT= 56 10 % RRR Simva — 22. 2% 1704 events EZ/Simva — 20. 4% 1544 events Cannon et al. N Engl J Med 2015; 372: 2387 -2397

68 year old man with recurrent atherosclerotic events • 68 year old man with

68 year old man with recurrent atherosclerotic events • 68 year old man with history of recurrent atherosclerotic events (NSTEMI, TIA, UA) • Currently on 80 mg atorvastatin daily with an LDL-c of 98 mg/d. L • While on this therapy, he suffers another NSTEMI • What else can we do? We add ezetimibe 10 mg daily to his regimen and his LDL falls to 79 mg/d. L

2016 ACC Expert Consensus: “Thresholds” at which to consider adding a non-statin • Familial

2016 ACC Expert Consensus: “Thresholds” at which to consider adding a non-statin • Familial Hypercholesterolemia (or LDL > 190 mg/d. L) • If LDL-c >100 mg/d. L or < 30 -50% LDL-c reduction • Diabetes • If LDL-c >100 mg/d. L (or Non-HDL-c >130 mg/d. L) OR if < 3050% LDL-c reduction • Uncomplicated ASCVD • If LDL-c >100 mg/d. L • Complicated ASCVD (ASCVD + DM or FH, recent ACS or stroke, ASCVD event while on a statin) • If LDL-c >70 mg/d. L or < 50% LDL-c reduction Lloyd-Jones D et. al. J Am Coll Cardiol. 2016; 67(5): 558 -587.

2016 ACC Expert Consensus: Which Agents to use • Ezetimibe is the first choice

2016 ACC Expert Consensus: Which Agents to use • Ezetimibe is the first choice • Bile acid sequestration may be considered if Ezetimibe is not tolerated • PCSK 9 inhibitors may be considered if the goals of therapy have not been achieved on maximally tolerated statin plus ezetimibe Lloyd-Jones D et. al. J Am Coll Cardiol. 2016; 67(5): 558 -587.

Educational Objectives • Evaluate current data on hypertension management and review current guidelines •

Educational Objectives • Evaluate current data on hypertension management and review current guidelines • Review current ACC recommendations for the addition of nonstatin medications to statin therapy • Discuss the role of PCSK 9 inhibitors and other nonstatin lipid lowering agents in the management of dyslipidemia and cardiac risk

PCSK 9 (Proprotein convertase subtilisin/kexin type 9) • A secreted protein which targets the

PCSK 9 (Proprotein convertase subtilisin/kexin type 9) • A secreted protein which targets the LDL receptor for degradation • Gain of function mutations cause high LDL-C • Loss of function mutations cause low LDL-C • Inhibition of PCSK 9 lowers LDL-C levels

How is cholesterol removed from blood? LIVER Circulating LDL particles (which contain a large

How is cholesterol removed from blood? LIVER Circulating LDL particles (which contain a large Apo. B protein) are “grabbed” by an LDL receptor

How is cholesterol removed from blood? LIVER The entire complex is then internalized into

How is cholesterol removed from blood? LIVER The entire complex is then internalized into the hepatocyte for LDL destruction

How is cholesterol removed from blood? Then the LDL particle is destroyed LIVER Before

How is cholesterol removed from blood? Then the LDL particle is destroyed LIVER Before the LDL particle is destroyed, the LDL receptor migrates back to the hepatocyte cell surface so that it can grab more LDL molecules

How is cholesterol removed from blood? When PCSK 9 is present, however, the LDL

How is cholesterol removed from blood? When PCSK 9 is present, however, the LDL receptor gets “stuck” and cannot migrate back to the surface LIVER It therefore gets destroyed along with the LDL And surface LDL receptors are depleted from the cell surface

The theory behind PCSK 9 inhibitors X If PCSK 9 is inhibited, the LDL

The theory behind PCSK 9 inhibitors X If PCSK 9 is inhibited, the LDL receptor can migrate back to the cell surface LIVER And surface LDL receptors will be restored which will lower serum cholesterol

FDA approved PCSK 9 Inhibitors Molecule Description Alirocumab Fully human Ig. G 1 m.

FDA approved PCSK 9 Inhibitors Molecule Description Alirocumab Fully human Ig. G 1 m. Ab Evolocumab Fully human Ig. G 1 m. Ab

FOURIER Trial - Evolocumab Sabatine MS et al. Am H J 2016; 173: 94

FOURIER Trial - Evolocumab Sabatine MS et al. Am H J 2016; 173: 94 -101

Fourier Trial lipid results Sabatine MS et al. Am H J 2016; 173: 94

Fourier Trial lipid results Sabatine MS et al. Am H J 2016; 173: 94 -101

Fourier Trial: Primary Outcome 15% RRR Sabatine MS et al. Am H J 2016;

Fourier Trial: Primary Outcome 15% RRR Sabatine MS et al. Am H J 2016; 173: 94 -101

Fourier Trial: MI/Stroke/CV Death 20% RRR Sabatine MS et al. Am H J 2016;

Fourier Trial: MI/Stroke/CV Death 20% RRR Sabatine MS et al. Am H J 2016; 173: 94 -101

The PCSK 9 inhibitor Evolocumab • ↓ LDL-C by 59% – Mean LDL-C achieved

The PCSK 9 inhibitor Evolocumab • ↓ LDL-C by 59% – Mean LDL-C achieved 30 mg/d. L ( interquartile range 19 -46 mg/d. L) • ↓ cardiovascular events in patients already on statin – 15% ↓ in primary endpoint (MI, stroke, CV death, UA, revascularization) – 20% ↓ in CV death, MI or stroke • Was safe and well tolerated But is it worth the price? ~$14, 000 / year Kazi DS et al. JAMA. 2016; 316(7): 743 -753.

Alirocumab: ODYSSEY LONGTERM Study Design Double-blind treatment (18 months) Patients with He. FH or

Alirocumab: ODYSSEY LONGTERM Study Design Double-blind treatment (18 months) Patients with He. FH or high CV risk -on maximally tolerated statin -LDL-C > 70 mg/d. L Alirocumab 150 mg SC Q 2 W R Placebo SC Q 2 W Robinson JG, et al. NEJM. March 15, 2015. doi: 10. 1056/NEJMoa 1501031.

Alirocumab (ODYSSEY LONGTERM) LDL-Cholesterol Levels Over Time (ITT) Least-Squares Mean Calculated LDL-C Level (mg/d.

Alirocumab (ODYSSEY LONGTERM) LDL-Cholesterol Levels Over Time (ITT) Least-Squares Mean Calculated LDL-C Level (mg/d. L) 140 120 100 80 -52. 4%* 60 -61. 0%* 40 20 0 Placebo + statin therapy at maximum tolerated dose +/- LLT Alirocumab + statin therapy at maximum tolerated dose +/- LLT 0 4 8 12 16 24 36 52 64 78 Week Robinson JG, et al. NEJM. March 15, 2015

Post hoc Analysis of a Subgroup of Major Adverse Cardiovascular Events 1. 0 0.

Post hoc Analysis of a Subgroup of Major Adverse Cardiovascular Events 1. 0 0. 06 Cumulative probability of event 0. 8 0. 04 0. 6 0. 02 0. 4 0. 00 0. 2 Cox model analysis HR = 0. 52 (95% CI 0. 31 to 0. 90) Nominal P-value = <0. 01 0 12 24 36 52 64 78 86 0. 0 0 12 24 36 52 64 78 86 Time (weeks) No. at Risk Placebo 788 776 731 700 670 653 644 597 Alirocuma b 1550 1533 1445 1392 1342 130 6 1266 1170 Placebo + statin therapy at maximum tolerated dose +/- LLT Alirocumab + statin therapy at maximum tolerated dose +/- LLT Robinson JG, et al. NEJM. March 15, 2015.

Evolocumab (OSLER-1 and OSLER-2) Incidence of Cardiovascular Events Sabatine MS, et al. NEJM March

Evolocumab (OSLER-1 and OSLER-2) Incidence of Cardiovascular Events Sabatine MS, et al. NEJM March 15, 2015.

68 year old man with recurrent atherosclerotic events • 68 year old man with

68 year old man with recurrent atherosclerotic events • 68 year old man with history of recurrent atherosclerotic events (NSTEMI, TIA, UA) • Currently on 80 mg atorvastatin and ezetimibe 10 mg daily with an LDL-c of 79 mg/d. L • We add PCSK 9 inhibitor to his regimen. His LDL falls to 38 mg/d. L Is this low LDL level safe?

EBBINGHAUS: - A Cognitive Study of Patients Enrolled in the FOURIER Trial RP Giugliano,

EBBINGHAUS: - A Cognitive Study of Patients Enrolled in the FOURIER Trial RP Giugliano, F Mach, K Zavitz, AC Keech, TR Pedersen, MS Sabatine, P Sever, C Kurtz, N Honarpour, BR Ott, on behalf of the EBBINGHAUS Investigators American College of Cardiology – 66 th Annual Scientific Session Late-Breaking Clinical Trial March 18, 2017

Cognition and Statins – Case series and 2 small, short (6 month) trials with

Cognition and Statins – Case series and 2 small, short (6 month) trials with statins raised concern regarding cognitive deficits – In 2012 FDA issued an advisory saying adverse cognitive effects had been reported with statins – However large scale RCTs do not support these findings and a NLA 2014 Statin Cognitive Safety Task Force* concluded that statins are not associated with cognitive side effects. *The National Lipid Task Force. Rojas-Fernandez CH, et al. J Clin. Lipidol. 2014; 8(3 Suppl): S 5 -16.

EBBINGHAUS: Hypothesis The addition of evolocumab to statin therapy in patients with clinically evident

EBBINGHAUS: Hypothesis The addition of evolocumab to statin therapy in patients with clinically evident vascular disease would not adversely affect cognitive function EBBINGHAUS analyzed a subset of FOURIER patients (1974 subjects) Giugliano RP et al. Clin Card 2017; 40: 59– 65

EBBINGHAUS Endpoints 1. Cambridge Neuropsychological Test Automated Battery (CANTAB) Assessments. Primary: Spatial working memory

EBBINGHAUS Endpoints 1. Cambridge Neuropsychological Test Automated Battery (CANTAB) Assessments. Primary: Spatial working memory strategy index 2. Secondary: Patient survey of cognition* at study end 3. Secondary Investigator report of cognitive AEs *Memory and executive function domains Owen 1990 PMID: 2267054; Sahakian 1988, PMID: 3382917; Owen 1996 PMID: 8714706; Kollins PMID: 21476931 Giugliano RP et al. Clin Card 2017; 40: 59 -65

Primary Endpoint Spatial Working Memory Strategy Index Mean Number of boxes 25 Placebo Evolocumab

Primary Endpoint Spatial Working Memory Strategy Index Mean Number of boxes 25 Placebo Evolocumab 20 15 17. 8 17. 6 17. 5 Baseline Post baseline 10 5 0 -5 -0. 29 -0. 21 Cha nge

Mean D of boxes Cognitive Assessments by Nadir Achieved LDL-C and Treatment 4 Placebo

Mean D of boxes Cognitive Assessments by Nadir Achieved LDL-C and Treatment 4 Placebo Evolocumab Primary CANTAB Endpoint* Change from Baseline 2 0 -2 -4 No. pts 661 <25 mg/d. L 206 13 115 969 25 -39 mg/d. L Nadir LDL-Achieved (mg/d. L) ≥ 40 mg/d. L Mean D –Z score P=NS between treatments and across LDL values achieved 1 Composite Global Score Change from Baseline 0. 5 0 -0. 5 -1 <25 mg/d. L 25 -39 mg/d. L > 40 mg/d. L Negative score -> improvement. Lower scores are better

Secondary Endpoint: Patient Self-Report: of Everyday Cognition (23 questions) 4 Placebo Evolocumab 3 P

Secondary Endpoint: Patient Self-Report: of Everyday Cognition (23 questions) 4 Placebo Evolocumab 3 P = 0. 42 2 1 P = 0. 83 1. 14 1. 16 1. 17 Total Score Memory P = 0. 28 1. 11 1. 12 Executive Functioning Patient self-report at end of study as compared to randomization, graded as 1. Better or no change; 2. Questionable / occasionally worse 3. Consistently a little worse; 4. Consistently much worse *Includes sub-domains of planning, organization, and divided attention Results shown are in the full study population

Secondary Endpoint: Investigator Reported Cognitive Adverse Events 10 Placebo Evolocumab % of patients 8

Secondary Endpoint: Investigator Reported Cognitive Adverse Events 10 Placebo Evolocumab % of patients 8 6 4 P = 0. 42 P = 0. 59 2 0 8/618 Primary Cohort (N=1204) 16/990 Full Population (N=1973)

Cognition and Cholesterol The brain synthesizes cholesterol locally *Lipinski MJ, et al. Eur Heart

Cognition and Cholesterol The brain synthesizes cholesterol locally *Lipinski MJ, et al. Eur Heart J. 2016; 37(6): 536 -545.

Summary • Reducing BP to < 140/90 mm. Hg is an appropriate goal for

Summary • Reducing BP to < 140/90 mm. Hg is an appropriate goal for the majority of patients with HTN • Reducing BP to < 120 mm Hg may be appropriate in HIGH risk patients with hypertension • Reducing LDL-c beyond currently achieved levels may improve outcomes in high risk patients • BUT remember, whenever you intensify drug therapy, you may have increased side effects • Cost benefit analyses of newer cholesterol agents will be crucial