Educational Objectives

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 PCSK9 inhibitors and other nonstatin lipid lowering agents in the management of dyslipidemia and cardiac risk Let’s discuss the first educational objective first. And we’ll start off with a case

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 ; e69-171

Even if you make it to age 65 without HTN, you’ll likely develop it
100 Men 80 Risk of hypertension (%) 60 Women 40 In a Framingham cohort study, the lifetime risk of developing hypertension (blood pressure [BP] ≥140/90 mm Hg) was 90% both for participants who reached the age of 55 years free of hypertension (data not shown) and for participants who reached the age of 65 years free of hypertension. The high lifetime risk for hypertension was similar for men and women and did not differ for participants aged 55 years versus 65 years. More than half of the 55-year-old participants and about two thirds of the 65-year-old participants developed hypertension within 10 years of follow-up, indicating the importance of adopting lifestyle changes for maintaining optimal BP and preventing the development of hypertension. References Vasan RS, Beiser A, Seshadri S, et al. Residual lifetime risk for developing hypertension in middle-aged women and men. The Framingham Heart Study. JAMA. 2002;287: 20 65 67 69 71 73 75 77 79 81 83 85 age Vasan RS et al. JAMA. 2002;287:

Blood Pressure Distribution in the Population According to Age
BP trajectory accelerates about the time of menopause Women Men 150 150 130 130 PP PP 110 110 80 80 There is an age-related rise in BP in the general population. Systolic BP continues to rise with age. Diastolic BP peaks at years of age and then tenfds to fall away. Much oft he hypertension in oled age groups is Isolated Systolic Hypertension (ISH). 70 70 30-39 40-49 50-59 60-69 70-79  80 30-39 40-49 50-59 60-69 70-79  80 Age PP=Pulse Pressure. Age Adapted from : Third National Health and Nutrition. Examination Survey, Hypertension 1995;25:305-13 6

Reducing SBP Reduces CV Mortality
HOPE MIDAS/NICS/VHAS UKPDS C vs A NORDIL INSIGHT HOT L vs H HOT M vs H STOP ACEIs STOP CCBs CAPPP UKPDS L vs H Syst-China STONE Syst-Eur MRC1 MRC2 SHEP HEP EWPHE RCT70-80 STOP-1 PART 2/SCAT ATMH 1.50 P = 0.003 1.25 1.00 Odds Ratio 0.75 0.50 Relationship Between SBP Reduction and CV Mortality In this slide we see a meta-analysis of a large number of outcomes studies performed in hypertensive patients. This clearly demonstrates that reducing systolic BP decreases cardiovascular mortality and confirms that the greater the reduction in systolic BP, the greater the cardiovascular benefit. Reference: Staessen JA, et. al. Cardiovascular Protection and Blood Pressure Reduction: a Meta-analysis. Lancet 2001;358: 0.25 - 5 5 10 15 20 25 Difference in SBP (mmHg) Staessen JA, et al. Lancet. 2001;358:

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

JAMA. Published online December 18, 2013. doi:10.1001/jama.2013.284427

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

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 – 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: < 140/85 ASH/ISH: < 140/90 CHEP: < 130/80 ADA: < 140/80 ACP AAFP: < 140/90 JNC 8: < 140/90 And virtually every other worldwide guideline

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 > 60 years JNC 8: < 150/90 ESH/ESC: < 150/90 CHEP: < 150/90 NICE: < 150/90 ASH/ISH: < 150/90 > 80 years > 80 years > 80 years > 80 years

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

HYVET Trial: Study Design
Hypertension lecture-Karol E. Watson, MD, PhD 9/12/2018 7:44 PM HYVET Trial: Study Design 3,845 patients > 80 years with SBP ≥ 160 mm Hg Exclusion Criteria: Standing SBP < 140mmHg 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 mmHg 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 17

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 IndapamideSR ±perindopril N Engl J Med 2008;358/ACC 2008

Total Mortality (21% reduction)
Placebo P=0.019 Indapamide ±perindopril Placebo IndapamideSR ±perindopril N Engl J Med 2008;358/ACC 2008

Fatal Stroke (39% reduction)
Placebo Indapamide ±perindopril P=0.046 Placebo IndapamideSR ±perindopril N Engl J Med 2008;358/ACC 2008

Heart Failure (64% reduction)
Placebo P<0.0001 Indapamide ±perindopril Placebo IndapamideSR ±perindopril N Engl J Med 2008;358/ACC 2008

Hypertension in the Very Elderly Trial (HYVET)
CVD events (3845 Participants) HR 95% CI P value All stroke - 34% 0.025 Total mortality - 28% 0.001 Fatal stroke - 45% 0.021 Cardiovascular mortality - 27% 0.029 Heart failure - 72% <0.001 Cardiovascular events - 37% N Engl J Med 2008;358/ACC 2008

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

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

SPRINT Serious Adverse Events
SAE reports 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) 1.35 (0.020) Acute kidney injury or renal failure 193 (4.1) 117 (2.5) 1.66 (<0.001) SPRINT. N Engl J Med 2015 November 9

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

Comparison of office, home and ambulatory BP measurements
Hypertension lecture-Karol E. Watson, MD, PhD 9/12/2018 7:44 PM Comparison of office, home and ambulatory BP measurements Study N Mean Systolic BP Office Self ABPM Kleinert 1984 93 148 138 131 Flapan 1987 24 167 151 126 Kenny 1987 19 156 147 139 Marolf 1987 31 134 130 Bialy 1988 15 129 James 1988 13 155 141 133 O’brien 1988 18 160 153 Mengden 1992 51 149 Mancia 1995 1438 128 119 118 Average 1702 131.6 122.5 120.7 Appel LJ, et. al. .Ann Intern Med, 118(11):

2013 ESH / ESC Guidelines for the Management of Hypertension: ELDERLY
Clinical scenario Recommendations Fit elderly patients aged <80 years Target SBP: <140 mmHg Elderly >80 years with initial SBP ≥160 mmHg Reduce SBP to mmHg 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:

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/dL While on this therapy, he suffers another NSTEMI What else can we do? Let’s look at another case. This is a gentleman with “complicated” ASCVD. Remember Complicated ASCVD is defined as: ASCVD + DM or FH recent ACS or stroke ASCVD event while on a statin Since he keeps having recurrent ASCVD events, even while on a statin (+ ezetimibe) we need to consider additional LDL lowering

We haven’t yet seen the floor of LDL-c lowering benefit
The reason for that is that we haven’t yet seen the floor of LDL lowering benefit. In this data we see that even when you get the LDL down to between 50-70, further lowering it to < 50 mg/dL confers benefit J Am Coll Cardiol 2014;64:485–94)

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

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? 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):

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

2016 ACC Expert Consensus: Which Agents to use
Ezetimibe is the first choice Bile acid sequestration may be considered if Ezetimibe is not tolerated PCSK9 inhibitors may be considered if the goals of therapy have not been achieved on maximally tolerated statin plus ezetimibe Ezetimibe is the first choice Bile acid sequestration may be considered if Ezetimibe is not tolerated PCSK9 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):

IMPROVE-IT Study Design
Patients < 10 days post ACS; LDL < 125mg/dL ASA plus standard medical therapy N=18,144 Simvastatin 40 mg Eze/Simva 10/40mg PROVE IT is a double-blind, randomized trial that has enrolled 4,160 patients, at approximately 400 sites in the US, Europe, Canada, and Australia, who have experienced an acute coronary syndrome (Q wave and non-Q-wave MI or unstable angina) within the previous 10 days. Patients received either 40 mg of pravastatin or 80 mg of atorvastatin within 10 days of their event and were followed for a mean follow-up period of 2 years. To study the role of infection in ACS, one half of the patients in the trial also received gatifloxacin 400 mg in addition to either pravastatin or atorvastatin. Gatifloxacin was started on day 15 after the initial episode of ACS for a treatment period of 14 days. Gatifloxacin was subsequently given as a pulsed dose of 400mg per day for 10 days each month for a mean of 2 years. The other half of the patient population received an antibiotic placebo. Let’s look at the data elevating ezetimibe to the first choice. The Improve-it trial is the basis for this recommendation. With the publication of the Improve It trial, ezetimibe became the only non statin therapy to show additional ASCVD risk reduction benefit on top of statins. In the Improve It trial, Patients within 10 days of suffering an ACS; and with an LDL < 125mg/dL were randomized to receive Simvastatin 40 mg daily or Ezetimibe 10 mg + Simvastatin 40 mg daily, on top of standard medical therapy. The Primary Endpoint: CV death, MI, Hopital Admission for Unstable angina, revascularization, or stroke The study was designed to last at least 2-1/2 years or 5250 events, whichever occurred later. It ended up taking almost 7 years to accrue enough events Since 2016, however we have had publication of the Fourier trial which showed additional ASCVD risk reduction benefit of the PCSK 9 inhibitor evolocumab on top of statins 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 38

Primary Endpoint CV death, MI, unstable angina requiring rehospitalization, coronary revascularization (≥30 days), or stroke 6 % RRR HR CI (0.887, 0.988) p=0.016 Simva — 34.7% 2742 events EZ/Simva — 32.7% 2572 events After almost 7 years, the individuals randomized to the combination of ezetimibe and simvastatin had a 6% RRR (2% absolute RR) in the primary outcome. Cannon et al. N Engl J Med 2015; 372:

CV Death, Non-fatal MI, or Non-fatal Stroke
10 % RRR HR 0.90 CI (0.84, 0.97) p=0.003 NNT= 56 Simva — 22.2% 1704 events EZ/Simva — 20.4% 1544 events After almost 7 years, the individuals randomized to the combination of ezetimibe and simvastatin had a 10% RRR (1.8% absolute RR) in the important secondary outcome of a composite of CV death, nonfatal MI or non fatal stroke. Cannon et al. N Engl J Med 2015; 372:

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/dL While on this therapy, he suffers another NSTEMI What else can we do? Let’s look at another case. This is a gentleman with “complicated” ASCVD. Remember Complicated ASCVD is defined as: ASCVD + DM or FH recent ACS or stroke ASCVD event while on a statin Since he keeps having recurrent ASCVD events, even while on a statin (+ ezetimibe) we need to consider additional LDL lowering We add ezetimibe 10 mg daily to his regimen and his LDL falls to 79 mg/dL

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

2016 ACC Expert Consensus: Which Agents to use
Ezetimibe is the first choice Bile acid sequestration may be considered if Ezetimibe is not tolerated PCSK9 inhibitors may be considered if the goals of therapy have not been achieved on maximally tolerated statin plus ezetimibe Ezetimibe is the first choice Bile acid sequestration may be considered if Ezetimibe is not tolerated PCSK9 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):

PCSK9 (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 PCSK9 lowers LDL-C levels The medication class that will likely do this is the PCSK9 inhibitors

How is cholesterol removed from blood?
LIVER Circulating LDL particles (which contain a large ApoB protein) are “grabbed” by an LDL receptor Let’s review how cholesterol is removed from the blood: Circulating LDL particles (which contain a large ApoB protein) are “grabbed” by the LDL receptors

LIVER The entire complex is then internalized into the hepatocyte for LDL destruction When the LDL receptors grab the LDL particle, The entire complex is then internalized into the hepatocyte for LDL destruction. This is called receptor mediated endocytosis, and it is the mechanism for which Brown and Goldstein won the Nobel prize

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 Once the LDL molecule is brought into the hepatocyte, the LDL particle is destroyed. But before the LDL particle is destroyed, the LDL receptor migrates back to the hepatocyte cell surface so that it can grab more LDL molecules

When PCSK9 is present, however, the LDL receptor gets “stuck” and cannot migrate back to the surface LIVER It therefore gets destroyed along with the LDL When PCSK9 is present, however, the LDL receptor gets “stuck” and cannot migrate back to the surface It therefore gets destroyed along with the LDL And surface LDL receptors are depleted from the cell surface And surface LDL receptors are depleted from the cell surface

The theory behind PCSK9 inhibitors
If PCSK9 is inhibited, the LDL receptor can migrate back to the cell surface X LIVER The theory behind PCSK9 inhibitors, is that If PCSK9 is inhibited, the LDL receptor can migrate back to the cell surface, And surface LDL receptors will be restored which will lower serum cholesterol And surface LDL receptors will be restored which will lower serum cholesterol

FDA approved PCSK9 Inhibitors
Molecule Description Alirocumab Fully human IgG1 mAb Evolocumab Thus far, two PCSK9 inhibitors have been approved by the FDA

FOURIER Trial - Evolocumab
The Fourier trial was a randomized, double-blind, placebo-controlled trial involving 27,564 patients with atherosclerotic cardiovascular disease and LDL cholesterol levels of 70 mg per deciliter or higher who were receiving statin therapy. Patients were randomly assigned to receive evolocumab (either 140 mg every 2 weeks or 420 mg monthly) or matching placebo as subcutaneous injections. The primary end point was the composite of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization. The key secondary efficacy end point was the composite of cardiovascular death, myocardial infarction, or stroke. The median duration of follow-up was 2.2 years. Sabatine MS et al. Am H J 2016; 173:

Fourier Trial lipid results
At 48 weeks, the mean percentage reduction in LDL cholesterol levels with evolocumab, as compared with placebo, was 59%, from a median baseline value of 92 mg /dL (P<0.001). There was no significant drift over time Sabatine MS et al. Am H J 2016; 173:

Fourier Trial: Primary Outcome
15% RRR Relative to placebo, evolocumab treatment significantly reduced the risk of the primary end point (1344 patients [9.8%] vs patients [11.3%]; hazard ratio, 0.85; 95% confidence interval [CI], 0.79 to 0.92; P<0.001) Sabatine MS et al. Am H J 2016; 173:

Fourier Trial: MI/Stroke/CV Death
20% RRR Relative to placebo, evolocumab treatment also significantly reduced the risk of the key secondary end point of nonfatal MI, nonfatal stroke or CV death (816 [5.9%] vs [7.4%]; hazard ratio, 0.80; 95% CI, 0.73 to 0.88; P<0.001). The results were consistent across key subgroups, including the subgroup of patients in the lowest quartile for baseline LDL cholesterol levels There was no significant difference between the study groups with regard to adverse events (including new-onset diabetes and neurocognitive events), with the exception of injection-site reactions, which were more common with evolocumab (2.1% vs. 1.6%). Sabatine MS et al. Am H J 2016; 173:

The PCSK9 inhibitor Evolocumab
↓ LDL-C by 59% Mean LDL-C achieved 30 mg/dL ( interquartile range mg/dL) ↓ 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 Conclusions from the Fourier trial were that inhibition of PCSK9 with evolocumab on a background of statin therapy lowered LDL cholesterol levels to a median of 30 mg /dL and reduced the risk of cardiovascular events. These findings show that patients with atherosclerotic cardiovascular disease benefit from lowering of LDL cholesterol levels below current targets. But is it worth the price? Which currently is ~$14,000 per year But is it worth the price? ~$14,000 / year Kazi DS et al. JAMA. 2016; 316(7):

Alirocumab: ODYSSEY LONGTERM Study Design
Double-blind treatment (18 months) Patients with HeFH or high CV risk -on maximally tolerated statin -LDL-C > 70 mg/dL Alirocumab 150 mg SC Q2W R Placebo SC Q2W Alirocumab, the other FDA approved PCSK9 inhibitor also has a large outcomes study which is currently underway. Although the outcome study has not yet been reported, another long term study of Alirocumab has been reported. The Odyssey Longterm Study Design. In this study, patients with heterozygous Familial Hypercholesterolemia or high CV risk, who wer on maximally tolerated statin therapy and with an LDL cholesterol > or equal to 70 mg/dL were randomized to receive the PCSK9 inhibitor alirocumab 150 mg SC every two weeks or matching placebo SC injection every 2 weeks Robinson JG, et al. NEJM. March 15, doi: /NEJMoa

Alirocumab (ODYSSEY LONGTERM) LDL-Cholesterol Levels Over Time (ITT)
140 120 100 80 -52.4%* Least-Squares Mean Calculated LDL-C Level (mg/dL) 60 -61.0%* 40 LDL fell over 52% in the alirocumab group 20 Placebo + statin therapy at maximum tolerated dose +/- LLT Alirocumab + statin therapy at maximum tolerated dose +/- LLT 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 0.00 0.02 0.04 0.06 12 24 52 64 78 86 36 0.8 0.6 Cumulative probability of event 0.4 0. 2 Cox model analysis HR = 0.52 (95% CI 0.31 to 0.90) Nominal P-value = <0.01 Although this study was not powered to assess cardiovascular outcomes, a post hoc analysis of alirocumab trials indicated a possible 50% in cardiovascular events among patients randomized to alirocumab 0.0 12 24 36 52 64 78 86 Placebo + statin therapy at maximum tolerated dose +/- LLT Time (weeks) No. at Risk Placebo 788 776 731 700 670 653 644 597 Alirocumab 1550 1533 1445 1392 1342 1306 1266 1170 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
And, just like the alirocumab long term study, even lthough this Evolocumab study was not powered to assess cardiovascular outcomes, a post hoc analysis of cardiovascular events also indicated a possible 50% in cardiovascular events among patients randomized to evolocumab. When the true randomized controlled trial of evolocumab (Fourier) was performed however, the benefit was much smaller at 15% Sabatine MS, et al. NEJM March 15, 2015.

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/dL We add PCSK9 inhibitor to his regimen. His LDL falls to 38 mg/dL Is this low LDL level safe? So we add PCSK9 inhibitor to his regimen. His LDL falls to 38 mg/dL Is this low LDL level safe?

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 – 66th Annual Scientific Session Late-Breaking Clinical Trial March 18, 2017

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):S5-16.

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

Primary Endpoint Spatial Working Memory Strategy Index
Well in a parallel trial to the Fourier trial, a subgroup of patients were enrolled in a trial to assess neurocognitive function. Formal cognitive testing was performed pre-PCSK9 treatment, then again following treatment with a median follow up of 19.8 months. There was no significant difference in any cognitive test between placebo and evolocumab groups

Cognitive Assessments by Nadir Achieved LDL-C and Treatment
Placebo Evolocumab No. pts P=NS between treatments and across LDL values achieved <25 mg/dL 25-39 mg/dL > 40 mg/dL Negative score -> improvement. Lower scores are better

Secondary Endpoint: Patient Self-Report: of Everyday Cognition (23 questions)
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
8/618 16/990

Cognition and Cholesterol
The brain synthesizes cholesterol locally That may seem counterintuitive, but we have to remember that the brain synthesizes cholesterol locally. So even in serum cholesterol levels fall significantly, the brain will have plenty of cholesterpol *Lipinski MJ, et al. Eur Heart J. 2016;37(6):

Summary Reducing BP to < 140/90 mmHg 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

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