CV Updates: Pharmacists Technicians Hypertension and 1.Outline - - PDF document

SLIDE 1

1

CV Updates:

Hypertension and Hypercholesterolemia

Joseph Saseen, PharmD, BCPS, BCACP Professor and Vice Chair University of Colorado

Learning Objectives

Pharmacists

1.Outline the 2017 ACC-AHA hypertension guideline recommendations for BP goal values and drug therapy for the management hypertension 2.Examine the evidence supporting lower BP goals for the treatment of patients with hypertension 3.Compare and contrast the 2013 ACC-AHA guidelines for the treatment of hypercholesterolemia with the ACC Expert Consensus Decision Pathway on the Role of Non-Statin Therapies 4.Interpret results from large outcome studies evaluating nonstatin therapies 5.Create treatment plans for patients presenting with hypertension and hypercholesterolemia

Technicians

1. List BP goals for patients with hypertension 2. Identify antihypertensive medications that are recommended as first-line agents 3. Identify moderate-intensity and high-intensity statin doses 4. Name the two patient populations that the PCSK9 inhibitors are indicated for

Pre/Post Question #1

Which of the following BP goals is recommended by the 2017 American College of Cardiology-American Heart Association hypertension guidelines for a 55-year-old patient with diabetes and cardiovascular disease?

• A. <120/80 mm Hg.
• B. <130/80 mm Hg.
• C. <140/90 mm Hg.
• D. <150/90 mm Hg.

Pre/Post Question #2

The SPRINT trial evaluated intense blood pressure lowering versus standard blood pressure lowering. Which of the following clinical events were lower with intensive blood pressure lowering versus standard blood pressure lowering?

• A. The first occurrence of electrolyte abnormalities.
• B. Adverse events that were fatal or life-threatening.
• C. Acute kidney injury and/or acute renal failure.
• D. The first the occurrence of a cardiovascular event.

Pre/Post Question #3

Which of the following medication regimens does the American College of Cardiology/American Heart Association (ACC/AHA) recommend in their 2013 guidelines as initial therapy for patients with a baseline low-density lipoprotein cholesterol (LDL-C) of ≥190 mg/dL?

• A. Atorvastatin 20 mg daily.
• B. Evolocumab 140 mg every 2 weeks.
• C. Rosuvastatin 20 mg daily.
• D. Simvastatin 40 mg daily with ezetimibe.

Pre/Post Question #4

What are the long-term effects of adding evolocumab therapy for patients with stable ASCVD who are already treated with maximally tolerated statin therapy?

• A. Decreased CV events and an increased risk of cataracts.
• B. No change in CV events, but greater than a 50% decrease in

LDL-C.

• C. Decreased CV events and an increased risk of injection site

reactions.

• D. No change in CV events, but a trend toward decreased risk of

major CV events after 2.2 years.

SLIDE 2

2 2014 Goal BP Recommendations

ASH/ISH = American Society of Hypertension/International Society of Hypertension; JNC = Joint National Committee; CKD = chronic kidney disease Weber MA et al. J Hypertens. 2014;32(1):14-26. James PA et al. JAMA. 2014; 311(5):507-20.

ASH/ISH Guidelines

Age < 80 years:

• <140/90 mm Hg

Age ≥ 80 years:

• <150/90 mm Hg
• <140/90 mm Hg if diabetes or CKD

JNC 8 Report

Age < 60 years:

• <140/90 mm Hg

Age ≥ 60 years:

• <150/90 mm Hg
• <140/90 mm Hg if diabetes or CKD

Hypertension in the U.S.

31.6 34.7 39.7 43.3 48.4 53.1 51.8 53.9 48.3 28.4 27.9 29.9 29.1 29.6 28.6 28.7 29.3 29 20 25 30 35 40 45 50 55 60

99-00 00-02 03-04 05-06 07-08 09-10 11-12 13-14 15-16

Percentage Years

Control (BP<140/90 mm Hg) Prevalence

Fryar CD, et al. NCHS Data Brief 2017;289

Hot off the press…

https://www.acc.org/guidelines/hubs/high-blood-pressure

2017 ACC-AHA Hypertension Guideline

Class of Recommendation (COR) - Strength Level of Evidence (LOE) - Quality

Whelton PK, et al. Hypertension. 2017 [Epub ahead of print].

Class I (Strong) Benefit >>> Risk

• Is recommended, is indicated, should be p

erformed

Class IIa (Moderate) Benefit >> Risk

• Is reasonable, can be useful

Class IIb (Weak) Benefit ≥ Risk

• May/might be reasonable/considered, effectiveness unknown

Class III: No Benefit (Moderate) Benefit = Risk

• Is not recommended, is not useful

Class III: Harm (Strong) Benefit < Risk

• Potentially harmful, causes harm

Level A

• High-quality evidence from > one randomized clinical trial (RCT)
• Meta-analyses of high-quality RCTs

Level B-R (Randomized)

• Moderate-quality evidence from > one RCT
• Meta-analyses of moderate-quality RCTs

Level B-NR (Nonrandomized)

• Moderate-quality from nonrandomized studies, observational, registry

Level C-D (Limited Data) Level C-EO (Expert Opinion)

2017 ACC-AHA: BP Categories

BP Category SBP (mm Hg) DBP (mm Hg)

Normal <120 and <80 Elevated 120–129 and <80 Hypertension Stage 1 130–139

• r

80–89 Hypertension Stage 2 ≥140

• r

≥90

If SBP and DBP in 2 different categories, apply the higher category; Based on an average of ≥2 properly measured values obtained on ≥2 occasions DBP, diastolic blood pressure; and SBP systolic blood pressure. Whelton PK, et al. Hypertension. 2017 [Epub ahead of print].

Recall the last time your BP was measured…

Was it measured properly?

SLIDE 3

3 2017 ACC-AHA: BP Measurements

Whelton PK, et al. Hypertension. 2017 [Epub ahead of print].

COR LOE Accurate Measurement of BP I C-EO For diagnosis and management, proper methods are recommended for accurate measurement and documentation of BP

Proper BP Measurements

Step 1: Properly prepare the patient Step 2: Use proper technique for BP measurements Step 3: Take the proper measurements needed for diagnosis and treatment Step 4: Properly document accurate BP readings Step 5: Average the readings Step 6: Provide BP readings to patient

Whelton PK, et al. Hypertension. 2017 [Epub ahead of print].

2017 ACC-AHA Hypertension Guideline

Goal BP of <130/80 mm Hg for most

• Different evidence-based rankings based on ASCVD risk and/or

presence of other comorbidities

• Applies to healthier older patients ≥ 65 yr

Whelton PK, et al. Hypertension. 2017 [Epub ahead of print].

Systolic Blood Pressure Intervention Trial (SPRINT)

• Multicenter, randomized, controlled trial
• 9,361 patients with hypertension randomized open-label to:
• Intensive treatment: SBP <120 mm Hg
• Standard treatment: SBP <140 mm Hg
• Primary outcome: first the occurrence of a MI, acute coronary

syndrome, stroke, heart failure, or CV disease death

Ambrosius WT, et al. Clin Trials. 2014;11(5):532–546.

SPRINT: Study Criteria

Inclusion

• ≥ 50 years old
• SBP 130–180 mm

Hg

• Increased risk for

ASCVD based on additional criteria

Exclusion

• Secondary hypertension
• Diabetes, previous stroke, or CV event

within 3 months

• Symptomatic heart failure within 6 months
• r EF < 35%
• Proteinuria (> 1 g/day), polycystic kidney

disease, glomerulonephritis, eGFR< 20 mL/min/1.73m2 or end-stage renal disease

Ambrosius WT, et al. Clin Trials. 2014;11(5):532–546.

SPRINT: Protocol Procedures

• Medication choice:
• ACEi, ARB, CCB, thiazide first-line; beta-blocker in coronary disease
• Chlorthalidone encouraged as the primary thiazide
• Amlodipine as the preferred CCB
• Titration of medications was based on:
• Mean of three office BP measurements, seated with automated device
• Frequent routine measurement of BP and screening for

hypotension

Ambrosius WT, et al. Clin Trials. 2014;11(5):532–546.

SLIDE 4

4 SPRINT: Patient Characteristics

Intensive Treatment N=4678 Standard Treatment N=4683 Baseline Characteristics

• Mean SBP (mm Hg)
• Women (%)
• Mean Age (yr)
• Age ≥75 yr (%)
• CKD (%)
• Black/Hispanic

139.7 36.0 67.9 28.2 28.5 29.5/10.8 139.7 35.2 67.9 28.2 28.1 30.4/10.3 Results:

• Mean SBP at 1 year (mm Hg)
• Mean no. BP medications

121.4 2.8 136.2 1.8

Sprint Research Group, et al N Engl J Med. 2015;373(22):2103-2106.

SPRINT: Primary Endpoint

Hazard Ratio

Sprint Research Group, et al N Engl J Med. 2015;373(22):2103-2106.

SPRINT Safety Outcomes and NNH

Outcome Intensive Treatment N=4678; no.(%) Standard Treatment N=4683; no.(%) Hazard Ratio (P-Value) Serious Adverse Event ‡ 1793 (38.3) 1736 (37.1) 1.04 (0.25) Individual Serious Adverse Event

• Hypotension
• Syncope
• Electrolyte abnormality
• Injurious fall
• Acute kidney injury/acute renal failure

110 (2.4) 107 (2.3) 144 (3.1) 105 (2.2) 191 (4.3) 66 (1.4) 80 (1.7) 107 (2.3) 110 (2.3) 117 (2.5) 1.67 (0.001) 1.33 (0.05) 1.35 (0.02) 0.95 (0.71) 1.66 (<0.001) Emergency department visit or SAE

• Hypotension
• Syncope
• Electrolyte abnormality
• Injurious fall
• Acute kidney injury/acute renal failure

158 (3.4) 163 (3.5) 177 (3.8) 334 (7.1) 204 (4.4) 93 (2.0) 113 (2.4) 129 (2.8) 332 (7.1) 120 (2.6) 1.70 (<0.001) 1.44 (0.003) 1.38 (0.006) 1.00 (0.97) 1.71 (<0.001)

‡ Serious adverse event defined as fatal or life-threatening or that resulted in clinically significant or persistent disability Sprint Research Group, et al N Engl J Med. 2015;373(22):2103-2106.

SPRINT-Senior: Results

123.4 124.3 134.8 135 115 120 125 130 135 140

Overall Frail

Mean SBP Achieved (mm Hg) Intensive Treatment Standard Treatment Outcome Intensive Treatment N=1317

• no. (%)

Standard Treatment N=1319

• no. (%)

Hazard Ratio (95% CI) CVD Primary Outcome 102 (7.7) 148 (11.2) 0.66 (0.51-0.85) All-Cause Mortality 73 (5.5) 107 (8.1) 0.67 (0.49-0.91) Primary Outcome

• r Death

144 (10.9) 205 (15.5) 0.68 (0.54-0.84)

Williamson JD, et al. JAMA 2016;315(24):2673-82.

SBP Reduction and CVD/Mortality

Bundy JD, et al. JAMA Cardiology 2017;2(7):775-781.

Systematic review and network meta-analysis; 42 trials (N=144,220)

Mean Achieved Systolic BP (mm Hg) Major CVD All-cause Mortality

120-124 vs 130-134 0.71 (0.60-0.83) 0.73 (0.58-0.93) 120-124 vs 135-139 0.68 (0.55-0.85) 0.79 (0.59-1.05) 120-124 vs 140-144 0.58 (0.48-0.72) 0.59 (0.45-0.77) 130-134 vs 140-144 0.83 (0.74-0.94) 0.82 (0.68-0.93)

2017 ACC-AHA: BP Goals

Whelton PK, et al. Hypertension. 2017 [Epub ahead of print].

COR LOE Patients With Hypertension I SBP: B-RSR Known CVD, diabetes, CKD, or 10-year ASCVD event risk of ≥10% a BP target <130/80 mm Hg DBP: C-EO IIb SBP: B-NR Without additional markers of increased CVD risk, a BP target <130/80 mm Hg may be reasonable. DBP: C-EO

CVD = cardiovascular disease CKD = chronic kidney disease SR indicates systematic review

SLIDE 5

5 2017 ACC-AHA: BP Thresholds for

Pharmacological Therapy

Clinical Condition(s) Threshold, mm Hg Goal, mm Hg General Clinical CVD or 10-year ASCVD risk ≥10% ≥130/80 <130/80 No clinical CVD and 10-year ASCVD risk <10% ≥140/90 <130/80 Older persons (≥65 yr; noninstitutionalized, ambulatory, community-living) ≥130 (SBP) <130 (SBP) Specific comorbidities Diabetes mellitus ≥130/80 <130/80 Chronic kidney disease ≥130/80 <130/80 Chronic kidney disease after renal transplantation ≥130/80 <130/80 Heart failure ≥130/80 <130/80 Stable ischemic heart disease ≥130/80 <130/80 Secondary stroke prevention ≥140/90 <130/80 Secondary stroke prevention (lacunar) ≥130/80 <130/80 Peripheral arterial disease ≥130/80 <130/80

ASCVD, atherosclerotic cardiovascular disease; BP, blood pressure; CVD, cardiovascular disease; and SBP, systolic blood pressure . Whelton PK, et al. Hypertension. 2017 [Epub ahead of print].

Meta-Analyses Supporting Lower BP Goals

• Bundy et al: 42 trials

(N=144,220)

• Major CVD and all-cause

mortality lower with lower BP goals

• Brunström et al: 74 trials

(N=306,273)

• Major CVD and all-cause

mortality lower with lower BP goals

• Primary prevention patients with

baseline SBP below 140 mm Hg

• Lower BP goals were not better

Bundy JD, et al. JAMA Cardiology 2017;2(7):775-781. Brunström B, et al. JAMA Internal Med. 2018;178(1):28-36.

2017 ACC-AHA: BP Goals

Whelton PK, et al. Hypertension. 2017 [Epub ahead of print].

COR LOE Older Persons I A SBP treatment goal <130 mm Hg for non-institutionalized ambulatory community-dwelling adults ≥65 yr IIa C-EO ≥65 yr with high burden of comorbidity and limited life expectancy, clinical judgment, patient preference, and a team-based approach to assess risk/benefit for decisions regarding intensity of treatment

2017 ACC/AHA: Treatment Algorithm

Whelton PK, et al. Hypertension. 2017 [Epub ahead of print].

Normal BP

< 120/80 mm Hg

Elevated BP

120-129/<80 mm Hg

Stage 1 HTN

130-139/80-89 mm Hg

Stage 2 HTN

≥ 140/90 mm Hg

Promote Optimal Lifestyle Habits Reassess in 1 yr

Class IIa

NonPharm Tx

Class I

Reassess in 3-6 mo

Class I

NonPharm Tx and Medications

Class I

NonPharm Tx and Medication

Class I

NonPharm Tx

Class I

Clinical ASCVD or 10-yr ASCVD Risk Score ≥10%

Reassess in 3-6 mo

Class I

Reassess in 1 mo

Class I

Reassess in 1 mo

Class I No Yes

2017 ACC-AHA: Lifestyle Changes

COR LOE Nonpharmacological Interventions

I A Weight loss in adults who are overweight or obese I A Healthy diet (e.g., DASH) that facilitates achieving desirable weight I A Sodium reduction I A Potassium supplementation (preferably diet) unless contraindicated I A Increased physical activity with a structured exercise program I A Drink no more than 2 (men) or 1 (women) standard drinks/day

DASH = Dietary Approaches to Stop Hypertension Whelton PK, et al. Hypertension. 2017 [Epub ahead of print].

2017 ACC-AHA: Medication Selection

COR LOE Initial Medication

I ASR First-line: thiazide diuretics, CCBs, and ACE inhibitors or ARBs

Whelton PK, et al. Hypertension. 2017 [Epub ahead of print].

COR LOE Initial Monotherapy Versus Combination Therapy

I C-EO 2 first-line agents of different classes in stage 2 hypertension and BP > 20/10 mm Hg above goal

COR LOE Race and Ethnicity

I B-R Black patients without HF or CKD (with or without diabetes), initial treatment should include a thiazide diuretic or CCB I C-LD 2+ medications are recommended to achieve a BP <130/80 mm Hg in most adults, especially in black patients

SLIDE 6

6 2017 ACC-AHA: Compelling Indications

Co-morbidity 1st Line Agent(s) Diabetes Thiazide, CCB, ACE-I, or ARB Diabetes with albuminuria ACE-I or ARB Chronic kidney disease ACE-I or ARB Heart failure with reduced EF Beta-blocker, ACE-I, or ARB, mineralocorticoid receptor antagonist Heart failure with preserved EF Beta-blocker, ACE-I, or ARB Stable ischemic heart disease Beta-blocker, ACE-I, or ARB (CCB if angina) Secondary stroke prevention Thiazide, ACE-I, or ARB

Whelton PK, et al. Hypertension. 2017 [Epub ahead of print].

Combination Therapy

Thiazide diuretics Beta-blockers Other agents Angiotensin Receptor Blockers Calcium Channel Blockers ACE Inhibitors

Preferred Combinations Useful Combination with limitations Not Recommended Possible but less well tested Mancia G et al. J Hypertens. 2013; 31:1281-357.

Quarter-Dose BP Lowering Medications

• Systematic review and

meta-analysis

• 42 RCTs (n=20,284)
• Quarter-dose

antihypertensive medications comparted to placebo and standard dosing

Bennett A, et al. Hypertension 2017;70:85-93. *P<0.001 RCT = randomized controlled trial

• Significantly fewer adverse events

compared with quarter-dose vs. standard-dose

vs Placebo One Drug* Two Drugs* Four Drugs* Mean BP change (mm Hg)

• 4.7/-2.4
• 6.7/-4.4
• 22.4/-13.1

vs Standard Dose One Drug* Two Drugs Four Drugs* Mean BP change (mm Hg) +3.7/+2.6 +1.3/−0.3 −13.1/−7.9

2017 ACC-AHA: Hypertension Guideline

Whelton PK, et al. Hypertension. 2017 [Epub ahead of print].

BP Category Systolic BP (mm Hg) Diastolic BP (mm Hg) Treatment/Follow-up* Normal <120 and <80 Encourage healthy lifestyle changes Elevated 120-129 and <80 Healthy lifestyle changes and reassess in 3-6 months Hypertension: Stage 1 130-139

• r

80-89 10-yr ASCVD risk <10%:

• Healthy lifestyle changes and reassess in 3-6 months

10-yr ASCVD risk ≥10%, known CVD, diabetes, or CKD:

• Healthy lifestyle changes, start ONE medication and

reassess in 1 month Hypertension: Stage 2 ≥140

• r

≥90 Healthy lifestyle changes, start TWO medications (from different classes), especially when >20/10 mm Hg from goal and reassess in 1 month

*http://static.heart.org/riskcalc/app/index.html#!/baseline-risk

Case: RP

• 40-year-old Black man with a history of gout
• Social History:
• Smoker (0.5 pack/day for 20 years)
• Follows no specific diet, alcohol 7 to 10 drinks per week; minimal to no exercise
• Medications: allopurinol 300 mg PO daily
• Laboratory values:
• TC 250 mg/dL, LDL-C 159 mg/dL, HDL 35 mg/dL, TG 280 mg/dL
• Other values:
• BP 138/86 mm Hg (138/88 when repeated); same at last visit
• A1C 5.5%, BMI 28.8 kg/m2; SCr is 1.22 mg/dL (eGFR is 85 mL/min/1.73m2), potassium is

4.4 mEq/L, uric acid = 5.8 mg/dL, All other labs are normal

• 10-yr ASCVD Risk Score = 7.2%

Case: RP

• What would you recommend for RP:
• Lifestyle Modifications:
• Pharmacotherapy:
• Follow-up plan:

SLIDE 7

7 Case: RP… 5 year later

• 45-year-old Black man with a history of hypertension, gout, type 2 diabetes
• Social History:
• Former smoker (quit 5 years ago)
• Avoids sodium and restricts red meat, alcohol 10 to 15 drinks per week; exercises three

times/week for 45 minutes (elliptical machine at the gym)

• Medications: allopurinol 300 mg PO daily, metformin 1000 mg PO twice daily
• Laboratory values:
• TC 240 mg/dL, LDL-C 150 mg/dL, HDL 40 mg/dL, TG 250 mg/dL
• Other values:
• BP 154/94 mm Hg (152/94 when repeated)
• A1C 7.2%, BMI 29.5 kg/m2; SCr is 1.30 mg/dL (eGFR is 76 mL/min/1.73m2), potassium is

4.1 mEq/L, uric acid = 5.9 mg/dL, All other labs are normal

• 10-yr ASCVD Risk Score = 11.8%

Case: RP

• What would you recommend for RP?

Expert Cholesterol Recommendations

• 2013:

ACC/AHA Guidelines

• 2014:

NLA Recommendations

• 2016:

ACC Expert Consensus Decision Pathway

• 2017:

ACC Expert Consensus Decision Pathway

2018/2019: ACC/AHA Guidelines

ACC/AHA = American College of Cardiology/American Heart Association NLA = National Lipid Association Clinical ASCVD LDL-C ≥190 mg/dL Diabetes Type 1 or 2 Age 40-75 yr ≥7.5% estimated 10-yr ASCVD risk Agea 40-75 yr

Moderate-to-high intensity statin

• High-intensity statin if age ≤75 yr
• Moderate-intensity statin if age >75 yr or not

candidate for high-intensity High-intensity statin Moderate-intensity statin High-intensity statin if 10-year ASCVD risk ≥7.5%

ACC/AHA 2013 Guidelines: Four ASCVD Statin Benefit Groups

Stone NJ et al. Circulation. 2014;129(25 suppl 2):S1-S45.

ACC/AHA 2013 Blood Cholesterol Guideline: Statin Intensity

High-Intensity Moderate-Intensity Low-Intensity Daily dose lowers LDL-C on average by ~ ≥50% Daily dose lowers LDL-C on average by ~30% to <50% Daily dose lowers LDL-C on average by <30% Atorvastatin (40)–80 mg Rosuvastatin 20 (40) mg Atorvastatin 10 (20) mg Rosuvastatin (5) 10 mg Simvastatin 20–40 mg Pravastatin 40 (80) mg Lovastatin 40 mg Fluvastatin XL 80 mg Fluvastatin 40 mg bid Pitavastatin 2–4 mg Simvastatin 10 mg Pravastatin 10–20 mg Lovastatin 20 mg Fluvastatin 20–40 mg Pitavastatin 1 mg

Specific statins and doses are noted in bold that were evaluated in randomized controlled trials (RCTs). Statins and doses that are approved by the U.S. FDA but were not tested in the RCTs reviewed are listed in italics. Stone NJ et al. Circulation. 2014;129(25 suppl 2):S1-S45.

Drugs Affecting Lipoprotein Metabolism

LDL-C HDL-C TG

Statins 18-55% 5-15% 7-30% Bile acid sequestrants 15-30% 3-5% 0-10% Nicotinic acid 5-25% 15-35% 20-50% Fibric acids 5-20% 10-20% 20-50% Ezetimibe 13-20% 3-5% 5-11% Omega-3 fatty acids 6-25% 5-7% 19-44% PCSK9 inhibitors 40-72% 0-10% 0-17% Primarily for LDL-C lowering Primarily for hypertriglyceridemia

Jacobson TA et al. J Clin Lipidol. 2014;8:473-488. Shimada YJ et al. Eur Heart J. 2015; 36:2415-2424

SLIDE 8

8

Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Inhibitors

Lambert G et al. J Lipid Research 2012;53:2515-2524. Hepatocyte LDL Receptor (LDL-R) LDL Particle Recycling

• f LDL-R

Endosome Clathrin- coated vesicle

LDL degradation and LDL-R recycling

Hepatocyte LDL Receptor (LDL-R) LDL Particle Lysosome Clathrin- coated vesicle

PCSK9-mediated LDL-R degradation

Endocytosis PCSK9

PCSK9 Inhibitors

• Fully human monoclonal antibodies
• FDA approval:
• Adjunct to diet and maximally tolerated statin therapy in adults with

heterozygous familial hypercholesterolemia (FH) or clinical atherosclerotic cardiovascular disease, who require additional lowering of LDL-C

• Evolocumab is also approved for homozygous FH, as monotherapy and to

reduce CV events in ASCVD Dosing

Alirocumab 75 mg subcutaneous every 2 weeks increase to 150 mg if needed, or 300 mg once monthly Evolocumab 140 subcutaneous every 2 weeks or 420 mg once monthly

Statin therapy ABSOLUTELY reduces CV events in many patient populations… but…

…does adding a non-statin further reduce CV events?

IMProved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT)

• Double-blind trial in 18,144 patients with acute coronary syndrome,

age ≥50 yr with a high CV risk feature, LDL-C 50-125 mg/dL (50- 100 if on therapy)

• Randomized to simvastatin 40 mg or ezetimibe/simvastatin 10/40

mg for 4.9 yr

• Primary endpoint: CV death, MI, hospitalization for unstable

angina, coronary revascularization, stroke

• Mean LDL-C values
• Simvastatin alone

69.9 mg/dL

• Ezetimibe /simvastatin

53.2 mg/dL

Cannon CP et al. N Engl J Med 2015;372:2387-97.

IMPROVE-IT: Primary Endpoint

Cannon CP et al. N Engl J Med 2015;372:2387-97.

5.4% RRR

HR 0.936 (95% CI, 0.89-0.99) P=0.016

7-yr event rates:

• 34.7% vs. 32.7%

Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER)

• Double-blind trial in 27,564 patients with ASCVD
• Age 40-85 yr, and LDL-C ≥70 mg/dL
• On optimal (high-intensity preferred, minimum atorvastatin 20 mg

daily or equivalent) therapy

• Randomized to placebo or evolocumab for 2.2 yr
• Primary endpoint:
• CV death, MI, stroke, hospitalization for unstable angina, or coronary

revascularization

Sabatine MS et al. N Engl J Med 2017;376:1713-22.

SLIDE 9

9 FOURIER – Patient Characteristics

Evolocumab N=13,784 Placebo N=13,780 Diabetes mellitus (%) 36.7 36.5 Statin use (%):

• High intensity
• Moderate intensity
• Low intensity/unknown

69.5 30.2 0.3 69.1 30.7 0.2 Ezetimibe (%) 5.3 5.2 Other cardiovascular medications (%):

• Antiplatelet medication
• Beta-blocker
• ACEi or ARB, aldosterone antagonist, or both

92.7 75.8 78.4 92.0 75.4 77.9 Baseline LDL-C (mg/dL) 92 92 Mean LDL-C at 48 weeks (mg/dL) 30 89

Sabatine MS et al. N Engl J Med 2017;376:1713-22.

FOURIER: Results

15% RRR

HR 0.85 (95% CI, 0.79-0.92) P<0.0001 Month Patients with Primary Endpoint (%) Sabatine MS et al. N Engl J Med 2017;376:1713-22. 0% 2% 4% 6% 8% 10% 12% 14% 16% Evolocumab Placebo 6 12 18 24 30 36 12.6% 14.6%

FOURIER: Landmark Analysis

Sabatine MS et al. N Engl J Med 2017;376:1713-22. 0% 2% 4% 6% 8% 0% 2% 4% 6% 8%

Evolocumab Placebo

Month 3 9 12 24 30 36 6 12 18

Patients with Primary Endpoint (%) 16% RRR HR 0.84 (95% CI, 0.74-0.96) P=0.008 25% RRR HR 0.75 (95% CI, 0.66-0.85) P<0.00001

FOURIER: Safety

Evolocumab (N=13,769) Placebo (N=13,756) Adverse events (%)

• Any
• Serious
• Injection-site reaction*
• Treatment-related leading to stopping study drug
• Muscle related
• Cataract
• New onset diabetes
• Neurocognitive

77.4 24.8 2.1 1.6 5.0 1.7 8.1 1.6 77.4 24.7 1.6 1.5 4.8 1.8 7.7 1.5 Laboratory Abnormality (%):

• Aminotransferase >3 x upper limit of normal
• Creatine kinase >5 x upper limit of normal

1.8 0.7 1.8 0.7 Binding/Neutralizing antibody production (%) 0.3/none n/a *P<0.001

Sabatine MS et al. N Engl J Med 2017;376:1713-22.

Cognitive Function in FOURIER: EBBIGINGHAUS

• Prospective subgroup study in 1204 patients from FOURIER

(median of 19 months)

• Cognitive function assessed using the Cambridge

Neuropsychological Test Automated Battery at baseline, week 24, yearly, and at the end of the trial:

• Primary endpoint: Spatial working memory strategy index of executive

function

• Results:
• No significant differences in cognitive function
• No associations between LDL-C levels and cognitive changes, even when

LDL-C <25 mg/dL

Giugliano RP, et al. N Engl J Med 2017;377:633-43.

Cost-effectiveness Analysis of PCSK9 Inhibitors Based on the FOURIER Trial

• Cardiovascular Disease Model used to estimate the cost-

effectiveness of PCSK9 inhibitors or ezetimibe added to statin therapy among US adults with ASCVD

• Drug costs based on wholesale acquisition costs of: $3818 for

ezetimibe and $14,542 for PCSK9 inhibitors

• Results
• 8.9 million US adults met the FOURIER treatment criteria
• Reducing annual drug costs by 71% (to ≤ $4215) would be needed for

PCSK9 inhibitors to be cost-effective at a threshold of $100,000/Quality Adjusted Life Years

Kazi DS, et al. JAMA 2017;318(8):748-750.

SLIDE 10

10 EXPERT CONSENSUS DECISION PATHWAY

2017 Focused Update of the 2016 ACC Expert Consensus Decision Pathway on the Role of Non-Statin Therapies for LDL-Cholesterol Lowering in the Management of Atherosclerotic Cardiovascular Disease Risk

• A Report of the American College of Cardiology Task Force on

Expert Consensus Decision Pathways Endorsed by the National Lipid Association

Lloyd-Jones DM, et al. J Am Coll Cardiol 2017

Optional nonstatin medications to consider

2017 ACC ECDP:

≥ 21 years, clinical ASCVD without Comorbidities

≥50% LDL-C reduction (may consider LDL-C <70 mg/dL or non-HDL-C <100 mg/dL) on maximally tolerated statin CLINICIAN-PATIENT DISCUSSION REGARDING TREATMENT FACTORS Consider ezetimibe first Consider adding or replacing with PCSK9 inhibitor second ≥50% LDL-C reduction (may consider LDL-C <70 mg/dL or non-HDL-C <100 mg/dL) on maximally tolerated statin Continue to monitor adherence with treatment and LDL-C response

Yes Yes No Decision for no additional medication 1 2 No No

Lloyd-Jones DM, et al. J Am Coll Cardiol 2017

2017 ACC ECDP:

≥ 21 years, clinical ASCVD with Comorbidities

≥50% LDL-C reduction (may consider LDL-C <70 mg/dL or non-HDL-C <100 mg/dL) on maximally tolerated statin CLINICIAN-PATIENT DISCUSSION REGARDING TREATMENT FACTORS ≥50% LDL-C reduction (may consider LDL-C <70 mg/dL or non-HDL-C <100 mg/dL) on maximally tolerated statin Continue to monitor adherence with treatment and LDL-C response

Yes Yes No Decision for no additional medication No No

Lloyd-Jones DM, et al. J Am Coll Cardiol 2017

Optional nonstatin medications to consider

Consider either ezetimibe or PCSK9 inhibitor as initial nonstatin agent, and addition of other agent as second if needed

2017 ACC ECDP: Comorbidities

• Diabetes
• Recent (<3 mo) ASCVD event
• ASCVD event while already

taking statin therapy

• Poorly controlled other major

ASCVD risk factors

• HDL-C <40 mg/dL for men and

<50 mg/dL for women

• Current daily cigarette smoking
• hs-CRP >2 mg/L
• Elevated Lp(a)
• Age ≥ 65 yr
• CKD
• Symptomatic heart failure or

maintenance hemodialysis

• Prior MI or non-hemorrhagic

stroke

• Symptomatic PAD
• History of non-MI-related

coronary revascularization

• Residual coronary artery

disease with ≥40% stenosis in ≥2 large vessels

Lloyd-Jones DM, et al. J Am Coll Cardiol 2017

2017 ACC ECDP: Recommendations

Lloyd-Jones DM, et al. J Am Coll Cardiol 2017

Statin Benefit Group LDL-C Threshold: %Reduction or LDL-C value (mg/dL) Nonstatin Add-On Therapy No comorbidities ≥50% or <70 Ezetimibe first, PCSK9i second Comorbidities ≥50% or <70 Ezetimibe or PCSK9i No clinical ASCVD ≥50% or <100 Ezetimibe or PCSK9i Clinical ASCVD ≥50% or <70 10-yr ASCVD risk <7.5% and no high risk markers 30-49% or <100 Ezetimibe‡ Most patients ≥50% or <100 No high risk markers 30-49% or <100 Ezetimibe‡ High risk markers ≥50% or <100

‡May consider a bile acid sequestrant as optional alternative agent if ezetimibe intolerant and triglycerides <300 mg/dL Clinical ASCVD LDL-C ≥190 mg/dL Diabetes Type 1 or 2 Age 40-75 yr ≥7.5% estimated 10-yr ASCVD risk Age 40-75 yr

2017 ACC ECDP: High Risk Markers

• 10-yr ASCVD risk ≥20%
• Baseline LDL-C ≥160 mg/dL
• Poorly controlled other major risk factor
• Family history of premature ASCVD
• Subclinical atherosclerosis (e.g., coronary artery calcification)
• Elevated hs-CRP
• Other risk modifying condition (chronic kidney disease, HIV,

chronic inflammatory disorders)

Lloyd-Jones DM, et al. J Am Coll Cardiol 2017

SLIDE 11

11 Stepped Approach to Lipid Management

Step 1

Fixed Intensity Statin Therapy if in ACC/AHA Statin Benefit Group*ⱡ

Step 2

Maximize Statin Dosing/Therapy if not at ACC Expert Consensus Decision Pathway Threshold

Step 3

Consider Addition of a Nonstatin Medication if not at ACC Expert Consensus Decision Pathway Threshold

*If serum triglyceride values are >/= 500 mg/dL, triglyceride lowering therapy may be needed ⱡ Patients who are not in one of the 4 statin benefit groups may also be treated with statin therapy

Case: RP

• 46-year-old Black man with a history of hypertension, gout, type 2

diabetes

• Social History:
• Smoker (0.5 pack per day; restarted 1 year ago)
• Avoids sodium and restricts red meats, alcohol 10 to 15 drinks per week;

exercises three times/week

• Medications: allopurinol 300 mg PO daily, metformin 1000 mg PO twice

daily, amlodipine/benazepril 10/40 mg daily

• Laboratory values:
• TC 240 mg/dL, LDL-C 150 mg/dL, HDL 40 mg/dL, TG 250 mg/dL
• Other values:
• BP 134/82 mm Hg (132/80 when repeated)
• A1C 6.8%, BMI 27.7 kg/m2; SCr is 1.29 mg/dL (eGFR is 76 mL/min/1.73m2),

potassium is 4.1 mEq/L, uric acid = 5.9 mg/dL, All other labs are normal

• 10-yr ASCVD Risk Score = 25.9%

Case: RP

• What would you recommend for RP?

Case: RP… 4 years later

• 50-year-old Black man with a history of hypertension, gout, type 2 diabetes,

and coronary artery disease (myocardial infarction last year)

• Social History:
• Former smoker (quit after myocardial infarction)
• Avoids sodium and restricts red meats, alcohol none; exercises three times/week
• Medications: allopurinol 300 mg PO daily, metformin 1000 mg PO twice daily,

empagliflozin 25 mg PO daily, amlodipine/benazepril 10/40 mg daily, metoprolol succinate 100 mg PO daily, aspirin 81 mg PO daily, rosuvastatin 10 mg PO daily (could not tolerate higher dose or atorvastatin)

• Laboratory values:
• TC 160 mg/dL, LDL-C 90 mg/dL, HDL 40 mg/dL, TG 150 mg/dL
• Other values:
• BP 124/76 mm Hg (120/78 when repeated)
• A1C 6.5%, BMI 27.4 kg/m2; All other labs are normal

Case: RP

• What would you recommend for RP?

Concluding Statements

• <130/80 mm Hg is the BP goal for most patients
• Evidence from SPRINT and meta-analyses prove that lower SBP

goals are better at reducing CV events and mortality, and is well tolerated even in older patients

• First-line antihypertensive agents include ACEi, ARB, CCB and

thiazides with selection based race and comorbid diseases

• Patients in a statin benefit group should start therapy with fixed

intensity statin therapy followed by evaluation of response and titration of the dose as appropriate

• Ezetimibe and evolocumab are now proven to further reduce CV

events in ASCVD when added to statin therapy

SLIDE 12

12 Pre/Post Question #1

Which of the following BP goals is recommended by the 2017 American College of Cardiology-American Heart Association hypertension guidelines for a 55-year-old patient with diabetes and cardiovascular disease?

• A. <120/80 mm Hg.
• B. <130/80 mm Hg.
• C. <140/90 mm Hg.
• D. <150/90 mm Hg.

Pre/Post Question #2

The SPRINT trial evaluated intense blood pressure lowering versus standard blood pressure lowering. Which of the following results were seen when intensive blood pressure lowering was compared to standard blood pressure lowering?

• A. Incidence of injurious falls was higher with intensive lowering.
• B. Serious adverse effects were higher with intensive lowering.
• C. Acute kidney injury risk was lower with intensive lowering.
• D. First occurrence of a CV event was lower with intensive lowering.

Pre/Post Question #3

Which of the following medication regimens does the American College of Cardiology/American Heart Association (ACC/AHA) recommend in their 2013 guidelines as initial therapy for patients with a baseline low-density lipoprotein cholesterol (LDL-C) of ≥190 mg/dL?

• A. Atorvastatin 20 mg daily.
• B. Evolocumab 140 mg every 2 weeks.
• C. Rosuvastatin 20 mg daily.
• D. Simvastatin 40 mg daily with ezetimibe.

Pre/Post Question #4

What are the long-term effects of adding evolocumab therapy for patients with stable ASCVD who are already treated with maximally tolerated statin therapy?

• A. Decreased CV events and an increased risk of cataracts.
• B. No change in CV events, but greater than a 50% decrease in

LDL-C.

• C. Decreased CV events and an increased risk of injection site

reactions.

• D. No change in CV events, but a trend toward decreased risk of

major CV events after 2.2 years.