New Strategies for Dyslipidemia Management:
Minimizing Risk With Maximal LDL-C Reduction
New Strategies for Dyslipidemia
Management: Minimizing Risk
With Maximal LDL-C Reduction
Learning Objectives
Develop dyslipidemia treatment targets for individual patients based on
level of overall ASCVD risk as described in professional guidelines
• Formulate evidence-based treatment strategies for patients with
dyslipidemia, including those not reaching goals on maximally tolerated
statin therapy
• Implement strategies to improve adherence to lipid-lowering therapy
•
2
ASCVD = atherosclerotic cardiovascular disease.
85.6 Million Adults in the United States Aged ≥20 Years Have
CVD: NHANES, 2009-2012
100
90
Men
Women
% of Population
85.9
84.7
80
69.1
70
67.9
60
50
40.5
40
35.5
30
20
10
0
11.9
10.0
20-39
40-59
60-79
80+
Age (Years)
CVD = cardiovascular disease; NHANES = National Health and Nutrition Examination Survey.
3
Mozaffarian D, et al. Circulation. 2015;131:e29-e322.
PCE 2017 Series 1
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New Strategies for Dyslipidemia Management:
Minimizing Risk With Maximal LDL-C Reduction
Residual ASCVD Risk Despite LDL-C–Lowering Therapy
End Point Reduction (Relative Risk Reduction)
ASCVD Event Reduction in Major Statin Trials
4S
WOSCOPS
CARE
LIPID
MIRACL
PROSPER
–16
–15
ASCOT-LLA
CARDS
SPARCL
KLIS
–15
–14
MEGA
0
20
–24
–30
–24
–31
–36
–33
–37
40
60
Residual ASCVD Risk ~70%
80
100
Simva
(N = 4444)
Prava
(N = 6595)
Prava
(N = 4159)
Prava
(N = 9014)
Atorva
(N = 3086)
Prava
Atorva
Atorva
(N = 5804) (N = 10,305) (N = 2838)
Atorva
(N = 4731)
Prava
Prava
(N = 3853) (N = 7832)
Atorva = atorvastatin; Prava = pravastatin; Simva = simvastatin.
4
Baigent C, et al. Lancet. 2005;366:1267-1278.
High Residual CVD Risk Remains, Even With High-Dose
Rosuvastatin (JUPITER)
Cumulative Incidence
0.08
Primary trial end point:
MI, stroke, unstable
angina/revascularization,
CVD death
0.06
Placebo
251/8901
–44%
HR: 0.56 (95% CI: 0.46-0.69)
P <.00001
0.04
NNT5 = 25
Rosuvastatin 20 mg/d
142/8901
0.02
0.00
0
1
Patients at Risk
Rosuvastatin
8901
Placebo
8901
8631
8621
8412
8353
2
Follow-up (Years)
6540
6508
3893
3872
1958
1963
4
5
544
534
157
174
3
1353
1333
983
955
CI = confidence interval; HR = hazard ratio; MI = myocardial infarction; NNT5 = number needed to treat for 5 years.
5
Ridker PM, et al. N Engl J Med. 2008;359:2195-2207.
Non–HDL-C: Another Predictor of Risk for ASCVD
Triglyceride
Cholesterol
All atherogenic lipoproteins
HDL
LDL
IDL
Apo AI
Apo B
Apo B
VLDL
Apo B
Chylomicron remnant
Apo B48
Non-HDL
Non–HDL-C = TC – HDL-C
Apo = apolipoprotein; IDL = intermediate-density lipoprotein cholesterol; TC = total cholesterol; VLDL = very low-density lipoprotein.
6
National Cholesterol Education Program. http://www.nhlbi.nih.gov/files/docs/guidelines/atp3xsum.pdf. Accessed April 28, 2016.
PCE 2017 Series 1
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New Strategies for Dyslipidemia Management:
Minimizing Risk With Maximal LDL-C Reduction
Case Study: Alejandro
7
•
New patient; Hispanic man, age 62
Laboratory Values
•
Prior coronary artery bypass graft at age 58;
taking aspirin
Lipids (mg/dL)
•
Body mass index: 29 kg/m2
•
•
Sporadic exercise; job involves significant
travel
Smoker, 1 pack/day
•
Blood pressure: 125/73 mm Hg
•
Dyslipidemia, treated with lovastatin 40 mg/d
•
Type 2 diabetes mellitus (treated with
metformin 2000 mg/d)
TC
178
TG
142
HDL-C
27
LDL-C
170
Non–HDL-C
155
Fasting plasma
glucose (mg/dL)
130.7
A1C (%)
7.4
A1C = glycated hemoglobin; TG = triglycerides.
2013 ACC/AHA Cholesterol Guidelines
•
8
Emphasis on moderate- to high-intensity statin therapy
‒ Achieving specific LDL-C and non–HDL-C goals optional
‒ Clinicians encouraged to:
• Assess response and confirm adherence to prescribed therapy
• Consider additional therapy in individuals with significant residual risk (but no
specific guidance on therapy beyond high-intensity statin)
Goff DC, et al. Circulation. 2014;129(25 Suppl 2):S49-S73; Stone NJ, et al. Circulation. 2014;129(25 Suppl 2):S1-S45.
2013 ACC/AHA Statin Benefit Groups
High-intensity statin therapy
‒ Clinical ASCVD
‒ Primary elevations of LDL-C ≥190 mg/dL (high intensity preferred)
‒ Aged 40-75 years with diabetes, LDL-C 70-189 mg/dL, without clinical ASCVD
but 10-year risk ≥7.5%a
• Moderate-intensity statin therapy
‒ Aged 40-75 years with diabetes, LDL-C 70-189 mg/dL, without clinical ASCVD
and 10-year risk <7.5%a
•
ahttp://www.cvriskcalculator.com/
9
Goff DC, et al. Circulation. 2014;129(25 Suppl 2):S49-S73; Stone NJ, et al. Circulation. 2014;129(25 Suppl 2):S1-S45.
PCE 2017 Series 1
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New Strategies for Dyslipidemia Management:
Minimizing Risk With Maximal LDL-C Reduction
AACE/ACE 2017 Guidelines: Risk Categories and Factors
Treatment Goals (mg/dL)
LDL-C
Non–HDL-C
Apo B
• Progressive ASCVD, including unstable angina, after achieving
an LDL-C <70 mg/dL
• Established clinical CVD, as well as diabetes, CKD 3/4, or HeFH
• History of premature ASCVD (male age <55, female age <65)
<55
<80
<70
• Established or recent hospitalization for ACS, coronary, carotid,
or peripheral vascular disease; 10-year risk >20%
• Diabetes or CKD 3/4 with ≥1 risk factor
• HeFH
<70
<100
<80
Risk Category
Risk Factors/10-Year Risk
Extreme risk
Very high risk
High risk
• ≥2 risk factors and 10-year risk 10%-20%
• Diabetes or CKD 3/4 with no other risk factors
<100
<130
<90
Moderate risk
• ≥2 risk factors and 10-year risk <10%
<100
<130
<90
Low risk
• 0 risk factors
<130
<160
NR
AACE = American Association of Clinical Endocrinologists; ACE = American College of Endocrinology; ACS = acute coronary syndrome;
CKD = chronic kidney disease; HeFH = heterozygous familial hypercholesterolemia; NR = not recommended.
10
Jellinger PS, et al. Endocr Pract. 2017;(Suppl 2):1-87.
NLA Risk Category Criteria
Category
Criteria
Very high
•
•
ASCVD
Diabetes mellitus (type 1 or 2)
– ≥2 other major ASCVD risk factors; or
– Evidence of end-organ damage
High
•
•
≥3 major ASCVD risk factors
Diabetes mellitus (type 1 or 2)
– ≤1 other major ASCVD risk factor; and
– No evidence of end-organ damage
CKD stage 3B or 4
LDL-C ≥190 mg/dL
•
•
Moderate
•
•
2 major ASCVD risk factors
Specific factors should be considered to reclassify risk, such as risk calculators, atherosclerosis imaging,
and/or biomarkers
Low
•
•
≤1 major ASCVD risk factor
Specific factors should be considered to reclassify risk, such as risk calculators, atherosclerosis imaging,
and/or biomarkers
NLA = National Lipid Association.
11
Jacobson TA, et al. J Clin Lipidol. 2014;8:473-488.
ACC 2016 Update: Use of Nonstatin Therapies for
Secondary Prevention
Clinical ASCVD with comorbidities
Has ≥50% LDL-C ↓ (may consider LDL-C <70 mg/dL; in patients with diabetes,
may consider non–HDL-C <100 mg/dL) on maximum tolerated statin
No
Clinician-patient factors to consider:
1. Potential for additional ASCVD risk reduction with addition of nonstatin
2. Potential for AEs or drug interactions from addition of nonstatin
3. Patient preference
Optional nonstatin medications
Consider ezetimibe first
Consider adding/replacing with PCSK9
inhibitor second
No
Patient has ≥50% LDL-C ↓ (may consider LDL-C <70 mg/dL or may consider
non–HDL-C <100 mg/dL in patients with diabetes) on maximum tolerated statin
AE = adverse event.
12
Adapted from Lloyd-Jones DM, et al. J Am Coll Cardiol. 2016;68:92-125.
PCE 2017 Series 1
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New Strategies for Dyslipidemia Management:
Minimizing Risk With Maximal LDL-C Reduction
ACC 2016 Update: Use of Nonstatin Therapies for
Primary Prevention
No clinical ASCVD, baseline LDL-C ≥190 mg/dL, no comorbidities
≥50% LDL-C ↓ (may consider LDL-C <100 mg/dL on maximum tolerated statin)
No
Clinician-patient factors to consider:
1. Potential for additional ASCVD risk reduction with addition of nonstatin
2. Potential for AEs or drug interactions from addition of nonstatin
3. Patient preference
Optional nonstatin medications
Consider ezetimibe first
Consider PCSK9 inhibitor
Patient has ≥50% LDL-C ↓ (may consider LDL-C <70 mg/dL) on maximum tolerated statin
No
Repeat clinician-patient discussion, add other nonstatin, consider specialist referral
13
Adapted from Lloyd-Jones DM, et al. J Am Coll Cardiol. 2016;68:92-125.
NLA 2014 Recommendations: Levels for Considering Drug
Therapy, Treatment Goals
Risk Category
•
•
14
Consider Drug Therapy
Treatment Goal
Non–HDL-C and LDL-C (mg/dL)
Non–HDL-C and LDL-C (mg/dL)
Very high
≥100
≥70
<100
<70
High
≥130
≥100
<130
<100
Moderate
≥160
≥130
<130
<100
Low
≥190
≥160
<130
<100
Lifestyle therapy is always advocated as the basis for ASCVD prevention
For patients with ASCVD or diabetes mellitus, consider use of moderate- or high-intensity statins,
irrespective of baseline atherogenic cholesterol levels
Jacobson TA, et al. J Clin Lipidol. 2014;8:473-488.
Case Study (cont’d)
You educate Alejandro on the risks of obesity, dyslipidemia, and CVD,
and you counsel him on smoking cessation strategies
• You refer him to a dietitian for counseling and urge him to engage in an
exercise he enjoys (eg, walking, using hotel gyms while traveling) for
45 minutes/day, 4-5 days/week
• You discuss the need to intensify his statin treatment, and he agrees to
begin taking atorvastatin 80 mg
• You educate him about his new regimen and advise him to notify you
immediately if AEs occur
•
15
PCE 2017 Series 1
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New Strategies for Dyslipidemia Management:
Minimizing Risk With Maximal LDL-C Reduction
Dyslipidemia Management Strategies
•
Encourage a healthy lifestyle (dietary measures, aerobic physical activity, healthy body
weight, smoking avoidance, controlling hypertension and diabetes when present)
•
Implement a patient-centered approach to decision making before utilizing statin therapy
(especially for primary prevention in patients at lower ASCVD risk)
•
Start statins per ACC/AHA guidelines or NLA recommendations
•
Monitor response to therapy
‒ If suboptimal, increase statin potency (not dose)/add nonstatin in patients receiving
maximally tolerated statin
‒ Monitor side effects
16
Stone NJ, et al. Circulation. 2014;129(25 Suppl 2):S1-S45; Jacobson TA, et al. J Clin Lipidol. 2014;8:473-488.
Statin-Associated Muscle AEs and Risk Factors
Statin-associated muscle AEs:
‒ Myalgia
‒ Myopathy
‒ Myositis
‒ Myonecrosis
‒ Rhabdomyolysis
• Risk factors:
‒ Female sex, older age, diabetes, renal/hepatic dysfunction
‒ Concomitant agents that inhibit CYP3A4 or CYP2C9
‒ History of myopathy with other LLT
•
CYP = cytochrome P; LLT = lipid-lowering therapy.
17
Rosenson RS, et al. J Clin Lipidol. 2014;8(3 Suppl):S58-S71.
Management of Statin Myopathy
•
•
•
•
•
18
Limit daily dosage, reduce dosing frequency, or institute drug “holidays”1,2
ACC/AHA and NLA guidelines:
– Consider nonstatin with or without concomitant statin3-5
• Ezetimibe, bile acid sequestrants often used1,2
• Niacin (extended release) and fenofibrate (delayed release) no longer approved in combination
with statins6
Newer agents: PCSK9 inhibitors (alirocumab, evolocumab)
Vitamin D deficiency may contribute to statin myalgia7; limited evidence that vitamin D repletion
improves tolerability7,8
Measure thyroid-stimulating hormone in patients with myalgias/myopathy9
1. Bitzur R, et al. Diabetes Care. 2013;36(Suppl 2):S325-S330; 2. Fernandez G, et al. Cleve Clin J Med. 2011;78:393-403; 3. Stone NJ, et al.
Circulation. 2014;129(25 Suppl 2):S1-S45; 4. Jacobson TA, et al. J Clin Lipidol. 2014;8:473-488; 5. Guyton JR, et al. Clin Lipidol. 2014;
8(3 Suppl):S72-S81; 6. Federal Register. https://www.federalregister.gov/articles/2016/04/18/2016-08887/abbvie-inc-et-al-withdrawal-of-approvalof-indications-related-to-the-coadministration-with-statins. Accessed April 26, 2016; 7. Lee JH, et al. J Am Coll Cardiol. 2008;52:1949-1956;
8. Linde R, et al. Dermatoendocrinol. 2010;2:77-84; 9. Banach M, et al. Arch Med Sci. 2015;11:1-23.
PCE 2017 Series 1
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New Strategies for Dyslipidemia Management:
Minimizing Risk With Maximal LDL-C Reduction
Lack of Adherence and Persistence to Statin Therapy Is
Common: USAGE Study
Population survey of statin use over 18 months (N = 10,138)
• One-fourth of patients discontinued statin after 1 month
• Half discontinued within 3 months
• As many as three-fourths discontinued use in first year
‒ 57% stopped after an AE and had no further prescriptions filled
‒ One-third stopped without asking or telling their clinician
• On average, 2 statins were tried before stopping altogether
19
Cohen JD, et al. J Clin Lipidol. 2012;6:208-215.
Adherence Obstacles and Barriers
Obstacles
• Muscle-related AEs of statins are the primary reason for lack of adherence and treatment discontinuation1
• More common than reported in clinical trials1
Patient-Centered Barriers2
• Lack of knowledge about risks of dyslipidemia
• Lack of motivation
• Lack of confidence in adherence
– Concerns about cognitive impairment
– Concerns about diabetes
• Unclear expectations about treatment outcome
• Lack of conviction concerning consequences of
poor adherence
20
Clinician-Centered Barriers3,4
• Insufficient knowledge and skills
• Insufficient confidence
• Insufficient attention to patient education about
dyslipidemia and importance of treatment
• Lack of effective communication with patients to
emphasize need for good adherence
1. Fernandez G, et al. Cleve Clin J Med. 2011;78:393-403; 2. Casula M, et al. Patient Prefer Adherence. 2012;6:805-814;
3. Cohen JD, et al. J Clin Lipidol. 2012;6:208-215; 4. Wei MY, et al. J Clin Lipidol. 2013;7:472-483.
Traditional Therapies for Elevated LDL-C
21
Therapy
Mechanisms of Action
Statin1
Inhibits 3-hydroxy-3-methyl-glutaryl coenzyme A reductase, the
rate-limiting step in cholesterol synthesis; results in upregulation of
LDL receptors and improved LDL clearance from circulation
Cholesterol absorption inhibitor
(ezetimibe)2
Inhibits intestinal sterol absorption
Bile acid sequestrant3
Interferes with intestinal reabsorption of bile acid by binding these
breakdown products of cholesterol in the gut and promoting
excretion
Niacin4
Various mechanisms (eg, inhibition of peripheral mobilization of free
fatty acids, reducing hepatic VLDL synthesis/hepatic secretion)
1. Stancu C, Sima A. J Cell Mol Med. 2001;5:378-387; 2. Patel J, et al. Proc (Bayl Univ Med Cent). 2003;16:354-358;
3. Shepherd J. Cardiology. 1989;76(Suppl 1):65-71; 4. Kamanna VS, et al. Am J Cardiol. 2008;101(8A):20B-26B.
PCE 2017 Series 1
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New Strategies for Dyslipidemia Management:
Minimizing Risk With Maximal LDL-C Reduction
Newer Therapies for Elevated LDL-C
Therapy
Mechanisms of Action
PCSK9 inhibitor (alirocumab,
evolocumab)a
Blocks binding of PCSK9 enzyme to LDL receptors on surface of
hepatocytes
•
Protects receptors from destruction
•
Increases number of receptors on hepatocytes
•
Facilitates LDL-C clearance from blood
aApproved
for HeFH or ASCVD when additional lowering of LDL-C is needed, even with maximally tolerated statin therapy;
evolocumab also approved for HoFH.
HoFH = homozygous familial hypercholesterolemia.
22
Gouni-Berthold I, Berthold HK. Nutrients. 2014;6:5517-5533; Rader DJ, Kastelein JJ. Circulation. 2014;129:1022-1032.
ACC 2016 Update: Use of Nonstatin Therapies for LDL-C
Lowering
Therapy
Role in Lipid Lowering
Dietary measures (including
phytosterol and fiber supplements)
Part of every LDL-C lowering regimen; consider before initiating
nonstatin therapy
Ezetimibe
Appropriate in all patients; first-line nonstatin therapy in patients
with ASCVD and baseline LDL-C <190 mg/dL
Bile acid sequestrant
Second-line therapy after ezetimibe in patients with fasting TG
<300 mg/dL; colesevelam in patients with type 2 diabetes due to
modest hypoglycemic effect
PCSK9 inhibitor
Patients with clinical ASCVD; patients without ASCVD but with
baseline LDL-C ≥190 mg/dL
Niacin
No longer recommended in combination with statins due to
potential harms/lack of benefit
Patients with FH should be treated by specialist
FH = familial hypercholesterolemia.
23
Lloyd-Jones DM, et al. J Am Coll Cardiol. 2016;68:92-125.
Blockade of PCSK9/LDL-R Interaction
Lowers LDL-C Levels
LDL-R = LDL receptor; SREBP = sterol regulatory element-binding protein.
24
Adapted from LaGace TA. Curr Opin Lipidol. 2014;25:387-393.
PCE 2017 Series 1
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New Strategies for Dyslipidemia Management:
Minimizing Risk With Maximal LDL-C Reduction
ODYSSEY MONO: Alirocumab Versus Ezetimibe
Monotherapy
On-Treatment Analysis
Ezetimibe
Alirocumab
LS Mean (SE) LDL-C (mg/dL)
160
140
–17.2
(2.0%)
–20.4
(2.0%)
120
100
–53.2
(2.0%)
80
60
–54.1
(2.0%)
*
*
40
20
N = 103
0
4
0
8
12
*P <.0001 vs ezetimibe.
16
20
24
Week
LS = least squares; SE = standard error.
25
Roth EM, et al. Int J Cardiol. 2014;176:55-61.
Mean % Change in
LDL-C From BL
MENDEL-2: Evolocumab Monotherapy Versus Ezetimibe
or Placebo
Ezetimibe (n = 77)
Placebo (n = 76)
10
0
–10
–20
–30
–40
–50
–60
Biweekly injection
Week 4
Week 2
BL Day 1
Week 6
Week 8
Ezetimibe (n = 77)
Placebo (n = 78)
Mean % Change in
LDL-C From BL
Evolocumab biweekly (n = 153)
Week 10
Week 12
Evolocumab monthly (n = 153)
10
0
–10
–20
–30
–40
–50
–60
Monthly injection
Week 4
Week 2
BL Day 1
Week 8
Week 6
Week 12
Week 10
BL = baseline.
26
Koren MJ, et al. J Am Coll Cardiol. 2014;63:2531-2540.
ODYSSEY LONG TERM: Alirocumab Plus Statin in
Patients at High Risk
140
118.9
122.6
0.8%
3.6%
LS Mean Calculated
LDL-C Level (mg/dL)
120
100
80
57.9
60
48.3
–52.4%
40
–61.0%
20
Placebo + statin therapy at maximum tolerated dose ± other LLT
Alirocumab + statin therapy at maximum tolerated dose ± other LLT
0
0
4
8
12
16
24
36
52
64
78
Week
Post-hoc analysis: decrease in MACE with alirocumab + statin (3.3% vs 1.7%; nominal P = .02)
MACE = major adverse CV events: death from coronary heart disease, nonfatal MI, fatal or nonfatal ischemic stroke, or unstable angina
requiring hospitalization.
27
Robinson JG, et al. N Engl J Med. 2015;372:1489-1499.
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New Strategies for Dyslipidemia Management:
Minimizing Risk With Maximal LDL-C Reduction
LAPLACE-2: Evolocumab + Statin
30
20
10
Mean % Change
From BL in LDL-C
0
–10
–20
–30
–40
–50
–60
–70
Atorvastatin
80 mg
–80
Rosuvastatin
40 mg
Atorvastatin
10 mg
High-Intensity Statin
Placebo every 2 weeks
Placebo every month
Rosuvastatin
5 mg
Simvastatin
40 mg
Moderate-Intensity Statin
Evolocumab every 2 weeks
Evolocumab every month
Ezetimibe every day + placebo every 2 weeks
Ezetimibe every day + placebo every month
All treatment differences vs placebo and ezetimibe: P <.001.
No notable differences between the mean of weeks 10 and 12 and week 12 alone.
28
Robinson JG, et al; LAPLACE-2 Investigators. JAMA. 2014;311:1870-1882.
GAUSS-2: Evolocumab in Patients With Statin Intolerance
Mean % Change in
LDL-C From BL
0
Ezetimibe (N = 51)
–40
–60
Biweekly injection
–80
Week 2
Mean % Change in
LDL-C From BL
BL Day 1
Week 4
Week 6
Week 8
Ezetimibe (N = 51)
0
Week 10
Week 12
Evolocumab 420 mg every month (N = 102)
–20
–40
–60
Monthly injection
–80
BL Day 1
29
Evolocumab 140 mg every 2 weeks (N = 103)
–20
Week 2
Week 4
Week 6
Week 8
Week 10
Week 12
Stroes E, et al. J Am Coll Cardiol. 2014;63:2541-2548.
GLAGOV: Lowering LDL-C With a PCSK9 Inhibitor Causes
Atheroma Regression
Change in Percent Atheroma Volume (%)
0.2
0.05
P <.0001
0
P = NS
-0.2
• Multicenter international RCT
• Patients with ASCVD
randomized to statin or statin
+ evolocumab
P <.0001
-0.4
-0.6
-0.8
-0.95
-1
Statin Monotherapy
(n = 423)
Statin + Evolocumab
(n = 423)
NS = not significant; RCT = randomized controlled trial.
30
Nicholls SJ, et al. JAMA. 2016;316:2373-2384.
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New Strategies for Dyslipidemia Management:
Minimizing Risk With Maximal LDL-C Reduction
FOURIER: Evolocumab Plus Statin in CV Outcomes
25%
15% relative reduction in clinical
events at 48 weeks
Evolocumab (n = 13,784)
Placebo (n = 13,780)
% of Patients
20%
15%
10%
•
P <.001
11.3%
9.8%
P <.001
P <.001
•
P <.001
7.4%
7.0%
5.9%
P = .001
4.6%
5%
5.5%
Patients on optimized
moderate- to highintensity statin therapy
randomized to placebo
or evolocumab
Median duration of
follow-up: 2.2 years
3.4%
1.8% 1.7%
1.7% 1.7%
1.5% 1.9%
Hospitalization
for Unstable
Angina
Stroke
0%
Primary End
Point
Secondary End
Point
CV Death
MI
Coronary
Revascularization
Primary end point: CV death, MI, stroke, hospitalization for unstable angina, or coronary revascularization. Key secondary end point: CV death, MI,
or stroke.
31
Sabatine MS, et al. N Engl J Med. 2017;376:1713-1722.
ODYSSEY LONG TERM: Alirocumab and MACE
in Patients With ASCVD
• Patients maximally tolerated statin
therapy
• Randomized to placebo or
alirocumab 150 mg every 2 weeks
• 56% absolute MACE reduction for
alirocumab
No. of events, % (n)
HR (95% CI) vs placebo
2-sided P value vs placebo
0.08
Placebo: 5.1 (19) Alirocumab: 2.3 (16)
0.438 (0.225-0.852)
0.0149
0.06
Placebo (n = 373)
Alirocumab (n = 702)
0.04
0.02
0.00
• 26.5% MACE reduction for each
38.6 mg/dL decrease in LDL-C
No. at risk
Placebo
Alirocumab
32
Time to First Event
0.10
Cumulative Incidence of Event
• Post hoc analysis MACE rates in
patients with ASCVD (with/without
HeFH) plus 1 additional risk factor
0
12
24
373
702
364
692
340
650
36
48
60
Time (Weeks)
322
631
308
604
304
594
72
84
294
569
289
555
Robinson JG, et al. ACC 2017.
Candidates for PCSK9 Inhibitors: Indications
•
33
Prescribed as an adjunct to diet and maximally tolerated statin therapy
in adults with:
– ASCVD (eg, MI, stroke, peripheral artery disease) who require
additional lowering of LDL-C
– HeFH
– HoFH (evolocumab only)
Praluent [prescribing information]. Sanofi-Aventis; 2015; Repatha [prescribing information]. Amgen; 2015; Lloyd-Jones DM, et al. J Am
Coll Cardiol. 2016;68:92-125.
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New Strategies for Dyslipidemia Management:
Minimizing Risk With Maximal LDL-C Reduction
Familial Hypercholesterolemia
Autosomal codominant disorder
Very high levels of LDL-C, TC
• Early CVD
• HeFH – 1:200-1:300
• HoFH – 1:160,000-1:360,000
– Extreme hypercholesterolemia with rapidly accelerated atherosclerosis
– Very high mortality rate if left untreated
– Diagnosis based on LDL ≥190 mg/dL and ACC/AHA consensus pathway
– Should be referred to a lipidologist; LDL apheresis, mipomersen, lomitapide are
treatment options
•
•
34
Goldberg AC, et al. J Clin Lipidol. 2011;5(3 Suppl):S1-S8.
PCSK9 Inhibitors: Dosing and Administration
35
Alirocumab
Evolocumab
Route
Subcutaneous
Subcutaneous
Delivery
Prefilled, single-dose,
1-mL syringe or pen
Prefilled, single-dose pen or
on-body infusor with prefilled
monthly dose
Recommended starting
dose
75 mg every 2 weeks
140 mg every 2 weeks
Maximum dose
150 mg every 2 weeks
420 mg monthly
(recommended dose for HoFH)
Praluent [prescribing information]. Sanofi-Aventis; 2015; Repatha [prescribing information]. Amgen; 2015.
PCSK9 Inhibitors: Follow-up After Initiating Treatment
Measure LDL-C levels within 4-8 weeks of initiating or titrating to assess
response and adjust dose if needed
If a dose is missed:
– Instruct patient to administer injection within 7 days of missed dose, then
resume original schedule
– If missed dose not administered within 7 days, instruct patient to wait until the
next dose on the original schedule
• If allergic reactions appear, discontinue and treat patient according to standard of
care
•
•
36
Praluent [prescribing information]. Sanofi-Aventis; 2015; Repatha [prescribing information]. Amgen; 2015.
PCE 2017 Series 1
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New Strategies for Dyslipidemia Management:
Minimizing Risk With Maximal LDL-C Reduction
Common AEs Associated With PCSK9 Inhibitors (>5% of Patients)
Alirocumab
Nasopharyngitis (11.3%)
•
•
Injection site reactions (7.2%)
•
Upper respiratory tract infection (9.3%)
•
Influenza (5.7%)
•
Influenza (7.5%)
•
AEs leading to discontinuation:
5.3% (vs 5.1% with placebo)
•
Back pain (6.2%)
•
Injection site reactions (5.7%)
•
AEs leading to discontinuation: 2.2% (vs 1% with placebo)
•
37
Evolocumab
•
Nasopharyngitis (10.5%)
Serious hypersensitivity reactions requiring hospitalization have occurred with both agents
•
Potential for immunogenicity with all therapeutic proteins
•
Recent prospective EBBINGHAUS trial found no evidence for memory loss or cognitive issues with
evolocumab + statin therapy
Praluent [prescribing information]. Sanofi-Aventis; 2015; Repatha [prescribing information]. Amgen; 2015; Giugliano RP, et al. ACC 2017.
Abstract 17-LB-16161-AC.
Navigating Insurance Issues With PCSK9 Inhibitors
•
•
38
~80% initial denial rate for PCSK9 prescriptions
‒ 25% of commercial and 50% of Medicare claims received final approval
‒ Up to 17 pages of paperwork for prior authorization
“Town hall” meetings of the American Society for Preventive Cardiology, ACC, NLA,
AACE, and others organized to identify solutions
‒ Inconsistencies in interpretation of the approved prescribing information for PCSK9s
have resulted in discrepancies in payer approval and reimbursement practices
‒ Town hall meetings developed 5 key recommended definitions of terms in the
prescribing information to facilitate approval of prescriptions
Symphony Health Solutions. http://symphonyhealth.com/wp-content/uploads/2017/03/PCSK9-Inhibitors-Payer-Dynamics-Feb-2017.pdf.
Accessed April 26, 2017; Baum SJ, et al. Clin Cardiol. 2017;40:243-254; Jacoby DS. Personal communication, 2017. Data on file.
PCSK9 Inhibitors and Prior Authorization
•
Excerpt from “town hall” prior authorization template:
•
Defines maximally tolerated statin dose; HeFH, HoFH, clinical ASCVD
management/prevention, need for additional LDL-C lowering
Template and an appeals letter template available in the Supporting Information
section at http://onlinelibrary.wiley.com/doi/10.1002/clc.22713/full
•
39
Excerpted from Baum SJ, et al. Clin Cardiol. 2017;40:243-254; Jacoby DS. Personal communication with Practicing Clinicians
Exchange, 2017. Data on file.
PCE 2017 Series 1
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New Strategies for Dyslipidemia Management:
Minimizing Risk With Maximal LDL-C Reduction
Case Conclusion: Alejandro’s Management
• You initiate therapy with a PCSK9 inhibitor every 2 weeks
• You encourage Alejandro to continue efforts at lifestyle changes, including diet,
exercise, and smoking cessation
• You educate him about his new regimen and advise him to notify you
immediately if AEs develop
• Alejandro makes an appointment for follow-up in 3 months
40
Principles for Collaborating With Patients in Treatment
Selection
Ensure optimal pharmacotherapy through prudent use and monitoring of
medications
• Educate patients about treatment options
• Encourage lifestyle changes that can reduce CVD risk
•
41
PCE Action Plan
 Encourage a healthy lifestyle to improve lipid lowering; involve patients
in decision making regarding medical therapy
 Consider strategies to manage muscle symptoms in patients taking
statins
 Address obstacles to medication adherence
 Collaborate with patients in selecting lipid-lowering therapy to improve
outcomes
PCE Promotes Practice Change
42
PCE 2017 Series 1
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