Download Strategies for Managing Dyslipidemia Updated

Strategies for
Managing
Dyslipidemia Patients
with Residual
CVD Risk
Acknowledgements
We acknowledge the work of Lynne T. Braun,
PhD, CNP, FAHA, FPCNA, FAAN in the
development of this presentation.
Disclosures:
• Consultant/advisory board on UpToDate Inc.
• Affiliated with Practice Point.
Presenter
Speaker
Disclosures
Objectives
• Outline secondary prevention strategies in CVD
patients with residual risk despite taking the
maximum tolerated dose of statin therapy.
• Describe the clinical steps taken to identify statin
intolerance.
• Differentiate between the indications for statins,
PCSK9 inhibitors and other LDL-lowering therapies.
• Identify the potential barriers to treatment
adherence for patients requiring LDL-lowering
therapies and solutions to address the barriers.
Case Study: Ms. Green
• Ms. Green is a 56-year-old Caucasian patient who
recently had a NSTEMI. This is her follow-up
appointment 2 weeks later.
– Risk factors: untreated hypertension,
hypercholesterolemia, obesity (BMI is 30.6 kg/m2)
– Past medical history: pre-diabetes, degenerative disc
disease
– Family history of premature CVD (father had MI at age 45)
• Discharge meds include atorvastatin 80 mg,
lisinopril 20 mg, metoprolol XL 25 mg, and ASA 81
mg daily.
Initiating Statin Therapy in Patients with
Clinical ASCVD
Clinical ASCVD
Not on statin
therapy
Initial evaluation:
Lipid panel, ALT, CK, others
as needed to eval
secondary causes
TG > 500
LDL>190
ALT > 3 times ULN
Age < 75
Age > 75
Without contraindication
or statin safety concerns
High-Intensity Statin
Moderate-Intensity Statin
Healthy lifestyle
Healthy Lifestyle
Stone NJ et al JACC 2014;63:2889-2934.
Evaluate and treat lab
abnormalities:
Case Study: Ms. Green Continued
• Upon 2-week follow-up:
– Reported feeling achy and tired, attributed this to
recently having a heart attack
– Referred to cardiac rehab
• One month later:
– Ms. Green scheduled an appointment because of severe
leg and low back pain; she had difficulty exercising
during cardiac rehab.
– HCP asked her to temporarily stop atorvastatin
– TSH, vitamin D, LFTs, and CK levels were ordered (a
baseline CK was not available).
Ms. Green Continued
• Muscle pain resolved 2 weeks after stopping atorvastatin.
• CK mildly elevated; vitamin D low; LFTs and TSH normal.
• Atorvastatin restarted at 40 mg,
• Muscle symptoms occurred again after 1 month.
• Ms. Green experienced leg pain from simvastatin in the past.
• Hypercholesterolemia was untreated until the time of her
heart attack.
• Atorvastatin was again stopped, and after resolution of
symptoms, rosuvastatin 10 mg was begun.
• Thus far, Ms. Green has tolerated moderate-intensity
rosuvastatin, but is hesitant to increase the dose.
• Her LDL-C is 90 mg/dL (vs 140 mg/dL untreated).
Evaluating Statin-Associated Muscle
Effects
Statin-Associated Muscle Effects
• Myalgia
• Unexplained muscle discomfort
• Often described as “flu-like” symptoms with normal CK level
• Myopathy
• Muscle weakness
• Myositis
• Muscle inflammation
• Myonecrosis: muscle enzyme elevations or hyperCKemia
• Mild > 3-fold above untreated baseline CK level
• Moderate ≥ 10-fold above untreated baseline CK level
• Severe ≥ 50-fold above untreated baseline CK level
• Myonecrosis with myoglobinuria or AKI
• Increase in serum creatinine ≥ 0.5 mg/dL (clinical rhabodomyolysis)
Rosenson RS et al., J Clin Lipidol 2014;8:S58-S71
Assessing Muscle Symptoms
• Myalgia
– Often described as muscle aches, soreness,
stiffness, tenderness, cramps with or shortly
after exercise
• Muscles commonly affected
– Symmetric hip flexors/thigh aches
– Symmetric calf aches
– Symmetric upper arm aches
Rosenson RS et al., J Clin Lipidol 2014;8:S58-S71
Options for the Patient Intolerant to
Multiple Statins
• Use a systematic approach to evaluate statin intolerance
• Careful history of symptoms: description, timing
• Rule out other causes
• Hypothyroidism, vitamin D deficiency, recent exercise,
rheumatologic disorders, vitamin D deficiency, primary
muscle diseases)
• Evaluate for drug-drug interaction
• Lower the statin dose
• Switch to another statin
• Reduce the dose frequency to less than daily
• Consider using a nonstatin lipid-lowering agent
• Adding co-enzyme Q10 to statin (inconclusive results)
Cannon CP et al., N Engl J Med 2015; DOI: 10.1056/NEJMoa1410489
Parker BA et al., J Clin Lipidol 2013;7:187-193
Statin Safety Recommendations:
ACC/AHA Guidelines
• Use moderate-intensity statin therapy in patients who are
predisposed to statin-associated adverse effects.
– Multiple or serious comorbidities, including impaired renal or
hepatic function
– History of previous statin intolerance or muscle disorders
– Unexplained ALT elevations > 3 times ULN
– Concomitant use of drugs affecting statin metabolism
– > 75 years of age
– History of hemorrhagic stroke
– Asian ancestry
• CK should not be routinely measured, although it is reasonable to
measure baseline CK in persons at increased risk for adverse
muscle events
Stone NJ et al., Circulation 2013, DOI: 10.1161/01.cir.0000437738.63853.7a
Monitoring Statin Therapy
• Obtain baseline lipid panel , ALT, CK.
• Repeat lipid panel in 4 to 12 weeks to determine
adherence.
• Thereafter, assess every 3 to 12 months as
clinically indicated.
• If dose adjustment, repeat lipid panel in 4 to 12
weeks.
Question/Discussion:
• What are some secondary prevention strategies
that can be implemented in CVD patients with
residual risk despite taking the maximum tolerated
dose of statin therapy?
Lloyd-Jones DM et al, JACC 2016, DOI: 10.1016/j.jacc.2016.03.519
Decision Pathway: Patients with Clinical ASCVD
with Comorbidities, on Statin for Secondary
Prevention
Patients with ASCVD
with comorbidities on
statin for secondary
prevention
Patient has > 50% LDL-C
reduction or LDL-C < 70
mg/dL or Non – HDL-C <
100 mg/dL
Continue to monitor
adherence to meds,
lifestyle, and LDL-C
response to therapy
Patient has < 50% LDL-C
reduction and/or has not
reached expected
targets
•Address statin
adherence, Intensify
lifestyle, Increase to
high-intensity statin,
evaluate for statin
intolerance, control
other risk factors
Lloyd-Jones DM et al, JACC 2016, DOI: 10.1016/j.jacc.2016.03.519
Barriers to Adherence to
Lipid-Lowering Therapies
and Strategies to Overcome
These Barriers
Factors That Place Patients at Rise of
Non-Adherence
•
•
•
•
•
•
•
Cost of medication
Concern over adverse effects
Complexity of medication regimen
Taking multiple medications
“Silent” conditions
Forgetfulness
Negative previous experience with drug therapies
Assess Adherence by Starting with a
Single Question
• “In the past 2 weeks, what percent of your
cholesterol medicine would you say you have
taken?”
• (If less than 100%)……..”What is the main reason
you might miss your medication?”
Morisky Medication Adherence Scale:
MMAS-4
• Do you ever forget to take your medicine?
• Are you careless at times about taking your
medicine?
• Sometimes if you feel worse when you take the
medicine, do you stop taking it?
• When you feel better, do you sometimes stop
taking your medicine?
 0 = high adherence
 1-2 = medium adherence
 3-4 = low adherence
Med Care. 1986;24:67-74
Strategies for Low Health Literacy
• Create a shame-free environment.
• All staff should be made aware of literacy issues.
• Speak slowly to foster a patient-centered
approach.
• Use plain, nonmedical language.
• Use supplemental materials with visual images,
video, and audio sources to improve recall.
• Limit the amount of information and repeat it.
Med Care. 1986;24:67-74
Educating the Patient
• Assess patient’s need for information (verbal
explanation, written materials)
• Specifically relate the reason for prescribing a lipid
modifying agent to an individual patient’s condition:
– FH and + family history
– Recent cardiac event (in the case of Ms. Green)
– Diabetes as a high-risk condition
– Presence of CAC
Educating the Patient
• Address the importance of 3 forms of therapy to modify
lipids and reduce CHD risk:
– Heart-healthy diet
– Regular physical activity
– Medication
• Use teach-back method to ensure
patient’s understanding
• Create a collaborative environment to encourage
questions
• Stress the “life-saving, event prevention” nature of
statins for high-risk patients
Discuss Potential Adverse Effects at
Drug Initiation
• Discuss the potential for muscle aches and describe
how muscle aches feel (statins).
• Tell patients you want to be called if they believe they
are experiencing an adverse effect.
• Explain that although statins are one“class” of drugs,
they are very different from one another; a problem
with one doesn’t usually mean every statin should be
avoided.
Intensify Lifestyle
Strategies
Lifestyle as the Foundation for Risk
Reduction
• A critical component of health promotion and ASCVD
risk reduction
– Heart-healthy diet
– Regular exercise
– Avoidance of tobacco products
– Maintenance of a healthy weight
Eckel RH et al., Circulation 2013, DOI: 10.1161/01.cir.0000437740.48606.d1
Dietary Recommendations for LDL
Lowering
• Consume a dietary pattern that
emphasizes intake of vegetables, fruits,
whole grains; includes low-fat dairy
products, poultry, fish, legumes,
nontropical vegetable oils, nuts; and
limits intake of sweets, sugar-sweetened
beverages, and red meats
– Strong recommendation (I, LOE A)
Eckel RH et al., Circulation 2013, DOI: 10.1161/01.cir.0000437740.48606.d1
Dietary Recommendations for LDL
Lowering
• Adapt this dietary pattern to appropriate calorie
requirements, personal and cultural food
preferences, and nutrition therapy for other medical
conditions (including diabetes).
• Achieve this pattern by following plans such as the
DASH dietary pattern, the USDA Food Pattern, or the
AHA Diet.
Eckel RH et al., Circulation 2013, DOI: 10.1161/01.cir.0000437740.48606.d1
Dietary Recommendations for LDL
Lowering
• Aim for a dietary pattern that achieves 5 to 6% of
calories from saturated fat.
• Reduce per cent of calories from saturated fat.
• Reduce per cent of calories from trans fat.
– All strong recommendations (I, LOE A)
Eckel RH et al., Circulation 2013, DOI: 10.1161/01.cir.0000437740.48606.d1
Physical Activity Recommendations for
Lipid Management
• Advise adults to engage in aerobic
physical activity to reduce LDL-C and
non-HDL-C:
– 3 to 4 sessions a week, lasting on
average 40 minutes per session,
and involving moderate-to-vigorous
intensity physical activity
– Moderate recommendation (IIa,
LOE A)
Eckel RH et al., Circulation 2013, DOI: 10.1161/01.cir.0000437740.48606.d1
PCNA Materials
PCNA Materials
Non-Statin Agents for Additional Risk
Reduction
Clinician-Patient Discussion
When treatment goal is not met on
statin.
1. Potential for additional ASCVD risk
reduction from addition of non-statin
therapy to lower LDL-C.
2. Potential for adverse events or
drug-drug interactions from addition
of non-statin therapy
3. Patient preference
Lloyd-Jones DM et al, JACC 2016, DOI: 10.1016/j.jacc.2016.03.519
Consider adding ezetimibe and
continue to monitor adherence to
meds, lifestyle and LDL-C response
to therapy.
Consider adding or replacing statin
with PCSK 9 inhibitor and continue
to monitor adherence to meds,
lifestyle and LDL-C response to
therapy.
Shared Decision-Making
• Engage in a clinician–patient discussion before initiating
treatment
• When deciding on statin therapy for primary prevention
• When deciding on option for a statin intolerant patient
• Treatment plan informed by:
• clinical judgment
• statin safety issues
• consideration of patient preferences
• The more empowered patients feel, the more likely they will
be motivated to manage their condition and adhere to
medications.
Lin GA, Fagerlin F. Circ Cardiovasc Qual Outcomes 2014
DOI: 10.1161/CIRCOUTCOMES.113.000322
Options for Non-Statin
Therapies
Non-Statin Strategies for Management
of LDL-Related ASCVD Risk
Strategy/Agent
Mechanism of Action
Mean % LDL
Reduction
Consider referral to lipid
specialist
Ezetimibe
Reduces cholesterol absorption in small Monotherapy 18%;
intestine
Combined with statin
25%
PCSK9 inhibitors
Human monoclonal antibody to PCSK9.
Binds to PCSK9 and increases number
of LDL receptors available to clear
circulating LDL.
Lloyd-Jones DM et al, JACC 2016, DOI: 10.1016/j.jacc.2016.03.519
Added to statin:
Alirocumab 43-47%
Evolocumab 58-64%
Non-Statin Strategies for Management of LDLRelated ASCVD Risk
Strategy/Agent
Mechanism of Action
Mean % LDL
Reduction
Bile acid sequestrants
Bind bile acids in intestine and impede
their absorption. More cholesterol is
converted to bile acids increasing
demand for cholesterol and increasing
HMG-CoA reductase. Hepatic LDL
receptors increase which increases LDL-C
clearance from the blood.
Colesevelam
monotherapy 15%,
Phytosterols
Decrease cholesterol transport toward
the intestinal brush border; may also
interfere with transporter-mediated
cholesterol uptake.
5-15%
Soluble/viscous fiber
Traps cholesterol and bile acids in small
intestine; results in decreased
absorption.
10-12%
Lloyd-Jones DM et al, JACC 2016, DOI: 10.1016/j.jacc.2016.03.519
added to statin 10-16%;
Cholestyramine
monotherapy 10.4%;
Colestipol 16-27%
Non-Statin Strategies for Management
of LDL-Related ASCVD Risk
Strategy/Agent
Mechanism of Action
Mean % LDL
Reduction
Mipomerson
Antisense oligonucleotide targeted to
human mRNA for apoB-100; inhibits
translation of the apoB-100 protein.
For HoFH: addition to
maximally tolerated
lipid lowering therapy
25%
Lomitapide
Inhibits MTP, preventing the assembly of
apoB-containing lipoproteins; inhibits the
synthesis of VLDL and thus LDL.
For HoFH: 40-50%
when added to other
lipid lowering therapy
LDL apheresis
Selectively removes apoB-containing
lipoproteins, producing an acute reduction
in LDL-C.
Weekly or biweekly
treatment: 50-60%
Lloyd-Jones DM et al, JACC 2016, DOI: 10.1016/j.jacc.2016.03.519
Ezetimibe
• Inhibitor of intestinal cholesterol absorption
• Reduces elevated LDL-C either alone or in
combination with a statin or other lipid-lowering
medication
• Dose is 10 mg once daily, with or without food
• Outcome data was shown by the IMPROVE-IT trial
when given in combination with simvastatin
Improve-It Trial
• Evaluated the clinical efficacy of combination
Ez/simva vs simvastatin alone in ACS patients ≥ 50
years of age
• LDL-C 50-125 mg/dL (or 50-100 mg/dL if prior lipidlowering treatment)
• Primary endpoint: CV death, MI, hospital admission
for UA, coronary revascularization, or stroke
• Absolute RR over 7 years was 2%
– 32.7% in the Ez/simva arm experiencing a primary
endpoint vs 34.7% in the simvastatin arm
Cannon CP et al., N Engl J Med, 2015: DOI: 10.1056/NEJMoa1410489
41
IMPROVE-IT: Kaplan Meier Curves for
Primary Efficacy Endpoint
Cannon CP et al., N Engl J Med 2015;372:2387-2397
PCSK9 INHIBITORS
• PCSK9 is a protein secreted by the hepatocyte
• Loss of function mutations in PCSK9 decrease LDL-C
and CV risk
• Clinical trials with monoclonal antibodies to PCSK9
demonstrate 60%-70% reductions in LDL-C
• Injectable cholesterol-lowering drugs
• Clinical outcomes studies not yet complete
Novel Lipid-Regulating Drug Targets.
Marina Cuchel et al. Eur Heart J 2014;eurheartj.ehu274
© The Author 2014. Published by Oxford University Press on behalf of the European Society of Cardiology
Praluent (Alirocumab)
• Indications -- diet + maximally tolerated statin:
• Adults with heterozygous FH
• Clinical ASCVD who require additional LDL lowering
• Most common adverse effects:
• Nasopharyngitis, injection site reactions, influenza
• Neurocognitive effects 0.8% vs. 0.7% (placebo)
• Abnormalities in liver enzymes 2.5% vs. 1.8% (placebo)
• D=Discontinuation of treatment 0.3% vs <0.1% (placebo)
• Allergic reactions leading to discontinuation of
treatment 0.6% vs 0.2% (placebo)
Source: Praluent product information
ODYSSEY LONG TERM Study Design:
Alirocumab
Hefh or high cv-risk
patients on maximally
tolerated satin
• Other lipid-lowering
therapy
LDL-C ≥ 70 mg/dl
Followup (8
weeks)
Double-blind treatment (18 months)
N=
1553
Alirocumab 150 mg Q2W SC
N = 788
Placebo Q2W SC
(single 1 mL injection using prefilled syringe
for self-administration)
R
W4
W12
W52
W24
W64
W78
Assessments
W0
W8
W16
W36
Primary
Efficacy Endpoint
Pre-specified Analysis
Efficacy: all patients up to W52 (ITT)
Safety: all patients randomized and treated
• 85.8% (2009/2341) completed 52 weeks (both treatment arms)
• 26.1% (405/1553 alirocumab) and 25.6% (202/788 placebo) had
completed 78 weeks by time of this analysis
• Mean treatment duration: 65 weeks (both treatment arms)
.
ClinicalTrials.gov identifier: NCT01507831
Odyssey Trial: LDL Cholesterol Levels
Over Time
LDL Cholesterol Levels Over Time
Repatha (Evolocumab)
• Indications – diet + maximally-tolerated statin:
• HeFH
• Clinical ASCVD who require additional LDL lowering
• HOFH who require additional LDL lowering
• Common adverse effects:
• Nasopharyngitis, upper respiratory tract infection, flu, back
pain, and reactions such as redness, pain, or bruising at
injection site
• Neurocognitive effects 0.2% vs. 0.7% (placebo)
• Abnormalities in liver enzymes 0.8% vs. 1% (placebo)
• Adverse effects leading to discontinuation 2.2% vs.
1% (placebo)
Source: Praluent product information
Osler 1 and 2 Trials: Evolocumab
• 4465 patients who completed 1 of 12 phase 2 or 3
studies (parent trials)
• Randomly assigned in a 2:1 ratio to receive either
evolocumab (140 mg every 2 weeks or 420 mg
monthly) plus standard therapy or standard therapy
alone
• Followed for median of 11.1 months
• Assessed for lipid levels, safety, and CV events (death,
MI, unstable angina, coronary revascularization, stroke
TIA, and HF) as a prespecified exploratory analysis
Sabatine MS et al., N Engl J Med 2015;372:1500-1509.
Osler Trials: LDL-C Levels
Sabatine MS et al., N Engl J Med 2015;372:1500-1509.
Osler Trials: Cumulative Incidence of
Cardiovascular Events
Sabatine MS et al., N Engl J Med 2015;372:1500-1509.
Patients with Clinical ASCVD with
Comorbidities
• Consider BAS as alternative to ezetimibe if TG < 300 mg/dL.
• Patient with ASCVD and baseline LDL-C ≥ 190 mg/dL with
< 50% reduction in LDL-C (may consider LDL-C ≥ 70 mg/dL):
– Reasonable to consider a PCSK9 inhibitor as a first add-on
medication (rather than ezetimibe or BAS)
• If < 50% reduction in LDL-C (may consider LDL-C ≥ 70 mg/dL)
with triple therapy, refer to lipid specialist and RDN.
– Specialized therapies (mipomersen, lomitapide, LDL
apheresis) may be needed for patients with baseline LDL-C ≥
190 mg/dL and inadequate response to statins, ezetimibe,
and PCSK9 inhibitors.
Lloyd-Jones DM et al, JACC 2016, DOI: 10.1016/j.jacc.2016.03.519
Lessons Learned: Obtaining Approval
for PCSK9 Inhibitors
• Given high cost of drugs, oversight by insurers and
pharmacy programs is intense.
• Work closely with reps. Learn if one agent is
preferred by a particular insurance/pharmacy plan.
• Clearly identify the indication on enrollment form.
• Clearly describe any statin failures (drug, dose, LDL-C,
adverse effect).
• Include most recent labs.
• Enlist the help of specialty pharmacist if available.
• Other tips?
Summary
• Clinicians should thoroughly assess muscle symptoms in
patients taking statins.
• Statins are the class of medications with proven outcomes. In a
patient with clinical ASCVD, several attempts should be made to
find a medication regimen that is tolerated.
• Strategies for reducing residual risk in patients with ASCVD on
maximally-tolerated statin therapy include:
• Evaluate and introduce strategies to improve statin
adherence
• Intensify lifestyle
• Control other risk factors
• Consider the addition of non-statin agents
Summary
• The IMPROVE-IT trial showed a modest outcome benefit
for ACS patients who received simvastatin plus
ezetimibe versus simvastatin alone.
• PCSK9 inhibitors are generally well-tolerated and show
a profound reduction in LDL-C. However, outcome data
is not yet available.
• Patients should be engaged in a discussion before
initiating treatment and when making decisions about
treatment options.
Discussion Questions
1. Is statin intolerance something you commonly manage in
your practice? How do you evaluate someone with
complaints of intolerance?
2. Have you used the PCSK9’s in your practice? What was
your experience? Ease of getting the medication covered
by insurance? Patients response to an injectable
medicine? Patient results/outcomes?
3. What other non-statin medications do you use when
patients can’t/refuse to take statins.