Download Interpreting the ACC-AHA Guidelines on Cardiovascular Disease Prevention and Cholesterol Management

Interpreting the ACC-AHA Guidelines on
Cardiovascular Disease Prevention and
Cholesterol Management
Nathan D. Wong, PhD, FACC, FAHA
Professor and Director
Heart Disease Prevention Program
Division of Cardiology
University of California, Irvine
Past President, American Society for Preventive
Cardiology
Disclosures
 Research contracts to institution from Amgen,
Bristol Myers-Squibb, and Regeneron
 Consultant, Amgen and Re-Engineering Healthcare,
Quinne Manuel
Nov. 12, 2013
C-DAY
Cholesterol?
Controversy?
Confusion?
Conundrum?
Courage…...?
I have some bad news for you. While your
cholesterol has remained the same, the research
findings have changed.
New CVD Prevention Guidelines
1) AHA/ACC Guideline on Cardiovascular Risk
Assessment (November)
2) AHA/ACC Guideline on Lifestyle Management
(November)
3) AHA/ACC Guideline on Obesity Management
(November)
4) AHA/ACC Guideline on Cholesterol Management
(November)
5) AHA Advisory on Blood Pressure Control
(November)
6) Guidelines on Hypertension by Members Appointed
to JNC-8 (December)
7) ASH/ISH Guidelines on Hypertension (December)
NHLBI Charge to the Expert Panel
Evaluate higher quality randomized controlled
trial (RCT) evidence for cholesterol-lowering drug
therapy to reduce ASCVD risk
 Use Critical Questions (CQs) to create the evidence
search from which the guideline is developed
• Cholesterol Panel: 3 CQs
• Risk Assessment Work Group: 2 CQs
• Lifestyle Management Work Group: 3 CQs
 RCTs and systematic reviews/meta-analyses of RCTs
independently assessed as fair-to-good quality
 Develop recommendations based on RCT evidence
• Less expert opinion than in prior guidelines
Preventive cardiology efforts begin with assessment of
cardiovascular disease risk
Recommendation to begin with a global risk
assessment using the Pooled Cohort Equations to
estimate 10-year ASCVD Risk
(other risk assessment algorithms include the
European SCORE, PROCAM, or Framingham scores)
Why Use Risk Scores?
1) Risk functions provide an “economic and efficient
method of identifying persons at high cardiovascular
risk who need preventive treatment….” (Kannel 1976)
2) Intensity of treatment should match a person’s risk
(ACC Bethesda Conf, JACC 1996).
3) A physician’s estimate is only accurate 24% of the
time (Pignone, 2003).
4) Can be used to communicate risk in patients and
motivate adherence to lifestyle and other therapies.
5) Routine use of global risk scores leads to greater use
of guideline-based therapy and improved outcomes
(Sheridan, 2008).
ATP III Update ( 2004 )
LDL-C Treatment Targets based on 10-year
Hard CHD Risk from Framingham Risk Score
Risk Category
LDL-C Goal
Initiate
TLC
Consider
Drug Therapy
High risk:
CHD or CHD risk
equivalents
(10-year risk >20%)
<100 mg/dL
(optional goal: 100 mg/dL
<70 mg/dL)
100 mg/dL
(<100 mg/dL:
consider drug Rx)
Moderately high risk:
2+ risk factors
(10-year risk 10% to
20%)
<130 mg/dL
(optimal <100
mg/dL)
130 mg/dL
130 mg/dL
(100-129 mg/dL:
consider Rx )
Moderate risk:
2+ risk factors (risk
<10%)
<130 mg/dL
130 mg/dL
160 mg/dL
Lower risk:
0-1 risk factor
<160 mg/dL
160 mg/dL
190 mg/dL
Adapted from Grundy SM, et al. Circulation. 2004;110:227-239.
ASCVD Risk Calculator: Development
 NHLBI charge to the workgroup: To Develop or


Recommend an Approach to Quantitative Risk
Assessment That Could be Used to Guide Care
Risk Assessment Work Group judged new risk tool
was needed that was Inclusive of African Americans
and with expanded endpoint including stroke
Sought cohorts representative of the U.S. population
as a whole
• Community- or population-based
• Whites and African Americans (at a minimum)
• Recent follow-up data of at least 10 years
10-year follow-up from other ethnicities not
available at time of development
ASCVD Risk Calculator: Development (cont.)
 Pooled Cohort Equations
• Atherosclerosis Risk in Communities (ARIC)
• Cardiovascular Heath Study (CHS)
• Coronary Artery Risk Development in Young



Adults (CARDIA)
• Framingham Original and Offspring
Hard ASCVD
• CHD death, nonfatal MI, fatal/nonfatal stroke
(but does not include angina, PCI/CABG or other
CVD such as HF or PVD)
Models tested using traditional RFs + newer markers
when possible
Internal and external validation
Recommendations for Assessment of 10Year Risk of a First Hard ASCVD Event
I IIa IIb III
The race- and sex-specific Pooled Cohort Equations* to
predict 10-year risk of a first hard ASCVD event should be
used in non-Hispanic African Americans and non-Hispanic
whites, 40 to 79 years of age.
I IIa IIb III
Use of the sex-specific Pooled Cohort Equations
for non-Hispanic whites may be considered for
estimation of risk in patients from populations
other than African Americans and non-Hispanic
whites.
*Derived from the ARIC study, CHS, CARDIA study, Framingham original and
offspring cohorts.
2013 Prevention Guidelines
ASCVD Risk Estimator
ASCVD Risk Estimator
•
•
•
•
Provides 10-year
ASCVD risk for those
40-79 and lifetime risk
for those 20-59
This is intended to
drive discussions of
greater adherence to
heart-healthy lifestyle
Initiates risk
discussion with patient
Not an automatic
prescription for a statin
Recommendations for Use of Newer Risk Markers
After Quantitative Risk Assessment
I IIa IIb III
If, after quantitative risk assessment, a riskbased treatment decision is uncertain,
assessment of ≥1 of the following—family
history, hs-CRP, CAC score, or ABI—may be
considered to inform treatment decision
making.†
I IIa IIb III
Routine measurement of carotid intima-media
thickness is not recommended in clinical
practice for risk assessment for a first ASCVD
event.†
No Benefit
†Based on new evidence reviewed during ACC/AHA update of evidence.
If the risk decision is uncertain, the following factors
can help inform the treatment decision and revise
the risk estimate upward:
1) LDL-C ≥ 160 mg/dl
2) Family hx premature ASCVD (prior CAD or
stroke in male first degree relative age <55 or
female first degree relative <65)
3) Increased lifetime risk
4) hs-CRP≥ 2 mg/L
5) CAC score ≥ 300 or 75th%tile
6) ABI < 0.9
Ankle- Brachial Index (ABI)
Measure of lower-extremity
occlusive peripheral arterial disease
Ankle SBP *
Brachial Artery SBP
ABI
ABI < 0.90 is abnormal
Sensitivity = 90% specificity= 98% for stenosis >
50%.
Can detect asymptomatic disease.
* dorsalis pedis or posterior tibial artery by doppler probe
ABI and Total Mortalty
(ABI Collaboration, JAMA 2008)
Coronary Calcium and Atherosclerosis:
Pathology Evidence
 Coronary calcium invariably
indicates the presence of
atherosclerosis, but
atherosclerotic lesions do not
always contain calcium (1-3).
 Calcium deposition may occur
early in life, as early as the
second decade, and in lesions
that are not advanced (4-5).
 Correlates with plaque burden;
highly sensitive for angiographic
disease
1) Wexler et al., Circ 1996; 94: 1175-92, 2) Blankenhorn and Stern, Am J Roentgenol 1959;
81: 772-7, 3) Blankenhorn and Stern, Am J Med Sci 1961; 42: 1-49, 4) Stary, Eur Heart J
1990; 11(suppl E): 3-19, 5) Stary, Arteriosclerosis 1989; 9 (suppl I): 19-32.
Cumulative Incidence of Any Coronary
Event: MESA Study
(Detrano et al., NEJM 2008)
Annual CHD Event Rates (in %) by Calcium Score Events by
CAC Categories in Subjects with DM, MetS, or Neither Disease
(Malik and Wong et al., Diabetes Care 2011)
Coronary Heart Disease
4
Annual
CHD
Event
Rate
4
3.5
3
2.5
2
1.5
1
0.5
0
3.5
1.9
1.5
0.4
0.8
0.2
0.1
0
2.1
0.4
1-99
2.2
1.3
DM
MetS
Neither MetS/DM
100-399
400+
Coronary Artery Calcium Score
ACCF/AHA 2010 Guideline: CAC Scoring for CV risk assessment in
asymptomatic adults aged 40 and over with diabetes (Class IIa-B)
Can Screening for Atherosclerosis Identify Those Most
Likely to Benefit from Lipid-Lowering Therapy?
2010 ACC/AHA Greenland et al. Risk Assessment
ACC/AHA 2013 Guideline: IIb-B
“..Assessing CAC is likely to be the most useful of the current approaches
to improving risk assessment among individuals found to be at intermediate
risk after formal risk assessment”
Intermediate Risk
MESA Subjects
(n=1330)
C-statistics:
FRS alone 0.623
FRS+CAC 0.784 (p<0.001)
FRS+CIMT 0.652 (p=0.01)
FRS+FMD 0.639 (p=0.06)
FRS+CRP 0.640 (p=0.03)
FRS+FamHx 0.675
(p=0.001)
FRS+ABI 0.650 (p=0.01)
Yeboah J et al, JAMA 2012
dd
Lifestyle management remains the cornerstone
for reducing cardiovascular disease risk
including achieving and maintaining optimal
risk factor levels
Critical Question: Among adults, what is the effect of dietary
patterns and/or macronutrient composition on CVD risk factors,
when compared to no treatment or to other types of
interventions?
Advise adults who would benefit from
LDL-C or BP lowering* to:
I IIa IIb III
Consume a dietary pattern that emphasizes intake of
vegetables, fruits, and whole grains; includes low-fat dairy
products, poultry, fish, legumes, nontropical vegetable oils
and nuts; and limits intake of sweets, sugar-sweetened
beverages, and red meats.
• 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 U.S. Department of
Agriculture (USDA) Food Pattern, or the AHA Diet.
*Refer to 2013 Blood Cholesterol Guideline for guidance on who would benefit from
LDL-C lowering.
Physical Activity
I IIa IIb III
Lipids:
In general, 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 vigorousintensity physical activity.
I IIa IIb III
BP:
In general, advise adults to engage in aerobic
physical activity to lower BP: 3 to 4 sessions a week,
lasting on average 40 minutes per session, and
involving moderate- to vigorous-intensity physical
activity.
Cardiac Rehabilitation:
Benefits Following a Myocardial Infarction (MI)
Effect of cardiac rehabilitation in randomized controlled trials following a MI
1.5
Pooled Odds Ratio
1.15
1
*
0.76 *
0.75**
0.5
0
All Cause Death
CV Mortality
Nonfatal Recurrence
Cardiac rehabilitation reduces CV events after a MI
*p<0.0125
CV=Cardiovascular
Oldridge NB et al. JAMA 1988;260:945-950
……even modest weight loss (3-5% of body weight) can result in
clinically meaningful benefits for triglycerides, blood glucose,
glycated hemoglobin, and development of diabetes (type 2)….
.
Advise overweight and obese individuals who would benefit from
weight loss to participate for ≥6 months in a comprehensive lifestyle
program adhering to a lower-calorie diet and in increasing physical activity
Prescribe on-site, high-intensity (i.e., ≥14 sessions in 6 months)
comprehensive weight loss interventions provided in individual or group
sessions by a trained interventionist (dietitian, exercise physiologist, etc.)
What’s New in the Cholesterol Guideline?
1)
2)
3)
4)
5)
Focus on ASCVD reduction: 4 Statin Benefit Groups
New Perspective on LDL-C and/or Non-HDL-C Treatment Goals
Emphasis on the Clinician-Patient Risk Discussion
Global Risk Assessment for Primary Prevention
Safety Recommendations
Critical questions addressed the evidence for LDL-C and non-HDL-C goals
primary and secondary prevention and the evidence for reduction in
ASCVD events in relation to cholesterol lowering drugs available.
What’s Similar to ATP 3?
 Emphasis on lifestyle measures as crucial
 Focus on treatment of LDL cholesterol
(LDL-C)
 Greatest intensity of treatment for patients
at highest risk
 Preference for statins over other
medications lowering LDL-C (although this
is greater in the new ACC/AHA Guideline)
4 Statin Benefit Groups
 Clinical ASCVD*
 LDL–C >190 mg/dL, Age >21 years
 Primary prevention – Diabetes: Age 40-75 years, LDL–C
70-189 mg/dL
 Primary prevention - No Diabetes†: ≥7.5%‡ 10-year
ASCVD risk, Age 40-75 years, LDL–C 70-189 mg/dL,
*Atherosclerotic cardiovascular disease
†Requires risk discussion between clinician and patient before statin initiation.
‡Statin therapy may be considered if risk decision is uncertain after use of ASCVD
risk calculator.
These identified statin benefit groups to not imply that other groups
(e.g., those outside the specified age ranges) will not benefit and
should not be treated
Individuals Not in a Statin Benefit Group
 In those for whom a risk decision is uncertain:
 These factors may inform clinical decision making:
•
•
•
•
•
Family history of premature ASCVD
Elevated lifetime risk of ASCVD
LDL–C ≥160 mg/dL
hs-CRP ≥2.0 mg/L
Coronary artery calcium (CAC) score
≥300 Agaston units
• Ankle brachial index (ABI)<0.9
Their use still requires discussion
between clinician and patient
Clinician - Patient Risk Discussion
Before Statin Rx Especially Primary
Prevention
✔ Estimate 10 yr
ASCVD Risk (when no CVD)
Review other risk factors
& risk factor control
✔ Review potential for
- benefit from statins and
potential for adverse
effects & drug-drug
interactions
✔ Review potential for benefit
from heart-healthy lifestyle /
consider referral to dietitian and
exercise physiologist
✔ Patient Preferences
*Factors if risk decision uncertain:
LDL-C ≥ 160, family hx premature ASCVD, increased lifetime
risk, hs-CRP≥ 2, CAC score ≥ 300 or 75th% , ABI < 0.9
Summary of Statin Initiation Recommendations to
Reduce ASCVD Risk (Revised Figure)
Summary of Statin Initiation Recommendations to
Reduce ASCVD Risk (Revised Figure)
That’s what it says “one tablespoon full 30 times
a day”
Intensity of Statin Therapy
High- Moderate- and Low-Intensity Statin Therapy (Used in the RCTs reviewed by the Expert Panel)*
High-Intensity Statin Therapy
Daily dose lowers LDL-C on average,
by approximately ≥50%
Atorvastatin (40†)-80 mg
Rosuvasatin 20 (40) mg
Moderate-Intensity Statin
Therapy
Low-Intensity Statin
Therapy
Daily dose lowers
LDL-C on average, by
approximately 30% to <50%
Daily dose lowers LDL-C on
average, by <30%
Atorvastatin 10 (20) mg
Rosuvastatin (5) 10 mg
Simvastatin 20-40 mg‡
Pravstatin 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
*Individual responses to statin therapy varied in the RCTs and should be expected to vary in clinical practice.
There might be a biologic basis for a less-than-average response.
†Evidence from 1 RCT only: down-titration if unable to tolerate atorvastatin 80 mg in IDEAL (Pedersen et al).
‡Although simvastatin 80 mg was evaluated in RCTs, initiation of simvastatin 80 mg or titration to 80 mg is not
recommended by the FDA due to the increased risk of myopathy, including rhabdomyolysis.
Targets?
LDL cholesterol and benefit in clinical trials
Is lower better ?
30
4S - Placebo
25
Rx - Statin therapy
PRA – pravastatin
ATV - atorvastatin
Secondary Prevention
4S - Rx
20
15
LIPID - Placebo
CARE - Placebo
LIPID - Rx
CARE - Rx
Primary Prevention
HPS - Rx
TNT – ATV10 HPS - Placebo
PROVE-IT - PRA
WOSCOPS – Placebo
TNT – ATV80
PROVE-IT – ATV
AFCAPS - Placebo
TNT
10
5
JUPITER
6
AFCAPS - Rx
WOSCOPS - Rx
ASCOT - Placebo
ASCOT - Rx
0
40
(1.0)
60
(1.6)
80
100
120
140
(2.1)
(2.6)
(3.1)
(3.6)
LDL-C achieved mg/dL (mmol/L)
Adapted from Rosensen RS. Exp Opin Emerg Drugs 2004;9(2):269-279
LaRosa JC et al. N Engl J Med 2005;352:e-version
160
(4.1)
180
(4.7)
200
(5.2)
New Perspective
on LDL–C & Non-HDL–C Goals
• Lack of RCT evidence to support titration of drug
therapy to specific LDL–C and/or non-HDL–C goals
• Strong evidence that appropriate intensity of statin
therapy should be used to reduce ASCVD risk in
those most likely to benefit
• Quantitative comparison of statin benefits with statin
risk (evaluation of net clinical benefit)
• Nonstatin therapies – did not provide
ASCVD risk reduction benefits or safety profiles
comparable to statin therapy
Proportion of Patients Experiencing
Major Cardiovascular Event
TNT: Primary Efficacy Outcome Measure: Major
Cardiovascular Events*
0.15
Atorvastatin 10 mg
Atorvastatin 80 mg
Relative
risk
reduction
22%
Mean LDL-C level = 101 mg/dL
0.10
0.05
Mean LDL-C level = 77 mg/dL
HR=0.78 (95% CI 0.69, 0.89); P<.001
0
0
1
2
3
Time (Years)
4
5
* CHD death, nonfatal non–procedure-related MI, resuscitated cardiac arrest,
fatal or nonfatal stroke.
LaRosa et al. N Engl J Med. 2005;352:1425-1430.
6
CTT Meta-analysis 26 Trials
Proportional effects on MAJOR VASCULAR EVENTS
per mmol/L LDL-C reduction, by baseline LDL-C
No. of events (% pa)
Statin/more
Control/less
Relative risk (CI) per
mmol/L LDL-C reduction
More vs less statin
<2.0
2,<2.5
704 (17.9%)
795 (20.2%)
0.71 (0.52 - 0.98)
1189 (18.4%)
1317 (20.8%)
0.77 (0.64 - 0.94)
2.5,<3.0
1065 (20.1%)
1203 (22.2%)
0.81 (0.67 - 0.97)
3,<3.5
517 (20.4%)
633 (25.8%)
0.61 (0.46 - 0.81)
3.5
303 (23.9%)
398 (31.2%)
0.64 (0.47 - 0.86)
Total
3837 (19.4%)
4416 (22.3%)
0.72 (0.66 - 0.78)
<2.0
2,<2.5
206 (9.0%)
217 (9.7%)
0.87 (0.60 - 1.28)
339 (7.7%)
412 (9.1%)
0.77 (0.62 - 0.97)
2.5,<3.0
801 (8.2%)
1022 (10.5%)
0.76 (0.67 - 0.86)
3,<3.5
1490 (10.8%)
1821 (13.3%)
0.77 (0.71 - 0.84)
3.5
4205 (12.6%)
5338 (15.9%)
0.80 (0.77 - 0.84)
Total
7136 (11.0%)
8934 (13.8%)
0.79 (0.77 - 0.81)
Statin vs control
All trials
<2.0
2,<2.5
910 (14.7%)
1012 (16.4%)
0.78 (0.61 - 0.99)
1528 (14.0%)
1729 (15.9%)
0.77 (0.67 - 0.89)
2.5,<3.0
1866 (12.4%)
2225 (14.7%)
0.77 (0.70 - 0.85)
3,<3.5
2007 (12.3%)
2454 (15.2%)
0.76 (0.70 - 0.82)
3.5
4508 (13.0%)
5736 (16.5%)
0.80 (0.76 - 0.83)
Total
10973 (13.0%)
13350 (15.8%)
0.78 (0.76 - 0.80)
99% or
95% CI
0.5
0.75
Statin/more better
1
1.25
1.5
46
Control/less better
Primary prevention 5 to <10% 5-year major CVD risk
Per 1 mmol reduction LDL-C with a statin*
• Significantly greater 34% reduction in relative risk of
major CVD than higher risk groups
• 17% reduction in total mortality
*1 mmol/L (39 mg/dl) LDL-C reduction was the average in the primary prevention RCTs excluding JUPITER
CTT Collaborators. Lancet 2012; 380: 581-590
Primary Prevention Statin Therapy
 Thresholds for initiating statin therapy derived
from 3 exclusively primary prevention RCTs
 Placebo group 10 yr event rates:
JUPITER – 7.6%; MEGA 5.1%;
AFCAPS-TEXCAPS 6.9%
Guideline Panel’s recommendation:
 As a matter of caution, to avoid over-treating, the
Panel identified those with risk ≥7.5% as a group
in which statins provide benefit.
Statins and Diabetes Risk
1) Meta-analysis of 170,255 patients from 76 randomized
clinical trials show overall a 9% increased risk for development of
incident diabetes among statin users (Sattar, Lancet 2010)
2) Increased risk of diabetes only seen in those with multiple
risk factors; obesity, elevated triglycerides, glucose, and
hypertension are more strongly related than statins to
development of diabetes
3) Many persons on statins have pre-diabetes to begin with;
statins may accelerate the progression to diabetes, but on
average diabetes occurs 5 weeks later in those on placebo.
4) For every case of diabetes associated with statin use,
approximately 5-9 cardiovascular events are prevented
5) Most experts contend the benefits outweigh the risks
regarding increases in glucose / A1c.
A moderate intensity statin shows net clinical benefit down to a
10-year ASCVD risk of <5% where NNT is 60-<100 and
NNT=100
A 7.5% 10-year ASCVD threshold provides net clinical benefit
from NNT of 30 vs. NNH of 33.
Monitoring Statin Therapy: Lipid
Measurements Still Recommended
I IIa IIb III
Adherence to medication and lifestyle,
therapeutic response to statin therapy,
and safety should be regularly
assessed. This should also include a
fasting lipid panel performed within 4 to
12 weeks after initiation or dose
adjustment, and every 3 to 12 months
thereafter. Other safety measurements
should be measured as clinically
indicated.
Insufficient Response to Statin Therapy
I IIa IIb III
In individuals who have a less-thananticipated therapeutic response (>=50% on a
high intensity statin or 30-<50% on a
moderate intensity statin) or are intolerant of
the recommended intensity of statin therapy,
the following should be performed:
 Reinforce medication adherence.
 Reinforce adherence to intensive lifestyle
changes.
 Exclude secondary causes of
hyperlipidemia.
Insufficient Response to Statin
Therapy May Warrant Non-Statin Drug
In individuals at higher ASCVD risk receiving the
maximum tolerated intensity of statin therapy who
continue to have a less-than-anticipated
therapeutic response, addition of a nonstatin
cholesterol-lowering drug(s) (ideally with proven
efficacy from clinical trials) may be considered if
the ASCVD risk-reduction benefits outweigh the
potential for adverse effects.
Non-Statin Therapies
Ezetimibe –IMPROVE-IT showed additional risk reduction
Bile Acid Resins
Niacin (no benefit from AIM-HIGH and HPS2 TRIVE)
Fibrates (Fenofibrate – no overall benefit from ACCORD
Lipid Trial)
5) Therapies for HoFH (Lomitapide, Mipomersin)
1)
2)
3)
4)
Emerging Therapies in Development
1) CETP Inhibitors (Anacetrapib and Evacetrapib)
2) PCSK9 Inhibitors
Improve-IT Study Design
Patients stabilized post ACS ≤ 10 days:
LDL-C 50–125*mg/dL (or 50–100**mg/dL if prior lipid-lowering Rx)
N=18,144
*3.2mM
**2.6mM
Standard Medical & Interventional Therapy
Simvastatin
40 mg
Uptitrated to
Simva 80 mg
if LDL-C > 79
(adapted per
FDA label 2011)
Ezetimibe / Simvastatin
10 / 40 mg
Follow-up Visit Day 30, every 4 months
90% power to detect
~9% difference
Duration: Minimum 2 ½-year follow-up (at least 5250 events)
Primary Endpoint: CV death, MI, hospital admission for UA,
coronary revascularization (≥ 30 days after randomization), or stroke
Cannon CP AHJ 2008;156:826-32; Califf RM NEJM 2009;361:712-7; Blazing MA AHJ 2014;168:205-12
LDL-C and Lipid Changes
1 Yr Mean
LDL-C
TC
TG
HDL
hsCRP
Simva
69.9
145.1
137.1
48.1
3.8
EZ/Simva
53.2
125.8
120.4
48.7
3.3
Δ in mg/dL
-16.7
-19.3
-16.7
+0.6
-0.5
Median Time avg
69.5 vs. 53.7 mg/dL
Primary Endpoint — ITT
Cardiovascular death, MI, documented unstable angina requiring
rehospitalization, coronary revascularization (≥30 days), or stroke
HR 0.936 CI (0.887, 0.988)
p=0.016
Simva — 34.7%
2742 events
NNT= 50
EZ/Simva — 32.7%
2572 events
6% relative risk reduction,
but 2% absolute risk
reduction
7-year event rates
IMPROVE-IT: How Much Really is the IMPROVEment?
Expert Analysis Dec 18, 2014
Nathan D. Wong, PHD, F.A.C.C.; Michael Blaha, MD, MPH
- http://www.acc.org/latest-in-cardiology/articles
1) Provides the first evidence from a large-scale trial that
additional lipid treatment beyond a statin provides further
CVD event reduction in high-risk ACS patients
2) Involved exclusively high-risk persons with a recent
ACS so may not apply to lower risk persons….implications
of this trial beyond the study population should be
generalized with caution.
3) A relative risk reduction of 6% (hazard ratio of 0.94)
is not impressive, but the high baseline risk resulted in a
reasonable NNT of 50; such added therapy is a reasonable
option in high-risk ACS subjects
4) Not clear if patients starting at lower LDL-C levels
(eg from a high intensity statin) would derive similar benefit
Management of Muscle Symptoms
on Statin Therapy
• It is reasonable to evaluate and treat muscle
symptoms including pain, cramping, weakness,
or fatigue in statin-treated patients according to
the management algorithm
• To avoid unnecessary discontinuation of
statins, obtain a history of prior or current
muscle symptoms to establish a baseline
before initiating statin therapy
Management of Muscle Symptoms
on Statin Therapy (con’t)
If unexplained severe muscle symptoms
or fatigue develop during statin therapy:
• Promptly discontinue the statin
• Address possibility of rhabdomyolysis
with:
 CK
 Creatinine
 urine analysis for myoglobinuria
Statin Assignment using the 2013 ACC/AHA Cholesterol
Guideline Identifies More Persons with Significant CAD
versus the 2001 NCEP ATP III Guideline (Johnson and
Dowe, JACC 2014)
1) 3,076 subjects studied who had CCTA plaque
measured
2) From the NCEP ATP III Guideline based on
LDL-C thresholds for initiating statin use, 59% of
subjects with >=50% left main stenosis and 40% with
>=50% stenosis of other branches would not have been
treated.
3) Comparable numbers from the 2013 ACC/AHA
Cholesterol Guideline were 19% and 10%
4) The use of targets in the NCEP ATP III
caused many with significant stenosis not to be identified
for treatment.
Question 1
A 48 year old white woman with diabetes and
microalbuminuria has a lipid panel
TC 197; TG 300; HDL-C 42; LDL-C 95
Her BMI is 34; weight up 4 lbs
Systolic BP 134. A1c 8.4%. Non-smoker
In addition to adherence to an optimal lifestyle what
is the next step to reduce her risk for heart attack and
stroke?
Question 1
A. Moderate intensity statin; no followup lipids needed
B. No need to use the risk estimator; she has diabetes
C. Moderate intensity statin, regular lipid follow-ups to
determine adherence and response to therapy.
D. US guidelines don’t allow a non-statin to be added
.
E. Time spent on adherence not useful; missing 25% of doses
per month not likely to affect potential for benefit
Question 1
Answer C.
She’s in a statin “benefit” group.
Why not an LDL-C or non HDL-C? The evidence points to
proper intensity of therapy
Why not high intensity statin therapy?
She has only a 3.1% 10 year risk. Had she been a smoker, her
risk would be 9.3%. Then appropriate measures to aid tobacco
cessation as well as a more intensive dose of statin if tolerated
would have been appropriate
.
Her A1c is elevated. Can a bile acid sequestrant be used? Yes
Non-statins can be used in any of the high risk groups if it is felt
that optimal adherence to statin therapy gives a less than
anticipated response.
Question 2
79 yo man had acute MI & received a stent to his LAD.
Home on atorvastatin 40 mg daily &usual 2o prevention Rx
TC 150; TG 150; HDL-C 45; LDL-C 75; Non HDL-C 105
Which of these is a true statement?
A. Getting under 70 will provide an outcomes difference for him
B. Statin dose should be atorva 80 mg/day or rosuva 40 mg/d
C. Guidelines recommend lipids monitored periodically to assess
adherence to statin/lifestyle; also for safety issues
D. No need to have lipids checked. It's a set it and go on strategy
Question 2
Answer is C. Since he is over 75, use of 40 mg atorvastatin
would be reasonable, even though there is data to support high
dose statin after age 75.
The issue of competing comorbidities, multiple medications, and
greater potential for side-effects with a high-intensity statin affect
the decision here. What is crucial is to monitor lipids periodically
and discuss safety issues.
After checking lipids 4-12 weeks after the statin is started, they
should be checked 3-12 months regularly with the interval
dependent on how likely the patient is to have problems with
adherence or safety issues
Question 3
60 yo overweight white man with diabetes and hypertension for
past 10 years on metformin. He is a non-smoker. He comes in
25 minutes into an acute ST elevation anterior MI and has a PCI
with a drug eluting stent placed in his LAD. His lipid panel on
admission shows: TC 168 TG 220 HDL 30 LDL 94 His non
HDL-C was 138. He was on simvastatin 10 mg daily.
Post MI, he is given aspirin, clopidogrel, lisinopril, and a long
acting beta blocker. He is discharged on atorvastatin 20 mg
daily. Four weeks later, his LDL-C has fallen to 70 mg/dl.
He has met LDL-C targets of <100 and 70 or less for primary and
secondary prevention. Is his care optimal?
Question 3
An example of how fixed “targets” can give less than optimal Rx
Although he attained the LDL-C target of <100 mg/dl, he needed
a higher intensity statin. When he had an LDL-C of 94, this 60 yo
man with diabetes and hypertension should have been on a
moderate intensity statin.
After an acute coronary event, he now merited as a first
consideration, a high intensity statin. The evidence based choice
is atorvastatin 80 mg daily. In the PROVE-IT trial, those with
acute MI randomized to a high intensity statin (atorvastatin 80
mg/d)) had improvement in outcomes as compared to those on a
moderate intensity statin (pravastatin 40 mg/d)
Cannon C et al N Engl J Med 2004;350:1495-504.
FH is more common than many well
known genetic diseases
•
•
•
•
•
1:300 – 1:500 worldwide
Autosomal dominant
620,000 FH patients in US
Average LDL is 220 mg/dl
20 fold increased risk of
coronary heart disease
• Causes 20% of MIs before
age 45 and 5% before age
60
Hopkins et al. J. Clinical Lipidology. 2011
Goldberg et al. J. Clinical Lipidology. 2011
FH exposes people to very high cholesterol from
birth, thus reaching a threshold for CHD earlier in life
Cumulative exposure (cholesterol yrs) by age:
FH vs unaffected (healthy) individuals
Cholesterol year score (g/dL-years)
Homozygous FH
10
Heterozygous
FH
Healthy individuals
Threshold for
CHD: reached by
age 40 for those
with HeFH and
age 20 for HoFH,
> 70 yrs in healthy
individuals
5
0
1
20
40
Age (years)
60
80
Adapted from Horton et al. J Lipid Res. 2009;50:S172-S177
Da Vinci’s Mona Lisa: FH ?
Xanthelasma
???
???
Leonardo da Vinci, in addition to his art is famed for his remarkable
efforts in scientific work including investigations of atherosclerosis.
Indeed, careful clinical examination of the Mona Lisa reveals a
yellow irregular leather-like spot at the inner end of the left upper
eyelid and a well-defined swelling on the right hand beneath the
index finger, probably signifying the first case of this disease.
www.powerofthegene.com
Died in 1516 @ age 37 suddenly , cause unknown
FH is a “Winnable battle”
Nordestgaard B G et al. Eur Heart J 2013;eurheartj.eht273
The FHF national patient registry
“What’s measured improves”
Peter F. Druker
Long term goal is to have
90% of FH patients
DIAGNOSED and TREATED
LDL Apheresis
 FDA approved
 Dextran sulfate adsorption (DSA)
 Heparin-mediated extracorporeal precipitation
(HELP)
 60-80% LDL reduction
 Largest observational study  Small RCTs- regression
 Potential vascular benefits
72% event reduction
 Endothelial function
 Reduction in inflammatory markers (CRP, VCAM, MCP-1)
Mehta P, Baer J, Nell C, Sperling LS. Current Treatment Options
in CV Medicine 2009,11:279-288
LDL apheresis
Re-Priming
Solution
Heparin Pump
Regeneration
Solution
Regeneration
Pump
Blood Pump
Plasma Pump
Plasma
Separator
Blood Return
LIPOSORBER®
Columns
Plasma Line
Waste Line
Time averaged LDL
LDL-C
Diet Therapy
Diet & Drug Therapy
LIPOSORBER® Treatment
Pre
Time Average
Post
Time
New Therapies to Lower LDL-C
Beyond Underlying Statin Therapy (courtesy P. Wilson)
Drug
Lomitapide
Mipomersen
Proprotein convertase
subtilisin/kexin type9
PCSK9 mAb
Delivery
Oral
(pill)
Injection
Injection
(subq every week) (subq every 4 weeks)
Action
MTP inhibitor
Anti-sense ApoB
oligonucleotide
LDL-C
Effect in
statin Rx
HoFH
 40-50%
Antibodies to PCSK9
 25%
 50-70%
Availability REMS*
REMS*
Monitor
Liver Ftn Tests
Liver Ftn Tests
Concerns
Hepatotoxicity
Hepatotoxicity
Site injection rxn
Drug interactions
Flu symptoms
Antibody development
Cost
$300,000/pt/yr
Not available
$300,000/pt/yr
In research trials
*REMS= Risk Evaluation and Mitigation Strategies
The Role of PCSK9 in the Regulation
of LDL Receptor Expression
For illustration purposes only
Impact of PCSK9 mAb
on LDL Receptor Expression
For illustration purposes only
LAPLACE-2: LDL-C Response at Mean of Weeks
10 and 12
Mean Percent Change
from Baseline in LDL−C
Evolocumab Q2W & QM: 63 to 75% reductions in LDL-C versus placebo
Ezetimibe: 17 to 24% reductions in LDL-C versus placebo
Atorvastatin
80 mg
Placebo Q2W
Placebo QM
Rosuvastatin
40 mg
Atorvastatin
10 mg
Ezetimibe QD + Placebo Q2W
Ezetimibe QD + Placebo QM
All treatment differences versus placebo and ezetimibe were statistically significant (P<0.001).
No notable differences were observed between the mean of weeks 10 and 12 and week 12 alone.
LDL-C, low-density lipoprotein cholesterol; Q2W, biweekly; QM, monthly. Vertical lines represent 95% CIs.
Rosuvastatin
5 mg
Simvastatin
40 mg
Evolocumab Q2W
Evolocumab QM
82
GAUSS-2 in Statin Intolerant Pts:
Evolocumab Mean LDL-C % Change
Treatment Difference vs Ezetimibe
Average at weeks 10 and 12
At week 12
-37%
-38%
P<0.001
Mean Percent Change in
LDL-C from Baseline
0
-18%
-20
-40
-56%
-60
-80
BL Day 1 Week 2
Week 4
Study drug
administration
Biweekly SC
Week 6
Week 8
Week 10
Week 12
Study Week
1: Ezetimibe (N = 51)
2: Evolocumab 140 mg Q2W (N = 103)
BL, baseline. Vertical lines represent the standard error around the mean. Plot is based on observed data
with no imputation for missing values. P values are multiplicity adjusted.
83
1)
2)
3)
4)
High risk subjects for cardiovascular disease whose LDL-C was suboptimal despite maximally
tolerated statin and/or other lipid-lowering therapy.
Follow-up: 78 weeks. Subjects (N=2,341) with LDL-C >70 mg/dL, 18% of whom had heterozygous
familial hypercholesterolemia (HeFH)
Randomized to alirocumab 150 mg Q2W SC or matching placebo.
Mean baseline LDL-C was 123 mg/dL and 122 mg/dL, respectively. The primary endpoint was
percent LDL-C reduction from baseline at 24 weeks.
28-36% of Guideline-Recommended Patients Not on Statins: ACC NCDR
PINNACLE Registry (Maddox et al., JACC 2014)
Kaiser Permanente (KP) is utilizing the 2013 ACC/AHA
Cardiovascular Risk and Cholesterol Guidelines in an effort to
prevent more heart attacks and strokes
KP is pivoting from a focus on LDL <100 to an emphasis on statin use rates
in members of the four statin benefit groups outlined in the new guidelines
August 2014 - KP Southern California (KPSC) region made available to
providers at the point of care the ACC/AHA 10-year ASCVD risk estimator
(A-Risk), with variables filled in automatically – A summary page of their
electronic health record shows for example: "ASCVD risk 17%, start
atorvastatin 40 mg daily…” also on the summary page is the last lipid panel
result and date, and a medication list with dates of last refill
Pay for Performance? What
should we measure?
 On treatment LDL ?
Should be be penalized if our
patient does not reach LDL-C<100?
 % reduction of LDL from baseline?
 Appropriate intensity of statin used?
 Meaningful discussion between clinician & patient
(informed clinical decision making)………
 NCQA will retire the measure focusing on LDL-C
treatment targets in persons with ASCVD and align
with the latest guidelines focusing on statin therapy
in patients with established ASCVD and not on
LDL-C control or screening.
Synopsis of Recommendations
1. Encourage adherence to a healthy lifestyle (provide
support for medical nutrition therapy and physical activity
counseling)
2. Statin therapy recommended for adult groups
demonstrated to benefit
3. Statins have an acceptable margin of safety when used
in properly selected individuals and appropriately monitored
4. Engage in a clinician-patient discussion before initiating
statin therapy – especially for primary prevention in patients
with lower ASCVD risk – includes discussion of global risk
reduction, benefits and risks of treatment, and patient
preferences
Stone NJ, et al. Ann Int Med. 2014 [epub ahead of print]
Synopsis of Recommendations
5. Use the newly developed pooled cohort
equations for estimation 10-year ASCVD risk
6. Initiate proper intensity of statin therapy
7. Evidence is inadequate to support treatment to
specific LDL-C or non-HDL-C goals
8. Regularly monitor patients for adherence to
lifestyle and statin therapy
Stone NJ, et al. Ann Int Med. 2014 [epub ahead of print]
“Evidence-Based” Not “EvidenceBound”
Three Key Dimensions
Scientific
evidence
Patient
preference
Clinical
Judgment
“Clinical practice guidelines such as
these should not take the place of sound
clinical judgment. These guidelines should
enable a discussion between a patient and
their health care provider about the best way
to prevent a heart attack or stroke, based on
the patient’s personal health profile and their
preferences”
John Gordon Harold, MD, MACC
ACC Past President
Thank You!
UCI Heart Disease
Prevention Program
www.heart.uci.edu
American Society for Preventive
Cardiology: www.aspconline.org
Microsomal Triglyceride Transfer Protein
(MTP)
• MTP is an intracellular lipid-transfer protein found in the lumen of the endoplasmic
reticulum (ER) responsible for binding and shuttling individual lipid molecules between
membranes1
• Normal concentrations and function of MTP are necessary for the proper assembly and
secretion of apo B-containing lipoproteins in the liver and intestines2
Intestinal
Epithelial Cell
Liver Cell
Cytoplasm
Cytoplasm
ER
ER
Lumen
MTP
1. Hussain M, et al. Journal of Lipid Research. 2003:44;22-32.
2. Liao W, et al. Journal of Lipid Research. 2003:44;978-985.
Lumen
MTP
©2013 Aegerion Pharmaceuticals, Inc.
MTP Inhibitors – Mechanism of Action
MTP inhibitors1,2
 Prevent the assembly of apo B-containing
lipoproteins in hepatocytes and
enterocytes. This inhibits the synthesis of
VLDL and chylomicrons.
 The inhibition of the synthesis of VLDL and
intestinal chylomicron
secretion lowers plasma lipids.
1. Wetterau JR, et al. Science. 1998:282;751-754.
2. Hussain MM, et al. Nutrition Metabolism. 2012:9;14.
©2013 Aegerion Pharmaceuticals, Inc.
Phase 2 Study Design
•
•
•
•
Single arm, open label study
16-week treatment duration - lomitapide as monotherapy (no background lipid-lowering
therapies)
Dose escalated from a low starting dose (mean doses at each of the four titration steps
were: 2.0, 6.7, 20.1, and 67.0 mg/day)
Low-fat diet (prescribed diet of <10% energy from fat)
6 Patients
Lomitapide
0.03 mg/kg
Lomitapide
0.1 mg/kg
Lomitapide
0.3 mg/kg
Lomitapide
1.0 mg/kg
Washout
4 weeks
4 weeks
4 weeks
4 weeks
4 weeks
Key Inclusion Criteria:
- Patients aged 18-40 yrs.
- Clinical Diagnosis of HoFH and one of the following
- documented functional mutation in both LDL receptor alleles
OR
- skin fibroblast LDL receptor activity <20% normal
OR
- TC >500 mg/dl + TGs <300 mg/dl + both parents with TC >250mg/dl
Cuchel, M. et al. NEJM 2007; 356:148-56.
©2013 Aegerion Pharmaceuticals, Inc.
Phase 2 HoFH Study: Efficacy
51% Reduction in LDL-C
51%
Reduction
p<0.001
Mean
Dose (mg):
2.0
6.7
20.1
67.0
Cuchel, M. et al. NEJM 2007; 356:148-56.
©2013 Aegerion Pharmaceuticals, Inc.
Antisense Oligonucleotides and
Apo B Synthesis Inhibition
Brautbar A and Ballantyne CM. Nat Rev
Mipomersen and LDL Lowering in
Homozygous FH
n=17
n=34
Baseline LDL-C: 405 mg/dl
200mg SC/Q week
Raal F. Lancet