Critical Statin Trials
That You Should Know
Gregory Landry, MD
Professor of Surgery
Knight Cardiovascular Institute
• No Disclosures
Critical Statin Trials
• Statin Guidelines
• Secondary Prevention of Cardiovascular
disease
• Primary Prevention of Cardiovascular
disease
• Peripheral Arterial Disease
• Complications of statin therapy
• Future therapies
What are statins?
• Metabolite of red rice
yeast
• HMG-CoA reductase
inhibitor
– Rate limiting step of
cholesterol synthesis
• Decreased hepatic
cholesterol
biosynthesis
• ↓LDL, ↓TG, ↑HDL
Pleiotropic effects of statin
Inhibition of G
proteins
Upregulate nitric oxide
synthetase
Inhibit cytokine
expression in
macrophages
Prevention of vascular
inflammation
Inhibit
vasoconstriction,
promote
reendothelialization
Atherosclerotic
plaque stabilization
Cholesterol management
Who Should Get a Cholesterol Test
• US Preventive Services
Task Force
– All men >35
– Men and women > 20
with other risk factors
(diabetes, obesity,
smoking)
– Men 20-35, Women >20
without risk factors – no
specific
recommendation
What is available in the US
How do statins differ from each other
• Lipophilic (atorva, lova, simva), can cross BBB (insomnia)
• Drug interactions
– Prava less plasma protein binding, less likely to displace plasma
bound drugs such as warfarin
– Metabolism by different liver enzymes
• Food interactions (lova increases with food; atorva, fluva,
prava decrease with food)
• Atorva and fluva do not need to be adjusted for renal insuff.
• Differences in half life, different recommendations on what
time of day to take
• Different potency although all effective in LDL lowering
• Similar safety profiles
ACC/AHA Guidelines
Stone NJ, et al. JACC
& Circulation, 2014
Cholesterol Management
• 2014 AHA Guidelines
– Statin Therapy
Recommended for the
Following Groups:
1. People without CV disease, 40-75 yo, ≥7.5% risk
of MI/stroke within 10 years
2. People with CV disease (MI, stroke, PAD)
3. People ≥ 21 yo with LDL ≥ 190 mg/dL
4. People with type I or II DM 40-75 yo
Heart Risk Calculator
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Age
Gender
Race
Total cholesterol
HDL cholesterol
Systolic blood pressure
Diastolic blood pressure
Treated for HBP
Diabetes
Smoker
AHA Guidelines
• No longer target specific LDL, HDL levels
• Prior guidelines
– LDL < 100 for primary prevention
– LDL < 70 for secondary prevention
• Recommend appropriate intensity of
therapy for different risk groups
Intensity of Statin Therapy
High Intensity
Moderate Intensity Low Intensity
LDL > 190
40-75, LDL<190,
>7.5% ASCVD risk
DM, 40-75, >7.5% >75, hx ASCVD
ASCVD risk
<75, hx ASCVD
Risk of side effects
from high dose:
>75, renal/liver,
med interaction,
Asian
Currently on a
low intensity
statin and doing
well on it
AHA Guidelines
• No longer recommend additional
medications (fibrates, niacin) on top of
statins to meet specific targets
Niacin
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Vitamin B3, nicotinic acid
Has been shown to ↑HDL, ↓TG, ↓LDL
Requires high doses to be effective
Notable side effects (flushing)
“No flush” niacin
does not have
nicotinic acid
AIM HIGH
• 3400 patients with hx of
cardiovascular dz
• Simvastatin + niacin vs
Simvastatin + placebo
• Composite endpoint of
MI, stroke, coronary
death
• Trial stopped early
NEJM, 2011
AIM HIGH
• Elevated HDL
35 to 42
• Decreased LDL
74 to 62
• Decreased TG
164 to 122
Ezetimibe
• Reduces cholesterol absorption in small
intestine
• Monotherapy (Zetia, Ezetrol)
– Limited efficacy (15-20% LDL lowering)
• Combination therapy (Vytorin)
IMPROVE-IT
Cannon, NEJM,2015
• 18000+ patients with ACS
• Simvastatin + Ezetimibe vs
Simvastatin + placebo
• Ezetimibe: reduce GI
cholesterol absorption
• Slight improvement in
death/MACE (32% vs 34%)
• Secondary Prevention
– CARE
– PROVEIT-TIMI
– SPARCL
CARE: Cholesterol and Recurrent Events
• 4159 patients with hx
of MI (3-20 months
prior to randomization)
• US/Canada
• Total cholesterol <240
• Pravastatin 40mg qday
vs placebo
• Primary endpoint fatal
coronary event or
nonfatal MI
Sacks, NEJM, 1996
CARE
• Median 5 year f/u
• 24% reduction (3%
absolute) in MI
• 27% reduction (2.5%
absolute) in CABG or
angioplasty
• 31% stroke reduction
(0.8% absolute)
• Greater benefit in
women, non-DM,
higher LDL
PROVE IT-TIMI 22
• 4162 patients with
acute coronary
syndrome (<10 days)
• US,Canada, Europe
• Intensive statin
therapy (atorvastatin
80mg po qday) vs
moderate statin
therapy (pravastatin
40mg po qday)
• Composite endpoint
death, MI, unstable
angina, revasc, stroke
Cannon, NEJM, 2004
PROVE IT-TIMI 22
Ridker, NEJM, 2005
• Greater protection
against composite
endpoint with more
intensive statin
regimen
• Levels of both LDL and
CRP were important in
MI risk reduction
• CRP levels reduced to
a greater degree with
more intensive statin
therapy
SPARCL
• 4731 subjects with
stroke/TIA within 6
months
• LDL 100-190
• No history of coronary
artery disease
• Atorvastatin 80mg po
qday vs placebo
NEJM, 2006
SPARCL
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Absolute risk reduction 2.2%
HR 0.84 for ischemic stroke
HR 1.55 for hemorrhagic stroke
NNTT 46 for five years
• Absolute risk reduction 3.5%
• HR 0.74
• NNTT 29 for five years
Strong evidence in favor of
statin therapy for secondary
prevention of cardiovascular
disease
• Primary Prevention
– PROSPER
– ASCOT
– JUPITER
PROSPER
• 5804 patients age 70-82
• History of or risk for
vascular disease
• Scotland, Ireland,
Netherlands
• Pravastatin 40 mg po
qday vs placebo
• Composite endpoint of
MI, CVA, death
• 3.2 years mean follow
up
Shepherd, Lancet 2002
composite
MI
• 34% reduction in LDL
• 5% increase in HDL
• 13% reduction in TG
• 15% decrease in
composite endpoint
• 19% decrease MI
• No change in stroke
– 25% decrease in TIA
stroke
• Effect more
pronounced in men
PROSPER
• Effects the
same for
both
primary
and
secondary
prevention
ASCOT TRIAL
Sever, Lancet, 2003
• 10,305 hypertensive
patients, age 40-79,
with normal fasting
cholesterol levels
• UK/Scandinavia
• Atorvastatin 10mg po
qday vs placebo
• Primary composite
endpoint nonfatal MI
and fatal CHD
• 5 year intended follow
up, trial stopped at
median 3.3 years
• 36% risk reduction of
primary endpoint
• No significant benefit
in women
JUPITER TRIAL
Ridker, NEJM, 2008
• ½ of all MI and CVA occur
in people with normal
cholesterol
• 17,802 subjects with
elevated CRP but normal
LDL
• Rosuvastatin (20mg/day)
vs placebo
• Combined endpoint (MI,
CVA, Revasc., unstable
angina, CV death)
• Trial stopped early
JUPITER TRIAL
• NNTT 25 at five years to
prevent one composite
endpoint
• Higher incidence of
physician reported DM
Strong evidence in favor of
statin therapy for primary
prevention of cardiovascular
disease in selected patient
populations with normal
cholesterol levels
Prevalence of PAD Increases
with Age
Patients with PAD (%)
Rotterdam Study (ABI <0.9)1
San Diego Study (PAD by noninvasive tests)2
60
50
40
30
20
10
0
55-59
60-64
65-69
70-74
75-79
Age Group (y)
80-84
85-89
Peripheral Arterial Disease (PAD)
Mortality*
Survival (% of Patients)
100
Normal Subjects
75
Asymptomatic LV-PAD†
50
Symptomatic LV-PAD†
Severe Symptomatic LV-PAD†
25
0
0
2
4
6
8
Year
*Kaplan*Kaplan-Meier survival curves based on mortality from all causes.
†LargeLarge-vessel PAD.
Criqui MH et al. N Engl J Med. 1992;326:381-386.
10
12
Effects of Statins on Peripheral Arterial Disease
• Systematic review of
trials in which statins
targeted to PAD
population
– Lower all cause
mortality
– Lower MACE
– Lower MALE
Statins in PAD: Heart Protection Study
• 6748 UK adults with PAD
• 13,788 high risk people
• 40 mg simvastatin vs
placebo
• 5 year study
• Endpoints
– First major vascular event
(coronary, stroke, or
peripheral revascularization)
J Vasc Surg, 2007
Heart Protection Study
• 20-25% reduction
in vascular
events
irrespective of
initial LDL levels
Incremental Decrease in End Points Through
Aggressive Lipid Lowering Study: IDEAL
• 8888 patients with
CAD randomized to
high dose (ator) vs low
dose (simva)statin
• 5 year follow up
• Endpoints
– No PAD: new diagnosis
requiring intervention
– + PAD: recurrence
requiring intervention
Stoekenbroek, Heart –BMJ, 2015
IDEAL Study
• 30% decrease in
incident PAD events
with high dose statin
in patients without
PAD hx
• In PAD patients,
significant decrease in
overall coronary events
and coronary
revascularization
Claudication
• Scandinavian Simvastatin
Survival Study
• + secondary prevention
for MACE
• New or worsening
claudication decreased
with simvastatin
Graft patency
• PREVENT III
Schanzer, JVS 2008
4S, Am J Cardiol 1998
Statin use after endovascular procedures
• Retrospective review of
646 patients undergoing
endovascular
intervention for CLI
– 319 statin
– 327 no statin
Aiello, J Vasc Surg, 2012
• Groups were well
matched for
demographics, lesion
location, lesion severity,
and procedure
performed (PTA, stent,
atherectomy)
Statins after endovascular procedures
AAA Growth
Takagi, EJVES, 2012
Fewer RCT but still good
evidence in favor of statin
therapy for prevention of
cardiac events in people with
PAD.
May improve PAD symptoms,
stent patency, but data less
strong
Complications
Do Statins Cause Diabetes?
• Potential for causing
type II DM
– Increase insulin
resistance
– Impair ability of
pancreas to secrete
insulin
Statins and Diabetes
• 10-12% increased risk of type II DM
• NNTT 255 for 1 case DM
• Despite increased DM risk, cardiovascular events
markedly decreased
Statin Diabetes Safety Task Force: 2014
TNT: Treating to New Targets
IDEAL: Incremental Decrease in Endpoints
Through Aggressive Lipid Lowering
• Risk Factors
– Fasting blood
glucose > 100
mg/dl
– Fasting
triglyceride level
> 150 mg/dl
– BMI> 30 kg/m2
– Hx of
hypertension
Complications in Primary Prevention Trials
Finegold, E J Prev Cardiol, 2014
Myalgia
• 5-10% incidence in
observational studies
• Probably underestimated in
clinical trials
– Based on CPK elevation
– Not systematically reported
– Exclusion of patients most
likely to get myalgias
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Renal insufficiency
Liver insufficiency
Elderly
Drugs (CSA, protease inh, Abx)
Hx of muscle symptoms
Effect of Statins on Muscle Performance:
STOMP Trial
• Atorvastatin vs
placebo, 6 months,
n=420
• Myalgia definition
– New muscle pain not
associated with exercise
– > 2wks duration
– Resolved within 2 wks
after stopping drug
– Recurred within 4 wks
after restarting
Parker, Circulation, 2013
• Myalgia:
Atorvastatin 9%,
Placebo 5%, p<0.05
• No difference in
muscle strength
• Overall no
difference in
physical activity
Recommendations for myalgia
• Severe forms rare (>CPK) but mandate
alternative therapies
• Mild/moderate forms common but rarely
mandate stopping drug
• 40-90% can reestablish and maintain use
with adjusted dosage, frequency, agents
What about Coenzyme Q10 (CoQ10)?
• Part of the mitochondrial transport pathway
• Produced by the cholesterol metabolic pathway
• Deficiency may lead to abnormalities of skeletal
muscle metabolism
Banach, Mayo Clin Proc, 2015
I almost forgot,
what about statins and memory loss?
• 2012 FDA
warning that
some patients
may develop
memory loss on
statins
• Synapses and
glial cells in the
brain depend on
cholesterol for
proper function
• Meta analysis of 25
RCT
• No adverse cognitive
effects
Ott, J Gen Int Med, 2015
Current evidence strongly
shows that the benefits of
statins outweigh risks
PCSK9 Inhibitors
• LDL cleared from
circulation through
LDL receptor
• PCSK9 is a gene
associated with LDL
receptor degradation
• Prevents LDL
clearance
• PCSK9 levels
elevated 32% by
statins (JUPITER)
• Inhibiting PCSK9 may
augment effect of
statins
PCSK9 Inhibitors: Phase III trials
• Evolocumab:
– LAPLACE, DESCARTES, MENDEL,TESLA, RUTHERFORD
– Added to statins, ezetamibe or monotherapy
– Q2-4 wk injections
– 30-75% LDL reduction
• Alirocumab:
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–
–
–
ODYSSEY
With statins, ezetamibe or monotherapy
Q2-4 wk injections
50% LDL reduction
• Side effects
– Allergic reaction at injection site
PCSK9 Inhibitors:
Barriers to $€££ing
• $7000-$15000/year
• Likely applications
– Familial
hypercholesterolemia
– Statin intolerance
What about red rice yeast?
• Lowers LDL due to
monacolin K, natural
form of lovastatin
• 20-30% LDL
reduction in RCT
• No standardization of
levels in supplements
• Likely more
expensive than
generic statins
Summary
• Strong evidence for statin use in primary
and secondary prevention of
cardiovascular disease and in patients
with PAD
• Benefits outweigh risks
• AHA guidelines and risk calculators help
determine proper patients and intensity of
therapy