Statins and Cardiovascular Disease
Ruth Campbell BSc (Pharm)
Interior Health Authority
Provincial Academic Detailing Service
It is a matter of perspective
RAMADA INN
When we look with care:
Benefit is most apparent in the secondary
population
Primary population – in terms of MCE reduction
 High risk men benefit
 Women do not
 Elderly do not
We lack evidence to “treat to target”
Why the confusion
• Interpretation of relative risk reduction as
being the most important thing
• Composite Endpoints
• Calculating risk and inferring statin benefit
Our drug reduces your
risk by 50%
Drooping Ear Lobe disease
disappears overnight in 50% of
cases
Primary Composite Outcome
MI, Coronary Heart Disease Death, All Cause mortality
Stroke
Coronary revascularization and Hospitalization for
unstable Angina
Is the benefit illusion? Should we care?
COMPOSITE OUTCOMES
PRIMARY OUTCOME = combination of 5 different events
CHD Death, MI, Stroke and Revascularization and Hospitilization
Canon NEJM 2004:350:1495-504
COMPOSITE OUTCOMES
FATAL EVENTS
Canon NEJM 2004:350:1495-504
COMPOSITE OUTCOMES
NON-FATAL EVENTS
Canon NEJM 2004:350:1495-504
COMPOSITE OUTCOMES
CLINICIAN-DRIVEN ENDPOINTS (procedures, medical decisions)
“Softer outcomes”
Canon NEJM 2004:350:1495-504
COMPOSITE OUTCOMES - what is true?
Statistical significance is reached only in coronary
revascularization and hospitalization for unstable
angina
Canon NEJM 2004:350:1495-504
COMPOSITE OUTCOMES
FATAL EVENTS
Canon NEJM 2004:350:1495-504
Balance the risk with the benefit
What is the risk?
Run In Periods eliminate those at risk
Those studied less likely to be at risk
Harm reporting – illusions in statistics
Serious Adverse Events aren’t consistently reported
Risk
Myopathies
Incident diabetes
Neuropathies
Hemmorhagic stroke
Cancer?
Confusion?
Who Benefits?
Secondary prevention
Secondary Prevention - What is the
benefit?
Treating 28 patients for 5 years prevents
one Major Coronary Event
A reduction in all cause mortality has not
been documented in women
And the Elderly?
RECENT ISCHEMIC STROKE or TIA SPARCL
non-disabling stroke or TIA, no history of CHD
recent (non-acute); in the past 1-6 months
No cardiac sources AFib, subarachnoid hemorrhage
atorvastatin 80 mg vs. placebo x 5 years
RESULTS
subsequent stroke
ARR = 1.9%; NNTB 53 x 5 years
major coronary events
ARR = 1.7%; NNTB 59 x 5 years
all-cause mortality
neutral
Amarenco N Engl J Med 2006;355:549-59
Women – Primary prevention
Lack of Evidence for benefit in women
No Statistically significant benefit for:
Non fatal MI
Coronary Heart Disease death
All Cause Mortality
“ Conclusion—JUPITER demonstrated that in
primary prevention rosuvastatin reduced CVD
events in women with a relative risk reduction
similar to that in men, a finding supported by
meta-analysis of primary prevention statin
trials.”
Evidence for benefit in women?
No Statistically significant benefit for:
• Non fatal MI
• Coronary Heart Disease death
• All Cause Mortality
Statistically Significant improvement in:
• hospitalization for unstable angina
• coronary revascularization
Primary prevention elderly?
Prosper?
“Interpretation: Pravastatin given for 3 years
reduced the risk of coronary disease in elderly
individuals. PROSPER therefore extends to
elderly individuals the treatment strategy
currently used in middle aged people”
Men and Women benefit differently
Mean age 75
52% women
Prior CVD 44%
SBP 155
DBP 84
TC 5.7
HDL-C 1.3
LDL-C 3.8
Smokers 27%
Shepherd Lancet 2002;360:1623-30
PRIMARY PREVENTION OF CHD: Older Adults
n = 26 K
Cochrane Database of Systematic Reviews 2009, Issue 2, CD003160
PRIMARY PREVENTION: Decision Making
Calculate Risk –
determining the benefit
of statins for men at risk
Use the right tool for
the job
www.framinghamheartstudy.org/risk/index.html
FRS-CHD
www.framinghamheartstudy.org/risk/index.html
FRS-CVD
www.framinghamheartstudy.org/risk/index.html
PRIMARY PREVENTION: Decision Making
61 yr old ♂, SBP 145/90, no Rx for HTN
non-smoker, non-DM, no family history of premature CVD
TC 5.4 mmol/L, HDL-C 1.20 mmol/L, LDL-C 2.2 mmol/L
FRS-CHD 10 years
12%
Major coronary events
NFMI
CHD death
FRS-CVD 10 years
22%
13%
Cardiovascular events
NFMI
CHD death
Coronary insufficiency
Angina
Ischemic stroke
Hemorrhagic stroke
TIA
Peripheral artery disease
Heart failure
Cardiovascular events
PRIMARY PREVENTION: Decision Making
61 yr old ♂, SBP 145/90, no Rx for HTN
non-smoker, non-DM, no family history of premature CVD
TC 5.4 mmol/L, HDL-C 1.20 mmol/L, LDL-C 2.2 mmol/L
FRS-CHD 10 years
12%
Major coronary events
NFMI
CHD death
FRS-CVD 10 years
22%
13%
Cardiovascular events
NFMI
CHD death
Coronary insufficiency
Angina
Ischemic stroke
Hemorrhagic stroke
TIA
Peripheral artery disease
Heart failure
Cardiovascular events
NFMI
PRIMARY PREVENTION: Decision Making
61 yr old ♂, SBP 145/90, no Rx for HTN
non-smoker, non-DM, no family history of premature CVD
TC 5.4 mmol/L, HDL-C 1.20 mmol/L, LDL-C 2.2 mmol/L
FRS-CHD 10 years
12
Major coronary events
NFMI
CHD death
FRS-CVD 10 years
22%
Cardiovascular events
NFMI
CHD death
Coronary insufficiency
Angina
Ischemic stroke
Hemorrhagic stroke
TIA
Peripheral artery disease
Heart failure
PRIMARY PREVENTION: Decision Making
61 yr old ♂, SBP 145/90, no Rx for HTN
non-smoker, non-DM, no family history of premature CVD
TC 5.4 mmol/L, HDL-C 1.20 mmol/L, LDL-C 2.2 mmol/L
FRS-CHD 10 years
12%
Major coronary events
NFMI
CHD death
FRS-CVD 10 years
22%
Cardiovascular events
NFMI
CHD death
Coronary insufficiency
Angina
Ischemic stroke
Hemorrhagic stroke
TIA
Peripheral artery disease
Heart failure
PRIMARY PREVENTION: Decision Making
61 yr old ♂, SBP 145/90, no Rx for HTN
non-smoker, non-DM, no family history of premature CVD
TC 5.4 mmol/L, HDL-C 1.20 mmol/L, LDL-C 2.2 mmol/L
FRS-CHD 10 years
12%
Major coronary events
NFMI
CHD death
Estimated 5-year benefit from statin
therapy (30% relative reduction)
very roughly 6%
 4%
FRS-CVD 10 years
22%
Cardiovascular events
NFMI
CHD death
Coronary insufficiency
Angina
Ischemic stroke
Hemorrhagic stroke
TIA
Peripheral artery disease
Heart failure
Cardiovascular events
NFMI
www.bcguidelines.ca
iPhone, BB, android apps
• Qx Calculate
• Framingham Risk Score (ATP-III)
• Framingham General Cardiovascular Risk
predictor – predicts cardiovascular risk
Fatal or non-fatal MI
Haffner NEJM 1998;339:229-34
Fatal or non-fatal MI
Bulugahapitiya Diabet Med 2009;26:142-8
Non-diabetic,
primary prevention
8%
Diabetic,
primary prevention
12%
Non-diabetic,
secondary
prevention
24%
CTT Lancet 2008;131:117-25
Non-diabetic,
primary prevention
8%
Diabetic,
primary prevention
12%
Non-diabetic,
secondary
prevention
24%
CTT Lancet 2008;131:117-25
Non-diabetic,
primary prevention
8%
Diabetic,
primary prevention
12%
Non-diabetic,
secondary
prevention
24%
CTT Lancet 2008;31:117-25
www.dtu.ox.ac.uk/riskengine/index.php
Statin use in Diabetics vs non-diabetics
Similar absolute reductions in major coronary events
No diabetes (n = 71 370) ARR = 2.4%
Diabetes (n = 18 686)
ARR = 2.2%
CTT Lancet 2008;371:117-25
Treating to Target
Trials which look at clinical outcomes after
titrating dose to achieve particular targets
LDL-C TREATMENT PARADIGM (CTT)
Relative reduction in
major vascular events
Absolute reduction in LDL-C
Observation of a trend  greater proportional reductions in major
vascular events being associated with greater LDL cholesterol reductions
in different statin trials CTT 2005
CTT Lancet 2005;366:1267-78
LDL-C TREATMENT PARADIGM
LDL-C TREATMENT PARADIGM
Genest Can J Cardiol 2009:25:567-79
Statistically significant reduction in MAJOR CORONARY EVENTS
Acute Corononary Events
Stable Coronary Artery Disease
PROVE-IT
A TO Z
TNT
IDEAL
SEARCH
Atorv 80
vs
Prav 40
Sim 80
vs
Simv 20
Ator 80
vs
Ator 10
Ator 80
vs
Simv 20
Simv 80
vs
Simv 20
LDL-C OBSERVED IN HIGH DOSE ARM
1.6
1.7
2.0
2.1
2.2
MCE
NSS
MCE
NOT
SS
MCE
SS
MCE
NOT
SS
MCE
NOT
SS
LDL-C TREATMENT PARADIGM
LDL-C < 2 mmol/L was achieved in ~ 50% of patients
Josan CMAJ 2008:178:576-84
LDL-C TREATMENT PARADIGM
ezetimibe
fenofibrate, clofibrate
torcetrapid, dalcetrapid
fibrate + statin
niacin + statin
Good for lipids
Clinical Outcomes???
Hayward Circ Cardiovasc Qual Outcomes 2012:5:2-5; Hayward Ann Intern Med 2006:145:520-30
PRIMAY PREVENTION SUMMARY
In patients without a history of coronary heart disease (but with risk
factors for coronary heart disease), statins have been shown to
reduce the risk of major coronary events.
This benefit has not been documented for women or older adults.
PRIMARY PREVENTION: Fixed Dosages
 major coronary events in primary prevention
SECONDARY PREVENTION SUMMARY
In patients with a history of coronary heart disease, statins have
been shown to reduce the risk of major coronary events and allcause mortality.
In patients with a history of recent, ischemic stroke, statins have
been shown to reduce the risk of major coronary events, but not allcause mortality.
SECONDARY PREVENTION: Fixed Dosages
 all-cause mortality in secondary prevention
NON-PHARMACOLOGIC INTERVENTIONS
www.bcguidelines.ca