Ruth Campbell BSc (Pharm)

Interior Health AuthorityProvincial Academic Detailing Service

Statins and Cardiovascular Disease

It is a matter of perspective

AMADA INNR

When we look with care:

Benefit is most apparent in the secondary population

Primary population – in terms of MCE reductionHigh risk men benefit Women do notElderly 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

Canon NEJM 2004:350:1495-504

PRIMARY OUTCOME = combination of 5 different events CHD Death, MI, Stroke and Revascularization and Hospitilization

COMPOSITE OUTCOMES

Canon NEJM 2004:350:1495-504

FATAL EVENTS

COMPOSITE OUTCOMES

Canon NEJM 2004:350:1495-504

NON-FATAL EVENTS

COMPOSITE OUTCOMES

Canon NEJM 2004:350:1495-504

“Softer outcomes”

CLINICIAN-DRIVEN ENDPOINTS (procedures, medical decisions)

COMPOSITE OUTCOMES - what is true?

Canon NEJM 2004:350:1495-504

Statistical significance is reached only in coronary revascularization and hospitalization for unstable

angina

COMPOSITE OUTCOMES

Canon NEJM 2004:350:1495-504

FATAL EVENTS

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 reportedSerious Adverse Events aren’t consistently reported

Risk

MyopathiesIncident diabetesNeuropathies

Hemmorhagic strokeCancer?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 CHDrecent (non-acute); in the past 1-6 months

No cardiac sources AFib, subarachnoid hemorrhageatorvastatin 80 mg vs. placebo x 5 years

RESULTS

subsequent strokeARR = 1.9%; NNTB 53 x 5 years

major coronary eventsARR = 1.7%; NNTB 59 x 5 years

all-cause mortalityneutral

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 deathAll 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

Shepherd Lancet 2002;360:1623-30

Mean age 75

52% women

Prior CVD 44%

SBP 155DBP 84

TC 5.7HDL-C 1.3LDL-C 3.8

Smokers 27%

PRIMARY PREVENTION OF CHD: Older Adults

Cochrane Database of Systematic Reviews 2009, Issue 2, CD003160n = 26 K

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 Making61 yr old , SBP 145/90, no Rx for HTN♂

non-smoker, non-DM, no family history of premature CVDTC 5.4 mmol/L, HDL-C 1.20 mmol/L, LDL-C 2.2 mmol/L

FRS-CHD 10 years FRS-CVD 10 years

12% 22%13%

Major coronary eventsNFMICHD death

Cardiovascular eventsNFMICHD deathCoronary insufficiencyAnginaIschemic strokeHemorrhagic strokeTIAPeripheral artery diseaseHeart failure

Cardiovascular eventsNFMICVD deathStrokeRevascularization

PRIMARY PREVENTION: Decision Making61 yr old , SBP 145/90, no Rx for HTN♂

non-smoker, non-DM, no family history of premature CVDTC 5.4 mmol/L, HDL-C 1.20 mmol/L, LDL-C 2.2 mmol/L

FRS-CHD 10 years FRS-CVD 10 years

12% 22%13%

Major coronary eventsNFMICHD death

Cardiovascular eventsNFMICHD deathCoronary insufficiencyAnginaIschemic strokeHemorrhagic strokeTIAPeripheral artery diseaseHeart failure

Cardiovascular eventsNFMICVD deathStrokeRevascularization

PRIMARY PREVENTION: Decision Making61 yr old , SBP 145/90, no Rx for HTN♂

non-smoker, non-DM, no family history of premature CVDTC 5.4 mmol/L, HDL-C 1.20 mmol/L, LDL-C 2.2 mmol/L

FRS-CHD 10 years FRS-CVD 10 years

12 22%Major coronary events

NFMICHD death

Cardiovascular eventsNFMICHD deathCoronary insufficiencyAnginaIschemic strokeHemorrhagic strokeTIAPeripheral artery diseaseHeart failure

PRIMARY PREVENTION: Decision Making61 yr old , SBP 145/90, no Rx for HTN♂

non-smoker, non-DM, no family history of premature CVDTC 5.4 mmol/L, HDL-C 1.20 mmol/L, LDL-C 2.2 mmol/L

FRS-CHD 10 years FRS-CVD 10 years

12% 22%Major coronary events

NFMICHD death

Cardiovascular eventsNFMICHD deathCoronary insufficiencyAnginaIschemic strokeHemorrhagic strokeTIAPeripheral artery diseaseHeart failure

PRIMARY PREVENTION: Decision Making61 yr old , SBP 145/90, no Rx for HTN♂

non-smoker, non-DM, no family history of premature CVDTC 5.4 mmol/L, HDL-C 1.20 mmol/L, LDL-C 2.2 mmol/L

FRS-CHD 10 years FRS-CVD 10 years

12% 22%Major coronary events

NFMICHD death

Estimated 5-year benefit from statin therapy (30% relative reduction)

very roughly 6% 4%

Cardiovascular eventsNFMICHD deathCoronary insufficiencyAnginaIschemic strokeHemorrhagic strokeTIAPeripheral artery diseaseHeart failure

Cardiovascular eventsNFMICVD deathStrokeRevascularization

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 MIHaffner NEJM 1998;339:229-34

Fatal or non-fatal MIBulugahapitiya Diabet Med 2009;26:142-8

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

Non-diabetic, primary prevention

8%

Diabetic, primary prevention

12%

Non-diabetic, secondary prevention

24%

www.dtu.ox.ac.uk/riskengine/index.php

Statin use in Diabetics vs non-diabetics

CTT Lancet 2008;371:117-25

Similar absolute reductions in major coronary events

No diabetes (n = 71 370) ARR = 2.4%Diabetes (n = 18 686) ARR = 2.2%

Treating to Target

Trials which look at clinical outcomes after titrating dose to achieve particular targets

CTT Lancet 2005;366:1267-78

Observation of a trend greater proportional reductions in major vascular events being associated with greater LDL cholesterol reductions in different statin trials CTT 2005

LDL-C TREATMENT PARADIGM (CTT)

Absolute reduction in LDL-C

Relative reduction inmajor vascular events

LDL-C TREATMENT PARADIGM

LDL-C TREATMENT PARADIGM

Genest Can J Cardiol 2009:25:567-79

Acute Corononary Events Stable Coronary Artery Disease

PROVE-IT A TO Z TNT IDEAL SEARCHAtorv 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

MCENSS

MCENOTSS

MCESS

MCENOTSS

MCENOTSS

Statistically significant reduction in MAJOR CORONARY EVENTS

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

ezetimibefenofibrate, clofibratetorcetrapid, dalcetrapidfibrate + statin niacin + statin

Hayward Circ Cardiovasc Qual Outcomes 2012:5:2-5; Hayward Ann Intern Med 2006:145:520-30

Good for lipidsClinical Outcomes???

PRIMAY PREVENTION SUMMARYIn 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 SUMMARYIn patients with a history of coronary heart disease, statins have been shown to reduce the risk of major coronary events and all-cause mortality.In patients with a history of recent, ischemic stroke, statins have been shown to reduce the risk of major coronary events, but not all-cause mortality.

SECONDARY PREVENTION: Fixed Dosages

all-cause mortality in secondary prevention

NON-PHARMACOLOGIC INTERVENTIONS

www.bcguidelines.ca