Primary Prevention of Coronary Artery Disease

Raj Thaman Consultant Cardiologist

Wrexham Maelor

Objectives • Define primary prevention and discuss why

primary prevention is necessary. • review current approaches to primary prevention • Discuss the limitations of the Framingham Risk

Assessment model and others • additional methods of refining risk stratification • Review the evidence base for earlier and more

aggressive treatment of hypercholesterolemia

Primary prevention of CVD • Refers to interventions that aim to

prevent or delay the onset of cardiovascular disease in people who have no clinical evidence of CVD (MeSH definition)

33% of deaths in the UK are caused by cardiovascular disease

Men Women

Coronary Heart Disease Statistics, 2010. British Heart Foundation: London. http://www.bhf.org.uk/heart-health/statistics/mortality.aspx Last accessed August 2011.

CVD: cardiovascular disease; CHD: coronary heart disease

Causes of death in the UK

There are regional variations in mortality from cardiovascular disease

Coronary Heart Disease Statistics, 2010. British Heart Foundation: London. http://www.bhf.org.uk/heart-health/statistics/mortality.aspx Last accessed August 2011.

Deaths from CVD in the UK

CVD: cardiovascular disease

Males Females Regional variations exist in the incidence of CVD, with Scotland showing the highest

rates for men and women

What is responsible for reduction in mortality

• 50% of decline in CVD mortality is due to earlier diagnosis and more aggressive treatment

• 50%changes in risk factor profiles, decline

in smoking, more aggressive management of BP and lipids

• CVD (CHD, CVD, PVD) is the single most common cause of death in the UK

• Almost 30% (67,000) of the deaths can be classified as premature (that is, they occurred before the age of 75 years)

(equates to 35% and 27% of all premature deaths in men and women) • CVD is also a significant cause of morbidity and can have a major impact on quality of life. (In US it is estimated that the cost of treating coronary artery

disease will rise to more than $1 trillion annually by 2030, thus prevention is needed)

Cardiovascular disease is associated with high healthcare costs

Adapted from Coronary Heart Disease Statistics, 2010. British Heart Foundation: London. http://www.bhf.org.uk/heart-health/statistics/economic-costs-of-cvd.aspx Last accessed August 2011.

Breakdown of healthcare costs associated with cardiovascular disease

Primary care 6% Outpatient care 2%

Accident and emergency care 0.5%

Inpatient care 72%

Medications 20%

Cardiovascular disease cost the UK healthcare system approximately £14.4 billion in 2006

Primary prevention of CHD

• The fundamental principle in primary prevention of Coronary Heart Disease is the identification of individuals with coronary risk factors and modify those risk factors

• Case control study of acute MI in 52 countries • Nine risk factors account for >90% of the population

attributable risk of MI

Yusuf S, et al. Lancet. 2004; 364:937–952.

MI: myocardial infarction

• Abnormal lipids

• Diabetes

• Abdominal obesity

• Inadequate consumption of fruit and vegetables

• Lack of regular physical exercise

• Smoking

• Hypertension

• Psychosocial factors

• Excess alcohol

Modifiable factors increase the risk of myocardial infarction (MI)

Abnormal lipids and current smoking status are associated with the highest risk of developing acute myocardial infarction

Adapted from Yusuf S, et al. Lancet. 2004; 364: 937–952. *Lipid profile as measured by apolipoprotein B/apolipoprotein A1 ratio

Odds ratios for risk factors most associated with the development of acute myocardial infarction

Cumulative incidence of CVD adjusted for the competing risk of death for men and women according to aggregate risk factor (RF) burden at 50 years of age

Lloyd-Jones, D. M. et al. Circulation 2006;113:791-798

IDEAL RISK FACTOR PROFILE

BP 120/80

CHOL <180

NONSMOKER

NON DIABETIC

Rationale

• Primary prevention reduces MI and HF, decreases the need for coronary revascularization procedures, and extends and improves QOL

•Treating hypercholesterolaemia in patients who do have evidence of CHD

Principles • For primary prevention of cardiovascular disease (CVD),

people at risk need to be identified before CVD has become established

• To assess risk in those likely to be at high risk (for example, people with hypertension) a validated assessment tool is needed that evaluates a range of modifiable and non-modifiable risk factors.

• Epidaemiological data showing that there is a continuous graded relationship between the total plasma cholesterol concentration and CHD events and mortality

Risk Stratification Calculators

• Framingham • Joint British Societies • Q Risk • ASSIGN (Scotland only)

Framingham • Major risk factors in asymptomatic

individuals: smoking, hypertension, high cholesterol (and various cholesterol fractions). Low HDL, diabetes and “age”

• Obesity, physical inactivity, family

history of premature CHD, hypertriglycideaemia, small LDL, increased lipoprotein a, increased serum homocysteine and abnormalities in several coagulation factors (fibrinogen), “Insulin resistance”

Major RF’s (85% of excess risk

Framingham Cardiovascular Risk Calculator For Primary Prevention This calculator should not be used if patient has known CVD or diabetes (already

known to be at high risk)

Age (30-74) Smoking Status

Sex Glucose (normal, impaired, diabetic)

Systolic BP LVH on ECG yes/ no

Diastolic BP Central Obesity yes/ no

Total Cholesterol South Asian Origin yes/ no

HDL Cholesterol Family History of CVD (Men )

Total /HDL Ratio

Serum TG mmol/L

10-year risk of cardiovascular event is……. %

adjustments as suggested by the Joint British Societies' (JBS2) paper and the JBS Cardiovascular Risk Assessor

Values used should have been recorded <6 months before the date of the risk assessment and before any treatment for hypertension.

Advantage of Framingham Risk Estimate:

allows calculations over various time

periods (4 to 12 years) and for different outcomes:

cardiovascular disease, stroke, coronary

disease, myocardial infarction and death from either coronary or cardiovascular disease

Limitations of Framingham Risk Estimate

• Age and gender are the predominant factors in risk estimate

• Life time risk estimate may be more relevant than 10 year estimate

• Over-estimate risk in low risk populations • Overestimates risk in high risk populations (upt o 50%).

• should not be used in people with pre-existing CVD (coronary heart

disease, angina, stroke, TIA, PVD,diabetes, CKD (if estimated GFR < below 60), familial hypercholesterolemia, or in people already taking lipid- lowering medication before a new diagnosis of hypertension

• Guidelines emphasize coronary event reduction rather than preventing atherosclerosis

Joint British Societies (JBS) • Published in the BNF

and based on JBS guidelines.

• Based on Framingham data

• JBS/BNF calculates

cardiovascular disease risk, based on the sum of the coronary disease and stroke risks (i.e. not individualised).

Q risk

• 2010: NICE decided it could no longer recommend that the Framingham risk equation be the equation of choice [NICE clinical guideline 67 (reissued in February 2010) ]

• coincided with the emergence of the QRISK® calculator which has

been shown to predict risk more accurately

• The QRISK® cardiovascular calculator calculates lifetime risk • validated using data from a UK primary care database.

About You Age Sex male/ female Ethnicity Postcode

Clinical Information Do you smoke at all? Do you have diabetes? Are you on regular steroid tablets? Do you have high blood pressure requiring treatment? Have you had a heart attack, angina, stroke or TIA Has anyone in your immediate family* had angina or a heart attack whilst under 60 Do immediate family* have diabetes? Have you been diagnosed with rheumatoid arthritis? Have you been diagnosed with chronic kidney disease? Have you been diagnosed with atrial fibrillation or irregular heartbeat? Do you have congestive cardiac failure? Do you have hypothyroidism? Do you have liver failure?

Cholesterol/HDL ratio: Systolic blood pressure (mmHg): Body mass index Weight (kg):Height (cm):

Calculate

Advantages of Q risk • More personalized

• More risk factors: rh art, AF, renal disease, treated hypertension

• Takes into account your postcode, areas of deprivation • Other ethnic variables

• At the 10year risk threshold of 20%,the population identified by

QRISK2 was at higher risk of a CV event than the population identified by the modified algorithm

Are scoring algorithms accurate • Risk factors change with age • What is the impact of those emerging risk factors

or others such as childhood obesity • Low absolute risk does not mean low lifetime

risk • Scores don’t take into account severity of risk

factors (heavy smoking, marked hypertension) • Patients aged over 75 years ?? Secondary

prevention • Most scoring systems underestimate risk

Effect of individual RF’s on Atherogenesis

Each of major RF’s

Smoking, BP

Clinical effectiveness of primary prevention

• Nurses Health study: 120,000, 20 yrs, women who maintained a desirable body weight, ate healthy diet, exercised regularly, and didn’t smoke had an 84% reduction in CVD events (3-5% low risk)

• . Meta analysis of PP trials (including a minority of

people with established CVD), found that statin therapy was associated with a reduction in the risk of all cause mortality, fatal and nonfatal MI and the composite outcomes of CHD death, nonfatal MI, fatal or nonfatal stroke and coronary revascularization

Study Year

Number Mean Age M/F LDL Event Reduction MI/CV Death

WOSCOPS 1995 Pravastatin

6595 55 M 190 140

31% (5 years)

AFCAPS/ TEXCAPS 1998 Lovastatin

6605 58 85/15 150 112

37% (5 years)

ASCOT 2003 Atorvastatin

10305 63 80/20 132 85

36%

Primary prevention trials

Independent of other predictors of outcome Meta analysis of PP trials (including a minority of people with established CVD), found that statin therapy was associated with a reduction in the risk of all cause mortality, fatal and nonfatal MI and the composite outcomes of CHD death, nonfatal MI, fatal or nonfatal stroke and coronary revascularization

Are statins effective over a wide range of LDL-C

Ridker PM et al. Circulation. 2003; 108: 2292–2297. Ridker PM et al. Am J Cardiol. 2007; 100: 1659–1664.

Rosuvastatin 20 mg (n=8,901)

Placebo (n=8,901)

• Study population (n=17,802) • No history of cardiovascular

disease • LDL cholesterol < 3.4 mmol/l • C-reactive protein (CRP) ≥2

mg/l • Men ≥50 years

Women ≥60 years

Run in/eligibility Safety

Lipids CRP Safety

Lipids CRP Safety

Lipids CRP Safety HbA1C

Final 3–4 years 6 monthly

4 13

3 0

2 –4

1 –6

Median follow-up: 1.9 years JUPITER

JUPITER: post-hoc analysis of high-risk subgroup – baseline Framingham risk

score >20% Cumulative incidence of cardiovascular death/myocardial infarction/stroke

Koenig W, Ridker PM. Eur Heart J. 2011; 32: 75–83.

Cum

ulat

ive

inci

denc

e, %

0 1

2

3 4

5

6

7 8 9

10

0 1 2 3 4 5 Years

Placebo

Rosuvastatin

Hazard ratio: 0.50 (95% CI: 0.227-0.93) P = 0.028 NNT4y = 26

Rosuvastatin 749 359 131 63 24 Placebo 717 335 110 43 14

JUPITER: post-hoc analysis of high-risk subgroup – baseline Framingham risk

score >20% • In patients with a baseline Framingham risk score

>20% (n=1558 patients), there was:

– A significant reduction in the combined end-point of cardiovascular death, stroke and myocardial infarction (hazard ratio: 0.5; p=0.028 rosuvastatin vs. placebo)

– Absolute risk reduction (ARR) in the event rate per 1000 patient-years was 8.8

– Total mortality was unchanged (p=0.193)

Koenig W, Ridker PM. Eur Heart J. 2011; 32: 75–83. Crestor. Summary of Product Characteristics. February 2011.

Which patients should we intervene on

JBS 2. Heart 2005; 91(suppl V): v1-v52. HDL: high density lipoprotein

Evidence of atherosclerotic disease

Diabetes mellitus and aged over 40 years

Diabetes mellitus aged under 40 years and

additional risk factors Elevated blood pressure

Elevated total cholesterol to HDL cholesterol

ratio ≥6.0

Smoking status Obesity

Many factors contribute to cardiovascular risk

All patients

Risk Catergories • Who should receive cardioprotective drugs

– low: Modify risk (<10%) Cost effectiveness models have not shown

benefit of treating low risk patients with generic low intensity statins once adherenace is taken into account

– Intermediate: ???

– High: 20% ----- cardioprotective drugs

Invasive investigations

NICE recommends that patients at risk of cardiovascular events are regularly

screened

The National Collaborating Centre for Primary Care. Lipid modification: cardiovascular risk assessment and the modification of blood lipids for the primary and secondary prevention of cardiovascular disease. CG67. Quick reference guide. June 2008. Available at: http://guidance.nice.org.uk/CG67/QuickRefGuide/pdf/English Last accessed August 2011.

Is person 75 or over? Consider at increased risk of CVD, and likely to benefit from statin treatment, particularly if person smokes or has high blood pressure. Consider comorbidities, benefits and risks of treatment, and person’s preference

Use systematic strategy rather than opportunistic assessment to identify people aged 40–74 who are likely to be at high risk

Estimate risk using risk factors already recorded in primary care electronic medical records

10-YEAR RISK LESS THAN 20%

Review risk on an ongoing basis

10-YEAR RISK 20% OR GREATER

Prioritise for full format risk assessment Arrange discussion of risk assessment

Discuss process of risk assessment, including option to decline assessment RISK ASSESSMENT DECLINED

Yes

No

If the person has a history of CHD, angina, stroke or TIA, peripheral vascular disease, diabetes or a monogenic lipid disorder, do not include in risk assessment process as these patients are already considered at high risk

CHD: coronary heart disease; TIA: transient ischaemic attack; CVD: cardiovascular disease

JBS cont • (I) OBJECTIVE OF CVD PREVENTION IN CLINICAL PRACTICE • is to reduce the risk of CVD and its complications, including the need for

percutaneous or surgical revascularisation procedures in any arterial territory, and to improve quality of life and life expectancy.

• (II) PRIORITIES FOR CVD PREVENTION IN CLINICAL PRACTICE • CVD prevention should focus on all those people who are at high risk, and the

following groups of people have equal priority for CVD prevention in clinical practice.

– People with any form of established atherosclerotic CVD – Asymptomatic people without established CVD but who have a

combination of risk factors which puts them at high total risk (estimated multifactorial CVD risk ⩾ 20% over 10 years) of developing atherosclerotic CVD for the first time

– People with diabetes mellitus (type 1 or 2)

• In addition, other people with particularly elevated single risk factors also require CVD prevention because they too are at high cardiovascular risk, regardless of the presence of other risk factors:

– elevated blood pressure ⩾ 160 mm Hg systolic or ⩾ 100 mm Hg diastolic, or lesser degrees of blood pressure elevation with target organ damage

– elevated total cholesterol to high density lipoprotein (HDL) cholesterol ratio 6.0

– familial dyslipidaemia – People with a family history of premature CVD should be assessed and

then managed appropriately

Problems with this approach • The goal for reducing elevated serum cholesterol in

adults is to retard atherogenesis throughout life, not to prevent myocardial infarction in the next decade

• Reduction of serum cholesterol levels in patients with

advanced atherosclerotic disease does not substantially reduce mortality and morbidity from CHD

• High risk cohorts will have overall relatively few events,

most events will occur in those patients at intermediate risk.

Can we detect atherogenesis

• Calcification occurs in most atheroscerotic plaques sub-intimal space

• Total CAC proportional to total plaque area (CAC makes up about 15-20% of total plaque area)

• Coronary angiography: “luminography” • Using CT CAC can be visualised within a

few seconds at a low radiation exposure

Quantification of CAC • Agatston score (Agatston et al 1990) • If there is no CAC can rule out obstructive CAD (0.5%) • Acute coronary events can occur in patients with no detectable

CAC, eg young smokers • Independent risk factor for CV events (park et al 2002) • The higher the CAC score the greater the likelihood of MI or

cardiovascular death. • Independent of CV risk factors (Arad et al)

• Sensitivity 98% • Spec 40% • PPV 68% • NPP 93%

• A score >100 more predictive of CV event than traditional RF’s

Who should be screened with CTCS

• Asymptomatic patients • low risk patients: very few events are expected

in these patients so CAC is unlikely to reclassify patients

• Most high risk patients will remain high risk even with a relatively low CAC score.

• Intermediate risk patients are more likely to be reclassified

• In these patients a score >100 would reclassify them as high risk

Male>40 years Female >50 years

Framingham/ JBS/ Q Risk assessment

Low (<10%) Intermediate (10%-20%)

High (>20%)

Life style modification

CCS Scoring Secondary prevention

Absent CAC Any CAC

Use of CCS scoring

Summary • Primary prevention is extremely important, clinical

and cost implications • Patients should be risk stratified whenever possible

• Risk calculators have their limitations • Statins in primary prevention are associated with

substantial relative reductions in cardiovascular events

• Newer technologies may help refine risk

stratification in the future