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Kevin T. Schleich, PharmD, BCACP

Clinical Pharmacy Specialist, Department of Family Medicine

University of Iowa Hospitals and Clinics

Objectives

Discuss risk stratification and non-pharmacologic means of reducing primary cardiovascular risk

Compare and contrast pharmacologic agents for the prevention of cardiovascular disease

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Background Cardiovascular disease is the leading cause of

death in the United States

Atherosclerotic cardiovascular disease (ASCVD) afflicts ~33% of Americans as of 2017 Estimated it will affect up to 50% of Americans by 2030

ASCVD Acute coronary syndromes, history of myocardial infarction

(MI), stable/unstable angina, coronary/arterial revascularization, stroke, transient ischemic attack (TIA), peripheral artery disease (of presumed atherosclerotic origin)

Circulation. 2017 Mar 7;135(10):e146-e603J Am Coll Cardiol. 2014;63(25):2889-2934

Background

Primary prevention Strategies utilized to prevent the initial occurrence

of ASCVD

Relative paucity of evidence to support strong recommendations for pharmacology

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Secondary prevention Strategies utilized to prevent subsequent ASCVD

events

More clear recommendations for pharmacologic therapy in patients with established ASCVD

ASCVD Major Risk Factors

*Family history of cardiovascular disease in first degree relatives

Risk Factor

> 45 years Age > 55 years

< 55 years Family History* < 65 years

< 40 mg/dL Low HDL < 50 mg/dL

Current cigarette smoking

Hypertension ( > 140/ > 90 mmHg, or treated)

Diabetes

J Am Coll Cardiol. 2014;63(25):2889-2934

Estimating ASCVD Risk Framingham Risk Calculator (2001)

First risk assessment tool endorsed by National Cholesterol Education Panel (NCEP) Adult Treatment Panel (ATP-III)

Tried to predict 10-year risk of MI/death

Predominantly white population, therefore limited validity for a portion U.S. population

Reynolds Risk Score (2008) Utilized framework of Framingham risk calculator, but

added family history and high-sensitivity C-reactive protein (hs-CRP)

More accurately predicted CV risk in women

Predicts 10-, 20- and 30-year risk of CV events

https://www.mdcalc.com/framingham-coronary-heart-disease-risk-scorehttps://www.mdcalc.com/reynolds-risk-score-cardiovascular-risk-women

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Estimating ASCVD Risk

Pooled Cohort Equation (2013) Improved validity for U.S. population by including black

patients

Predicts 10-year and lifetime ASCVD risk

Helps predict risk of stroke

Lacks validity for other ethnicities

Million Hearts Longitudinal ASCVD Risk Assessment Tool (2017) Predicts 10-year ASCVD risk

Helps demonstrate the magnitude of effect of lifestyle modifications (i.e. starting aspirin, smoking cessation)

https://www.mdcalc.com/ascvd-atherosclerotic-cardiovascular-disease-2013-risk-calculator-aha-acchttp://tools.bigbeelabs.com/aha/tools/mlc/app.html/millionhearts

Further Risk Evaluation

www.google.com/images_heart_measurement_cartoon

Cardiovascular Risk Markers

High-Sensitivity C-Reactive Protein (hs-CRP)

Non-specific biomarker that may indicate vascular inflammation

When elevated to a specific degree, may be a reliable predictor of ASCVD risk 1-10 mg/L: possible vascular inflammation > 10 mg/L: acute illness, autoimmune disorders

Can be helpful to further stratify risk in patients at perceived low-risk utilizing Pooled Cohort Equation hs-CRP > 2 mg/L may warrant more aggressive prevention

strategies

N Engl J Med. 2008;359(21):2195-207

Cardiovascular Risk MarkersCoronary Artery Calcium (CAC) Score

Calcification of coronary arteries is a risk factor for ASCVD

Measurement of CAC can be done relatively quickly with a CT

Elevated scores predict increased ASCVD risk > 300 Agatston units > 75th percentile for age, sex, race

2013 ACC/AHA guidelines suggested this was the most useful tool aside from traditional risk calculators Still not routinely recommended due to cost and radiation

exposureJ Am Coll Cardiol. 2014;63(25):2889-2934J Am Coll Cardiol. 2014 Jul 1;63(25 Pt B):2935-59

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Lifestyle Modifications Diet

Mediterranean diet, DASH diet Fruits, vegetables, fish, nuts

Tobacco Cessation

Circulation. 2016;133:187-225Med Sci Sports Exerc. 2011 Jul;43(7):1334-59www.google.com/images

Exercise > 30 minutes of moderate-intensity exercise 5

days/week 25 minutes of vigorous aerobic activity 3 days/week Combination of two of the above + 2-3 days of

resistance

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Comorbid DiseaseOptimization

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Medication Management

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AH is a 52 year-old male with no significant past medical history who comes to clinic for his annual physical exam. He takes no medications aside from a multivitamin and aspirin 81 mg daily. He recently heard on NBC Nightly News that aspirin is likely doing nothing for him except increasing his bleed risk. You tell him:

How Smart Are We?

www.nbcnews.com

a) He’s probably right, the risk of aspirin likely exceeds the benefit for him

b) I’m interested to see where Lester Holt got his medical degree; keep taking the aspirin if you want to prevent a heart attack

c) I probably want some more information about you before deciding what to do about the aspirin

Aspirin Irreversibly inhibits platelet cyclooxygenase (COX)

At low doses (75-100 mg/day), aspirin will more selectively inhibit COX-1 and thromboxane A2 formation Inhibition of platelet aggregation

Little to no effect on COX-2 mediated adverse effects ○ Increased blood pressure, decreased renal function

COX-1 inhibition increases risk of upper GI bleed

http://www.scielo.br/.com

Aspirin Efficacy vs Safety

Thrombosis Journal (2015) 13:38

Aspirin RecommendationGeneral Population

* “… patients who place a higher value on the potential benefits than the potential harms may choose to initiate low-dose aspirin”.*

www.uspreventiveservicestaskforce.org

< 50 y.o. 50-59 y.o. 60-69 y.o. > 70 y.o.

Insufficient evidence to

assess risk vs.benefit of aspirin

for primary prevention

Initiate low-dose aspirinfor primary prevention in

the following patients:• ASCVD risk > 10%

• Low bleed risk• Life expectancy > 10

years• Willing to take aspirin

daily for > 10 years (Grade B)

*Individualized choice for the following patients:• ASCVD risk > 10%

• Low bleed risk• Life expectancy > 10

years• Willing to take aspirin

daily for >10 years* (Grade C)

Insufficient evidence to

assess risk vs.benefit of aspirin

for primary prevention

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www.google.com/images_heartanddiabetes_cartoon

Diabetes and ASCVD

Adults with diabetes are 2-3 times more likely to developASCVD compared to those without diabetes

Adults with diabetes are 2-4 times more likely to die from ASCVD than those without diabetes

Deaths Among Patients With Diabetes (age > 65 )

Heart Disease

Other

http://www.heart.org

68%

Aspirin RecommendationPatients With Diabetes Mellitus (DM)

Aspirin (75-162 mg/day) should be considered in patients > 50 y.o. with type 1 and type 2 DM at increased risk of ASCVD (> 1 risk factor) Family history of premature ASCVD Hypertension Dyslipidemia Current smoker Albuminuria (> 30 mcg/mg)

Aspirin should not be recommended for patients with DM < 50 y.o. with no other major ASCVD risk factors

Clinical judgement must be exercised when recommending aspirin for patients with DM < 50 y.o. with > 1 ASCVD risk factors

Diabetes Care Volume 40, Supplement 1, January 2017www.google.com/images_hearthealth

https://jamanetwork.com/journals/jama/fullarticle/1672562

More Thinking… TS is a 53 year-old female who comes to her

appointment today saying her best friend just had a heart attack “out of no where… she seemed so healthy”. TS wants to know if there are any medications she can take to prevent a heart attack. She has no significant past medical history. You tell her:

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a) Now you’re talking my language, atorvastatin 40 mg daily is just what the doctor ordered

b) My statin-ometer suggests you would be a good candidate for atorvastatin 10 mg daily

c) People like you haven’t really been shown to benefit from statin therapy… you’re too healthy

d) I again, need more information to decide if there’s anything I can offer you

Is the patient between age of 40‐75?

Utilize clinical judgement, but no evidence available to 

support statin use

Adults age 21‐39 y.o.• Insufficient evidence that screening for 

dyslipidemia before age of 40 has any effect on 

short‐ or longer‐term CV outcomes

• Consider significant family history of early CV 

disease

Adults > 76 y.o.• Adults in this age group were not included in any RCTs of statin use for primary prevention

• Weak evidence suggests a potential association between very low 

cholesterol levels and increased mortality

Does patient have one or more of the following cardiovascular risk factors:

1. Dyslipidemia (LDL > 130 mg/dL; HDL < 40 mg/dL)

2. Diabetes3. Hypertension 4. Smoker

Evidence does not support statin use 

Calculate ASCVD Risk using pooled cohort calculator

<7.5% 7.5% to 10% > 10%

Evidence does not support statin use 

May offer a low‐ to moderate‐dose statin 

(Grade C)

Recommend a low‐ to moderate‐dose statin 

(Grade B)

NO

NO

YES

YES

Am Fam Physician. 2017 Jan 15;95(2):online

USPSTF Statin Recommendation

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Statin Dose/Intensity

Low-Intensity Moderate-Intensity High-Intensity

Lowers LDL < 30% Lowers LDL ~30-50% Lowers LDL > 50%

Simvastatin 10 mg Pravastatin 10-20 mgLovastatin 20 mgFluvastatin 20-40 mgPitavastatin 1 mg

Atorvastatin 10-20 mgRosuvastatin 5-10 mgSimvastatin 20-40 mgPravastatin 40-80 mgLovastatin 40 mgFluvastatin XL 80 mgFluvastatin 40 mg twice dailyPitavastatin 2-4 mg

Atorvastatin 40-80 mgRosuvastatin 20-40 mg

J Am Coll Cardiol. 2013 Nov 7. pii: S0735-1097(13)06028-2www.google.com/images

Younger Patients Younger than 40 years of age

Screening for dyslipidemia < 40 years of age had no effect:○ Short-term cardiovascular outcomes○ Long-term cardiovascular outcomes

No studies evaluated effects of:○ Screening vs. not screening ○ Treating vs. not treating○ Delayed vs. earlier treatment

USPSTF makes no recommendation for or against screening for dyslipidemia in those 21 to 39 years of age

Risk vs. benefit analysis even more patient-specific in this age group

www.uspreventiveservicestaskforce.orgwww.google.com/images_youngpatient

Older Patients

JAMA. 2016 November 15; 316(19): 1971–1972

Trial Age Intervention Results

PROSPER* 70-82 y.o. Pravastatin 40 mg/d• No effect on primary composite outcome of coronary death, nonfatal MI, fatal/nonfatal stroke

JUPITER¥31% > 70

y.o. (n~5000)

Rosuvastatin 20 mg/d

• Statins were protective against MI, unstable angina, stroke, arterial revascularization or CV death• Rates of all-cause death not different

• Adverse events more common in statin group

HOPE-350% >65

y.o.(n~6300)

Rosuvastatin 10 mg/d• Statins were protective against death, CV death,

nonfatal MI and stroke

STAREE♣ > 70 y.o. Atorvastatin 40 mg/d

• Two co-primary clinical endpoints1. All-cause death, dementia, or development of

disability2. Major adverse CV events (MI, ischemic stroke, CV

death)

* Additional risk factors: smoking, HTN, DM¥ CRP > 2.0 mg/L; stopped early which limits results with regards to adverse effects♣ Ongoing trial in Australia; results expected around 2020; excluded those with DM

www.google.com/images_heartanddiabetes_cartoon

Statins: Patients With Diabetes

Diabetes Care Volume 40, Supplement 1, January 2017

< 40 y.o. 40-75 y.o. > 75 y.o.

Without additional ASCVD risk factors

N/AModerate-intensity

statin (Grade A)

Moderate-intensity statin

(Grade B)

With additional ASCVD risk factors

Moderate- to high-intensity statin

(Grade C)

High-intensity statin(Grade B)

Moderate- to high-intensity statin

(Grade B)

Who Else Could Benefit?

Circulation. 2012;125:3092-3098

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Statin Adverse Effects Myalgias

8.4-24.9% reported incidence depending on agent○ Meta-analysis of RCTs demonstrated similar degree of

myalgias in patients taking placebo

Reasonable to obtain baseline creatinine kinase (CK); only check again if suspicious for rhabdomyolysis

Can try alternative statin if myalgias develop

www.uspreventiveservicestaskforce.orgAm Heart J 2014; 168:6www.google.com/images_petergriffin_injury

Statin Adverse Effects New-onset diabetes

Very small increased risk of developing new-onset DM

Meta-analysis of primary prevention trials demonstrate:○ 0.1 cases/100 patients years with moderate-intensity statin○ 0.3 cases/100 patient years with high-intensity statin

Cognitive impairment No clear relationship between decreased cognitive

function and statin use

https://www.cdc.gov/heartdisease/facts.htmwww.uspreventiveservicestaskforce.orgJAMA. 2016;316(19):1997-2007www.theawkwardyeti.com

33% of patients have ASCVD○ Heart disease deaths account for

23.5% of deaths as of 2008

Supplements Omega-3 fatty acids

Docosahexaenoic acid (DHA): 1.25 to 4 grams daily Eicosapentaenoic acid (EPA): 600 mg three times

daily (1.8 g/day)

GI intolerance, belching, fishy taste, prolonged bleeding, bruising

Ethyl-EPA only formulation shown to reduce mortality in patients with coronary artery disease (CAD)

https://naturalmedicines.therapeuticresearch.comhttps://www.walmart.com

Supplements English walnuts

Increased dietary consumption of walnuts and other nuts may decrease risk of CAD

Basis behind much of the Mediterranean diet

8-11 walnuts per day (30-56 g/day) when substituted for other dietary fats

www.naturalmedicines.therapeuticresearch.comwww.google.com/images

Green tea Epidemiological evidence suggests a 28%

reduction in CAD risk

Dose/amount very difficult to ascertain for CV benefit

Cautious with caffeine content

Supplements A few other supplements have some data supporting their

use in patients with established cardiovascular disease: Magnesium may decrease anginal symptoms in those with CAD L-carnitine may improve symptoms of heart failure Ribose may improve heart’s tolerance to ischemia in those with

CAD

A number of supplements have been shown to be ineffective or have insufficient evidence to recommend for prevention of ASVCD Coconut oil, cranberry, DHEA, Dong Quai, garlic, L-arginine,

pomegranate, Reishi mushroom, zinc, citrus bergamot, fenugreek, red yeast rice, Hawthorne extract, ginseng

Importantly, a number of these have potentially severe adverse effects associated with them

www.naturalmedicines.therapeuticresearch.com

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Summary Primary prevention of cardiovascular disease is much less

studied and understood compared to secondary prevention

Appropriately stratifying a patient’s perceived ASCVD risk is essential for helping guide decisions for ASCVD prevention

Aspirin, when taken for > 10 years can be a viable option for preventing ASCVD in appropriately selected patients

Statins, in a similar manner, can be effective at reducing ASCVD risk in patients who meet a prespecified risk criteria

Discussions with patients about the risks and benefits of therapy are paramount in making appropriate therapeutic decisions

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