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2/20/2018
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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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