Preventive Cardiology: Aspirin, Omega-3, and Lipid Therapy

• Update in Internal Medicine: Advance Changing Practice

• Aryan Aiyer, MD• Assistant Professor of Medicine, UPSOM• Director, Lipid Clinic, UPMC HVI• Director, Inpatient Cardiology Consult Service, UPMC Presbyterian

No Disclosures Related to this Talk

Objectives

• Follow the 2018 update to the ACC/AHA Blood Cholesterol guidelines in order to improve identification of those patients that may benefit most from aggressive lipid intervention

• Improve patient outcomes by reviewing recent data regarding the use of aspirin in primary prevention

• Implement precision based risk assessment in daily practice so as to improve identification of primary prevention patients who may benefit from statin therapy

Guidelines

Evolution of NHLBI Supported Guidelines

Angiographic trials (FATS, POSCH, SCOR, STARS, Ornish, MARS)Meta-analyses(Holme, Rossouw)

NCEP ATP I1988

NCEP ATP II1993

NCEP ATP III2001

HPSPROVE-ITASCOT-LLAPROSPERALLHAT-LLT

NCEP ATP IIIUpdate 2004

FraminghamMRFITLRC-CPPTCoronaryDrug ProjectHelsinki HeartCLAS

4SWOSCOPSCARELIPIDAFCAPS/TexCAPS

TNTIDEAL

AHA/ACC Update2006

More Intensive Treatment Recommendations

Evolution of NHLBI Supported Guidelines

AHA/ACC 2013

AHA/ACC2018

Therapy based on risk status using risk calculator (PCE)

IMPROVE ITFOURIERODYSSEY

MESA

“Know your risk” “Know your risk and levels”

Secondary Prevention

Intensity of Statin Therapy

*Individual responses to statin therapy varied in the RCTs and should be expected to vary in clinical practice. There might be a biologic basis for a less-than-average response. †Evidence from 1 RCT only: down-titration if unable to tolerate atorvastatin 80 mg in IDEAL (Pedersen et al).‡Although simvastatin 80 mg was evaluated in RCTs, initiation of simvastatin 80 mg or titration to 80 mg is not recommended by the FDA due to the increased risk of myopathy, including rhabdomyolysis.

2018 ACC Blood Cholesterol Guidelines

Risk-Enhancing Factors

• Family history of premature ASCVD (males, age <55 y; females, age <65 y)• Primary hypercholesterolemia (LDL-C, 160–189 mg/dL [4.1–4.8 mmol/L);

non–HDL-C 190–219 mg/dL [4.9–5.6 mmol/L])*• Metabolic syndrome (increased waist circumference, elevated triglycerides

[>175 mg/dL], elevated blood pressure, elevated glucose, and low HDL-C [<40 mg/dL in men; <50 in women mg/dL] are factors; tally of 3 makes the diagnosis)

• Chronic kidney disease (eGFR 15–59 mL/min/1.73 m2 with or without albuminuria; not treated with dialysis or kidney transplantation)

• Chronic inflammatory conditions such as psoriasis, RA, or HIV/AIDS• History of premature menopause (before age 40 y) and history of pregnancy-

associated conditions that increase later ASCVD risk such as preeclampsia• High-risk race/ethnicities (e.g., South Asian ancestry)

Risk-Enhancing Factors

• Lipid/biomarkers: Associated with increased ASCVD risko Persistently* elevated, primary hypertriglyceridemia (≥175 mg/dL);o If measured: Elevated high-sensitivity C-reactive protein (≥2.0 mg/L) Elevated Lp(a): A relative indication for its measurement is family history

of premature ASCVD. An Lp(a) ≥50 mg/dL or ≥125 nmol/L constitutes a risk-enhancing factor especially at higher levels of Lp(a). Elevated apoB ≥130 mg/dL: A relative indication for its measurement

would be triglyceride ≥200 mg/dL. A level ≥130 mg/dL corresponds to an LDL-C >160 mg/dL and constitutes a risk-enhancing factor ABI <0.9

Case Examples

Case 1

23 year old woman comes in for well visit

No meds or past history

Non-smoker, vegan, yoga

Mother had MI at 59

PE and vitals are normal

Labs: Chol 320, HDL 55, TG 135, LDL 238

What do we do?

Case 2

60 year old white man here to establish care after job move

No PMHx, meds

Non-smoker, no exercise

Father had MI at age 80

PE: BMI 25, BP 136/78

Labs: Chol 221, HDL 55, TG 133, LDL 140

Calculated 10-year ASCVD risk…9.8%

What do we do?

How can coronary calcium measurement help guide clinical decision-making?

Implications of Coronary Calcium Testing Among Statin Candidates

• Multi-ethnic Study of Atherosclerosis (MESA)

• 6814 subjects without ASCVD at enrollment

• Ages 45-84• 6 centers in the US for enrollment

(NYC, LA, Chicago, Baltimore, St. Paul, MN, and Forsyth County, NC

• Self-identified race/ethnicity

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Implications of Coronary Calcium Testing Among Statin Candidates

• Aim was to see how CAC reclassifies ASCVD risk

• Excluded the following• Age > 75• Missing LDL levels and LDL < 70• Already on lipid lowering

medication• Missing variables so that ASCVD

risk couldn’t be calculated• Total remaining cohort of 4758 subjects

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Impact of the Absence of CAC in Reclassifying Risk Below Threshold for Statin Consideration

Case 2 (cont’d)

Risk Discussion

Patient was averse to taking a statin

Agreed to have a coronary calcium scan

CAC score = 0

Based on this result, no statin was initiated as it re-classified the patient’s risk to a lower level.

Lifestyle measures recommended (e.g. exercise, diet)

Case 3

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48 year old male of South Asian descent

• History of mixed dyslipidemia (↓HDL, ↑TG)• Prediabetes

Medical History:

No meds

• Little formal exercise• Indian food, non-vegetarian

Lifestyle

Case 3 (cont’d)

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Strong Family history of Heart Disease• Father had MI at 50• Mother had CABG at 60• Paternal uncle had CABG in his 50s• Both parents and sister have gestational diabetes

Physical Exam: 163 lbs, BMI 23, BP 135/85

Lipids: Chol 203, LDL 127, HDL 32, TG 220

Hgb A1C 6.3

Calculated 10-year ASCVD Risk….5.2%

What do we do?

Case 3 (cont’d)

Risk Enhancers• Ethnicity (South Asian background)• Metabolic syndrome• Family History• Persistently elevated triglycerides

Recommendations• Change lifestyle• Consider starting a statin (Class IIb level of

evidence)

Patient reluctant to take meds

Do we do anything else?

Case 3 (cont’d)

Coronary calcium assessment

CAC score = 481

After these results, he agreed to start a statin

Impact of Statins on CV outcomes after CAC scoring

• Retrospective analysis of consecutive subjects without ASCVD at Walter Reed Medical Center from 2002-2009 who underwent CAC scans

• Statin use monitored by filled prescriptions• Sought to determine whether CAC could

predict which patients would benefit the most from statins

• 13644 patients (mean age 50, 71% men)• Median follow up of 9.4 years• Primary Outcome was MACE: composite

of MI, stroke, or cardiovascular death

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Impact of Statins on CV outcomes after CAC scoring

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Joshua D. Mitchell et al. JACC 2018;72:3233-3242

Joshua D. Mitchell et al. JACC 2018;72:3233-3242

Case 4

72 year old diabetic with recent NSTEMI 3 months ago

PCI to LAD. Non-obstructive CAD elsewhere

Uncomplicated hospital course

Discharged on standard post-MI meds

aspirin, clopidogrel, B-blocker, ACE-inhibitor

High intensity statin (Atorvastatin 80 mg po qd)

Cardiac rehab referral

Case 4 (cont’d)

Physical exam: BP 122/78, HR 62, BMI 27

Lipids: Chol 150, LDL 85, HDL 40, TG 125,

HgbA1C: 6.7

What should we do?

Secondary Prevention

Aspirin

Use of Aspirin for Primary PreventionUSPSTF Update in 2016

Population Recommendation GradeAge 50-59>10% 10-year CVD Risk

Low dose aspirinLow bleeding riskShould take for 10 yearsLife expectancy of at least 10 years

B

Age 60-69>10% year CVD Risk

Low dose aspirinLow bleeding riskShould take for 10 yearsLife expectancy of at least 10 years

C

Age < 50 IAge > 70 I

Recommendations of Other Groups (2018)

AHA/ACC 10-year ASCVD Risk threshold of 6% threshold

American College of Chest Physicians

Age over 50

American Academy of Family Physicians

USPSTF guidelines

American Diabetes Association

> 10% 10-year ASCVD risk

European Society of Cardiology

Don’t use aspirin for primary prevention (class III)

Recent Prevention Trials with Aspirin

Trial Primary Endpoints/Events Adverse Events (Primary safety outcome)

ASCENDN = 15,480DiabeticsASA 100 mgMean F/U 7.4 years

First serious Vascular event • CV death• Nonfatal MI or Stroke or TIA

Major bleeding• Intracranial hemorrhage• GI• Bleeding requiring Hospitalization or

transfusion

ARRIVEN = 12,546Intended to enroll high risk w/o DMASA 100 mgMedian F/U 5 years

First serious Vascular event • CV death• Nonfatal MI or Stroke or TIA• Unstable angina

Hemorrhagic events

ASPREEN=19,114Age > 70 yearsASA 100 mg Median F/U 4.7 years

Composite primary endpoint• Death• Dementia• Physical DisabilitySecondary Endpoint - MACE

Major Hemorrhage• Hemorrhagic stroke• Symptomatic intracranial bleeding• Extracranial bleeding requiring

hospitalization or transfusion

Recent Prevention Trials with Aspirin

Trial Primary Endpoints/Events Adverse Events (Primary safety outcome)

ASCENDN = 15,480, Diabetics, UK populationmean age 63, 96% white, 63% male47% obese, 76% on statinsMean F/U 7.4 years

First Serious Vascular Event:ASA 8.5%Placebo 9.6%RR 0.88; CI 0.79-0.97, P=0.01

Major Hemorrhage:ASA 4.1%Placebo 3.2%RR 1.29; CI 1.09-1.52, P=0.003

ARRIVEN = 12,546, estimated high risk w/o DM> 93% European, 28% smokersMean age 64, 98% white, 70% maleMedian F/U 5 years

First Serious Vascular Event:ASA 4.3%Placebo 4.5%HR 0.96; CI 0.81-1.13, P=0.6(Event rates lower than expected)

GI Bleeding Events:ASA 3.28%Placebo 1.36%HR 2.1; CI 1.36-3.28, P<0.001

ASPREEN=19,114, Australia (87%) and USA (13%)Median age 74, 92% white, 56% women11% diabetics, 4% smokersMedian F/U 4.7 years

Death, Dementia, Disability:HR 1.01; CI 0.92-1.1, P=0.79

MACE:HR 0.95; CI 0.83-1.08,

Major Hemorrhage:ASA 8.6 events per 1000 person-yearsPlacebo 6.2HR 1.38; CI 1.18-1.62, P<0.001

PM Ridker. N Engl J Med 2018;379:1572-1574.

Aspirin and All-Cause Mortality in 14 Primary Prevention Trials.

2019 ACC/AHA Guidelines on the Primary Prevention of CVD

• “Aspirin should be used infrequently in the routine primary prevention of ASCVD because of the lack of net benefit.”

Omega-3 PUFA

Conditions postulated to benefit from fish oils• Severe Hypertriglyceridemia• Primary prevention• Heart Failure• Stroke• Atrial Fibrillation• Secondary prevention from

prior MI or ASCVD

2017 AHA Science Advisory

Siscovick et.al. Circulation 2017;135:e867-884

Secondary prevention

• Coronary heart disease and sudden cardiac death among patients with prevalent CAD – IIa recommendations

• Secondary prevention in patients with heart failure – IIa

• No benefit to prevent recurrent stroke or AFib

Primary prevention – no benefit (Class III)

REDUCE IT Trial

Summary

• In very high risk ASCVD patients…• goal of LDL less than 70 mg/dl and non-

HDL less than 100 mg• non-statin drugs such as ezetimibe and

PCSK9 inhibitors may be reasonable

• Risk enhancers and coronary calcium assessment may be useful to further risk stratify those in the intermediate risk range

• Recent clinical trials have shown limited to no CV benefit of aspirin for primary prevention while there is consistent risk of bleeding

• EPA may be the preferred Omega-3 PUFA. Use for secondary prevention in high risk patients with residual TG elevation may be useful. Jury is still out for primary prevention in general population.