B P4 C25 Primary Prevention of Cardiovascular Disease Flashcards by Shadow Fox

The largest contributors to the age-adjusted decline in cardiovascular death are:

Lower cholesterol and blood pressure
Smoking cessation

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_____ prevention is the prevention of the development of risk factors

Primordial prevention

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_____ prevention aims to prevent the clinical manifestation of cardiovascular disease in individuals without clinical cardiovascular disease

Primary prevention

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_____ prevention focuses on social determinants of health and health inequities (e.g.,poverty and living conditions, urbanization, air pollution, education, sedentary behavior, psychosocial stress)

Primordial prevention

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_____ prevention focuses on controlling cardiovascular risk factors among high-risk individuals through lifestyle approaches and treatment of established risk factors.

Primary prevention

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_____ prevention targets patients with established disease to reduce risk of recurrent cardiovascular events and mortality.

Secondary prevention

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____ prevention can eliminate most cardiovascular events

Primordial and primary prevention

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According to the PURE (Prospective Urban Rural Epidemiology) study, the largest contributors to as to CV risk, all-cause death, and MI are:

CV risk: Hypertension (22%), non-HDL cholesterol (8%)

All-cause deaths: Behavioral risk factors (26%), low education (12.5%)

MI: non-HDL cholesterol, followed by hypertension, smoking, abdominal obesity, and diabetes

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The AHA introduced Life’s Simple 7 cardiovascular health metrics in 2010 to shift the focus from disease toward cardiovascular and overall health and well-being. The seven health metrics are:

Smoking status
Body mass index (BMI)
Physical activity
Diet
Cholesterol
Blood pressure
Glucose

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Ideal cardiovascular health is defined as the:

Absence of clinical cardiovascular disease

Ideal levels of all seven components

Absence of medication treatment

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AHA’s Life’s Simple 7

Get active
Eat better
Lose weight
Stop smoking
Control cholesterol
Manage blood pressure
Reduce blood sugar

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Specific AHA’s Life’s Simple 7:

At least 150 minutes moderate activity /week or at least 75 minutes vigorous activity/week
Eat a healthy diet (4–5 components of healthy diet score:
1) 4.5 cups or more of fruits and vegetables per day;
2) two or more 3.5-oz servings of fish per week;
3) three servings per day of whole grains;
4) less than 1500 mg of sodium per day; and
5) 36 ounces or less of sugar-sweetened beverages per)
Have a normal body weight (BMI<25)
Never smoked or quit >1 year ago
Total cholesterol <200 mg/dL
Blood pressure <120/<80 mm Hg
Fasting blood glucose <100 mg/dL

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_____, that is, the number of years that a population can anticipate living in good health (commonly known also as healthy life expectancy)

Health-adjusted life expectancy (HALE)

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_____ risk assessment was developed to address limitations of 10-year risk assessments and has been highlighted in recent guidelines

Lifetime risk

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Of several imaging techniques developed over the past decade, _____ has emerged as a leading imaging tool for the preventive cardiology community.

Computed tomography to detect coronary artery calcification (CAC)

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The AHA/ACC guidelines suggest use of CAC among those with estimated 10-year risk between _____% in the context of shared decision-making when either the physician or patient is otherwise uncertain about use of specific preventive therapies, in particular statins

5-20%

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____ only detects calcified plaques (which are less likely to rupture) and does not detect the noncalcified thin-capped lesions that underlie many clinical events.

CAC

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CAC scores of zero do not eliminate atherosclerotic risk, particularly over long-term follow-up, and repeat testing after ___ years may be needed.

5 years

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An the open-label, parallel-group _____ trial of 4146 patients with stable chest pain, participants randomized to CCTA as compared to usual care

Low- to intermediate-risk patients with chest pain were randomized to evaluation with coronary CTA (n = 2,073) versus standard care (n = 2,073).

Lower rate of nonfatal myocardial infarction or coronary death at 5 years randomized to CCTA, an effect due to earlier use of coronary revascularization and more aggressive use of preventive and anti-anginal therapies

SCOT-HEART trial (Scottish Computed Tomography of the HEART)

Although CTA was associated with an increase in invasive therapy and revascularization in the short-term, there was no difference in invasive therapy and revascularization between treatment arms at 5 years. Since there was no difference in overall revascularization rates, long-term benefit from CTA may have been due to lifestyle modification and statin therapy. SCOT-HEART (and PROMISE) shows that coronary CTA is an alternative to standard care (including conventional stress testing) in the evaluation of patients with chest pain.

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Moreover, among patients with stable chest pain, _____ plaque burden most strongly predicted fatal or nonfatal myocardial infarction, irrespective of risk score, CAC, or coronary artery area stenosis, and nearly half of all incident infarctions occurred among those without clear obstructive disease

Low- attenuation noncalcified plaque burden

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The guidelines recommend assessing 10-year ASCVD risk every __ years in all asymptomatic adults age 40 to 75 years old, using the sex- and race-specific PCE.

5 years

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ACC/AHA Atherosclerotic Cardiovascular Disease Risk Enhancers Used in the ACC/AHA Guidelines

Family history of premature ASCVD (men <55 years, women <65 years)
Primary hypercholesterolemia (LDL-C ≥160 mg/dL [4.1 mmol/L]; non-HDL-C ≥190 mg/dL [4.9 mmol/L])
Chronic kidney disease (eGFR 15–59 mL/min/1.73 m2, not on dialysis or kidney transplant)
Metabolic syndrome
Conditions specific to women (e.g., preeclampsia, premature menopause)
Chronic inflammatory conditions (especially rheumatoid arthritis, lupus, psoriasis, HIV)
High-risk race/ethnicity (e.g., South Asian ancestry)

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ACC/AHA Atherosclerotic Cardiovascular Disease Risk Enhancers Used in the ACC/AHA Guidelines (Biomarkers/Lipids)

Persistently elevated triglycerides (≥175 mg/dL [2 mmol/L], fasting or nonfasting)
In selected individuals if measured:
hsCRP ≥2 mg/L
Lipoprotein(a) ≥50 mg/dL or ≥125 nmol/L
Apolipoprotein B ≥130 mg/dL
Ankle-brachial index <0.9

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Lipid analysis for estimation of total risk of CVD. (IC)

Total cholesterol

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Lipid analysis for further refining risk estimation. IC

HDL-C

Lipid analysis for the primary lipid analysis method for screening, diagnosis, and management. IC

LDL-C

Lipid analysis recommended for risk assessment, particularly if high TGs, DM, obesity, or very low LDL-C.IC

Non-HDL-C

Treatment goals for LDL-C in primary prevention

In individuals at very high risk, LDL-C reduction ≥50% and an LDL-C goal of <1.4 mmol/L (<55 mg/dL). IC In individuals at high risk, LDL-C reduction ≥ 50% and LDL-C goal of <1.8 mmol/L (<70 mg/dL). IA

As described in the 2020 Surgeon General’s report on smoking, _____ remains the single most important preventable cause of death and disability in the United States.

Tobacco use

Prospective studies indicate that death from both coronary disease and stroke increases progressively from blood pressure levels as low as _____.

115 mm Hg systolic and 75 mm Hg diastolic

The core strategies to prevent and treat high blood pressure are:

Lifestyle (weight loss,sodium reduction,potassium supple- mentation, healthy diet, increased activity, and moderation of alcohol intake) Drug therapy

Dietary Approaches to Stop Hypertension (DASH) intervention (low sodium combined with high fruits, vegetables, low- fat dairy, and naturally high potassium) having the largest mean effect on lowering blood pressure (up to ____ mm Hg reduction in systolic blood pressure, and ____mm Hg reduction in diastolic blood pressure), with clinically meaningful blood pressure-lowering benefits also seen for low-sodium, high-potassium, low-calorie, or Mediterranean diets

−7.6/4.2 mm Hg

Physical activity protects against hypertension. In a meta-analysis of 29 studies of greater than 330,000 individuals, the risk of incident hypertension was lower by ___% for each __ metabolic equivalents (MET hour/week) increment in leisure-time physical activity, with more benefit with higher activity (e.g.,up to 33% lower risk of hypertension with 60 MET hour/week)

6% lower for each 10 MET increment

Weight loss of ____ kilogram achieved through lifestyle/diet is associated with approximately 1 mm Hg systolic blood pressure reduction in a dose-response manner, with greater reductions in patients with higher blood pressures.

1 kg = 1 mm Hg

Multiple randomized trials in patients with hypertension have demonstrated that blood pressure reductions as small as _____ mm Hg result in large and clinically significant reductions in risk for stroke, cardiovascular mortality, congestive heart failure, and coronary disease in middle-aged subjects, elderly persons, and specified high-risk patients such as those with diabetes and peripheral arterial disease

3-5 mm Hg

The presence of diabetes confers an equivalent risk to aging _____ years

15 years

Metabolic syndrome is a cluster of:

- Glucose intolerance and hyperinsulinemia accompanied by hypertriglyceridemia (both fasting and postprandial) - Low-HDL cholesterol levels - Predominance of small dense LDL particles and elevation of LDL particles and apolipoprotein B (apoB) levels - Central obesity - Hypofibrinolysis - Hypertension - Microalbuminuria - Elevated inflammatory biomarkers such as hsCRP

Beyond diet, exercise, and other lifestyle interventions, multiple randomized trials now demonstrate cardiovascular risk reduction among those with diabetes using new classes of glucose-lowering agents, in particular for _____, which both reduce cardiovascular events and improve glycemic control

Glucagon-like peptide-1 receptor agonists (GLP-1RA) Sodium-glucose cotransporter 2 (SGLT-2) inhibitors

The pharmaceutical grade preparation of the n-3 fatty acid eicosapentaenoic acid (EPA, icosapent ethyl) administered in high dose (2 g twice daily) to patients who met the entrance criteria for ____ (Trial) did benefit in improving CV outcomes Eligible patients were randomized in a 1:1 fashion to either IPE (2 g twice daily with food) (n = 4,089) or matching placebo (n = 4,090). Randomization was stratified by primary vs. secondary prevention, use of ezetimibe, and geographic region

REDUCE-IT Trial (Reduction of Cardiovascular Events With Icosapent Ethyl–Intervention Trial) The results of this trial indicate that the use of IPE 2 g twice daily was superior to placebo in reducing TGs, CV events, and CV death among patients with high TGs and either known CV disease or those at high risk for developing it, and who were already on statin therapy with relatively well-controlled LDL levels. Results were consistent among patients with diabetes and those with prior MI, and across the spectrum of kidney function. Rates of revascularization and MI (all types) were lower, while atrial fibrillation/flutter and bleeding were higher with IPE. Results were maintained in the US cohort, and whether events were investigator-reported vs. CEC-adjudicated. These are very interesting findings and come on the heels of several negative trials with n–3 fatty acid supplementation. One aspect of this medication is that it has a higher dose of purified EPA (4 g/day) than what was tested in other clinical trials. Other trials with moderate to high doses of EPA are ongoing. This is one of the first non-LDL targeted trials to show a CV benefit and will likely be featured in future guidelines.

Low-dose aspirin may be considered for primary prevention of cardiovascular disease in patients with diabetes and increased cardiovascular risk who are not at increased risk of bleeding given the recent _____ trial showing 12% risk reduction in the primary cardiovascular endpoint, although at the cost of 30% increased risk of major bleeding, while aspirin should be used in those with diabetes and cardiovascular disease unless there is a contraindication. The goal of the trial was to evaluate aspirin compared with placebo among diabetics with no known cardiovascular disease (CVD). Patients with diabetes and no known CVD were randomized to aspirin 100 mg daily (n = 7,740) versus placebo (n = 7,740).

ASCEND Trial (A Study of Cardiovascular Events in Diabetes - Aspirin) Among diabetic patients with no known CVD, aspirin was associated with a 12% relative reduction in major adverse cardiovascular events compared with placebo. Aspirin was associated with a 29% relative increase in major bleeding events compared with placebo. The increase in bleeding was mainly due to GI hemorrhage. The absolute risk reduction for major adverse cardiovascular events was 1.1%, while the absolute risk increase for major bleeding was 0.9%. There was no reduction in GI cancer, HF events, or dementia from the use of aspirin. The use of aspirin among diabetics with no known CVD needs to be individualized. Similarly, there was no effect of omega-3 fatty acid on HF events.

BMI classification:

BMI of ≥25 kg/m2: overweight BMI ≥30 kg/m2: obesity BMI ≥35 kg/m2: severe obesity

By contrast to medical intervention trials, randomized trials indicate that _____improves diabetes control, hypertension, lipid levels, sleep apnea, and osteoarthritis and show a trend toward improved mortality.

Metabolic surgery

Within the _____ trial, those subjects with a family history of premature atherosclerosis experienced a 62% reduction in first vascular events associated with statin therapy as compared with a 39% reduction among those without a family history, with even greater statin-related risk reductions seen in women with family history versus men, which has led recent US guidelines to emphasize family history as a risk-enhancing factor when considering statin treatment.

JUPITER Trial (Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin) The JUPITER trial was designed to assess whether apparently healthy persons with levels of low-density lipoprotein (LDL) that do not mandate statin treatment, as per current guidelines (<130 mg/dl), but with levels of high-sensitivity C-reactive protein (hs-CRP) ≥2 mg/L, would benefit from taking rosuvastatin. Rosuvastatin 20 mg daily or placebo The results of the JUPITER trial indicate that rosuvastatin is associated with a significant reduction in major cardiovascular events, including death, in apparently healthy persons with LDL cholesterol <130 mg/dl, but hs-CRP ≥2 mg/L. Individuals who had the greatest percent reduction in LDL (not the absolute LDL level), experienced the greatest reduction in adverse events with rosuvastatin. Among those at risk for diabetes, rosuvastatin versus placebo was associated with an increased risk for developing diabetes. Rosuvastatin did not reduce the risk for fractures.

In the _____ study of 154,169 participants from 20 countries, lower educational level associated strongly with 1.5- to 2-fold increased risk of cardiovascular events and mortality independent of household wealth and other risk factors, with the strongest association noted in low- and middle-income countries and to a lesser degree in high-income countries.

PURE study

Notably, in the PURE study, out of 14 potentially modifiable cardiovascular risk factors, the largest contributor to death was _____ which accounted for 16% of deaths, exceeding that of smoking or hypertension (11% each), household pollution, diet, or grip strength (8% each).

Low education

The ABI for lower extremities is obtained noninvasively and calculated by _____.

Dividing each of the ankle pressures by the higher of the brachial artery pressures

For cardiovascular risk assessment, the _____ ABI between the two legs is used.

Lowest

A normal resting ABI is greater than _____ (borderline abnormal is ABI _____). An ABI ____ is abnormal (low), diagnostic for lower extremity arterial disease, and is associated with more than doubling of the 10- year cardiovascular risk, while ABI ____ is also abnormal (high) as it represents arterial stiffening, vascular calcification, and noncompressibility, and is also associated with higher cardiovascular risk

Normal: 1.00 - 1.40 Borderline abnormal: 0.91 to 0.99 Abnormal (low): ≤0.9 Abnormal (high): >1.4

The AHA/ACC guidelines consider ABI less than ____ as a risk-enhancing factor that can be useful for further risk stratification and statin decisions among individuals with borderline or intermediate risk based on the PCE equations

<0.9

Cholesterol screening for children with a nonfasting sample should start early (age __ years) and be repeated every _____ years.

Start at 10 years Repeated every 5 years

If there is a family history of hypercholesterolemia or premature cardiovascular disease, cholesterol screening should start earlier at age __ and repeated every 3 to 5 years for early identification of familial hypercholesterolemia and hereditary dyslipoproteinemias, even if the initial profile is normal

Start at age 2 Repeated every 3-5 years

Adults should have the traditional cardiovascular risk factors assessed at least every ___ years starting at age __, and by age 40 all adults should undergo a cardiovascular risk assessment with a global risk score to estimate the absolute 10-year risk of ASCVD to guide discussions and decisions about preventive therapies.

Age 20: CV risk factor assessment every 5 years Age 40: Global risk score assessment (10 yr risk of ASCVD)

Most guidelines, including the latest US and European guidelines, define elevated non- fasting triglycerides as ≥____mg/dL (≥___ mmol/L) based on a cut point that has been prospectively validated.

≥175 mg/dL ≥2 mmol/L

On average, the lowering of LDL cholesterol by 1% corresponds to approximately a __% lower risk of cardiovascular events.

1% decrease in LDL-C = 1% decrease in risk of CV events

In this trial, cholesteryl ester transfer inhibition with anacetrapib increased HDL cholesterol by twofold, but the modest clinical benefit (9% relative risk reduction) may have been due to the concomitant modest reduction in atherogenic particles.

REVEAL (Randomized Evaluation of the Effects of Anacetrapib Through Lipid Modification) Large clinical trials have found no evidence that increasing HDL cholesterol reduces clinical events

In general, observational data suggest that each 1 mg/dL higher increment in HDL cholesterol is associated with approximately _____% lower risk of total cardiovascular disease, in particular for coronary events.

Each 1mg/dL HDL higher increment = 2-3% lower total CVD risk

In general, observational data suggest that each 1 mg/dL higher increment in HDL cholesterol is associated with approximately ____% lower risk of total cardiovascular disease, in particular for coronary events.

Each 1mg/dL higher increment in HDL = 2-3% lower total CVD risk

In the _____ trial, cholesteryl ester transfer inhibition with anacetrapib increased HDL cholesterol by twofold, but the modest clinical benefit (9% relative risk reduction) may have been due to the concomitant modest reduction in atherogenic particles

Randomized Evaluation of the Effects of Anacetrapib Through Lipid Modification (REVEAL)

In a meta-analysis of randomized trials (N = 374,358 from 25 statin trials and 24 nonstatin trials),triglyceride lowering is associated with lower cardiovascular risk (approximately ___% lower risk per 1 mmol/L reduction in triglycerides), which was somewhat lower than for LDL cholesterol (approximately ___ % lower risk per 1 mmol/L reduction in LDL cholesterol)

1 mmol/L dec in TG = 15% lower CV risk 1 mmol/L Dec in LDL = 20% lower CV risk

Nonfasting triglycerides are associated equally or more strongly with cardiovascular endpoints than fasting levels. Guidelines consider nonfasting triglycerides ≥ ___ mmol/L (___ mg/dL) as abnormal, while for fasting triglycerides the corresponding level is ≥ ___ mmol/L (___ mg/dL).

Nonfasting TG: ≥ 2 mmol/L (175 mg/dL) Fasting TG: ≥ 1.7 mmol/L (150 mg/dL)

There are some differences in the guideline cut points for severe hypertriglyceridemia, defined as fasting triglycerides ≥ ___ mg/dL (___ mmol/L) in US guidelines and greater than __ mmol/L (___mg/dL) in European guidelines.

US: ≥ 500 mg/dL (5.7 mmol/L) Europe: > 885 mg/dL (10 mmol/L)

Agents for reducing triglycerides include _____, which moderately reduce triglycerides.

n-3 fatty acid supplements and Fibrates

Fibrates are weak peroxisome proliferator-activated receptor (PPAR)-α agonists and reduce triglycerides by approximately ____% depending on baseline levels

25-50%

____ is an apoCIII inhibitor used for familial hyperchylomicronemia syndrome as an adjunct to diet and reduces triglycerides by 70%

Volanesorsen

_____ is a monoclonal anti-ANGPTL3 antibody that binds circulating ANGPTL3 to form immune complexes.This augments plasma lipase activity, reducing triglycerides (approximately 50% to 75%).

Evinacumab

_____ is a novel potent SPPARM that reduces triglycerides by up to 45% in patients with diabetes and hypertriglyceridemia, in addition to reducing non-HDL cholesterol and remnant cholesterol, apoB and apoCIII, and increasing HDL cholesterol, without significant effect on LDL cholesterol

Pemafibrate

_____ is an international phase 3 randomized placebo-controlled trial in approx- imately 10,000 patients (two thirds with prior cardiovascular disease) with type 2 diabetes and mild to moderate hypertriglyceridemia (2.26 to 5.64 mmol/L, or 200 to 499 mg/dL) and low HDL cholesterol (≤1.03 mmol/L or 40 mg/dL) that is evaluating efficacy of pemafibrate on a background of statin therapy in reducing cardiovascular events.

PROMINENT (Pemafibrate to Reduce Cardiovascular Outcomes by Reducing Triglycerides in Patients With Diabetes)

Individuals with higher numbers of _____ repeats have lower circulating lipoprotein(a) levels.

kringle IV type 2

_____ is a sulfhydryl-containing amino acid derived from the demethylation of dietary methionine

Homocysteine

In patients with rare inherited defects of methionine metabolism, severe hyperhomocysteinemia (plasma levels >____ mmol/L) can develop; such patients have greatly elevated risk for premature atherothrombosis as well as venous thromboembolism.

>100 mmol/L

Inflammatory cytokines such as interleukin _____ implicated in atherogenesis and activated by the ____ inflammasome, elicit the expression of the messenger cytokine _____, which can travel from local sites of inflammation to the liver and change the program of protein synthesis to produce the acute-phase response.

IL-1 NLRP3 IL-6

In clinical practice, the best-studied and most easily applied bio- marker of this inflammatory process is the downstream acute-phase reactant _____.

CRP

Based on JUPITER and other studies, current US guidelines consider hsCRP ≥___ mg/L as a risk-enhancing factor that could be used in global risk evaluation, in particular when statin decision making is otherwise uncertain (borderline- or intermediate-risk individuals), while hsCRP levels of less than 1 mg/L are lower risk

≥2 mg/L: Risk-enhancing <1 mg/L: Low risk

Values of hsCRP in excess of ___ mg/L may represent an acute-phase response caused by an underlying inflammatory disease or intercurrent infection and should lead to repeat testing in approximately 2 to 3 weeks

>8 mg/L

Autopsy data support this hypothesis: elevated hsCRP levels are more common in patients with _____ plaques than in those with erosive disease or those who died of nonvascular causes.

Frankly ruptured

In **primary prevention**, _____ are the first-line interventions for those with **elevated hsCRP**, as with elevated LDL cholesterol or other risk factors.

Diet Exercise Smoking cessation

The large-scale multinational _____ trial demonstrated that statin therapy, previously shown to lower hsCRP levels independent of LDL cholesterol lowering, markedly reduces vascular event rates among apparently healthy men and women with hsCRP ≥2 mg/L and LDL cho- lesterol less than 130 mg/dL Population: healthy persons with levels of low-density lipoprotein (LDL) that do not mandate statin treatment, as per current guidelines (<130 mg/dl), but with levels of high-sensitivity C-reactive protein (hs-CRP) ≥2 mg/L, would benefit from taking rosuvastatin Placebo vs Rosuvastatin 20mg

JUPITER Trial (Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin)

In this trial, random allocation to rosuvastatin 20 mg daily as compared to placebo resulted in a 44% lower risk of the trial primary endpoint of all vascular events, a 54% reduction in myocardial infarction, a 48% reduction in stroke, a 46% reduction in need for arterial revascularization, and a 20% reduction in all-cause mortality.

JUPITER Trial (Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin)

JUPITER influenced clinical guidelines and resulted in much wider use of statin therapy. However, by using a statin—an LDL-lowering drug with concomitant anti-inflammatory effects—JUPITER was not a formal test of the inflammation hypothesis of atherothrombosis That evidence arose from the____ trial which provided direct proof-of-principle that inflammation inhibition in the absence of lipid lowering can significantly reduce cardiovascular event rates.

Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS)

Patients with MI and elevated hsCRP were randomized to canakinumab 50 mg (n = 2,170) vs. canakinumab 150 mg (n = 2,284) vs. canakinumab 300 mg (n = 2,263) vs. placebo (n = 3,344). Evaluated canakinumab compared with placebo among patients with a history of myocardial infarction (MI) and elevated high-sensitivity C-reactive protein (hsCRP). Canakinumab is a monoclonal antibody targeting interleukin-1β. This study showed that among 10,061 stable atherosclerosis patients with residual inflammatory risk who were already on statin therapy, those allocated to higher doses of canakinumab—a monoclonal antibody that binds IL-1β—experienced a 15% reduction in major adverse cardiovascular events when compared to a placebo.

CANTOS Trial (Canakinumab Anti-Inflammatory Thrombosis Outcomes Study) Among patients with a history of MI and elevated hsCRP, canakinumab was effective at preventing adverse cardiac events over a median of 3.7 years. The only dose that achieved significance after multiplicity-adjusted threshold for statistical significance was the 150 mg group. Canakinumab was not associated with a reduction in incident diabetes. Canakinumab was effective at reducing hsCRP in a dose-response relationship. Canakinumab was effective among those with chronic kidney disease, especially those who achieved the greatest reduction in hsCRP. Residual inflammatory risk is a significant determinant of recurrent cardiovascular risk. Canakinumab was associated with an increased risk of fatal infection or sepsis despite exclusion of patients with chronic or recurrent infection.

In contrast ,the _____ of 4786 stable atherosclerosis patients with diabetes or metabolic syndrome reported that low-dose methotrexate did not reduce major adverse cardiovascular events.

Cardiovascular Inflammation Reduction Trial (CIRT)

In _____ trial, treatment with colchicine 0.5 mg daily as compared to placebo over a 2-year period among 4745 **post-myocardial infarction** patients resulted in a 23% relative reduction in the primary trial endpoint inclusive of myocardial infarction, stroke, resuscitated cardiac arrest, urgent hospitalization for angina leading to revascularization, and cardiovascular death. While the benefit of colchicine was significant only for the coronary revascularization and stroke components of this primary endpoint, all cardiovascular outcomes were directionally consistent, providing reassurance

COLCOT Trial (Colchicine Cardiovascular Outcomes Trial)

In _____, colchicine 0.5 mg as compared to placebo among 5522 patients with **stable coronary disease** resulted in a similar 28% relative reduction in major recurrent adverse cardiovascular events. Rates of coronary revascularization and coronary death were also reduced although no reduction in all-cause mortality was observed

LoDoCo2 trial (Low-Dose Colchicine vs. Placebo in Patients With Chronic Coronary Disease)

In cardiovascular practice, three times as many patients have “residual inflammatory risk” defined as a post-statin LDL cholesterol less than __ mg/dL but an hsCRP greater than __mg/L than have “residual cholesterol risk” defined as a post-statin LDL cholesterol greater than __ mg/dL and an hsCRP less than __mg/L.

Residual Inflammatory risk Post-statin LDL: <70 mg/dL hsCRP: >2 mg/L Residual Cholesterol risk Post-statin LDL hsCRP

The two recently added risk-enhancing factors specific for women, specifically _____, increase cardiovascular risk to a similar extent as standard risk factors.

Premature menopause (<40 years old) Preeclampsia (elevated blood pressure and proteinuria after 20 weeks of gestation)

Because of its risks, many professional organizations have recommended against (class III) the use of ____ therapy at any age to prevent coronary heart disease and other chronic diseases.

Hormone therapy Women’s Health Initiative (WHI) trial provided clear evidence that postmenopausal hormone therapy did not prevent coronary disease in women who started treatment distant from menopause onset (>10 years).

The AHA’s Life’s Simple 7 includes healthy diet as one of the simple 7 cardiovascular health metrics, with an ideal diet defined as 4 to 5 components (and poor diet one or less) of the following five diet elements:

(1) >/= 4.5 cups of fruits and vegetables/day (2) 2 or more 3.5-oz servings of fish/week (3) 3 servings per day of whole grains (4) < 1500 mg of sodium per day (5) 36 ounces or less of SSB/week

The _____ was a secondary prevention trial in central, non-Mediterranean France comparing a **low-fat diet with a Mediterranean diet** which included a **margarine high in alpha-linolenic-acid**. There were significantly **fewer primary cardiovascular events in the Mediterranean diet group** (8/302) compared with the control group (33/303).

Lyon Heart Study

More recently, the _____ study was a large-scale primary prevention parallel-group randomized trial conducted in 7447 Spanish men and women at high cardiovascular risk recruited based on cardiovascular risk factors.The study was originally published in 2013, but because of some trial irregularities in the randomization procedures, the study was retracted and republished in 2018. Over a follow-up period of 4.8 years, this trial found that a Mediterranean dietary intervention supplemented either with nuts or extra virgin olive oil compared with a low-fat dietary pattern significantly reduced the primary endpoint of major cardiovascular events by 30% and favorable reduction in other outcomes.

Prevención con Dieta Mediterránea (PREDIMED) study ---------- Mediterranean dietary intervention supplemented either with nuts or extra virgin olive oil compared with a low-fat dietary pattern **significantly reduced the primary endpoint of major cardiovascular events by 30%** and favorable reduction in other outcomes.

Though cultural norms vary widely, mild to moderate alcohol consumption is typically defined as roughly one drink-equivalent per day using as a reference a _____ for an approximate 12 to 14 g of alcohol per beverage.

12-ounce regular beer (5% alcohol) 5 fluid ounces of wine (12% alcohol) 1.5 fluid ounce of 80-proof distilled spirit (40% alcohol)

**Habitual heavy** alcohol consumption, defined as __ or more drinks per week for women, __ or more drinks per week for men, or binge drinking for either gender, is a major cause of preventable death

8 or more/wk in women 15 or more/wk in men Because of the health hazards of alcohol associated with higher intake, moderate alcohol use does not offer a population-based strategy to reduce cardiovascular risk, even for myocardial infarction where epidemiologic data remain consistent

Among older women (mean age 72 years), as few as ____steps/day was associated with 40% risk reduction in mortality compared with 2700 steps/day, with greater benefit for more steps taken per day until approximately 7500 steps/day.

4400 steps/day

The authors estimated that for every 1 hour of sitting time, there was _____% increased risk of mortality that was independent of activity levels, and that television viewing (which was worse than sitting) accounted for approximately 5% of cardiovascular mortality, 8% of all-cause mortality, and 29% of type 2 diabetes, suggesting an important burden of deaths that could be avoided with decreasing television viewing.

1 hour sitting time = 1-2% increased mortality risk

Such tools could provide personalized estimates for the potential for absolute risk reduction (number needed to treat, NNT) with a medication or intervention weighed against the potential for adverse events (num- ber needed to harm,NNH),with net clinical benefit calculated as _____.

NNT minus NNH

The 2019 ACC/AHA prevention guidelines gave a class _____ for **shared decision-making** in **cardiovascular disease prevention** based on data supporting that patient input and collaboration with clinicians decreases potential barriers to treatments.

I (LOE B-R [moderate quality evidence])

Statins inhibit cholesterol synthesis by inhibiting the enzyme hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase and preventing the formation of _____, the rate-limiting step of sterol synthesis

Mevalonate

Statins lower LDL cholesterol in a non-linear dose-response manner. Statins vary in intensity from high-intensity (average lowering of LDL cholesterol by ____%) to moderate-intensity (_____%) and low-intensity (____%)

High intensity: ≥50% Moderate intensity: 30% -49% Low intensity: <30%

Statins do not reduce _____.

Lp(a)

The **major side effects of statins** are muscle symptoms (statin-associated muscle symptoms [SAMS]) ranging from **diffuse myalgias (normal creatine kinase without functional loss)**, seen in up to _____% of statin users, to **myositis, defined as diffuse muscle pain with evidence of muscle inflammation and elevated creatine kinase levels**, which necessitate discontinuation of use of the drug in _____% of patients. ____, statin use is associated with rhabdomyolysis, which is often associated with predisposing factors (advanced age, frailty, renal failure, shock, concomitant use of antifungal agents, antibiotics, the fibric acid derivative gemfibrozil, and hypothyroidism).

Diffuse myalgias: 10-15% * Normal CK, no functional loss Myositis: <1% * Elevated CK, (+) Muscle pain Rhabdomyolysis: Rarely

In the _____ meta-analysis of 27 randomized statin trials (N = 174,149 individuals, 27% women), every 1 mmol/L (39 mg/dL) in LDL cholesterol with statin versus placebo (22 trials) or more versus less intensive statin (5 trials) was associated with 21% reduction in major vascular events over median follow-up of 4.9 years, with significant risk reductions in all-cause mortality (10%) driven by reduction in vascular mortality (12%),major coronary events (23%), coronary revascularization (24%), and stroke (15%), with no effect on incident cancer or cancer mortality.

Cholesterol Treatment Trialists Each 1mmol/L = 21% RR in MVE

Before initiation of statin therapy, either a fasting or nonfasting lipid panel should be obtained along with baseline _____.

ALT, Creatine kinase

After initiation of statin therapy, the response should be checked with a repeat lipid panel (fasting or nonfasting) within the first ____ months to determine the patient’s adherence and response

1-3 months

European guidelines suggest that although LDL cholesterol is the primary target of lipid-lowering therapy, _____ are secondary treatment targets, in particular for patients who also have cardiometabolic risk factors (e.g., triglycerides >175 mg/dL, obesity, metabolic syndrome, or diabetes) or low LDL cholesterol.

Non-HDL cholesterol or apoB

Low-dose aspirin provides proven clinical benefit in the _____ prevention of cardiovascular disease.

Secondary

In 2018, three contemporary primary prevention trials of aspirin were reported:

ASCEND (a trial of patients with diabetes) - statistically powered ARRIVE (a trial intended to evaluate high-risk patients without diabetes) ASPREE (a trial of older individuals).

This trial randomly allocated 15,480 patients with diabetes (estimated absolute 10-year risk of cardiovascular disease 10%, i.e., intermediate risk) to aspirin 100mg daily or matching placebo. During a mean follow-up of 7.4 years, aspirin was associated with a 12% reduction in cardiovascular events, yet at a cost of a 29% increase in major bleeds.In this trial, all-cause mortality was neutral.

ASCEND trial (A Study of Cardiovascular Events in Diabetes) 12% reduction in CVE 29% increase in major bleed Neutral all cause mortality

This trial was intended to investigate the role of 100 mg aspirin daily or placebo among **higher-risk primary prevention patients without diabetes**. During 5 years of follow-up among 12,456 participants, however, observed risk estimates were substantially lower than predicted and the trial was underpowered.Thus, this trial should be interpreted as a trial of **borderline to intermediate risk primary prevention** (estimated 10-year risk of cardiovascular disease 7%). In this context, aspirin conferred no vascular benefit but resulted in a significant twofold increase in gastrointestinal bleeding. In this trial, all-cause mortality was again neutral.

ARRIVE (Aspirin to Reduce Risk of Initial Vascular Events) *borderline to intermediate risk No vascular benefit 2-fold increase in GIB Neutral all cause mortality

This trial included 19,114 participants **70 years of age and older (estimated 10-year risk of cardiovascular disease 8%) who were free of cardiovascular disease**, dementia, or disability at trial entry and who were randomly allocated to 100 mg enteric coated aspirin or placebo for up to 5 years. In this trial, aspirin as compared to placebo conferred no benefit on the primary endpoint of survival without dementia or persistent physical disability.

ASPREE trial (Aspirin in Reducing Events in the Elderly) The ASPREE trial showed that aspirin did not prevent disability-free survival, but did increase major bleeding compared with placebo

Statins in primary prevention are associated with a __% reduction in cardiovascular events for every 1 mmol/L reduction in LDL cholesterol, without the bleeding complications associated with aspirin

1 mmol/L LDL decrease = 25% CV event risk reduction

In the _____ trial, a daily fixed-dose combination **polypill (simvastatin, ramipril, atenolol, and hydrochlorothiazide) plus low-dose aspirin (75 mg)** as compared to placebo among 5713 **intermediate risk** individuals (mostly Asian) resulted in a **31%** relative risk reduction in the primary cardiovascular endpoint, with **increases in dizziness and hypotension in the polypill arm.** Notably, the combination of the polypill (which included a statin) with aspirin was more effective than the polypill alone (31% vs.21% relative risk reductions)

International Polycap Study-3 (TIPS-3) trial 31% RR of CVE with PP + Asa 21% RR of CVR with PP

Major risk factors for gastrointestinal bleeding include:

* Male sex * History of UGIB * Older age (doubling with each decade, and particularly increased for age >70 years) * Hepatic or renal disease * Multiple cardiovascular risk factors * Use of other medicines (e.g., non-steroidal anti-inflammatory drugs, corticosteroids, antiplatelets, antithrombotics, and selective serotonin reuptake inhibitors)

With the exception of the _____ (for n-3 fatty acids) that was conducted in a general **primary prevention American** population at usual risk, the rest of the trials were conducted in patients from secondary prevention or at high cardiovascular risk.

VITamin D and OmegA-3 TriaL (VITAL)

For example, a 2018 meta-analysis from the _____ examined aggregate study-level data from 10 randomized trials (EPA dose ranged from 226 to 1800 mg/day; 9 trials tested combined EPA+DHA) conducted in high-risk populations (n = 77,917 individuals; 12,001 cardiovascular events) and found no significant reduction in major cardiovascular or coronary events, with a trend toward 7% relative risk reduction in coronary deaths

Omega-3 Treatment Trialists’ Collaboration

The _____ trial is the only primary prevention trial of n-3 fatty acid supplementation in a general usual-risk population selected only on age and not selected on high cardiovascular risk.

VITAL Trial

This trial was a randomized, double-blind, placebo-controlled trial of **marine n-3 fatty acids (1 g/day Omacor** fish-oil capsule with 840 mg of n-3 FAs, including EPA+DHA (1.3:1 ratio) versus placebo (olive oil), and in a 2×2 factorial design also tested vitamin D3 (2000 IU/day) versus placebo in the primary prevention of cardiovascular disease and cancer among 25,871 US men aged ≥ 50 and women ≥ 55 with no prior cardiovascular disease. Compared with placebo, n-3 fatty acids **did not significantly reduce** the primary endpoint of major cardiovascular events (a composite of myocardial infarction, stroke, and cardiovascular mortality; hazard ratio (HR)=0.92 [95% confidence interval 0.80 to 1.06]) but **significantly reduced myocardial infarction (a prespecified secondary endpoint) by 28% and total coronary heart disease events by 17%**.

VITAL Trial

In 2018, ______ trial reported results of supplementation with **1g/day fish oil capsule (840 mg EPA+DHA, same ratio and formulation as used in the VITAL trial)** versus placebo (olive oil), and in a 2×2 factorial design, which **also tested low dose aspirin** versus placebo in 15,480 UK patients with **diabetes** but without clinical evidence of cardiovascular disease. There was no n-3 treatment-related reduction in composite vascular events over a 7.4-year follow-up period. In this trial, there was a **significant reduction in vascular death (19%), driven by coronary death, with no reduction in stroke or stroke death.**

A Study of Cardiovascular Events in Diabetes (ASCEND)

Subsequently, in a higher-risk patient population than ASCEND, _____ trial examined a **high-risk patient population of statin-treated patients** (N = 8179;90% white),with elevated triglycerides (median baseline triglycerides 216 mg/dL, LDL cholesterol 75 mg/dL) and with either known cardiovascular disease (70.7% of the study population) or **high-risk patients with diabetes** and one or more additional cardiovascular risk factors. The trial tested a **high-dose purified synthetic EPA (icosapent ethyl, 4 g/day)** versus placebo (mineral oil). Over a 5-year follow-up, there was a **significant 26%** reduction in major cardiovascular events, including significant reductions of 31%, 28%,and 20% in total myocardial infarction, total stroke, and cardiovascular death, respectively. The n-3 intervention arm had more atrial fibrillation (5.3% vs. 3.9%) and a trend toward increased bleeding.

The Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial (REDUCE-IT) Trial Significant reductions: 26% MACE 31% MI 28% Stroke 20% CV death The n-3 intervention arm had more atrial fibrillation (5.3% vs. 3.9%) and a trend toward increased bleeding.

The _____ trial tested a different high-dose purified formulation of n-3 carboxylic acids (Epanova 4 g/day, EPA+DHA, ratio 2.75:1) versus placebo (corn oil). The trial was **stopped early in 2020 for futility to reduce major cardiovascular events** in 13,086 patients with hypertriglyceridemia and low HDL cholesterol on maximally tolerated statins and with established atherosclerotic disease or at high cardiovascular risk.

Statin Residual Risk Reduction With EpaNova in HiGh CV Risk PatienTs With Hypertriglyceridemia (STRENGTH)

However, in the _____ trial of intermediate risk individuals (mostly Asian), a fixed-dose combination polypill plus aspirin versus double placebo resulted in 31% relative risk reduction in cardiovascular events, with greater benefit seen when aspirin was added to the polypill versus polypill alone

TIPS-3

Formally, _____ medicine in cardiovascular settings has been described as an **integrative approach that considers an individual’s genetics, lifestyle, and exposures** as determinants of their overall cardiovascular health and disease phenotypes

Precision Medicine

Give class 1 recommendations in initiating statin therapy? 3 subgroups and target LDL reduction in % 1. 2. 3.

1. Patients from **secondary prevention** with **clinical ASCVD** (history of acute coronary syndrome, myocardial infarction, stable or unstable angina, coronary or arterial revascularization, stroke, transient ischemic attack, or peripheral arterial disease) should be treated with **maximally tolerated statin and nonstatin therapy** to achieve LDL cholesterol reduction of **50% or more** 2. Individuals from **primary prevention** with LDL cholesterol **greater than or equal to 190 mg/dL**, as this indicates **primary hypercholesterolemia** and should be treated with **high-intensity statin or the highest intensity** tolerated, aiming for LDL cholesterol reduction of **50% or more** which can be achieved with addition of non-statin medication 3. Patients from **primary prevention** with **diabetes, age 40 to 75 years old, and LDL cholesterol 70 to 189 with no clinical ASCVD**, should be treated with **moderate-intensity therapy**, or **high intensity if multiple ASCVD risk factors** present in addition to diabetes

Give diabetes specific risk enhancers that are independent of other risk factors

* Long duration of diabetes * Nephropathy (eGFR <60 mL/min/1.73 m 2 or albuminuria ≥ 30 μg albumin/mg creatinine) * Retinopathy * Neuropathy * ABI < 0.9

The _____________, a surrogate for centripetal or abdominal obesity, independently predicts cardiovascular risk in women and older men.

Waist-to-hip ratio

The AHA/ACC and ESC guidelines support screening ABI measurements particularly among individuals at increased risk of peripheral arterial disease Factors that increase risk of PAD:

* Age > 65 years old * Presence of other cardiovascular risk factors (e.g., diabetes, history of smoking, hyperlipidemia, hypertension) * Family history of PAD * Known atherosclerosis in another vascular bed (coronary or non-coronary)

The US federal government issued its first-ever physical activity guidelines in 2008 and updated them in 2018, asking adults to do at least _____________ (2.5 to 5 hours) per week of moderate-intensity aerobic physical activity (e.g., brisk walking), or ____________________ of vigorous aerobic activity (e.g., jogging), or a combination of activities of both intensities that expends an equivalent amount of energy, preferably spread throughout the week.

Moderate intensity - 150 to 300 minutes per week Vigorous aerobic - 75 to 150 minutes per week

The use of statins is associated with a small but significant dose-dependent increase in new-onset ____________ of approximately 1 per 1000 person years

Diabetes in particular among adults with other diabetes risk factors The overwhelming benefits of statins in subjects at high risk for or in the secondary prevention of cardiovascular disease exceeds the small risk for development of diabetes.

Based on the VITAL study results and previous studies, a reasonable approach would be to consider using n-3 fatty acid supplements among primary prevention adults with ________________ or among African Americans. For secondary prevention or high-risk primary prevention patients, high-dose EPA provides additional cardiovascular benefit among maximally statin-treated patients with high triglycerides and other risk factors.

Low fish consumption