1.1

Assessment of ASCVD risk

In primary prevention, the American College of Cardiology (ACC)/American Heart Association (AHA) Pooled Cohort Equations risk estimator is used to estimate an individual’s 10-year risk for an atherosclerotic cardiovascular disease (ASCVD) event (Class of Recommendation (COR) I, Level of Evidence (LOE) B-NR). In addition to risk enhancing factors, which can be used when treatment decisions are uncertain, the 2018 AHA/ACC Multisociety Guideline recommends a coronary artery calcium (CAC) test to help further stratify risk and determine appropriateness for preventive therapies (COR IIA, LOE B-NR).

In 2020, the National Lipid Association released a scientific statement on CAC scoring to guide preventive strategies for ASCVD risk reduction . It concluded that CAC testing was optimally used in the primary prevention setting among those with a 10-year ASCVD risk <20%, diabetes mellitus (DM) or the metabolic syndrome, and/or severe hypercholesterolemia. In addition, it recommended intervals for repeat CAC testing in adults with CAC=0, which ranged from 5 to 7 years in low-risk adults (<5% 10-year risk) to as frequently as 3 years in high-risk adults (>20% 10-year risk or presence of DM) . Lastly, a CAC scan can still be used for risk prediction in patients on statin therapy and is useful for guiding the allocation of nonstatin therapy, aspirin, as well as antihypertensive therapy .

1.2

Antiplatelet/Anticoagulation

The role of aspirin therapy in primary prevention witnessed a complete paradigm shift over the last few years, culminating in the 2019 ACC/AHA CVD Prevention Guideline recommending consideration of its use among only very high-risk individuals (COR IIb, LOE A) . In 2020, the role of long-term aspirin in secondary prevention of ASCVD was also called into question despite a COR I, LOE A recommendation for its use in all patients with coronary artery disease unless contraindicated [ , ].

In certain situations, including immediately following an acute coronary syndrome (ACS) or percutaneous coronary intervention (PCI), the use of aspirin remains incontrovertible. However, despite a current recommendation from the European Guideline for the secondary prevention of chronic coronary syndrome, its lifelong use in all of these patients may not be necessary . This is particularly relevant to those individuals who are concomitantly taking a P2Y12 inhibitor or anticoagulation therapy.

Recent trials of early aspirin discontinuation following PCI or among secondary prevention patients on oral anticoagulation for indications such as atrial fibrillation (AF) provides no evidence for increased ischemic risk as long as a single antiplatelet agent is prescribed. In a secondary analysis from the AUGUSTUS trial, among patients with AF and recent ACS or PCI, the benefit from aspirin as part of dual antiplatelet therapy was lost after 30 days due to increased bleeding without reduction of ischemic events .

In a 2020 systematic review and meta-analysis, which sought to determine the safety and efficacy of discontinuing aspirin on a background of another antiplatelet agent following PCI, stopping aspirin 1 to 3 months post-PCI and continuing a P2Y12 inhibitor reduced the risk of bleeding without an increased risk of major adverse cardiovascular events (MACE) . With regards to specific anticoagulation regimens, apixaban was associated with fewer ischemic and bleeding events compared to warfarin, for up to 6 months after ACS or PCI.

In the 2020 ESC guideline for the management of patients with ACS, specifically non-ST elevation myocardial infarction (MI), post-treatment antiplatelet therapy and triple antithrombotic therapy were addressed . Recommendations included dual antiplatelet therapy in most cases for up to 12 months following PCI, with special considerations required for individuals based on ischemic and bleeding risk, the occurrence of adverse events, comorbidities, comedications and availability of medications.

For those individuals who require anticoagulation following PCI, triple antithrombotic therapy is recommended for up to 1 week (1 month when ischemic risk outweighs the bleeding risk) followed by a transition to a novel oral anticoagulant plus a single antiplatelet therapy, preferably clopidogrel. While future trials will help answer specifically which secondary prevention patients on optimal preventive treatments can forego long-term aspirin therapy, consideration should be given now to those individuals who are at greater risk for harm from concomitant aspirin therapy.

1.3

Anti-Inflammatory

Following the COLCOT trial, which demonstrated reduction of ischemic cardiovascular events with colchicine in patients following an acute MI, the Low Dose Colchicine 2 (LoDoCo2) trial evaluated the impact of colchicine in patients with stable coronary heart disease (CHD) . The study randomized 5522 patients with chronic CHD to daily colchicine (0.5 mg/day) or placebo. Following a median of 29 months, rates of the primary composite endpoint (cardiovascular death, spontaneous, nonprocedural MI, ischemic stroke, or ischemia-driven coronary revascularization) were significantly lower among those receiving colchicine vs. placebo (6.8% vs. 9.6%, hazard ratios (HR) 0.69, p <0.001). Furthermore, the benefits of colchicine occurred early and continued to increase with up to five years of treatment.

However, in LoDoCo2, colchicine therapy was also associated with an increased risk of non-cardiovascular death and higher rates of side effects, including myalgias and gastrointestinal intolerance, leading to medication discontinuation in 15% during the run-in phase. In addition, it is unclear if colchicine had a greater effect in patients with higher levels of systemic inflammation, as inflammatory markers were not reported. Future investigation will need to determine which individuals will receive a net clinical benefit from anti-inflammatory therapy, such as colchicine, for primary and secondary CVD prevention.

1.4

Body weight

With rates of overweight and obesity exceeding two-thirds of the adult population nationwide, strategies to achieve a healthy body weight are imperative (COR I, LOE B-R). Cardiovascular disease accounts for the majority of morbidity and mortality among the obese, with over two-thirds of deaths attributable to high body mass index (BMI) coming mainly from coronary artery disease (CAD). While there is a clear J-shaped association between obesity and all-cause and CVD mortality, higher BMI is also associated with increased risk of aortic valve stenosis, AF, ischemic stroke and abdominal aortic aneurysms [ , ].

Despite significant efforts to adhere to a heart healthy diet and achieve daily recommendations for physical activity, many obese individuals are unable to significantly lower their risk for CVD morbidity and mortality. Among adults with a BMI ≥40 with obesity-related comorbid conditions refractory to pharmacotherapy and behavioral treatments bariatric surgery can be considered . Based on long-term data from a UK nationwide nested cohort study, obese individuals who underwent bariatric surgery experienced a ~60% reduction in MACE (mainly MI) and new heart failure diagnosis compared to a matched control group .

1.5

Blood pressure

Optimal cardiovascular health, which is determined by control of multiple CVD health behaviors and factors, such as diet, BMI, smoking, physical activity, blood pressure, cholesterol, and glucose, is associated with a lower risk of incident hypertension . However, in the United States, many of these factors are poorly or sub-optimally controlled from an early age; this has prompted recommendations to shift and prioritize earlier risk assessment. In adults 40–75 years of age with an estimated 10-year ASCVD Risk <10% and ≥10%, treatment with blood pressure-lowering medications is recommended when blood pressure is ≥140/90 mmHg (COR I, LOE C-LD) and ≥130/80 mmHg (COR I, LOE A), respectively. Because the age of onset of hypertension correlates with subsequent risk for CVD and mortality, early control can help to reduce the risk of CVD development and progression and should be guided by the individuals ASCVD risk and other comorbidities including age, diabetes and chronic kidney disease .

In a recent multi-ethnic cohort study, there was a stepwise increase in the presence of coronary artery calcium and the risk of incident ASCVD with an increase in systolic blood pressure beyond 90 mm Hg . Previously, detecting hypertension, especially in young individuals, did not result in treatment because priority is given to lifestyle and behavioral modifications and many are hesitant to start lifelong medications at an early age. This is particularly evident in women, who may develop CVD later but have an earlier onset of hypertension . Now, with more data indicating the importance of early blood pressure control for preventing the development of atherosclerosis and progression to CVD, prevention strategies should start at an early age.

1.6

Cholesterol and other lipids

In 2018 and 2019, the American and European Cholesterol guidelines were published and provided recommendations for managing ASCVD risk via reduction in low-density lipoprotein cholesterol (LDL-C) [COR I, LOE A]. Prior to 2020, statin, ezetimibe and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor therapy were the primary treatments used to lower LDL-C and ASCVD risk.

An additional lipid lowering therapy that has recently gained traction for reducing ASCVD risk is icosapent ethyl. Building on the REDUCE-IT trial, data emerged on the significant effect of icosapent ethyl (4 g/day) on both first and total cardiovascular events among individuals at high risk for ASCVD (prior ASCVD or DM plus multiple risk factors) with well-controlled LDL-C but elevated triglycerides . Following this, many clinicians felt the armamentarium for managing residual ASCVD risk should now include icosapent ethyl in those with elevated triglycerides.

Later in 2020, the STRENGTH trial was completed, which sought to determine effects of omega-3 carboxylic acid (4 g/day) on cardiovascular outcomes among individuals on statin therapy with atherogenic dyslipidemia and high cardiovascular risk . Compared to the control group who received corn oil, omega-3 carboxylic acid did not result in a significant difference in a composite outcome of MACE. Consistent with REDUCE-IT, however, patients receiving omega-3 carboxylic acid more commonly experienced investigator-reported AF. Further studies are therefore required to help resolve the discrepancy between STRENGTH and REDUCE-IT. Some of the disparate findings may be due to the lower dose of EPA used, choice of the placebo comparator and/or to the addition of DHA to the high dose EPA in STRENGTH.

Additionally, the results of two other therapies to treat elevated LDL-C were published in 2020. In the first, investigators enrolled patients with ASCVD or an ASCVD risk equivalent from Orion-10 and Orion-11 and randomized them to inclisiran, which inhibits hepatic synthesis of PCSK9, or placebo . Patients who received inclisiran injections every 6 months had a ~50% reduction in LDL-C levels, with a favorable safety profile only notable for injection-site adverse events. Similarly, in individuals with heterozygous familial hypercholesterolemia, inclisiran resulted in significantly lower LDL-C levels compared to placebo (~48% reduction) without an increase in adverse events .

The second trial enrolled patients with homozygous familial hypercholesterolemia on stable lipid-lowering therapy to intravenous infusion of evinacumab (15 mg/kg of body weight), a monoclonal antibody against angiopoietin-like 3, every 4 weeks or placebo . At 24 weeks, evinacumab therapy resulted in a 49% reduction in LDL-C compared to placebo with an absolute difference between groups of 132 mg/dL.

In another placebo-controlled trial, patients with or without heterozygous familial hypercholesterolemia who had refractory hypercholesterolemia (LDL- C ≥ 70 mg/dL + atherosclerosis or LDL- C ≥ 100 mg/dL without atherosclerosis) were randomized to receive subcutaneous or intravenous evinacumab or placebo [ , ]. At 16 weeks, evinacumab resulted in significant reductions of LDL-C, including >50% at the maximum dose. Both therapies will require favorable results with regards to cardiovascular outcomes before considered broadly for LDL-C and ASCVD risk reduction.

While LDL-C remains the primary target for ASCVD risk, lipoprotein(a) [Lp(a)] is a heritable risk factor for the development of ASCVD and to date few therapies are available to reduce Lp(a) concentrations. In a randomized placebo-controlled trial, 286 patients with established ASCVD and screening Lp(a) levels ≥ 60 mg/dL (150 nmol/L) were randomized to hepatocyte directed antisense oligonucleotide AKCEA-APO(a)-L _Rx or placebo . Treatment with AKCEA-APO(a)-L _Rx resulted in dose-dependent decreases in Lp(a) levels, with mean decreases ranging from 35% at a dose of 20 mg every 4 weeks to 80% at 20 mg every week compared to 6% with placebo. The most common reported side effects included injection-site reactions. While the results are favorable, implementation into clinical practice will depend on additional large trials evaluating its impact on cardiovascular outcomes.

1.7

Cessation of smoking

While the rates of cigarette use have decreased significantly throughout the United States over the last two decades, the introduction of the electronic cigarettes (e-cigarette) has introduced new challenges especially among the younger generation. Originally advertised as a safe alternative and bridge to quitting, e-cigarette use results in significant exposure to toxic compounds including nicotine, propylene glycol and glycerin, and is associated with increased CVD morbidity and mortality .

Not only do e-cigarettes negatively affect the cardiovascular system by increasing arterial stiffness and the risk of developing hypertension and generating free radicals , but their use is also associated with various forms of pneumonitis, which are more commonly known as vaping-induced lung injury . Therefore, clinicians should advise patients to avoid e-cigarettes for any purpose and if they do use e-cigarettes direct them to cessation interventions immediately [COR I, LOE A] .

1.8

COVID-19 and cardiovascular disease

Since the beginning of 2020 in the United States, the rapid spread of the novel coronavirus disease 2019 (COVID-19) has resulted in a devastating pandemic causing upwards of ~25 million cases and ~400k deaths nationwide, and still counting. While it primarily affects the respiratory system, diverse cardiovascular manifestations are not uncommon, particularly in severe hospitalized cases [ , ]. In addition, individuals with pre-existing CVD or CVD-specific risk factors, such as obesity, are frequently more severely affected when infected with COVID-19 [ , ].

As a result, control of CVD risk factors and continuation of CVD-related medications, including renin-angiotensin-aldosterone-system inhibitors, blood thinners and anti-inflammatory therapy, could be beneficial in the management of COVID-19 and minimize infection-related complications . Moreover, patients with increased CVD risk should be encouraged and prioritized for vaccine administration as part of a stepwise approach to reduce COVID-19 associated morbidity and mortality .

1.9

Cardio-obstetrics

Cardiovascular disease is the primary cause of pregnancy related mortality in the United States . The field of Cardio-obstetrics is focused on the prevention, early detection and appropriate management of CVD in order to avoid cardiovascular-related complications during pregnancy . By promoting cardiovascular health and appropriately addressing cardiac conditions during pregnancy, including hypertensive disorders, cardiomyopathies, arrhythmias, thromboembolic disease, aortic disease and cerebrovascular diseases, cardio-obstetrics specialist can work to prevent adverse pregnancy outcomes and reduce the rates of maternal morbidity and mortality worldwide.

1.10

Cardio-oncology

Understanding the challenges for managing patients at risk for or with CVD and cancer remains a primary concern for both specialties as they are the number one and two leading causes of death worldwide, respectively. The emergence of Cardio-oncology as a sub-specialty in cardiology has filled a necessary void and has improved the treatment of those individuals who have survived cancer treatment but now face an increased risk of CVD mortality and CVD events such as heart failure, ACS and arrhythmias . Ultimately, if cardiovascular risk factor profiles are optimized through adherence to lifestyle, behavioral and pharmacologic interventions, both cardiovascular and cancer outcomes will improve.

1.11

Diabetes

In 2013, the ACC/AHA recommended treating all individuals with DM with statin therapy given the concomitant increase in CVD risk (COR I, LOE A) . In 2020, the European Society of Cardiology released a guideline on the management of DM/pre-DM and CVD risk . The document recommended classification of patients with DM into three levels of cardiovascular risk—very high, high or moderate risk. Based on the estimated risk and presence or absence of other CVD risk factors, treatment recommendations were provided to improve cardiovascular outcomes in patients with DM.

The backbones of CVD risk-reducing treatment for DM are sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1 RA) [COR IIb, LOE B-R]. In 2019, trials such as Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy (CREDENCE) , Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes (DECLARE-TIMI 58) , Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction (DAPA-HF) , Dulaglutide and Cardiovascular Outcomes in Type 2 Diabetes (REWIND) , and Cardiovascular Safety of Oral Semaglutide in Patients with Type 2 Diabetes (PIONEER-6) , demonstrated the marked effects of SGLT2 inhibitors and GLP-1 RA in reducing CVD outcomes in individuals with DM.

In 2020, additional data emerged for use of these therapies in patients with diabetes at risk for MACE. The first was the Evaluation of Ertugliflozin Efficacy and Safety Cardiovascular Outcomes (VERTIS) trial, which randomized patients with type 2 DM and ASCVD to ertugliflozin (5 mg or 15 mg daily) or placebo . Ertugliflozin was noninferior to placebo with regards to MACE (incidence rate 11.9% vs. 11.9%, hazard ratio (HR) 0.97; 95 confidence interval (CI) 0.85–1.11, p <0.001 for noninferiority).

In the Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure (EMPEROR-Reduced) trial, investigators randomized patients with Class II, III or IV heart failure and an ejection fraction ≤40% to empagliflozin (10 mg daily) or placebo (including recommended heart failure therapy) . Following a median of 16 months, compared to those receiving placebo, those receiving empagliflozin had a lower risk of cardiovascular death or hospitalization for heart failure independent of diabetic status (HR 0.75, 95% CI 0.65–0.86).

In a 2020 meta-analysis, researchers sought to determine the association of SGLT2 inhibitors with cardiovascular and kidney outcomes among patients with type 2 DM . Based on data from six trials (4 different SGLT2 inhibitors) totaling over 46,000 patients, SGLT2 inhibitors were associated with a reduced risk of MACE (HR 0.90, 95% CI 0.85–0.95). Of note, the reduction in risk of hospitalization for heart failure and chronic kidney disease progression was the most notable across the included trials.

Similarly, a meta-analysis based on seven cardiovascular outcome trials including over 56,000 patients sought to determine the efficacy and safety of GLP-1 RA in adults with type 2 DM . A 12% reduction in the three-point MACE endpoint was demonstrated when GLP-1 RA was used for treatment in individuals with type 2 DM (HR 0.88, 95% CI 0.80–0.96). Thus, SGLT2 inhibitors or GLP-1 RA should be prioritized in individuals with type 2 DM and known ASCVD to prevent complications associated with cardiovascular and kidney disease .

1.12

Diet

There are ongoing efforts to refine the heart healthy diet to promote ideal cardiovascular health (COR I, LOE B-R). In 2020, priority was also given to identifying why adherence to certain diets, specifically the Mediterranean diet, varies from individual to individual. Using PREDIMED and three United States cohorts, researchers identified 67 metabolites that correlated with the diet’s adherence . These metabolites also predicted future CVD risk independent of traditional risk factors. While preliminary, these findings suggest that one day clinicians may be able to individualize dietary recommendations based on the results of metabolomic profiling related to dietary response and adherence as well as disease risk.

Another dietary pattern generating significant interest across the world for its potential health benefits is intermittent fasting. Among 116 overweight and obese participants, a prospective randomized clinical trial was completed to determine the effect of 16:8 hour time-restricted eating (TRE) on weight loss and metabolic health . Time-restricted eating was associated with a modest and statistically insignificant decrease in weight (1.2% vs. 0.8%) without providing cardiometabolic benefits. In another feasibility study, 20 individuals (mean BMI 34.1) were randomized to TRE (8-hour window) versus non-TRE for 12 weeks. Compared to non-TRE individuals, the TRE group had a statistically significant decrease in weight (−3.7%), fat mass (−3.0%) and visceral fat (−11.1%) .

In addition to diet, the effect of alcohol intake on CVD risk remains unclear. Using Mendelian randomization, researchers sought to predict the effect of alcohol consumption on eight cardiovascular diseases . They found sufficient evidence for a causal relationship between higher alcohol consumption and increased risk of stroke and peripheral arterial disease.

Another randomized clinical trial evaluated the effect of excessive alcohol intake vs. abstinence on secondary prevention of AF in individuals with paroxysmal or persistent AF. Compared to individuals who continued drinking 10 or more drinks per week, those who abstained from alcohol had a longer period before recurrence (HR 0.55, 95% CI 0.36–0.84) and a significantly lower burden of AF during 6-month follow-up (% of time in AF: 0.5% vs. 1.2%, p = 0.01) .

1.13

Digital health & devices

The increasing adoption of mobile health technologies have the potential to expand the continuum of care for patients and improve cardiovascular related outcomes. Two specific areas in CVD prevention that are primed for mobile health integration are physical activity and weight loss. In a 2020 systematic review and meta-analysis, which studied the effect of text messaging interventions on physical activity, text message interventions resulted in higher objectively measured post-intervention physical activity compared to that in the control groups .

Similarly, a recent systematic review evaluated the effect of text messaging on behavior change interventions for weight management . According to this analysis, behavior change interventions using text messages resulted in significantly greater weight loss (−2.3 kg) and weight loss maintenance compared to placebo groups.

The COVID-19 pandemic also brought a new direction in CVD prevention and digital health patient engagement in 2020. One example was the approval of telehealth services for the provision of cardiac rehabilitation services as part of COVID-19 Public Health Emergency by the Centers for Medicare and Medicaid Services. This provided an important opportunity to promote secondary CVD prevention using technology enhanced home-based cardiac rehab programs .

1.14

Disparities

The COVID-19 pandemic and recent police killings in our nation, which disproportionately affect marginalized communities, have highlighted that simply acknowledging differences in risk based on individual racial and ethnic groups is not enough . Instead, there must be an acknowledgement that the poor health outcomes and disparities in CVD are in part due to the presence of structural racism.

To improve the path forward for these communities, the social determinants of health that have perpetuated these health disparities for generations need to be addressed (COR I, LOE B-NR). The AHA has taken a small, but significant step by starting to identify the social determinants of health that affect a specific subset of patients with heart failure to try and improve not only their outcomes, but also their quality of life .

1.15

Dream (sleep)

The evidence to support proper sleep hygiene as a means for achieving optimal cardiovascular health continues to accumulate. In fact, new data from the UK Biobank suggest that a healthy sleep pattern can reduce the risk of CAD and stroke by 34% . Alternatively, sleep disturbances can negatively impact CVD outcomes. Among almost 400k participants, ~10% of CVD events could be attributed to unhealthy sleep patterns and behaviors. One important example is the high prevalence of AF in individuals with sleep apnea . Among 188 individuals with AF, >80% were found to have sleep apnea using a home sleep apnea test.

1.16

Exercise

The benefits of physical activity cannot be overstated and adherence to guideline recommendations, which include at least 150 min of moderate intensity or 75 min of vigorous intensity exercise weekly, is required to optimize cardiovascular health (COR I, LOE B-R/NR). This extends to all ages as low levels of cardiorespiratory fitness and obesity in adolescence is associated with cardiovascular disease later in life .

Despite abundant evidence that guideline recommended physical activity and cardiorespiratory fitness levels are inversely related to cardiovascular morbidity and mortality, less is known about the effects of excessive endurance exercise on cardiovascular health. To address this uncertainty, the AHA released a scientific statement to help clinicians advise patients on the benefits and risks of this level of activity .

While they warn individuals unaccustomed to exercise about the risks of sudden cardiac death, MI, and cardiac remodeling, they conclude that the benefits associated with long-term exercise training outweigh the risks for the majority of the population. However, as a precaution, they recommend that inactive individuals should start slowly and increase the intensity as able.

In addition to its role in preventing the development of CVD, physical activity also plays a critical role in lowering the complications from various cardiovascular diseases. In patients with AF, physical activity and higher levels of cardiorespiratory fitness were associated with a lower long-term risk of CVD and all-cause mortality .

1.17

Factors of the environment

The social determinants of health, including differences in income and education, are known risk factors for CVD. In more than one million Danish employees, low education level was associated with a higher risk of incident CVD and CVD mortality . In the extreme cases, when the stress from these social determinants translates into psychological distress and depression, the detrimental effect on CVD risk is accentuated. A recent European Society of Cardiology work group concluded that depression is associated with a 30% increased risk for future CAD .

1.18

Genetics

Both biologic, genetically determined sex as well as gender significantly impact CVD risk. In 2020, we gained further insight into sex and gender differences for various cardiovascular conditions, including a higher incidence of heart failure with preserved ejection fraction, Takotsubo syndrome and myocardial infarction with nonobstructive coronary arteries (MINOCA) in women compared to men . To address an excess of adverse events with conditions like MINOCA, the ESC published new approaches for the diagnosis, risk stratification and management . In addition, presenting symptoms of cardiovascular events such as ACS differ between men and women and therefore personalized treatment protocols to account for these differences may be required .