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Cardiovascular Health Risk Assessment and Primary Prevention of Atherosclerotic Cardiovascular Disease

Melvyn Rubenfire Richard L. Weinberg Sina Jamé Elif A. Oral Kenneth A. Jamerson Robert Brook

DOI : https://doi.org/10.31546/2633-7916.1008

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Abstract
This review of cardiovascular health risk assessment and therapeutic approach to prevention of atherosclerotic cardiovascular disease (ASCVD) is intended to provide an experienced perspective for health care professionals, and not to replace judgement.  Reducing risk factors for ASCVD and related events by prevention affects the most important causes of death and disability in the modern world. Yet ideal cardiovascular health, which is also associated with less cancer, is rare despite the collective efforts of providers, non-profit organizations, governments, employers, the media, and insurance carriers. In fact, there is a worldwide increase in modifiable risk factors.

While optimizing lifestyle is the essential focus for primordial and primary prevention, available generic drugs for the evidence-based prevention treatments are cost effective. And the recent availability of reasonably well calibrated risk estimators (number actual versus number predicted CV events) and recent clinical trials that better inform promotes a more cost/benefit selection process.  Herein we review the literature to support the evidence-based rationale and approach to primary prevention of ASCVD from youth to the elderly, discuss the use of risk-estimators and utility of risk enhancers and coronary calcium scores, review guidelines for statin use, aspirin, metabolic syndrome/diabetes, hypertension, and summarize importance of lifestyle.

It’s essential a team-based care approach be the strategy to prevent ASCVD that can/should include the primary care physician, nurses, physician extenders, wellness coaches, nutrition and exercise specialists, community health and wellness centers, and referral to prevention specialists as indicated. 

Keywords: Primary prevention, Atherosclerotic heart disease, Risk estimate, Guidelines.

Introduction
Cardiovascular disease, in particular atherosclerotic cardiovascular diseases (ASCVD), and contributing risk factors, are the most important causes of death and disability in the developed and many underdeveloped countries in the world [1,2]. Of the nearly 57 million deaths worldwide in 2016, 27% were due to ischemic heart disease and stroke which have been the leading causes of death globally for many years [1].

The concept of ASCVD prevention has several  stages include primordial referring to preventing the development of cardiovascular risk factors (CRF) throughout life in individuals and populations by optimizing lifestyle; primary referring to identifying individuals with CRF with the intention of treating to prevent ASCVD and cardiovascular events (CVE); and secondary referring to strategies to reduce complications, recurrent CVE, and other ASCVD events [3].
That about 25% of the US population is at risk for ASCVD in the next 10 years underscores the importance and value of identifying those most at risk and implementing the very cost-effective proven strategies [4]. The rationale and key role for screening younger and middle-aged persons for primary prevention is well documented.About 50% of CV deaths occur in persons without previous symptoms, and 50% of persons, particularly those with premature ASCVD events, were not aware of or underestimated their risk [5].

Assessment of ASCVD risk
An estimate of the 10-year and lifetime risk of heart events and stroke is the foundation of primary prevention that for the individual, including young adults, needs a frank discussion with providers. The enlightened provider helps overcome the bravado of youth and provides each generation the understanding of the importance of a healthy lifestyle, and that treatment of risk factors can prevent premature disability and deaths from heart and vascular diseases, cancer, and all-cause mortality [6].

Experts throughout the globe have developed guidelines for lifestyle, statins, aspirin, and treatment of hypertension which have been shown to reduce ASCVD events in population observational and placebo-controlled trials [7, 8]. Historically, publicity and marketing by pharmaceutical industry using trial results encouraged physicians to prescribe expensive medication with little to no long-term evidence of value, and an inability to decide who would benefit. While there was evidence of relative risk reduction of events from aspirin, statins, and anti-hypertensive treatments, the number needed to treat (NNT) or harm (NNH) to prevent an event and cost/benefit was not known, particularly for sub-groups. More recently, US, European, and World Health Organization experts developed guidelines and encouraged use of electronic and paper chart risk estimators utilizing population observational studies, and clinical trial outcomes with the goal of matching need and intensity of preventive therapies to absolute risk (generally 10 yr and lifetime) for ASCVD events [8,9]. The free and easily accessible online tools for estimating cardiovascular outcomes provides the opportunity to select the risk estimator that fits the patient by variables that include age, sex, ethnicity, country, socioeconomic status, and high versus low risk. The most recent ACC/AHA US iteration, http://tools.acc.org/ascvd-risk-estimator-plus [9], provides an estimate of 10 yr or lifetime risk of ASCVD (including fatal and non-fatal), defined as acute coronary syndromes, myocardial infarction, stable or unstable angina, arterial revascularization, stroke/transient ischemic attack, peripheral arterial disease, and includes expected risk reduction based upon clinical trials of statins, anti-hypertension drugs, and aspirin [10]. It is both useful for the clinician to assess risk and inform the patient on the value of treatments that include estimate of risk reduction. The European Heart Score (SCORE, http://www.heartscore.org was developed to estimate the 10 yr cumulative risk of a fatal ASCVD event in persons up to 65 yrs [11]. Total CVD event risk is about 3x higher than risk for fatal CVD events.

Deciding treatment options and indications for prevention of ASCVD
There is a highly significant difference in guideline recommendations between US and low risk European countries. In Europe, a 65yr old man with BP 140mmHg, total cholesterol 220mg/dL, and HDL-C 42 has a 5% 10yr risk of a CV death using Q-RISK3.
As 5% is defined as low risk in the guideline, recommendation is limited to diet and exercise. The same patient in the U.S. has a 17% 10yr risk of an ASCVD event using ACC/AHA ASCVD risk+ (intermediate risk), and is recommended a statin, anti-hypertensive drug to lower the sBP to <130mmHg and low dose aspirin which together lowers the 10yr risk of ASCVD events to 8.8%.  Of course, the recommendation for aspirin in patients at moderate risk of CVD was not supported in the most recent trial [12]. Amongst the limitations of the risk estimator/treatment guideline tools is the difficulty of updating evidence-based treatments.

The US ACC/AHA guideline estimates 10yr ASCVD risk (AR10) for asymptomatic adults 40-79yrs. Categories are low <5%, borderline 5-7.4%, intermediate >7.5% to <20%, and high risk >20% [10]. The accuracy of the estimated risk applies to persons with the risk factors assessed but limited in those whose risk may be higher or lower depending on many unmeasured variables such as lifelong lifestyle, education, race/ethnicity, social determinants, metabolic risk factors, and renal function.  The US guidelines suggest using risk-enhancers to decide initiation or intensification of statin therapy in patients who are borderline or intermediate risk (Figure 1) [10].  While important to supplement judgement the risk estimators are far from perfect.  However, when the risk calculator is utilized and shared with the patients, more guideline adherence is observed [13]. Guidelines with risk estimates provide dosing of statins and under dosing statins has significant consequences. In a prospective study of primary care patients without ASCVD, using a guideline of >40% reduction in LDL-C from baseline as optimal, over half had a sub-optimal response [14].  Compared to optimal responders, subsequent incident CVD for sub-optimal responders was 22% higher (adjusted for baseline untreated LDL-C).

2018 US cholesterol guidelines incorporate other risk factors and markers, enhanced estimates, and ‘the lower is better hypothesis’
The 2018 ACC/AHA cholesterol guideline emphasizes reducing risk of ASCVD through lipid management for persons at risk and with established ASCVD [10]. It emphasizes a more intensive personalized approach based upon recent controlled studies:  in high-risk patients the lower the LDL-C, regardless of treatment type, the better the outcome. It includes a novel risk-estimator for primary prevention that can be used for decisions regarding statins, hypertension and aspirin use and incorporates personalized treatment options (to be discussed).

Table 1 is a modified version of the key perspectives from the 2018 ACC/AHA guideline [10] focusing on primary prevention with suggestions added in italics.

Cost-effectiveness of Statins
There is evidence for cost-saving by statins in CHD which improves with intensifying dosing as well as adding additional lipid lowering drugs such as ezetimibe [20,21].  Statin therapy for primary prevention of ASCVD using the ACC/AHA cholesterol guidelines with 10yr threshold of 7.5% (AR10), the threshold for intermediate risk, has been shown to be cost effective [22], but initial calculations have not considered those with higher LDL-C have greater absolute reduction in events from statins and may be cost-saving.  A recent simulation study assessed the cost-effectiveness of expanding statin treatment eligibility in men and women age 40 years at baseline from standard threshold of 7.5% to AR10 5.0% to 7.4% (definition of borderline risk) [23]. Treating with a statin for individuals with borderline AR10 and LDL-C levels of 160 to 189 mg/dL would be cost-saving; treating borderline AR10 and LDL-C levels of 130 to 159 mg/dL would also be cost-saving; and treating all individuals with AR10 of at least 5.0% would be highly cost-effective ($33,558/QALY) and of course prevent the most ASCVD events. Cost-effectiveness increases with LDL-C level and AR10 [23]. In view of the low cost and no to minimal evidence of longterm harm, consideration should be given to statin therapy for the borderline risk group of 5% to 7.4% AR10 with LDL-C >129mg/dL, and possibly lower LDL-C particularly in the presence of risk enhancers (Figure 1).

Statins for the Elderly
Treatment strategies for those over 60yrs (statin, aspirin, BP) are less clear because of the limited number of elderly in population and RCT’s from which to derive risk estimate [24].  The decision algorithm regarding statins should not change in the elderly who have a life expectancy of at least 5 years. In a recent meta-analysis of randomized placebo-controlled statin trials, there was a 21% proportional reduction in major CVE per ~40mg/dL reduction in LDL-C, which decreased insignificantly with age, but was significant in all age groups [25] Statins and more intensive statins are associated with 25% reduction in proportional risk of coronary revascularization and a 16% reduction in risk of stroke which does not differ across age groups. The benefit of statins is similar for both men and women and persons over 75 yrs [26,27]. Further, at an average of 2.4yrs of follow-up of elderly on statins, the 14% who discontinued statins for at least 3mo had 33% more CV events (46% coronary and 26% cerebrovascular) [27]. 

Statins are safe in the elderly and have no effect at any age on non-vascular mortality, cancer death, or cancer incidence. Given the aging population and lack of evidence from randomized controlled trials in people >75 years, physicians and their patients must use shared decision-making on when to use statins for primary prevention. Particularly considering that simply by the age of 70yrs, women have an 8% 10-year risk for ASCVD events.  Absence of informed data should not be confused with lack of effect given the high absolute risk and very low cost of statins that reduce stroke risk.

Statins in younger persons
The 2018 AHA/ACC cholesterol guidelines for men and women 20-39 years emphasize a healthy lifestyle for all, as well as estimating the life-time risk which can be done with the ASCVD Risk Estimator Plus [9] or for 30 years and above with the QRISK-lifetime cardiovascular risk calculator [28]. QRISK lifetime was developed in the UK primary care population and reasonably approximates the US. Low risk for survival to age 95 years is 5% and high risk is over 39%. Statins should be considered for those 20-39 years if there is a family history of premature ASCVD and LDL-C >160mg/dL; a high lifetime risk estimate; diabetes or elevated Lp(a) with another major risk factor; or a CAC score >0 [10].

Enhancing ASCVD Risk Estimates with Quantitative Tools
After using the tools for ASCVD risk estimate, clinical judgment should be based on individual patient’s preferences, and presence of other risk enhancers. Adding these variables and selective use of coronary artery calcium scoring (CAC score) can help to overcome most issues of mis-calibration for each of the many risk prediction equations [29]. The use of CAC scoring by chest computed tomography has increased with the increase in evidence of value and decreasing fees. It can be obtained without a physician order in some states in the US, is generally not covered by insurance, and fee can range from $75 to $250. Scoring techniques are well standardized and provide a reproducible means of assessing risk of major cardiovascular outcomes. CAC testing in asymptomatic populations is cost-effective through a broad range of baseline risk [30]. Further, the CAC score identifies persons most likely to benefit from statins. The number needed to treat to prevent one MACE outcome over 10 years ranges from 100 for CAC 1-100 to 12 with CAC >100 [31].     

The Multi-Ethnic Study of Atherosclerosis (MESA) study confirmed that coronary calcium scoring by computed tomography can predict CHD events independent of classic risk factors and novel risk markers [32,33]. Despite the complexity of atherosclerotic plaque that results in CHD events , the predictive value of increasing CAC provides an estimate of both hard and soft non-calcified so called ‘vulnerable plaque’[34-36]. A CAC score >100 has a 7-fold increase in CHD event rate compared to CAC =0 [36].
The value of high CAC for predicting major cardiovascular events (MACE) and the value of statins has been well established, but the ‘Power of CAC=0’ is equally, and to some extent, more valuable [36]. There is a clear difference between risk with a CAC = 0 and CAC range 1-10, particularly in young persons. The 2018 guideline on cholesterol management suggests a CAC scan is indicated when the decision for statin therapy is uncertain. This may include patients who appear to be at intermediate or higher risk but remain skeptical; those at low risk (<5%) based upon age but with a family history of premature CHD; an isolated CV risk factor such as low HDL-C, LDL-C >160mg/dL, or high Lp(a), and importantly those with statin intolerance [10].                            
A risk estimator using the MESA data was developed to incorporate the CAC score and was validated in 2 other cohorts [37]. The risk estimate combines the CAC score with standard risk factors and prevention treatment at the time of the CAC study. MESA Risk Estimate improves discrimination for CHD events including myocardial infarction, angina if followed by revascularization, resuscitated cardiac arrest, and CHD death, but does not include stroke.  However, in population studies with a relatively low stroke risk (0.3% per year) CAC score has a strong relationship with ischemic stroke independent of the LDL-C, (range CAC =0 0.1%/yr to CAC = 400 0.70%/yr [38]. Use of the MESA risk score and treatment alone, can influence patient decisions and enhance compliance with treatment.
https://mesanhlbi.org/MESACHDRisk/MesaRiskScore/RiskScore.aspx  

A summary of recommendations for interpretation of CAC score is as follows [10, 30, 36].
1. CAC = 0: Most often below threshold for statin benefit. Consider avoiding or postponing drug therapy with exception of diabetics, current heavy smokers, or a strong family history of premature ASCVD. Can be used to delay therapy in heterozygous familial hypercholesterolemia (HeFH), particularly in women of child baring age who are not using any birth control methods. If statins are held because of a CAC = 0, the CAC score should be repeated in 4-5 years.
2. CAC > 100 or >75th percentile for age/sex/race: Recommend statin therapy, intermediate or high intensity.
3. CAC 1-99 and <75th percentile score for age/sex/race: Subclinical atherosclerosis is present; use MESA risk-estimate with CAC score as a continuous variable. Use a statin if estimate is 7.5% or greater and consider statin with score 5%-7.4% if there are risk enhancers.
4. Consider statins for men and women with a CAC > 0, particularly if 20-39 years old.  Repeat discussion with patient if there is new information. If statin is postponed based upon CAC, consider repeating CAC score in 4-5 years.

Aspirin for primary prevention
The results of 3 recent pivotal trials did not support low dose aspirin even for what would intuitively be high risk patients, including the healthy elderly [39], those at moderate risk for CVD [12], and diabetics [40]. A subsequent systematic review and meta-analysis of RCT’s included the three recent trials [41].  A total of 13 trials had 164,225 participants with >1 million participant-years of follow-up; average age 62yrs (range 53-74), 47% men, 19% had diabetes, and the median baseline 10yr risk of the primary CV outcome was 9.2% (ranges 2.6% - 15.9%).

It was concluded that aspirin in persons without CVD was associated with a lower risk of CVE but with an increased risk of major bleeding. The absolute risk reduction was 0.38% (NNT 265) and absolute increase in major bleeding (mostly gastrointestinal) of 0.47% (NNH 210) [42]. However, taking the data in its totality, low dose aspirin could be considered in specific cohorts with low risk for GI bleeding and intracranial hemorrhage (<70yrs for each) who are on statins with good BP control and at least a 10% AR10 for CV events based upon the ACC/AHA risk estimate, active smokers, and possibly lipoprotein (a) >50mg/dL [12,41,42].

Lifestyle intervention
The value of physician provided advice for a healthy lifestyle, even in persons who do not appear at risk, should not be underestimated. That physicians impact patient behavior is the rationale for the US Preventive Service Task Force  recommending patient education as part of routine care [43]. The most common and readily detectable risk factors amenable to primary prevention for ASCVD as well as all-cause and cancer mortality in young and middle-aged persons occur in clusters and are each interactive with lifestyle [2].

These factors include smoking; hypertension; obesity; physical inactivity; high risk lipids; pre-diabetes, diabetes, and the metabolic syndrome; psychological distress and depression, and poor oral health [44-51]. The benefit of exercise, exercise intensity, and aerobic cardiorespiratory fitness on long-term mortality is particularly impressive in those over 70yrs and with hypertension [52]. The amount of time older women spent doing light physical activity (similar to leisurely walking) is independently associated with a lower likelihood of CVE.
Each additional hour-per-day increment in light physical activity is associated with a 10% lower risk of CVE. The incremental risk for reduced fitness is comparable to or greater than the presence of CHD, diabetes, and smoking and provides further support for achieving aerobic fitness as a modifiable risk factor for long-term mortality [52].
Amongst the reasons for the very high risk of ASCVD in poor countries and poor cities and rural areas in all countries is related to lack of health care providers, appropriate medication/education, healthy foods, and smoking. The recent HOPE-4 study demonstrated that a low-cost community-based identification and treatment of hypertension and other CV risk factors can be very effective in populations with little knowledge and low socioeconomic status [53]. There are no reasons why similar programs could not be implemented in urban and rural communities in need in the US and other developed and underdeveloped countries.

Approach to hypertension
Hypertension (HTN) is the most important treatable risk factor responsible for the sum of major CVE including acute coronary syndromes, heart failure, atrial fibrillation, strokes, and CV deaths [54]. The overall prevalence of HTN defined as sBP/dBP >130/80 mmHg in the US is 46% and for men and women 65-74yrs it is about 75%. The 2017 ACC/AHA Guideline for defining, testing, and treating HTN is summarized in Table-2 [55].  

It stresses the importance of out of office measures as home and 24-hour ambulatory values better predict CVE and facilitate screening for white coat (high BP in office and normal at home) and masked hypertension (normal BP in the office and elevated BP at home). Emphasis is on life-style modification with the DASH-Mediterranean diet, exercise, weight control, and the importance of screening for and managing other CVD risk factors.   Use of BP lowering medication is recommended for primary prevention in adults with an estimated AR10 =10% and sBP =130 mm Hg or dBP =80 mm Hg (http://tools.acc.org/ascvd-risk-estimator-plus/#!/calculate/estimate/). Use of BP-lowering medication is also recommended in adults with an estimated AR10 <10% and sBP =140 mm Hg or a dBP =90 mm Hg. The recommended goal for BP is <130/80 mmHg for primary prevention, diabetes, chronic kidney disease, and ASCVD. 

Obesity, metabolic syndrome, and type 2 diabetes mellitus (T2DM)
Obesity is defined by body mass index (BMI) > 30 kg/m2 in U.S. Caucasians and African Americans, and > 25kg/m2 in Asians, Middle Eastern, and Mediterranean cohorts.  It tends to reflect family lifestyle and genetics and independently increases risk for dyslipidemia, impaired fasting blood glucose or pre-diabetes (FBG 100-125mg/dL, A1c 5.7-6.4%), type 2 diabetes mellitus (T2DM, A1c > 6.5%), and hypertension [55]. The metabolic syndrome, which is associated with a fasting serum insulin disproportionate to the FBG (insulin resistance) has an -
approximate 2-fold lifetime risk of diabetes and ASCVD. Risk factors associated with insulin resistance include dyslipidemia with increased triglycerides and decreased HDL-C, small atherogenic LDL particles and increased atherogenic VLDL remnant particles, hypertension, hyperglycemia, reduced fibrinolysis, increased inflammation, and endothelial dysfunction. It is inherited, increases with age, obesity, and sedentary lifestyle, results from polycystic ovary syndrome, and often causes or may be precipitated by non-alcoholic fatty liver disease. [56]. 

The definition of the metabolic syndrome in the U.S. includes 3 of the following 5 criteria: BP >130/85mmHg or on anti-hypertensive medication, impaired fasting glucose, diabetes or use of hypoglycemic drugs, triglycerides (trig) >150mg/dL or on trig lowering drugs, HDL-C in men <40mg/dL and in women <50mg/dL, and abdominal obesity defined as > 40” in men and >35” in women. Normal weight or mildly overweight metabolic syndrome is not uncommon and important to consider for prevention of T2DM and ASCVD. In contrast, metabolically healthy obesity and the obesity paradox of improved survival from major cardiovascular events have been well described [57].

Recommendations for obesity, metabolic syndrome, and diabetes without ASCVD as modified from guidelines are reviewed in Table-3 [55,56,57]. Treatments delay the onset of diabetes and microvascular complications. Most importantly, moderate weight loss (>5%) in the year following the diagnosis of T2DM is associated with improvement in risk factors and a 48% lower hazard of CVD at 10 years [57]. While there is documented  benefit of physician referral to multidisciplinary diet and exercise programs designed to improve the components of the metabolic syndrome, there is no evidence for persistence of benefit or a legacy effect [58].

The choice of agents for diabetes varies considerably among experts and is highly dependent on insurance and cost. The introduction of the sodium-glucose co-transporter 2 (SGLT-2) inhibitors and glucagon-like protein 1 (GLP-1) receptor agonists has created a new paradigm for treating T2DM, particularly with ASCVD, CKD, CHF, hypertension, and obesity [56]. Clinical trials in progress will inform their cost-effectiveness in diabetes at high risk for ASCVD. 
Another breakthrough in diabetes management was reported in REDUCE-IT, a randomized placebo-controlled trial of icosapent ethyl (Vascepa™ a synthetic eicosapentaenoic acid) [59].   Participants with ASCVD or diabetes with at least 1 risk factor and fasting triglycerides 135mg to 500mg/dL (mean 216mg/dL) on an appropriate dose of a statin (on trial baseline LDL-C 75mg/dL) were randomized to 2 grams twice daily of icosapent ethyl or matching placebo. Nearly 30% enrolled on the basis of primary prevention in diabetes. There was a 25% reduction in the primary endpoint of combination of cardiovascular deaths, non-fatal MI, non-fatal stroke, coronary vascularization or unstable angina. The benefit did not correlate with baseline triglycerides or reduction of triglycerides suggesting non-lipid benefits of icosapent ethyl.

Acknowledgements:  None

Authorship Statement
Principle author, conceptual design, responsible for writing and editing: (MR). Contributed manuscript materials and sections: (RLW, RB).  Preparation of figure and tables, manuscript review: (JS). Contribution of diabetes and obesity information: (EAO).  Contribution of hypertension information: (RB, KJ). Review and approval of final manuscript version: all authors.

Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Conflict of Interest
The authors have no conflicts of interest to declare. Kenneth Jamerson, MD is a paid consultant for Cunjupro Bio-Pharmaceutical and ReCor Pharma.

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