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Introduction

Numerous studies have demonstrated a reduction in cardiovascular risk with the use of statins. As a result, statin therapy is integral to the treatment of atherosclerotic cardiovascular disease (ASCVD). The greatest benefit is seen in those at the highest risk: patients with a known history of ASCVD (myocardial infarction or stroke). Hence, statins are universally recommended for the secondary prevention of ASCVD.¹

However, the decision to initiate statin therapy for primary prevention, i.e. in those without a history of ASCVD, is more complex. The barriers to widespread use of a statin for primary prevention include older data suggesting a potential lack of mortality benefit in certain subgroups,² costs associated with lifelong therapy (less so with generic preparations), and risk of statin-associated side effects including muscle symptoms, hyperglycemia/diabetes, and case reports of cognitive deficits.³ Additionally, there is clinical disutility (aversion to therapy given potential harms and inconvenience) of statin therapy even among the highest-risk group individuals.⁴

In contrast, the strongest argument for use of statins for primary prevention is made based on a recent individual level meta-analysis from the Cholesterol Treatment Trialists' Collaboration demonstrating a 9% relative reduction in all-cause mortality per 1 mmol/L (39 mg/dL) reduction in LDL-C with statin therapy.⁵ This benefit was consistent across subgroups of age, sex, and ASCVD risk. Similarly, a Cochrane review demonstrated a 14% reduction in all-cause mortality with statin therapy.⁶

Unsurprisingly, given this complex landscape of risks and benefits, statin therapy for primary prevention is not straightforward. Herein, we explore the heterogeneity of risk across the primary prevention patient population and describe possible tools to clarify risk assessment for the clinician-patient discussion prior to initiating statin therapy.

Similar to prior guidelines, the 2013 ACC/AHA guidelines for treatment of cholesterol recommended the use of traditional risk factors to estimate an individual's risk over 10 years, though with an updated risk estimator that took into account ethnicity and accounted for stroke risk.^1,7 Based on the cholesterol treatment guidelines, statin therapy (moderate or high intensity) should be considered in individuals with an estimated 10-year risk of 5% or higher. An important emphasis in these guidelines is the clinician-patient risk discussion before the initiation of statin therapy.⁸ This discussion should encompass the potential benefits and risks from statin therapy and interactions with other drugs and, most importantly, should incorporate the patient's beliefs and preferences regarding initiation of statin therapy. When the decision to initiate statin therapy remains unclear, additional risk markers (high sensitivity C-reactive protein, ankle brachial index, LDL-C ≥160 mg/dL, coronary artery calcium, or a premature family history of ASCVD) can be informative. The use of these additional risk markers may improve cardiovascular risk estimation, thereby allowing clinical providers and patients to make an informed choice with regards to initiating statin therapy.

Of these additional risk markers, the coronary artery calcium (CAC) score provides the best incremental risk assessment.⁹ CAC, a marker of subclinical atherosclerotic burden (Figures 1 & 2), integrates the cumulative exposure to all cardiovascular risk factors (hypertension, elevated cholesterol levels, environmental exposures, etc.) across an individual's lifetime.¹⁰ Among the additional risk markers recommended for assistance with statin therapy decision-making, CAC is the only one that has significantly improved risk prediction over traditional risk factors across multiple prospective cohorts.^11-13

In the Multi-Ethnic Study of Atherosclerosis (MESA), compared with a CAC score of 0, at median 5 years of follow-up, individuals with CAC score 1-100 had a four-fold increase in risk for events (HR 3.6, C.I. 1.9 – 6.6) and those with score >100 had seven-fold increase in risk (HR 7.7, C.I. 4.1 – 14.4).¹⁴ This has been validated in additional cohorts such as the Heinz Nixdorf Recall study cohort in Germany and the Dallas Heart Study in Texas.¹¹ Additionally, its non-invasive nature combined with low cost ($75–$125 in most major cities) and minimal radiation exposure with recent technology (equivalent to about two mammograms) make it an attractive test that allows for identification of higher- and potentially lower-risk groups in primary prevention.

A recent concept that has gained traction is the utilization of negative predictive value of the absence of CAC, i.e., CAC = 0. Multiple studies have demonstrated low incidence of ASCVD (~1% out to 5 years) in populations with a CAC = 0 (Table 1).¹⁵ In fact, Joshi et al. and Shaw et al. demonstrated a low event rate of 2.9 ASCVD events and two deaths per 1000 patient-years at 10 and 15 years of follow-up, respectively.^16,17 Blaha et al. demonstrated CAC = 0 as the most powerful negative predictor across a number of predictors including various imaging techniques, biochemical markers and clinical history in the MESA population.¹⁸

Nasir et al. applied the 2013 guidelines to the MESA population and studied the incidence of ASCVD events across the cardiovascular risk spectrum stratified by the presence or absence of CAC.¹⁹ The authors noted that among individuals in whom a risk discussion to consider statin therapy would be recommended based on the 2013 guidelines (10-year risk ASCVD risk ≥ 7.5%) but with a CAC score of 0, the incidence of ASCVD events was only 4.9%. This striking finding of a relatively low actual ASCVD event rate was persistent in those with 10-year ASCVD risk up to 20%. Similarly, among individuals (with CAC = 0) in whom statin therapy would be considered (10-year ASCVD risk 5 - 7.5%) based on the new guidelines, the 10-year ASCVD event rate was actually 1.5%. Given the low absolute risk in these individuals, the use of statins should be discussed with the expectation that it would not significantly impact 10-year risk, but perhaps longer term, or lifetime risk.

The absence of CAC in higher-risk subgroups highlights the significant heterogeneity in ASCVD risk that is not entirely captured by risk estimators such as that from the Pooled Cohorts Equation. Across a variety of risk factors, CAC = 0 identifies of a low risk group despite considerable risk factor burden (Table 1). For example, 15-20% of patients older than 75 who have not already experienced an ASCVD event, have CAC = 0 and event rates that are much lower than the threshold to start a statin (Table 1).²⁰ Among participants with three or more CVD risk factors (smoking, LDL-C > 130 mg/dL, low HDL-C, diabetes, and hypertension), 35% have CAC = 0 and a CHD event rate over 7 years of approximately 3/1,000 person years.²¹

The converse finding of elevated CAC in the setting of low risk factor burden is not uncommon, and is a harbinger of high risk (Table 2). CAC scoring can identify those who are at the higher end of the CV risk spectrum despite a low burden of traditional risk factors, and could subsequently derive more benefit from statin therapy, particularly if the patient is uncertain with the decision to initiate statin therapy.

Tota-Maharaj demonstrated that among 4% of the participants who were younger than 45 years of age had CAC > 100 and significant all-cause mortality of 12 per 1000 person-years.²⁰ Similarly, among participants with no risk factors (smoking, LDL-C > 130 mg/dL, low HDL-C, diabetes, and hypertension), 12% had CAC > 100 and experienced an elevated coronary heart disease event rate of 9.2 per 1000 person-years.²¹

This heterogeneity between risk factor burden and subclinical atherosclerotic burden is key to the additive value of CAC scoring. In an era of shared decision making with an appropriate emphasis on patient preference, a CAC scan can significantly impact this important decision in primary prevention.

In addition to CAC, emerging risk markers are currently being explored to further assist in risk assessment. HDL cholesterol efflux capacity, a measure of reverse cholesterol transport from the periphery to the liver, has shown promise as a risk marker.²² Our work on cholesterol efflux capacity from the Dallas Heart Study cohort, demonstrated improved risk prediction above and beyond CAC scores.²³ However, given the lack of standardization of the efflux assay and current logistical hurdles in bringing it to the patient's bedside, cholesterol efflux capacity is not quite ready for prime time.

In conclusion, the use of statins for primary prevention of ASCVD is a highly individualized decision requiring a discussion with the patient. We advocate informing the patient of all available tools to best estimate the potential benefits and harms of statin therapy, thereby allowing the patient to make an informed decision regarding statin therapy. In our experience, and based on present evidence, the CAC score can be extremely helpful in this nuanced decision-making process.

Table 1. "High Risk," No CAC (CAC = 0). Event rates are consistently low among participants with a high risk factor burden, but absent CAC (CAC = 0).

Study	Risk Factor	# with Low Risk Factor (%)	# with CAC = 0 among High Risk (%)	Event Type and Follow-up Time	Event Rate (per 1,000 person-yrs)*
Tota-Maharaj20 (n = 43,909) Retrospective	Age ≥ 75 years	1,663 (4%)	266 (16%)	All-cause Mortality Mean 5.6 yrs	2.8
MESA24 Age (n = 6,809) Prospective	Age 75-84 years	965 (14%)	180 (19%)	CHD events Median 8.5 yrs	1.5
MESA Lipids25 (n = 5,534) Prospective	3 Lipid Abnormalitiesa	330 (6%)	165 (50%)	CVD events Median 7.6 yrs	5.9
Graham26 (n = 44,052) Retrospective	Hypertension	10,566 (34%)	3,381 (32%)	All-cause Mortality Mean 5.6 yrs	1.7
MESA Diabetes27 (n = 6,603) Prospective	Diabetes or Metabolic Syndrome	2,567 (39%)	1,094 (43%)	CVD events Median 6.4 yrs	~5.2
McEvoy28 (n = 44,042) Retrospective	Current Smokers	6,020 (14%)	2,288 (38%)	All-cause Mortality Mean 5.6 yrs	3.3
MESA Smoking29 (n = 6,796) Prospective	Current Smokers	971 (14%)	494 (51%)	CVD events Median 10.2 yrs	7.4
MESA JUPITER30 (n = 2,083) Prospective	hsCRP ≥ 2 mg/L	950 (46%)	444 (47%)	CVD events Median 5.8 yrs	3.7
Nasir31 (n = 44,052) Retrospective	≥ 3 Risk Factorsb	6,386 (14%)	2,123 (33%)	All-cause Mortality Mean 5.6 yrs	2.7
MESA Risk Factors21 (n = 6,698) Prospective	≥ 3 Risk Factorsc	1,205 (18%)	422 (35%)	CHD events Mean 7.1 yrs	3.1

Table 2. "Low Risk," High CAC (>100). Event rates are consistently high among participants with a low risk factor burden, but elevated CAC >100.

Study	Risk Factor	# with Low Risk Factor (%)	# with CAC > 100 among Low Risk (%)	Event Type and Follow-up Time	Event Rate (per 1,000 person-yrs)*
Tota-Maharaj20 (n = 43,909) Retrospective	Age < 45 years	8,143 (19%)	326 (4%)	All-cause Mortality Mean 5.6 yrs	~12.0
MESA Age24 (n = 6,809) Prospective	Age 45-54 years	1,947 (29%)	116 (6%)	CHD events Median 8.5 yrs	21.1
MESA Lipids25 (n = 5,534) Prospective	No Lipid Abnormalitiesa	1,975 (36%)	395 (20%)	CVD events Median 7.6 yrs	22.7
Graham26 (n = 44,052) Retrospective	No Hypertension	33,486 (66%)	6,362 (19%)	All-cause Mortality Mean 5.6 yrs	~9.3
MESA Diabetes27 (n = 6,603) Prospective	No Diabetes or Metabolic Syndrome	4,036 (61%)	807 (20%)	CVD events Median 6.4 yrs	~20.6
McEvoy28 (n = 44,042) Retrospective	No current smoking	38,022 (86%)	7,985 (21%)	All-cause Mortality Mean 5.6 yrs	~10.0
MESA Smoking29 (n = 6,796) Prospective	Never Smoker	3,218 (47%)	615 (19%)	CVD events Median 10.2 yrs	27.5
MESA hsCRP30 (n = 2,083) Prospective	hsCRP < 2 mg/L	1,133 (54%)	317 (28%)	CVD events Median 5.8 yrs	24.0
Nasir31 (n = 44,052) Retrospective	No Risk Factorsb	18,819 (43%)	2,930 (16%)	All-cause Mortality Mean 5.6 yrs	16.9
MESA Risk Factors21 (n = 6,698) Prospective	No Risk Factorsc	1,067 (16%)	128 (12%)	CHD events Mean 7.1 yrs	~9.2

Figure 1. CAC > 100. Example of an elevated coronary artery calcium (CAC) score of 263 from a 50-year-old man whose only risk factor is a family history of premature CHD. (A) Volumetric reconstruction showing CAC in the left anterior descending and right coronary arteries. (B) Axial slice from CT scan showing dense CAC in the left anterior descending artery.

Figure 2. CAC = 0. Example of a coronary artery calcium (CAC) score of 0 from a 52-year-old man with hyperlipidemia and hypertension. (A) Volumetric reconstruction showing no calcium (CAC = 0). (B) Axial slice from CT scan showing no CAC.

References

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Keywords: Ankle Brachial Index, Atherosclerosis, Biomarkers, C-Reactive Protein, Cholesterol, HDL, Cognition Disorders, Coronary Artery Disease, Diabetes Mellitus, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Hypercholesterolemia, Hyperglycemia, Hypertension, Myocardial Infarction, Primary Prevention, Risk Assessment, Risk Factors, Secondary Prevention, Smoking, Stroke, Dyslipidemias

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