Clinical Feature: Primary Prevention as a Strategy in Identifying the High-Risk Patient in the Absence of Traditional Risk Factors

Primary Prevention Often Comes too Late
Primary prevention is concentrated on risk-factor evaluation and threshold levels of cholesterol and blood pressure values.¹ By focusing treatment exclusively on risk factors and these threshold levels, guidelines often disregard individuals with levels below these thresholds who still are at risk for an atherosclerotic cardiovascular event in which non-traditional or unknown cardiovascular risk contributors are involved. Most everyone can recall someone who appeared to be healthy and had no history of lipid abnormality or elevated blood pressure but then had a cardiovascular event. The major goal of cardiovascular primary preventive therapy should be reducing cardiovascular morbidity and mortality, not just reducing calculated risk-factor levels, especially in patients who appear to be at low risk and have a healthy lifestyle but whose family history predisposes them to cardiovascular disease.

A Biostatistical Approach vs. an Early Disease Approach
Efforts to prevent atherosclerotic morbid events primarily have focused on risk-factor prevention and intervention. These approaches, based on the statistical association of risk factors with events, have dominated clinical practice in the past generation. Because the cardiovascular abnormalities eventuating in morbid events are now detectable in the arteries and heart before the development of symptomatic disease, recent efforts have focused on identifying the presence of these abnormalities as a more sensitive and specific guide to the need for therapy, especially in subjects with low cardiovascular risk scores, but with the presence of non-traditional risk factors.²

Evaluation for early cardiovascular disease should then take priority over risk-factor assessment in determining who should be treated to reduce the progression of “silent early cardiovascular disease” in those who have not yet developed symptoms of overt cardiovascular disease. Those with advancing disease despite a lack of symptoms need aggressive pharmacotherapy beyond lifestyle modification, regardless of their risk-factor levels. Since the functional and structural cardiovascular abnormalities detected in an evaluation can be tracked over time, the effectiveness of therapy in slowing progression and reducing cardiovascular abnormalities can be monitored. Rather than depending on risk-factor targets alone, an alternative strategy can be to favorably impact early disease markers. Because cardiovascular symptoms most often represent advanced disease, early identification — before symptoms have developed — is paramount to effectively preventing morbid events.

Advances in noninvasive techniques for studying the vasculature now provide the opportunity to use early disease detection beyond risk factor assessment as a tool for clinical decision making. The problem with the messaging that focuses on the prevention and treatment of risk factors is that it may be good public health policy but does not provide enough information to determine what patient care strategy is best for the individual patient, especially those at “low calculated risk.”

The Problem with Low-Risk Calculation
The major problem regarding primary prevention has been the gaps in the American Heart Association/American College of Cardiology (AHA/ACC) guidelines, specifically because these recommendations have focused a population between 40 and 75 years old — the age range for enrollment in most cardiovascular preventive clinical trials.³ The major challenge in preventive cardiovascular therapy is deciding when to start medical management versus using only lifestyle-modification therapies, especially in low-risk patients. Evidence-based medical data suggests that, even in the low-risk category, statin therapy can reduce a patient’s risk of a cardiovascular event.^5-7

Scoring calculators based on population statistics provide only risk estimates for individual patients and must be combined with clinical judgment. This is particularly true when applied to groups that may differ in average risk level compared with the population from which the equations were developed. In some patients, the atherosclerotic cardiovascular disease risk estimate will be in the moderate or high category, based primarily on non-lipid risk factor such as smoking or hypertension. In such cases, attention to these risk determinants may be of primary importance.

A Tailored Approach in the Low-Risk Category
Patients with only one — or no — major atherosclerotic cardiovascular disease (ASCVD) risk factors generally are at low risk for an event (<5  percent 10- year ASCVD event risk). Quantitative risk scoring typically is not necessary for such patients. Lifestyle therapies are the primary modalities for management of atherogenic cholesterol levels in such patients, although consideration may be given to pharmacotherapy in those with non-high-density lipoprotein cholesterol (non-HDL-C) 190 mg/dL to 219 mg/dL (low-density lipoprotein cholesterol [LDL-C] 160 mg/dL to 189 mg/dL).⁷ Also, in some people, a severe disturbance in a single major ASCVD risk factor (e.g., a strong family history of coronary heart disease or a multipack-per-day smoking habit), a known disturbance in a secondary risk factor (e.g., lipoprotein (a) ≥50 mg/ dL), or evidence of subclinical disease (e.g., coronary artery calcium [CAC] ≥300 Agatston units) might justify classifying the patient in the moderate or the high- risk category, prompting consideration of pharmacotherapy at lower levels of atherogenic cholesterol. Other risks need to be taken into consideration, such as ankle-brachial index <0.90, presence of carotid artery plaque, high-sensitivity C-reactive protein ≥2.0 mg/, urine albumin/creatinine ratio ≥ 30 mg/g. If information about secondary risk factors or subclinical disease is known for such patients, then this should be considered when assigning the risk category and when making decisions about the use of pharmacotherapy.⁷ Last, but not least, is the importance of an accurate and detailed family history with each cardiovascular risk assessment. A family history of early coronary heart disease in a first-degree male relative 55 years old or younger and/ or a first-degree female relative 65 years old or younger should be considered a major risk factor for atherosclerotic cardiovascular disease. Those with high lifetime risk for ASCVD should also be considered for early pharmacologic intervention. There is an unmet need for further research in the domain of genetic testing and discovery, especially in people who are categorized as low risk but have a strong family history of premature atherosclerotic disease and an absence of traditional cardiovascular risk factors. This knowledge may lead to the discovery of new therapies above and beyond lipid-lowering therapy to halt or reverse the atherosclerotic cardiovascular disease process, leading to a decrease in cardiovascular morbidity and mortality with an increase in quality of life.

Disclosure statement: Lynn Hoke has no disclosures to report. Dr. Duprez received a research grant as a principal investigator for Regeneron, Sanofi-Aventis, and Pfizer. He received consulting and speaker honoraria from Lundbeck. He received honoraria as part of the speakers bureau for AstraZeneca and Amgen.

References are listed on page 37 of the PDF.