Primary Prevention of Cardiovascular Disease: Title and subTitle BreakTime to Get More or Less Personal?

In the 1980s, Rose coined the term prevention paradox to describe the fact that a large proportion of cardiovascular disease (CVD) events occur among the many individuals with average risk factor values.¹ He distinguished between 2 approaches to CVD prevention.¹ The high-risk strategy, which aims to truncate the upper tail of the normal distribution of risk factors, focuses on individuals who are most likely to benefit personally from preventive treatment. By contrast, the population-based strategy aims to shift the entire risk distribution. At the time, the available lipid-lowering therapies were limited, none was well tolerated, and the risk-benefit profile for clofibrate, for instance, argued against its widespread use.¹

Soon, the high-risk approach came to be synonymous with the use of drugs, and the population approach was identified with efforts to shift norms about diet, physical activity, or smoking. Modest lifestyle changes could be recommended to the population at large because evolutionarily sensible interventions such as a low-salt diet may be “presumed to be safe.”¹ The real-world effects of such recommendations have been limited. Targeting high-risk individuals with preventive drug therapies optimizes the benefits for the individuals concerned but does little to reduce the overall burden of CVD in the population.

In the 1990s, evidence emerged documenting the efficacy of a new class of potent low-density lipoprotein (LDL)–cholesterol-lowering agents, the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins), first in patients with coronary disease and subsequently in primary prevention. Meta-analyses of large statin trials have demonstrated an approximately 25% relative reduction in risk of CVD events in both primary and secondary prevention populations and in patients with a varying risk factor profile.² For this reason, the number needed to treat to prevent 1 CVD event depends largely on the baseline absolute risk.

When evidence of the benefits of statins first emerged and the potential for high-volume use was recognized, a strategy was necessary to maximize benefit and to limit any potential harm because of the high initial cost of these agents and the uncertainty about their long-term safety. In the United States, individuals considered for statin therapy were originally identified according to an agreed LDL cholesterol threshold. Because LDL cholesterol does not perform well as a CVD screening test, a threshold based on absolute risk was adopted in the United Kingdom. This absolute risk–based approach reduces the number needed to treat to prevent 1 event and maximizes the health benefits for a given cost. In the United Kingdom, it is now routine for family practitioners to use tables or computer programs based on validated risk equations to estimate individual risk at the point of care.

The widely used risk models accurately assign individuals to different categories of risk in such a way that the observed event rates for the risk groups are close to the predicted rates. It is not widely appreciated, however, that risk models fail to efficiently distinguish or discriminate between patients who will or will not experience events.³ Recent research efforts have therefore focused on new biomarkers and vascular imaging tools to improve discrimination and risk stratification. Of these, C-reactive protein (CRP) has been associated with risk of CVD events, and a US consensus statement suggests a CRP cut point of 3 mg/L may aid the identification of high-risk patients. The fact that mendelian randomization studies suggest that CRP is not a cause of vascular disease⁴ is not important for the purpose of prediction. Nevertheless, when assessed with appropriate metrics of predictive performance, a CRP measurement, like LDL cholesterol alone, is a poor discriminator of future CVD events and only marginally enhances risk stratification using established risk factors.⁵ Vascular imaging techniques are costly and some involve radiation exposure, which may limit their applicability for primary prevention.

New metrics for assessing predictive performance have been advocated based on reclassification.⁶ These assess the extent to which the addition of a new marker to an established risk model reassigns individuals into risk categories that better reflects the eventual outcome. For CRP, accurate reclassifications of eventual cases to higher-risk categories and healthy individuals to lower-risk categories is nearly matched by incorrect reclassifications⁵ with the result that the net improvement is marginal. In general, for any new marker or multivariable risk score—for which the association with risk is continuous and graded over the entire range of values and the population distribution is normal (or lognormal)—a large number of events are expected among the majority with intermediate values. Neither new markers nor new metrics have managed to completely evade the prevention paradox.

Two recent developments provide an opportunity for a fresh approach. First, the cost of the original statins has decreased precipitously with patent expiration and development of generic formulations. Second, the efficacy and safety of statins, especially at low to moderate doses, can be ensured from the many large long-term trials and high-volume clinical experience.

For an inexpensive treatment, known to be safe and effective, should the eligibility be widened? A new UK initiative for the systematic risk profiling of adults older than 40 years coupled with recommendations to reduce the risk threshold for intervention is estimated to prevent an additional 9500 myocardial infarctions and strokes annually.⁷ But what are the consequences of this systematic risk-based approach, and how do they compare with the alternatives?

The widely accepted threshold of a 10-year CVD risk of 20% means that a large proportion of men 50 years and older is already eligible for statins with the result that long-term mass preventive therapy will occur de facto in this group. However, a woman with an average risk factor profile may not cross the 20% threshold until well advanced in years. Because 96% of all CVD events occur in persons older than 55 years and because risk equations are poor at discriminating events, an alternative proposal is simply to offer generic statins, perhaps as part of a combination-drug polypill,⁸ to all adults on the basis of an age threshold regardless of the level of LDL cholesterol, CRP, or absolute risk. Preparations containing a statin and effective and safe blood pressure–lowering agents such as low-dose diuretics are already being evaluated for wider use and could be adopted for this purpose.⁹ This age-based approach obviates the need for a resource-intensive vascular check but would extend preventive drug therapies to individuals at lower individualized assessment of individual risk, whose personal gain would be less.

Evaluation of the comparative efficacy of interventions is an established principle in England and Wales through NICE (UK National Institute for Health and Clinical Excellence), and comparative effectiveness is the subject of current attention in the United States.¹⁰ However, scant information is available on the cost and the public acceptability of a policy of widening the eligibility for generic statins with minimal monitoring of response on the one hand vs a more resource-intensive individualized risk management based on vascular health checks (perhaps incorporating new biomarkers and imaging tools) together with treatment targets on the other. The comparative effectiveness of the alternative options for primary prevention needs to be studied and debated with wider involvement of the stakeholders, including individuals at risk. Whether, in the end, a more or less personalized approach to CVD risk stratification improves health outcomes for the intermediate-risk population and at acceptable cost are empirical questions that can and should eventually be asked and answered by additional trials and studies.