The epidemiological concept of residual risk.

Residual cardiovascular risk can be defined as the residual risk of incident vascular events or progression of established vascular damage persisting in patients treated with current evidence-based recommended care including the risk that established from risk factors, such as dyslipidemia, high blood pressure, and the risk related to emerging or newer risk factors. The concept clearly derives from intervention trials, mainly the statin trials, and there is a lot of debate about the residual risk conferred by other lipid components, in particular low levels of HDL cholesterol and high levels of triglycerides. A meta-analysis of 53 fibrates (16,802 subjects) and 30 niacin trials (4,749 subjects) revealed an average HDL-C increase of 10% with fibrates and 16% with niacin, a triglyceride decrease of 36% with fibrates and 20% with niacin, and a LDL-C decrease of 8% with fibrates and 14% with niacin. These lipid changes resulted in similar overall reductions in major coronary events evidenced by a 25% decrease with fibrates and 27% with niacin. However, recent analyses of the primary and secondary prevention trials like JUPITER, Treating to New Targets (TNT) and PROVE-IT TIMI 22 force to reconsider the issue. In these three trials, HDL-C was useful in the initial risk assessment but when LDL-C was aggressively lowered the residual risk predictive value of HDL-C was markedly attenuated. Also epidemiological studies evaluate the residual risk in treated hypertensives and dyslipidemic subjects within a general population. The PRIME study in Northern Ireland and France and the Progetto CUORE study in Italy, both with a 10-year follow-up were able to test the hypothesis of the residual cardiovascular risk in treated hypertensives, because the proportion of treated dyslipidemic subjects was too low at baseline. In both studies treatment with antihypertensive agents was associated with a sizeable residual cardiovascular risk with the hazard ratio of 1.5-1.7, suggesting that more efficient risk reduction strategies in hypertension should be developed as a priority. In conclusion residual cardiovascular risk should be better studied in cardiovascular epidemiology, refining the methods to evaluate it, to consider measures of exposure to the modifiable risk factors and indicators of treatment (both at pharmacological and lifestyle level) over the time. Repeated measures and cohortal follow-up are needed and also new statistical methods are necessary to evaluate the residual risk to understand how to reduce it.