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Rischio genetico e terapia con statine
Il rischio di aterosclerosi coronarica dipende da molti fattori, alcuni acquisiti e altri di origine genetica, che complessivamente rendono conto del 30-60% della variazione del rischio. Nello studio della Mega e coll, sono stati presi in considerazione 27 varianti genetiche che precedenti analisi avevano provato essere associate ad un aumentato rischio di malattia coronarica. Sulla base di queste varianti è stato costruito un punteggio genetico di rischio che ha dimostrato, come atteso, di essere predittivo di eventi coronarici. La terapia con statine ha determinato una maggiore riduzione del rischio nel gruppo dei pazienti a più alto rischio genetico che in quelli a rischio più basso, suggerendo così che l'indagine genetica possa essere utile nel selezionare i pazienti da trattare.
Genetic risk, coronary heart disease events, and the clinical benefit of statin therapy: an analysis of primary and secondary prevention trials.
Mega JL, Stitziel NO, Smith JG, Chasman DI, Caulfield MJ, Devlin JJ, Nordio F, Hyde CL, Cannon CP, Sacks FM, Poulter NR, Sever PS, Ridker PM, Braunwald E, Melander O, Kathiresan S, Sabatine MS
Lancet 2015;385:2264-2271
BACKGROUND: Genetic variants have been associated with the risk of coronary heart disease. In this study, we tested whether or not a composite of these variants could ascertain the risk of both incident and recurrent coronary heart disease events and identify those individuals who derive greater clinical benefit from statin therapy.
METHODS: A community-based cohort study (the Malmo Diet and Cancer Study) and four randomised controlled trials of both primary prevention (JUPITER and ASCOT) and secondary prevention (CARE and PROVE IT-TIMI 22) with statin therapy, comprising a total of 48,421 individuals and 3477 events, were included in these analyses. We studied the association of a genetic risk score based on 27 genetic variants with incident or recurrent coronary heart disease, adjusting for traditional clinical risk factors. We then investigated the relative and absolute risk reductions in coronary heart disease events with statin therapy stratified by genetic risk. We combined data from the different studies using a meta-analysis.
FINDINGS: When individuals were divided into low (quintile 1), intermediate (quintiles 2-4), and high (quintile 5) genetic risk categories, a significant gradient in risk for incident or recurrent coronary heart disease was shown. Compared with the low genetic risk category, the multivariable-adjusted hazard ratio for coronary heart disease for the intermediate genetic risk category was 1.34 (95% CI 1.22-1.47, p<0.0001) and that for the high genetic risk category was 1.72 (1.55-1.92, p<0.0001). In terms of the benefit of statin therapy in the four randomised trials, we noted a significant gradient (p=0.0277) of increasing relative risk reductions across the low (13%), intermediate (29%), and high (48%) genetic risk categories. Similarly, we noted greater absolute risk reductions in those individuals in higher genetic risk categories (p=0.0101), resulting in a roughly threefold decrease in the number needed to treat to prevent one coronary heart disease event in the primary prevention trials. Specifically, in the primary prevention trials, the number needed to treat to prevent one such event in 10 years was 66 in people at low genetic risk, 42 in those at intermediate genetic risk, and 25 in those at high genetic risk in JUPITER, and 57, 47, and 20, respectively, in ASCOT.
INTERPRETATION: A genetic risk score identified individuals at increased risk for both incident and recurrent coronary heart disease events. People with the highest burden of genetic risk derived the largest relative and absolute clinical benefit from statin therapy.
FUNDING: National Institutes of Health.
