3.4.2.0 Statins and PCSK9 In­hibitors

Placebo-con­trolled tri­als eval­u­at­ing the ad­di­tion of the PCSK9 in­hibitors evolocum­ab and alirocum­ab to max­i­mal­ly tol­er­at­ed doses of statin ther­a­py in par­tic­i­pants who were at high risk for ASCVD demon­strat­ed an av­er­age re­duc­tion in LDL choles­terol rang­ing from 36% to 59%. These agents have been ap­proved as ad­junc­tive ther­a­py for pa­tients with ASCVD or fa­mil­ial hypercholes­terolemia who are re­ceiv­ing max­i­mal­ly tol­er­at­ed statin ther­a­py but re­quire ad­di­tional low­er­ing of LDL choles­terol (95,96).

The ef­fects of PCSK9 in­hi­bi­tion on ASCVD out­comes was in­ves­ti­gat­ed in the Fur­ther Car­dio­vas­cu­lar Out­comes Re­search With PCSK9 In­hi­bi­tion in Sub­jects With El­e­vat­ed Risk (FOURI­ER) trial, which en­rolled 27,564 pa­tients with prior ASCVD and an ad­di­tional high-‍risk fea­ture who were re­ceiv­ing their max­i­mal­ly tol­er­at­ed statin ther­a­py (two-‍thirds were on high-‍in­ten­si­ty statin) but who still had an LDL choles­terol ≥70 mg/dL or a non-‍HDL choles­terol ≥100 mg/dL (93). Pa­tients were ran­dom­ized to re­ceive sub­cu­ta­neous in­jec­tions of evolocum­ab (ei­ther 140 mg every 2 weeks or 420 mg every month based on pa­tient pre­ference) ver­sus place­bo. Evolocum­ab re­duced LDL choles­terol by 59% from a me­di­an of 92 to 30 mg/dL in the treat­ment arm.

Dur­ing the me­di­an fol­low-‍up of 2.2 years, the com­pos­ite out­come of car­dio­vas­cu­lar death, MI, stroke, hos­pi­tal­iza­tion for angi­na, or revas­cu­larization oc­curred in 11.3% vs. 9.8% of the place­bo and evolocum­ab groups, re­spectively, rep­re­sent­ing a 15% rel­a­tive risk re­duc­tion (P < 0.001). The com­bined end point of car­dio­vas­cu­lar death, MI, or stroke was re­duced by 20%, from 7.4% to 5.9% (P < 0.001). Im­por­tant­ly, sim­i­lar benefits were seen in pre­specified sub­group of pa­tients with di­a­betes, com­pris­ing 11,031 pa­tients (40% of the trial) (97).