Achievement of dual low-density lipoprotein cholesterol and high-sensitivity C-reactive protein targets more frequent with the addition of ezetimibe to simvastatin and associated with better outcomes in IMPROVE-IT.
BACKGROUND
Statins lower low-density lipoprotein cholesterol (LDL-C) and high-sensitivity C-reactive protein (hs-CRP); addition of ezetimibe to statins further reduces LDL-C and hs-CRP. An analysis of the relationship between achieved LDL-C and hs-CRP targets and outcomes for simvastatin and ezetimibe/simvastatin was prespecified in Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT).


RESULTS
The IMPROVE-IT trial randomly assigned 18 144 patients stabilized after acute coronary syndrome to simvastatin or ezetimibe/simvastatin. LDL-C and hs-CRP were measured at baseline and 1 month after randomization. Outcomes were assessed in those achieving one or both of the prespecified targets of LDL-C<70 mg/dL and hs-CRP<2 mg/L versus achieving neither target, adjusting for differences in baseline characteristics. An exploratory analysis examined targets of LDL-C<50 mg/dL and hs-CRP<1 mg/L. Patients meeting both targets at baseline, with no 1-month values, or with end points before 1 month were excluded. Of 15 179 patients, 39% achieved the dual LDL-C (<70 mg/dL) and hs-CRP (<2 mg/L) targets at 1 month, 14% met neither target, 14% met only the hs-CRP target, and 33% met only the LDL-C target. Those achieving dual targets had lower primary end point rates than those meeting neither target (cardiovascular death, major coronary event, or stroke; 38.9% versus 28.0%; adjusted hazard ratio, 0.73; 0.66-0.81; P<0.001). More patients treated with ezetimibe/simvastatin met dual targets than those treated with simvastatin alone (50% versus 29%, P<0.001). The association of dual-target attainment with improved outcomes was similar irrespective of treatment assignment (P-interaction=0.65). Similar findings were observed using the exploratory targets.


CONCLUSIONS
Significantly more patients treated with ezetimibe/simvastatin met prespecified and exploratory dual LDL-C and hs-CRP targets than patients treated with simvastatin alone. Reaching both LDL-C and hs-CRP targets was associated with improved outcomes after multivariable adjustment.


BACKGROUND
URL: http://www.clinicaltrials.gov; Unique identifier: NCT00202878.
From TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (E.A.B., R.P.G., C.P.C., J.Z., S.A.M., E.B.); Duke Clinical Research Institute, Durham, NC (J.W., M.A.B.); and Merck, Kenilworth, NJ (A.M.T.). ebohula@partners.org.
Erin A
EA
Bohula
From TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (E.A.B., R.P.G., C.P.C., J.Z., S.A.M., E.B.); Duke Clinical Research Institute, Durham, NC (J.W., M.A.B.); and Merck, Kenilworth, NJ (A.M.T.).
Robert P
RP
Giugliano
From TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (E.A.B., R.P.G., C.P.C., J.Z., S.A.M., E.B.); Duke Clinical Research Institute, Durham, NC (J.W., M.A.B.); and Merck, Kenilworth, NJ (A.M.T.).
Christopher P
CP
Cannon
From TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (E.A.B., R.P.G., C.P.C., J.Z., S.A.M., E.B.); Duke Clinical Research Institute, Durham, NC (J.W., M.A.B.); and Merck, Kenilworth, NJ (A.M.T.).
Jing
J
Zhou
From TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (E.A.B., R.P.G., C.P.C., J.Z., S.A.M., E.B.); Duke Clinical Research Institute, Durham, NC (J.W., M.A.B.); and Merck, Kenilworth, NJ (A.M.T.).
Sabina A
SA
Murphy
From TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (E.A.B., R.P.G., C.P.C., J.Z., S.A.M., E.B.); Duke Clinical Research Institute, Durham, NC (J.W., M.A.B.); and Merck, Kenilworth, NJ (A.M.T.).
Jennifer A
JA
White
From TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (E.A.B., R.P.G., C.P.C., J.Z., S.A.M., E.B.); Duke Clinical Research Institute, Durham, NC (J.W., M.A.B.); and Merck, Kenilworth, NJ (A.M.T.).
Andrew M
AM
Tershakovec
From TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (E.A.B., R.P.G., C.P.C., J.Z., S.A.M., E.B.); Duke Clinical Research Institute, Durham, NC (J.W., M.A.B.); and Merck, Kenilworth, NJ (A.M.T.).
Michael A
MA
Blazing
From TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (E.A.B., R.P.G., C.P.C., J.Z., S.A.M., E.B.); Duke Clinical Research Institute, Durham, NC (J.W., M.A.B.); and Merck, Kenilworth, NJ (A.M.T.).
Eugene
E
Braunwald
D054058:Acute Coronary Syndrome / Q000097:blood / Q000188:drug therapy*; D000368:Aged; D000924:Anticholesteremic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D015415:Biomarkers; D002097:C-Reactive Protein / Q000032:analysis*; D002318:Cardiovascular Diseases / Q000401:mortality; D002548:Cerebral Revascularization; D008078:Cholesterol, LDL / Q000097:blood*; D015897:Comorbidity; D003404:Creatinine / Q000097:blood; D004311:Double-Blind Method; D016903:Drug Monitoring; D004359:Drug Therapy, Combination; D004562:Electrocardiography; D000069438:Ezetimibe / Q000008:administration & dosage / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000097:blood / Q000188:drug therapy; D009204:Myocardial Revascularization; D019821:Simvastatin / Q000008:administration & dosage / Q000627:therapeutic use*; D016896:Treatment Outcome
D000924:Anticholesteremic Agents; D015415:Biomarkers; D008078:Cholesterol, LDL; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D002097:C-Reactive Protein; D019821:Simvastatin; D003404:Creatinine; D000069438:Ezetimibe
C-reactive protein; acute coronary syndrome; cholesterol, LDL; ezetimibe; hydroxymethylglutaryl-CoA reductase inhibitors; secondary prevention