Long-term mipomersen treatment is associated with a reduction in cardiovascular events in patients with familial hypercholesterolemia

被引:98
作者
Duell, P. Barton [1 ]
Santos, Raul D. [2 ]
Kirwan, Bridget-Anne [3 ,4 ]
Witztum, Joseph L. [5 ]
Tsimikas, Sotirios [6 ,7 ]
Kastelein, John J. P. [8 ]
机构
[1] Oregon Hlth & Sci Univ, Knight Cardiovasc Inst, Portland, OR 97201 USA
[2] Univ Sao Paulo, Med Sch Hosp, Lipid Clin Heart Inst InCor, Sao Paulo, Brazil
[3] SOCAR Res SA, Nyon, Switzerland
[4] London Sch Hyg & Trop Med, London, England
[5] Univ Calif San Diego, Div Endocrinol & Metab, La Jolla, CA 92093 USA
[6] Univ Calif San Diego, Div Cardiovasc Med, Sulpizio Cardiovasc Ctr, La Jolla, CA 92093 USA
[7] Ionis Pharmaceut, Carlsbad, CA USA
[8] Univ Amsterdam, Acad Med Ctr, Dept Vasc Med, NL-1100 DD Amsterdam, Netherlands
关键词
Mipomersen; Antisense; LDL-Cholesterol; Major adverse cardiovascular events; Familial hypercholesterolemia; CORONARY-HEART-DISEASE; B SYNTHESIS INHIBITOR; LDL CHOLESTEROL; LIPOPROTEIN APHERESIS; MORTALITY; EFFICACY; THERAPY; INTERVENTION; ROSUVASTATIN; IMPACT;
D O I
10.1016/j.jacl.2016.04.013
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
BACKGROUND: Familial hypercholesterolemia (FR) is characterized by severely elevated LDL-cholesterol and up to a 20-fold increase in premature cardiovascular disease (CVD). OBJECTIVE: Mipomersen has been shown to lower the levels of these atherogenic lipoproteins, but whether it lowers major adverse cardiac events (MACEs) has not been addressed. METHODS: This post hoc analysis of prospectively collected data of three randomized trials and an open-label extension phase included patients that were exposed to months of mipomersen. MACE rates that occurred during 24 months before randomization in the mipomersen group were compared to MACE rates after initiation of mipomersen. Data from the trials included in this report are registered in Clinicaltrials.gov (NCT00607373, NCT00706849, NCT00794664, NCT00694109). The occurrence of MACE events, defined as cardiovascular death, nonfatal acute myocardial infarction, hospitalization for unstable angina, coronary revascularization and nonfatal ischemic stroke, was obtained from medical history data pre-treatment and adjudicated by an independent adjudication committee for events occurring post-treatment with mipomersen. RESULTS: MACEs were identified in 61.5% of patients (64 patients with 146 events [39 myocardial infarctions, 99 coronary revascularizations, 5 unstable angina episodes, 3 ischemic strokes]) during 24 months before mipomersen treatment, and in 9.6% of patients (10 patients with 13 events [1 cardiovascular death, 2 myocardial infarctions, 6 coronary interventions, 4 unstable angina episodes]) during a mean of 24.4 months after initiation of mipomersen (MACE rate 25.7 of 1000 patient-months vs 3.9 of 1000 patient-months, OR = 0.053 [95% CI, 0.016-0.168], P < .0001 by the exact McNemar test). The reduction in MACE coincided with a mean absolute reduction in LDL-C of 70 mg/dL (-28%) and of non-HDL cholesterol of 74 mg/dL (-26%) as well as reduction in Lp(a) of 11 mg/dL (-17%). CONCLUSION: Long-term mipomersen treatment not only lowers levels of atherogenic lipoproteins but may also lead to a reduction in cardiovascular events in FH patients. (C) 2016 National Lipid Association. All rights reserved.
引用
收藏
页码:1011 / 1021
页数:11
相关论文
共 29 条
[1]   Relationship of Apolipoproteins A-1 and B, and Lipoprotein(a) to Cardiovascular Outcomes The AIM-HIGH Trial (Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglyceride and Impact on Global Health Outcomes) [J].
Albers, John J. ;
Slee, April ;
O'Brien, Kevin D. ;
Robinson, Jennifer G. ;
Kashyap, Moti L. ;
Kwiterovich, Peter O., Jr. ;
Xu, Ping ;
Marcovina, Santica M. .
JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY, 2013, 62 (17) :1575-1579
[2]   Lipoprotein(a) Levels in Familial Hypercholesterolemia An Important Predictor of Cardiovascular Disease Independent of the Type of LDL Receptor Mutation [J].
Alonso, Rodrigo .
JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY, 2014, 63 (19) :1983-1989
[3]  
[Anonymous], 2008, BMJ, DOI DOI 10.1136/BMJ.A2423
[4]   Acute impact of apheresis on oxidized phospholipids in patients with familial hypercholesterolemia [J].
Arai, Kiyohito ;
Orsoni, Alexina ;
Mallat, Ziad ;
Tedgui, Alain ;
Witztum, Joseph L. ;
Bruckert, Eric ;
Tselepis, Alexandros D. ;
Chapman, M. John ;
Tsimikas, Sotirios .
JOURNAL OF LIPID RESEARCH, 2012, 53 (08) :1670-1678
[5]   Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170 000 participants in 26 randomised trials [J].
Baigent, C. ;
Blackwell, L. ;
Emberson, J. ;
Holland, L. E. ;
Reith, C. ;
Bhala, N. ;
Peto, R. ;
Barnes, E. H. ;
Keech, A. ;
Simes, J. ;
Collins, R. .
LANCET, 2010, 376 (9753) :1670-1681
[6]   EFFECT OF PARTIAL ILEAL BYPASS-SURGERY ON MORTALITY AND MORBIDITY FROM CORONARY HEART-DISEASE IN PATIENTS WITH HYPERCHOLESTEROLEMIA - REPORT OF THE PROGRAM ON THE SURGICAL CONTROL OF THE HYPERLIPIDEMIAS (POSCH) [J].
BUCHWALD, H ;
VARCO, RL ;
MATTS, JP ;
LONG, JM ;
FITCH, LL ;
CAMPBELL, GS ;
PEARCE, MB ;
YELLIN, AE ;
EDMISTON, WA ;
SMINK, RD ;
SAWIN, HS ;
CAMPOS, CT ;
HANSEN, BJ ;
TUNA, N ;
KARNEGIS, JN ;
SANMARCO, ME ;
AMPLATZ, K ;
CASTANEDAZUNIGA, WR ;
HUNTER, DW ;
BISSETT, JK ;
WEBER, FJ ;
STEVENSON, JW ;
LEON, AS ;
CHALMERS, TC .
NEW ENGLAND JOURNAL OF MEDICINE, 1990, 323 (14) :946-955
[7]   15 YEAR MORTALITY IN CORONARY DRUG PROJECT PATIENTS - LONG-TERM BENEFIT WITH NIACIN [J].
CANNER, PL ;
BERGE, KG ;
WENGER, NK ;
STAMLER, J ;
FRIEDMAN, L ;
PRINEAS, RJ ;
FRIEDEWALD, W .
JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY, 1986, 8 (06) :1245-1255
[8]   Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes [J].
Cannon, Christopher P. ;
Blazing, Michael A. ;
Giugliano, Robert P. ;
McCagg, Amy ;
White, Jennifer A. ;
Theroux, Pierre ;
Darius, Harald ;
Lewis, Basil S. ;
Ophuis, Ton Oude ;
Jukema, J. Wouter ;
De Ferrari, Gaetano M. ;
Ruzyllo, Witold ;
De Lucca, Paul ;
Im, KyungAh ;
Bohula, Erin A. ;
Reist, Craig ;
Wiviott, Stephen D. ;
Tershakovec, Andrew M. ;
Musliner, Thomas A. ;
Braunwald, Eugene ;
Califf, Robert M. .
NEW ENGLAND JOURNAL OF MEDICINE, 2015, 372 (25) :2387-2397
[9]   DELETION IN THE GENE FOR THE LOW-DENSITY-LIPOPROTEIN RECEPTOR IN A MAJORITY OF FRENCH-CANADIANS WITH FAMILIAL HYPERCHOLESTEROLEMIA [J].
HOBBS, HH ;
BROWN, MS ;
RUSSELL, DW ;
DAVIGNON, J ;
GOLDSTEIN, JL .
NEW ENGLAND JOURNAL OF MEDICINE, 1987, 317 (12) :734-737
[10]   Familial Hypercholesterolemias: Prevalence, genetics, diagnosis and screening recommendations from the National Lipid Association Expert Panel on Familial Hypercholesterolemia [J].
Hopkins, Paul N. ;
Toth, Peter P. ;
Ballantyne, Christie M. ;
Rader, Daniel J. .
JOURNAL OF CLINICAL LIPIDOLOGY, 2011, 5 (03) :S9-S17