Universität zu Köln

Tsimikas, Sotirios, Karwatowska-Prokopczuk, Ewa, Gouni-Berthold, Ioanna, Tardif, Jean-Claude, Baum, Seth J., Steinhagen-Thiessen, Elizabeth, Shapiro, Michael D., Stroes, Erik S., Moriarty, Patrick M., Nordestgaard, Borge G., Xia, Shuting, Guerriero, Jonathan, Viney, Nicholas J., O'Dea, Louis and Witztum, Joseph L. (2020). Lipoprotein(a) Reduction in Persons with Cardiovascular Disease. N. Engl. J. Med., 382 (3). S. 244 - 256. WALTHAM: MASSACHUSETTS MEDICAL SOC. ISSN 1533-4406

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Abstract

Background Lipoprotein(a) levels are genetically determined and, when elevated, are a risk factor for cardiovascular disease and aortic stenosis. There are no approved pharmacologic therapies to lower lipoprotein(a) levels. Methods We conducted a randomized, double-blind, placebo-controlled, dose-ranging trial involving 286 patients with established cardiovascular disease and screening lipoprotein(a) levels of at least 60 mg per deciliter (150 nmol per liter). Patients received the hepatocyte-directed antisense oligonucleotide AKCEA-APO(a)-L-Rx, referred to here as APO(a)-L-Rx (20, 40, or 60 mg every 4 weeks; 20 mg every 2 weeks; or 20 mg every week), or saline placebo subcutaneously for 6 to 12 months. The lipoprotein(a) level was measured with an isoform-independent assay. The primary end point was the percent change in lipoprotein(a) level from baseline to month 6 of exposure (week 25 in the groups that received monthly doses and week 27 in the groups that received more frequent doses). Results The median baseline lipoprotein(a) levels in the six groups ranged from 204.5 to 246.6 nmol per liter. Administration of APO(a)-L-Rx resulted in dose-dependent decreases in lipoprotein(a) levels, with mean percent decreases of 35% at a dose of 20 mg every 4 weeks, 56% at 40 mg every 4 weeks, 58% at 20 mg every 2 weeks, 72% at 60 mg every 4 weeks, and 80% at 20 mg every week, as compared with 6% with placebo (P values for the comparison with placebo ranged from 0.003 to <0.001). There were no significant differences between any APO(a)-L-Rx dose and placebo with respect to platelet counts, liver and renal measures, or influenza-like symptoms. The most common adverse events were injection-site reactions. Conclusions APO(a)-L-Rx reduced lipoprotein(a) levels in a dose-dependent manner in patients who had elevated lipoprotein(a) levels and established cardiovascular disease. (Funded by Akcea Therapeutics; ClinicalTrials.gov number, NCT03070782.)

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Tsimikas, Sotirios UNSPECIFIED UNSPECIFIED UNSPECIFIED Karwatowska-Prokopczuk, Ewa UNSPECIFIED UNSPECIFIED UNSPECIFIED Gouni-Berthold, Ioanna UNSPECIFIED UNSPECIFIED UNSPECIFIED Tardif, Jean-Claude UNSPECIFIED UNSPECIFIED UNSPECIFIED Baum, Seth J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Steinhagen-Thiessen, Elizabeth UNSPECIFIED UNSPECIFIED UNSPECIFIED Shapiro, Michael D. UNSPECIFIED UNSPECIFIED UNSPECIFIED Stroes, Erik S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Moriarty, Patrick M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Nordestgaard, Borge G. UNSPECIFIED UNSPECIFIED UNSPECIFIED Xia, Shuting UNSPECIFIED UNSPECIFIED UNSPECIFIED Guerriero, Jonathan UNSPECIFIED UNSPECIFIED UNSPECIFIED Viney, Nicholas J. UNSPECIFIED UNSPECIFIED UNSPECIFIED O'Dea, Louis UNSPECIFIED UNSPECIFIED UNSPECIFIED Witztum, Joseph L. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-348769
DOI:	10.1056/NEJMoa1905239
Journal or Publication Title:	N. Engl. J. Med.
Volume:	382
Number:	3
Page Range:	S. 244 - 256
Date:	2020
Publisher:	MASSACHUSETTS MEDICAL SOC
Place of Publication:	WALTHAM
ISSN:	1533-4406
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language OXIDIZED PHOSPHOLIPIDS; APOLIPOPROTEIN B-100; TARGETING APOLIPOPROTEIN(A); DOUBLE-BLIND; GENETICS; INSIGHTS; OUTCOMES; THERAPY; STROKE; RISK Multiple languages Medicine, General & Internal Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/34876