Relation of different measures of low-density lipoprotein cholesterol to risk of coronary artery disease and death in a meta-regression analysis of large-scale trials of statin therapy.
Multiple randomized controlled trials (RCTs) have established the efficacy of statins for the prevention of cardiovascular disease. The benefits observed are often framed in terms of percentage reductions in low-density lipoprotein (LDL) cholesterol from baseline or percentage reductions between control and treatment groups, although epidemiologic data suggest that the absolute intergroup difference in LDL cholesterol (DeltaLDL(Control-Rx)) is the more informative measure. A systematic review of large-scale trials of statins versus placebo, usual care, or active (lower dose statin) control was conducted to calculate updated summary estimates of risk reduction in coronary artery disease and all-cause mortality. Meta-regression analysis was used to ascertain the relations of different LDL cholesterol metrics to outcomes. In 20 eligible RCTs, there were significant overall reductions for coronary artery disease (odds ratio 0.72, 95% confidence interval 0.67 to 0.78) and mortality (odds ratio 0.89, 95% confidence interval 0.84 to 0.94), but with substantial variability in trial results. DeltaLDL(Control-Rx) was the strongest determinant of coronary artery disease risk reduction, particularly after excluding active-comparator studies, and was independent of baseline LDL cholesterol. In contrast, baseline LDL cholesterol edged out DeltaLDL(Control-Rx) as the strongest determinant of mortality, but neither was significant after the exclusion of active-comparator studies. The exclusion of 3 RCTs involving distinct populations, however, rendered DeltaLDL(Control-Rx) the predominant determinant of mortality reduction. In conclusion, these findings underscore the primacy of absolute reductions in LDL cholesterol in the design and interpretation of RCTs of lipid-lowering therapies and in framing treatment recommendations on the basis of the proved coronary benefits of these drugs.
Kizer
Jorge R
JR
Department of Medicine, Weill Cornell Medical College, New York, NY, USA. jok2007@med.cornell.edu
Madias
Christopher
C
Wilner
Brian
B
Vaughan
Carl J
CJ
Mushlin
Alvin I
AI
Trushin
Paula
P
Gotto
Antonio M
AM
Pasternak
Richard C
RC
D008078:Cholesterol, LDL / Q000097:blood*; D003324:Coronary Artery Disease / Q000097:blood / Q000188:drug therapy / Q000453:epidemiology; D016757:Death, Sudden, Cardiac / Q000453:epidemiology* / Q000209:etiology; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D011379:Prognosis; D016032:Randomized Controlled Trials as Topic; D012044:Regression Analysis; D012307:Risk Factors; D014481:United States / Q000453:epidemiology
D008078:Cholesterol, LDL; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors
Circulation. 1998 Mar 17;97(10):946-52
9529261
Circulation. 2004 Jul 13;110(2):227-39
15249516
Ital Heart J. 2000 Dec;1(12):810-20
11302109
JAMA. 2005 Nov 16;294(19):2437-45
16287954
BMJ. 2002 Jun 29;324(7353):1570-6
12089098
Lancet. 1994 Nov 19;344(8934):1383-9
7968073
JAMA. 2002 Dec 18;288(23):2998-3007
12479764
JAMA. 1998 May 27;279(20):1615-22
9613910
N Engl J Med. 2008 Apr 3;358(14):1431-43
18376000
N Engl J Med. 1998 Nov 5;339(19):1349-57
9841303
N Engl J Med. 2008 Nov 20;359(21):2195-207
18997196
Stroke. 2004 Dec;35(12):2902-9
15514180
JAMA. 1999 Dec 22-29;282(24):2340-6
10612322
N Engl J Med. 2005 Apr 7;352(14):1425-35
15755765
N Engl J Med. 1996 Oct 3;335(14):1001-9
8801446
N Engl J Med. 2007 Nov 29;357(22):2248-61
17984166
Curr Med Res Opin. 2002;18(4):220-8
12201623
N Engl J Med. 2006 Aug 10;355(6):549-59
16899775
Stat Med. 2002 Jun 15;21(11):1559-73
12111920
Lancet. 2005 Oct 8;366(9493):1267-78
16214597
JAMA. 2002 Dec 18;288(23):3042-4
12479771
Lancet. 2002 Jul 6;360(9326):7-22
12114036
Lancet. 2002 Nov 23;360(9346):1623-30
12457784
BMJ. 1996 Sep 21;313(7059):735-8
8819447
Lancet. 2003 Apr 5;361(9364):1149-58
12686036
JAMA. 2006 May 3;295(17):2046-56
16670413
Ann Intern Med. 2001 Dec 4;135(11):982-9
11730399
N Engl J Med. 1995 Nov 16;333(20):1301-7
7566020
J Am Coll Cardiol. 2005 Nov 15;46(10):1855-62
16286171
BMJ. 2001 Jul 14;323(7304):101-5
11451790
Lancet. 2006 Sep 30;368(9542):1155-63
17011942
Lancet. 2004 Aug 21-27;364(9435):685-96
15325833
Diabetes Care. 2006 Jul;29(7):1478-85
16801565
BMJ. 2003 Sep 6;327(7414):557-60
12958120