Effect of Different Antilipidemic Agents and Diets on Mortality. A Systematic Review

Article (PDF Available)inArchives of Internal Medicine 165(7):725-30 · May 2005with69 Reads
Impact Factor: 17.33 · DOI: 10.1001/archinte.165.7.725 · Source: PubMed
Abstract
Guidelines for the prevention and treatment of hyperlipidemia are often based on trials using combined clinical end points. Mortality data are the most reliable data to assess efficacy of interventions. We aimed to assess efficacy and safety of different lipid-lowering interventions based on mortality data. We conducted a systematic search of randomized controlled trials published up to June 2003, comparing any lipid-lowering intervention with placebo or usual diet with respect to mortality. Outcome measures were mortality from all, cardiac, and noncardiovascular causes. A total of 97 studies met eligibility criteria, with 137,140 individuals in intervention and 138,976 individuals in control groups. Compared with control groups, risk ratios for overall mortality were 0.87 for statins (95% confidence interval [CI], 0.81-0.94), 1.00 for fibrates (95% CI, 0.91-1.11), 0.84 for resins (95% CI, 0.66-1.08), 0.96 for niacin (95% CI, 0.86-1.08), 0.77 for n-3 fatty acids (95% CI, 0.63-0.94), and 0.97 for diet (95% CI, 0.91-1.04). Compared with control groups, risk ratios for cardiac mortality indicated benefit from statins (0.78; 95% CI, 0.72-0.84), resins (0.70; 95% CI, 0.50-0.99) and n-3 fatty acids (0.68; 95% CI, 0.52-0.90). Risk ratios for noncardiovascular mortality of any intervention indicated no association when compared with control groups, with the exception of fibrates (risk ratio, 1.13; 95% CI, 1.01-1.27). Statins and n-3 fatty acids are the most favorable lipid-lowering interventions with reduced risks of overall and cardiac mortality. Any potential reduction in cardiac mortality from fibrates is offset by an increased risk of death from noncardiovascular causes.

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Available from: Matthias Briel, Mar 18, 2014
REVIEW ARTICLE
Effect of Different Antilipidemic Agents
and Diets on Mortality
A Systematic Review
Marco Studer, MD; Matthias Briel, MD; Bernd Leimenstoll, MD; Tracy R. Glass, MSc; Heiner C. Bucher, MD, MPH
Background: Guidelines for the prevention and treat-
ment of hyperlipidemia are often based on trials using
combined clinical end points. Mortality data are the most
reliable data to assess efficacy of interventions. We aimed
to assess efficacy and safety of different lipid-lowering
interventions based on mortality data.
Methods: We conducted a systematic search of ran-
domized controlled trials published up to June 2003, com-
paring any lipid-lowering intervention with placebo or
usual diet with respect to mortality. Outcome measures
were mortality from all, cardiac, and noncardiovascular
causes.
Results: A total of 97 studies met eligibility criteria, with
137140 individuals in intervention and 138 976 indi-
viduals in control groups. Compared with control groups,
risk ratios for overall mortality were 0.87 for statins (95%
confidence interval [CI], 0.81-0.94), 1.00 for fibrates (95%
CI, 0.91-1.11), 0.84 for resins (95% CI, 0.66-1.08), 0.96
for niacin (95% CI, 0.86-1.08), 0.77 for n-3 fatty acids
(95% CI, 0.63-0.94), and 0.97 for diet (95% CI, 0.91-
1.04). Compared with control groups, risk ratios for car-
diac mortality indicated benefit from statins (0.78; 95%
CI, 0.72-0.84), resins (0.70; 95% CI, 0.50-0.99) and n-3
fatty acids (0.68; 95% CI, 0.52-0.90). Risk ratios for non-
cardiovascular mortality of any intervention indicated no
association when compared with control groups, with the
exception of fibrates (risk ratio, 1.13; 95% CI, 1.01-
1.27).
Conclusions: Statins and n-3 fatty acids are the most fa-
vorable lipid-lowering interventions with reduced risks
of overall and cardiac mortality. Any potential reduc-
tion in cardiac mortality from fibrates is offset by an in-
creased risk of death from noncardiovascular causes.
Arch Intern Med. 2005;165:725-730
L
IPID-LOWERING AGENTS ARE
basic drugs for primary and
secondary prevention of car-
diovascular diseases and have
been now in use for more
than 4 decades. The first lipid-lowering
drugs with proven efficacy to lower both car-
diovascular morbidity and overall mortal-
ity in a large-scale clinical trial were 3-hy-
droxymethyl-3-methylglutaryl coenzyme A
reductase inhibitors (statins).
1
In previous
meta-analyses, only statins showed statis-
tically significant and clinically relevant re-
ductions in coronary heart disease (CHD)
and overall mortality.
2,3
In addition to the
potent lipid-lowering capacity of statins,
more recent findings indicate that the posi-
tive effects of statins could also be the re-
sult of reductions in platelet aggregability
and endothelial inflammation.
4
Over the past 5 years, large trials of sev-
eral statins and other lipid-lowering inter-
ventions provided important information on
the efficacy of these drugs in various risk
groups and settings as well as in generally
underinvestigated populations, such as
women or the elderly. Large-scale meta-
analyses of randomized controlled trials are
important tools to document the overall
benefit of interventions and to explore effect
sizes of clinically relevant outcomes in
important subgroups.
5
The goal of the
present meta-analysis is to investigate the
efficacy and safety of different lipid-
lowering interventions in the primary and
secondary prevention of CHD based on
mortality data.
METHODS
SEARCH FOR RELEVANT STUDIES
We included references from previous meta-
analyses
2,6
and 2 of us (M.S. and M.B.) searched
MEDLINE, EMBASE, PASCAL, and the
Cochrane Controlled Trials Register together
Author Affiliations: Basel
Institute for Clinical
Epidemiology (Drs Studer,
Briel, and Bucher and Ms Glass)
and Department of Internal
Medicine (Drs Studer and
Leimenstoll), University
Hospital Basel, Basel,
Switzerland.
Financial Disclosure: None.
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with a professional librarian to identify
all randomized controlled trials pub-
lished between 1965 and June 2003
that compared lipid-lowering agents or
dietary interventions with placebo or
usual care. No language restrictions
were imposed.
STUDY SELECTION
AND DATA ABSTRACTION
Trials were considered eligible for this
meta-analysis if they compared any lipid-
lowering intervention with placebo or
usual care, used random allocation, had
a follow-up of at least 6 months, and re-
ported mortality data. We excluded trials
that were restricted to heart transplant
recipients; trials in coronary artery by-
pass grafts or acute coronary syn-
dromes; trials using hormone therapy in
men or those using postmenopausal hor-
mone therapies (because these therapies
were shown to be harmful for CHD pre-
vention
2,7
); trials using any combination
of lipid-lowering intervention (not allow-
ing us to classify the intervention to 1
drug); and trials with outdated interven-
tions such as ileal bypass surgery. De-
tails of included and excluded trials are
provided at http://www.bice.ch/engl
/publications_reports.htm.
Two of 3 investigators (M.S., M.B.,
and B.L.) assessed study eligibility and
quality blinded to one another’s rating
and resolved any disagreement by con-
sensus. Data of eligible trials were ab-
stracted in duplicate, and authors of the
original trials were contacted for addi-
tional data if needed. We assessed the
quality of included trials with respect to
concealment of treatment allocation;
blinding of patients, caregivers, or asses-
sors of clinical outcomes; and complete-
ness of follow-up.
8
When the article failed
to provide explicit information about a
quality component, we assumed it was not
present.
Based on pharmacological character-
istics, we classified trials according to the
following groups
9
: statins (35 trials [A1-
A35]), fibrates (17 trials [A36-A52]), res-
ins (8 trials [A53-A60]), niacin (2 trials
[A39 and A61]), n-3 fatty acids (14 trials
[A67-A79]), and dietary interventions
(17 trials [A53 and A80-A95]). We lim-
ited the analysis to interventions with at
least 1000 individuals per group. There-
fore data on policosanol (3 trials [A62-
A64]), probucol (3 trials [A20,A65, and
A66]), and garlic (2 trials [A96 and
A97]) are only presented in an addi-
tional table at http://www.bice.ch/engl
/publications_reports.htm. Trials in pri-
mary prevention of CHD were defined
as trials with less than 10% of partici-
pants with CHD, whereas secondary pre-
vention trials comprised 100% partici-
pants with CHD. The percentage of total
cholesterol reduction for each trial was
calculated as the difference in the mean
change from baseline to end of fol-
low-up in the intervention and control
groups. End points of interest for over-
all benefit of lipid-lowering interven-
tions were overall mortality and cardiac
mortality (eg, death from myocardial in-
farction, sudden death, or heart failure)
and deaths from noncardiovascular
causes.
STATISTICAL ANALYSIS
We pooled treatment effects across stud-
ies for each of 6 predefined lipid-
lowering interventions and calculated a
weighted average risk ratio (RR) of all
outcomes in the treatment and control
groups by using a random effects model.
We investigated the presence of publi-
cation bias by means of funnel plots.
10
We tested for heterogeneity with the
Cochran Q test and measured inconsis-
tency (I
2
; the percentage of total varia-
tion across studies that is due to hetero-
geneity rather than chance) of treatment
effects across different lipid-lowering in-
terventions.
11,12
We tested for the differences in the
relative risk estimates of subgroups by
calculating a z score, the difference in
the subgroup logarithmic relative risk di-
vided by the standard error of the dif-
ference.
13
For sensitivity analysis we ex-
amined treatment effects according to
quality components and in trials of pri-
mary and secondary prevention of CHD.
We used inverse variance-weighted
meta–regression analysis to investigate
any association between overall mortal-
ity and the extent of cholesterol reduc-
tion, items about trial quality, percent-
age of patients with established CHD in
trials, and the type and duration of lipid-
lowering intervention.
14
Numbers
needed to treat per year to prevent 1
death in patients with and without pre-
existing CHD were calculated by mul-
tiplying of the averaged-weighted mean
annual baseline risk with the mean rela-
tive risk reduction in each intervention
category.
15
All statistical analyses were
done using Stata 8.2 (StataCorp, Col-
lege Station, Tex) and S-PLUS 2000
(MathSoft Inc, Cambridge/Mass) soft-
ware.
RESULTS
We identified 10 977 trials that com-
pared lipid-lowering interventions to
placebo or usual care. Of these, 127
were randomized controlled trials re-
porting mortality data. We ex-
cluded 30 trials for reasons stated in
the “Methods” section, thus leav-
ing 97 trials for analysis (for details
see http://www.bice.ch/engl
/publications_reports.htm). Four of
these trials (A20, A39, A53, and
A72) had multiple treatment
arms, so the control group was
used for comparison against all
treatment arms. In total, there
were 137140 individuals in the
intervention and 138 976 individu-
als in the control groups. Analysis
for publication bias indicated no
evidence for such bias for any of
the interventions.
The average relative reduction in
levels of total cholesterol for statins
was 20% (range, 7%-36%), for
fibrates 8% (range, 0%-14%),
for resins 15% (range, 8%-24%), for
niacin 11% (range, 8%-14%),
for n-3 fatty acids 2% (range, –2%
to 9%), and for diet 10% (range,
1%-24%) (
Table 1).
OVERALL MORTALITY
Risk ratios for overall mortality were
statistically significantly reduced for
statins (0.87; 95% CI, 0.81-0.94; test
of heterogeneity, P =.05; I
2
=30%
[95% uncertainty interval [UI], 0%-
54%]), and n-3 fatty acids (0.77; 95%
CI, 0.63-0.94; P=.01; I
2
=53% [95%
UI, 14%-75%]) (Figure). For stat-
ins this effect was consistent in trials
of primary and secondary preven-
tion of CHD, but there was insuf-
ficient evidence to support a bene-
ficial effect of n-3 fatty acids in
primary prevention of CHD
(Table 1). For trials with statins, n-3
fatty acids, and fibrates (RR, 1.00;
95% CI, 0.91-1.11; P=.01; I
2
=33%
[95% UI, 0%-63%]) we found mod-
erate heterogeneity (P < .10;
I
2
25%). When exploring hetero-
geneity in sensitivity analyses, sum-
mary estimates of statin and fibrate
trials with lower methodological
quality had mostly higher risk re-
ductions compared with summary
estimates from trials that fulfilled re-
spective quality components, but
these differences were not statisti-
cally significant (
Table 2). Hetero-
geneity for n-3 fatty acids was mainly
due to 1 trial (Burr et al [A79; see
http://www.bice.ch/engl/publications
_reports.htm]) that contrasted the
favorable risk reductions found in
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the remaining n-3 fatty acid trials.
The quality of that trial in compari-
son with the other trials was low.
16
With exclusion of that trial, the RR
for overall mortality was 0.75 (95%
CI, 0.65-0.87), and heterogeneity
was substantially reduced (P=.36;
I
2
=9% [95%UI, 0%-47%]).
CARDIAC MORTALITY
Risk ratios for cardiac deaths indi-
cated a statistically significant ben-
efit from statins (0.78; 95% CI, 0.72-
0.84; P =.42; I
2
=3% [95% UI, 0%-
30%]), resins (0.70; 95% CI, 0.50-
0.99; P =.83; I
2
=0% [95% UI, 0%-
68%]), and n-3 fatty acids (0.68; 95%
CI, 0.52-0.90; P=.001; I
2
=66% [95%
UI, 37%-81%]). Again, when ex-
cluding Burr et al (A79) in sensitiv-
ity analysis from the group of n-3
fatty acids, heterogeneity de-
creased immensely (RR, 0.70; 95%
CI, 0.61-0.80; P=.47; I
2
=0% [95%
UI, 0%-60%]).
MORTALITY FROM
CAUSES OTHER THAN
CARDIOVASCULAR DISEASE
Risk ratios for death from causes
other than cardiovascular disease
were all nonsignificant except for fi-
brates, for which we found an in-
creased risk of death (RR, 1.13; 95%
CI, 1.01-1.27; P=.80, I
2
=0% [95%
UI, 0%-54%]). In a post hoc sub-
group analysis, we did not find an
increased risk of death from neo-
plasia in fibrate trials; however, the
limited number of trials providing
detailed noncardiovascular, cause-
specific mortality data precluded a
more detailed analysis of noncar-
diovascular mortality.
META-REGRESSION ANALYSIS
In univariate meta-regression analy-
sis, only the percentage of patients
with established CHD (coefficient,
–0.001; 95% CI, –0.003 to –0.0003)
and trial duration (coefficient, 0.043;
95% CI, 0.014 to 0.072) were asso-
ciated with and explained a statisti-
cally significant degree of variability
in the log odds ratio for overall mor-
tality. This indicates that the magni-
tude of the effect of a lipid-lowering
intervention tends to increase in trials
with a higher percentage of partici-
pants with established CHD and to
decrease in trials of longer duration.
Cholesterol level reduction was only
statistically significant in the model
Table 1. Effects of Different Lipid-Lowering Interventions on Overall Mortality
Type of Intervention*
Trials,
No.
Individuals,
T/C
Follow-up,
Mean ± SD,
y
Cholesterol
Reduction, Mean
(Range), %
Overall
Deaths,
T/C
Overall
Mortality,
RR (95% CI)
Heterogeneity,
P Value
Inconsistency,
I
2
(95% UI), %
Statins (all trials) 35 53 417/48 460 2.9 ± 1.6 20 (7 to 36) 3793/4290 0.87 (0.81 to 0.94) .05 30 (0 to 54)
Primary prevention
of CHD
9 13 341/13 300 3.3 ± 1.0 17 (13 to 22) 388/450 0.86 (0.76 to 0.99) .50 0 (0 to 65)
Secondary prevention
of CHD
20 13 584/13 548 2.6 ± 1.7 21 (6 to 36) 972/1242 0.78 (0.71 to 0.86) .42 3 (0 to 50)
Fibrates (all trials) 17 13 761/15 429 4.4 ± 1.6 8 (0 to 14) 1257/1682 1.00 (0.91 to 1.11) .01 33 (0 to 63)
Primary prevention
of CHD
3 7463/7409 4.4 ± 1.3 10 (9 to 12) 281/224 1.25 (1.05 to 1.48) .50 0 (0 to 90)
Secondary prevention
of CHD
9 5182/6892 5.2 (1.4) 8 (0 to 14) 779/1239 0.96 (0.86 to 1.08) .21 26 (0 to 65)
Resins (all trials) 8 3280/3257 3.2 ± 2.2 15 (8 to 24) 112/134 0.84 (0.66 to 1.08) .86 0 (0 to 68)
Primary prevention
of CHD
1 1906/1900 7.4 8 (NA) 68/71 0.95 (0.69 to 1.32) NA NA
Secondary prevention
of CHD
2 101/102 4 ± 1.4 20 (15 to 24) 5/10 0.56 (0.18 to 1.82) .30 7 (NA)
Niacin (all trials) 2 1196/2932 4.7 ± 2.1 11 (8 to 14) 288/736 0.96 (0.86 to 1.08) .81 0 (NA)
Primary prevention
of CHD
0NANANANANA NANA
Secondary prevention
of CHD
2 1196/2932 4.7 ± 2.1 11 (8 to 14) 288/736 0.96 (0.86 to 1.08) .81 0 (NA)
n-3 Fatty acids (all
trials)
14 10 122/10 138 1.9 ± 1.2 2 (–2 to 9) 918/1038 0.77 (0.63 to 0.94) .01 53 (14 to 75)
Primary prevention
of CHD
1 51/105 2.0 –1 (NA) 1/0 6.1 (0.25 to 148) NA NA
Secondary prevention
of CHD
9 9270/9236 2.1 ± 1.5 1 (–2 to 4) 860/945 0.84 (0.66 to 1.06)† .01† 59 (14 to 80)†
Diet (all trials) 17 54 411/60 899 4.2 ± 2.5 10 (1 to 24) 3553/4775 0.97 (0.91 to 1.04) .19 23 (0 to 56)
Primary prevention
of CHD
5 48 137/54 675 6.7 ± 2.0 8 (1 to 24) 2909/4111 0.99 (0.94 to 1.03) .54 0 (0 to 79)
Secondary prevention
of CHD
9 1253/1231 3.0 ± 1.3 10 (3 to 18) 200/236 0.85 (0.66 to 1.09) .10 41 (0 to 73)
Abbreviations: CHD, coronary heart disease; CI, confidence interval, NA, not applicable; RR, risk ratio; T/C, number of individuals in treatment/control groups;
UI, uncertainty interval.
*Trials in primary prevention of CHD were defined as trials with less than 10% of participants with CHD, while secondary prevention trials comprised 100%
participants with CHD. There are some trials with mixed study populations (eg, 55% of participants with CHD) that could not be confined to either category; these
are therefore not included in this subgroup analysis.
†Sensitivity analysis without the trial of Burr et al (A79; see http://www.bice.ch/engl/publications_reports.htm): RR for overall mortality, 0.80 (95% CI,
0.69-0.92; P=.40; I
2
=6% [95% UI, 0%-69%]).
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when n-3 fatty acid trials were ex-
cluded (coefficient, –0.92; 95% CI,
–1.52 to –0.32). When each lipid-
lowering intervention was exam-
ined separately (eg, trials of fibrates
vs trials of interventions other than fi-
brates), use of fibrates was the only
intervention that explained a statis-
tically significant degree of variabil-
ity in the log odds ratio for overall
mortality (coefficient, 0.14; 95% CI,
0.004 to 0.27), indicating a positive
association of fibrates with overall
mortality.
In meta-regression analysis
within subgroups of different lipid-
lowering interventions, the percent-
age of patients with established CHD
explained all between-trial vari-
ance in the subgroup of trials with
statins (
2
=0.011) and trials with fi-
brates (
2
=0.017). These findings are
consistent with the observed de-
crease in heterogeneity in sub-
groups of primary and secondary
prevention trials for these interven-
tions (Table 1).
COMMENT
This systematic review of random-
ized controlled trials examines the as-
sociation between different lipid-
lowering interventions and mortality
from various causes. Our study con-
firms the benefit of statins in reduc-
ing the risk of overall and cardiac mor-
tality
2
in patients with or without
CHD and additionally shows that n-3
fatty acids reduce overall and car-
diac mortality in patients with CHD.
We estimated that 248 (95% CI, 170-
538) patients in a secondary preven-
tion situation with a mortality rate
higher than 3% per year and 855 (95%
CI, 585-1852) patients in a primary
prevention situation with a mortal-
ity rate lower than 1% per year have
to be treated with a statin for 1 year
to prevent 1 death. For n-3 fatty ac-
ids, 140 (95% CI, 87-538) patients in
a secondary prevention situation have
to be treated for 1 year to prevent 1
death.
In contrast, we found no reduc-
tion in overall mortality and an in-
creased risk of death from noncar-
diovascular causes in individuals
taking fibrates compared with indi-
viduals in placebo or control groups.
We found little evidence of hetero-
geneity in the summary estimates for
noncardiovascular mortality in fi-
brate trials (test of heterogeneity
P=.80; I
2
=0%), suggesting a consis-
tent effect in trials using various fi-
brates. Niacin and fibrates have ex-
cellent properties to increase high-
density lipoprotein cholesterol levels
and reduce triglyceride levels. Cur-
rent guidelines recommend the use of
either drug in patients with hypertri-
glyceridemia, high levels of low-
density lipoproteins, and meta-
bolic syndrome.
17,18
If used in ap-
propriate doses, n-3 fatty acids are
as effective as fibrates to reduce tri-
glyceride levels
19
but are associated
with a reduction in overall mortal-
ity. However, n-3 fatty acids lower
total cholesterol level to a very small
extent, which indicates that benefi-
cial effects must be mediated by
other means. Studies suggest that n-3
fatty acids may have antiarrhyth-
mic properties with membrane-
sta bilizing effects in addition to an-
tithrombotic and anti-inflamma-
tory properties on the endothelial
level.
16
Summary estimates for res-
ins and dietary interventions indi-
cated possible benefit in cardiac mor-
tality, though confidence intervals
were large or included an RR of 1.
However, for both interventions we
found little evidence that these in-
terventions may affect overall mor-
tality in primary or secondary pre-
vention of CHD.
Statins (n = 35)
Fibrates (n
= 17)
Resins (n
= 8)
Niacin (n = 2)
n-3 FA (n
= 14)
Diet (n
= 18)
Overall Mortality
A
Statins (n = 33)
Fibrates (n
= 17)
Resins (n = 8)
Niacin (n
= 2)
n-3 FA (n = 12)
Diet (n = 18)
Cardiac Mortality
B
Statins (n = 26)
Fibrates (n
= 15)
Resins (n
= 4)
Niacin (n
= 2)
n-3 FA (n
= 9)
Diet (n = 15)
Risk Ratio (95% CI); Heterogeniety (P );
Inconsistency I
2
) [95% UI], %
0.87 (0.81-0.94); P
=
.05; I
2
=
30 [0-54]
1.00 (0.91-1.11); P
=
.01; I
2
=
33 [0-63]
0.84 (0.66-1.08); P
=
.86; I
2
=
0 [0-68]
0.96 (0.86-1.08); P
=
.81; I
2
=
0
0.77 (0.63-0.94); P
=
.01; I
2
=
53 [14-75]
0.97 (0.91-1.04); P
=
.19; I
2
=
23 [0-56]
Risk Ratio (95% CI); Heterogeniety (P );
Inconsistency I
2
) [95% UI], %
0.78 (0.72-0.84); P
=
.42; I
2
=
3 [0-30]
0.93 (0.81-1.08); P
=
.13; I
2
=
28 [0-60]
0.70 (0.50-0.99); P
=
.83; I
2
=
0 [0-68]
0.95 (0.82-1.10); P
=
.75; I
2
=
0
0.68 (0.52-0.90); P <.001; I
2
=
66 [37-81]
0.91 (0.82-1.02); P
=
.14; I
2
=
27 [0-59]
Risk Ratio (95% CI); Heterogeniety (P );
Inconsistency I
2
) [95% UI], %
0.97 (0.91-1.04); P
=
.78; I
2
=
0 [0-43]
1.13 (1.01-1.27); P
=
.80; I
2
=
0 [0-54]
1.08 (0.74-1.58); P
=
.82; I
2
=
0 [0-85]
1.13 (0.77-1.67); P
=
.81; I
2
=
0
0.97 (0.84-1.13); P
=
.95; I
2
=
0 [0.65]
1.01 (0.96-1.07); P
=
.71; I
2
=
0 [0-54]
Mortality From Causes Other Than Cardiovascular Diseases
C
Favors
Treatment
Favors
Control
0.5 0.8 1.251.0 2.0
Risk Ratio
0.5 0.8 1.251.0 2.0
Risk Ratio
Favors
Treatment
Favors
Control
0.5 0.8 1.251.0 2.0
Risk Ratio
Favors
Treatment
Favors
Control
Figure. Summary estimates for overall mortality (A), cardiac mortality (B), and mortality from causes
other than cardiovascular diseases (C) for different types of lipid-lowering interventions. The Cochrane
Q test for heterogeneity. I
2
as measure of inconsistency (in percent). CI indicates confidence interval;
UI, uncertainty interval; n, number of trials available for analysis; n-3 FA, n-3 fatty acid.
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Our study has several strengths
and limitations. We have con-
ducted an extensive literature search
to retrieve all relevant eligible trials.
Although formal testing for publi-
cation bias indicated little evidence
for such bias, it cannot be ruled out.
For clinical end points we exclu-
sively used mortality data that may
be less prone to ascertainment bias.
Given the heterogeneity in all in-
cluded trials (P .001; I
2
=37% [95%
UI, 19%-51%]), a subgroup analy-
sis was justifiable. We have limited
our subgroup analyses to the clini-
cally relevant question of whether
different lipid-lowering interven-
tions provide similar benefit in trials
for primary and secondary preven-
tion of CHD. Nevertheless, such
analyses may be prone to bias and
should be carefully interpreted.
20
In
particular, our evaluation of differ-
ent lipid-lowering interventions re-
lies on between-trial rather than
within-trial comparisons. Thus, ap-
parent differences in efficacy be-
tween interventions inferred from
between-trial comparisons may ac-
tually be due to factors other than the
intervention, including differences in
study design and populations. Fi-
nally, it may be argued that our clas-
sification of lipid-lowering interven-
tions combines antilipidemic agents
or diets with important pharmaco-
logical differences or mechanisms of
action.
9
For example, trials of n-3 fatty
acids used different dietary and non-
dietary sources with food supple-
ments of n-3 fatty acids or n-3 fatty
acid precursors.
In conclusion, this systematic re-
view suggests that statins and n-3
fatty acids offer the most favorable
benefits by reducing the risk of car-
diac and overall mortality. Use of fi-
brates may be associated with an in-
creased risk of noncardiovascular
mortality. Future trials should ex-
plore whether n-3 fatty acids in com-
bination with statins lead to addi-
tional reduction in CHD mortality,
especially in patients with meta-
bolic syndrome.
Accepted for Publication: Novem-
ber 16, 2004.
Correspondence: Heiner C. Bucher,
MD, MPH, Basel Institute for Clini-
cal Epidemiology, University Hos-
pital Basel, Kantonsspital Basel,
Hebelstrasse 10, CH-4031 Basel,
Switzerland (hbucher@uhbs.ch).
Funding/Support: Drs Bucher and
Briel and Ms Glass are supported by
Santésuisse, Solothurn, Switzerland,
and the Gottfried and Julia Bangerter-
Rhyner Foundation, Berne, Switzer-
land.
Acknowledgment: We are grateful
to Peter Wolf, Dr phil nat, for assis-
tance with the literature search. We
thank all original investigators who
contributed additional information
from their trials.
REFERENCES
1. 4S-Group. Randomised trial of cholesterol low-
ering in 4444 patients with coronary heart dis-
ease: the Scandinavian Simvastatin Survival Study
(4S). Lancet. 1994;344:1383-1389.
2. Bucher HC, Griffith LE, Guyatt GH. Systematic re-
view on the risk and benefit of different cholesterol-
lowering interventions. Arterioscler Thromb Vasc
Biol. 1999;19:187-195.
3. Ross SD, Allen IE, Connelly JE, et al. Clinical out-
comes in statin treatment trials: a meta-analysis.
Arch Intern Med. 1999;159:1793-1802.
4. Rosenson RS, Tangney CC. Antiatherothrom-
botic properties of statins: implications for car-
diovascular event reduction. JAMA. 1998;279:
1643-1650.
5. Pogue J, Yusuf S. Overcoming the limitations of
current meta-analysis of randomised controlled
trials. Lancet. 1998;351:47-52.
6. Smith GD, Song F, Sheldon TA. Cholesterol low-
ering and mortality: the importance of consider-
ing initial level of risk. BMJ. 1993;306:1367-
1373.
7. Rossouw JE, Anderson GL, Prentice RL, et al.
Risks and benefits of estrogen plus progestin in
healthy postmenopausal women: principal
results from the Women’s Health Initiative ran-
domized controlled trial. JAMA. 2002;288:321-
333.
8. Juni P, Witschi A, Bloch R, Egger M. The hazards
of scoring the quality of clinical trials for
meta-analysis. JAMA. 1999;282:1054-1060.
9. McAlister FA, Laupacis A, Wells GA, Sackett
DL. Users’ Guides to the Medical Literature,
XIX: applying clinical trial results B: guidelines
for determining whether a drug is exerting
(more than) a class effect. JAMA. 1999;282:
1371-1377.
10. Egger M, Davey SG, Schneider M, Minder C.
Bias in meta-analysis detected by a simple, graphi-
cal test. BMJ. 1997;315:629-634.
Table 2. Sensitivity Analysis of Quality Components for Statins, Fibrates, and n-3 Fatty Acids
Quality Component
Statins
Fibrates n-3 Fatty Acids
Trials,
No.
Overall
Mortality,
RR (95% CI)
Difference
P Value
Trials,
No.
Overall
Mortality,
RR (95% CI)
Difference
P Value
Trials,
No.
Overall
Mortality,
RR (95% CI)
Difference
P Value
Concealed allocation
Yes 11 0.90 (0.83-0.98)
.18
6 1.00 (0.92-1.08)
.88
5 0.76 (0.55-1.06)
.95
No 24 0.82 (0.71-0.93) 11 0.97 (0.77-1.23) 9 0.75 (0.55-1.03)
Blinded patients and caregivers
Yes 29 0.87 (0.80-0.94)
.46
14 1.01 (0.91-1.12)
.56
9 0.59 (0.41-0.86)
.07*
No 6 0.77 (0.54-1.09) 3 0.81 (0.43-1.54) 5 0.82 (0.65-1.04)*
Blinded outcome assessors
Yes 20 0.85 (0.80-0.92)
.59
9 1.01 (0.90-1.15)
.69
11 0.72 (0.61-0.86)
.001†
No 15 0.96 (0.67-1.36) 8 0.95 (0.75-1.21) 3 1.15 (0.98-1.34)†
Follow-up 90%
Yes 24 0.87 (0.81-0.93)
.90
13 1.01 (0.89-1.14)
.76
8 0.78 (0.60-1.01)
.56
No 11 0.91 (0.51-1.63) 4 0.96 (0.74-1.24) 6 0.71 (0.56-0.91)
Abbreviations: CI, confidence interval; RR, risk ratio.
*Sensitivity analysis without the trial of Burr et al (A79; see http://www.bice.ch/engl/publications_reports.htm): RR for overall mortality, 0.75 (95% CI, 0.60-0.92);
difference P value, .15.
†Sensitivity analysis without the trial of Burr et al (A79): RR for overall mortality, 1.25 (95% CI, 0.31-5.07); difference P value, .78.
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Page 5
11. Higgins JP, Thompson SG, Deeks JJ, Altman DG.
Measuring inconsistency in meta-analyses. BMJ.
2003;327:557-560.
12. Higgins JP, Thompson SG. Quantifying hetero-
geneity in a meta-analysis. Stat Med. 2002;21:
1539-1558.
13. Fleiss JL. The statistical basis of meta-analysis.
Stat Methods Med Res. 1993;2:121-145.
14. Thompson SG, Sharp SJ. Explaining heterogene-
ity in meta-analysis: a comparison of methods. Stat
Med. 1999;18:2693-2708.
15. Marx A, Bucher HC. Numbers needed to treat de-
rived from meta-analysis: a word of caution. ACP
J Club. 2003;138:A11-A12.
16. Din JN, Newby DE, Flapan AD. Omega 3 fatty ac-
ids and cardiovascular disease—fishing for a natu-
ral treatment. BMJ. 2004;328:30-35.
17. Expert Panel on Detection EaToHBCiA. Execu-
tive Summary of The Third Report of The
National Cholesterol Education Program
(NCEP) Expert Panel on Detection, Evaluation,
and Treatment of High Blood Cholesterol in
Adults (Adult Treatment Panel III). JAMA. 2001;
285:2486-2497.
18. Grundy SM, Cleeman JI, Merz CN, et al. Implica-
tions of recent clinical trials for the National Cho-
lesterol Education Program Adult Treatment Panel
III guidelines. Arterioscler Thromb Vasc Biol. 2004;
24:e149-e161.
19. Bucher HC, Hengstler P, Schindler C, Meier G.
N-3 polyunsaturated fatty acids in coronary heart
disease: a meta-analysis of randomized con-
trolled trials. Am J Med. 2002;112:298-304.
20. Oxman AD, Guyatt GH. A consumer’s guide to sub-
group analyses. Ann Intern Med. 1992;116:
78-84.
Correction
Omissions in Byline. In the Original Investigation by
Cohen et al titled “Emerging Credentialing Practices, Mal-
practice Liability Policies, and Guidelines Governing
Complementary and Alternative Medical Practices and
Dietary Supplement Recommendations: A Descriptive
Study of 19 Integrative Health Care Centers in the United
States,” published in the February 14 issue of the
A
RCHIVES (2005;165:289-295), 2 authors were inadvert-
ently omitted from the byline on page 289. The byline
should have appeared as follows: “Michael H. Cohen, JD;
Andrea Hrbek; Roger B. Davis ScD; Steven C. Schachter,
MD; Kathi J. Kemper, MD, MPH; Edward W. Boyer, MD,
PhD; David M. Eisenberg, MD.”
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    • "Currently, there are no synthetic ligands for PPAR-δ in clinical use (Sahebkar et al. 2014). In the secondary prevention of cardiovascular disease, there is evidence that n3-polyunsaturated fatty acids (n3-PUFAs) are effective (Studer et al. 2005). A study with HD patients failed to show a reduction in cardiovascular events or death after treatment with an n3-PUFA (Svensson et al. 2006). "
    [Show abstract] [Hide abstract] ABSTRACT: High-density lipoprotein (HDL) has attracted interest as a therapeutic target in cardiovascular diseases in recent years. Although many functional mechanisms of the vascular protective effects of HDL have been identified, increasing the HDL plasma level has not been successful in all patient cohorts with increased cardiovascular risk. The composition of the HDL particle is very complex and includes diverse lipids and proteins that can be modified in disease conditions. In patients with chronic kidney disease (CKD), the accumulation of uremic toxins, high oxidative stress, and chronic micro-inflammatory conditions contribute to changes in the HDL composition and may also account for protein/lipid modifications. These conditions are associated with a decreased protective function of HDL. Therefore, the HDL quantity and the functional quality of the particle must be considered. This review summarizes the current knowledge of dyslipidemia in CKD patients, the effects of lipid-modulating therapy, and the structural modifications of HDL that are associated with dysfunction.
    Full-text · Article · Jan 2015
    • "and all‐cause mortality (relative risk 0.8; 95% CI 0.7–0.9). In a meta‐ analysis including 14 studies involving over 20,000 patients, Studer et al. [93] reported that compared with control, very long chain n‐3 fatty acids lower the risk of cardiac mortality (relative risk 0.68; 95% CI 0.52–0.90) and all‐cause mortality (relative risk 0.77; 95% CI 0.63–0.94). "
    [Show abstract] [Hide abstract] ABSTRACT: Omega-3 (n-3) fatty acids are a family of polyunsaturated fatty acids that contribute to human health and well-being. Functionally the most important n-3 fatty acids appear to be eicosapentaenoic acid (EPA) and docosahexaenoioc acid (DHA), but roles for n-3 docosapentaenoic acid (DPA) are now emerging. Intakes of EPA and DHA are usually low, typically below recommended intakes. Increased intakes are reflected in greater incorporation into blood lipid, cell and tissue pools. Increased content of EPA and DHA modifies the structure of cell membranes and the function of membrane proteins involved as receptors, signaling proteins, transporters, and enzymes. EPA and DHA modify the production of lipid mediators and through effects on cell signaling can alter patterns of gene expression. Through these actions EPA and DHA alter cell and tissue responsiveness in a manner that seems to result in more optimal conditions for growth, development, and maintenance of health. The effects of n-3 fatty acids are evident right through the life course, meaning that there is a need for all sectors of the population to have a sufficient intake of these important nutrients. EPA and DHA have a wide range of physiological roles which are linked to certain health or clinical benefits. Practical application: Very long chain omega-3 (n-3) fatty acids are found in seafood, especially fatty fish, and in supplements. They exert a range of health benefits as a result of their molecular, cellular and physiological actions. Consequently, very long chain n-3 fatty acids play important roles in growth, development, optimal function, and maintenance of health and well-being right across the life course. Therefore, all sectors of the population need to ensure sufficient intake of these important nutrients. This can be achieved through eating fatty fish or, failing that, use of good quality supplements.
    Article · Oct 2014
    • "They improve endothelial dysfunction and reduce the growth of atherosclerotic plaque [4]. Available evidence does not strongly suggest clear clinical benefit of other lipid-lowering agents in such situations [5]. All of the available statins have small differences in terms of pharmacokinetics and pharmacodynamics and hence in clinical efficacy and side effects profile [6]. "
    [Show abstract] [Hide abstract] ABSTRACT: Background. Treatment of hyperlipidemia is helpful in both primary and secondary prevention of coronary heart disease and stroke. Aim. To compare lipid-lowering efficacy of rosuvastatin with atorvastatin. Methodology. This open-label randomized controlled trial was carried out at 1 Mountain Medical Battalion from September 2012 to August 2013 on patients with type 2 diabetes, hypertension, myocardial infarction, or stroke, meriting treatment with a statin. Those with secondary causes of dyslipidemia were excluded. Blood samples for estimation of serum total cholesterol, triglycerides, HDL-C, and LDL-C were collected after a 12-hour fast. Patients were randomly allocated to receive either atorvastatin 10 mg HS or rosuvastatin 5 mg HS daily. Lipid levels were rechecked after six weeks. Results. Atorvastatin was used in 63 patients and rosuvastatin in 66. There was a greater absolute and percent reduction in serum LDL-C levels with rosuvastatin as compared to atorvastatin (0.96 versus 0.54 mg/dL; P = 0.011 and 24.34 versus 13.66%; P = 0.045 ), whereas reduction in all other fractions was equal. Myalgias were seen in 5 (7.94%) patients treated with atorvastatin and 8 (12.12%) patients treated with rosuvastatin (P: 0.432). Conclusion. Rosuvastatin produces a greater reduction in serum LDL-C levels and should therefore be preferred over atorvastatin.
    Full-text · Article · Mar 2014
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