Journal of the American College of Cardiology
© 2008 by the American College of Cardiology Foundation
Published by Elsevier Inc.
Vol. 51, No. 7, 2008
ISSN 0735-1097/08/$34.00
doi:10.1016/j.jacc.2007.10.038
Lipids and CAD
Impact of Triglyceride Levels Beyond
Low-Density Lipoprotein Cholesterol After Acute
Coronary Syndrome in the PROVE IT-TIMI 22 Trial
Michael Miller, MD, FACC,* Christopher P. Cannon, MD, FACC,† Sabina A. Murphy, MPH,†
Jie Qin, MS,† Kausik K. Ray, MD, MRCP,‡ Eugene Braunwald, MD, MACC,†
for the PROVE IT-TIMI 22 Investigators
Baltimore, Maryland; Boston, Massachusetts; and Cambridge, United Kingdom
Objectives
The purpose of this study was to assess the impact of on-treatment triglycerides (TG) on coronary heart disease
(CHD) risk after an acute coronary syndrome (ACS).
Background
The PROVE IT-TIMI (Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis In Myocardial Infarction) 22 trial demonstrated that low-density lipoprotein cholesterol (LDL-C) ⬍70 mg/dl was associated with
greater CHD event reduction than LDL-C ⬍100 mg/dl after ACS. However, the impact of low on-treatment TG on
CHD risk beyond LDL-C ⬍70 mg/dl has not been explored.
Methods
The PROVE IT-TIMI 22 trial evaluated 4,162 patients hospitalized for ACS and randomized to atorvastatin 80 mg
or pravastatin 40 mg daily. The relationship between on-treatment levels of TG and LDL-C and the composite
end point of death, myocardial infarction (MI), and recurrent ACS were assessed 30 days after initial presentation.
Results
Low on-treatment TG (⬍150 mg/dl) was associated with reduced CHD risk compared with higher TG in univariate analysis (hazard ratio [HR] 0.73, 95% confidence interval [CI] 0.62 to 0.87; p ⬍ 0.001) and in adjusted analysis (HR 0.80, 95% CI 0.66 to 0.97; p ⫽ 0.025). For each 10-mg/dl decrement in on-treatment TG, the incidence
of death, MI, and recurrent ACS was lower by 1.6% or 1.4% after adjustment for LDL-C or non–high-density
lipoprotein cholesterol and other covariates (p ⬍ 0.001 and p ⫽ 0.01, respectively). Lower CHD risk was also
observed with TG ⬍150 mg/dl and LDL-C ⬍70 mg/dl (HR 0.72, 95% CI 0.54 to 0.94; p ⫽ 0.017) or low ontreatment TG, LDL-C, and C-reactive protein (⬍2 mg/l) (HR 0.59, 95% CI 0.41 to 0.83; p ⫽ 0.002) compared
with higher levels of each variable in adjusted analysis.
Conclusions
On-treatment TG ⬍150 mg/dl was independently associated with a lower risk of recurrent CHD events, lending
support to the concept that achieving low TG may be an additional consideration beyond low LDL-C in patients
after ACS. (The PROVE IT-TIMI 22 trial; NCT00382460) (J Am Coll Cardiol 2008;51:724–30) © 2008 by the
American College of Cardiology Foundation
Epidemiologic surveys have observed that elevated levels of
total cholesterol and low-density lipoprotein cholesterol
(LDL-C) are associated with increased risk of coronary
heart disease (CHD) (1), and therapeutic strategies that lead
to a statistically significant reduction in LDL-C lower CHD
event rates (2). The magnitude of CHD risk reduction as a
consequence of LDL-C lowering often ranges between 25%
and 35% (3). One potential impediment limiting further
reduction in CHD events despite low on-treatment LDL-C is
residual elevation in serum triglyceride (TG) levels (4). Historically, elevated TG has predicted CHD events in univariate
analysis, only to weaken after adjustment for other covariates,
including plasma glucose and high-density lipoprotein cholesterol (HDL-C), to which it is strongly and inversely correlated
From the *University of Maryland Medical Center, Baltimore, Maryland; †TIMI Study
Group, Brigham and Women’s Hospital, Boston, Massachusetts; and the ‡University of
Cambridge, Cambridge, United Kingdom. The PROVE IT-TIMI trial was funded by
Bristol-Myers Squibb and Sankyo. Dr. Miller was funded by a Veterans Affairs Merit
Award and a National Institutes of Health grant (HL-61369). Dr. Miller has received
research grant support and honoraria for lectures from Abbott, AstraZeneca, Merck–
Schering-Plough, Pfizer, Reliant, and Sanofi-Aventis. Dr. Cannon has received research
grant support from AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, Merck,
Sanofi-Aventis, and Schering-Plough. Dr. Ray has received research grant support from
Bristol-Myers Squibb and Pfizer and honoraria for lectures and consulting fees from Pfizer.
Dr. Braunwald has received research support from Bristol-Myers Squibb, Merck, and
AstraZeneca and honoraria for lectures from Bristol-Myers Squibb, Sanofi, and Pfizer. See
accompanying online Cardiosource Slide Set.
Manuscript received August 21, 2007; revised manuscript received October 18,
2007, accepted October 22, 2007.
Miller et al.
Impact of Triglycerides After ACS
JACC Vol. 51, No. 7, 2008
February 19, 2008:724–30
(5). Yet, even after adjustment for HDL-C, detailed evaluation
of population-based prospective studies has disclosed an independent effect of TG on CHD events (6). Coupled with the
knowledge that combined hyperlipidemia (i.e., elevated
LDL-C and TG) promotes CHD to a significantly greater
extent than either high LDL-C or TG alone (7), the
present analysis was undertaken to test the hypothesis that
low on-treatment levels of TG when added to low LDL-C
would be superior to low LDL-C alone in reducing subsequent CHD events after an acute coronary syndrome
(ACS).
Methods
Study population and protocol. The study population originated from the PROVE IT-TIMI (Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis In Myocardial Infarction) 22 trial, a study prospectively designed to
compare the effect of intensive versus standard therapy to
reduce LDL-C, as previously reported (8,9). Briefly, 4,162
men and women hospitalized for ACS with total cholesterol
⬍240 mg/dl, or ⬍200 mg/dl if receiving lipid-lowering therapy, were randomly assigned to receive intensive therapy
(atorvastatin 80 mg daily) or standard therapy (pravastatin 40
mg daily) for a mean follow-up period of 2 years. In addition,
gatifloxacin versus placebo was tested concomitantly in a
factorial design. Total cholesterol, TG, and HDL-C were
measured using an enzymatic colorimetric assay (Roche Modular system, Roche Diagnostics, Indianapolis, Indiana) after
the recommended 12-h overnight fast (10). The LDL-C was
estimated using the formula: total cholesterol ⫺ (TG/5 ⫹
HDL-C) (11), or directly measured if TG exceeded 400
mg/dl. Lipid and lipoprotein levels were obtained at baseline, 1, 4, 8, 16, and 24 months, and the final visit. The
725
composite end point of death,
Abbreviations
and Acronyms
myocardial infarction (MI), or
recurrent ACS was used as preACS ⴝ acute coronary
viously outlined (12).
syndrome
Statistical analysis. KaplanCHD ⴝ coronary heart
Meier event rates for the comdisease
posite end point of interest were
CRP ⴝ C-reactive protein
determined during follow-up (at
HDL-C ⴝ high-density
2 years) after censoring patients
lipoprotein cholesterol
with events within 30 days of the
LDL-C ⴝ low-density
initial ACS event. Hazard ratios
lipoprotein cholesterol
(HRs) and associated 95% confiMI ⴝ myocardial infarction
dence intervals (CIs) were calcuTG ⴝ triglycerides
lated using selected cut-points as
referents. Cut-points were derived from the National Cholesterol Education Program
Adult Treatment Panel III guidelines (13,14) and included:
LDL-C ⬍70 mg/dl, the optional target goal in ACS
patients; TG ⬍150 mg/dl, the normal designate also used in
the metabolic syndrome classification; and HDL-C ⬍40
mg/dl in men and ⬍50 mg/dl women, as similarly classified
(14). In addition, other selected cut-points for TG (100 and
200 mg/dl) and non–HDL-C (100 and 130 mg/dl) were
evaluated (13–15). The impact of TG ⬍150 mg/dl with
achieved dual parameters of low LDL-C (⬍70 mg/dl) and
C-reactive protein (CRP; ⬍2 mg/l) (16) on recurrent CHD
events was also examined. A Cox proportional hazards
model included clinically important variables (e.g., age,
gender, smoking, hypertension, obesity, diabetes), potential
confounders or effect modifiers (e.g., low HDL-C, peripheral vascular disease, prior statin therapy, prior ACS), and
intervention (atorvastatin 80 mg/day vs. pravastatin 40
mg/day) to estimate the effect of on-treatment LDL-C and
Baseline Characteristics by TG Quintile at 30 Days After an ACS
Table 1
Baseline Characteristics by TG Quintile at 30 Days After an ACS
TG Quintile
1 (n ⴝ 763)
2 (n ⴝ 753)
3 (n ⴝ 737)
4 (n ⴝ 732)
5 (n ⴝ 733)
Mean age, yrs
59.7
59.2
58.8
57.5
55.3
58.1
Men, %
81.9
78.9
76.0
74.0
82.0
78.6
Current smoker
30.0
34.0
33.7
41.3
42.4
36.2
Hypertension
46.7
45.3
51.7
51.8
51.6
49.4
Obesity (BMI ⬎30 kg/m2)
28.4
34.8
39.2
43.8
51.3
39.4
Diabetes
13.8
16.1
16.4
19.1
20.6
17.2
Prior ACS
22.4
23.5
28.1
28.3
34.8
27.4
Prior statin use
20.3
21.9
26.5
27.1
31.8
25.5
4.6
6.1
5.4
5.5
6.6
5.6
Characteristic
General
Total (n ⴝ 3,718)
Mean
Coronary risk factors, %
Peripheral vascular disease
Lipids and lipoproteins, median (IQR)
TG, mg/dl
69 (59–77)
97 (90–102)
123 (116–130)
162 (150–177)
254 (218–317)
120 (100–146)
130 (112–153)
138 (118–160)
152 (127–178)
170 (147–193)
LDL-C, mg/dl
63 (47–82)
68 (53–88)
73 (54–92)
78.5 (57–102)
81 (59–101)
HDL-C, mg/dl
42 (36–50)
41 (35–47)
40 (34–47)
38 (32–45)
35 (30–42)
Total cholesterol, mg/dl
High-sensitivity CRP, mg/l
1.41 (0.66–3.31)
1.90 (0.87–4.26)
1.93 (0.95–4.36)
2.15 (1.02–4.43)
2.36 (1.14–4.43)
ACS ⫽ acute coronary syndrome; BMI ⫽ body mass index; CRP ⫽ C-reactive protein; HDL-C ⫽ high-density lipoprotein cholesterol; IQR ⫽ interquartile range; LDL-C ⫽ low-density lipoprotein cholesterol;
TG ⫽ triglycerides.
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Miller et al.
Impact of Triglycerides After ACS
JACC Vol. 51, No. 7, 2008
February 19, 2008:724–30
RiskDays
30
Variables
Estimates*
After ACS
forUsing
Death,
Selected
MI, andContinuous
Recurrent ACS
Table 2
Variable
Risk Estimates* for Death, MI, and Recurrent ACS
30 Days After ACS Using Selected Continuous
Variables
Unadjusted Risk
Estimates (95% CI)
Adjusted Risk
Estimates (95% CI)
p Value,
Adjusted
Analysis
LDL-C
1.040 (1.009–1.068)
1.016 (0.984–1.055)†
0.302
Non–HDL-C
1.048 (1.024–1.073)
1.020 (0.986–1.055)‡
0.252
Triglycerides
1.018 (1.011–1.026)
1.016 (1.007–1.025)†
⬍0.001
1.014 (1.003–1.025)‡
0.010
0.401
HDL-C
1.034 (0.959–1.114)
1.038 (0.952–1.132)†
1.031 (0.944–1.126)‡
0.497
CRP
1.008 (1.002–1.014)
1.004 (0.998–1.011)‡
0.195
adjustment that included LDL-C (p ⬍ 0.001) or non–
HDL-C (p ⫽ 0.010).
Effect of lowering TG levels on the composite end
point. A Cox proportional model was also used to assess
the effect of TG lowering on the composite end point in
statin-naïve subjects (n ⫽ 2,587). For each 10% lowering of
TG that was attained during the first month of therapy,
there was a 2.7% (p ⫽ 0.003) reduced incidence of subsequent events in unadjusted analysis and a 2.3% (p ⫽ 0.035)
lower incidence after adjustment for other covariates including high LDL-C (⬎70 mg/dl) and low HDL-C (⬍40
mg/dl in men and ⬍50 mg/dl and women).
*Relative decrease in hazard for each 10-mg/dl change in LDL-C, TG, or HDL-C or 1-mg/l change in
CRP. †Model includes continuous LDL-C, continuous TG, continuous HDL-C, age, gender, smoking,
hypertension, obesity, diabetes, prior statin therapy, prior ACS, peripheral vascular disease, and
treatment effect. ‡Model includes continuous non–HDL-C, continuous TG, continuous HDL-C, CRP,
age, gender, smoking, hypertension, obesity, diabetes, prior statin therapy, prior ACS, peripheral
vascular disease, and treatment effect.
CI ⫽ confidence interval; MI ⫽ myocardial infarction; other abbreviations as in Table 1.
TG in the adjusted analysis. The proportional hazards
assumption was evaluated for each model. Additionally, risk
estimates were used to determine the relative decrease in
hazard associated with each on-treatment change of 10
mg/dl for lipids and lipoproteins. We also assessed the
relative change in hazard for each 10% lowering of TG that
occurred between baseline and the first month of therapy in
statin-naïve patients. All analyses were conducted on data
through 2 years of follow-up. Statistical analysis was performed using Stata/SE version 9.2 (StataCorp, College
Station, Texas).
Results
Study population and baseline characteristics. Of the
4,162 patients initially enrolled in the PROVE IT-TIMI 22
trial, the present analysis focuses on the incidence of death,
MI, or rehospitalization for ACS beginning after an eventcensored interval of 30 days (n ⫽ 3,718), with follow-up
through 2 years. Baseline characteristics (Table 1) identified
a predominantly male cohort (79%), with a relatively high
percentage of smokers (36%), hypertension (49%), and
obesity (39%). At increasing TG quintiles, there were
corresponding increases in LDL-C and decreases in
HDL-C. A scatterplot analysis demonstrated a positive
correlation between TG and LDL-C (Spearman rho ⫽
0.20; p ⬍ 0.0001) and inverse correlation between TG and
HDL-C (Spearman rho ⫽ ⫺0.24; p ⬍ 0.0001).
Continuous risk estimates for LDL-C, TG, and HDL-C.
A Cox proportional hazards model was used to evaluate
LDL-C, non–HDL-C, TG, HDL-C, and CRP as continuous variables (Table 2). The univariate relative decrease in
hazard associated with each 10-mg/dl reduction in LDL-C
and non–HDL-C was 4.0% and 4.8%, respectively (p ⬍
0.01), whereas each 10 mg/dl decrement in TG was
associated with a 1.8% reduction in risk (p ⬍ 0.001).
However, only TG remained statistically significantly associated with death, MI, and recurrent ACS after covariate
Figure 1
Kaplan-Meier Curves
Estimates of death, myocardial infarction, and recurrent acute coronary syndrome
between 30 days and 2 years of follow-up based on (A) achieved low-density
lipoprotein cholesterol (LDL-C) ⬍70 mg/dl and (B) triglycerides (TG) ⬍150 mg/dl.
The 95% confidence intervals are in parentheses. HR ⫽ hazard ratio.
Miller et al.
Impact of Triglycerides After ACS
JACC Vol. 51, No. 7, 2008
February 19, 2008:724–30
Figure 2
Risk of Recurrent Events Using
Selected Cut-Points of LDL-C and TG
Event rate and adjusted hazard of death, myocardial infarction (MI), and recurrent acute coronary syndrome (ACS) between 30 days and 2 years of follow-up
with achieved LDL-C and TG based on the designated cut-points of 70 mg/dl
and 150 mg/dl, respectively. The referent (Ref) group is LDL-C ⱖ70 mg/dl and
TG ⱖ150 mg/dl. This model is adjusted for age, gender, low HDL-C, smoking,
hypertension, obesity, diabetes, prior statin therapy, prior ACS, peripheral vascular disease, and treatment effect. The 95% confidence intervals are located
below the HRs. Abbreviations as in Figure 1.
On-treatment effects using various cut-points of
LDL-C, TG, and non–HDL-C. The subsequent series of
analyses focused on events based on National Cholesterol
Education Program cut-points for LDL-C and TG. At 30
days, 34.6% of patients had TG ⱖ150 mg/dl. Between 30
days and the 2-year follow-up, significantly fewer events
occurred among patients with LDL-C ⬍70 mg/dl (13.0%)
than with LDL-C ⱖ70 mg/dl (16.2%) (HR 0.81, 95% CI
0.68 to 0.96; p ⫽ 0.015) (Fig. 1A). Similarly, fewer events
occurred with TG ⬍150 mg/dl (13.2%) than with TG
ⱖ150 mg/dl (17.6%) (HR 0.73, 95% CI 0.62 to 0.87; p ⬍
0.001) in univariate analysis (Fig. 1B) and after adjustment
for age, gender, high LDL-C, low HDL-C, smoking,
hypertension, obesity, diabetes, prior statin therapy, prior
ACS, peripheral vascular disease, and treatment effect (HR
0.80, 95% CI 0.66 to 0.97; p ⫽ 0.025). A Cox proportional
model further examined the relationship between achieved
LDL-C and TG at 30 days and risk of recurrent events.
Compared with LDL-C ⱖ70 mg/dl and TG ⱖ150 mg/dl
(referent), lower CHD risk was observed with low on-
727
treatment TG (⬍150 mg/dl) and LDL-C (⬍70 mg/dl)
(HR 0.72, 95% CI 0.54 to 0.94; p ⫽ 0.017), with a graded
response among patients with LDL-C ⱖ70 mg/dl and TG
⬍150 mg/dl (HR 0.85, 95% CI 0.67 to 1.08; p ⫽ 0.180) in
adjusted analysis (Fig. 2). Low HDL-C was not associated
with increased risk of CHD events after covariate adjustment (HR 1.01, 95% CI 0.84 to 1.22; p ⫽ 0.911). Similarly,
evaluation of LDL-C ⬍70 mg/dl with varying cut-points of
TG (100 and 200 mg/dl) and non–HDL-C (100 and 130
mg/dl), identified a statistically significantly lower risk with
TG ⬍200 mg/dl (HR 0.60, 95% CI 0.45 to 0.81; p ⫽
0.001) and a nonsignificant trend with TG ⬍100 mg/dl
(HR 0.82, 95% CI 0.61 to 1.10; p ⫽ 0.189), non–HDL-C
⬍130 mg/dl (HR 0.79, 95% CI 0.61 to 1.02; p ⫽ 0.067),
and non–HDL-C ⬍100 mg/dl (HR 0.83, 95% CI 0.66 to
1.05; p ⫽ 0.123) compared with higher levels of LDL-C,
TG, or non–HDL-C in adjusted analysis (Table 3).
Attainment of LDL-C <70 mg/dl and TG <150 mg/dl
with atorvastatin 80 mg/day and pravastatin 40 mg/
day. The proportion of patients with achieved LDL-C
⬍70 mg/dl or TG ⬍150 mg/dl, the dual parameter
(LDL-C ⬍70 mg/dl and TG ⬍150 mg/dl), or the triple
parameter (LDL-C ⬍70 mg/dl, CRP ⬍2 mg/l, and TG
⬍150 mg/dl) at 30 days stratified by treatment arm is shown
in Table 4. Overall, a higher percentage of atorvastatin 80
mg/day patients attained any of these parameters than
pravastatin 40 mg/day patients (p ⬍ 0.0001 for each
comparator). However, even with the more intensive lipidlowering regimen, only 56.1% of atorvastatin-treated patients attained LDL-C ⬍70 mg/dl and TG ⬍150 mg/dl,
and only 35% achieved all 3 parameters.
On-treatment effects of LDL-C <70 mg/dl, CRP <2
mg/l, and TG <150 mg/dl. The association between TG
and recurrent CHD events was further assessed in the
presence of achieved LDL-C ⬍70 mg/dl and CRP ⬍2
mg/l, previously noted to be associated with improved
event-free survival (16). The risk of death, MI, or recurrent
ACS after achieving 1, 2, or all 3 parameters (i.e., LDL-C
⬍70 mg/dl, CRP ⬍2 mg/l, and/or TG ⬍150 mg/dl) is
shown in Table 5. Between 30-day and 2-year follow-up,
RiskSelected
and
of Death,On-Treatment
MI, or Recurrent
TG orACS
Non–HDL-C
With LDL-C
Cut-Points
<70 mg/dl
30 Days After ACS
Risk of Death, MI, or Recurrent ACS With LDL-C <70 mg/dl
Table 3
and Selected On-Treatment TG or Non–HDL-C Cut-Points 30 Days After ACS
LDL-C <70 mg/dl
ⴙ Variable
Patients, n
Rate, %
Unadjusted Hazard Ratio
(95% CI)
Adjusted Hazard Ratio
(95% CI)*
p Value,
Adjusted Analysis
TG ⱖ200 mg/dl
603
20.3
1.00
0.76 (0.52–1.12)
0.170
TG ⬍200 mg/dl
2,796
13.5
0.64 (0.53–0.78)
0.60 (0.45–0.81)
0.001
TG ⱖ100 mg/dl
2,259
15.4
1.00
0.90 (0.71–1.14)
0.368
TG ⬍100 mg/dl
1,140
13.4
0.85 (0.71–1.03)
0.82 (0.61–1.10)
0.189
Non–HDL-C ⱖ130 mg/dl
741
17.9
1.00
0.83 (0.26–2.63)
0.755
Non–HDL-C ⬍130 mg/dl
2,652
13.9
0.77 (0.63–0.93)
0.79 (0.61–1.02)
0.067
Non–HDL-C ⱖ100 mg/dl
1,676
16.5
1.00
1.07 (0.73–1.56)
0.722
Non–HDL-C ⬍100 mg/dl
1,718
13.1
0.79 (0.66–0.94)
0.83 (0.66–1.05)
0.123
*Adjusted for age, gender, low HDL-C, smoking, hypertension, obesity, diabetes, prior statin therapy, prior ACS, peripheral vascular disease, and treatment effect compared with higher levels of LDL-C and
TG or non–HDL-C.
Abbreviations as in Tables 1 and 2.
Miller et al.
Impact of Triglycerides After ACS
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JACC Vol. 51, No. 7, 2008
February 19, 2008:724–30
Percentage
AtorvastatinAttaining
and/or
CRP
Designated
of
30
and
TG
Days
Pravastatin-Treated
Reduction
After
Cut-Points
ACS
and for
Proportion
LDL-C,
Patients
TG,
of
Table 4
Percentage of TG Reduction and Proportion of
Atorvastatin- and Pravastatin-Treated Patients
Attaining Designated Cut-Points for LDL-C, TG,
and/or CRP 30 Days After ACS
Atorvastatin
80 mg
Pravastatin
40 mg
Mean
22.8%
⫺0.7%*
Median
30.3%
8.6%*
72.5%
21.6%*
TG reduction
LDL-C ⬍70 mg/dl
TG ⬍150 mg/dl
74.4%
56.3%*
LDL-C ⬍70 mg/dl, TG ⬍150 mg/dl
56.1%
12.0%*
LDL-C ⬍70 mg/dl, CRP ⬍2 mg/l, TG ⬍150 mg/dl
35.0%
6.6%*
*p ⬍ 0.001 between the treatment groups.
Abbreviations as in Tables 1 and 2.
the risk of the composite end point was 28% lower in the
presence of any 1 parameter (p ⫽ 0.017), 32% lower with
any 2 parameters (p ⫽ 0.007), and 41% lower when all 3
parameters were achieved compared with their absence (p ⫽
0.002) in an adjusted analysis.
Discussion
In this analysis of the PROVE IT-TIMI 22 trial, the most
noteworthy finding was the reduced risk of CHD with low
on-treatment TG (⬍150 mg/dl) that was independent of
the level of LDL-C. For each 10-mg/dl decline in ontreatment TG, we observed a 1.6% lower risk of the
composite end point (p ⬍ 0.001) after adjustment for
LDL-C and other covariates. Moreover, the combination of
low LDL-C (⬍70 mg/dl) and low TG (⬍150 mg/dl) was
associated with the lowest event rates compared with higher
LDL-C, higher TG, or both. Our observations on the
relationship between lower event rates with reduced ontreatment TG are consistent with 2 recent studies. They
include a large Chinese prospective study that found TG to
be predictive of CHD mortality, even in the setting of low
total cholesterol (17), and the Prospective Cardiovascular
Münster study stratified by HDL-C, which identified a
higher CHD risk with high TG (⬎150 mg/dl) in subjects at
all levels of LDL-C (18). Taken together, aiming for low
on-treatment levels of LDL-C and TG may be particularly
effective after ACS where residual CHD risk remains
elevated despite recent diagnostic and therapeutic advancements (19).
The PROVE IT-TIMI 22 trial (9) and the Heart
Protection Study (20) served as the impetus for the National
Cholesterol Education Program’s optional recommended
LDL-C target of ⬍70 mg/dl (14). Whereas lowering
LDL-C to ⬍70 mg/dl has been recommended, the impact
of low on-treatment TG beyond achieved LDL-C ⬍70
mg/dl has been less well defined. For example, although TG
levels ⬍150 mg/dl are defined as normal, the National
Cholesterol Education Program does not recommend TG
lowering as a primary target of therapy. Rather, non–
HDL-C (e.g., total cholesterol ⫺ HDL cholesterol) has
become a secondary target when TG levels exceed 200
mg/dl (13).
However, several lines of evidence support TG as a
biomarker of CHD risk owing to the role of TG-rich
lipoproteins in atherothrombosis. Following the hydrolysis
of exogenously derived chylomicrons or endogenously secreted very-low-density lipoprotein, cholesterol-enriched
remnant by-products enter the subendothelial space. In
hypertriglyceridemic states, remnants accumulate, resulting
in a proinflammatory and oxidative milieu that may enhance
adhesion molecule expression, foam cell formation, and
smooth muscle cell toxicity (21). Indirectly, high levels of
TG may also be associated with hypertriglyceridemic HDL
particles, which are thought to be less efficient in reverse
cholesterol transport (22,23), as well as an increased proportion of small, dense LDL particles which may be more
susceptible to oxidative modification (24,25). The fact that
plasma TG correlates with atherogenic remnants (26),
coupled with the excess risk of CHD with combined
elevation of LDL-C and TG (27), supports the notion that
low on-treatment LDL-C and TG may improve CHD risk
beyond low LDL-C alone. The 1.6% reduction in risk
associated with each 10-mg/dl decrement in on-treatment
TG that is independent of the reduction in risk associated
with decreases in LDL-C or non–HDL-C is noteworthy
because it includes adjustment of other closely aligned TG
covariates (e.g., diabetes, hypertension, obesity, and
HDL-C). Moreover, the 2.3% lower incidence of recurrent
CHD events associated with each 10% lower TG concentration (after adjustment for high LDL-C and low
HDL-C) raises the possibility that additional reduction in
CHD risk may be attained through efforts aimed at lowering both LDL-C and TG compared with lowering LDL-C
Risk of Death, Myocardial Infarction, or Recurrent ACS by Number of Parameters Achieved* 30 Days After ACS
Table 5
Risk of Death, Myocardial Infarction, or Recurrent ACS by Number of Parameters Achieved* 30 Days After ACS
Variable
No parameters
Patients, n
Rate, %
Unadjusted Hazard Ratio
(95% CI)
Adjusted Hazard Ratio
(95% CI)†
p Value,
Adjusted Analysis
445
21.1
1.00
1.00
Any 1 parameter
1,168
15.7
0.72 (0.56–0.93)
0.72 (0.56–0.94)
0.017
Any 2 parameters
1,262
13.7
0.64 (0.49–0.83)
0.68 (0.52–0.90)
0.007
757
10.9
0.50 (0.37–0.67)
0.59 (0.41–0.83)
0.002
All 3 parameters
*Parameters are defined as LDL-C ⬍70 mg/dl, TG ⬍150 mg/dl, and CRP ⬍2 mg/l. †Adjusted for age, gender, low HDL-C, smoking, hypertension, obesity, diabetes, prior statin therapy, prior ACS, peripheral
vascular disease, and treatment effect.
Abbreviations as in Tables 1 and 2.
Miller et al.
Impact of Triglycerides After ACS
JACC Vol. 51, No. 7, 2008
February 19, 2008:724–30
alone. Accordingly, if a combined strategy of low LDL-C
and low TG proves to be more effective in reducing CHD
events than intensive LDL-C lowering alone, then additional strategies might be considered after ACS, including
replacement of saturated and trans fats with mono- and
polyunsaturated fats (28), especially derivatives such as
omega-3 fatty acids that are cardioprotective and at high
doses possess TG-lowering properties (29,30), or the addition of niacin- or fibrate-based therapy, which is currently
under investigation for CHD event rate reduction beyond
LDL-C lowering (31,32).
In the present analysis, lower HDL-C levels were not
associated with an increased risk of death, MI, or recurrent
ACS when used as either a categoric or continuous variable.
Although placebo-assigned patients with low HDL-C have
traditionally had the highest event rates (33), this association may have been partly minimized in the PROVE
IT-TIMI 22 trial, because all patients received statin
therapy that may have attenuated the excess risk associated
with low HDL-C (34). The basis for this effect may reflect,
in part, statin-mediated reduction in atherogenic lipoproteins and remnants (35) as well as the potential decrease in
cellular adhesion molecule expression (36) that may be
up-regulated in patients with low HDL-C (37). Previously,
the combination of LDL-C ⬍70 mg/dl and CRP ⬍2 mg/l
was shown to be associated with statistically significant
reductions in recurrent MI or vascular death compared with
higher levels of LDL-C and CRP (38). Moreover, in the
PROVE IT-TIMI 22 trial, high CRP was also found to be
associated with each of the factors comprising the metabolic
syndrome (39). In the present study, there was a 41% lower
risk of CHD events between 30 days after ACS and the
2-year follow-up with attainment of LDL-C ⬍70 mg/dl,
CRP ⬍2 mg/l, and TG ⬍150 mg/dl compared with higher
levels in all 3 parameters after adjustment for other covariates. Mechanistically, if elevated TG represents in part a
prothrombotic state (40,41), then low on-treatment levels of
LDL-C, CRP, and TG may be a consideration in ACS
patients, owing to the intimate linkage between lipids,
inflammation, and thrombosis (42). This may justify consideration of other therapies (29 –31,43– 46) if future clinical
trials demonstrate clinical benefit beyond LDL-C lowering.
Study limitations. There are several important limitations
associated with the present study. First, it was not designed
a priori to address whether combined low on-treatment
LDL-C and TG was superior to low on-treatment LDL-C
alone. Second, greater intraindividual variability has been
reported for TG than for LDL-C (47). Nevertheless,
although standard statistical methods were used to account
for known variability, a recent evaluation of repeat TG
measurements over a 4- or 12-year period (n ⫽ 2,312)
identified long-term stability of TG that was similar to
blood pressure and other lipid measurements (6). Third, the
results of the present study are not generalizable to
nonstatin-based therapies. Finally, although the study assessed outcomes of patients who were observed to have TG
729
⬍150 mg/dl at different levels of LDL-C, it remains to be
confirmed in randomized trials whether, and to what extent,
targeting a lower on-treatment TG (15) may provide
additional clinical benefit.
Conclusions
Among patients receiving statin therapy after ACS, ontreatment TG ⬍150 mg/dl was associated with a lower risk
of recurrent CHD events independently of the level of
LDL-C. These data lend support to the concept that
achieving both a low LDL-C and a low TG may be
important therapeutic parameters in patients following
ACS.
Reprint requests and correspondence: Dr. Michael Miller, University of Maryland Hospital, Division of Cardiology, Room
S3B06, 22 South Greene Street, Baltimore, Maryland 21201.
E-mail: [email protected].
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