Author + information
- Received March 1, 2015
- Revision received March 10, 2015
- Accepted March 17, 2015
- Published online June 2, 2015.
- Gregory G. Schwartz, MD, PhD∗∗ (, )
- Markus Abt, PhD†,
- Weihang Bao, PhD‡,
- David DeMicco, PharmD‡,
- David Kallend, MD†,
- Michael Miller, MD§,
- Hardi Mundl, MD† and
- Anders G. Olsson, MD, PhD‖,¶
- ∗Cardiology Section, VA Medical Center and University of Colorado School of Medicine, Denver, Colorado
- †Pharma Development, F. Hoffmann-La Roche, Basel, Switzerland
- ‡Pfizer, Inc., New York, New York
- §Division of Cardiovascular Medicine, University of Maryland School of Medicine, Baltimore, Maryland
- ‖Stockholm Heart Center, Stockholm, Sweden
- ¶University of Linköping, Linköping, Sweden
- ↵∗Reprint requests and correspondence:
Dr. Gregory G. Schwartz, Cardiology Section 111B, Denver VA Medical Center, 1055 Clermont Street, Denver, Colorado 80220.
Background Most patients with acute coronary syndrome (ACS) are treated with statins, which reduce atherogenic triglyceride-rich lipoproteins. It is uncertain whether triglycerides predict risk after ACS on a background of statin treatment.
Objectives This study examined the relationship of fasting triglyceride levels to outcomes after ACS in patients treated with statins.
Methods Long-term and short-term relationships of triglycerides to risk after ACS were examined in the dal-OUTCOMES trial and atorvastatin arm of the MIRACL (Myocardial Ischemia Reduction with Acute Cholesterol Lowering) trial, respectively. Analysis of dal-OUTCOMES included 15,817 patients (97% statin-treated) randomly assigned 4 to 12 weeks after ACS to treatment with dalcetrapib (a cholesteryl ester transfer protein inhibitor) or placebo and followed for a median 31 months. Analysis of MIRACL included 1,501 patients treated with atorvastatin 80 mg daily beginning 1 to 4 days after ACS and followed for 16 weeks. Fasting triglycerides at initial random assignment were related to risk of coronary heart disease death, nonfatal myocardial infarction, stroke, and unstable angina in models adjusted for age, sex, hypertension, smoking, diabetes, high-density lipoprotein cholesterol, and body mass index.
Results Fasting triglyceride levels were associated with both long-term and short-term risk after ACS. In dal-OUTCOMES, long-term risk increased across quintiles of baseline triglycerides (p < 0.001). The hazard ratio in the highest/lowest quintile (>175/≤80 mg/dl) was 1.61 (95% confidence interval: 1.34-1.94). There was no interaction of triglycerides and treatment assignment on the primary outcome. In the atorvastatin group of MIRACL, short-term risk increased across tertiles of baseline triglycerides (p = 0.03), with a hazard ratio of 1.50 (95% confidence interval: 1.05 to 2.15) in highest/lowest tertiles (>195/≤135 mg/dl). The relationship of triglycerides to risk was independent of low-density lipoprotein cholesterol in both studies.
Conclusions Among patients with ACS treated effectively with statins, fasting triglycerides predict long-term and short-term cardiovascular risk. Triglyceride-rich lipoproteins may be an important additional target for therapy. (A Study of RO4607381 in Stable Coronary Heart Disease Patients With Recent Acute Coronary Syndrome; NCT00658515)
Despite evidence-based treatments including intensive statin therapy, patients with acute coronary syndrome (ACS) face a high risk of recurrent cardiovascular events (1–3). The extent to which this residual risk is attributable to persistent lipoprotein abnormalities and might be reduced by additional therapies to modify lipoproteins remains uncertain.
Lipid interventions after ACS have focused primarily on lowering of low-density lipoprotein cholesterol (LDL-C) or raising high-density lipoprotein cholesterol (HDL-C). Triglyceride-rich lipoproteins comprise a third category of particles that may influence cardiovascular risk. In particular, the action of lipases on very low-density lipoprotein (VLDL) and chylomicrons results in the formation of remnant particles with increased cholesterol content and potential for atherogenicity (4). Observational cohort studies and meta-analyses (5–8) and post-hoc analyses of trials with fibrates or statins (9–12) suggest that higher levels of triglyceride-rich lipoproteins correlate with higher residual risk, although the relationships are, in some cases, attenuated by adjustment for factors associated with elevated triglycerides, including age, hypertension, smoking, diabetes, obesity, and low HDL-C.
Recent genetic studies support a causal relationship between triglyceride-rich lipoproteins and cardiovascular risk. In an evaluation of more than 73,000 subjects, investigators from the Copenhagen City Heart Studies performed Mendelian randomization analysis of several alleles that affect cholesterol content of triglyceride-rich lipoproteins, but not HDL-C or LDL-C (13). By use of the Friedewald formula, the cholesterol content of triglyceride-rich remnant lipoproteins was estimated as the portion of total cholesterol not contained in either LDL or HDL. There was a strong correlation between the number of alleles associated with remnant cholesterol and the incident risk of coronary heart disease. Two recent large studies demonstrated that polymorphisms of the gene encoding apolipoprotein C-III that resulted in lower triglyceride levels were associated with lower cardiovascular risk (14,15). However, most subjects included in these genetic analyses were initially free of cardiovascular disease, few were treated with a statin, and none had recent ACS.
Although the efficacy of intensive statin therapy after ACS has been firmly established in both short-term and long-term studies (1,3), residual risk remains high despite such treatment (2,16). Statins reduce triglyceride-rich lipoproteins along with LDL-C; however, it remains uncertain whether triglycerides predict residual risk after ACS in patients under effective statin treatment, and thus whether triglyceride-rich lipoproteins should be a target for additional therapy. In JELIS (Japan EPA Lipid Intervention Study), eicosapentaenoic acid plus low-dose statin resulted in an approximately 5% reduction in triglycerides and a 19% reduction in coronary events, compared with low-dose statin alone (17). Benefit was demonstrated in a subgroup of patients with established coronary disease, but patients with ACS were not studied. In the current study, we examined relationships between fasting triglycerides and cardiovascular risk after ACS in 2 large trials of patients treated with statins.
The design and principal results of the dal-OUTCOMES (A Study of RO4607381 in Stable Coronary Heart Disease Patients With Recent Acute Coronary Syndrome) and MIRACL (Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering) trials have been described previously (1,2,18,19). The institutional review boards at each participating site approved the studies, and all subjects gave informed consent.
In brief, dal-OUTCOMES was a randomized, double-blind comparison of the cholesteryl ester transfer protein inhibitor dalcetrapib with placebo in 15,871 patients with recent ACS (acute myocardial infarction or unstable angina pectoris). Treatment began 4 to 12 weeks (median 6 weeks) after ACS and median follow-up was 31 months. The study was performed between 2008 and 2012 at 935 sites in 27 countries. Patients were excluded if triglycerides exceeded 400 mg/dl, but there were no exclusions on the basis of levels of HDL-C or LDL-C. Evidence-based statin treatment was advised, although no specific statin agent or dose was specified. In fact, 97% of patients were treated with a statin at random assignment with a median LDL-C of 73 mg/dl. The primary outcome measure was a composite of CHD death, nonfatal myocardial infarction, ischemic stroke, unstable angina with objective evidence of myocardial ischemia requiring urgent re-hospitalization, and cardiac arrest with resuscitation. The present analysis includes data from 15,817 patients in both treatment groups who had a standard fasting lipid profile determined at random assignment by a central laboratory.
The MIRACL trial was a randomized, double-blind comparison of atorvastatin 80 mg daily with placebo in a total of 3,086 patients with ACS (non–Q-wave acute myocardial infarction or unstable angina). The study was performed between 1997 and 2000 at 122 sites in 19 countries. Treatment began 24 to 96 h after admission to hospital for ACS and continued for 16 weeks. Patients with total cholesterol >270 mg/dl (>7 mmol/l) were excluded, but there were no exclusions on the basis of LDL-C, HDL-C, or triglycerides. Patients were excluded if coronary revascularization had been performed during hospitalization for the index ACS event or was planned or anticipated at the time of random assignment. The primary endpoint was the composite of death, nonfatal myocardial infarction, unstable angina with objective evidence of myocardial ischemia requiring urgent re-hospitalization, or cardiac arrest with resuscitation. Fatal or nonfatal stroke was a secondary endpoint. To align outcome measures from MIRACL and dal-OUTCOMES for the present analysis, the outcome measure from MIRACL was either a primary study endpoint or stroke. The present analysis includes data from 1,501 patients in MIRACL assigned to treatment with atorvastatin 80 mg who had a fasting lipid profile determined at random assignment. In 1,299 of these patients, a lipid panel was also measured at 6 weeks of assigned treatment. In both MIRACL and dal-OUTCOMES, LDL-C was calculated by the Friedewald formula.
In each trial, hazard ratios were determined for a 10 mg/dl increment in triglycerides at baseline, both in univariate relationships and in relationships adjusted for age, sex, history of hypertension, current smoking, diabetes, HDL-C, and body mass index; that is, factors associated with levels of triglycerides. The distribution of triglyceride levels at baseline was described in quintiles for dal-OUTCOMES and in tertiles in MIRACL because of the smaller number of endpoint events in the latter study. Univariate and adjusted hazard ratios for occurrence of endpoint events were determined for each quintile or tertile of triglycerides, with quintile 1 or tertile 1 serving as the referent group, and p values for trend across quintiles or tertiles were determined. In dal-OUTCOMES, the interaction of triglyceride concentration (as a continuous variable) and treatment assignment (dalcetrapib or placebo) on risk of an endpoint was assessed. To determine the interaction of LDL-C and triglyceride levels on cardiovascular risk, relationships were examined in patients with LDL-C above or below the median level at initial random assignment (73 mg/dl) in dal-OUTCOMES. A value of p < 0.05 was considered significant.
Baseline characteristics of the patients are shown in Table 1. In dal-OUTCOMES, there were larger proportions of male and hypertensive patients and fewer current smokers than in MIRACL. Coronary revascularization for the index ACS event was performed before random assignment in more than 90% of patients in dal-OUTCOMES but was an exclusion criterion in MIRACL. The use of platelet P2Y12 antagonists, β-blockers, and angiotensin-converting enzyme inhibitors or angiotensin receptor blockers was more frequent in dal-OUTCOMES than in MIRACL. Prior to random assignment, 97% of patients in dal-OUTCOMES were treated with a statin, compared with none in MIRACL.
Table 2 shows lipid levels at random assignment and on assigned treatment in the 2 trials. In dal-OUTCOMES, the median triglyceride concentration at random assignment was 115 mg/dl. On treatment with dalcetrapib or placebo, triglyceride levels changed minimally from baseline and remained similar in both groups (median 111 and 116 mg/dl, respectively). Consistent with the broad and effective application of statins, median LDL-C at random assignment was 73 mg/dl and did not change significantly after 1 month of treatment with dalcetrapib or placebo. As expected, treatment with dalcetrapib raised HDL-C.
In MIRACL, lipid levels at random assignment were obtained before statin treatment; therefore, median concentrations of triglycerides (160 mg/dl) and LDL-C (120 mg/dl) were higher than at random assignment in dal-OUTCOMES. As expected, 6 weeks of treatment with atorvastatin 80 mg substantially lowered triglycerides (to a median 110 mg/dl) and LDL-C (to a median 60 mg/dl).
Relation of triglyceride levels to long-term risk after ACS
During a median 31-month follow-up period in dal-OUTCOMES, 1,289 patients (8.1%) had at least 1 primary endpoint event. The risk was similar in both the dalcetrapib group and the placebo group (8.3% and 8.0%, respectively). Triglyceride concentration at random assignment was significantly related to risk. In unadjusted analysis, a 10-mg/dl increment in triglycerides was associated with hazard ratio of 1.016 (95% confidence interval [CI]: 1.010 to 1.022; p < 0.001). Adjustment for age, sex, hypertension, current smoking, diabetes, HDL-C, and body mass index did not attenuate the relationship (hazard ratio: 1.018; 95% CI: 1.011 to 1.024; p < 0.001). Risk increased monotonically across quintiles of triglycerides (p < 0.001 for trend) (Figure 1). Relative to the lowest quintile (≤80 mg/dl), risk in the highest quintile of triglycerides (>175 mg/dl) was 1.50 (95% CI: 1.05 to 2.15). There was no significant interaction of treatment assignment (dalcetrapib or placebo) and triglycerides on the risk of a primary endpoint event (p = 0.278). The Central Illustration (right panel) shows Kaplan-Meier analysis by quintile of baseline triglycerides. The cumulative incidence of endpoint events diverged according to quintile of triglycerides, beginning shortly after random assignment and continuing throughout the observation period. When baseline LDL-C was dichotomized at its median of 73 mg/dl, significant relations between triglycerides and risk of a primary endpoint event were evident in both subgroups (p < 0.002) (Figure 2), without significant interaction of LDL-C and triglycerides on risk (p = 0.781).
Relation of triglyceride levels to short-term risk after ACS
In the atorvastatin group of MIRACL, 220 patients (14.7%) with at least one measurement of lipids died or had nonfatal myocardial infarction, stroke, cardiac arrest, or hospitalization for unstable angina during the 16 weeks after ACS. The adjusted hazard ratio associated with a 10 mg/dl increment in triglycerides at random assignment was 1.014 (95% CI: 0.996 to 1.032); that is, similar to the long-term hazard ratio in dal-OUTCOMES. Relative to the lowest tertile (≤135 mg/dl), adjusted risk in the highest tertile of triglycerides (>195 mg/dl) was 1.50 (95% CI: 1.05 to 2.15) (Figure 3). Across the 3 tertiles of triglycerides, there was a significant gradient of risk (p value for trend = 0.03). Further adjustment for baseline LDL-C had no effect on this relationship (p value for trend = 0.03). The cumulative incidence of endpoint events according to tertile of triglycerides in the atorvastatin group is shown in the Central Illustration, left panel. Lipid values were measured at 1 intermediate time point in MIRACL, at 6 weeks of assigned treatment. The relationship between triglyceride levels achieved at week 6 and risk of an endpoint event between week 6 and week 16 was examined. The percentage of patients with an endpoint event in the lowest tertile of achieved triglycerides (≤90 mg/dl; 2.7%) was less than that in the upper 2 tertiles (>90 to 135 mg/dl, 4.4%; >135 mg/dl, 4.0%). However, the total number of events (45) provided little power and therefore a test for significance was not meaningful.
Relationships of LDL-C and HDL-C to risk after ACS
Despite effective use of statins in dal-OUTCOMES, LDL-C remained strongly related to long-term risk (Table 3). With adjustment for age, sex, hypertension, current smoking, diabetes, HDL-C, and body mass index, a 10 mg/dl increment in LDL-C was associated with a hazard ratio of 1.083 (95% CI: 1.063 to 1.103; p < 0.001), with a significant gradient of risk across LDL-C quintiles (p < 0.001). In contrast, there was no relationship of HDL-C to long-term risk in dal-OUTCOMES (hazard ratio for 10 mg/dl increment: 0.980; 95% CI: 0.931 to 1.031; p = 0.435). Treatment assignment (dalcetrapib or placebo) had no interaction with either LDL-C or HDL-C on the risk of a cardiovascular endpoint event. In the atorvastatin group of MIRACL, baseline LDL-C was unrelated to short-term (16-week) risk. With adjustment for each of the factors indicated earlier, risk across LDL-C quintiles was essentially flat (p = 0.92 for trend). However, a significant, inverse relation between quintile of HDL-C and short-term risk after ACS was identified (p = 0.002).
Triglyceride-rich lipoproteins, including denser forms of VLDL, intermediate-density lipoproteins, and their remnants, are believed to be atherogenic (4). Statins not only reduce LDL-C, but also have significant effects to lower concentrations of triglycerides and of cholesterol contained in triglyceride-rich lipoproteins (20).
Despite a background of effective statin treatment, we found a strong, unfavorable relationship of fasting triglyceride levels to long-term and short-term prognosis after ACS. The hazard associated with increasing triglycerides was nearly identical in univariate analysis and after adjustment for risk factors usually associated with triglyceride levels, including age, sex, hypertension, smoking, diabetes, HDL-C, and body mass index, as well as LDL-C. This observation suggests that triglyceride-rich lipoproteins may have a causal relationship to risk after ACS. After adjustment for conventional risk factors, plasma triglyceride levels have predicted incident cardiovascular risk in some (6–8), but not all observational cohort studies (5) and in patients with stable coronary heart disease treated with statins (10,12). In patients with unstable coronary disease, the PROVE-IT TIMI 22 trial showed a relationship of triglycerides to long-term prognosis beginning 30 days after ACS on a background of intensive statin treatment (11). The present analysis extends these findings to a much larger cohort of patients with ACS and indicates that elevated triglycerides, reflecting the burden of triglyceride-rich lipoproteins, are associated with both long-term and short-term risk after ACS.
In dal-OUTCOMES, long-term risk after ACS was higher in quintiles 3, 4, and 5 of the triglyceride distribution, compared with quintile 1. Because the lower bound of quintile 3 corresponded to a triglyceride concentration of just 105 mg/dl, increased risk associated with triglyceride rich lipoproteins was manifest at concentrations that are generally considered to be normal. In this regard, the present findings are consistent with a scientific statement by the American Heart Association that optimal fasting triglyceride levels may be <100 mg/dl (21). The incremental long-term cardiovascular risk associated with a 10-mg/dl increment in triglycerides was similar to that for a 10-mg/dl increment in LDL-C and was evident in subgroups either above or below the median LDL-C of 73 mg/dl. This observation supports the use of non-HDL-C as a long-term risk indicator reflecting the cholesterol content of both LDL and triglyceride-rich lipoproteins (22). Treatment with either dalcetrapib or placebo had no interaction with triglyceride levels on the risk of a cardiovascular endpoint event. This observation may be particularly important and timely with regard to ongoing cardiovascular outcomes trials with 2 other compounds in the same class as dalcetrapib (23). The MIRACL trial had smaller sample size, shorter observation period, and fewer endpoint events than dal-OUTCOMES; nonetheless, elevated triglycerides were associated with an adverse short-term prognosis after ACS on a background of treatment with atorvastatin 80 mg daily. Thus, optimal statin treatment may lower levels of triglyceride-rich lipoproteins, but does not abrogate the risk associated with these particles.
MIRACL and dal-OUTCOMES were performed approximately 10 years apart. During that interval, standard treatment for ACS evolved to include more widespread use of early coronary revascularization and dual antiplatelet therapy. Nonetheless, the relationships of triglycerides to risk of recurrent ischemic events were qualitatively similar in both studies. Baseline triglycerides were measured in the absence of statin treatment in MIRACL but on statin treatment in dal-OUTCOMES. Hence, the distribution of triglyceride levels differed between the 2 studies, with higher levels in MIRACL. Both sets of observations are important because a substantial fraction of patients who present with ACS are statin-naive (3). Therefore, the relationship of baseline triglycerides to outcomes observed in MIRACL (without background statin treatment) and in dal-OUTCOMES (on statin treatment) each contribute information that may be useful in predicting clinical risk when a patient presents with ACS. In both the MIRACL and dal-OUTCOMES studies, a majority of patients were white and male. Applicability of findings to other populations is uncertain. Some studies have indicated a stronger relationship of triglycerides to incident cardiovascular events in women (24). Adjustment for diabetes may account for some of the risk caused by insulin resistance. However, many nondiabetic patients with ACS are insulin resistant (25). Therefore, it is possible that insulin resistance remains an unaccounted variable that influenced the relationship between triglycerides and risk. In both dal-OUTCOMES and MIRACL, baseline triglycerides were measured under fasting conditions. Therefore, the present analysis cannot determine whether post-prandial excursions in triglycerides exert further influence on risk after ACS, as has been suggested in some analyses (26). In dal-OUTCOMES, no interaction was found between assigned treatment (dalcetrapib or placebo) and triglycerides on risk of an endpoint event; however, it remains uncertain whether inhibition of cholesteryl ester transfer protein could affect the atherogenic potential of hypertriglyceridemia. Triglycerides were measured in this study, but it is the cholesterol content of triglyceride-rich remnant lipoproteins that is believed to confer atherogenicity to these particles. Research methods are available to measure remnant lipoprotein cholesterol (4) and may prove useful to define risk and determine therapeutic efficacy in future studies. In the present analyses, LDL-C was calculated with the use of the Friedewald formula, which is subject to inaccuracies related to variability in the actual ratio of triglycerides/VLDL cholesterol across levels of triglycerides and cholesterol. When LDL-C was calculated with the use of a nomogram that takes into account the variability of triglycerides/VLDL cholesterol (27), there was minimal quantitative and no qualitative impact on the results or conclusions (data not shown).
The present data indicate a strong association of fasting triglyceride levels with residual risk after ACS in patients receiving effective statin therapy. However, it remains uncertain whether triglyceride-rich lipoproteins should be a target of therapy after ACS, above and beyond statin treatment. The question will remain open until trials specifically test the efficacy of triglyceride-lowering interventions after ACS. Newer agents, such as potent omega-3 fatty acid derivatives (28) or antisense oligonucleotide to apolipoprotein C-III (29), have the potential to lower triglyceride-rich lipoproteins dramatically and may provide useful tools to answer this question in the future. In addition, antibodies to PCSK9, although primarily intended to lower LDL-C concentrations, also significantly reduce cholesterol contained in triglyceride-rich lipoproteins (30).
COMPETENCY IN MEDICAL KNOWLEDGE: Statin drugs lower LDL-C and cardiovascular risk in survivors of ACS, but serum triglycerides often remain persistently elevated despite statin treatment. Data from 2 large, randomized trials demonstrate that among patients with ACS well-treated with statins, triglyceride levels are associated with both short- and long-term risk of recurrent ischemic events.
TRANSLATIONAL OUTLOOK: It remains uncertain whether triglyceride-rich lipoproteins are causally related to residual risk after ACS, and additional studies should evaluate the efficacy of novel approaches to triglyceride lowering, including potent omega-3 fatty acid formulations or modulators of apolipoprotein CIII.
The dal-OUTCOMES trial was funded by F. Hoffmann-La Roche Ltd. The MIRACL trial was funded by Pfizer. Dr. Schwartz, through his institution, has received research grants from Anthera, Pfizer, Resverlogix, Roche, and Sanofi. Dr. Abt is an employee of F. Hoffmann-La Roche, Ltd. Drs. Bao and DeMicco are employees of Pfizer. Drs. Kallend and Mundl were employees of F. Hoffmann-La Roche at the time the dal-OUTCOMES study was performed and data collected. Dr. Miller has served as a consultant for Amarin, AstraZeneca, Pronova, and Zydus. Dr. Olsson has received research grants from Amgen, AstraZeneca, Karobio, Merck, Pfizer, Roche, and Sanofi; and has received consultation fees from AstraZeneca, Karobio, Merck, Pfizer, and Roche. Dr. Kallend is currently affiliated with The Medicines Company, Zurich, Switzerland. Dr. Mundl is currently affiliated with Bayer Pharmaceuticals, Berlin, Germany.
Portions of this work have been previously presented in abstract form (American College of Cardiology 63rd Scientific Sessions; J Am Coll Cardiol 2014;63 Suppl A:A63).
- Abbreviations and Acronyms
- acute coronary syndrome(s)
- high-density lipoprotein cholesterol
- low-density lipoprotein cholesterol
- very low-density lipoprotein
- Received March 1, 2015.
- Revision received March 10, 2015.
- Accepted March 17, 2015.
- American College of Cardiology Foundation
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