Triglyceride levels predict recurrent risk in ACS patients receiving statin therapy

Schwartz GG, Abt M, Bao W, et al.
JACC 2015; 65(21):2267-2275. http://dx.doi.org/10.1016/j.jacc.2015.03.544

Background

Intensive statin therapy after acute coronary syndrome (ACS) has firmly shown its effectivity [1,2]. Still, residual risk of recurrent cardiovascular events remains high [3,4]. Along with reducing LDL-C, statins also reduce triglyceride-rich lipoproteins. It remains to be investigated, however, whether triglyceride (TG) level predicts residual risk after ACS in patients receiving effective statin treatment. The present study examined, in 2 complementary trials, the long-term and short-term association between fasting TG levels and recurrent atherosclerotic cardiovascular risk after ACS in patients treated with statins. Post-hoc analyses were, firstly, performed on data from the long-term dal-OUTCOMES trial (A Study of RO4607381 in Stable Coronary Heart Disease Patients With Recent Acute Coronary Syndrome) with 15,871 participants of whom 97% was statin-treated. Four to 12 weeks after ACS, patients were randomly assigned either to treatment with dalcetrapib (a cholesteryl ester transfer protein inhibitor) or placebo and followed for a median 31 months [5,6]. Secondly, data were used from the atorvastatin arm of the short-term MIRACL trial (Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering) which included 1,501 participants. Patients were statin-naïve treated with atorvastatin (80 mg daily), starting 1 to 4 days after ACS and followed for 16 weeks. Fasting TGs 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.

Main results

Dal-OUTCOMES (median follow-up of 31 months)

• 1,289 patients (8.1%) had at least 1 primary endpoint event. The event rates were similar in the dalcetrapib group and the placebo group (8.3% and 8.0%, resp).
• The median TG concentration at baseline (random assignment) was 115 mg/dl. Dalcetrapib or placebo changed TG levels minimally (median: 111 and 116 mg/dl, resp.).
• Baseline TG concentration was significantly related to risk. A 10-mg/dl increment in TG was associated with increased cardiovascular risk (adjusted HR: 1.018; 95% CI: 1.011- 1.024; p < 0.001).
• Higher TG levels were related to a higher CV risk than lower TG levels. The hazard ratio (HR) in the highest versus lowest quintile (>175 versus ≤80 mg/dl) was 1.61 (95% confidence interval (CI): 1.34-1.94).
• There was no significant interaction of treatment assignment (dalcetrapib or placebo) and TG on the risk of a primary endpoint event (p= 0.278).
• There was no relation beween 10 mg/dl increment in HDL-C and risk (HR: 0.980; 95% CI: 0.931- 1.031; p= 0.435). 

MIRACL (follow-up of 16 weeks in the atorvastatin arm)

• 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. There were less patients with an endpoint event in the lowest tertile of achieved TG (≤90 mg/dl; 2.7%) than in the upper 2 tertiles (>90-135 mg/dl: 4.4%; >135 mg/dl: 4.0%).
• Median concentrations (obtained before statin treatment) of TG was 160 mg/dl and of LDL-C was 120 mg/dl). This was higher than in dal-OUTCOMES. Six weeks of treatment with atorvastatin substantially lowered TGs (median: 110 mg/dl) and LDL-C (median: 60 mg/dl).
• Risk increased across tertiles of baseline TG. The highest tertiles showed an increased risk versus lowest tertiles (>195 vs  ≤135 mg/dl: HR=1.50; 95% CI: 1.05-2.15).
• In both studies, the relationship between TG levels and risk was independent of low density lipoprotein cholesterol. 

Conclusions

Fasting triglyceride levels were associated with both long-term and short-term residual cardiovascular risk after ACS in patients receiving effective statin therapy. Statins not only reduce LDL-C, but also have significant effects to lower concentrations of triglycerides and of cholesterol contained in triglyceride-rich lipoproteins [7]. Although the two trials under research were different in terms of patient demographics, coronary revascularization and medication use, the present study showed that optimal statin treatment may lower levels of triglyceride-rich lipoproteins. This, however, does not cancel the risk associated with these particles. Future randomized controlled studies should clarify whether triglyceride rich lipoproteins should be a therapeutic target after ACS, on top of statin treatment. 

Editorial

Joshi et al. [8] evaluated the results of Schwartz et al. and stated that “[…] The authors found a
consistent, significant, 50% to 60% increase in hazard for recurrent events among those in the highest triglyceride TG categories compared with those in the lowest, after adjustment for several risk factors and independent of LDL-cholesterol levels”. […] “The differences between the trials merit attention. The event rate among statin-treated patients (i.e., residual risk) was strikingly high at 15%
over only 16 weeks in MIRACL. This was markedly improved a decade later, though still high at
nearly 8% over 31 months in dal-OUTCOMES. Both trials enrolled patients shortly after ACS, although MIRACL participants did not undergo revascularization, which had become standard of care by the time dal-OUTCOMES was conducted. The difference in treatment strategies probably contributed to the discrepancy in event rates while also providing a spectrum of risk ranging from the lower-risk dal-OUTCOMES population to the higher-risk, statinnaive MIRACL population. The consistent association of TG with risk across these diverse populations is timely, given recent findings related to ASCVD and remnants.” […]
“The questions of whether residual risk for recurrent atherosclerotic cardiovasular disease (ASCVD) can be attributed to remnant lipoproteins, and to what degree, carry significant potential therapeutic implications. With the rise in metabolic syndrome and resultant increases in remnants, lifestyle modifications take on even greater importance as part of a structured preventive program. Inspired by the simple elegance of the iconic Jackson 5, we prefer the ABCs approach to prevention. Specifically, modest weight loss may reduce TG by ~20% and moderate to intense physical activity may reduce TGs by ~20% to 30%” […]
“Schwartz et al. add strong support that a residually high TG level on statin therapy is a biomarker of risk. Only more compelling randomized, controlled trial results showing a reduction in
ASCVD among participants on statins and undergoing intensive lifestyle therapy, but with residual
remnant elevation, will tell us if TG or remnants in particular must be a target of pharmacotherapy”.

References

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