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12 July 2005
In coronary heart disease patients treated with conventional- or high-dose statins, plasma triglycerides predict residual risk of cardiovascular events

Pooled data from the TNT and IDEAL trials show that 5-year risk of recurrent cardiovascular events in patients treated with statins may vary by 63% depending from on-treatment triglyceride level

Faergeman O, Holme I, Fayyad R, Bhatia S, Grundy SM, Kastelein JJ, LaRosa JC, Larsen ML, Lindahl C, Olsson AG, Tikkanen MJ, Waters DD, Pedersen TR
Summary
Comments & References
STUDY SUMMARY
Objective To test the hypothesis that increased triglycerides (TG) are associated with risk of recurrence of cardiovascular events in patients with stable coronary disease.
Study population

7,232 patients from the IDEAL trial and 8,547 patients from the TNT trial

  • With clinically-evident coronary heart disease (IDEAL) or with a history of myocardial infarction (TNT)
  • Treated with conventional-dose statin (atorvastatin 10 mg/d or simvastatin 20-40 mg/d) or high-dose statin (atorvastatin 80 mg/d); data from all groups of the two studies were pooled for the present analysis
  • A mandatory entry criterion in the present analysis was availability of lipid and apolipoprotein measurements (apoB, apoA1) performed during the first year of treatment
Study design Post-hoc analysis.
Methods

Statistical analysis of the relationship between on-treatment plasma triglyceride levels at one year and risk of subsequent cardiovascular events (coronary death, non-fatal myocardial infarction, resuscitation after cardiac arrest, fatal or non-fatal stroke, coronary revascularization, hospitalization for unstable angina or a primary diagnosis of heart failure, and peripheral artery disease).

Main results
  • Risk of cardiovascular events was 30% higher in patients with TG >150 mg/dL than <150 mg/dL (hazard ratio 1.30; 95% confidence interval (CI) 1.21-1.40; p <0.001)
  • Risk was 63% higher in patients in the fifth TG quintile compared with those in the lowest quintile (hazard ratio 1.63; 95%CI 1.46-1.81; p <0.001)
  • Rates of cardiovascular events tended to be higher in any TG quintile above the first
  • The comparison between quintiles of TG in patients with LDL cholesterol <100 mg/dL yielded significant differences of the same magnitude
Author's conclusion Even slightly increased TG levels are associated with higher risk of recurrence of cardiovascular events in statin-treated patients and should be considered as a useful marker of risk.

COMMENT

This study was conducted in the overall population of two landmark randomized clinical trials comparing conventional-dose and high-dose statin therapy in secondary cardiovascular prevention. Compared with the conventional-dose treatment, the high-dose treatment resulted in a non-significant 11% reduction of major coronary events but a significant 17% reduction in non-fatal myocardial infarction (p = 0.02) in IDEAL,1 and a significant 22% reduction of major cardiovascular events (major coronary events + stroke) in TNT.2 Although the conventional-dose regimens differed in the two trials, their inclusion criteria were similar as was duration of treatment (mean follow-up: 4.8 and 4.9 months in the IDEAL and TNT trial, respectively). This enabled the authors to pool patients’ data from the two trials. The primary analysis was performed on the whole population of patients, irrespective of their statin treatment regimen (conventional- or high-dose). However, a specific analysis was carried out in those patients reaching a LDL cholesterol level <100 mg/dL.

The occurrence of any cardiovascular event, used as outcome measurement for the present analysis, encompassed major coronary events and/or the development of heart failure. The authors acknowledge that the causes and mechanisms of these two types of events are different, but underline that heart failure accounted for less than 2% of reported events, and thus could not markedly impact the results.

The most striking result is the 63% difference in relative risk of cardiovascular events between patients in the highest and lowest quintiles of fasting plasma triglycerides (TG). Guidelines have defined 150 mg/dL as the threshold defining normal and elevated fasting TG. The difference in cardiovascular risk between these two categories was 30% in the present analysis. However, the difference in cardiovascular risk between the first and second TG quintiles was already significant, which suggests that the increased risk is present with plasma TG levels well below the conventional 150 mg/dL cutoff.

Results reported above are adjusted for age, gender, and trial (TNT or IDEAL). Entering HDL-cholesterol and the apoB/apoA1 ratio into the statistical model markedly attenuated the higher-to-lower triglycerides quintile difference (19% increase in risk of cardiovascular events; p=0.044). This may be explained by the permanent metabolic trade and exchanges (including mutual transfer of cholesterol and TG) between VLDL and HDL particles mediated by the cholesteryl ester transfer protein (CETP). Accordingly, the TG-rich VLDLs give away their TG to HDLs, from which they acquire cholesteryl esters in exchange. The rate of exchange increases when concentrations of VLDLs are high. As a result, HDL particles become depleted in cholesteryl esters, more sensitive to subsequent TG depletion by lipoprotein lipase and more subject to breakdown, which explains why HDL cholesterol level tend to be lowered when TG are elevated.

Conclusions

This analysis shows that even slightly elevated plasma TG levels are a marker of recurrent, and thus of residual cardiovascular risk, in patients with coronary heart disease treated with statins. Results were similar when only the group of patients with normalized LDL-cholesterol levels (< 100 mg/dL) was considered for analysis. In patients with elevated TG while being treated with a statin, lifestyle changes and/or triglyceride-lowering drugs with evidenced clinical benefit should be considered to further reduce this residual vascular risk.

References
  1. 1. Pedersen TR et al., Incremental Decrease in End Points Through Aggressive Lipid Lowering (IDEAL) Study Group. JAMA 2005;294:2437-45.
  2. 2. LaRosa JC, et al. N Engl J Med 2005;352:1425-35.