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Macrovascular Residual Risk THROUGH LANDMARK STUDY

11 May 2010
HDL-C levels are predictive of major CV events in patients treated with statins, even in those whose LDL-C levels < 70 mg/dL

HDL Cholesterol, Very Low Levels of LDL Cholesterol, and Cardiovascular Events. N Engl J Med 2007;357:1301-10. (Clinical-Trials.gov number, NCT00327691).

Barter P, Gotto AM, LaRosa JC, Maroni J, Szarek M, Grundy SM, Kastelein JJP, Bittner V, Fruchart J-C
Summary
Comments & References
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STUDY SUMMARY
Objective: To examine the relationship between the frequency of major cardiovascular (CV) events and HDL cholesterol (HDL-C) levels in a post hoc analysis of data from the TNT study.
Study population:
9770 men and women, aged 35-75 years with clinically evident coronary heart disease treated with atorvastatin 10 or 80 mg.
Primary endpoint:
Time to a first major CV event.
Secondary endpoint:
Relationship between HDL-C levels and specific LDL-C strata and time to first major CV event at the third month of statin therapy.
Study design:
Post hoc analysis of a randomized, double-blind, parallel-group, multicenter trial.
Method: Univariate and multivariate analysis of the TNT study data.
Main results:
  • The CV risk was reduced by 25% between the highest and lowest HDL-C quintiles.
  • HDL-C levels were predictive of major CV events (P = 0.04).
  • The relationship between HDL-C level and major CV events was borderline when stratified according to LDL-C level (P = 0.05).
  • In patients with LDL-C <70 mg/dL (1.8 mmol/L) at month 3, less risk for major CV events was observed at highest levels of HDL-C (P = 0.03); the CV risk was reduced by 39% between the highest and lowest HDL-C quintiles
Author's conclusion: HDL-C levels were predictive of major CV events in patients treated with statins. This relationship was also observed among patients with LDL-C levels <70 mg/dL.

COMMENT

Substantial residual risk for major cardiovascular (CV) events remains in many patients despite lowering of low-density-lipoprotein cholesterol (LDL-C) with statins. One explanation is the relationship of high-density-lipoprotein cholesterol (HDL-C) with the risk of major CV events. An analysis of data from four large studies concludes that each increase of 1 mg/dL (0.0259 mmol/L) in HDL-C is associated with a decrease of 2 to 3% in the risk of future coronary heart disease.1 The effect of HDL-C may be independent of LDL-C, and HDL-C may be a more potent risk factor for CV disease than LDL-C.2,3

HDL-C is predictive of major CV events
In a post hoc analysis of data from 9770 patients with coronary heart disease on statin therapy in the Treating to New Targets (TNT) trial4, HDL-C levels were found to be a significant predictor of major CV events, with a reduction of CV event rate by 25% in the highest HDL-C quintile compared with the lowest (HR, 0.75, 95% CI, 0.60 to 0.95). This was found across the entire study cohort, even after inclusion of all other baseline risk factors, including baseline LDL-C level. The effect was most pronounced when HDL-C levels were analyzed as a continuous variable rather than stratified into quintiles of HDL-C levels at month 3 of statin therapy (Figure 1).
In the analysis it was also key to establish wether a low HDL-C level was still a significant risk factor even in patients whose LDL-C was reduced to very low levels.
The analysis showed that after adjustment for covariates, the predictive value of HDL-C levels was of borderline siginficance (p = 0.05), with no evidence of an interaction with LDL-C levels.

This result was consistent with the proposition that in patients with coronary heart disease, higher HDL-C levels may offset the increased risk associated with higher LDL-C levels.

In a further analysis the relationship of HDL-C levels with major CV events remained significant, with a reduction of CV event rate by 39% in the highest HDL-C quintile compared with the lowest (HR, 0.61, 95% CI, 0.38 to 0.97), even in patients whose LDL-C level was in the lowest LDL-C stratum (< 70 mg/dL or 1.8 mmol/L) (Figure 2), which is the target for therapy in patients with established coronary heart disease or other forms of atherosclerotic disease in the American College of Cardiology 2006 guidelines.

HDL-C and residual risk reduction
The results of this post hoc analysis of the TNT study confirm that HDL-C levels are predictive of major CV events in patients receiving statin therapy and this was independent of LDL-C levels.
Despite achievement of low level of LDL-C with intensive statin therapy, HDL-C remains a significant predictor of major CV events.
This suggests that HDL-C levels could be key to residual risk reduction. Further studies are required to establish any coincident effect of HDL-C with other CV risk factors, such as metabolic syndrome.

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Figure 1: HDL-C levels and 5-year risk of major CV events
at month 3 of atorvastatin therapy
 


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Figure 2: HDL-C levels and 5-year risk of major CV events
in patients with LDL-C <70 mg/dL
at month 3 of atorvastatin therapy

These data suggest that, instead of a “statin for all” single-strategy, lipid-related cardiovascular prevention should target all risk factors present in individuals with diabetes, including those not receiving proper consideration or hierarchical priority in current recommendations and guidelines.

Together with statin therapy in patients with elevated LDL-C and/or high cardiovascular risk, glycemic control, blood pressure control, lifestyle changes, smoking cessation, and antiplatelet therapy are key measures to be adapted to individual diabetic patients. However, even with this up-to-date approach, patients with diabetes remain exposed to an important residual risk of cardiovascular events and microvascular complications. Targeting atherogenic dyslipidemia also appears to be a most promising strategy to reduce micro- and macrovascular residual risk.

Figure 1. ASPEN primary end point. Cumulative hazard ratios in the overall study population.

References
  1. Gordon DJ, Probstfield JL, Garrison RJ, et al. Circulation 1989;79:8-15.
  2. Gordon T, Castelli WP, Hjortland MC, Kannel WB, Dawber TR. Am J Med 1977;62:707-14.
  3. Sacks FM, Tonkin AM, Shepherd J, et al. Circulation 2000;102:1893-900.
  4. La Rosa JC, Grundy SM, Waters DD, et al. N Engl J Med 2005;352:1425-35
Key words HDL cholesterol – LDL cholesterol –- predictive on major cardiovascular events