Prognostic Significance of Serum Total Cholesterol and Triglyceride Levels in Patients Hospitalized for Heart Failure With Reduced Ejection Fraction (from the EVEREST Trial).

Greene SJ, Vaduganathan M, Lupi L, et al.
Am J Cardiol. 2013;111:574-81. doi: 10.1016/j.amjcard.2012.10.042.

Background

There is a reciprocal association between traditional cardiovascular risk factors, including hyperlipidemia, and poor clinical outcomes in heart failure (HF) [1]. The mechanism of this “cholesterol paradox” is presently unclear, but relations with persistent malnutrition and inflammation frequently seen in chronic disease states are hypothesized [2,3].
This study analyzed 3,957 patients hospitalized for worsening HF with ejection fractions ≤40% in a post hoc analysis of the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan (EVEREST) study [4-6]. Goals of this analysis were to report the distribution of total cholesterol and triglycerides, to describe the baseline clinical characteristics by total cholesterol level, and to assess the association between total cholesterol and triglyceride levels and postdischarge morbidity and mortality in patients hospitalized for HF with reduced ejection fraction (EF).

Main results

• Patients with lower total cholesterol tended to have lower blood pressure, EF, serum sodium, and albumin, higher natriuretic peptide and serum creatinine levels, and were more likely to have worse HF functional class, to receive ACE-inhibitors or ARBs and statins, and to have histories of diabetes mellitus, renal insufficiency, and coronary revascularization (all p values <0.001).
• Baseline total cholesterol  was strongly predictive of all-cause mortality and cardiovascular mortality or hospitalization for HF at median follow-up of 9.9 months, after adjustment for baseline risk factors (HR 0.73, 95% CI 0.63 - 0.85, p <0.001; HR 0.73, 95% CI 0.66 - 0.82, p <0.001, respectively); lower baseline triglyceride levels were also associated with worse outcomes (Figure 1 & 2)
• Patients on statin therapy had a 51% reduction in the hazard of mortality per 25 mg/dl increase in total cholesterol (HR 0.49, 95% CI 0.40 to 0.60) compared to a 40% reduction in those who were not taking statins (HR 0.60, 95% CI 0.52 to 0.70) (p = 0.003)

Conclusion

In patients hospitalized for worsening HF with reduced EF, lower baseline total cholesterol correlates with several high-risk prognostic factors and is a marker of disease severity. The therapeutic implications of these findings are presently unclear. Future prospective studies are necessary to better characterize the clinical role of these lipid indices in patients hospitalized for HF.

References

1. Kalantar-Zadeh K, Block G, Horwich T, Fonarow GC. Reverse epidemiology of conventional cardiovascular risk factors in patients with chronic heart failure. J Am Coll Cardiol 2004;43:1439e1444
2. Anker SD, Negassa A, Coats AJ, et al. Prognostic importance of weight loss in chronic heart failure and the effect of treatment with angiotensin-converting-enzyme inhibitors: an observational study. Lancet 2003;361:1077e1083.
3. Horwich TB, Fonarow GC. Reverse epidemiology beyond dialysis patients: chronic heart failure, geriatrics, rheumatoid arthritis, COPD, and AIDS. Semin Dial 2007;20:549e553.
4. Gheorghiade M, Orlandi C, Burnett JC, et al. Rationale and design of the multicenter, randomized, double-blind, placebo-controlled study to evaluate the Efficacy of Vasopressin antagonism in Heart Failure: Outcome Study With Tolvaptan (EVEREST). J Card Fail 2005;11:260e269.
5. Gheorghiade M, Konstam MA, Burnett JC Jr, et al. Short-term clinical effects of tolvaptan, an oral vasopressin antagonist, in patients hospitalized for heart failure: the EVEREST Clinical Status Trials. JAMA 2007;297:1332e1343.
6. Konstam MA, Gheorghiade M, Burnett JC Jr, et al. Effects of oral tolvaptan in patients hospitalized for worsening heart failure: the EVEREST Outcome Trial. JAMA 2007;297:1319e1331.Background:
Lower cholesterol levels are associated with worse outcomes in patients with chronic heart failure (HF) and have been shown to predict in-hospital mortality. The relation between lipid profile and postdischarge outcomes in patients hospitalized for worsening HF is less clear.

Methods:
In this post hoc analysis of the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan (EVEREST), 3,957 patients hospitalized for worsening HF with ejection fractions ≤40% were examined. Baseline total cholesterol and triglyceride levels were measured <48 hours after admission and evaluated as continuous variables. The primary end points of all-cause mortality and cardiovascular mortality or hospitalization for HF were compared using Cox regression models. Patient characteristics at randomization were also compared among quartiles of total cholesterol.

Results:
Patients with lower total cholesterol tended to have lower blood pressure, ejection fractions, serum sodium, and albumin, and were more likely to have worse HF functional class, to have higher natriuretic peptide levels, and to have histories of diabetes mellitus, renal insufficiency, and coronary revascularization (all p values <0.001). After adjustment for baseline clinical risk factors, total cholesterol was predictive of all-cause mortality (hazard ratio 0.73, 95% confidence interval 0.63 to 0.85, p <0.001) and cardiovascular mortality or hospitalization for HF (hazard ratio 0.73, 95% confidence interval 0.66 to 0.82, p <0.001) at median follow-up of 9.9 months. Lower baseline triglyceride level was also associated with worse outcomes.

Conclusions:
In conclusion, lower baseline total cholesterol is correlated with a high-risk patient profile and is a marker of disease severity in patients hospitalized for worsening HF with reduced ejection fraction. Baseline total cholesterol and triglyceride levels are predictive of mortality and HF rehospitalization beyond traditional risk factors.