Statin therapy in diastolic heart failure

Many patients with heart failure have high cholesterol levels and might potentially benefit from treatment with HMG-CoA reductase inhibitors (statins). There is concern, however, that a low cholesterol level may be associated with worse survival in patients with heart failure.1 Recent studies have shown a significant association between statin therapy and lower mortality in patients with heart failure and a reduced ejection fraction.2,3 Nearly half of patients with heart failure, however, have a normal ejection fraction (diastolic heart failure).4 The survival benefit of statins in these patients is unknown.

We evaluated the correlation between treatment with statins and 2-year survival in patients with heart failure and a normal ejection fraction.

Patients and methods

From November 2001 to August 2002, we assessed 137 consecutive patients at Wake Forest University Baptist Medical Center who had heart failure and an ejection fraction of 50% or above. Patients were 65 ± 14 years of age, and 57% were women; 80% of patients had hypertension, 23% had diabetes, and 58% had coronary artery disease. Those with dialysis-dependent renal failure, malignancy, active myocardial ischemia, myocardial infarction, or hemodynamically significant valvular disease were excluded. We ascertained medication status according to initial management following the cardiac examination. In February 2005, follow-up was determined. The patients’ physicians made all decisions regarding therapy. Unless hospitalizations were clearly related to a noncardiac cause, they were considered cardiovascular.

Kaplan-Meier survival curves were calculated for patients grouped by statin therapy and were compared with the log-rank test. Cox proportional hazards regression analysis was used to ascertain the relative risk of clinical variables for death. Multivariate Cox hazards regression models were used to determine the independent association of statin treatment with mortality. Propensity analysis was done to adjust for the nonrandomized assignment of patients to treatment with a statin.

Results

At study entry, 68 patients (50%) received statins. Twenty-three patients were prescribed statins according to the recent guidelines,5 and 45 patients were already taking statins for hy-

perlipidemia. Among the 68 patients taking statins, 1 (1%) took fluvastatin (Lescol XL; 80 mg/day), 7 (10%) took pravastatin (Pravachol; 30 ± 11 mg/

day), 14 (21%) took simvastatin (Zocor; 37 ± 26 mg/day), and 46 (68%) took atorvastatin (Lipitor; 22 ± 18 mg/day). Patients who took statins were more likely to have coronary artery disease and diabetes, to have higher serum creatinine values and lower plasma B-type natriuretic peptide (BNP) levels, and to be male with hypertension compared with those not taking statins. Both groups (those taking statins and those not taking statins) were similar in New York Heart Association functional class, other medication status, and Doppler echocardiographic indexes.

Data on lipid factors at the start of the study were available for 47 patients who were not receiving statins, and data before and after treatment were available for 21 patients. Patients receiving statins had higher baseline low-density lipoprotein (LDL) cholesterol levels than those not receiving statins (153 ± 45 versus 98 ± 33 mg/dL, P < .01). Following statin therapy, LDL cholesterol levels fell to a similar level (101 ± 32 mg/dL) as patients not receiving statins (98 ± 33 mg/dL). Only 6 of the 47 patients who did not receive statins at study entry had a clear indication to receive them (LDL cholesterol level >130 mg/dL). After a follow-up period of 21 (± 12) months, data were available for 132 of the 137 patients. Forty-three patients were hospitalized for cardiovascular reasons, and 20 patients died.

Treatment with statins was associated with a substantial improvement in survival (Figure 1). After adjusting for differences in baseline clinical variables, such as serum creatinine levels, coronary artery disease, diabetes, and hypertension, and for the most powerful univariate predictors (ratio of mitral inflow to annular velocities, age, serum hemoglobin, and BNP), the association of statin therapy with improved survival remained significant (Table). Furthermore, statin therapy correlated with improved survival and a trend toward improved survival without cardiovas-cular hospitalization after propensity matching was performed (Figure 2).

Discussion

Although large randomized trials have shown the survival benefit of statins in patients with coronary artery disease, these trials have excluded patients with heart failure.6,7 Recent observational studies have shown a marked correlation between statin therapy and lower mortality in patients with heart failure and a decreased ejection fraction.2,3 Our study shows that the survival benefit of statins is also present in patients with diastolic heart failure.

Diastolic heart failure most frequently occurs in elderly patients with long-standing hypertension; coronary artery disease, whether recognized or unrecognized, is quite common. Thus, the improved survival shown in our study might be the result of the known favorable effects of statins in patients with coronary artery disease.6,7 In addition, patients with diastolic heart failure are likely to have diabetes and impaired renal function. Part of the benefit shown in the diastolic heart failure patients in our study might be explained by the fact that statins may improve outcomes in diabetes patients and those with impaired renal function.8,9

We observed after statin therapy that treated and untreated patients had similar LDL cholesterol levels. This suggests that effects other than a decrease in cholesterol level may contribute to improved survival in diastolic heart failure.

The potential benefits of statins, in addition to decreasing lipid levels, that may directly affect diastolic heart failure include regression of left ventricular hypertrophy and fibrosis,10 improvement of arterial stiffness,11 and prevention of left ventricular remodeling.12 These beneficial effects may contribute to improvement of left ventricular relaxation, thereby improving diastolic function.

Anti-inflammatory and antioxidant effects are possible additional benefits of statins not limited to diastolic heart failure.13 Worse symptoms in heart failure are associated with increased inflammatory markers.14 Elevated production of reactive oxygen free radicals, resulting in myocardial oxidative stress, also contributes to the development of heart failure.14

Conclusion

We found that statin therapy is associated with lower mortality in patients with diastolic heart failure. Our study suggests that patients with diastolic heart failure and high cholesterol levels will benefit from statin therapy.