Statin Use in Heart Failure

Corresponding Author

O ne of the puzzling challenges in clinical car- diology has been the difficulty with regard to the demonstration of a benefit from statin therapy in patients with heart failure, even in those with ischemic heart failure.Nearly 15 years ago, the Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA) 1 and the Gruppo Italiano per lo Studio del Sopravvivenza nell'Insufficienza cardiaca (GISSI-HF) 2 trials evaluated statin therapy in heart failure populations.CORONA largely randomized those with ischemic heart failure while GISSI-HF included ischemic and nonischemic heart failure patients.Both studies were deemed negative and heralded an end to an otherwise long run of successful clinical trials evaluating statin therapy in a variety of clinical conditions.

GISSI-HF AND CORONA
The GISSI-HF trial randomized 4,574 patients with ischemic and nonischemic heart failure to rosuvastatin 10 mg daily or placebo for 3.9 years.The primary end points were time to death and time to death or admission for heart failure.The hazard ratios (HRs) for the time to death was 1.00 (95% CI: 0.898-1.122,P ¼ 0.943) and time to death or admission for heart failure was 1.01 (95% CI: 0.908-1.112,P ¼ 0.903).The CORONA trial randomized 5,011 participants with ischemic heart failure to rosuvastatin 10 mg or placebo for a median time of 32.8 months with a primary outcome composite of cardiovascular death, nonfatal myocardial infarction, and/or nonfatal stroke.The primary end point HR was 0.92 (95% CI: 0.83-1.02,P ¼ 0.12).While the primary end point was not significantly reduced, there were fewer hospitalizations in those randomized to rosuvastatin.
Multiple hypotheses have been advanced about why statin therapy failed to reduce significantly the measured primary end points in both trials but especially CORONA. 3,4Perhaps it was a type 2 statistical error due to an inadequate sample size or number of accrued events.Others have suggested that the recruited population was too old and/or that symptomatic advanced heart failure may produce clinical sequela which cannot be mitigated by statin therapy.
Regardless, most clinicians remained perplexed as to why statin therapy was not demonstrated as beneficial in the heart failure population.

STATIN THERAPY REVISITED
Given the clinical conundrum of a lack of statin efficacy in heart failure juxtaposed against a body of robust evidence of benefit in atherosclerotic cardiovascular disease (ASCVD) patients, in this issue of JACC: Advances, Anderson et al 5 1) who were treated with a variety of statin therapies and doses (Figure 1).While not explicitly stated, the data from this study appear to have evaluated those with systolic heart failure.The investigators examined overall differences across several end points between patients treated with statins vs those not treated (Figure 2).The team at Intermountain also evaluated the impact of statin therapy in primary and secondary prevention cohorts, exploring whether the presence of established ASCVD might impact outcomes.The end points chosen included: 1) the major adverse cardiovascular events (MACEs) of death, myocardial infarction, and stroke as a composite, as well as individual end points of: 2) MACE þ heart failure hospitalization, 3) death, 4) myocardial infarction, 5) ischemic stroke, and 6) hospitalization for heart failure.Patients treated with statins had substantially fewer MACE events over the follow-up period: 52.1% vs 60.5%, ARR (absolute risk reduction, 8.4% (P < 0.0001) HR 0.53 (95% CI: 0.51-0.56)).Figure 2 illustrates the consistent and robust reductions associated with statin use across each of the end points.MACE þ heart failure hospitalization was significantly lower: HR 0.41 (95% CI: 0.39-0.43),ARR 18.1%, P < 0.0001; death was significantly lower, HR 0.57 (95% CI: 0.51-0.62),ARR 6.2%, P < 0.0001; myocardial infarction was significantly lower, HR 0.41 (95% CI: 0.34-0.48),ARR 2.6%, P < 0.0001; ischemic stroke rates were lower, HR 0.54 (95% CI: 0.46-0.63),ARR 1.7% P < 0.0001 and rates of HF hospitalization were significantly lower, HR 0.41 (95% CI: 0.39-0.43),ARR 20.7%, P < 0.0001.Separate examinations of these end points in the secondary as well as primary prevention subgroup analysis were consistent with the overall data, demonstrating a robust reduction in clinical events.In summary, there were no subcategories of patients who did not benefit from statin therapy.
The Intermountain data are extremely impressive and provocative, and expand what we know about statin use in heart failure beyond the evidence of CORONA and GISSI-HF.There is likely some degree of bias that cannot be accounted for statistically despite multivariable modeling and best efforts by the investigators.Nonetheless, these data demonstrate a consistent reduction across cardiac, cerebrovascular, and heart failure-associated clinical events and lower

WHAT CAN WE LEARN FROM THE INTERMOUNTAIN STUDY?
First, the data are generalizable to the broad population of patients we treat with systolic heart failure.
This was not a subselected, narrowly focused population.The patients evaluated resemble those we evaluate and treat in clinic or at the hospital.In this wright.scott@mayo.edu.

FIGURE 1
FIGURE 1 Statin Doses Utilized in Intermountain Study and the CORONA and GISSI-HF Trials

FIGURE 2
FIGURE 2 Endpoints and Impact From Associated Statin Use

TABLE 1
Key Variables Across the Intermountain Study, the CORONA and