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• W2039283873 abstract "The topic of hyperlipidemia in patients with chronic heart failure (HF) has created considerable controversy. Clearly, hyperlipidemia is a major risk marker for development and progression of coronary heart disease (CHD), a leading contributor of chronic HF.1 On the other hand, the concept of “reverse epidemiology” has emerged in which lower cholesterol and its lipid fractions (along with lower systolic blood pressure and body weight) have been associated with a worse overall prognosis in advanced stages of HF.2, 3 Although statin therapy, with its potent lipid-altering as well as pleiotropic effects, may reduce major CHD events that may then lead to reduced HF risk, once HF is well-established, this therapy may not be as beneficial and could even theoretically be detrimental.4 Non–lipid-lowering potent pleiotropic effects of statins, including potential benefits on myocardial cellular function, down-regulation of tissue renin-angiotensin-aldosterone system activation, restoration of autonomic function, neoangiogenesis, and inhibition of pro-inflammatory cytokines could favorably influence the natural history of HF.4 Statins possess powerful anti-inflammatory effects and decrease vascular cell adhesion molecule-1 levels in HF.5 Additionally, circulating lipids have the capacity to detoxify bacterial lipopolysaccharides (endotoxins), which stimulate the release of inflammatory cytokines in HF.6 Taken together, the rationale supporting the potential benefits of statin therapy in HF is well grounded. Horwich and colleagues7 described the potential disease-modifying effects of statins in HF, including reducing the risk of sudden cardiac death and progression of HF. Ramasubbu and colleagues8 analyzed 13 observational studies to assess the role of statins in HF, demonstrating that these agents provided a disease-modifying effect that was independent of HF etiology. Certainly, this evidence supports the performance of the recently completed Controlled Rosuvastatin Multinational Study in Heart Failure (CORONA)9 and Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico–Insufficienza Cardiaca (GISSI-HF)10 trials, both of which evaluated one particular statin, 10 mg of rosuvastatin, in HF. The CORONA trial evaluated 5011 elderly patients with New York Heart Association (NYHA) class II through IV HF and CHD.9 Despite the significant lipid-lowering and antiinflammatory effects of rosuvastatin, this therapy was not associated with reduction in major cardiovascular (CV) events, although significantly fewer hospitalizations for CV causes were noted in the rosuvastatin-treated patients. The GISSI-HF trial studied 4500 class II through IV HF patients with both ischemic and nonischemic etiologies of HF, and rosuvastatin was not associated with any major CV benefits during a nearly 4-year follow-up period.10 Although these trials were well done, both had “issues” worthy of clinical interpretation. For example, CORONA enrolled mostly an older cohort with 60% NYHA class III or IV HF, and this trial was “event driven,” by total mortality as opposed to nonfatal events. If a trial enrolls a population likely to have a preponderance of one event (such as pump failure–related mortality) and a lower time-dependent occurrence of a statin-modifiable event (such as ischemia-triggered mortality), a trial could be stopped early because the numerical mortality numbers are met. This appears to have been the case in CORONA. In addition, this population of patients had a quite low rate of implantable cardioverter-defibrillator usage. The reduction in hospitalizations likely represents a significant clinical effect of therapy, and longer follow-up may have allowed for a higher prevalence of “vascular events” in which statin therapy may have produced clinical benefits. In GISSI-HF, patients already taking statins were excluded from enrollment, and this trial likely had too short a follow-up with relatively few major vascular events. Taken together, these trials provide credence to the school of “statin naysayers” in HF. In the current issue of the Journal, Sumner and colleagues analyzed the Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) trial11 database and demonstrated that statin exposure is associated with improved survival in patients with advanced HF receiving cardiac resynchronization therapy (CRT). No survival benefit was seen, however, in patients receiving statins and other contemporary HF therapy but without CRT. Although the notion of potential statin benefits in CRT patients is intriguing, this paper suffers from the typical problem of confounding by indication in nonrandomized controlled trials (RCTs) (eg, the lower the cholesterol, the sicker the patient and therefore the less likely to receive statin therapy). There are 2 baseline factors that support this notion, including the fact that those receiving statins had a higher prevalence of left ejection fraction >20% and a higher use of β-blocker therapy than those not treated with statins. Additionally, CRT itself could allow for better application of therapies (such as β-blockers) and this would explain why patients receiving statins in the CRT group were less sick at baseline and perhaps more responsive to CRT, although the authors attempted to adjust for these factors in multivariate analyses. Therefore, the presence of statin therapy serves as a marker of improved survival in this unique cohort and a cause-and-effect relationship cannot be definitively established. How should clinicians currently use this information? Did CORONA and GISSI-HF deliver a knock-out punch for statins in HF intervention? Clearly, the observational trials and recent RCTs of statins in HF support the rationale for their use, and the RCTs reveal safety of this therapy even in advanced HF. If statins are required to treat CHD and its progression, this therapy is indicated in patients with concomitant HF. Based on GISSI-HF, however, there is no rationale for routine statin therapy in nonischemic HF. However, one must recognize that both CORONA and GISSI-HF were performed using low doses of rosuvastatin, and this trial cannot determine whether higher doses of rosuvastatin, such as 20 mg or 40 mg, which were very effective in primary prevention12 and advanced CHD,13 would have produced a different benefit. Additionally, it remains plausible that just as in the case of β-blockers, the statin effect in HF may be drug dependent and not a class effect. Indeed, high-dose atorvastatin (eg, 80 mg), which has produced benefits in numerous CHD trials,14-16 demonstrated a reduction in HF hospitalizations in those patients with an underlying diagnosis of HF and stable CHD in the Treating to New Targets (TNT) study.17 Although this study excluded patients with a left ventricular ejection fraction <30% and advanced HF at entry, this post hoc analysis resulted in an official indication from the Federal Drug Administration for the prevention of HF hospitalizations in secondary CHD prevention. Certainly, the potential exists for such a “class dissociation” effect of various statins in HF (although this was not noted in the current paper by Sumner and colleagues11), and pharmacokinetics and pleiotropic effects as a function of area under the curve of different statins are a potential area of further exploration. Additionally, low levels of high-density lipoprotein cholesterol also predict worse prognosis in advanced HF, 18 and therapies beyond statins that improve this lipid component as well as the high-density lipoprotein/triglyceride axis may also need to be assessed in advanced HF." @default.
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• W2039283873 title "Statins and Advanced Heart Failure-Alive But Barely Breathing After CORONA and GISSI-HF" @default.
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