Coronary heart disease, the most important indication for treatment with statins, is at the same time the most common cause of heart failure. However, a benefit of CSE inhibitors in the latter indication has not been confirmed. To date, patients with heart failure, at least severe forms, have been excluded from placebo-controlled endpoint studies (1-5) of the secondary prevention of atherosclerotic diseases with statins (see table) (6-9). We find data on the frequency of symptomatic heart failure at the start of a study only in the CARE* study (4%) (2). In the HPS*, which excluded the fewest heart failure patients, the diagnosis at the start of the study was not recorded (10). We find a relevant subgroup analysis only in the CARE study. Furthermore, this study related only to left-ventricular dysfunction (ejection fraction ≤ 40%), not to symptomatic heart failure. According to it, affected patients (17% of participants) benefit from pravastatin (PRAVASIN, generics) as far as coronary complications are concerned, as do patients with an ejection fraction of over 40% (2).

However, the development of heart failure in the course of these studies does not appear to be a reason for discontinuing the investigational medicinal product. In a subsequent analysis of the 4-S* study, the onset of heart failure in the active-substance arm seems to be reduced (8.3% vs. 10.3%), and a post-hoc analysis of the HPS (3.4% vs. 3.9%) (10,11) also found a non-significant reduction in hospital admissions or deaths from heart failure.

Two endpoint studies of statin therapy in patients with symptomatic heart failure (NYHA II to IV) were published in 2007 and 2008 for the first time (12,13). However, both studies used rosuvastatin (CRESTOR, see a-t 2009; 40: 17-8), which has not yet been investigated in secondary prevention. The CORONA* study involved 5,011 ischaemia-induced systolic heart failure patients with a mean age of 73 years. The exclusion criteria included the need for cholesterol-lowering treatment in the judgement of the investigator. The number of patients pretreated with statins is not stated; 60% had a history of myocardial infarction. Despite a 45% reduction in LDL levels compared with placebo, a daily dose of 10 mg rosuvastatin for 2.7 years had no significant effect on the primary endpoint, a combination of myocardial infarction, stroke or death from cardiovascular causes (11.4% versus 12.3%; hazard ratio [HR] 0.92; 95% confidence interval [CI] 0.83-1.02), its individual components, or overall mortality (11.6% vs. 12.2%; HR 0.95; 95% CI 0.86-1.05). In addition, no effect on the NYHA class was found. There was a nominally significant effect in terms of the rate of patients admitted to hospital for cardiovascular reasons (22.9% vs. 25%; HR 0.92; 95% CI 0.85-0.99; p = 0.04) (12).

The GISSI-HF* study involved 4,631 patients with a mean age of 68 years with ischaemic (40%) and non-ischaemic symptomatic heart failure with or without left-ventricular dysfunction. Statin pre-treatment was an exclusion criterion (14). Here, too, rosuvastatin (10 mg daily) had no effect, including in patients with ischaemic heart failure (overall mortality in 3.9 years 29% vs. 28%; HR 1.03; 95% CI 0.92-1.15; myocardial infarction 2.7% vs. 3.1%; HR 0.88; 95% CI 0.63-1.24; stroke 3.6% vs. 2.9%; HR 1.25; 95% CI 0.91-1.73; hospital admissions 56%) (13).

The majority of international guidelines on heart failure were produced before the publication of the two studies (15-20). Many make no recommendations about statin therapy but some clearly assume that at least a proportion of patients are taking a statin (18). In 2003, Britain's NICE**, referring to the ongoing studies on the subject, recommended statin therapy of heart failure patients only in the presence of concomitant established indications (15). On this basis, the European Society of Cardiology, whose 2008 guidelines already take account of the CORONA study, recommends that statin therapy is considered in elderly patients with symptomatic heart failure and systolic dysfunction due to coronary heart failure in order to reduce hospital admissions (20).

Whether the negative results of the CORONA and GISSI-HF studies should be interpreted as a class effect of statins, in the sense that the reduction in vascular complications by these drugs does not influence the disease course decisively, or whether they should be attributed to a specific profile of action of rosuvastatin are questions that will have to remain unanswered for the time being. As knowledge stands at present, we believe that the following approach makes sense:

  If a patient who is taking a statin for coronary heart disease or another established indication develops symptomatic heart failure, the statin should not be discontinued. The consequences of statin withdrawal in heart failure are not known. In acute situations such as acute coronary syndrome, discontinuation might be dangerous (21,22). This approach is also consistent with the secondary prevention studies conducted to date.

  We see no indication for the initiation of statin treatment in a patient with non-ischaemic heart failure. New prescriptions of statins in patients with severe ischaemic heart failure should also be avoided.

(R = randomised study)

1

Scandinavian Simvastatin Survival Study Group: Lancet 1994; 344: 1383-9

2

SACKS, F.M. et al.: N. Engl. J. Med. 1996; 335: 1001-9

3

The LIPID Study Group: N. Engl. J. Med. 1998; 339: 1349-57

4

SERRUYS, P.W.J.C. et al.: JAMA 2002; 287: 3215-22

5

Heart Protection Study Collaborative Group: Lancet 2002; 360: 7-22

6

The 4-S-Study Group: Am. J. Cardiol. 1993; 71: 393-400

7

SACKS, F.M. et al.: Am. J. Cardiol. 1991; 68: 1436-46

8

The LIPID Study Group: Am. J. Cardiol. 1995; 76: 474-9

9

Heart Protection Study: Protocol, Section 3; http://www.ctsu.ox.ac.uk/~hps/protocol/cover.shtml

10

Heart Protection Study Collaborative Group: J. Am. Coll. Cardiol. 2007; 49: 311-9

11

KJEKSHUS, J. et al.: J. Cardiac Fail. 1997; 3: 249-54

12

KJEKSHUS, J. et al.: N. Engl. J. Med. 2007; 357: 2248-61

13

GISSI-HF Investigators: Lancet 2008; 372: 1231-9

14

TAVAZZI, L. et al.: Eur. J. Heart Fail. 2004; 6: 635-41

15

NICE Guideline: Chronic Heart Failure, 2003; http://www.nice.org.uk/nicemedia/pdf/Full_HF_Guideline.pdf

16

ACC/AHA: Circulation 2005; 112: E153-E235

17

National Heart Foundation of Australia: Guidelines for the Prevention, Detection and Management of Chronic Heart Failure in Australia, 2006 http://www.heartfoundation.org.au/SiteCollectionDocuments/ CHF%202006%20Guidelines%20NHFA-CSANZ%20WEB.pdf

18

Scottish Intercollegiate Guidelines Network: Management of Chronic Heart Failure, Febr. 2007; http://www.sign.ac.uk/pdf/sign95.pdf

19

Institute for Clinical System Improvement: Health Care Guideline: Heart Failure in Adults, August 2007; http://www.icsi.org/heart_failure_2/heart_failure_in_adults_.html

20

European Society of Cardiology: Eur. Heart J. 2008; 29: 2388-442

21

LAUFS, U. et al.: Heart 2008; 94: 1138-40

22

ENDRES, M., LAUFS, U.: Stroke 2006; 37: 2640-3

*

4S = Scandinavian Simvastatin Survival Study; CARE = Cholesterol and Recurrent Events; CORONA = Controlled Rosuvastatin Multinational Trial in Heart Failure; GISSI-HF = Gruppo Italiano per lo Studio della Sopravvivenza nell' Insuffizienza cardiaca; HPS = Heart Protection Study; LIPID = Long-Term Intervention with Pravastatin in Ischemic Disease

**

NICE = National Institute for Health and Clinical Excellence