1. Healthcare

Cardiovascular Research 71 (2006) 443 – 454
www.elsevier.com/locate/cardiores
Review
Statins in the treatment of chronic heart failure: Biological and
clinical considerations
Pim van der Harst a,⁎, Adriaan A. Voors a , Wiek H. van Gilst b , Michael Böhm c ,
Dirk J. van Veldhuisen a
a
Department of Cardiology, Thoraxcenter, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9700RB Groningen,
The Netherlands
b
Department of Clinical Pharmacology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
c
Klinik and Poliklinik Innere Medizin III, Universitat des Saarlandes, Homburg, Germany
Received 5 February 2006; received in revised form 6 April 2006; accepted 19 April 2006
Available online 27 April 2006
Time for primary review 24 days
Patients with increased cholesterol levels are at increased risk to experience cardiovascular events and to die from vascular disease. Statins
have been proven to effectively reduce cholesterol levels and subsequently reduce cardiovascular events in patients with coronary artery
disease or at increased risk to develop coronary artery disease. However, in patients with chronic heart failure (CHF), not high, but low levels
of cholesterol are related to increased mortality. This phenomenon of reverse epidemiology is not unique to CHF, but also exists in other
critical diseases and in the elderly in general as well. An important rationale has been provided by the endotoxin hypothesis, which suggests
that cholesterol has an important scavenger function regarding harmful endotoxins. Indeed, these lines of evidence predict a harmful effect of
statin treatment in patients with CHF. However, statins not only lower cholesterol, but also have been reported to exhibit a plethora of
pleiotropic effects, including reduction of inflammation and improvement of endothelial function. In order to reconcile these contradictory
lines of evidence, it is necessary to examine the pharmacological mechanisms of effects of statin treatment. Understanding the pharmacology
of statin intervention in CHF models and patients may facilitate the development of therapeutic strategies. In this review, we provide an
overview of the known associations between serum cholesterol and CHF in human subjects. In addition, we review the available lines of
evidence in animal models and humans predicting both harmful and beneficial effects of statin treatment in CHF. We emphasize the
importance of additional research specifically in CHF models and patients.
© 2006 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.
Keywords: Chronic heart failure; Statins; Cholesterol; HMG-CoA reductase inhibitors
The efficacy of 3-hydroxy-3-methylglutaryl co-enzymeA inhibitors, or statins, in reducing morbidity and mortality
in patients with documented coronary artery disease (CAD)
or those at increased risk of CAD has been overwhelmingly
and indisputably demonstrated [1–15]. The result is that
statin therapy is the treatment of choice in the primary and
secondary prevention of cardiovascular disease for almost
every suitable patient. But what if statin treatment has not
been initiated? Is it still beneficial to begin statin treatment in
⁎ Corresponding author. Tel.: +31 503612355; Tel./fax: +31 503614391.
E-mail address: [email protected] (P. van der Harst).
end stage CAD that has resulted in chronic heart failure
(CHF)? Or might we do more harm than good? Evidence for
statin treatment in patients with established chronic heart
failure (CHF) has not been well established and remains a
subject of debate [16,17]. CHF patients have been
systematically excluded from large clinical statin trials.
Although a few smaller, uncontrolled trials do provide some
evidence for the use of statins in CHF, there is some reason to
think that statins may have harmful effects in patients with
CHF. For example, recent data suggests that high cholesterol
levels are beneficial in a state of CHF, even when CAD
coexists. In this article, the potentially harmful and beneficial
0008-6363/$ - see front matter © 2006 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.cardiores.2006.04.011
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Abstract
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effects of statins in CHF patients will be reviewed, both from
a pathophysiological and a clinical perspective.
1. Cholesterol in CHF
2. Potentially harmful effects of statin treatment in CHF
Potentially harmful effects of statins in CHF are not farfetched. In addition to the observed inverse relationship
between cholesterol and survival in CHF, there are other
lines of evidence suggesting adverse effects of statins. Most
noteworthy are the endotoxin–lipoprotein hypothesis, the
coenzyme Q10 (ubiquinone) hypothesis, and the selenoprotein hypothesis.
2.1. Endotoxin lipoprotein hypothesis
Rauchhaus et al. were the first to propose that higher levels
of cholesterol are beneficial in CHF on the basis of the ability
of serum lipoproteins to modulate the inflammatory immune
function [41]. CHF patients have increased serum cytokine
levels, which might be linked to increased endotoxin levels
[42]. Circulating cholesterol- and triglyceride rich lipoproteins are natural nonspecific buffers of endotoxins (Fig. 1).
They have the capacity to bind and detoxify bacterial
lipopolysaccharides (LPS). LPS are very strong stimulators
of the release of inflammatory cytokines from circulating
immune competent cells and LPS are an important stimulus
of proinflammatory cardio-depressive cytokine production in
CHF. For example, LDL receptor deficient mice, with
consequently very high plasma cholesterol concentrations
are protected against lethal endotoxaemia and severe gramnegative infections [43]. Edematous and severely affected
CHF patients show substantial immune activation in parallel
with raised LPS plasma concentrations, comparable to
patients with sepsis and liver cirrhosis [42]. In CHF patients,
episodes of endotoxaemia can occur, and lowering of
lipoproteins could adversely effect LPS bioactivity modification [41]. This hypothesis suggests that normal patients
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Hypercholesterolemia is a well-known risk factor for the
development of CAD and long-term morbidity and mortality,
at least in middle-aged persons. However, controversial
associations have been found in elderly patients and in
patients with a wide range of chronic and acute diseases [18–
24]. It seems that with advancing age or in critically diseased
patients, the traditional association between elevated cholesterol and increased morbidity and mortality no longer
applies. In fact, serum cholesterol levels are inversely
correlated with in-hospital mortality in patients with
infectious diseases [18,19] as well as acutely ill patients
[20], regardless of malnutrition, frailty, inflammation, and
comorbidity. In the Framingham study, dyslipidemia initially
appeared to be a risk factor for the development of CHF [25].
However, subsequent studies have challenged this finding
[26–28]. Importantly, in a more detailed analysis of the same
Framingham database, the association between total cholesterol and all-cause mortality was positive at 40 years of age,
negligible at 50–70 years, and negative at age 80 years and
above [29]. Since both the incidence and prevalence of CHF
is increasing steeply with age, the accepted association
between cholesterol and CHF might change [30]. Several
observational studies have addressed the relationship
between serum cholesterol levels and outcome, specifically
in CHF patients. In 1998, Vredevoe et al., were the first to
report that lower total cholesterol was significantly associated with increased mortality in patients with advanced,
idiopathic CHF [31]. This observation has been confirmed in
other studies, indicating that both in ischemic and nonischemic CHF, higher cholesterol levels are associated with
decreased mortality [32–37]. Based on Receiver Operating
Characteristic (ROC) curves analysis, the best cut-off level
for total cholesterol in predicting mortality in CHF patients is
estimated to be around 4.9–5.2 mmol/L (190–200 mg/dL)
[32,35]. Mortality increased 25% for each mmol/L decrease
in total cholesterol.
This phenomenon of ‘reverse epidemiology’ in CHF has
not only been observed for serum cholesterol levels, but also
for body mass index and blood pressure [38]. Nevertheless,
previously mentioned studies were observational and do not
prove causality. Low cholesterol could merely be a
consequence of advanced CHF, without a causal role, or
high cholesterol could be an indicator of a greater metabolic
reserve to deal with the disease [39,40]. Although several
studies corrected for general health indicators, like nutritional
status, and cachexia, it remains possible that low cholesterol
carries a poor prognosis because it is a marker of poor health
or a consequence of CHF. Consequently, the association with
mortality could be a consequence of inadequate adjustment
for other confounding factors. Alternatively, lower mortality
among patients with elevated cholesterol could be a
consequence of a selection bias. Patients surviving elevated
cholesterol could represent a selected subgroup with
advantageous genetic or other characteristics that protect
them from the harmful effects of high cholesterol. Finally,
lower cholesterol might just mark an end-stage disease
epiphenomenon, due to reduced hepatic cholesterol synthetic
capacity. Any of the aforementioned possibilities do not
exclude the possibility that cholesterol may, even in a state of
CHF, still be a pro-atherogenetic factor. Further research into
the mechanism to explain the inverse associations remains
obligatory. Since it has not been established whether low
cholesterol is causally involved or is simply a marker,
interventions aimed at lowering cholesterol will remain
controversial. However, such an association between
increased mortality and lipid lowering therapy has as yet
not been demonstrated. Although high cholesterol seems
advantageous in elderly patients, treatment with statins does
not necessarily cause harm in these patients [8,10]. These
seemingly contradictory findings might thus be explained by
a difference in intrinsicly low cholesterol levels as compared
to pharmacologically induced low cholesterol levels.
P. van der Harst et al. / Cardiovascular Research 71 (2006) 443–454
445
with CAD should be treated differently from patients with
ischemic CHF.
2.2. Ubiquinone hypothesis
The mode of action of statins through the inhibition of
mevalonate synthesis, decreases the production of ubiquinone (Coenzyme Q10; Fig. 1). Indeed, in humans, statins
have been shown to cause decreased levels of ubiquinone in
several studies [44–46]. In the heart, ubiquinone is most
abundant and represents an essential component of the
mitochondrial respiratory chain. Ubiquinone is involved in
the production of ATP and is therefore related to the
metabolic demands of cells (Fig. 1) [47–50]. Another
fundamental characteristic of ubiquinone is its antioxidant
(free radical scavenging) property. By affecting mitochondrial function through ubiquinone, statins might have
deleterious effects on skeletal or cardiac muscles. This
mechanism is thought to be involved in toxic myopathy, an
adverse effect of statins, and might also be relevant in cardiac
muscle. This hypothesis is supported by the finding that in
CHF patients, deficiencies of ubiquinone have been found
frequently, and are more prominent with increasing NYHA
class [51]. The reported decrease of ubiquinone with statin
treatment, in both animal and human experimental studies,
might therefore be harmful in CHF [44–46]. A clinical trial
in CHF evaluating the efficacy of ubiquinone as an
adjunctive treatment in major adverse cardiovascular events
is currently ongoing [52].
2.3. Selenoprotein hypothesis
Reduction of mevalonate results in the reduction of isopentenyl-pyrophosphate (Fig. 1). Selenocysteine-tRNA[Ser]sec
(Sec-tRNA) controls the expression of all selenoproteins
[53]. However, Sec-tRNA is only functional after essential
post-transcriptional modification, one of which is the isopentenylation of adenoseine. Isopentenylation of Sec-tRNA
is undertaken by tRNA isopentenyl transferase, which uses
isopentenyl pyrophosphate (Fig. 1) as a substrate [54].
The seloprotein hyopthesis postulates that statins interfere
with the mevalonate pathway, which interferes with the
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Fig. 1. The hypothetical effects of statins on Chronic Heart Failure through the intermediates of the mevalonate pathway. HMG-CoA: 3-hydroxy-3methylglutaryl co-enzyme-A; Sec-tRNA: Selenocysteine-tRNA[Ser]sec; Farnesyl-PP: Farnesyl pyrophosphate; t-t GGPP: trans–trans geranylgeranyl diphosphate;
ATP: adenosine triphosphate; AT-1 receptor: angiotensin II type 1 receptor; NADPH: nicotinamide adenine dinucleotide phosphate-oxidase; eNOS: endothelial
nitric oxide synthase.
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P. van der Harst et al. / Cardiovascular Research 71 (2006) 443–454
enzyme isopentenylation of Sec-tRNA, and consequently
statins prevent its maturation to a functional tRNA
molecule [55]. Indeed, a strongly reduced selenoprotein
synthesis has already been demonstrated in cell culture
after the addition of lovastatin [56]. Considering that
individuals with statin-induced myopathy have very similar
clinical and pathological features to those with syndromes
associated with severe selenoprotein deficiency, the fall in
available selenoproteins might be particularly harmfull in
CHF [55].
3. Potential beneficial effects of statin treatment in CHF
Besides reduction in cholesterol, statins also influence
other isoprenoid intermediates of the cholesterol biosynthetic
pathway (Fig. 1). These intermediates are key moieties for
posttranslational modification of numerous proteins. Some
of these influences are of particular interest in CHF.
3.1. Capillary density and vascular function
(Fig. 4A) [75]. This effect of statins on angiogenis is highly
dependent on eNOS and is absent in eNOS deficient mice
(Fig. 4B) [76]. Recently, the effects of statins on circulating
endothelial progenitor cells in humans have been reported
[77,78]. These findings might provide another explanation
for the possible beneficial effects of statins on capillary
density and vascular function in CHF patients.
3.2. Neurohormonal activation
The principal neurohormonal systems involved in the
pathophysiology of CHF are the renin–angiotensin–aldosteron system and the sympathic system. Therapies aimed at
modifying activation of these systems, such as angiotensinconverting enzyme (ACE) inhibitors, angiotensin-receptor
blockers (ARB), aldosteron inhibitors and beta-blockers
have all been proven to be beneficial in the treatment of CHF.
However, statins also modify these neurohormonal systems.
In humans, high levels of cholesterol are known to increase
the expression of angiotensin type 1 receptors, and
consequently amplify the biological effects of angiotensin
II [79]. In this regard, it is of particular interest that increased
expression of cardiac angiotensin type 1 receptors is related
to decreased myocardial microvessel density after experimental myocardial infarction [80]. Recently, we have
demonstrated that vasoconstrictor responsiveness to angiotensin II can be modified by statin treatment in patients with
diseased coronary arteries [81]. Oral treatment with statins
inhibits rac1-GTPase activity and reduces angiotensin II
induced NADPH oxidase activity, and subsequent oxidative
stress, and might therefore be of particular relevance in the
ventricles of CHF patients [82]. Additionally, statins can
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Coronary blood flow reserve is strongly and inversely
related to serum cholesterol levels [57,58]. Several studies
have indicated that in patients with normal left ventricular
function, cholesterol lowering drug therapy can improve
coronary blood blow [59,60]. These effects can be observed
very quickly after cholesterol lowering, as has been shown
by single LDL apheresis, which improved coronary blood
flow within 24 h [61]. CHF is characterized by a relative
microvascular insufficiency. The increase in myocytes in
both thickness and length is not adequately matched by a
proportional increase in vasculature. In animal studies, it has
been found that the eccentric hypertrophy associated with
CHF lacks the compensatory angiogenesis, in contrast to
physiological (i.e. exercise or anemia-induced) hypertrophy
of the heart [62,63]. Consequently, in patients with increased
cholesterol levels and CHF, coronary flow reserve is
jeopardized for two reasons (Fig. 2). A recent study from
Japan showed that cardiac function in CHF patients was
improved after statin treatment in parallel with decreasing
inflammation [64]. It is tempting to speculate that an increase
in coronary blood flow was responsible for this effect [65].
Furthermore, dysfunction of the endothelium, in both
coronary and peripheral arteries, and independently of
serum cholesterol has been well documented in patients
with CHF [66,67]. Endothelial dysfunction in CHF patients
was associated with increased mortality risk [68]. Endothelial dysfunction in CHF is thought to reflect predominantly
decreased NO bioavailability (Fig. 3) [69]. Indeed, the
effects of statins on eNOS are the basis of the well described
favourable effects of statins on endothelial dependent
vasomotor function [70–73]. In patients with documented
CAD, statins reduced transient myocardial ischemia [74].
Their anti-ischemic properties are thought to be a consequence of protein kinase Akt activation, subsequently
promoting collateral growth and increasing capillary density
Fig. 2. Three-dimensional bar graph showing hypothetical relation of
decreased coronary blood flow reserve (vertical axis) in relation to
increasing levels of cholesterol (horizontal axis) and decreasing Left
Ventricular Ejection Fraction (LVEF; diagonal axis). Coronary blood flow is
reduced in hypercholesterolemia [57,58] and in CHF a relative microvascular insufficiency exists [62,63]. Therefore, in patients with increased
cholesterol levels and CHF, coronary flow is jeopardized for two reasons.
P. van der Harst et al. / Cardiovascular Research 71 (2006) 443–454
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Fig. 3. Simplified schematic overview of the known processes involved in atherosclerosis and the established effects of statin treatment.
Fig. 4. (A) Adapted with permission from Kureishi et al. [75]. Alkaline phosphatase staining of the adductor muscle from ischemic limbs showing greater
capillary density in statin treated animals (statin = 253 ± 23 capillaries/mm2; control = 163 ± 9 capillaries/mm2); P < 0.01. (B) Adapted with permission from
Landmesser et al. [76]. Effect of statin treatment on capillary density in infarct border zone of wild type (WT) and eNOS−/− mice after myocardial infarction (MI).
Average number of endothelial cells per high-powered field in border zone for each experimental group is shown, as determined by platelet and endothelial cell
adhesion-molecule immunohistochemical staining.
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inhibit VEGF-induced ACE upregulation in endothelial cells
[83] and enhance the efficacy of angiotensin receptor
blockers [84–87].
Besides the renin–angiotensin system, statins can also
modify the sympathetic system. β-Adrenergic receptor
stimulation of cardiac myocytes leads to apoptosis. In rats,
statins inhibit β-adrenergic receptor activation of Rac1 and
consequently inhibit the activation of the mitochondrial
death patways and apoptosis [88]. Statin treatment also
decreases sympathetic activity and delays the time of onset
of cardiac decompensation in pacing-induced dilated
cardiomyopathy in dogs [52,53].
3.3. Left ventricular hypertrophy (LVH)
3.4. Atherosclerosis
Statins reduced the progression of coronary atherosclerosis in clinical studies [100,101]. Some studies even
demonstrated regression of atherosclerotic plaques with
high doses of statins (Fig. 3) [102].
3.5. Inflammation
In patients with CHF, elevated systemic levels of
inflammatory parameters have been extensively documented
and associated with progression of CHF and death [103–
106]. Several clinical trials have demonstrated the efficacy of
statin treatment in reducing C-reactive protein [107,108] and
other inflammatory markers (Fig. 3) [109,98].
3.6. Matrix metalloproteinase (MMPs)
Recent studies have documented that activated MMPs
play an important role in the development of CHF [110]. In
experimental studies, production of MMPs was inhibited by
statins [111,112]. Inhibition of MMP attenuated cardiac
fibrosis and failure in murine models [113].
The clinical relevance of all of these potentially beneficial
effects remains to be established in clinical studies.
4.1. Animal experiments
Several animal studies have suggested beneficial effects
of statins in the treatment of CHF. Cerivastatin treatment
(starting 1 week after myocardial infarction) significantly
improved left ventricular systolic and diastolic function in
rats with CHF after experimental myocardial infarction
[114]. In a murine model of CHF after myocardial infarction,
treatment with fluvastatin 6 h after infarction increased
survival, without affecting infarct size [115]. Fluvastatin not
only attenuated LV dilatation, but also decreased LV enddiastolic pressure and improved LV ejection performance.
However, not all studies favoured statin treatment in CHF. In
female hamsters with inherited cardiomyopathy, lovastatin
treatment significantly reduced median survival time from
89 to 30 days [48].
4.2. Retrospective clinical studies
Several post-hoc subgroup analyses from large clinical
trials have been published on the effects of statins in CHF. In
the Cholesterol and Recurring Events (CARE) trial pravastatin significantly reduced coronary events in patients with
decreased left ventricular ejection fractions (LVEF), although the study excluded symptomatic CHF patients and
patients with a LVEF < 25% [4]. In the Evaluation of
Losartan in Elderly II (ELITE II) trial, a retrospective
analysis suggested that symptomatic CHF patients using
statins had decreased mortality compared to patients not on
statin therapy [116]. The effects of statins on mortality were
independent of treatment with either captopril or losartan.
The Scandinavian Simvastatin Survival Study (4S) [2]
reported a long-term reduction in the development of CHF
in patients with a history of myocardial infarction who were
randomized to statin therapy [117]. The PROSPER study
evaluated the benefits of pravastatin treatment in an elderly
cohort with a high risk of developing cardiovascular disease
and stroke [10]. Although PROSPER excluded CHF patients
with NYHA III/IV, the pre-specified outcome parameter
‘Heart failure hospitalization’ did not differ between
pravastatin treated and placebo treated elderly patients
(Table 1). A post-hoc analysis of the Heart Protection
Study, involving more than 20,000 patients randomized to
simvastatin or placebo treatment, reported a non-significant
trend toward fewer CHF deaths due to any cause (70 (0.7%)
vs. 86 (0.8%) patients; RR 0.81 [0.59–1.10]; P = 0.2), which
was supported by a marginally significant reduction in first
hospital admission for worsening CHF or CHF death (354
(3.4%) vs. 405 (3.9%); RR 0.86 [0.75–1.00]; P = 0.05) [118].
An important limitation of the Heart Protection Study data
was that the presence of heart failure at study entry was not
routinely recorded. A subanalysis of the data from the
Prospective Randomized Amlodipine Survival Evaluation
(PRAISE) trial was aimed at evaluating associations of statin
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Small G proteins are the molecular switches regulating
cardiac hypertophy and fibrosis. Ras, RhoA and Rac1 are
key mediators of the hypertrophic response [89,90]. By
blocking the synthesis of mevalonate, statins inhibit
farnesylation and geranylgeranylation of Ras, RhoA, and
Rac (Fig. 1) [91]. By inhibiting Rac, statins can inhibit
angiotensin II induced [92–95] and noradrenalin [96]
induced cardiac radical production and hypertrophy. In rat
models of cardiac hypertrophy, induced by coarctation of the
abdominal aorta, simvastatin treatment reduced the development of LVH [97,98]. Simvastatin was even more potent
in its reduction of LVH than captopril treatment [98]. Also,
pravastatin reduced left ventricular mass in patients with
hypertension and hyperlipidemia, on top of anti-hypertensive treatment [99].
4. Studies on statin therapy in CHF
P. van der Harst et al. / Cardiovascular Research 71 (2006) 443–454
449
Table 1
Large (> 1000 patients) placebo controlled statin trials and CHF patients
Trial acronym, date
Number
of patients
Intervention
Prevention
CHF patients
PMSGCRP, 1993 [1]
4S, 1994 [2]
WOSCOPS, 1995 [3]
CARE, 1996 [4]
1062
4444
6595
4159
Pravastatin 20 mg
Simvastatin 10–40 mg
Pravastatin 40 mg
Pravastatin 40 mg
Primary
Secondary
Primary
Secondary
Excluded
Excluded
Excluded
Symptomatic CHF excluded
AFCAPS/TexCAPS,
1998 [5]
LIPID, 1998 [6]
MIRACL, 2001 [7]
GREACE, 2002 [11]
6605
Primary
Excluded
9014
3086
1600
Lovastatin
20–40 mg
Pravastatin 40 mg
Atorvastatin 80 mg
Atorvastatin 24 mg
Secondary
Secondary
Secondary
Symptomatic CHF excluded
Excluded NYHA IIIb/IV.
NYHA III and IV excluded
MRC/HPS, 2002 [8]
20,536
Simvastatin 40 mg
Secondary
Severe heart failure excluded
1677
5804
Fluvastatin 80 mg
Pravastatin 40 mg
Excluded LVEF < 30%
Excluded NYHA III/IV.
CARDS, 2004 [15]
10,355
Pravastatin 20–40 mg
Secondary
Primary/
Secondary
Primary
10,305
Atorvastatin 10 mg
Primary
Excluded
Fluvastatin 40 mg and
increased to 80 mg
after 2 years
Atorvastatin 10 mg
Renal
transplant
Not reported
Primary
Excluded
2102
2838
therapy with total mortality among 1153 patients with severe
heart failure (ejection fraction < 30% and NYHA class IIIB
or IV symptoms) of ischemic and nonischemic etiologies
[33]. Only 134 patients (12%) used a statin, but in
multivariate analysis this was associated with a 62% lower
risk of death, which represents a major absolute risk
difference. In the Optimal Trial in Myocardial Infarction
with the Angiotensin II Antagonist Losartan (OPTIMAAL)
[119], the effect of initiating statin treatment in heart failure
or left ventricular dysfunction in the acute phase after acute
myocardial infarction was studied post-hoc [120]. After
adjustment for risk variables before inclusion, statin
treatment was associated with a 26.1% decreased mortality.
However, the reported protective associations of statin
use in CHF do not prove causality, and are susceptible to
considerable confounders and biases. First, probably the
single largest major confounder in non-statin randomised
trials can be found in the patient characteristics associated
with the choice of the physician to prescribe a statin. Statin
treatment could therefore have represented a selected
subgroup. Such characteristics may include ones not
registered, thus unknown in the study databases and
unadjused for in multivariate analysis, e.g. socioeconomic
status, and healthy-heart behaviors. A major potential
confounder is that patients with a short life expectation
will generally not be treated with statins. In addition, since
LVEF 26–40% (n = 706);
beneficial effect of statin treatment
No information on CHF
No difference in new or worsening CHF
Reduction development of CHF
(n = 11 vs. n = 22). Beneficial effect of
statin treatment in patients with NYHA II
(n = 118).
Non-significant trend toward fewer heart
failure deaths due to any cause and
marginally significant reduction in first
hospital admission for worsening
heart failure or heart failure death. [118]
No information on CHF
No difference in CHF hospitalisation.
Excluded
cholesterol levels inversely correlate with mortality in CHF
patients, (also in the aforementioned studies in patients not
using statins [33]) the possibility remains that statin therapy
in these patients is simply a marker of higher pre-statin
cholesterol levels (often unavailable in study databases),
predicting lower baseline risk. Second, some of these CHF
studies were conducted at a time when beta-blockers and
spironolactone were not generally used in severe heart
failure. Third, most of the patients receiving statin treatment
at discharge were on statin treatment before inclusion in the
study, further complicating this analysis. Finally, although
statin therapy seems to reduce new onset heart failure, it
could be related to effects on reduction of recurrent
myocardial infarction and subsequent CHF, rather than
development of CHF without recurrent infarctions.
In conclusion, the effect of statin treatment in established
CHF has not been definitely addressed by these studies.
4.3. Prospective clinical studies
There are limited data on the effects of statins in
established CHF. One of the most noteworthy studies has
been performed in idiopathic dilated cardiomyopathy. Fiftyone patients were randomly assigned to simvastatin (up to
10 mg/day) or placebo [64]. Using M-mode echocardiograpy
with 2D monitoring before and after 14 weeks of treatment,
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LIPS, 2002 [9]
PROSPER,
2002 [10,128]
ALLHAT-LLT,
2002 [12]
ASCOT-LLA,
2003 [13]
ALERT, 2003 [14]
Subgroup and secondary analysis
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mortality or cardiovascular hospitalisations. These two
studies are complementary in their inclusion of CHF patients
and will provide a more definite answer to the question of
whether or not we should start statin treatment in patients
with established CHF.
5. Conclusion
Despite the widespread clinical use of statins for
hypercholesterolaemia and prevention of CAD, data are
lacking on the effects of statins on clinical outcome in CHF.
Theoretical considerations and animal experimental data
indicate both beneficial and harmful effects of statins in
CHF. In contrast, the currently available small-scale studies
and post-hoc analyses suggest a neutral or beneficial effect of
statins, but no harmful effects. Currently, two large placebo
controlled trials are evaluating the efficacy of statin treatment
in CHF [125,126]. Until the results are presented, we are
practicing non-evidence based medicine when prescribing
statins to CHF patients. Currently, we do prescribe statins to
CHF patients of non-ischemic etiology when cholesterol
levels need to be treated according to the guidelines (based
on non-CHF populations). In CHF patients with coronary
heart disease, most physicians also feel more comfortable
prescribing statins than withholding them.
If statins prove to reduce mortality and morbidity in
patients with CHF, future research should be aimed at
elucidating the precise mechanism. This is of particular
importance since, in CHF, statins cholesterol lowering
efficacy might be of secondary importance [127].
Acknowledgements
P.v.d.H. is supported by Zon-MW 920-03-236 of The
Netherlands Organization for Health Research and Development. D.J. van Veldhuisen is an Established Investigator
of the Netherlands Heart Foundation (grant D97-017). We
like to thank Maren White for her comments on a previous
version of the manuscript.
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Node et al. demonstrated improved functional capacity in
patients who received simvastatin compared to placebo. In
the statin group, 39.1% of patients had an improved
functional class and 4.3% deteriorated. In contrast, in the
placebo group, 16% of patients improved and 12%
deteriorated (P < 0.01 between the groups). The functional
improvement was associated with improved left ventricular
ejection fraction in the simvastatin group (from 34% to 41%,
P < 0.05), but not in the placebo group. Furthermore, plasma
concentrations of TNF-a, IL-6 and BNP were significantly
lower in simvastatin treated patients. Another prospective,
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[121]. Quality of life and exercise capacity significantly
increased in the statin group, but not in the placebo group. In
addition, there was a trend towards increased left ventricular
ejection fraction and improved endothelial function. A small
study involving few CHF patients demonstrated improvement of reactive hyperaemia, associated with decreased
plasma concentrations of components of the thrombosis–
fibrinolysis system and inflammation [122,123]. The
recently published Treating to New Targets (TNT) study
involving 10,001 CAD patients investigated the efficacy of
80 mg versus 10 mg atorvastatin. The TNT study excluded
patients with a LVEF < 30%. However, a prespecified
secondary outcome of the TNT trials was the incidence of
hospitalisation with a primary diagnosis of CHF. A total of
164 (3.3%) of the patients on atorvastatin 10 mg vs. 122
(2.4%) of the patients on atorvastatin 80 mg were
hospitalized with a primary diagnosis of CHF; representing
a 26% decreased hospitalization rate for congestive heart
failure in the high dose statin group (HR 0.74 [0.59–0.94];
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suggests that the incidence of new onset CHF can be reduced
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etiology [125]. CORONA is an endpoint-driven trial that is
expected to last 52 months. The primary outcome is the
composite endpoint of cardiovascular death or non-fatal
myocardial infarction or non-fatal stroke (time to first event).
The GISSI heart failure trial will enrol approximately
7000 patients to be randomised to n-3 polyunsaturated
fatty acids or matching placebo and where there is no clear
indication for cholesterol-lowering therapy patients will be
further randomized to receive rosuvastatin or matching
placebo [126]. In contrast to the CORONA trial, the GISSI
heart failure trial will enroll patients with both ischemic and
non-ischemic heart failure. The GISSI heart failure trial is
also event driven and has two co-primary endpoints, namely
all-cause mortality and the combined endpoint of all-cause
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