Nephrol Dial Transplant (2004) 19: 528-531
Nephrol Dial Transplant Vol. 19 No. 3 (c) ERA-EDTA 2004; all rights reserved
Editorial Comment
Statins to prevent cardiovascular events in hypertensive patients. The ASCOT-LLA study
Julio I. Osende2,
Marta Ruiz-Ortega1,
Luis Miguel Blanco-Colio1 and
Jesus Egido1
1Renal and Vascular Research Laboratory, Fundación ‘Jiménez-Díaz’ (Autonoma University) and 2Cardiology Service, ‘Gregorio Marañón’ General University Hospital, Madrid, Spain
Correspondence and offprint requests to: Professor Jesús Egido, Renal and Vascular Research Laboratory, Fundación Jimenez-Diaz. Avda Reyes Católicos, 2, 28040 Madrid, Spain. Email: jegido{at}fjd.es
Keywords: hypertension; primary prevention; statins
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Introduction
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The recently published Lipid-Lowering Arm of the Anglo-Scandinavian
Cardiac Outcomes Study Trial (ASCOT-LLA) [
1] provides interesting
evidence for the use of statins in hypertensive patients with
average cholesterol levels and other cardiovascular risk factors.
In this study, 19 342 hypertensive patients with at least three
other cardiovascular risk factors were randomized to two antihypertensive
regimes (amlodipine and/or perindopril
vs atenolol and/or clorthalidone)
and were planned to be followed for 5 years.
The LLA was comprised of those patients with baseline total cholesterol levels 
6.5 mmol/l (
260 mg/dl), who were also randomized to receive daily atorvastatin 10 mg vs placebo. A total of 10 305 patients entered in the LLA, which was stopped prematurely by the safety committee after a mean follow-up of only 3.3 years due to a significantly lower incidence of the primary objective (non-fatal acute myocardial infarction and fatal coronary artery disease) in the atorvastatin group. The results showed that 100 patients in the atorvastatin arm and 154 in the placebo arm met criteria for the primary end-point (relative risk reduction 36%, P = 0.0005). The analysis also demonstrated that the clinical benefit started after only a year of treatment, similarly to secondary prevention randomized studies with statins. The study also showed a significant reduction in both fatal and non-fatal stroke in the atorvastatin group (relative risk reduction of 27%) [1]. Average serum cholesterol levels in the atorvastatin group decreased by 1.3 and 1.1 mmol/l after 1 and 3 years, respectively, with a total follow-up of 3 years compared with the placebo group.
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Comparison of the ASCOT-LLA trial with other major clinical statin trials
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These data confirm and expand the benefit of statin treatment
in patients at high risk of developing cardiovascular events.
A high-risk patient profile was initially considered to be represented
by those with previous myocardial infarction [
2], a patient
population known to have a higher incidence of events than the
general population. The benefit of statin treatment was later
expanded to those without a history of myocardial infarction
and either moderate hypercholesterolaemia [
3] or low levels
of high-density lipoprotein-cholesterol [
4]. The emerging new
concept that the ASCOT-LLA study addresses is the clinical management
of hypertensive patients without overt hypercholesterolaemia
but with at least three other cardiovascular risk factors, a
common finding in clinical practice. In this regard, both the
ASCOT-LLA and the recently published Heart Protection Study
(HPS) [
5] show clear benefit of statin treatment in patients
at high risk of developing cardiovascular events, even those
with normal baseline cholesterol levels in primary prevention.
However, differences between the two studies need to be pointed
out. The ASCOT-LLA targeted hypertensive patients meeting criteria
for high risk due to the concurrence of many risk factors, a
well-known prognostic marker. The presence of prior atherosclerotic
disease or diabetes (as a surrogate) was not required. The use
of a low dose of atorvastatin showed clinical benefit after
a mean follow up of 3.3 years. The HPS study patients had previous
atherosclerotic vascular disease or diabetes (known to have
a similar risk profile). In them, a relatively high statin dose
was associated with clinical benefit after a 5-year follow-up,
since this study was not finished prematurely. Patients in the
ASCOT-LLA study were apparently at lower risk than those in
the HPS study. Also, the ASCOT-LLA study design selected a relative
low dose of statin compared with the HPS, so a low incidence
of adverse effects would be anticipated, making it an attractive
long-term preventive therapy for a wide range of physicians.
The results of the ASCOT-LLA trial proved to be independent
of the degree of blood pressure reduction associated with intense
lipid lowering [
6], as both the atorvastatin and the placebo
group showed a similarly good blood pressure control.
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Mechanisms involved in the benefit of statin treatment in hypertensive patients
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The clinical benefit of atorvastatin in this patient population
is probably explained by both lipid-dependent and lipid-independent
effects of atorvastatin. These so-called pleiotropic effects
of statins [
7] may contribute to alter the progression of atherosclerosis,
independently of cholesterol lowering. Statins are known to
improve endothelial function [
8], reduce blood thrombogenicity
[
9] and exert anti-inflammatory actions [
10]. These non-lipid-related
actions could be due to the inhibition of isoprenoid intermediates
of the cholesterol biosynthetic pathway, such as farnesylpyrophosphate
(FPP) and geranylgeranylpyrophosphate (GGPP) [
7]. FPP and GGPP
mediate the post-translational modification (prenylation) of
many proteins, including the small G proteins (Ras, Rac, Rab
and Rho), which are involved in cell growth regulation/apoptosis,
actin cytoskeleton organization, membrane trafficking and gene
expression [
7]. The statin-induced inhibition of the prenylation
of these proteins impairs their submembranous localization,
limiting their activation and full functionality. In vascular
smooth muscle cells, we and others have shown that statins regulate
the cellular localization and activation of Ras and Rho proteins
[
11].
Table 1 summarizes the potential benefit of statin treatment in hypertensive patients. The statin-induced inhibition of Rho and its downstream target Rho-kinase function may have beneficial effects in hypertensive patients. Angiotensin-II (AngII), acting through AT1 receptors, plays a key role in the progression of vascular damage associated with hypertension. AngII regulates cell growth, hypertrophy, the production of extracellular matrix proteins and pro-inflammatory mediators [12]. AT1 receptors are coupled to G proteins and require functional small G proteins, including RhoA, Ras, Rac1 and the Rho/kinase system [12], to exert responses such as actin reorganization, vasoconstriction, hypertrophy, and monocyte chemoattractant protein 1 (MCP-1) and connective tissue growth factor (CTGF) expression. Experimental studies have established that statins regulate several AngII responses. In cultured vascular smooth muscle cells and monocytes, we have observed that atorvastatin decreased the activation of transcription factors AP-1 and NF-
B and inhibited the induction of pro-inflammatory genes [MCP-1 and interleukin-8 (IL-8)] caused by AngII [13]. These effects were reversed by intermediary compounds of the cholesterol pathway, such as mevalonate and the isoprenoids FPP and GGPP. We recently observed that in vascular smooth muscle cells, statins decreased AngII-induced CTGF production, mediated by inhibition of isoprenoids [14]. Statins also show antioxidant properties and restore nitric oxide bioactivity [15]. The AT1 receptor regulates reactive oxygen species (ROS) production through stimulation of NAD(P)H oxidase. Statins decrease the level of AT1 receptors [16], the expression of NAD(P)H oxidase subunits [17] and AngII-induced ROS production [18]. On the other hand, hypercholesterolaemia is associated with elevated AT1 receptor levels, suggesting a major biological response to AngII [16]. All these observations point to a direct interaction between statins and AngII-elicited intracellular signals that could have important clinical consequences.
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Table 1. Potential cholesterol-independent mechanisms implicated in the clinical benefit of statin treatment in hypertensive patients
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Unresolved issues in the ASCOT-LLA trial
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The safety committee board prematurely discontinued the ASCOT-LLA
trial, considering that stopping rules for the primary end-point
were significantly exceeded, although no significant reduction
in total mortality was shown. This fact also left some unresolved
issues open to discussion [
19]. For instance, although women
on atorvastatin treatment had 20% fewer events, this difference
did not reach significance probably due to the limited power
of the analysis (there were only 36 primary end-points among
women) at the time the trial was stopped. A comparable pattern
was described in diabetic patients, in whom no clear benefit
of atorvastatin treatment was found despite a 23% reduction
in cardiovascular events and procedures in the atorvastatin
group. Similarly, other important subgroups such as patients
with left ventricular hypertrophy, those
60 years old, patients
without renal dysfunction and patients with the metabolic syndrome
showed no benefit with atorvastatin. The low statistical power
of some of the available data for pre-specified subgroups is
therefore amenable to interpretation. However, as Trewby
et al. [
20] pointed out, the absolute risk reduction for preventive
treatments such as stains, ß-blockers, some antihypertensive
treatments, angiotensin-converting enzyme inhibitors and antiplatelet
drugs is < 1% per year even in high risk patients, and of
the same order of magnitude as atorvastatin in the ASCOT-LLA
trial. Therefore, the possibility of improving the prognosis
of hypertensive patients has to be welcome, despite the need
for further research to show better treatment options for our
patients.
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Acknowledgments
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Supported by grants 01/3130 (PI020822), 02/3093 and PI02/1047
from the "Fondo de Investigacio
Sanitaria", Spain, grant 08.4/0021.1/2003
from the "Comunidad Autonoma de Madrid", Spain and a grant from
the "Spanish Network on Cardiovascular Disease".
Conflict of interest statement. None declared.
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References
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Introduction
Comparison of the ASCOT-LLA...