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any survival benefit or a renal protective
effect. Although the effect on the primary
end point was similar in all subgroups,
the risk reduction was less prominent in
patients on dialysis (relative risk 0.90; 95%
CI 0.75–1.08) than in nondialysis patients
(relative risk 0.78; 95% CI 0.67–0.91). Thus,
the modest effect on cardiovascular risk in
patients on dialysis is of a similar magnitude
to that reported in previous studies of statins
(nonsignificant risk reductions of 8% in the
4D study and 4% in AURORA). Persistent
inflammation and comorbidities may influence
the effects of lipid- lowering treatment
in patients on dialysis. Although the precise
role of these factors and the mechanism/s
through which they interact with statin
treatment are not yet evident, it can be speculated
that if persistent inflammation serves
as a catalyst and magnifies risk, 1 the effect
of long-term statin treatment may differ
in patients on dialysis with and without
inflammation; these groups should be analyzed
separately. Comorbidities, such as diabetes,
may also influence the cardiovascular
effects of statin treatment in this patient
group. To determine whether rosuvastatin
might reduce the risk of cardiac events in
731 hemo dialysis patients with diabetes, a
post hoc analysis of the AURORA cohort
was performed. 5 Rosuvastatin treatment
significantly reduced the rates of cardiac
events by 32% among patients with diabetes.
However, it is a concern that although
there was no difference in overall stroke
incidence between the rosuvastatin and
the placebo groups, rosuvastatin-treated
patients with diabetes had a higher risk of
hemorrhagic strokes than the placebo group
(relative risk 5.21; 95% CI 1.17–23.27).
The high prevalence of atrial fibrillation
is another major clinical problem in dialysis
units. In a recent study based on 2.5 million
observations of hemodialysis patients,
Winkelmayer et al. 6 showed that the prevalence
of atrial fibrillation had increased
threefold from 1992 (3.5%) to 2006 (10.7%).
They also showed that mortality was twice
as high among hemodialysis patients with
atrial fibrillation compared to those without
atrial fibrillation. In 2011, the same group
also reported data from 2,313 hemodialysis
patients with new-onset atrial fibrillation.
Whereas patients treated with warfarin had
double the risk of hemorrhagic stroke compared
with nonusers, the risk of ischemic
stroke did not differ between users and nonusers
of warfarin. 7 As warfarin treatment
does not reduce the risk of ischemic stroke
and, in addition to increasing the risk of
Key advances
■ Inflammation interacts with other
cardiovascular risk factors in the
uremic milieu, such as asymmetric
dimethylarginine, and increases the risk
of poor outcomes 2
■ Short-term treatment with a recombinant
human IL-1 receptor antagonist reduces
inflammatory biomarkers in patients on
hemodialysis 3
■ Lipid-lowering treatment is associated
with beneficial effects on major
atherosclerotic events in the entire
chronic kidney disease population;
the effect is less pronounced in the
subpopulation of dialysis patients 4
■ The prevalence of atrial fibrillation in
North American hemodialysis patients
increased threefold between 1992 and
2006 6
■ Whereas warfarin treatment does not
reduce the risk of ischemic stroke, it
increases the risk of hemorrhagic stroke
in older hemodialysis patients with atrial
fibrillation 7
hemorrhagic stroke, may have a role in both
the progression of vascular calcification and
in the life-threatening condition calciphylaxis,
the risks of war farin treatment seem
to outweigh its potential bene ficial effects
in dialy sis patients with atrial fibrilla tion.
Thus, until an adequately powered RCT
settles the important question as to whether
warfarin reduces the overall risk of stroke
and improves survival it seems advisable not
to prescribe vitamin K antagonists, such as
warfarin, to patients on dialysis with atrial
fibrillation. This finding should also prompt
the initiation of studies to evaluate the safety
and efficacy of novel anti coagulant treatment
strategies in patients with advanced
chronic kidney disease, such as drugs targeting
factor IIa (dabigatran) and factor Xa
(rivaroxaban, apixaban and edoxaban)
in the coagulation cascade. Indeed, in a
recent RCT conducted in 18,201 patients
with atrial fibrillation (but without kidney
disease), apixaban was superior to warfarin
in preventing stroke or systemic embolism,
caused less bleeding, and resulted in
lower mortality. 8
The effects of the intensity of dialysis on
morbidity and mortality was first studied
in the 1981 National Cooperative Dialysis
study, which suggested that a longer hemodialysis
duration aiming at a predialysis
blood urea nitrogen level of 20 mmol/l
resulted in less morbidity than a shorter
hemodialysis duration. The results of the
2002 HEMO study 9 showed that aiming
NEPHROLOGY
at a higher dialysis dose did not result in
signifi cant benefits on mortality or morbidity
(over standard doses) in patients
undergoing thrice-weekly hemo dialysis. In
2010, the randomized study by the Frequent
Hemodialysis Network (FHN) studied the
effect of frequent hemo dialysis versus conventional
hemodialysis (six times weekly
versus three times weekly) in 245 patients
followed up for 1 year. 10 Frequent hemodialysis
was associated with significant
beneficial effects on the risk of an increase
in left ventricular muscle mass and the
risk of worse physical health scores as well
as improved control of hypertension and
hyperphosphatemia. The drawback was
a 71% increase in the risk of requiring
interventions related to vascular access.
Although frequent hemodialysis is a promising
modality, the cost–benefit ratio over
longer follow-up periods than in the FHN
study remains to be evaluated.
In conclusion, several studies published
in 2011 have provided the nephrology
community with new small pieces of
knowledge to add to the complex puzzle
of the increased risk of premature cardiovascular
death in patients on dialysis.
Based on current knowledge, we conclude
that inflammatory biomarkers and an
assessment of atrial fibrillation should be
included in the risk factor profile monitored
by nephrologists. Whereas statin
therapy seems to have a modest, but significant,
beneficial effect on cardiac events,
vitamin K antagonist treatment cannot be
advocated in dialysis patients with atrial
fibrillation until an RCT has proved its
safety and efficacy.
Division of Renal Medicine, Department of
Clinical Science, Intervention and Technology,
Karolinska University Hospital at Huddinge,
Karolinska Institutet, SE 141 86 Stockholm,
Sweden (P. Stenvinkel, P. Bárány).
Correspondence to: P. Stenvinkel
peter.stenvinkel@ki.se
Competing interests
P. Stenvinkel declares an association with the
following company: Gambro. See the article online
for full details of the relationship. P. Bárány declares
no competing interests.
1. Carrero, J. J. & Stenvinkel, P. Of persistent
inflammation as a catalyst for other risk factors
in chronic kidney disease. a hypothesis
proposal. Clin. J. Am. Soc. Nephrol. 4, S49–S55
(2009).
2. Tripepi, G. et al. Inflammation and asymmetric
dimethylarginine for predicting death and
cardiovascular events in ESRD patients. Clin. J.
Am. Soc. Nephrol. 7, 1714–1721 (2011).
3. Hung, A. M., Ellis, C. D., Shintani, A., Booker, C.
& Ikizler, T. A. IL-1β receptor antagonist reduces
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