European Heart Journal (2013) 34, 1772–1774 EDITORIAL
doi:10.1093/eurheartj/eht136
Chronic kidney disease and statin therapy: to
treat or not to treat?
C. Wanner*
Department of Medicine, Division of Nephrology and the Comprehensive Heart Failure Center, University Hospital, Würzburg, Germany
Online publish-ahead-of-print 19 April 2013
This editorial refers to ‘Effect of statin therapy on cardio- with data from RCTs carried out in dialysis patients. Hou et al.
vascular and renal outcomes in patients with chronic decided to do so by justifying that all the available clinical trial
kidney disease: a systematic review and meta-analysis’†, data should be synthesized in order to better define the balance
by W. Hou et al., on page 1807 of risks and benefits of statin therapy in patients with CKD and
also the effect of kidney function on statin use. They also observed
Scientific knowledge and available good quality studies are ranked that the beneficial effects demonstrated a progressively smaller
according to an accepted ‘evidence ladder’. The ladder is headed relative risk reduction with lower estimated GFR (eGFR) and
by a randomized controlled trial (RCT), if possible confirmed by appeared to be smaller in people with stage 5 kidney disease
a second, followed by prospective cohort studies and case– and those requiring dialysis. Thus, subgroup analysis showed that
control studies. The latter are observational studies, usually the statin effect was significantly modified by kidney function.
subject to bias and confounding. In case the evidence is insufficient Recently, another meta-analysis by Palmer and colleagues3 has
or of moderate quality, systematic reviews are undertaken, in reported similar results by looking separately at stages of CKD
order to integrate the available knowledge into a meta-analysis and renal replacement therapy (dialysis or transplantation). They
which then goes to the top of the hierarchy of evidence. found that statins decrease mortality and cardiovascular events in
Hou and colleagues now present a meta-analysis from a thera- persons with early stages of CKD and have little or no effect in
peutic area which has been studied most extensively in clinical persons receiving dialysis. To compare the published evidence,
medicine.1 The evidence is abundant and the issue of statin Table 1 outlines the data of Hou and co-workers as well as
therapy for elevated LDL-cholesterol in persons from the those of two recently published meta-analyses.1,3,4 The differences
general population is considered as being solved.2 Apparently in study selection, analysis criteria and outcome parameters are ap-
this is not the case for patients with chronic kidney disease parent. The selection criteria applied to studies for subsequent
(CKD), and the debate on who to treat and not to treat is analysis lead to a different number between 18 and 80 studies.
ongoing. Thus, the analyses of Hou and colleagues contribute to Thus, every meta-analysis has to be looked at separately according
solving these uncertainties. In their analysis, statin therapy pro- to its research aim and selection criteria in order to appreciate the
duced a 23% reduction in the risk of major cardiovascular events differences.
(but not cerebrovascular disease) or an 18% per 1 mmol/L lower- Hou and co-workers bring their results into context and explain
ing of LDL-cholesterol in patients with CKD including those receiv- methods of data extraction, quality assessment, and outcome esti-
ing dialysis. These results may be discussed controversially among mation.1 Although controversial, they are to some extent in line
nephrologists caring for dialysis patients. It is important to recog- with many clinicians who separate patients into a pre-dialysis
nize that in this meta-analysis, trials from non-dialysis and dialysis group (stage 3 –5 CKD) and a dialysis group (stage 5D). This ap-
patients were combined, although the trials exhibit different proach is used because the disease is heterogeneous with
levels of hierarchy on the ‘evidence ladder’. In the absence of respect to co-morbidities and vascular pathology. The risk of
many RCTs, meta-analyses tend to include observational studies, dying during progression of kidney disease, before entering a dialy-
and post-hoc analysis of large statin trials from the general popula- sis programme, is high. Those who develop end-stage renal disease
tion. It is certainly permissible to ask whether data from CKD sub- are considered a prevalent population of survivors, and data indi-
groups with mild or moderately impaired kidney function, cate that vascular disease is transforming from atherosclerosis to
extracted from the general population lipid trials by the use of arteriosclerosis. Causes of death are of cardiac and vascular
glomerular filtration rate (GFR) equations, should be combined origin, including stroke. In the late stage, risk factors also differ
* Corresponding author. Tel: +49 931 201 39030, Fax, +49 931201 639300, Email: wanner_c@medizin.uni-wuerzburg.de
The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.
†
doi:10.1093/eurheartj/eht065.
Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2013. For permissions please email: journals.permissions@oup.com
Downloaded from https://academic.oup.com/eurheartj/article-abstract/34/24/1772/653090
by guest
on 12 April 2018
Editorial
Table 1 Common characteristics and differences of systematic reviews and meta-analyses
Hou et al. 1 Palmer et al. 3 Upadhyay et al. 4
.............................................................................................................................................................................................................................................
Search period 1970– November 2011 February 2012 2000–November 2011
Source (databases) Cochrane, EMBASE, Medline Cochrane, EMBASE Medline, Cochrane
Type of studies RCTs RTs RCTs
No. of studies 31 80 18
Type of patients CKD CKD, TX CKD, TX
No. of patients 48 429 51 099 36 528
Type of events 6690 MCV events 11 782 MCV events
6653 deaths 11 363 deaths
Non-dialysis Dialysis Non-dialysis Dialysis ND + dialysis
All-cause mortality 0.86 (0.73 –1.00) 0.96 (0.90 –1.02) 0.81 (0.74 –0.88) 0.96 (0.88 –1.04) 0.91 (0.83– 0.99)
CV death 0.86 (0.77 –0.96) 0.96 (0.86 –1.08) 0.78 (0.68 –0.89) 0.94 (0.82 –1.07) 0.82 (0.74– 0.91)
CV events 0.76 (0.73 –0.80) 0.95 (0.87 –1.03) 0.78 (0.7– 0.86)
MI 0.55 (0.42 –0.72) 0.87 (0.71 –1.07) 0.74 (0.6– 0.81)
Stroke 0.61 (0.39 –0.95) 1.16 (0.91 –1.47) 0.61 (0.38 –0.98) 1.30 (0.79 –2.11)
CE 0.69 (0.58 –0.83) 0.91 (0.81 –1.02)
MCE 0.77 (0.70 –0.84)
CE or death 0.91 (0.84 –0.99)
Kidney failure 0.95 (0.90 –1.01)
Adverse hepatic events 0.87 (0.92 –1.39) NS NS
Muscular disorders 1.02 (0.95 –1.09) NS NS
CE, coronary events; CKD, chronic kidney disease; CV, cardiovascular; MCE, major cardiovascular events; MI, myocardial infarction; ND, non-dialysis; NS, not significant; RCT, randomized controlled trial; RT, randomized trial; TX,
transplantation.
1773
Downloaded from https://academic.oup.com/eurheartj/article-abstract/34/24/1772/653090
by guest
on 12 April 2018
1774 Editorial
substantially (traditional and non-traditional or uraemia related) initiate treatment’, because stopping treatment is not recom-
and treatment approaches are urgently awaited that take the mended by any guideline.
underlying pathophysiology into account. Thus, analyses according Despite the analysis of Hou et al. and in light of the other
to stages of CKD, or to pre-dialysis vs. dialysis, would match the meta-analyses, the debate ‘to treat or not to treat’ will continue
clinical situation and how clinicians would like to approach their among nephrologists who care for elderly dialysis patients with
patients. strong symptoms of wasting. The approach to handle the situation
The backbone of all meta-analyses outlined in Table 1 is three from a clinical point of view may be most appropriate. Parameters
RCTs, the 4D study (Die Deutsche Diabetes Dialyse Studie), such as advanced age, frailty, and short life expectancy provide a
AURORA (A Study to Evaluate the Use of Rosuvastatin in good rationale to limit treatment efforts in dialysis patients. In
Subjects on Regular Hemodialysis: An Assessment of Survival the case of doubt, one can be reassured by the present analysis
and Cardiovascular Events), and SHARP (Study of Heart and that no harm is apparent from doses of statins given in the
Renal Protection). 4D and AURORA assigned . 4000 diabetic various trials.
and non-diabetic dialysis patients to statin or placebo therapy,
whereas SHARP included a mixed cohort of 6029 patients not Conflict of interest: C.W. received lecture honoraria from MSD
on dialysis (mean GFR 27 mL/min/1.73 m2) and 3023 patients on and Astellas.
dialysis.5 – 7
A difficulty common to all the meta-analyses in the interpret-
ation of the randomized trials, as well as the observational trials
References
1. Hou W, Lv J, Perkovic V, Yang L, Zhao N, Jardine MJ, Cass A, Zhang H, Wang H.
with CKD subgroup results, is that primary endpoints are not Effect of statin therapy on cardiovascular and renal outcomes in patients with
uniform. This makes comparison of the trials and the interpretation chronic kidney disease: a systematic review and meta-analysis. Eur Heart J 2013;
of the meta-analysis difficult. In addition, endpoints of the three 34:1807 –1817.
2. Baigent C, Keech A, Kearney PM, Blackwell L, Buck G, Pollicino C, Kirby A,
RCTs were adjudicated differently. Re-adjudication of all patients Sourjina T, Peto R, Collins R, Simes R. Efficacy and safety of cholesterol-lowering
and analysis of single data of individual patients in the trials treatment: prospective meta-analysis of data from 90,056 participants in 14 ran-
would be ideal, but most probably is not feasible. domised trials of statins. Lancet 2005;366:1267 –1278.
3. Palmer SC, Craig JC, Navaneethan SD, Tonelli M, Pellegrini F, Strippoli GF. Ben-
The present analysis of Hou et al. is also of value for future efits and harms of statin therapy for persons with chronic kidney disease: a sys-
guideline writing, such as an update of the ESC/EAS Guidelines tematic review and meta-analysis. Ann Intern Med 2012;157:263 –275.
for the management of dyslipidaemias8 or the KDIGO (Kidney 4. Upadhyay A, Earley A, Lamont JL, Haynes S, Wanner C, Balk EM. Lipid-lowering
therapy in persons with chronic kidney disease: a systematic review and
Disease Improving Global Outcomes). The US National Kidney meta-analysis. Ann Intern Med 2012;157:251 –262.
Foundation KDOQI (Kidney Disease Outcomes Quality Initiative) 5. Wanner C, Krane V, Marz W, Olschewski M, Mann JF, Ruf G, Ritz E. Atorvastatin
has recently released a 2012 update recommendation of the 2007 in patients with type 2 diabetes mellitus undergoing hemodialysis. N Engl J Med
2005;353:238 –248.
KDOQI clinical practice guidelines for diabetes and CKD. They 6. Fellstrom BC, Jardine AG, Schmieder RE, Holdaas H, Bannister K, Beutler J,
recommend not initiating statin therapy in patients with diabetes Chae DW, Chevaile A, Cobbe SM, Gronhagen-Riska C, De Lima JJ, Lins R,
who are treated by dialysis.9 It is interesting to note that these Mayer G, McMahon AW, Parving HH, Remuzzi G, Samuelsson O, Sonkodi S,
Sci D, Suleymanlar G, Tsakiris D, Tesar V, Todorov V, Wiecek A, Wuthrich RP,
guidelines, based on clinical trial results, have not been followed Gottlow M, Johnsson E, Zannad F. Rosuvastatin and cardiovascular events in
in the past,10 and physicians may have preferred to wait for a patients undergoing hemodialysis. N Engl J Med 2009;360:1395 –407.
more condensed analysis. 7. Baigent C, Landray MJ, Reith C, Emberson J, Wheeler DC, Tomson C, Wanner C,
Krane V, Cass A, Craig J, Neal B, Jiang L, Hooi LS, Levin A, Agodoa L, Gaziano M,
The finding of a smaller relative risk reduction with lower GFR Kasiske B, Walker R, Massy ZA, Feldt-Rasmussen B, Krairittichai U,
may reactivate the discussion on the search for the so-called point Ophascharoensuk V, Fellstrom B, Holdaas H, Tesar V, Wiecek A, Grobbee D,
of no return, beyond which statins may lose their benefit. de Zeeuw D, Gronhagen-Riska C, Dasgupta T, Lewis D, Herrington W,
Mafham M, Majoni W, Wallendszus K, Grimm R, Pedersen T, Tobert J,
However, a strategy such as treat early and stop treatment once Armitage J, Baxter A, Bray C, Chen Y, Chen Z, Hill M, Knott C, Parish S,
the patient has reached dialysis is not applicable in clinical practice. Simpson D, Sleight P, Young A, Collins R. The effects of lowering LDL cholesterol
A wait and see strategy in the presence of conflict and unresolved with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of
Heart and Renal Protection): a randomised placebo-controlled trial. Lancet 2011;
issues is also not appropriate since vascular changes are logically a 377:2181 –2192.
continuous process. For example, the SHARP study has shown a 8. European Association for Cardiovascular Prevention & Rehabilitation, Reiner Z,
significant 17% relative risk reduction in 9052 patients across all Catapano AL, De Backer G, Graham I, Taskinen MR, Wiklund O, Agewall S,
Alegria E, Chapman MJ, Durrington P, Erdine S, Halcox J, Hobbs R, Kjekshus J,
stages of CKD. In fact, 3023 patients were already on dialysis Filardi PP, Riccardi G, Storey RF, Wood D; ESC Committee for Practice Guide-
and 2066 started dialysis therapy during the course of the study, lines (CPG) 2008 –2010 and 2010– 2012 Committees. ESC/EAS Guidelines for
making the discussion of a responsive pre-dialysis group vs. a non- the management of dyslipidaemias: the Task Force for the management of dysli-
pidaemias of the European Society of Cardiology (ESC) and the European Ath-
responsive dialysis condition less valid. In fact, discussion along erosclerosis Society (EAS). Eur Heart J 2011;32:1769 –1818.
these line is erroneous since treatment in earlier stages of nephro- 9. National Kidney Foundation. KDOQI Clinical Practice Guideline for Diabetes and
pathy is effective, and most, if not all, patients will be on a statin CKD: 2012 update. Am J Kidney Dis 2012;60:850 –886.
10. Lam NN, Jain AK, Hackam DG, Cuerden MS, Suri RS, Huo CY, Li P, Clark WF,
regimen once they start dialysis. Therefore, few practical conse- Garg AX. Results of a randomized controlled trial on statin use in dialysis patients
quences emerge when following the KDOQI guideline ‘not to had no influence on statin prescription. Kidney Int 2009;76:1172 – 1179.
Downloaded from https://academic.oup.com/eurheartj/article-abstract/34/24/1772/653090
by guest
on 12 April 2018
