Nephrol Dial Transplant (2013) 0: 111doi: 10.1093/ndt/gft281

Original Article

Long-term effects of addition of mineralocorticoid receptorantagonist to angiotensin II receptor blocker in patients withdiabetic nephropathy: a randomized clinical trial

Alireza Esteghamati1,

Sina Noshad1,

Sorour Jarrah2,

Mostafa Mousavizadeh1,

Seyed Hamid Khoee2

and Manouchehr Nakhjavani1

1Endocrinology and Metabolism Research Center (EMRC), Vali-Asr

Hospital, School of Medicine, Tehran University of Medical Sciences,

Tehran, Iran and2Faculty of Pharmacy, Department of Clinical Pharmacy, Tehran

University of Medical Sciences, Tehran, Iran

Correspondence and offprint requests to:Alireza Esteghamati; E-mail: esteghamati@tums.ac.ir

Keywords: blood pressure control, diabetic nephropathy,glomerular ltration rate, mineralocorticoid receptor antagonist,urinary albumin excretion

ABSTRACT

Background. Addition of spironolactone (SPR) to angioten-sin-converting enzyme (ACE) inhibitors or angiotensin II re-ceptor blockers (ARBs) might provide antiproteinuric effectsbeyond what is gained by either medication alone. This studywas designed to assess the long-term efcacy of SPR/ARBcombination in comparison with the standard ACE/ARBregimen in diabetic nephropathy.Methods. In an open-label, parallel-group, single-center, ran-domized clinical trial (NCT01667614), 136 patients with dia-betes and proteinuria, already treated with enalapril andlosartan, were included. In 74 patients, ACE inhibitors were dis-continued. After a wash-out period of 2 weeks, 25 mg SPR dailywas initiated. The remainder of the patients (n = 62) receivedACE inhibitors and ARBs as before. Patients were followedevery 3 months for 18 months. During each visit, systolic anddiastolic blood pressure (BP), urinary albumin excretion (UAE),serum creatinine, estimated glomerular ltration rate (eGFR)and serum potassium concentrations were determined.Results. After 18 months, three patients in the SPR/ARBgroup developed asymptomatic hyperkalemia. SPR/ARB sig-nicantly reduced both systolic and diastolic BP (P < 0.001

and 0.001, respectively). SPR/ARB decreased UAE by 46, 72and 59% after 3, 12 and 18 months, respectively. Comparedwith the continuation regimen, SPR/ARB was superior inUAE reduction (P = 0.017 after 18 months), independent ofBP change. In both groups, eGFR declined signicantly overthe trial course and the decline rate did not differ signicantlybetween the two groups.Conclusions. Addition of SPR to ARB provides addedbenets with respect to BP control and proteinuria dimin-ution. These antiproteinuric effects are not accompanied byprevention of eGFR loss compared with conventional therapywith ACE/ARB.

INTRODUCTION

The burden of diabetic nephropathy is staggeringconsuminga large proportion of health resources [1, 2]. A recent cost-of-illness study from Iran revealed that diabetic nephropathyaccounts for 23% of expenditures attributed to diabetes [3].Hypertension and proteinuria are established risk factors forprogression to advanced stages of kidney disease in diabeticpopulations [4]. Interruption of renin-angiotensin system

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(RAS) with angiotensin-converting enzyme (ACE) inhibitorsand angiotensin II receptor blockers (ARBs) is indicated inpatients with diabetes who present with micro- or macroalbu-minuria [5]. The efcacy of RAS blockade in slowing pro-gression of proteinuria in diabetic and non-diabeticpopulations is well recognized [68]. Nevertheless, treatmentwith ACE inhibitors and/or ARBs has limitations. A consider-able number of patients still progress to renal failure despitebeing treated with maximum recommended doses of ACEinhibitors and/or ARBs. Intriguingly, the ONTARGET trialdemonstrated that combination therapy with ramipril and tel-misartan is associated with higher rates of serum creatininedoubling and dialysis compared with either medication usedalone [9]. These impediments have provided an impetus todevelop more efcacious treatment strategies. It is suggestedthat blockade of aldosterone as the end product of RAS pro-vides additional benets in terms of prevention of kidneydamage by means of reducing inammation, oxidative stressand brosis [10]. It seems likely that mineralocorticoid recep-tor blockade using aldosterone antagonists, when used in com-bination with ACE inhibitors and/or ARBs, lowers the risk ofrenal disease progression independent of blood pressure (BP)-lowering effects [11, 12]. However, randomized clinical trialsin this regard have mainly evaluated the benecial effects ofaddition of aldosterone blockers to ACE inhibitors, or a com-bination of ACE inhibitors and ARBs (i.e. triple blockade ofRAS) [1315]. To date, evidence assessing whether addition ofaldosterone blockade to an ARB-based regimen offers benetssimilar to those of addition to an ACE inhibitor-based or com-bined ACE inhibitor/ARB-based regimen is lacking. Therefore,the present randomized clinical trial was designed to evaluatethe efcacy of spironolactone (SPR) plus losartan with respectto BP control, proteinuria reduction and renal function preser-vation in a sample of patients with type 2 diabetes and diabeticnephropathy.

SUBJECTS AND METHODS

Subject enrollment

At the diabetes clinic of Vali-Asr hospital (Tehran, Iran),between April and December 2010, we screened 373 consecu-tive patients who were known cases of type 2 diabetes accord-ing to the American Diabetes Association criteria [16]. Afterinitial assessment, 136 patients meeting the inclusion criteriawere recruited. The inclusion criteria were as follows:(i) urinary albumin excretion (UAE) 30 mg/24 h in at leasttwo out of three 24-h urine sample collections; (ii) taking acombination of an ACE inhibitor (enalapril) and an ARB (lo-sartan) with recommended doses for diabetic nephropathy forat least the past year and (iii) willingness to participate in thetrial. Subjects were excluded if they had non-diabetic kidneydisease, known cardiovascular or liver disease, chronic kidneydisease stages 4 and baseline serum potassium concen-trations 5.5 meq/L. No kidney biopsies were performed todistinguish diabetic nephropathy from other causes of chronickidney disease. Before enrollment, all subjects gave written in-formed consent. All interventions involving human subjects

were carried out according to the principles laid down in theDeclaration of Helsinki. The universitys ethics committee alsoapproved the trial protocol.

Study design

This single-center, open-label, parallel-group, randomizedclinical trial is registered with ClinicalTrials.Gov (registrationnumber NCT01667614). Using randomization software, eligiblesubjects were assigned to either arm of the trial. We hypoth-esized that the rate of loss to follow-up would be higher in theSPR/ARB arm. Therefore, an unbalanced randomizationscheme was employed so that the number of allocated partici-pants would be approximately 20% more in SPR/ARB than inthe ACE/ARB arm. In the SPR/ARB arm (n = 74), enalapril wasdiscontinued, and after a 2-week wash-out period of ACEinhibitor, a single-dose of SPR 25 mg daily was added. In theACE inhibitor/ARB arm (n = 62), a combination of xed doseenalapril (3040 mg per day) and losartan (50100 mg per day)was continued as before. Losartan dosage was comparablebetween the trial arms (P = 0.794). No dose adjustment for anti-hypertensive medications was done during the trial period.

After the baseline visit, regular follow-up visits for bothgroups were scheduled 3 months apart. At each visit, physicalexamination and laboratory assessments were conducted em-ploying the same protocol (see below). The baseline visit ofSPR/ARB patients was conducted within 1 week of stoppingACE inhibitor and before initiation of SPR. An extra visit inthe SPR/ARB group was also conducted 1 month after trialinitiation and measurement of serum potassium and an ECGwere done to evaluate asymptomatic hyperkalemia (denedas potassium concentrations >5.5 meq/L). Before medicationinitiation, all of the patients were instructed about the signsand symptoms of hyperkalemia via an educational leaet.The patients were also educated regarding the importance oflimiting salt intake and restricting protein consumption to rec-ommended daily amounts in patients with diabetic nephropathyand/or hypertension. No formal assessment about adherence tothese recommendations was done during the trial.

Assessment

Before study commencement, the patients were interviewedusing a pre-designed questionnaire. BP was measured using astandard mercury sphygmomanometer (Riester, Big Benadults, Germany) with the patient in sitting position after tenminutes of resting; The average of two readings ve minutesapart was recorded.

Laboratory evaluations

After an overnight 12-h fast, 10 mL of venous blood samplewas collected from each participant. At baseline and follow-upvisits, the patients were also instructed to collect 24-h urinesamples.

Fasting plasma glucose concentrations were measuredusing the Glucose Oxidase Method. Fasting insulin concen-trations were determined using radioimmunoassay techniques(Immunotech, Prague, Czech Republic). High-performanceliquid chromatography (HPLC) was performed to assess gly-cated hemoglobin A1c (HbA1c). Total cholesterol was

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measured using enzymatic methods (Pars Azmun, Karaj, Iran).Sodium and potassium concentrations were determined usingthe ame photometry method. The Jaffe method was employedto assess serum creatinine (Pars Azmun, Karaj, Iran). Estimatedglomerular ltration rate (eGFR) was calculated using theformula of Chronic Kidney Disease Epidemiology Collabor-ation (CKD-EPI) [17]. No calibration of creatinine levels tostandardized reference values was done before eGFR calcu-lation. UAE was measured by colorimetric methods using com-mercial kits (ZiestChem Diagnostics, Tehran, Iran).

Statistical analysis

Continuous variables with normal distribution are expressedas mean standard deviation (SD) and categorical variables asproportions or ratios. Distribution of UAE values did notcomply with the assumption of normality and logarithmictransformation was necessary to correct right-sided skewness.In all analyses log-transformed values were used instead. UAEvalues are presented as median (interquartile range). The base-line characteristics of the study participants were comparedusing independent t-test or chi square, where appropriate. Thebaseline characteristics of patients who completed the study andthose who were lost to follow-up were also compared to evaluatewhether loss to follow-up occurred at random. Within-groupchanges of outcome variables after 12 and 18 months were as-sessed using paired t-test. Comparative efcacy of interventionsin short term (3 months), medium term (12 months) and longterm (18 months) was determined using mixed betweenwithinanalysis of variance (ANOVA) method. In each analysis, effectsize was calculated from partial eta squared (based on Cohensrecommendations: 1% small effect, 6% medium effect, 13.8%large effect). Visit-to-visit changes in outcome variables wereexamined by post hoc analysis using the Tukeys least signicantdifference (LSD) method. Additionally, mixed betweenwithinANOVA models, with mean SBP and DBP introduced as cov-ariate, were constructed to assess whether the observed differ-ences between two interventions with respect to parameters ofkidney function are confounded by changes in BP over the trialperiod. All statistical analyses were performed using SPSSversion 19.0 (IBM Corporation, New York, United States).A P-value of

SPR/ARB group reached a nadir at around the 9th month, andit was relatively sustained thereafter. Post hoc analysis repli-cated the same; while UAE change from baseline to the 9thmonth was statistically signicant (P = 0.006), it did notchange considerably from the 9th to the 18th months(P = 0.381).

Neither intervention proved to be superior in preventingcreatinine increase or eGFR decline after three, 12 or18 months (Table 3). Similar ndings were replicated after

controlling for the effect of mean SBP and DBP (data notshown). Post hoc analysis of eGFR revealed a signicantdecline of 3.5 mL/min/1.73 m2 3 months after trial initiation(P = 0.015 for baseline to third month). After that, patientsin the SPR/ARB group experienced an indolent but progress-ive decline in eGFR. Similar analyses for ACE inhibitor/ARBgroup revealed no signicant difference in visit-to-visitdecline of eGFR (P > 0.05 for all tests). Overall, the monthlydecline rate of eGFR was 0.441 and 0.410 mL/min/1.73 m2 in

F IGURE 1 : Recruitment, randomization and follow-up of patients. Between April and December 2010, 373 type 2 diabetes patients werescreened. One hundred and thirty-six patients were eligible and were randomly allocated to trial arms. Patients were followed up regularly every3 months for up to 18 months and the trial was completed in May 2012. Intervention in three patients in the SPR/ARB group was discontinueddue to laboratory abnormalities in serum potassium. Another patient was asked to stop taking SPR due to bothersome gynecomastia. Mainreasons for discontinued intervention as stated by patients included (i) personal issues; (ii) nancial restraints keeping them from frequent travelto Tehran in those not residing in the capital and (iii) Preferring receiving care from the private sector rather than a teaching hospital.Abbreviations: SPR, spironolactone; ARB, angiotensin II receptor blocker; ACE inhibitor, angiotensin-converting enzyme inhibitor.

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SPR/ARB and ACE inhibitor/ARB, respectively. To assesswhether the decline rate between groups would be different ifthe early drop in SPR/ARB group is ignored, the analysis was

repeated with treating the third-month values as baseline.Again, between-group comparison indicated no signicantdifference (F = 0.099, P = 0.755).

Table 1. Baseline characteristics of the trial participants

SPR/ARB ACE inhibitor/ARB P-value

n 74 62

Age (years) 57.80 8.91 58.33 9.33 0.729

Sex (female/male) 23/51 22/40 0.587

Anti-diabetes medication 0.419

Metformin 34 (46%) 28 (45%)

Glibenclamide 4 (6%) 6 (10%)

Metformin + glibenclamide 35 (47%) 26 (42%)

Insulin 1 (1%) 2 (3%)

Duration of diabetes (years) 11.59 7.80 12.41 8.49 0.548

Hypertension (%) 45 (55%) 39 (62%) 0.497

Anti-hypertension medication 0.363

Beta blockers 25 (30%) 21 (33%)

Calcium channel blockers 6 (7%) 7 (11%)

Anti-hyperlipidemia medication 0.749

Statins 33 (44.6%) 33 (53.2%)

Fibrates 8 (10.8%) 7 (11.3%)

Statins + brates 6 (8.1%) 4 (6.5%)

FPG (mmol/L) 9.86 3.71 9.75 3.43 0.852

Fasting insulin (pmol/L) 73.96 54.80 89.73 42.64 0.442

HbA1c (mmol/mol) 64.63 12.33 63.19 11.71 0.604

Sodium (mmol/L) 139.95 2.46 139.87 2.61 0.855

Potassium (mmol/L) 4.40 0.43 4.32 0.44 0.304

Total cholesterol (mmol/L) 4.54 0.086 4.44 1.16 0.554

Triglycerides (mmol/L) 1.97 1.03 1.92 1.03 0.776

Target variables

SBP (mmHg) 134.27 18.12 140.08 18.67 0.061

DBP (mmHg) 82.26 8.54 83.17 10.29 0.558

UAE (mg/24 h) 112.0 (63.5, 317.3) 95.0 (50.0, 330.0) 0.727

Albuminriaa 0.796

Microalbuminuria 54 (73.0%) 44 (71.0%)

Marcoalbuminria 20 (27.0%) 18 (29.0%)

Serum creatinine (mol/L) 92.82 23.87 99.01 24.75 0.152

eGFR (mL/min/1.73 m2) 73.75 16.78 69.13 19.69 0.131

Abbreviations: SPR/ARB, spironolactone + angiotensin II receptor blocker; ACE inhibitor/ARB, angiotensin converting enzymeinhibitor + angiotensin II receptor blocker; FPG, fasting plasma glucose; HbA1c, glycosylated hemoglobin A1c; SBP, systolic blood pressure;DBP, diastolic blood pressure; UAE, urinary albumin excretion; eGFR, estimated glomerular ltration rate.aMicroalbuminuria was dened as 30 mg/24 hUAE < 300 mg/24 h, and macroalbuminuria as UAE 300 mg/24 h.

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DISCUSSION

In the present study, replacement of enalapril with SPR provedto be signicantly more effective than continuation of dualRAS blockade in reduction of both SBP and DBP over afollow-up period of 18 months (9 mmHg in SBP and 5 mmHgin DBP). Rossing and colleagues (2005) found a signicantreduction of about 10 mmHg in SBP and 5 mmHg in DBPafter addition of SPR 25 mg daily in 21 type 2 diabetes patients[15]. Contrary to these observations, some have reported thatSPR at the doses used for proteinuria reduction does not affectBP [18, 19]. Differences in the patients recruited with respect

to baseline kidney function, pre-existing hypertension andprevious anti-hypertensive treatments are likely to underlinethis discrepancy. In our sample, more than half of the partici-pants were already diagnosed with hypertension, and morethan two-thirds had baseline BP values higher than 130/80. Ina systematic review of SPR trials (2008), it was shown that veout of six trials that reported a signicant drop in BP enrolledsubjects with initial values of greater than 130/80 mmHg [20].

Herein, SPR/ARB reduced UAE independent of SBP andDBP. In a randomized trial of 165 patients with chronic glo-merulonephritis of idiopathic origin already treated with ACEinhibitor and/or ARB, addition of SPR 25 mg daily signi-cantly abated albuminuria by 58% after 12 months [13]. In

Table 2. Mean changes in target variables in the trial arms

Baseline 12 months Difference (95% CI)a P-value

SPR/ARB

SBP (mmHg) 133.57 17.20 126.71 12.59 6.86 (10.65, 3.06) 0.001

DBP (mmHg) 82.64 8.54 79.14 5.31 3.50 (5.62, 1.38) 0.002

UAE (mg/24 h) 106.0 (55.5, 306.3) 39.5 (19.0, 127.5) 52.5 (208.8, 13.8)

Table 3. Comparison of medication efcacy on improvement of blood pressure, microalbuminuria and renal function

Baseline 3 months F P-value Effect size

SPR/ARB ACE inhibitor/ARB SPR/ARB ACE inhibitor/ARB

SBP (mmHg) 134.27 18.12 140.08 18.67 130.00 14.74 137.38 17.74 7.04 0.009 4.7%

DBP (mmHg) 82.26 8.54 83.17 10.29 80.37 7.10 83.25 9.72 2.33 0.129 1.6%

UAE (mg/24 h) 112.0 (63.5, 317.3) 95.0 (50.0, 330.0) 69.5 (28.8, 168.5) 105.0 (48.6, 234.0) 1.53 0.218 1.1%

Serum creatinine (mol/L) 92.82 23.87 99.01 24.75 98.12 22.98 97.24 22.10 0.34 0.559 0.2%

eGFR (mL/min/1.73 m2) 73.75 16.78 69.13 19.69 70.82 17.91 70.78 19.43 0.77 0.382 0.5%

Baseline 12 months

SPR/ARB ACE/ARB SPR/ARB ACE/ARB

SBP (mmHg) 133.57 17.20 141.27 18.73 126.71 12.59 137.45 21.43 12.70 0.001 9.6%

DBP (mmHg) 82.64 8.54 83.40 10.42 79.14 5.31 81.20 7.73 4.07 0.046 3.3%

UAE (mg/24 h) 106.0 (55.5, 306.3) 74.0 (45.0330.0) 39.5 (19.0, 127.5) 63.0 (23.0205.0) 4.13 0.044 3.4%

Serum creatinine (mol/L) 91.94 22.10 98.12 23.87 105.20 41.55 105.20 28.29 0.02 0.900

F IGURE 2 : Mean changes in outcome variables over the trial course (18 months, seven visits). Variables are presented as mean standarderror. For UAE, log-transformed values are presented. P-values for between-group comparisons: systolic blood pressure (P < 0.001); diastolicblood pressure (P = 0.001); urinary albumin excretion (P = 0.017); serum creatinine (P = 0.802); estimated glomerular ltration rate (P = 0.674).Abbreviations: SPR, spironolactone; ARB, angiotensin II receptor blocker; ACE inhibitor, angiotensin-converting enzyme inhibitor.

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another trial of 81 type 2 diabetes patients, addition of SPR25 mg daily was more effective than addition of losartan(100 mg daily) to a maximally dosed ACE inhibitor regimen[21]. Similar results have been replicated using either SPR oreplerenone in diabetic populations [2224].

In patients taking SPR/ARB, the steepest decline in UAEwas observed in the rst 3 months. Congruently, in an 8-weektrial of SPR in 42 patients with chronic kidney disease, 75% ofantiproteinuric effects of SPR were apparent 2 weeks after trialinitiation [25]. It seems that there is an early kick-start in SPReffects on glomerular ltration of proteins; the proteinuria isthen sustained. It is unclear, however, for how long this ben-ecial effect is prolonged since the majority of studies in thisregard have followed patients for no longer than 12 months.To our knowledge, our study is among the rst to extend thefollow-up duration of patients to up to 18 months. Our resultspoint to a possible long-term benet for SPR in UAE dimin-ution, since albuminuria was maintained and did not return tobaseline values by the end of trial.

Here, a progressive decline in eGFR concentrations was ob-served in both groups, and the between-group difference didnot reach statistical signicance (about 9 mL/min/1.73 m2 inSPR/ARB group and 8 mL/min/1.73 m2 in ACE inhibitor/ARB group). Moreover, it persisted even after adjustment forSBP and DBP. SPR initiation resulted in a sudden and signi-cant decline in eGFR of about 4 mL/min/1.73 m2 after 3months. A similar observation has been made by other re-search groups [15, 26]. Bianchi and colleagues reported a sig-nicant drop of about 5 mL/min/1.73 m2 as early as 4 weeksafter SPR was added, followed by a stable rate of monthlydecline (0.323 versus 0.474 in case and control groups, respect-ively, P < 0.01) [13]. This was not the case in our study,however. Our analyses conrmed that even if the early eGFRchanges in the SPR/ARB group is disregarded, SPR does notoffer additional renoprotection with respect to eGFR decline.Similar initial drops have been reported with both captopriland irbesartan [27, 28]. While mechanisms underlying thisearly decline remain obscure for the most part, it is likely thathemodynamic alterations caused by suppression of genomiceffects of aldosterone contribute to this phenomenon [13, 26].

Asymptomatic hyperkalemia occurred in only three patientsin our trial (3.6%) and resolved soon after SPR discontinuation.Hyperkalemia is a major limiting factor in administration ofaldosterone antagonists and, if left undetected, could lead to sig-nicant mortality and morbidity [29, 30]. However, our resultsdemonstrated that the addition of SPR to ARB is relatively safe,mostly due to well-preserved renal function of trial participants(mean baseline eGFR in patients with hyperkalemia was 74 mL/min/1.73 m2). In line with previous reports [26, 29], in oursample, hyperkalemia occurred in patients who were older andhad higher baseline potassium concentrations. Therefore, fre-quent assessment of serum potassium in patients with elevatedpotassium due to prior treatment with ACE inhibitors and/orARBs, advanced age and diminished GFR is advisable.

The detrimental effects of aldosterone are not adequatelyarrested by the use of ACE inhibitor, ARB or a combination ofboth [31], and aldosterone escape might play an important rolein this regard [32]. It is believed that aldosterone escape occurs

quite commonly with reports indicating prevalence rates ashigh as 22% with ARBs [32] and 40% with ACE inhibitors [33].Treatment of aldosterone escape with SPR has been effective inreduction of proteinuria [32]. Hence, it is plausible thatadditional blockade of aldosteronevia mineralocorticoid re-ceptor antagonistsmay result in more efcacious blockade ofthe RAAS system. It is suggested that low doses of SPR exertantiproteinuric effects mainly via the non-genomic pathway;our ndings, along with a number of previous reports,indicate that these effects are indeed independent of BP control[14, 3436]. Non-genomic effects of aldosterone may involveinammation, oxidative stress, endothelial dysfunction and sub-sequent apoptosis and brosis in podocytes [10, 3739].

A number of limitations in our study should be considered.First, during the course of the trial, a relatively high rate of lossto follow-up was observed. Nevertheless, comparison of thebaseline characteristics of patients who completed the studyand who were lost to follow-up at the 12th and the 18thmonths revealed no signicant differences between the twogroups. This nding supports the notion that dropout ofpatients has occurred at random. Second, the present studywas an open-label trial and no placebo-control was carriedout. This might have contributed to potential bias in the as-sessment of patients. Despite these limitations, our study isunique in the sense that for the rst time, it examines theeffects of combined SPR/losartan regimen on diabetic nephro-pathy, and extends the duration of follow-up beyond that inprevious reports. Based on our ndings, addition of SPR to anARB-based regimen provides additional benets with respectto BP control and proteinuria diminution. However, benecialeffects of SPR on UAE reduction should be interpreted withcaution, since aldosterone blockade does not slow the pro-gression of eGFR loss during the 18 months of trial. Neverthe-less, it should be noted that there is ample evidence indicatingthat reduction of microalbuminuria per se offers renoprotec-tion in diabetic nephropathy [28, 40]. On the other hand, sus-tained BP-lowering effects of SPR also contributes topreservation of renal function in patients with diabetes andhypertension [4144]. What remains to be elucidated iswhether observed improvements with SPR does in fact preventhard outcomes including cardiovascular events, creatininedoubling, progression to ESRD and need for temporary or per-manent dialysis. Future large multicenter RCTs with event-based outcomes and longer durations of follow-up are para-mount to evaluate long-term effects of reduced proteinuria bySPR on eGFR preservation.

SUPPLEMENTARY DATA

Supplementary data are available online at http://ndt.oxford-journals.org.

CONFLICT OF INTEREST STATEMENT

None declared.

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Received for publication: 22.11.2012; Accepted in revised form: 11.5.2013

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