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Evidence-Based Diuretic Therapy for Improving CardiovascularPrognosis in Systemic Hypertension

Firas J. Al Badarin, MDa, Mohammad A. Abuannadi, MDa, Carl J. Lavie, MDb, andJames H. O’Keefe, MDa,*

Diuretics are among the most commonly prescribed cardiovascular (CV) medications. Thestrength of evidence supporting the effectiveness of diuretics in lowering blood pressureand for preventing major adverse CV events in patients with hypertension varies consid-erably among diuretic classes and even among agents within the same class. Unfortunately,common prescribing habits among American physicians, including specialists in CV dis-eases, are not in line with the existing evidence regarding diuretic therapy for improvingCV prognosis. In conclusion, although hydrochlorothiazide is the standard diuretic usedfor hypertension, the outcomes data suggest that chlorthalidone, indapamide, and possiblyeven the aldosterone receptor blockers (spironolactone and eplerenone) may be superior

agents. © 2011 Elsevier Inc. All rights reserved. (Am J Cardiol 2011;107:1178–1184)

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In this report, we review published data on the effects ofvarious diuretics on major clinical outcomes in patients withhypertension. As a practical matter, all the agents discussedin this review are widely available as generics, and a 30-daysupply of most can be purchased for $4. Thus, cost shouldnot be an issue when choosing the most effective diureticfor patients with hypertension, even those who areuninsured.

Thiazide Diuretics

The thiazide designation collectively encompasses agroup of thiazide derivatives (hydrochlorothiazide, chloro-thiazide, and others) and thiazide-like agents (chlorthali-done, indapamide, and metolazone) that principally act onthe distal convoluted tubules and inhibit the sodium chloridetransporter.1 Indapamide exerts some of its diuretic andntihypertensive effects through additional mechanisms thatre not yet fully elucidated.2

Since their advent, thiazide diuretics have been a cor-nerstone in hypertension treatment.3 However, thiazide

iuretics vary considerably in their blood pressure (BP)–owering potency. For example, chlorthalidone has a lon-er half-life and a larger volume of distribution comparedo hydrochlorothiazide.4 Therefore, it is 1.5 to 2 times

ore potent than hydrochlorothiazide and yields a largernd more sustained reduction in systolic BP (Figure 1),

aMid America Heart and Vascular Institute, Saint Luke’s Hospital andUniversity of Missouri–Kansas City, Kansas City, Missouri; and bJohnOchsner Heart and Vascular Institute, Ochsner Clinical School–The Uni-versity of Queensland School of Medicine, New Orleans, Louisiana. Man-uscript received October 21, 2010; revised manuscript received and ac-cepted December 15, 2010.

Dr. Lavie is a speaker and consultant for GlaxoSmithKline, ResearchTriangle Park, North Carolina; Pfizer, Inc., New York, New York; andAbbott Laboratories, Abbott Park, Illinois. Dr. O’Keefe is a speaker andconsultant for Pfizer, Inc., and a speaker for AstraZeneca, Wilmington,Delaware, and Forest Pharmaceuticals, Inc., New York, New York.

*Corresponding author: Tel: 816-751-8480; fax: 816-756-3645.

iE-mail address: jhokeefe@cc-pc.com (J.H. O’Keefe).

0002-9149/11/$ – see front matter © 2011 Elsevier Inc. All rights reserved.doi:10.1016/j.amjcard.2010.12.016

nd the 2 agents are not equivalent in their antihyperten-ive properties at low doses.5,6

The efficacy of thiazide diuretics as first-line therapiesfor preventing mortality and morbidity in patients withhypertension has been established.7 Furthermore, thiazidediuretics are as effective as many other classes of BP-lowering medications in preventing coronary heart disease(CHD) and stroke for a given reduction in BP.8 Hydrochlo-othiazide, chlorthalidone, and indapamide are the thiazideiuretics most commonly used in clinical practice and mostidely studied in major clinical trials. We herein will sum-arize and critically review clinically trials supporting the

ole of these diuretics in improving cardiovascular (CV)rognosis in patients with hypertension.

Hydrochlorothiazide and chlorthalidone: The inter-hangeability of hydrochlorothiazide and chlorthalidone haseen a matter of intense debate.9,10 This stems not only fromifferences in their pharmacokinetics but also from thetrength of the evidence base supporting their utility inmproving clinical outcomes.

Studies with chlorthalidone have demonstrated a 17%eduction in all-cause mortality,11 a 36% reduction introke, a 33% reduction in total CV events, and 41% reduc-ion in fatal and nonfatal congestive heart failure (CHF)ompared to placebo.12 The Antihypertensive and Lipid-

Lowering Treatment to Prevent Heart Attack Trial(ALLHAT) demonstrated chlorthalidone to be noninferiorto lisinopril or amlodipine in preventing fatal and nonfatalCV events as well as total mortality, and it was moreeffective in preventing CHF and major CHD proceduresthan either comparator (Figure 2).13 However, some edito-rials were critical of the design of ALLHAT, citing potentialbiases favoring diuretics.14 Yet the remarkable benefits ofhlorthalidone in this large randomized, double-blind, mul-icenter trial sponsored by the National Heart, Lung, andlood Institute formed the basis for the recommendation

hat a thiazide diuretic should be used as an initial therapy

n almost all patients with hypertension, according to the

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1179Review/Evidence-Based Diuretic Therapy for Hypertension

seventh report of the Joint National Committee on the de-tection, prevention, and treatment of hypertension.15

The evidence supporting the use of hydrochlorothiazideis less consistent. Hydrochlorothiazide plus triamterene re-sulted in a 38% reduction in CV mortality compared toplacebo in patients with hypertension aged �60 years.16

Hydrochlorothiazide plus amiloride was significantly moreeffective than atenolol plus placebo in preventing stroke,total CHD events, and all-cause mortality.17 The same com-ination of hydrochlorothiazide and amiloride was com-ared to nifedipine in the International Nifedipine GITStudy: Intervention as a Goal in Hypertension TreatmentINSIGHT), which showed that the 2 treatments werequally effective at reducing fatal and nonfatal CV events.18

However, in a randomized trial, the Oslo Study, hydro-chlorothiazide (compared to no treatment) did not improveoverall mortality or total CV events in asymptomatic pa-tients with hypertension, despite lowering BP by 17/10 mmHg.19 Although a reduction in the incidence of stroke was

Figure 1. Chlorthalidone (Chlor) was superior to hydrochlorothiazide(HCTZ) for reducing ambulatory BP in patients with hypertension.4

Figure 2. Rates of major CV events by treatment group (lisinopril vsamlodipine vs chlorthalidone). Data from ALLHAT.13 *p for chlorthali-one vs lisinopril � 0.02; p for chlorthalidone vs amlodipine � 0.28. †p forhlorthalidone vs lisinopril � 0.05; p for chlorthalidone vs amlodipine �.06. ‡p for chlorthalidone vs lisinopril �0.001; p for chlorthalidone vsmlodipine �0.001.

observed in the hydrochlorothiazide arm, it was, unfortu-

nately, offset by an increase in CHD events, which theinvestigators attributed to unfavorable metabolic effects ofactive treatment (95% of patients received hydrochlorothi-azide). The Second Australian National Blood PressureStudy (ANBP-2) group showed that hydrochlorothiazidewas inferior to enalapril for lowering the risk for a compos-ite of overall mortality and all CV events, which was drivenmainly by a higher rate of myocardial infarction in thehydrochlorothiazide arm.20 More recently, in a group of�11,000 high-risk patients with hypertension taking benaz-epril, the group randomized to hydrochlorothiazide had20% more adverse CV events than the group randomized toamlodipine (Figure 3).21 This was observed despite a sim-lar reduction in ambulatory and office visit BP measure-ents in the hydrochlorothiazide and amlodipine arms.22

There are a number of potential explanations for this lackof consistency with hydrochlorothiazide for improving out-comes, including study design flaws. However, in all studiesthat showed benefit with hydrochlorothiazide, a second di-uretic was used in combination,16–18 raising the possibilitythat hydrochlorothiazide alone is inadequate for optimizingCV prognosis. The prescribed dose of hydrochlorothiazidemight also be an important factor in this regard, because thelack of benefit with hydrochlorothiazide has been generallyseen in studies in which lower doses were used (�25 mg/day). Yet hydrochlorothiazide at these lower doses inducedBP reductions that were equivalent to those seen with thecomparators and still resulted in less than expected clinicalbenefit. Moreover, using hydrochlorothiazide at higherdoses (50 to 100 mg/day) was associated with a higherincidence of hypokalemia, which has been linked to in-creased rates of cardiac arrest and type 2 diabetes mellitus.23

Head-to-head comparison between hydrochlorothiazideand chlorthalidone in an outcomes-based clinical trial hasnot been performed and might never be done, because the 2medications are available generically.9 The best evidencefor the superiority of chlorthalidone to hydrochlorothiazidecomes from nonrandomized comparison of the 2 agents in

Figure 3. Kaplan-Meier curves for time to first CV event (benazepril �amlodipine vs benazepril � hydrochlorothiazide). Data from the AvoidingCardiovascular Events in Combination Therapy in Patients Living WithSystolic Hypertension (ACCOMPLISH) trial.21

the Multiple Risk Factor Intervention Trial (MRFIT),24 in

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1180 The American Journal of Cardiology (www.ajconline.org)

which hydrochlorothiazide use was associated with excessCHD and all-cause mortality compared to chlorthalidone.This trend was reversed after the trial’s steering committeedecided to switch from hydrochlorothiazide to chlorthali-done at all participating sites. A meta-analysis comparingthe efficacy of different thiazide-based antihypertensivetherapies showed no difference in major health outcomesbetween chlorthalidone-based and other thiazide-containingregimens.25 The technique used in this analysis providesindirect comparison of these agents to each other throughcomparing each of them to placebo. This statistically com-plex yet valid technique is used when clinical trials provid-ing direct comparison between therapies of interest arelacking. It is, however, fraught with several limitations.26

Despite the data suggesting stronger and more consistentlowering of BP and lower risk for adverse CV outcomes forchlorthalidone compared with hydrochlorothiazide, the lat-ter agent continues to be the most prescribed diuretic in theUnited States.14 This preference for hydrochlorothiazide, atleast by American clinicians, is likely due to many reasons,including clinical tradition, the widespread use of this agentin combination antihypertensive pills, and commonly rec-ognized abbreviations (HCT and HCTZ).27,28 Hydrochlo-othiazide is available in combination with a variety ofopular antihypertensive agents compared with chlorthali-one, which is available only in combination with atenolol,lonidine, and reserpine, all of which have serious short-omings. Hypokalemia is another concern with chlorthali-

Table 1Summary of major outcomes-based indapamide clinical trials

Study Agent Comparator E

PICXEL IND � perindopril Enalapril Change in LVMI

IVE IND Enalapril Change in LVMI

REASON IND � perindopril Atenolol LVM

NESTOR IND Enalapril Change in albumin

PREMIER IND � perindopril Enalapril Change in albumin

HYVET IND � perindopril Placebo Fatal or nonfatal sall-cause morta(secondary end

ADVANCE IND � perindopril Placebo Composite of macdeath, nonfataland microvascunephropathy or

PROGRESS IND � perindopril Placebo Fatal or nonfatal smajor CV evenmortality (secon

CI � confidence interval; IND � indapamide; LIVE � Left VentricuLVMI � left ventricular mass index; MI � myocardial infarction; NESTOMicroalbuminuria; PICXEL � Perindopril/Indapamide in a Double-Blind CPreterax in Albuminuria Regression; REASON � Regression of Arterial

one, although the risk for serious hypokalemia is less

roblematic when using doses not higher than 12.5 to 25g/day. Combining chlorthalidone (or 1 of the other diuret-

cs from this class) with another BP medication that canffset potassium loss, such as an angiotensin-convertingnzyme inhibitor, an angiotensin receptor blocker, or anldosterone receptor blocker, will not only potentiate BPowering but also mitigate the risk for hypokalemia.

Thiazide diuretics have some limitations that are worthentioning. For example, they lack vasculoprotective prop-

rties (increasing nitric oxide availability)29 and other non-BP-dependent vascular benefits possessed by some otherantihypertensive drugs.30 In addition, concerns related toadverse effects and potential safety issues (collectively re-ferred to by some investigators as the “dark side” of diuret-ics) have been raised.31 Hypokalemia, hyperuricemia, hy-erglycemia, and exacerbation of metabolic syndrome areommon side effects of thiazide diuretics.32 Focal glomer-lar and interstitial injury has also been seen in hydrochlo-othiazide-treated rats.33 Moreover, prolonged exposure to

medium or high doses of diuretics might be associated withan increased risk for renal cell carcinoma.34,35 However, theclinical significance of these potential liabilities of thiazidediuretics and their relevance to daily practice and choice ofantihypertensive agents remain uncertain.

Indapamide: Despite the similarities to other membersof the thiazide family, indapamide has unique features thatrender it a particularly efficacious and advantageous anti-

nt Key Findings

Greater reduction in LVMI with IND/perindoprilvs enalapril (�13.6 vs �3.9 g/m2, p �0.0001)

Greater reduction in LVMI with IND vs enalapril(�8.4 vs �1.9 g/m2, p �0.013)

Greater reduction in LVM with IND/perindoprilvs atenolol (�13.6 vs �4.3 g, p � 0.027)

IND is noninferior to enalapril in reducingalbuminuria (�46% vs �47%, p � NS)

Greater reduction in albuminuria withIND/perindopril vs enalapril (�40% vs 27%,p � 0.007)

rimary end point),CV mortality

30% reduction in stroke (p � 0.06), 21%reduction in all-cause mortality (p � 0.02),23% reduction in CV mortality (p � 0.06),and 64% reduction in CHF (p �0.001)

lar (cardiovascularnonfatal stroke)

or worseningathy) events

9% RRR in primary end point (p � 0.04), 18%RRR in CV death (p � 0.03), 14% RRR inall-cause mortality (p � 0.03), and 21% RRRin total renal events (p �0.001)

rimary end point),or all-caused points)

IND � perindopril: 43% (95% CI 30% to 54%)reduction in stroke, 40% (95% CI 29% to49%) reduction in major CV events

Perindopril alone: 5% (95% CI �19% to 23%)reduction in stroke, 4% (95% CI �15% to20%) reduction in major CV events

pertrophy: Indapamide Versus Enalapril; LVM � left ventricular mass;atrilix SR Versus Enalapril Study in Hypertensive Type 2 Diabetics Withled Study Versus Enalapril in Left Ventricular Hypertrophy; PREMIER �s in a Controlled Double-Blind Study; RRR � relative risk reduction.

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It produces a significant and sustained reduction in BP,and compared to other thiazide diuretics, it is associatedwith a lower incidence of serious hypokalemia and hyper-glycemia.36 Furthermore, unlike other thiazide diuretics,indapamide retains efficacy in patients with chronic kidneydisease.37

The impact of indapamide on clinical outcomes has beenstudied in several large randomized controlled trials (Table1). Indapamide was associated with greater reduction in leftventricular mass and regression of left ventricular hypertro-phy (LVH) compared to either enalapril or atenolol mono-therapy.38–40 Additionally, indapamide was noninferior tonalapril in reducing urinary albumin excretion in patientsith diabetes and hypertension,41 and the combination of

ndapamide with perindopril provided incremental renalrotection over enalapril alone.42

In the Perindopril Protection Against Recurrent StrokeStudy (PROGRESS), which enrolled 6,105 patients withhistories of stroke or transient ischemic attack, treatmentwith perindopril with or without indapamide resulted in a28% relative risk reduction in the risk for fatal and nonfatalstroke and a 26% reduction in major CV events relative toplacebo.43 Notably, statistically significant reductions introke and major CV events were noted only in patients whoeceived indapamide plus perindopril combination therapy,ot in patients who received perindopril only. Those in thendapamide plus perindopril combination therapy groupad superior reductions in BP compared to those in theerindopril-only group. This study suggests that the ad-ition of indapamide to an angiotensin-converting en-yme inhibitor improves BP control and provides addi-ional risk reduction in patients with hypertension anderebrovascular disease compared to angiotensin-con-erting enzyme inhibitor monotherapy (Figure 4). Unfor-unately, however, PROGRESS did not include an inda-amide monotherapy arm, precluding direct conclusionsbout its effects not in combination with perindopril.

The Action in Diabetes and Vascular Disease

Figure 4. Hazard ratios in the PROGRESS trial. Patients who received periIn contrast, patients who received indapamide � perindopril did have sign

ADVANCE) trial investigated the efficacy of fixed-dose

ndapamide plus perindopril combination in reducing aomposite of macro- and microvascular events (CVeath, nonfatal myocardial infarction, and new or wors-ning renal disease, including the development of mac-oalbuminuria, doubling of serum creatinine, need forenal replacement therapy, or death due to renal disease)ver 4.3 years in 11,140 patients with hypertension withype 2 diabetes.44 This randomized controlled trial

showed that indapamide plus perindopril (compared toplacebo) significantly reduced the occurrence of the pri-mary end point (9% relative risk reduction, p � 0.04).

his modest risk reduction was driven primarily by re-uctions in new-onset microalbuminuria (21% relativeisk reduction, p �0.0001) and, to a lesser extent, totalHD events (14% relative risk reduction, p � 0.02).

All-cause mortality, a secondary end point of the study,was also reduced (14% relative risk reduction, p �0.025), mainly because of fewer CV deaths in the activetreatment group (18% relative risk reduction, p � 0.027).

The efficacy of indapamide plus perindopril combina-tion was also investigated in 3,845 patients aged �80years with hypertension in the Hypertension in the VeryElderly Trial (HYVET).45 A reduction in the primary endpoint of fatal and nonfatal stroke was observed but didnot reach nominal statistical significance (30% relativerisk reduction, p � 0.06). However, the study was ter-minated prematurely because of striking reductions insecondary end points. The indapamide plus perindoprilcombination reduced all-cause mortality (21% relativerisk reduction, p � 0.02), fatal stroke (39% relative riskreduction, p � 0.046), and CHF (64% relative risk re-duction, p �0.001). Because only 1/4 of the patients inthe active treatment group received indapamide mono-therapy, these benefits must be attributed to the indap-amide plus angiotensin-converting enzyme inhibitorcombination therapy (Figure 5).46

In summary, indapamide has been shown to favorablyaffect important surrogate CV end points, including LVH

alone did not have significant reductions in stroke and adverse CV events.lower risks of stroke and adverse CV events.43 CI � confidence interval.

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1182 The American Journal of Cardiology (www.ajconline.org)

a large body of randomized controlled data indicate thatindapamide may be effective in improving CV outcomes,especially when used in combination with an angiotensin-converting enzyme inhibitor. Multicenter, randomized con-trolled trials comparing indapamide as monotherapy areneeded to definitively define the impact of indapamide onclinical outcomes.

Potassium-Sparing Diuretics

This group includes 2 main classes of diuretics: sodiumchannel blockers and aldosterone receptor blockers. Al-though the 2 groups work through closely related mecha-nisms, they differ vastly in the way they affect CV out-comes. Epithelial sodium channel blockers, exemplified byamiloride and triamterene, work on the principal cells of thecollecting tubule and inhibit sodium absorption from tubularfluid, hence leading to decreased potassium excretion. Al-dosterone antagonists, including spironolactone and epler-enone, are the other major class of potassium-sparing di-uretics. They work via competitive inhibition of aldosteronereceptors in the cortical segment of the collecting tubules.Activation of aldosterone receptors in the collecting tubulesof the kidneys results in salt and water retention and wastingof potassium. Eplerenone is a more selective aldosteronereceptor blocker with lower affinities for progesterone andandrogen receptors than spironolactone.47 This improvedspecificity for the aldosterone receptor translates into amuch lower incidence of sexual side effects, such as gyne-comastia, breast pain, and menstrual irregularities witheplerenone.48

Aldosterone antagonists: In addition to promoting fluidetention, elevated aldosterone levels have also been linkedo increased inflammation, oxidative stress, LVH, myocar-ial fibrosis,49 and higher all-cause and CV mortality.50

Several studies have demonstrated the effectiveness of spi-ronolactone and eplerenone in lowering BP as monotherapyas well as add-on agents. In an open-label study of 175patients with truly resistant hypertension, spironolactonereduced ambulatory BP by 16/9 mm Hg, and control of BPwas achieved in 48% of the patients.51 Importantly, spirono-lactone was effective in the treatment of patients with re-sistant hypertension, irrespective of their aldosterone/renin

Figure 5. Risk ratios (RRs) for main fatal and nonfatal end points in theimproved CV prognoses in elderly patients with hypertension.46 Death fromsudden death. Any CV event was defined as death from CV causes or str

ratios.52 Aldosterone antagonists also regress LVH and re- (

store serum potassium levels, especially in patients withmineralocorticoid-dependent hypertension.53 Moreover, in

cohort of 54 patients with hyperaldosteronism, the use ofldosterone improved long-term (mean follow-up 7.4 years)P and outcomes equally well as surgical removal of thedenoma.54

Although treatment with aldosterone antagonists im-proves survival and reduces hospitalizations in patients withLV dysfunction and CHF,55,56 the impact of this class ofmedications on CV outcomes in patients with hypertensionand preserved LV function is less clear. Studies examiningsurrogate markers of increased CV risk suggest improvedoutcomes using aldosterone antagonists, but data on hardCV outcomes are still lacking in hypertension. Eplerenonehas shown favorable effects on LV mass and markers ofcollagen turnover in the Eplerenone, Enalapril and Epler-enone/Enalapril–Left Ventricular Hypertrophy (4E-LVH)study.57 Eplerenone and enalapril resulted in significant andimilar regression in left ventricular mass, but the epler-none plus enalapril combination was superior to epler-none alone in inducing LVH regression and BP lowering

n-to-treat population of HYVET. Indapamide plus perindopril markedlyc causes was defined as fatal myocardial infarction, fatal heart failure, andocardial infarction, or heart failure. CI � confidence interval.

Figure 6. Adjusted mean change in left ventricular (LV) mass from base-line in the magnetic resonance imaging (MRI) cohort. The MRI cohort ofthe 4E-LVH study included all randomized patients who received double-blind treatment for �3 months and who underwent baseline MRI and endpoint MRI �21 days after a dose of study medication.57 ENAL � enal-april; EPL � eplerenone.

intentiocardia

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1183Review/Evidence-Based Diuretic Therapy for Hypertension

hypertension, spironolactone plus an angiotensin-convert-ing enzyme inhibitor was superior to an angiotensin-con-verting enzyme inhibitor alone in regressing left ventri-cular mass.58

The efficacy of spironolactone and eplerenone in reduc-ing albuminuria was also evaluated. Eplerenone is moreeffective than amlodipine in reducing albuminuria in pa-tients with hypertension.59 In addition, the 4E-LVH studyhowed significant reduction in albuminuria with epler-none alone and additional reduction with eplerenone plusnalapril combination.57 Dual renin-angiotensin-aldoste-

rone-system blockade using spironolactone or eplerenone inpatients also taking angiotensin-converting enzyme inhibi-tors or angiotensin receptor blockers also offers an attractiveoption for additional renal protection in patients with hy-pertension and chronic kidney disease. Although spirono-lactone use in this situation resulted in a significant reduc-tion in proteinuria, it had no impact on BP or renal functionand was associated with significant risk for hyperkalemia. Inaddition, the long-term effect of this approach with respectto CV and renal outcomes is still unknown.60

In the light of the known deleterious effects of sustainedhigh aldosterone levels on CV and renal systems, numerousrandomized clinical trials are under way to evaluate the roleof aldosterone antagonists in reducing CV risk in patientswith hypertension.

Sodium channel blockers: The use of sodium channelblockers has been principally reserved for treatment of hy-pokalemia in diuretic-treated patients with hypertension as“add-on” therapy.61 The efficacy of amiloride and tri-amterene as antihypertensive agents was evaluated in arecent systematic review, which showed no overall clini-cally or statistically significant effect on BP using low dosesof sodium channel blockers.62 The efficacy of higher dosesof these agents has not been investigated, and studies re-porting outcomes of long-term treatment are lacking; hence,the sodium-channel diuretics are of limited clinical utilityfor the treatment of hypertension.

Acknowledgment: We acknowledge Lori J. Wilson for herexpert help with the preparation of this report.

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