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Review Article |

Do Thiazide Diuretics Confer Specific Protection Against Strokes? FREE

Franz H. Messerli, MD; Ehud Grossman, MD; Anthony F. Lever, MD
[+] Author Affiliations

From the Department of Internal Medicine, Section on Hypertensive Diseases, Ochsner Clinic Foundation, New Orleans, La (Dr Messerli); Department of Internal Medicine D, The Chaim Sheba Medical Center, Tel-Hashomer, Israel (Dr Grossman); and Department of Medicine & Therapeutics, Western Infirmary, Glasgow, Scotland (Dr Lever). The authors have no relevant financial interest in this article.


Arch Intern Med. 2003;163(21):2557-2560. doi:10.1001/archinte.163.21.2557.
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Several large studies have suggested that therapy with thiazide diuretics confers a particular benefit in reducing the risk of strokes that seem to be, at least to some extent, independent of the blood pressure–lowering effect. Such a cerebroprotective effect was documented not only with monotherapy but also when diuretics were used in combination with other drugs. The cerebroprotective effect does not seem to be shared by other drug classes, such as the β-blockers or the angiotensin-converting enzyme inhibitors, in patients without manifest cardiovascular disease. Since stroke is one of the most devastating sequelae of high blood pressure, our data strongly favor the use of low-dose diuretics either as initial therapy or in combination in all hypertensive patients at risk for cerebrovascular disease.

Figures in this Article

Lowering blood pressure has been shown to reduce the risk of stroke in patients with hypertension by more than one third.1 Even in patients with isolated systolic hypertension, lowering systolic blood pressure reduced the risk of stroke by the same magnitude.2 In most trials in which a reduction in stroke rates was documented, antihypertensive therapy was diuretic based. However, it is not known whether the reduction in strokes was related to the fall in blood pressure per se and/or to a specific effect of diuretic therapy.

In the recent Perindopril Protection Against Recurrent Stroke Study (PROGRESS)3 in patients with cerebrovascular disease, combination therapy of a diuretic (indapamide) and angiotensin-converting enzyme (ACE) inhibitor (perindopril) reduced the risk of stroke by 43% compared with placebo. However, perindopril alone, despite lowering systolic blood pressure by 5 mm Hg, decreased stroke risk only by a nonsignificant 5%. In contrast to perindopril, indapamide monotherapy for a similar 5–mm Hg systolic blood pressure reduction lowered the risk of stroke by 29% in the Post-stroke Antihypertensive Treatment Study (PATS).4 This would indicate that in PROGRESS most of the benefits in prevention of recurrent strokes were related to diuretic therapy (Figure 1). Since the Medical Research Council (MRC) study in 1985,5 there has been some speculation whether diuretics can confer a specific cerebroprotective effect, that is, reduce the risk of stroke more than was expected from their antihypertensive efficacy. In the MRC trial, bendroflumethiazide was documented to be almost 3 times as efficacious as the β-blocker propranolol hydrochloride in preventing strokes.5 In some patient groups, such as male smokers, the difference between the diuretic and the β-blocker was even greater because propranolol, despite lowering blood pressure, provided no protection against strokes. In the MRC trial in elderly patients,6 when patients were subdivided according to systolic blood pressure strata, the stroke rate for any given systolic blood pressure was consistently lower in the diuretic group, even compared with patients receiving placebo. Thus, for a given blood pressure, diuretic therapy not only seemed to be more efficacious to prevent strokes than β-blockers, but it even had an advantage over placebo.

Place holder to copy figure label and caption

In the Perindopril Protection Against Recurrent Stroke Study (PROGRESS),3 a decrease of 5 mm Hg in systolic blood pressure (SBP) reduced strokes by a nonsignificant 5%. In the Post-stroke Antihypertensive Treatment Study,4 for the same decrease in blood pressure, indapamide therapy reduced strokes by 29%. The addition of indapamide to perindopril treatment reduced strokes by 43%.

Graphic Jump Location

Several other studies have attested to the superior efficacy of diuretic therapy in reducing the risk for cerebrovascular disease (Table 1).310 In a large meta-analysis, including 48 220 patients, Psaty et al11 found that high-dose diuretic therapy reduced the risk of stroke by 51%, whereas therapy with β-blockers reduced the risk by only 29% (P = .02). Klungel et al12 showed that among 1237 single-drug users with no history of cardiovascular disease, the adjusted risk of ischemic stroke was 2 to 2½ times higher among users of β-blockers, calcium antagonists, or ACE inhibitors than among users of a diuretic alone. Interestingly, even in patients with cardiovascular disease, diuretics still conferred a lower stroke risk than other drugs, although the difference was considerably smaller. More recently, the Captopril Prevention Project (CAPPP)8 showed an increased stroke risk with captopril therapy compared with diuretic or β-blocker therapy (relative risk, 1.25). Finally, in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT),9,10 patients treated with the α-blocker doxazosin mesylate and the ACE inhibitor lisinopril showed an increased risk of stroke compared with those receiving chlorthalidone.

Table Graphic Jump LocationTable 1. Prospective Studies Showing Superior Stroke Protection by Diuretics Compared With Placebo or Other Antihypertensive Treatment

Not only were diuretics in monotherapy consistently superior to other drug therapies for the prevention of cerebrovascular disease, but a similar phenomenon could be observed when diuretic monotherapy was compared with combination therapy. In the MRC studies,5,6 the addition of a β-blocker to the diuretic diminished cerebrovascular benefits in both the middle-aged and the older population. In the Systolic Hypertension in the Elderly Program (SHEP) study,7 patients receiving a combination of a β-blocker with a diuretic had a 34% higher risk of stroke than those receiving diuretic monotherapy. One might argue that it is not surprising for combination therapy to be associated with smaller benefits, since it was obviously given in patients who required more blood pressure lowering and, therefore, were at a higher risk than patients receiving monotherapy. However, in the MRC trial, the best reduction of cardiovascular risk occurred with diuretic monotherapy; when a β-blocker was added, efficacy diminished and became even weaker with β-blocker monotherapy.13 In the study by Klungel et al,12 nonthiazide combinations had a 2½-fold greater cerebrovascular disease risk than thiazide monotherapy, and the risk was consistently lower with all thiazide combinations (β-blockers, calcium antagonists, or ACE inhibitors) than with nonthiazide combinations.

We should also consider that age-adjusted mortality of strokes, which was falling dramatically in the 1970s and 1980s, seems to have plateaued in the United States14 and western Europe15 and to actually have increased in eastern Europe. Cooper et al16 pointed out that the annual death rate from stroke decreased by almost 5% in the 1970s, 3.5% in the 1980s, and only 0.7% in the 1990s. It is particularly intriguing that this plateau in stroke mortality occurred over the period during which control of blood pressure increased from 10% to 29%.17 Blood pressure control in the 1990s was achieved by using more and more drugs other than diuretics. In fact, the ratio between diuretics and drugs that suppress the renin angiotensin system decreased more than 5-fold since 1980.18 Could it be that diuretics confer a specific effect on the cerebrovascular circulation that is not shared by any other antihypertensive drug class and that the decline in diuretic use is causing stroke mortality to plateau?

If the answer is yes to the question above, what could be the pathophysiologic mechanism accounting for a greater cerebroprotective effect of diuretics compared with other antihypertensive drugs? A very bold hypothesis to explain this phenomenon was put forward by Brown and Brown19 after the publication of the MRC trial. These authors proposed that the activation of the renin angiotensin system and increased angiotensin II levels could have a protective effect against stroke. Angiotensin II, by predominantly constricting the larger cerebral blood vessels, would help protect the smaller reticular striate arteries where Charcot-Bouchard aneurysms usually are located, the rupture of which is a common cause of intracerebral hemorrhage in patients with hypertension. Fournier et al20 refined this hypothesis by suggesting that the protective effects against cerebrovascular disease were related to the angiotensin II non-AT1 receptors, which are only expressed in the ischemic zones of the brain. Non-AT1 receptors have been shown to become up-regulated after global ischemia in the brain and may serve as mediators of protective mechanisms by recruiting collateral circulation and decreasing neuronal apoptosis.21,22 Thus, blockade of the AT1 receptor (and sparing the non-AT1 receptor) by an angiotensin receptor blocker could be more protective against stroke than decreasing angiotensin II by ACE inhibition. In the Losartan Intervention for Endpoint reduction in hypertension (LIFE) study, AT1 blockade with losartan potassium decreased the stroke risk 25% better than did atenolol-based therapy at similar blood pressure levels.23 Indeed, the superiority of AT1 blockade over ACE inhibition at equipotent blood pressure reduction was confirmed in 2 different experimental models.24,25 Conceivably, a greater stimulation of these non-AT1 rescue mechanisms by diuretics (which increase the activity of the renin angiotensin system), angiotensin receptor blockers, and calcium antagonists compared with β-blockers or ACE inhibitors would account for a greater protection against strokes in patients without cardiovascular disease. In contrast, in patients with cardiovascular disease, a high percentage of strokes probably originates directly from cardiac disease or destabilization of atherosclerotic plaque. In such a population, reduction of circulating angiotensin II levels by ACE inhibition would more likely be beneficial by reversing or preventing cardiovascular disease. The Fournier hypothesis would allow us to explain the distinctly smaller difference in ischemic strokes between diuretic and nondiuretic therapy in patients with a history of cardiovascular disease compared with those with no cardiovascular disease in the Klungel study12 and the cerebrovascular benefits of the ACE inhibitor used in the Heart Outcomes Prevention Evaluation (HOPE) study,26 in which more than 80% of the patients had cardiovascular disease. If this hypothesis holds true, diuretics, angiotensin receptor blockers, and calcium antagonists should prove to be more cerebroprotective than β-blockers or ACE inhibitors in hypertensive patients without preexisting heart disease.

In 3 studies in which calcium antagonists were compared against diuretic therapy, cerebroprotection seemed to be not significantly different between treatment arms (Table 2).10,27,28 Of note, in the Multicenter Isradipine Diuretic Atherosclerosis Study (MIDAS),27 a short-acting (twice-a-day) calcium antagonist was used, whereas in Intervention as a Goal in Hypertension Treatment (INSIGHT)28 and ALLHAT,10 once-a-day compounds were compared against diuretic therapy.

Table Graphic Jump LocationTable 2. Prospective Studies Comparing Calcium Antagonists and Diuretics

Whatever the exact mechanism, several large studies suggest that thiazide diuretics confer a particular benefit in reducing the risk of stroke that seems to be, at least to some extent, independent of their blood pressure–lowering effect. This cerebroprotective effect does not seem to be shared by some other drug classes, such as the β-blockers and the ACE inhibitors, in patients without manifest cardiovascular disease. However, calcium antagonists seem to confer similar cerebroprotection as diuretics. Stroke is one of the most devastating sequelae of high blood pressure, and its prevention should be the utmost goal of antihypertensive therapy. These findings, if confirmed by currently ongoing studies, strongly favor the use of drugs that stimulate the AT2 receptor such as thiazide diuretics either as initial therapy or in combination in hypertensive patients at risk for cerebrovascular disease.

Corresponding author: Franz H. Messerli, MD, Ochsner Clinic Foundation, 1514 Jefferson Hwy, New Orleans, LA 70121 (e-mail: fmesserli@aol.com).

Accepted for publication January 8, 2003.

MacMahon  SPeto  RCutler  J  et al.  Blood pressure, stroke, and coronary heart disease, I: prolonged differences in blood pressure: prospective observational studies corrected for the regression dilution bias. Lancet. 1990;335765- 774
PubMed
Staessen  JAGasowski  JWang  JG  et al.  Risks of untreated and treated isolated systolic hypertension in the elderly: meta-analysis of outcome trials. Lancet. 2000;355865- 872
PubMed
PROGRESS Collaborative Group, Randomised trial of a perindopril-based blood-pressure lowering regimen among 6105 individuals with previous stroke or transient ischaemic attack. Lancet. 2001;3581033- 1041
PubMed
PATS Collaborating Group, Post-stroke Antihypertensive Treatment Study. Chin Med J (Engl). 1995;108710- 717
PubMed
Medical Research Council Working Party, MRC trial of treatment of mild hypertension: principal results. Br Med J (Clin Res Ed). 1985;29197- 104
PubMed
MRC Working Party, Medical Research Council trial of treatment of hypertension in older adults: principal results. BMJ. 1992;304405- 412
PubMed
Kostis  JBBerge  KGDavis  BRHawkins  CMProbstfield  J Effect of atenolol and reserpine on selected events in the Systolic Hypertension in the Elderly Program (SHEP). Am J Hypertens. 1995;81147- 1153
PubMed
Hansson  LLindholm  LHNiskanen  L  et al.  Effect of angiotensin-converting-enzyme inhibition compared with conventional therapy on cardiovascular morbidity and mortality in hypertension: the Captopril Prevention Project (CAPPP) randomised trial. Lancet. 1999;353611- 616
PubMed
ALLHAT Collaborative Research Group, Major cardiovascular events in hypertensive patients randomized to doxazosin vs chlorthalidone: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA. 2000;2831967- 1975
PubMed
The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group, The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial: major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA. 2002;2882981- 2997
PubMed
Psaty  BMSmith  NLSiscovick  DS  et al.  Health outcomes associated with antihypertensive therapies used as first-line agents: a systematic review and meta-analysis. JAMA. 1997;277739- 745
PubMed
Klungel  OHHeckbert  SRLongstreth  WT  Jr  et al.  Antihypertensive drug therapies and the risk of ischemic stroke. Arch Intern Med. 2001;16137- 43
PubMed
Lever  AFBrennan  PJ MRC trial of treatment in elderly hypertensives. High Blood Press. 1992;1132- 137
Howard  GHoward  VJKatholi  COli  MKHuston  S Decline in US stroke mortality: an analysis of temporal patterns by sex, race, and geographic region. Stroke. 2001;322213- 2220
PubMed
Sarti  CRastenyte  DCepaitis  ZTuomilehto  J International trends in mortality from stroke, 1968 to 1994. Stroke. 2000;311588- 1601
PubMed
Cooper  RCutler  JDesvigne-Nickens  P  et al.  Trends and disparities in coronary heart disease, stroke, and other cardiovascular diseases in the United States: findings of the National Conference on Cardiovascular Disease Prevention. Circulation. 2000;1023137- 3147
PubMed
Lenfant  CRoccella  E A call to action for more aggressive treatment of hypertension. J Hypertens Suppl. 1999;17 ((suppl 1)) S3- S7
PubMed
Fournier  AOprisiu  RMazouz  H  et al.  Stroke death rate annual decrease reversal and prescription decrease of antihypertensive drugs stimulating the angiotensin II formation [abstract]. Am J Hypertens. 2002;15106A
Brown  MJBrown  J Does angiotensin-II protect against strokes? Lancet. 1986;2427- 429
PubMed
Fournier  AMazouz  HPruna  A  et al.  Stroke prevention and antihypertensive treatment: may angiotensin receptor type 1 antagonist (AT1RA) be more protective than angiotensin converting enzyme inhibitor (ACEI)? Nieren Hochblutdruck Krankheiten. 2000;29S545- S554
Fernandez  LSpencer  DKaczmar  T Angiotensin II decreases mortality rate in gerbils with unilateral carotid ligation. Stroke. 1986;1782- 85
PubMed
Makino  IShibata  KOhgami  YFujiwara  MFurukawa  T Transient upregulation of the AT2 receptor mRNA level after global ischemia in the rat brain. Neuropeptides. 1996;30596- 601
PubMed
Dahlöf  BDevereux  RBKjeldsen  SE  et al.  Cardiovascular morbidity and mortality in the Losartan Intervention for Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet. 2002;359995- 1003
PubMed
Fernandez  LACaride  VJStromberg  CNaveri  LWicke  JD Angiotensin AT2 receptor stimulation increases survival in gerbils with abrupt unilateral carotid ligation. J Cardiovasc Pharmacol. 1994;24937- 940
PubMed
Dalmay  FMazouz  HAllard  JPesteil  FAchard  JMFournier  A Non-AT(1)-receptor-mediated protective effect of angiotensin against acute ischaemic stroke in the gerbil. J Renin Angiotensin Aldosterone Syst. 2001;2103- 106
PubMed
Yusuf  SSleight  PPogue  JBosch  JDavies  RDagenais  Gthe Heart Outcomes Prevention Evaluation Study Investigators, Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med. 2000;342145- 153
PubMed
Borhani  NOMercuri  MBorhani  PA  et al.  Final outcome results of the Multicenter Isradipine Diuretic Atherosclerosis Study (MIDAS): a randomized controlled trial. JAMA. 1996;276785- 791
PubMed
Brown  MJPalmer  CRCastaigne  A  et al.  Morbidity and mortality in patients randomized to double-blind treatment with a long-acting calcium-channel blocker or diuretic in the International Nifedipine GITS study: Intervention as a Goal in Hypertension Treatment (INSIGHT). Lancet. 2000;356366- 372
PubMed

Figures

Place holder to copy figure label and caption

In the Perindopril Protection Against Recurrent Stroke Study (PROGRESS),3 a decrease of 5 mm Hg in systolic blood pressure (SBP) reduced strokes by a nonsignificant 5%. In the Post-stroke Antihypertensive Treatment Study,4 for the same decrease in blood pressure, indapamide therapy reduced strokes by 29%. The addition of indapamide to perindopril treatment reduced strokes by 43%.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1. Prospective Studies Showing Superior Stroke Protection by Diuretics Compared With Placebo or Other Antihypertensive Treatment
Table Graphic Jump LocationTable 2. Prospective Studies Comparing Calcium Antagonists and Diuretics

References

MacMahon  SPeto  RCutler  J  et al.  Blood pressure, stroke, and coronary heart disease, I: prolonged differences in blood pressure: prospective observational studies corrected for the regression dilution bias. Lancet. 1990;335765- 774
PubMed
Staessen  JAGasowski  JWang  JG  et al.  Risks of untreated and treated isolated systolic hypertension in the elderly: meta-analysis of outcome trials. Lancet. 2000;355865- 872
PubMed
PROGRESS Collaborative Group, Randomised trial of a perindopril-based blood-pressure lowering regimen among 6105 individuals with previous stroke or transient ischaemic attack. Lancet. 2001;3581033- 1041
PubMed
PATS Collaborating Group, Post-stroke Antihypertensive Treatment Study. Chin Med J (Engl). 1995;108710- 717
PubMed
Medical Research Council Working Party, MRC trial of treatment of mild hypertension: principal results. Br Med J (Clin Res Ed). 1985;29197- 104
PubMed
MRC Working Party, Medical Research Council trial of treatment of hypertension in older adults: principal results. BMJ. 1992;304405- 412
PubMed
Kostis  JBBerge  KGDavis  BRHawkins  CMProbstfield  J Effect of atenolol and reserpine on selected events in the Systolic Hypertension in the Elderly Program (SHEP). Am J Hypertens. 1995;81147- 1153
PubMed
Hansson  LLindholm  LHNiskanen  L  et al.  Effect of angiotensin-converting-enzyme inhibition compared with conventional therapy on cardiovascular morbidity and mortality in hypertension: the Captopril Prevention Project (CAPPP) randomised trial. Lancet. 1999;353611- 616
PubMed
ALLHAT Collaborative Research Group, Major cardiovascular events in hypertensive patients randomized to doxazosin vs chlorthalidone: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA. 2000;2831967- 1975
PubMed
The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group, The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial: major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA. 2002;2882981- 2997
PubMed
Psaty  BMSmith  NLSiscovick  DS  et al.  Health outcomes associated with antihypertensive therapies used as first-line agents: a systematic review and meta-analysis. JAMA. 1997;277739- 745
PubMed
Klungel  OHHeckbert  SRLongstreth  WT  Jr  et al.  Antihypertensive drug therapies and the risk of ischemic stroke. Arch Intern Med. 2001;16137- 43
PubMed
Lever  AFBrennan  PJ MRC trial of treatment in elderly hypertensives. High Blood Press. 1992;1132- 137
Howard  GHoward  VJKatholi  COli  MKHuston  S Decline in US stroke mortality: an analysis of temporal patterns by sex, race, and geographic region. Stroke. 2001;322213- 2220
PubMed
Sarti  CRastenyte  DCepaitis  ZTuomilehto  J International trends in mortality from stroke, 1968 to 1994. Stroke. 2000;311588- 1601
PubMed
Cooper  RCutler  JDesvigne-Nickens  P  et al.  Trends and disparities in coronary heart disease, stroke, and other cardiovascular diseases in the United States: findings of the National Conference on Cardiovascular Disease Prevention. Circulation. 2000;1023137- 3147
PubMed
Lenfant  CRoccella  E A call to action for more aggressive treatment of hypertension. J Hypertens Suppl. 1999;17 ((suppl 1)) S3- S7
PubMed
Fournier  AOprisiu  RMazouz  H  et al.  Stroke death rate annual decrease reversal and prescription decrease of antihypertensive drugs stimulating the angiotensin II formation [abstract]. Am J Hypertens. 2002;15106A
Brown  MJBrown  J Does angiotensin-II protect against strokes? Lancet. 1986;2427- 429
PubMed
Fournier  AMazouz  HPruna  A  et al.  Stroke prevention and antihypertensive treatment: may angiotensin receptor type 1 antagonist (AT1RA) be more protective than angiotensin converting enzyme inhibitor (ACEI)? Nieren Hochblutdruck Krankheiten. 2000;29S545- S554
Fernandez  LSpencer  DKaczmar  T Angiotensin II decreases mortality rate in gerbils with unilateral carotid ligation. Stroke. 1986;1782- 85
PubMed
Makino  IShibata  KOhgami  YFujiwara  MFurukawa  T Transient upregulation of the AT2 receptor mRNA level after global ischemia in the rat brain. Neuropeptides. 1996;30596- 601
PubMed
Dahlöf  BDevereux  RBKjeldsen  SE  et al.  Cardiovascular morbidity and mortality in the Losartan Intervention for Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet. 2002;359995- 1003
PubMed
Fernandez  LACaride  VJStromberg  CNaveri  LWicke  JD Angiotensin AT2 receptor stimulation increases survival in gerbils with abrupt unilateral carotid ligation. J Cardiovasc Pharmacol. 1994;24937- 940
PubMed
Dalmay  FMazouz  HAllard  JPesteil  FAchard  JMFournier  A Non-AT(1)-receptor-mediated protective effect of angiotensin against acute ischaemic stroke in the gerbil. J Renin Angiotensin Aldosterone Syst. 2001;2103- 106
PubMed
Yusuf  SSleight  PPogue  JBosch  JDavies  RDagenais  Gthe Heart Outcomes Prevention Evaluation Study Investigators, Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med. 2000;342145- 153
PubMed
Borhani  NOMercuri  MBorhani  PA  et al.  Final outcome results of the Multicenter Isradipine Diuretic Atherosclerosis Study (MIDAS): a randomized controlled trial. JAMA. 1996;276785- 791
PubMed
Brown  MJPalmer  CRCastaigne  A  et al.  Morbidity and mortality in patients randomized to double-blind treatment with a long-acting calcium-channel blocker or diuretic in the International Nifedipine GITS study: Intervention as a Goal in Hypertension Treatment (INSIGHT). Lancet. 2000;356366- 372
PubMed

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