Prevention of Dementia and Cerebroprotection with Antihypertensive Drugs Olivier Hanon, MD, PhD, Marie Laure Seux, MD, Hermine Lenoir, MD, Anne Sophie Rigaud, MD, PhD, and Françoise Forette, MD

Address Hôpital Broca, CHU Cochin Port-Royal, Université René Descartes, Paris V, 54/56 Rue Pascal, 75013 Paris, France. E-mail: [email protected] Current Hypertension Reports 2004, 6:201–207 Current Science Inc. ISSN 1522-6417 Copyright © 2004 by Current Science Inc.

High blood pressure is a major risk factor for stroke and is also closely correlated with cognitive decline and dementia. Indeed, most longitudinal studies showed that cognitive functioning is often inversely proportional to blood pressure values measured 15 or 20 years previously. Because of the aging of the population, the frequency of stroke and dementia will dramatically increase in the coming years. Therefore, the prevention of cerebrovascular and cognitive disorders represents a major challenge. Antihypertensive drugs have shown clinical benefits in both primary and secondary prevention of strokes. Consensus is generally that blood-pressure lowering represents the major determinant of the benefit conferred by the antihypertensive treatment for stroke prevention; however, recent studies have suggested some differences between classes of antihypertensive drugs. The results of therapeutic trials (Systolic Hypertension in Europe [Syst-Eur], Perindopril Protection Against Recurrent Stroke Study [PROGRESS]) open the way to the prevention of dementia (vascular or Alzheimer’s type) by antihypertensive treatments. These two studies suggest different mechanisms for the prevention of cognitive decline using antihypertensive drugs. In this context, reduced incidence of dementia should be the primary outcome of future trials comparing different classes of antihypertensive drugs.

Introduction Hypertension is one of the main risk factors for cerebrovascular diseases. High blood pressure (BP) is a major risk factor for stroke and is also closely correlated with cognitive decline and dementia. Stroke and dementia are the most important neurologic disorders in the elderly. Stroke is the third leading cause of death worldwide, and it accounts for

3% of the world’s disability burden [1]. By 2020, stroke mortality will have almost doubled, mainly because of the aging of the population. Dementia represents one of the principal neurologic disorders in the elderly. In view of the increasing longevity of populations worldwide, prevention of dementia has turned into a major public health challenge. Without prevention, the number of demented patients will increase from 10 million in 2000 to 37 million in 2050 in developed countries. Alzheimer’s disease is the leading cause of dementia, accounting for almost 66% of cases in Western countries. The prevalence of Alzheimer’s disease doubles every 5 years after the age of 65. Therefore, if a preventive strategy could delay the age of onset by 5 years, the number of cases would be reduced by 50% in one generation. In this context, the prevention of cerebrovascular and cognitive disorders represents a major challenge in the coming years. The fact that antihypertensive treatment reduces those risks offers an opportunity to decrease the prevalence of such related disorders and to promote healthy aging. Recent studies have suggested some differences between the antihypertensive drugs in stroke and dementia prevention.

Antihypertensive Drugs and Stroke Effect of blood-pressure lowering for stroke prevention Stroke represents the third most common cause of death in the world after ischemic heart disease and all types of cancer combined. In a recent meta-analysis by the Prospective Studies Collaboration [2•], who collected individual data from 1 million participants, including 61 prospective observational studies, the risk of stroke was associated with systolic BP (SBP) or diastolic BP (DBP) levels. In 12.7 million person-years at risk, there were 12,000 stroke deaths. Each difference of 20 mm Hg higher than usual SBP or 10 mm Hg higher than usual DBP was associated with more than a twofold difference in the stroke death rate. Therapeutic studies have indicated that strokes can be prevented by lowering BP in people with hypertension. Evidence from hypertension treatment trials showed that

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Table 1. Stroke: comparisons of different active treatments Treatment ACEI vs D/BB CCB vs D/BB ACEI vs CCB ARB vs controls

Trials, n 5 9 5 4

Difference in BP * (mean SBP/DBP, mmHg) +2/0 +1/0 +1/+1 -2/-1

Relative risk, 95% CI 1.09 (1.00–1.18) 0.93 (0.86–1.00) 1.12 (1.01–1.25) 0.79 (0.69–0.90)

ACEI—angiotensin-converting enzyme inhibitor; ARB—angiotensin receptor blockers; BB—b-blocker; CCB—calcium-channel blocker; CI— confidence interval; D—diuretics; DBP—diastolic blood pressure; SBP—systolic blood pressure. * Difference in blood pressure in the group assigned the first-listed treatment compared with the group assigned the second-listed treatment. Adapted from Turnbull [13••].

a relatively small decrease in BP level (5 to 6 mm Hg in DBP) reduces the risk of stroke by 42% (95% confidence interval [CI], 35%–50%) [3]. Antihypertensive drugs have shown clinical benefit in both primary and secondary prevention of strokes. Reports of first-outcome trials, which focused attention on systolodiastolic hypertension showed a reduction of fatal and nonfatal strokes [4–6]. More recent trials specifically addressed the issue of isolated systolic hypertension [7,8]. In a meta-analysis by Staessen et al. [9], which included 15,693 patients with isolated systolic hypertension, antihypertensive treatment significantly reduced stroke by 30%. If the benefit of antihypertensive treatment is largely proven in terms of primary prevention, other studies also support the effect of antihypertensive agents in secondary prevention. A first meta-analysis has shown that in hypertensive stroke survivors, adequate BP-lowering drug treatment decreases stroke recurrence by 28% [10]. The results of the Perindopril Protection Against Recurrent Stroke Study (PROGRESS) [11•] indicate the beneficial effects of a BPlowering regimen in hypertensive and nonhypertensive patients with a history of stroke or transient ischemic attack (TIA) in reducing stroke after 4 years of follow-up. In this study, the BP-lowering regimen reduced the risk of stroke from 28% (95% CI, 17%–38%). Combination therapy with perindopril and indapamide produced larger BP reductions, 12/5 mm Hg, and larger stroke reductions (43% [95% CI, 30%–54%]) than single-drug therapy with perindopril alone, which reduced BP by 5/3 mm Hg and produced no significant reduction in the risk of stroke. Finally, a recent systematic review of seven randomized, controlled trials [12] in 15,527 patients with prior ischemic or hemorrhagic stroke or TIA, indicates that the use of antihypertensive drugs lowered BP and reduced stroke 24% (95% CI, 8%–37%).

Is there a class effect for stroke prevention? The comparative effects of different antihypertensive classes on cerebroprotection remain unclear. However, the recent meta-analysis of the Blood Pressure Lowering Treatment (BPLT) trialists’ collaboration [13••] from 29 randomized trials (n = 162,341 subjects) suggests some differences between treatments and their effect on stroke

prevention (Table 1). A trend toward a greater risk reduction was observed with treatments based on calcium antagonists compared with those based on diuretics, βblockers (7% [95% CI, -1%–14%]), or angiotensin-converting enzyme (ACE) inhibitors (12% [95% CI 1 to 25%]). Additionally, treatment based on diuretics or βblockers showed a greater risk reduction of stroke compared with regimens based on ACE inhibitors (9% [95% CI, 0%–18%]). A greater reduction in stroke risk was also reported with angiotensin-receptor blockers (ARB) compared with control regimens (other antihypertensive drugs, excluding ARB) that were less effective in reducing BP. BP lowering appears to be major determinant of the benefit conferred by the antihypertensive treatment. The greatest risk reduction of stroke was observed with treatments that targeted lower BP goals (23% [95% CI, 5%– 37%]). However, the hypothesis of a specific neuroprotective effect, independent from BP lowering, is suggested particularly for the calcium antagonists and ARBs. In a network meta-analysis [14•], from 42 clinical trials including 192,478 patients randomized to seven major treatment strategies, low doses of diuretics were associated with greater reduction of stroke risk compared with ACE inhibitors (14% [95% CI, 3%–23%]). Additionally, a systematic review by Messerli et al. [15], comparing the effects of conventional drugs (diuretics and β-blockers) used as first-line agents in 16,164 elderly hypertensive subjects, suggests that β-blockers were less efficient than diuretics for stroke prevention. Indeed, diuretic therapy was superior to β-blockers in preventing cerebrovascular events (risk reduction (RR) = 39% [95% CI, 28%–49%]) and fatal stroke (RR = 33% [95% CI, 10%–51%]). Additionally, the comparison between β-blockers and ARBs in patients with left ventricular hypertrophy showed a 25% further reduction in stroke with ARBs (95% CI [11%–37%]) than with β-blockers [16]. In conclusion, several recent studies based on large metaanalysis suggest an independent but modest effect of some antihypertensive drugs such as the calcium antagonists, diuretics, and ARBs compared with β-blockers or ACE inhibitors, for prevention of stroke. The mechanisms of such a neuroprotective effect remain unknown and need specific studies based on comparison of antihypertensive drugs.

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Table 2. Effect of antihypertensive drugs on dementia in randomized, placebo-controlled studies Study

Patients, n

SBP/DBP difference (active - placebo)

SHEP [27]

4736

- 12/4 mm Hg

Syst-Eur [29••]

2418

- 8.3/3.8 mm Hg

Syst-Eur 2 [30••] (open follow up)

2902

- 7/3.2 mm Hg

PROGRESS [31••]

6105

- 9/4 mm Hg

SCOPE [33]

4964

-3.2/1.6 mm Hg

Drugs

Follow-up, y

Reduction of dementia

BB± Diuretic CCB± ACEI± Diuretic CCB± ACEI± Diuretic ± Others ACEI± Diuretic

4.5

NS

2

50% (0 to 76%)

4

55% (24% to 73%)

4

ARB

3.7

All dementia: 12% (-8% to 28%) Dementia with recurrent stroke: 34% (3% to 55%) NS

ACEI—angiotensin-converting enzyme inhibitor; ARB—angiotensin-receptor blocker; BB—b-blocker; CCB—calcium-channel blocker; PROGRESS— Perindopril Protection Against Recurrent Stroke Study; SCOPE—Study on Cognition and Prognosis in the Elderly; SHEP—Systolic Hypertension in the Elderly Program; Syst-Eur—Systolic Hypertension in Europe.

Antihypertensive Treatment and Dementia Alzheimer’s disease and vascular dementia are the most common subtypes of dementia. Aging is associated with a large increase in the prevalence and incidence of both degenerative and vascular dementias, leading to a devastating loss of autonomy. Hypertension, which is associated with an increased risk for cognitive decline [17–19] and both vascular dementia and Alzheimer’s disease [20,21], appears to be good candidate for prevention. Indeed, most longitudinal studies indicate that cognitive level is often inversely proportional to BP values measured 15 or 20 years previously. The higher the former BP level, the poorer the cognitive function is. Data from recent therapeutic trials suggest that antihypertensive treatment might prevent the occurrence of dementia (vascular or Alzheimer’s type) in hypertensive patients aged 60 years and older.

Nonrandomized studies Observational studies have suggested the possible effectiveness of BP modifications by showing a reduced risk of cognitive impairment or dementia in treated hypertensive patients compared with nontreated ones. Meyer et al. [22] observed an improvement or a stabilization of the cognitive scores in subjects with multi-infarct dementia whose hypertension was controlled. Likewise, Guo et al. [23] indicate a beneficial effect of antihypertensive treatment, essentially with diuretics, in reducing the risk of dementia (RR = 0.7 [95% CI, 0.6–1.0]). In the Epidemiology of Vascular Aging (EVA) cohort [24], the risk of cognitive decline at 4 years of follow-up was 4.3 (95% CI, 2.1–8.8) in untreated hypertensive subjects versus 1.9 (95% CI, 0.8–4.4) in treated hypertensive subjects. Additionally, the 5-year follow-up of 1617 elderly black subjects indicates a significant

decrease of cognitive decline in treated hypertensive subjects compared with untreated subjects (odds ratio = 0.62 [95% CI, 0.45–0.84]) [25•].

Randomized therapeutic studies Five large, randomized, placebo-controlled trials (Table 2) on hypertension have been published and raised the issue of cognitive protection, evaluating the effects of different antihypertensive drugs. All of these studies demonstrated significant reduction in stroke incidence among treated subjects. Medical Research Council and SHEP studies (diuretics and/or β-blockers) The first studies evaluating the effects of diuretics and/or βblockers on cognition were negative. The results of the Medical Research Council’s project [26], in a subgroup of 2584 elderly subjects followed for 54 months, showed no difference in neuropsychometric tests in the treated group (diuretic or βblocker) compared with the placebo group. However, in this study, cognitive functioning was evaluated by only two tests, and it is possible that more detailed cognitive testing could reveal other cognitive domains affected by hypertension. Additionally, the 54-month follow-up period might have been too short to detect a difference between the two groups. In the Systolic Hypertension in the Elderly Program (SHEP) study [27], after 5 years of follow-up, the incidence of dementia was not statistically different in the group receiving active treatment with diuretic and/or β-blocker (1.6%) compared with the group receiving placebo (1.9%), even if it was slightly lower in the first group. However, in this study, differential dropout biased the cognitive evaluations and might have obscured the appraisal of a protective effect of treatment on the cognitive decline [28].

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Syst-Eur study (calcium-channel blocker with or without angiotensin-converting enzyme inhibitor with or without diuretic) The Vascular Dementia project included in the Systolic Hypertension in Europe (Syst-Eur) study [29••] was the first to demonstrate the reduction in the incidence of dementia by antihypertensive treatment. The study was conducted in patients who were at least 60 years of age, who had isolated systolic hypertension, and were randomized to receive the active treatment (n = 1238) or placebo (n = 1180). The active treatment was a calcium-channel blocker (nitrendipine), possibly associated with the ACE inhibitor enalapril and/or the diuretic hydrochlorothiazide. Calcium-channel antagonist was the only antihypertensive drug used in 60% of patients in the active group. The median follow-up was limited to 2 years because of early termination of the trial, owing to the demonstration of a significant benefit for stroke, the primary outcome. The incidence of dementia was reduced by 50%, from 7.7 cases in the placebo group to 3.7 cases per 1000 patientyears in the active treatment group (P = 0.05). These findings were based on 32 cases only. Nevertheless, the incidence of Alzheimer’s disease and vascular or mixed dementia was reduced. After the double-blind, placebo-controlled period, all patients withdrawing from double-blind were invited to continue or start the study antihypertensive treatment for a median period of 2 years (Syst-Eur 2) [30••]. The incidence of dementia was updated in patients treated since randomization (4 y) compared with patients actively treated since the end of the double-blind period only (2 y). There was still a significant difference in BP between the two groups: SBP/ DBP was 7.0/3.2 mm Hg higher in the former placebo group patients than in the subjects initially allocated to active treatment. The number of incident cases of dementia increased from 32 to 64. Long-active treatment compared with controls reduced the incidence of dementia by 55% from 7.4 to 3.3 cases per 1000 patient-years (P < 0.001). Both types of dementia (Alzheimer’s disease and vascular or mixed dementia) were reduced. After adjustment for sex, age, education, and entry BP, the relative hazard rate associated with the use of the calcium-channel blockers was 0.38 (95% CI, 0.23–0.64; P < 0.001). These results indicate that the treatment of 1000 patients for 5 years can prevent 20 cases of dementia (95% CI, 7–33). PROGRESS (angiotensin-converting enzyme inhibitor with or without diuretic) The randomized, placebo-controlled trial PROGRESS [31••] was run on hypertensive or normotensive patients with a previous history of stroke. Active treatment consisted of an ACE inhibitor, possibly associated with a diuretic. The primary outcome was that the incidence of strokes, dementia, and cognitive decline were secondary outcomes. After 4 years of follow-up, the risk of dementia

in the whole population was nonsignificantly reduced by 12% (95% CI, -8%–28%) in the active-treatment group, from 19 per 1000 patient-years in the placebo group (n = 3054) to 12 per 1000 patient-years in the active treatment group (n = 3051). However, a significant reduction of 34% (95% CI, 3%–55%, P = 0.03) of dementia with active treatment was observed in patients with recurrent stroke. Active treatment reduced the risk of cognitive decline by 19% in the whole population (95% CI, 4%–32%, P = 0.01), and by 45% (95% CI, 21%–61%, P = 0.001) in subjects with recurrent stroke. Combination therapy decreased BP level by 12/5 mm Hg and was more effective in reducing the risk of dementia (23%, 95% CI, 0%–41%) than monotherapy (-8%, 95% CI, -48%–21%), which decreased BP by 5/3 mm Hg. In patients without cognitive impairment at baseline (84%), active treatment significantly reduced the risk of dementia by 31% (95% CI, 6%– 49%), but there was no effect in patients with cognitive impairment at baseline (-5%, 95% CI, -42%–22%). Recent data from the Heart Outcomes Prevention Evaluation (HOPE) study [32] indicate a significant reduction, by 41% (95% CI, 6%–63%), of cognitive decline related to stroke with ACE inhibitors compared with placebo, in patients with vascular disease or diabetes and an additional risk factor. Benefits were reported particularly in terms of cognition, motor weakness, speech, and swallowing. The results were observed despite a relatively modest reduction of BP (3.8/2.8 mm Hg), but dementia was not evaluated. SCOPE study (angiotensin receptor inhibitor with or without diuretic) The Study on Cognition and Prognosis in the Elderly (SCOPE) study [33] has evaluated the effect on cognitive functions of a treatment with an angiotensin II type 1 (AT1) receptor inhibitor with or without a diuretic, in 4964 nondemented elderly hypertensive subjects, after 3.7 years of follow-up. The results indicate no significant difference between the two groups for cognitive functioning. However, the lack of benefit could probably be attributed to the small BP differences observed between the active treatment group and the control group (3.2/ 1.6 mm Hg), which drastically reduced the power to detect a difference. Although it was initially designed as a trial comparing the benefits of AT1 receptor inhibitor with placebo, most patients in the placebo group were treated with antihypertensive drugs other than the candesartan cilexitil. Therefore, the SCOPE study became almost a comparison between two active treatment groups. Moreover, cognitive evaluation was based only on the Mini Mental State Examination (MMSE). The lack of sensitivity of this test to detect a cognitive decline in nondemented subjects with higher scores (mean MMSE score = 28.5) could have biased the results toward the null effect and made the comparison between the two groups difficult.

Prevention of Dementia and Cerebroprotection with Antihypertensive Drugs • Hanon et al.

Is there a class effect for the prevention of dementia? The results of these studies suggest different mechanisms of antihypertensive drugs on the prevention of cognitive decline. For ACE inhibitors with or without diuretics, a decrease of cognitive decline (PROGRESS, HOPE) and of the stroke-related dementia incidence (PROGRESS) has been observed, but dementia without stroke was not reduced (PROGRESS). For β-blockers with or without diuretics, no effect on cognitive impairment has been observed (MRC, SHEP). For calcium-channel blockers, a marked reduction in both Alzheimer-type and vascular dementia has been demonstrated (Syst-Eur). Because none of these trials was mechanistic, it is not possible to draw any conclusion about the mechanisms of dementia prevention. However, some hypotheses can be raised. The discrepancy in the results of these trials, using different antihypertensive treatments, could suggest a class effect for the prevention of dementia. The mechanism of dementia prevention could involve a vascular protection provided by the BP reduction (PROGRESS, Syst-Eur), and a specific neuroprotection by the calcium-channel blockade (Syst-Eur). The arguments in favor of the reduction of BP for prevention of dementia are consistent in both trials. In the Syst-Eur study, the between-group differences in BP persisted after 4 years of follow-up, and in PROGRESS, monotherapy alone did not affect the stroke recurrence or the incidence of dementia, despite a BP reduction of 5/3 mm Hg. The combined therapy increased the BP reduction up to 12/5 mm Hg and significantly reduced the incidence of stroke-related dementias. Conversely, the observation that antihypertensive treatment did not protect against cognitive impairment in the SHEP and the MRC trials argues against direct prevention of dementia only by lowering BP. It could be hypothesized that calcium-channel blockers, which cross the blood-brain barrier, might have a specific neuroprotective, antidegenerative action in addition to their BP-lowering action. Indeed, the aging brain loses its ability to regulate intracellular calcium, leading to a cascade of cellular impairments and, ultimately, to cell death [34]. Therefore, it has been suggested that disruption of calcium homeostasis might be a molecular basis for the pathogenesis of Alzheimer’s disease. The neuronal toxicity of the beta amyloid and the hyperphosphorylation of tau proteins leading to the development of neurofibrillary tangles and cell death in Alzheimer’s disease could be influenced by an increased intracellular Ca2+ concentration [35]. In cultured neurons, both the direct neurotoxiciy of beta amyloid protein and the excitotoxic vulnerability were attenuated when the cells were incubated in a Ca2+-deprived medium, suggesting the involvement of Ca2+ influx in this process [36]. Recent trials have suggested that alterations in calcium homeostasis might be involved in the neurotoxic effects of apolipoprotein E4 in sporadic Alzheimer’s disease [37] or in the neu-

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ronal vulnerability of presenilin-1 mutation in familial cases [38]. In spontaneously hypertensive rats (SHR), neuronal decay could be counteracted by the calcium-channel blocker [39]. This effect could be discerned from its antihypertensive action, by using hydralazine as an equipotent antihypertensive tool, but with much less protective effect. In another experimental study, run-on, SHR-stroke prone (SP), calcium antagonists decreased the brain capillary wall damage beyond the control of BP [40], suggesting that chronic treatment of hypertensive SP rats with calciumchannel blockers could preserve microvascular integrity in the cerebral cortex. According to the evidence and hypotheses, it is, therefore, justified to speculate that the first-line drugs used in the SystEur trial (calcium-channel blockers) might have particular advantages in the preservation of cognitive functioning. In summary, the calcium-channel blockers could act as neuroprotective drugs by diminishing the massive toxic influx of calcium into the cell. However, further prospective dementia prevention trials comparing different classes of BP-lowering drugs are needed to improve the comprehension of the mechanisms of dementia prevention.

Conclusions Antihypertensive drugs have shown clinical benefit in primary and secondary prevention of stroke. BP-lowering appears as the major determinant of the benefit conferred by antihypertensive treatment. However, recent, large meta-analyses suggest an independent but modest effect of some antihypertensive drugs (calcium antagonists, ARBs, diuretics) compared with others (β-blockers or ACE inhibitors) for stroke prevention. Moreover, recent randomized, placebo-controlled trials have demonstrated that BP-lowering agents reduce the incidence of dementia in two populations: elderly patients with isolated systolic hypertension (Syst-Eur) and patients with a history of stroke or transient ischemic attack (PROGRESS). The hypothesis that calciumchannel blockers, which cross the blood-brain barrier, might exert a specific neuroprotective action and prevent various types of dementia, in particular Alzheimer’s disease, should be retested. In this context, incidence of dementia should constitute the primary outcome of future trials comparing different classes of antihypertensive drugs to better determine the best strategy to prevent dementia.

References and Recommended Reading Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance 1.

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Prevention of Dementia and Cerebroprotection with Antihypertensive Drugs • Hanon et al.

30.•• Forette F, Seux ML, Staessen JA, et al.: The prevention of dementia with antihypertensive treatment: new evidence from the Systolic Hypertension in Europe (Syst-Eur) study. Systolic Hypertension in Europe Investigators. Arch Intern Med 2002, 162:2046–2052. After the double-blind, placebo-controlled period (2 years), all patients were invited to continue or start the study antihypertensive treatment for a median period of 2 years. Long-active treatment compared with control reduced the incidence of dementia by 55% from 7.4 to 3.3 cases per 1000 patient-years (P < 0.001). These results indicate that the treatment of 1000 patients for 5 years can prevent 20 cases of dementia (95% CI, 7–33). 31.•• Tzourio C, Anderson C, Chapman N, et al.: Effects of blood pressure lowering with perindopril and indapamide therapy on dementia and cognitive decline in patients with cerebrovascular disease. PROGRESS Collaborative Group. Arch Intern Med 2003, 163:1069–1075. The randomized, placebo-controlled PROGRESS study was run on hypertensive or normotensive patients with a previous history of stroke. The results indicate, after 4 years of follow-up, a significant reduction of 34% of dementia with active treatment (ACE inhibitor ± diuretic) in patients with recurrent stroke. 32. Bosch J, Yusuf S, Pogue J, et al.: Heart outcomes prevention evaluation. Use of ramipril in preventing stroke: double blind randomised trial. HOPE Investigators. BMJ 2002, 324:699–702.

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