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 Table of Contents  
META ANALYSIS
Year : 2017  |  Volume : 130  |  Issue : 13  |  Page : 1586-1594

Account for Clinical Heterogeneity in Assessment of Catheter-based Renal Denervation among Resistant Hypertension Patients: Subgroup Meta-analysis


1 Department of Nephrology, Kidney Research Institute, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
2 Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, Michigan 48109, USA
3 Department of Nephrology, Kidney Research Institute, West China Hospital, Sichuan University; West China Biostatistics and Cost-benefit Analysis Center of Sichuan University, Chengdu, Sichuan 610041, China
4 Department of Burn and Plastic Surgery, Chengdu Second People's Hospital, Chengdu, Sichuan 610017, China
5 Department of Biostatistics, University of Michigan School of Public Health; Kidney Epidemiology and Cost Center, University of Michigan, Ann Arbor, Michigan 48109, USA

Date of Submission18-Feb-2017
Date of Web Publication16-Jun-2017

Correspondence Address:
Ping Fu
Department of Nephrology, Kidney Research Institute, West China Hospital, Sichuan University, Chengdu, Sichuan 610041; West China Biostatistics and Cost-benefit analysis center of Sichuan University, Chengdu, Sichuan 610041
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0366-6999.208238

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  Abstract 


Background: Catheter-based renal denervation (RDN) is a novel treatment for resistant hypertension (RH). A recent meta-analysis reported that RDN did not significantly reduce blood pressure (BP) based on the pooled effects with mild to severe heterogeneity. The aim of the present study was to identify and reduce clinical sources of heterogeneity and reassess the safety and efficacy of RDN within the identified homogeneous subpopulations.
Methods: This was a meta-analysis of 9 randomized clinical trials (RCTs) among patients with RH up to June 2016. Sensitivity analyses and subgroup analyses were extensively conducted by baseline systolic blood pressure (SBP) level, antihypertensive medication change rates, and coronary heart disease (CHD).
Results: In all patients with RH, no statistical differences were found in mortality, severe cardiovascular events rate, and changes in 24-h SBP and office SBP at 6 and 12 months. However, subgroup analyses showed significant differences between the RDN and control groups. In the subpopulations with baseline 24-h SBP ≥155 mmHg (1 mmHg = 0.133 kPa) and the infrequently changed medication, the use of RDN resulted in a significant reduction in 24-h SBP level at 6 months (P = 0.100 and P= 0.009, respectively). Subgrouping RCTs with a higher prevalent CHD in control showed that the control treatment was significantly better than RDN in office SBP reduction at 6 months (P < 0.001).
Conclusions: In all patients with RH, the catheter-based RDN is not more effective in lowering ambulatory or office BP than an optimized antihypertensive drug treatment at 6 and 12 months. However, among RH patients with higher baseline SBP, RDN might be more effective in reducing SBP.

Keywords: Antihypertensive Treatment; Hypertension; Randomized Controlled Trials; Renal Denervation; Subgroup Meta-analysis


How to cite this article:
Chen XH, Kim S, Zeng XX, Chen ZB, Cui TL, Hu ZX, Li Y, Fu P. Account for Clinical Heterogeneity in Assessment of Catheter-based Renal Denervation among Resistant Hypertension Patients: Subgroup Meta-analysis. Chin Med J 2017;130:1586-94

How to cite this URL:
Chen XH, Kim S, Zeng XX, Chen ZB, Cui TL, Hu ZX, Li Y, Fu P. Account for Clinical Heterogeneity in Assessment of Catheter-based Renal Denervation among Resistant Hypertension Patients: Subgroup Meta-analysis. Chin Med J [serial online] 2017 [cited 2017 Nov 22];130:1586-94. Available from: http://www.cmj.org/text.asp?2017/130/13/1586/208238

Xiao.Han Chen and Sehee Kim contributed equally to this work.





  Introduction Top


Resistant hypertension (RH), defined as blood pressure (BP) that remains above goal in spite of the concurrent use of 3 antihypertensive agents, can be a leading risk factor for cardiovascular disease and chronic kidney disease.[1] Recently, catheter-based renal denervation (RDN) has ignited expectations for the treatment of RH. However, evidence-based study results for the effect of RDN in lowering BP in patients with RH have been controversial. The first randomized clinical trial (RCT), SYMPLICITY HTN-2,[2] demonstrated significant reductions in both systolic and diastolic BP in patients with RH. However, the initial excitement turned into skepticism when a large RCT, SYMPLICITY HTN-3,[3] using a sham procedure as placebo, failed to achieve its primary efficacy. More recently, RCTs on RDN in RH have also shown discrepant results.[4],[5],[6],[7],[8],[9],[10] A recent meta-analysis based on 7 RCTs in patients with RH reported that RDN with the SYMPLICITY systems did not significantly reduce BP compared to antihypertensive drugs at 6 months after the intervention.[11] Their conclusions, however, were drawn with the pooled effects with much heterogeneity. The aim of our study was to seek possible sources of clinical heterogeneity, identify homogeneous subpopulations, and reconduct a systematic review for the safety and efficacy assessment of RDN by those subpopulations. In addition to the seven trials reviewed by Fadl Elmula et al.,[11] the present study further includes two more recent RCTs and evaluates both 6- and 12-month efficacy endpoints.[4],[5]


  Methods Top


Data sources

Publications in English or Chinese were identified by searching PubMed, Medline, Embase, and the Cochrane Central Register of Controlled Trials available up to June 2016. Search terms included “hypertension” and “blood pressure” and “denervation” and “RDN”. A more detailed search strategy is described in Supplementary text 1[Additional file 1], and a flow diagram for study selection is shown in [Figure 1].
Figure 1: Flow diagram for the study selection. RCTs :Randomized clinical trials.

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Study selection

We included all RCTs on human subjects that assessed the effect of RDN as the additional treatment to current antihypertensive drugs in use, and compared it with the continuation of antihypertensive drug use with or without a sham procedure. Use of the sham procedure in control group was not required for inclusion. We excluded single arm studies, meeting abstracts, letters, and case reports.

The inclusion criteria for eligible studies included (1) adult patients (>18 years old) with RH, defined as office BP >140/90 mmHg (1 mmHg = 0.133 kPa) or 24-h systolic BP (24-h SBP) >130 mmHg or 24-h daytime SBP >135 mmHg, in spite of the concurrent use of 3 antihypertensive agents of different classes at optimal dose amounts, including a diuretic;[1] (2) patients who underwent RDN using percutaneous catheters and radiofrequency probes; and (3) BP records measured as ambulatory BP or/and office BP at baseline and 6-month follow-up, or BP change from baseline to 6-month follow-up.

Outcomes

The primary outcomes were 24-h SBP and office SBP changes from baseline to 6-month and 12-month follow-ups, severe cardiovascular events rate, and all-cause mortality. The severe cardiovascular events included myocardial infarction, new-onset heart failure, stroke, hypertension crisis, angina needing a coronary stent, embolic event resulting in end-organ damage, and hospitalization for atrial fibrillation. The secondary outcomes were changes in 24-h diastolic BP (24-h DBP), office diastolic blood pressure (office DBP) at 6-month follow-up, and adverse events of RDN.

Data extraction, synthesis, and quality assessment

The following was extracted: the name of the first author, publication year, region, study design, total participants, number of participants receiving RDN, number of participants in the control group, trial inclusion and exclusion criteria, type of catheter used, method of BP measurement, maximal length of follow-up, office systolic and diastolic BP, 24-h SBP and DBP, daytime ambulatory SBP at baseline, 6-, 12-, 36-month follow-ups in both groups, and procedural complications. The methodological quality of RCTs was assessed independently by two reviewers using Jadad Scale.[12] The Jadad Scale is an assessment score based on the degree of participant randomization, application of the blinding method, and report of study withdrawals and dropouts. A threshold of ≥4 points is regarded as a high-quality study.[12] The risk of bias was assessed independently by two reviewers using the Cochrane Collaboration's tool. This tool evaluates each study in the following six specific domains: adequate random sequence generation, allocation sequence concealment, blinding of subjects/outcome assessors, incomplete outcome data, free of selective outcome reporting, and free of other bias. Every domain was scored to be high risk of bias, low risk of bias, or unclear. The overall assessment of each RCT was graded as “low risk” (if all the domains were assessed as low risk of bias), “unclear” (if there exists at least one domain unclear), or “high risk” otherwise.[13] With no disagreement between the reviewers in the list of studies included in the meta-analysis and their quality assessment, a third reviewer was waived.

Statistical analysis

We used a random effects model to combine the studies given significant heterogeneity in the treatment effects. The heterogeneity was statistically evaluated by the I2 statistic, where values of 0–24.9%, 25–49.9%, 50–74.9%, and 75–100% indicated no, mild, moderate, and severe heterogeneity, respectively.[14],[15] Extensive subgroup analyses were carried out to minimize possible sources of clinical heterogeneity by the (1) baseline SBP level, (2) frequency of antihypertensive medication changes, (3) race, and (4) coronary heart disease (CHD) prevalence. For survival outcomes, relative risk (RR) was used to assess the effect of treatment, while mean difference (MD) was used for continuous outcomes, along with the corresponding 95% confidence interval (CI). Two-tailed P< 0.05 was considered statistically significant. All statistical analyses were carried out using Review Manager 5.3 software (Nordic Cochrane Center, Copenhagen, Denmark).


  Results Top


Study characteristics

We identified 9 RCTs that met the inclusion criteria with a total of 1068 patients [Table 1]. All had similar inclusion criteria, except for one trial [6] [Supplementary Table 1] [Additional file 9] that enrolled mild RH patients who had 24-h SBP/DBP level just above 140/78 mmHg at baseline. In two trials, only ambulatory BP measurements [5],[6] were available, while both office and ambulatory BP were collected in the seven remaining trials. The maximum length of follow-up was at least 6 months in all studies, and up to 12 months in three trials [16],[17],[18] and 36 months in one trial.[19] There were five other trials [2],[3],[5],[6],[9] designed not to alter antihypertensive medication during the follow-up. In contrast, the baseline antihypertensive medication was allowed to be modified in four trials.[4],[7],[8],[10] Three trials [6],[7],[10] included only white population and one trial [9] included only Asian population. Regarding the patients given the antihypertensive drugs at baseline and 6-month follow-up, their characteristics are described in [Supplementary Table 2] [Additional file 10]. Only one trial [7] had reported that more antihypertensive drugs were used after 6 months in the control group, on average, than the RDN group (+0.3 drugs). Regarding the baseline BP severity, there were three studies [2],[3],[9] with baseline office SBP ≥175 mmHg, over 10–25 mmHg higher than that of other trials. Baseline level of 24-h SBP was not available in SYMPLICITY HTN-2.[2] The other two studies [3],[9] with baseline 24-h SBP ≥155 mmHg were about 7–24 mmHg higher than that of other trials. As shown in [Table 2], the Cochrane Collaboration's assessment suggested that most studies were at a high risk due to lack of blinding. However, the methodological quality of all included studies was rated as “high” [i.e., Jadad scale was ≥5 in [Table 2].
Table 1: Study and patient characteristics at baseline

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Table 2: Assessment of the methodological quality (Jadad scale) and risk of bias (Cochrane collection) of included studies

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Whole group analysis of 24-h systolic blood pressure and office systolic blood pressure at 6-month follow-up

We meta-analyzed BP outcomes from a total of nine RCTs. Summary of analysis results of the nine individual studies is provided in [Table 3]. The pooled effect of RDN, as the difference from the baseline BP level between RDN and control groups, was MD = −1.1 mmHg [95% CI: −4.7–2.5 mmHg; P= 0.55; [Figure 2] for 24-h SBP, and MD = −2.55 mmHg [95% CI: −12.90–7.80 mmHg; P= 0.63; [Figure 3] for office SBP. Given much heterogeneity in 24-h SBP (I2 = 67%) and office SBP (I2 = 90%), this study further conducted subgroup analyses and sensitivity analyses.
Table 3: Change in office and ambulatory BP (mmHg)

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Figure 2: Forest plot for mean difference in 24-h SBP at 6-month follow-up. SBP: Systolic blood pressure; CI: Confidence interval; RDN: Renal denervation.

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Figure 3: Forest plot for mean difference in office SBP at 6-month follow-up. SBP: Systolic blood pressure; CI: Confidence interval; office SBP: Office systolic blood pressure; RDN: Renal denervation.

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Subgroup analysis of 24-h systolic blood pressure at 6-month follow-up

By systolic blood pressure at baseline

Subgroup analysis results by baseline 24-h SBP level (≥155 mmHg or <155 mmHg) are shown in [Figure 4]. In the subpopulation with baseline 24-h SBP ≥155 mmHg, the pooled effect of RDN was marginally significant (MD = −2.92 mmHg; 95% CI: −6.36–0.53 mmHg; P= 0.10). There was no significant difference between two groups in the subpopulation with baseline 24-h SBP <155 mmHg (P = 0.61).
Figure 4: Forest plot for mean difference in 24-h SBP at 6-month follow-up by baseline SBP subgroup. 24-h SBP ≥155 mmHg (1 mmHg = 0.133 kPa) at baseline: an average 24 h blood pressure level at baseline >155 mmHg; 24-h SBP <155 mmHg at baseline: An average 24 h blood pressure level at baseline <155 mmHg; SBP: Systolic blood pressure; CI: Confidence interval; RDN: Renal denervation.

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By frequency of medication changes

Among the nine trials, three trials [2],[6],[9] with the medication change rate below 25% were categorized as the “infrequent medication change” group. The remaining six trials [3],[4],[5],[7],[8],[10] categorized as the “frequent medication change” group. In the infrequent medication change subgroup, the use of RDN resulted in a significant reduction in 24-h SBP level at 6 months [MD = −4.88; 95% CI: −8.54–−1.22 mmHg; P= 0.009; [Figure 5]. Whereas, in the frequent medication change subgroup, the difference between RDN and control was not statistically significant [MD = 1.41; 95% CI: –3.61–6.44 mmHg; P= 0.58; [Figure 5].
Figure 5: Forest plot for mean difference in 24-h SBP at 6-month follow-up by medication change rate subgroup. Frequent medication change: the medication change rate >25%; Infrequent medication change: The medication change rate <25%; SBP: Systolic blood pressure; CI: Confidence interval; RDN: Renal denervation.

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By race

In both Asian [9] and white [6],[7],[10] subpopulations, the effect of RDN was not significantly different in lowering 24-h SBP [I2 = 66% in white subgroup, [Supplementary Figure 1] [Additional file 2].

Improvement in heterogeneity

For 24-h SBP and with all 9 trials included, I2 = 67%. By restricting to trials with an average baseline SBP ≥155 mmHg,[3],[9] the heterogeneity reduced to I2 = 17%. The restriction to the trials with medication change rate <25%[2],[6],[9] resulted in no heterogeneity (I2 = 0%). By restricting the trials with white subpopulation,[6],[7],[10] the heterogeneity remained similar at 66%.

Subgroup analysis of office systolic blood pressure at 6-month follow-up

By systolic blood pressure at baseline

Subgroup analysis results by baseline office SBP level (≥175 mmHg or <175 mmHg) are shown in [Supplementary Figure 2] [Additional file 3]. There was no statistical difference in changes at 6-month follow-up in both subgroups.

By frequency of medication changes

In the infrequent medication change subgroup, the use of RDN resulted in a marginally significant reduction in office SBP level at 6 months [MD = −20.28; 95% CI: −42.12–1.55 mmHg; P= 0.07; [Supplementary Figure 3] [Additional file 4]. Whereas, in the frequent medication change subgroup, RDN did not significantly reduce office SBP level [MD = 3.47; 95% CI: −3.82–10.77 mmHg; P= 0.35; [Supplementary Figure 3].

By prevalence of coronary heart disease

Six trials [2],[3],[4],[7],[8],[10] reported the percentage of patients with CHD [Table 1]. From these reports, we have noticed that the prevalence of CHD varied considerably not only between the reviewed trials but also within the trial. As an example of the between-trial comparison, 60% of RDH patients (and 47% of control) had CHD in the SYMPLICITY-FLEX trial, whereas 6% of RDN patients (and 7% of control) had CHD in the Prague-15 trial. The OSLO trial was a good example of the within-trial comparison, where the trial was conducted under the most unbalanced study design with respect to the CHD prevalence (i.e., 11% of RDN and 60% of control patients had CHD). Therefore, we viewed the prevalent CHD as a potential source of clinical heterogeneity in trials and have identified three homogeneous subpopulation by (1) balanced CHD prevalence between RDN and control,[3],[7] (2) a higher prevalent CHD in RDN,[2],[8] and (3) a higher prevalent CHD in control.[4],[10]

In the subgroup of the higher prevalent CHD in control, the control treatment was significantly better than RDN in office SBP reduction at 6 months [MD = 16.59; 95% CI: 6.94–26.25 mmHg; P< 0.001; [Supplementary Figure 4] [Additional file 5]. In contrast, in the other subgroups by the higher CHD prevalence in RDN and the balanced CHD prevalence subgroups, there was no significant difference between the two therapies [Supplementary Figure 4].

Improvement in heterogeneity

For office SBP, when all seven trials [2],[3],[4],[7],[8],[9],[10] were included, there was severe heterogeneity (I2 = 90%). Even if we restrict the pooled analysis to trials with an average baseline SBP ≥175 mmHg [2],[3],[9] or trials with medication change rate <25%,[2],[9] the heterogeneity level still remained high (I2 = 94% and I2 = 88%). However, when the prevalence of CHD was considered, the heterogeneity reduced to 0% in the subgroup defined as a higher CHD prevalence in controls, and I2 = 9% in the subgroup defined as a balanced CHD prevalence.

Whole group analysis of office systolic blood pressure at 12-month follow-up

The office SBP, at 12-month follow-up, was available for the pooled analysis of two trials.[16],[19] There was no significant difference between the two groups [MD = 0.69 mmHg; 95% CI: −4.2–5.58; P= 0.78; [Figure 6], and no heterogeneity of the pooled effect (I2 = 0%; P= 0.37).
Figure 6: Forest plot for mean difference in office SBP at 12-month follow-up. CI: Confidence interval; SBP: Systolic blood pressure; RDN: Renal denervation.

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Whole group analysis of 24-h diastolic blood pressure and office diastolic blood pressure at 6-month follow-up

Regarding DBP outcomes, this analysis showed that the BP decrease was not statistically significant [MD = 0.14; 95% CI: −1.72–2.00 mmHg; P= 0.88; [Supplementary Figure 5] [Additional file 6] in 24-h DBP as well as office DBP [MD = −2.63; 95% CI: −6.70–1.44 mmHg; P= 0.21; [Supplementary Figure 6] [Additional file 7].

Sensitivity analysis

By excluding one trial at a time, we assessed sensitivity of meta-analysis. Although the approach reduced the level of heterogeneity to some extent in some cases, in most cases, it could not resolve the issue. Summary of sensitivity analysis is provided in [Supplementary Table 3[Additional file 11]],[Supplementary Table 4[Additional file 12]],[Supplementary Table 5[Additional file 13]],[Supplementary Table 6][Additional file 14].

Severe cardiovascular events and mortality

In five RCTs,[2],[3],[5],[7],[10] severe cardiovascular events were reported. The conclusions from these trials were consistent with our meta-analysis in that there was no statistical difference in the risk of severe cardiovascular events rate between two groups [RR = 1.43; 95% CI: 0.84–2.45; P= 0.19; I2 = 0; [Supplementary Figure 7] [Additional file 8]. Only one trial studied mortality as outcome measure,[3] where there was no significant difference in the risk of mortality rate between two groups (RR = 0.97; 95% CI: 0.09–10.61; P= 0.98).

Other adverse effect

In general, adverse events rarely occurred, while a pseudoaneurysm was the most frequent adverse event among them [Supplementary Table 7][Additional file 15].


  Discussion Top


Elevated sympathetic nervous system activity is crucial for the development and progression of systemic hypertension, by regulating renin release, tubular sodium reabsorption, and renal blood flow.[21] Afferent sympathetic nerves from the kidney contribute to regulation of whole-body sympathetic activity.[22] An early clinical evaluation has demonstrated that catheter-based RDN could lower BP in patients with RH by decreasing renal norepinephrine spillover, halving of renin activity, increasing renal plasma flow, and reducing central sympathetic drive.[23] However, RCTs designed to confirm the early clinical evaluation results have shown controversial results. Moreover, the results of Fadl Elmula et al.'s meta-analysis based on 7 trials revealed highly significant heterogeneity.[11] The present study, based on 9 RCTs, attempted to deal with the heterogeneity and find main reasons for the discrepant results among RCTs by conducting extensive subgroup and sensitivity analyses.

We considered both 24-h SBP and office SBP as the primary outcomes. Pooling all nine RCTs available, there was no difference between RDN and control in lowering SBP. However, an interesting finding is that, in the subpopulation with baseline 24-h SBP ≥155 mmHg, the effect of RDN was significantly better than control. Given that the patients with a higher BP tend to have an over-active sympathetic nerve system,[24] this finding might be explained by that the catheter-based RDN works better in decrease the sympathetic nerve activity than usual antihypertensive drugs. The role of the catheter-based RDN has been proven that it blocks the pathway of sympathetic nerve activation through a reduction whole-body norepinephrine spillover, which results in a sustained BP reduction.[23] In contrast, antihypertensive drugs that directly block the sympathetic activity directly were rarely used due to obvious adverse effects. This mechanism may also explain the nonsignificant RDN effect in mild RH (daytime SBP between 135 and 149 mmHg or daytime ambulatory DBP between 90 and 94 mmHg).[6] Another interesting finding is that, with patients changing their antihypertensive medications less frequently, this meta-analysis showed a significantly better effect on lowering 24-h SBP by the 6-month follow-up. We suspected that the reason for inconsistent conclusions by the individual nine studies (and the extremely high heterogeneity in the pooled analysis) might be because antihypertensive drugs were too frequently changes in most studies. Conducting the subgroup analysis with low medication change rates resolved this issue.

As demographic discrepancy in the study populations might contribute to inconsistent findings, we conducted subgroup analysis by race. Our results were consistent: no significant BP reduction at 6-month follow-up has been found in both Asian and white subpopulations.

There are a few limitations in this study. First, in subgroup analyses, the sample size was relatively small. However, significant differences were detected, which had not been observed in the pooled analyses with much larger sample sizes due to the severe heterogeneity. Second, due to lack of the longer follow-up details available, effects within 6 and 12 months after the intervention have been assessed. It is worth assessing a long-term effect (longer than 1-year follow-up), given that, in SYMPLICITY HTN-3, the 12-month office SBP change was greater than that observed at 6 months in RDN group. Further studies based on randomized controlled trials are needed to assess a successful ablation of RDN, while completely solving these issues and accounting for various BP levels and the sympathetic neural activity at the same time. This analysis focused on the catheter-based RDN. There are a few more RCTs still ongoing, which aim to evaluate the effect of RDN on decreasing BP [Supplementary Table 8] [Additional file 16]. The results of the clinical studies will affect the future of RDN.

Supplementary information is linked to the online version of the paper on the Chinese Medical Journal website.

Financial support and sponsorship

This work was supported by a grant from the National Nature Science Foundation of China (No. 81570668).

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]
 
 
    Tables

  [Table 1], [Table 2], [Table 3]



 

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