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 Table of Contents  
ORIGINAL ARTICLE
Year : 2020  |  Volume : 27  |  Issue : 4  |  Page : 317-324

Efficacy of nifedipine versus hydralazine in the management of severe hypertension in pregnancy: A randomised controlled trial


Department of Obstetrics and Gynaecology, Alex Ekwueme Federal University Teaching Hospital, Abakaliki, Nigeria

Date of Submission23-Aug-2020
Date of Decision04-Sep-2020
Date of Acceptance12-Oct-2020
Date of Web Publication04-Nov-2020

Correspondence Address:
Dr. Johnbosco Ifunanya Nwafor
Department of Obstetrics and Gynaecology, Alex Ekwueme Federal University Teaching Hospital, Abakaliki
Nigeria
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/npmj.npmj_275_20

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  Abstract 


Background: Despite the availability of effective antihypertensive drugs, the quality of evidence regarding the best antihypertensive agent for the treatment of hypertensive emergencies in pregnancy is still poor.
Aim: The aim of this study was to compare the efficacy and side effects of oral nifedipine and intravenous hydralazine for control of blood pressure (BP) in severe hypertension in pregnancy.
Materials and Methods: An open-label, parallel, randomised, controlled trial of 78 pregnant women (≥28 weeks' gestation) with severe hypertension was conducted. Severe hypertension was defined as systolic BP of 160 mmHg or above and/or diastolic BP of 110 mmHg or above. They were randomly (1:1 ratio) administered oral nifedipine 20 mg or intravenous hydralazine 10 mg every 30 min up to 5 doses or until the target BP of 140–150 mmHg systolic and 90–100 mmHg diastolic was achieved. Intravenous labetalol was given if the primary treatment failed. The primary outcome measure was the number of doses needed to achieve targeted BP. The secondary outcome measures were the time needed to achieve desired BP, maternal adverse effects and perinatal outcome. Results: The sociodemographic characteristics did not differ between the two study groups. The average number of dosages (nifedipine; 1.4 ± 0.6 vs. hydralazine; 1.7 ± 0.5, P = 0.008) needed to control the BP was lower in the nifedipine arm. Time (min) taken to control the BP was similar between the groups (hydralazine; 43.7 ± 19.7 vs. nifedipine; 51.2 ± 18.9, P = 0.113). Adverse maternal and perinatal effects did not differ in the study groups. Conclusion: Oral nifedipine and intravenous hydralazine showed comparable efficacy in the BP control in the severe hypertensive disorders of pregnancy without significant difference in adverse maternal and perinatal outcomes. However, further studies are required to explore the role of these drugs in BP control during hypertensive emergencies in pregnancy.
ClinicalTrials.gov (Identification number: NCT04435210).

Keywords: Hydralazine, nifedipine, pregnancy, severe hypertension


How to cite this article:
Adebayo JA, Nwafor JI, Lawani LO, Esike CO, Olaleye AA, Adiele NA. Efficacy of nifedipine versus hydralazine in the management of severe hypertension in pregnancy: A randomised controlled trial. Niger Postgrad Med J 2020;27:317-24

How to cite this URL:
Adebayo JA, Nwafor JI, Lawani LO, Esike CO, Olaleye AA, Adiele NA. Efficacy of nifedipine versus hydralazine in the management of severe hypertension in pregnancy: A randomised controlled trial. Niger Postgrad Med J [serial online] 2020 [cited 2020 Nov 24];27:317-24. Available from: https://www.npmj.org/text.asp?2020/27/4/317/299916




  Introduction Top


Hypertensive disorders of pregnancy are among the major contributors to maternal morbidity and mortality in obstetric practice, accounting for approximately 63,000 maternal deaths worldwide annually.[1] It complicates about 6%–12% of pregnancies.[2]

Hypertension in pregnancy is most worrisome when it is severe (the systolic blood pressure [BP] ≥160 mmHg and/or the diastolic BP ≥ 110 mmHg) because of the associated maternal end-organ damage, with associated maternal morbidity and mortality, as well as foetal complications.[3] The end-organ damage associated with severe hypertension includes renal impairment, heart failure, liver damage, pulmonary oedema and cerebral injury.[4] Other complications include placenta abruption, pre-term delivery and increased risk of caesarean delivery.[5]

In order to reduce the maternal complications associated with severe hypertension, immediate treatment to lower the severely elevated BP is needed. However, placenta functions as a low-resistance shunt without auto-regulation, lowering the BP either too fast or too far may lead to reduced utero-placental perfusion, which is detrimental to the foetus.[6] The main aim of this treatment is to prevent cerebral haemorrhage and hypertensive encephalopathy associated with severely elevated BP and not to alter the progression of the disease.[7] Nifedipine, labetalol and hydralazine are commonly used antihypertensives for BP control in severe hypertension in pregnancy.[8] These drugs have been compared with each other in different randomised controlled trials. While it is generally accepted that the three drugs are effective in controlling severe hypertension, different trials have recommended labetalol, hydralazine or nifedipine as the first-line agent; and the others, as alternatives, depending on the prevailing circumstances and considerations of the trials.[9],[10],[11],[12]

As a result of the differences in the outcomes of randomised controlled trials on the efficacy and safety of use of these drugs in pregnancy, there is no consensus on which agent is the safest and most effective.[9] A Cochrane review concluded that the choice of antihypertensives for acute control of BP in severe hypertension in pregnancy should be based on physician's experience with the drug, side effect profile and women's preferences until a good quality evidence is available.[13] Other factors that determine antihypertensive choice are availability, cost, fetal and maternal conditions at admission.[13] This leaves the choice of drugs to the physician's discretion which is very subjective. In Nigeria, there has been no clinical data, specifying the preferred antihypertensive drug for the acute control of BP during hypertensive crises in pregnancy. Drug use in such circumstances has generally been based on the studies done in America and Europe.[12]

Intravenous hydralazine is commonly used for acute BP control in pregnancy because of its long-term established safety, efficacy, availability and cost-effectiveness.[8] However, its administration requires more equipment (such as syringes, needles and intravenous cannula) and personnel (administered usually by doctors or occasionally and nurses) than that of oral agents.[14] Its common side effects, for example, headache, nausea and vomiting are the symptoms of worsening pre-eclampsia and thereby create confusion during management.[15] Furthermore, maternal hypotension is common with parenteral hydralazine, which has been shown to be associated with higher caesarean sections, abruptio placentae and low Apgar scores (<7) at 5 min compared to labetalol and nifedipine.[15] In view of these limitations of hydralazine, there is a need to find alternative drugs with equal efficacy in controlling severe hypertension but with fewer side effects and complexity of administration. Nifedipine is cheap, easy to administer, widely available and has less tendency to cause maternal hypotension resulting in fetal compromise.[7] As a result of these qualities, it is necessary to know if it is comparable with hydralazine in terms of efficacy and safety, with the hope of recommending its use for acute BP control in pregnancy in low-resource countries. Therefore, the aim of this study was to compare the efficacy and side effects of oral nifedipine and intravenous hydralazine for acute BP control in severe hypertension in pregnancy.


  Materials and Methods Top


Ethical approval and participants' consent

Ethical approval for the study was given on 26th October, 2017 by the Research and Ethics Committee of the Alex Ekwueme Federal University Teaching Hospital (formerly known as Federal Teaching Hospital), Abakaliki (Approval reference: FETHA/REC/VOL1/2017/590). Furthermore, the study was registered with the ClinicalTrials.gov (identification number: NCT04435210) (URL: clinicaltrials.gov/ct2/show/NCT04435210). The eligible participants were informed that the participation in the study was voluntary and that they could withdraw their consent to continue in the study at any time. Participants provided written informed consent before enrolment into the study.

Study design and setting

This is a non-inferiority, open-label, parallel, randomised controlled clinical trial conducted from 13th August 2018 to 20th February 2019 at the Obstetrics and Gynaecology Division of Alex Ekwueme Federal University Teaching Hospital, Abakaliki. The hospital caters for both primary and referral cases from Ebonyi State and environs, including Enugu, Cross River, Abia and Benue states, and other parts of the country. The consultants and the resident doctors, nurses and other ancillary health workers run the clinics. Each unit in the department of obstetrics and gynaecology is manned by a group of consultants with senior registrars, registrars and house officers.

Study participants and study criteria

Pregnant women admitted with persistent severe hypertension were approached for enrolment. Severe hypertension was defined as systolic BP ≥160 mmHg and/or diastolic BP ≥110 mmHg. The inclusion criteria were maternal age 18–45 years, gestational age ≥28 weeks, maternal heart rate 60–120 beats/min and presence of a reassuring fetal heart rate. Participants were excluded from the study if they had cardiac disease, chronic hypertension or used antihypertensive drug within the 24 h of admission.

The BP was measured on admission by the researchers or research assistants using the mercury sphygmomanometer after 5 min rest by the participant. The systolic and diastolic BPs were determined by Korotkoff I and V, respectively. Severe hypertension was defined as a measurement of systolic BP ≥160 mmHg and/or diastolic BP ≥110 mmHg with or without proteinuria on two separate occasions, at least 30 min apart.

Sample size calculation

The sample size (n) was determined using formula for non-inferiority randomised controlled trial.[16]



Where, n = sample size per study arm, Z1−α= proportion of normal distribution corresponding to the required significance level (5%) which is 1.96, Z1−β= power of 90% which is 1.28, P = response rate of standard treatment group (efficacy of hydralazine = 84%)[15]δo= a clinically acceptable margin of efficacy between the study arms (set at 30%).



n = 31.4, rounded to 32 participants per group. By adding 20% attrition rate, n = 38.4 in each study arm. The sample size was calculated to be 76.8, but 78 clients were enrolled into the study.

Enrolment and randomisation

Pregnant women admitted with severe hypertension in the study facility were given information about the study and were requested to participate in the study. Participant's medical history was taken and physical examination done. Relevant investigations, including blood group and Rhesus type, complete blood count, liver function tests, renal function tests, coagulation profile and urine analysis for proteinuria, were carried out.

The eligibility screening for participation in the study was done using a trial screening and register form. Specialist registrars on duty carried out the screening as the participants presented. Those screened eligible to participate in the study were allowed to sign the consent form.

Randomisation was done using a single block of sequential numbers from 1 to 78 and the letters A and B. An independent statistician, who was not aware of what A and B represented, generated a sequence of random numbers list using the online randomisation service, Research Randomizer®. The list was given to the hospital pharmacist, who prepared the drugs and defined what letters A and B (oral nifedipine or intravenous hydralazine) represented. Standardised, sequentially numbered, identical opaque envelopes were prepared in accordance with the randomisation list. Each envelope contained either nifedipine tablets or intravenous hydralazine ampoules. Information on the content of each envelope was masked until the completion of data analysis. Participants were randomly allocated to either study Group A or B in a 1:1 ratio. The envelopes were kept in the emergency ward and were serially drawn by nurses, who were not part of the study, until the study was completed. After an eligible participant had given consent, she was assign a number by the investigator who then called a nurse to draw the corresponding envelope. The envelop was given to the attending specialist registrar, who was not part of the study, to administer the drug to the participants as shown on the allocation paper in the envelope. The researchers and the participants were not masked to the group allocation.

Interventions

Participants allocated to the Group A received oral nifedipine 20 mg statim (Dexel® Pharmaceutical Company, Lagos, Nigeria). The 20 mg dose was repeated every 30 min until the target BP (140–150/90–100 mmHg) was reached or 5 doses had been given. The drug was given to the patient to swallow in the presence of a nurse. If a patient vomited within 10 min of administration of the drug, the dose was repeated. In cases where nifedipine failed to achieve the target BP after the 5th dose, another antihypertensive drug, intravenous labetalol, was administered.

Those in Group B received 10 mg of intravenous hydralazine (PAUCO® Pharmaceuticals, Anambra State, Nigeria), diluted with 10 ml of water for injection and given over 10 min. This was repeated 30 min apart until the required BP level (140–150/90–100 mmHg) was reached or up to 5 doses were administered. In cases where BP remained uncontrolled after the 5th dose, another antihypertensive drug, intravenous labetalol, was administered.

BP was recorded every 30 min using appropriate sized cuff mercury sphygmomanometer for 24 h after reaching the desired BP and the need for re-treatment observed for. Oral antihypertensive medication was commenced by attending obstetrician 2 h after the administration of the last study drug that achieved the desired BP level. Fetal heart rate was monitored electronically during the course of the trial. The study was abandoned when maternal or foetal status were nonreassuring or the participants developed significant hypotension and resuscitation protocol commenced. The participants were managed according to the departmental protocol without interference whatsoever from the researchers and they were followed up to delivery. After study completion, a questionnaire containing information on the occurrence of side effects during the study period was completed by the participants.

Outcome measures

The primary outcome measure was the number of doses of the drug needed to achieve targeted BP. The secondary outcome measures were: the time needed to achieve target BP, recurrence and retreatment of severe hypertension within 24 h and after 24 h of achieving BP control, maternal adverse effects and perinatal outcome.

Data collection and statistical analysis

Predesigned data extraction form was used for the data collection. Data were entered into Microsoft excel and imported into the SPSS version 22 (IBM Corp, Armonk, NY, USA) for analysis using per protocol principle. Normal distribution of continuous data was assessed using one-sample Kolmogorov–Smirnov test. Baseline characteristics of the participants were presented using the descriptive statistics. Chi-square or Fisher's exact tests were used to compare the categorical variables, whereas independent sample t-test or Mann–Whitney U-test was used for the comparison of continuous variables. Relative risk (RR) with 95% confidence intervals (CIs) was calculated for dichotomous data. Statistical significance was set at P < 0.05.


  Results Top


In this study, 78 clients were randomised to receive either oral nifedipine (n = 39) or intravenous hydralazine (n = 39). Adverse events did not occur during the study. [Figure 1] shows the participants' flow through the study.
Figure 1:CONSORT flowchart showing the flow of the participants through the study

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In the nifedipine arm, three participants withdrew consent to participate after enrolment. Also, two clients withdrew consent to continue the study after receiving intervention. Therefore, 34 participants were included data analysis.

For those allocated to the hydralazine arm, 35 participants completed the study and were analysed. Four women withdrew their consent to continue the study.

[Table 1] shows the baseline characteristics of the study groups. The study groups did not differ in their mean age (years) (P = 0.853), mean parity (P = 0.719) and mean gestational age on admission (weeks) (P = 0.549).
Table 1: Sociodemographic characteristics of the participants

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[Table 2] shows the BP on admission and BP changes after interventions. The mean systolic (P = 0.091) and diastolic (P = 0.192) BP on admission did not differ in both groups. Following the administration of 1st dose, the reduction in the mean systolic (P = 0.256) and diastolic (P = 0.528) BP did not differ between the groups. However, nifedipine significantly reduced both the systolic (P = 0.001) and diastolic (P = 0.029) BP more than hydralazine following the 2nd dose of the drugs. [Figure 2] is a graph showing the cumulative percentage of participants who achieved desired BP over time. Although acute control of BP was faster in the hydralazine arm (mean time [min]; 43.7 ± 19.7) when compared with nifedipine (mean time [min]; 51.2 ± 18.9), this difference was not significant (P = 0.113). The average number of dosages (nifedipine; 1.4 ± 0.6 vs. hydralazine; 1.7 ± 0.5, P = 0.008) required to achieve BP control was significantly different in both arms. None of the participants in either group had treatment failure, and therefore, intravenous labetalol was not used in the study.
Table 2: Blood pressure on admission and changes following treatment

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Figure 2: Cumulative percentage of the participants who achieved target blood pressure over time

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Recurrence and retreatment of severe hypertension within 24 h and after 24 h of achieving BP control are shown in [Table 3]. The risk of recurrence and retreatment of severe hypertension within 24 h of BP control was significantly lower in the nifedipine arm when compared with hydralazine group (nifedipine; 7 vs. hydralazine; 17, RR: 0.4, 95% CI: 0.2–0.9, P = 0.017). After 24 h of achieving BP control, the risk of recurrence and retreatment of severe hypertension did not differ between the study groups (nifedipine; 11 vs. hydralazine; 14, RR: 0.8, 95% CI: 0.4–1.5, P = 0.527).
Table 3: Comparison of recurrence and retreatment of severe hypertension after achieving blood pressure control

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[Table 4] shows the mode of delivery and maternal adverse effects. There were no significant difference in the rate of induction of labor (P = 0.543) and the mode of delivery (P = 0.676). The participants in the nifedipine group were four times more likely to have headache when compared to those in the hydralazine arm (nifedipine; 8 vs. hydralazine; 2, RR: 4.1, 95% CI: 0.9–18.0, P = 0.045). The risk of experiencing flushing was significantly lower in the nifedipine group when compared to hydralazine group (nifedipine; 4 vs. hydralazine; 17, RR: 0.2, 95% CI: 0.09–0.6, P = 0.001). Although participants in the nifedipine group were about three times more likely to experience nausea when compared with those in the hydralazine group, this difference was not significant (nifedipine; 5 vs. hydralazine; 2, RR: 2.6, 95% CI: 0.5–12.4, P = 0.259). There were no hypotension, vomiting, dizziness or maternal death in both study groups.
Table 4: Mode of delivery and maternal adverse effects

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Perinatal outcomes in the study groups are shown in [Table 5]. Fetal heart rate abnormalities (P = 0.614), mean birth weight (kg) (P = 0.081), Apgar scores <7 at 5th min (P = 0.673), stillbirths (P = 0.673) and admission into neonatal intensive care unit (P = 0.734) did not differ in the study groups.
Table 5: Perinatal outcome

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  Discussion Top


Severe hypertension is usually treated with rapidly-acting antihypertensive agents, which are usually given parenterally, and therefore, require expertise in constitution and administration.[14] This expertise may not be readily available in some health facilities in developing countries where low-skilled health workers attend to pregnant women. Although these patients may need to be referred to centres better equipped to manage the conditions, administering medications to reduce BP before such referral may be life-saving. Therefore, the availability of orally-administered and equally effective antihypertensive drug with minimal side effects will be of advantage in such circumstances. Nifedipine, an orally-administered antihypertensive drug, has been evaluated in studies on the control of severe hypertension in pregnancy. This study compared the efficacy and side effects of nifedipine with that of hydralazine in managing severe hypertension in pregnancy.

Adequate BP control was achieved in both study arms. This is due to the rapid action and high efficacy of both drugs in controlling severe hypertension. Hydralazine, being a direct vasodilator, acts rapidly and directly on vascular smooth muscles (more on arteries than veins), thus reducing peripheral resistance, resulting in lowering BP.[15] Nifedipine, on the other hand, being a calcium channel blocker, ultimately results in vasodilatation, thus causing a reduction in peripheral vascular resistance as obtained for hydralazine.[15] This finding was supported by several randomised control trials comparing nifedipine and hydralazine with each other or with labetalol.[5],[17],[18],[19]

From this study, nifedipine achieved BP control less rapidly than hydralazine, although the difference was not significant. This may be because they both achieved peripheral vasodilatation despite the different routes of administration. Magee et al. observed similar finding in a meta-analysis comparing hydralazine, nifedipine and labetalol.[12] Firoz et al. similarly found no difference in the time taken to achieve target BP when either drug was administered to patients.[14] This was contrary to the findings by Rezaei et al. which showed that oral nifedipine achieved BP reduction faster than intravenous hydralazine.[5] This is probably because nifedipine is absorbed quicker and is more efficacious than hydralazine.

Significantly lower doses of nifedipine than hydralazine were needed to control BP. This showed that nifedipine is more efficacious than hydralazine for acute BP control in severe hypertension in pregnancy. This may be due to its mechanism of action as a calcium-channel blocker, with a more sustained effect on vascular smooth muscles than hydralazine. Hydralazine is a direct vasodilator with fast but short duration of action, thus necessitating repeat doses at short intervals. This was similar to the findings by Rezaei et al.[5] and Aali and Nejad[18] in different randomized control trials as well as the findings by Sridharan et al.[19] in a meta-analysis of several randomized controlled trials involving hydralazine, labetalol and nifedipine.

Following administration of second doses of either drug (in those who required second doses), BP control was significantly better for the nifedipine group than for the hydralazine group. This might be due to the fact that the second doses of nifedipine were administered when the first doses were reaching the peak of their activity, thus culminating in synergistic activity with the first doses. This is unlike hydralazine whose activities have almost waned completely by the time of administration of the second doses. This agree with the findings by Aali and Nejad in a randomised controlled trial involving nifedipine and hydralazine.[18] Firoz et al. in a meta-analysis of several randomised controlled trials of nifedipine against hydralazine, however, found that relatively similar doses of nifedipine and hydralazine were needed to achieve BP control.[14] This might be due to the fact that sublingual nifedipine, with more rapid onset of action and shorter half-life, was used in the studies analyzed.

The need for retreatment of severe hypertension within 24 h of admission was significantly higher among patients who received hydralazine. This possibly resulted from the shorter duration of action of hydralazine compared to nifedipine. Similar findings have been reported in two separate meta-analyses on the pharmacological effects of these drugs.[12],[14] Firoz et al., did not find any difference in the need for repeat doses of either drug, as sublingual nifedipine with the rapid onset of action and shorter half-life than orally administered dose was used, thereby requiring repeat doses as much as hydralazine.[14]

There was no major maternal adverse effect of either drug in this study. The minor adverse effects observed in the study included flushing, nausea and headache. While flushing was statistically significantly higher in patients who received hydralazine, headache was significantly more in patients who received nifedipine. There was no maternal mortality among the participants. The caesarean section and labour induction rates did not differ in both study groups. These findings were similar to those by Firoz et al., Martins-Costa et al. and Aali and Nejad.[14],[17],[18] Fetal/neonatal outcomes (fetal heart rate irregularities, Apgar scores and neonatal intensive care admission) were not different between the study arms.

The strength of this study was its randomized controlled study design. Non-blinding of the researchers and the study participants to group allocation was one of the study's limitations. Applying blinding was not feasible due to the nature of the drugs administered to the participants. Another limitation of the study was that it was conducted in a single centre, which limited the generalisation of the study findings. To improve the generalisation of the study outcomes, a multicenter trial would have been conducted. We recommend that a multicenter study should be done in resource-limited settings to corroborate or refute these findings and to compare cost-effectiveness in both study arms.


  Conclusion Top


Both oral nifedipine and intravenous hydralazine are equally efficacious for acute control of BP in severe hypertension in pregnancy without adverse maternal and perinatal effects. However, nifedipine is cheap and orally administered when compared to hydralazine. This makes nifedipine very useful in low-income countries where many of these patients are under the care of low cadre of medical personnel.

Acknowledgements

The authors are grateful to resident doctors and nurses of department of obstetrics and gynaecology for their assistance during the study.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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Rezaei Z, Sharbaf FR, Pourmojieb M, Youefzadeh-Fard Y, Motevalian M, Khazaeipour Z, et al. Comparison of the efficacy of nifedipine and hydralazine in hypertensive crisis in pregnancy. Acta Med Iran 2011;49:701-6.  Back to cited text no. 5
    
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Firoz T, Magee LA, MacDonell K, Payne BA, Gordon R, Vidler M, et al. Community level interventions for pre-eclampsia (CLIP) Working Group. Oral antihypertensive therapy for severe hypertension in pregnancy and postpartum: A systematic review. BJOG 2014;121:1210-122.  Back to cited text no. 14
    
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Aali BS, Nejad SS. Nifedipine or hydralazine as a first-line agent to control hypertension in severe preeclampsia. Acta Obstet Gynecol Scand 2002;81:25-30.  Back to cited text no. 18
    
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