Safety and efficacy of low dose or no heparinization in cerebral angiography: A randomized controlled study (SELECT trial)

Abstract

INTRODUCTION:

Although systemic heparinization is a widely used technique during digital subtraction angiography (DSA), heparin is associated with a variety of complications including hemorrhage, thrombocytopenia, and hematomas. This study aimed to investigate the safety and efficacy of microdose systemic heparinization or no heparinization on cerebral angiography for cerebrovascular diseases.

MATERIALS AND METHODS:

We conducted a prospective, single-blind, randomized controlled study on patients who ought to be experienced cerebrovascular examination and underwent DSA. Participants were randomized into three groups: regular-dose systemic heparinization, microdose systemic heparinization, and no heparinization. Information on patient demographics, laboratory tests, perioperative complications, and back pain scores was collected. Safety endpoints were defined as cerebral ischemic events and local complications of the puncture site. Efficacy endpoints were defined as the recovery of the patients.

RESULTS:

A total of 180 patients were enrolled in the study and randomized into one of three groups. Patients were on average 54.4 ± 10.6 years old and 71.6% were male. Among the three groups, there was no significant difference in the incidence of postoperative thrombotic or ischemic events (regular dose vs. microdose vs. no heparinization: 1.7% vs. 3.3% vs. 1.7%, P = 0.774). The microdose or no heparinization group; however, experienced a significantly lower rate of postoperative subcutaneous hematoma (15.0% vs. 3.3% vs. 0%, P = 0.002), as well as significantly less back pain (21.7% vs. 5.0% vs. 1.7%, P < 0.001) compared to the regular-dose heparinization group.

CONCLUSIONS:

Microdose heparinization or heparin-free cerebral angiography demonstrated similar safety to conventional heparinization but significantly reduced local complications of the puncture site and accelerated recovery.

TRIAL REGISTRATION:

ClinicalTrials.gov, identifier NCT06365398.

Introduction

Cerebral angiography is a highly accurate diagnostic method for cerebrovascular diseases.[1,2,3] Heparin has become one of the most commonly used anticoagulants in angiography since Wallace et al. first recommended routine systemic heparinization in angiography.[4,5] Heparin is a mixture of polysaccharide chains of different lengths and molecular weights, with a complex composition (ungraded heparin 3–30 kDa, low molecular weight heparin 2–9 kDa).[6,7] Unfractionated heparin can active thrombin, factor Xa, and other prothrombin enzymes by binding to antithrombin through a unique pentasaccharide sequence.[8]

It is important to note that heparin has potential side effects and complications when used as an anticoagulant in angiography, such as spontaneous bleeding, heparin-induced thrombocytopenia, and heparin-induced allergic delayed-type hypersensitivity reactions.[7,9,10,11] Therefore, these should be carefully considered when deciding to use heparin in angiography. Another primary concern with systemic heparinization is postoperative recovery and nursing care.[12] Patients on systemic heparinization are recommended to stay in bed for a time to avoid the possible risk of bleeding, leading to difficulties in daily mobility and increasing the risk of postoperative complications and discomfort.

Several studies have shown that low or no heparin use in coronary angiography may be safe and effective, with a lower incidence of local complications compared to the conventional dose heparin group, without a significant increase in bleeding events.[13] However, few studies on the dose of heparin in cerebral angiography have been reported. Therefore, it is crucial to investigate the effect of low or no heparin used during cerebral angiography.

Materials and Methods

Study design

SELECT trial is a prospective randomized controlled trial, which has been conducted at a high-volume tertiary stroke center. The study is approved by ethics committees in the institutional review board and ethics committee (No. 2018-120) and has been registered at ClinicalTrials.gov with identifier number NCT06021808. Before their participation in the study, written informed consent was obtained from all patients. The trial has been carried out in compliance with the Declaration of Helsinki, Good Clinical Practice Guidelines, and other relevant laws and regulations.

Patient enrollment

This study enrolled patients who underwent cerebral angiography for cerebrovascular examination at our center between January 2018 and January 2022. Inclusion criteria were as follows: (1) aged 18–65 years; (2) patients who were suspected of ischemic cerebrovascular diseases, including vascular lesions of the carotid, middle cerebral, anterior cerebral, vertebral, basilar, and posterior cerebral arteries; (3) score of activity of daily living between 85 and 100; (4) normal coagulation function and no prior anticoagulant therapy before digital subtraction angiography (DSA); and (5) fully informed consent to participate in the study.

Exclusion criteria were defined as follows: (1) iodine allergy; (2) hepatic and/or renal insufficiency; (3) severe hypertension with poor blood pressure control; (4) hemorrhagic diseases; (5) hyperlipidemia; (6) poor glycemic control in diabetes; (7) pregnancy; (8) patients with atrial fibrillation; and (9) patients who underwent interventional treatment simultaneously. These criteria were established to ensure that the study participants were representative of the population being studied and to minimize any confounding factors that could affect the results.

Preoperative antiplatelet therapy

Patients were given either a daily dose of clopidogrel 75 mg and aspirin 100 mg before 5 days or a loading dose of clopidogrel 300 mg and aspirin 300 mg on the day before DSA for the patients who were diagnosed as transient ischemic attacks (TIAs) or ischemic stroke. We gathered all enrolled patients’ preoperative laboratory tests, such as routine blood, coagulation, and biochemistry.

Randomization and intervention

All patients enrolled were randomly divided into three groups according to the random number principle, which included the conventional systemic heparinization group, microdose systemic heparinization, and heparin-free angiography [Figure 1]. It was carried out with a 1:1:1 ratio and variable block sizes.

Figure 1.

Study design and flow chart. DSA: Digital subtraction angiography, ADL: Activity of daily living

The cerebral angiography was performed by neurosurgeons and neuroradiologists with at least 5 years of experience in endovascular treatment. The right femoral artery was punctured 1–2 cm below the inguinal ligament using a 20-gauge open-bore needle, following sterile preparation and injection of 1% lidocaine. We used 0.025″ straight guidewire covered with a 5-Fr hydrophilic sheath (RS * A50K10SQ, Terumo, Tokyo, Japan) after observing pulsatile flow. Once the sheath has been inserted, three different doses of heparin were administered according to the patient’s group assignment. Specifically, for the conventional systemic heparinization (regular-dose) group, systemic heparin was administered by intravenous injection at a dose of 83 units/kg. In the microdose systemic heparinization (microdose) group, systemic heparin was administered at a dose of 42 units/kg. Angiography was completed within 1 h, with imaging of the bilateral carotid arteries in extracranial and intracranial segments, the vertebral arteries in intracranial and extracranial segments, as well as the middle cerebral arteries, and basilar artery. For the no-heparinization group, there was no additional heparin administered through the sheath or arterial route.

Other operations were the same with standard procedure.[14] During the procedure, sheaths, catheters, and guidewires were flushed and moistened before entering the patient’s arteries, and once they were withdrawn from the body, the lumen and surface blood were flushed. At the end of the DSA, the patient’s activated clotting time value was measured, and the sheath could be removed if the activated clotting time of the patient was < 150 s.

As for operation, a standardized protocol was rigorously followed, providing doctors with clear specifications to adhere to. All operators at our center strictly adhere to this standardized protocol when conducting angiographic procedures. Furthermore, the angiographic procedures were conducted by experienced operators who worked independently. The timing of imaging sessions and the choice of instruments used during the operations exhibited minimal variation among the practitioners, ensuring consistency in the data collection process.

Nursing care after angiography

The sheath was removed in all three groups, and acupressure was applied for 15–20 min to stop bleeding. Postoperatively, patients were bandaged with pressure at the puncture site. For patients who received systemic heparinization, the limb on the operated side was immobilized for 8 h, and they were instructed not to move around until 24 h after the operation. Patients in the microdose group were immobilized for 6 h following the operation and could not move around until 12 h later. Those without heparinization were instructed not to move the limb on the operated side for 4 h, and they were not allowed to get up or move around until 6 h following DSA.

Endpoint assessment

In this study, we defined the safety endpoints as in-hospital postoperative cerebral infarction diagnosed by imaging. In addition, local complications after DSA such as bleeding at the puncture site, subcutaneous hematoma, and pseudoaneurysm diagnosed by computed tomography angiography were also included in the study. To further illustrate safety, all patients were required to conduct magnetic resonance imaging (MRI) within 48 h after cerebral angiography for examination of new-onset ischemic infarction. Cerebrovascular ischemia is highly suspected if the patient has a sudden onset of new neurological impairment, such as hemiplegia, hemiblindness, aphasia, dysphagia, sensory disturbance, or confusion, lasting more than 24 h. If a new cerebral infarction is found by diffusion-weighted MRI or computed tomography, it is defined as the occurrence of postoperative cerebral ischemic events.

The efficacy endpoints of the study were related to patient recovery within 48 h after the operation, including the numerical rating scale for back pain, the incidence of paralysis and pain of surgical limb, and the incidence of postoperative urethral catheterization.

Statistical analysis

The statistical analyses were carried out using SPSS software (version 24.0, IBM SPSS statistics) and Stata/SE software (version 14.1, Texas, USA). The distribution of all continuous variables was evaluated for normality using the Shapiro–Wilk test and reported as mean ± standard deviation or median (Q1, Q3) as appropriate. Nominal variables were compared among the three groups using the Chi-square test or Fisher’s exact test. One-way analysis of variance was performed to compare continuous variables among the three groups. A two-sided P < 0.05 was considered statistically significant. To eliminate the risk of bias due to differences in baseline characteristics, a logistic regression analysis was performed, including significant factors (P < 0.05) at baseline such as antiplatelet, oral hypoglycemic agents, age, and gender into the model. To ensure the safety and integrity of the study, data and safety monitoring board met every 6 months to monitor the study’s progress and the accumulated data. An interim efficacy analysis was planned when the sample size approached 33% and 66% of the intended size. The current study was the result of an interim analysis.

Results

Relevant clinical characteristics at baseline

A total of 320 patients with suspected ischemic cerebrovascular diseases underwent cerebral angiography consecutively. Among them, 180 eligible patients who met the 33% threshold of the initial sample size were randomly assigned into one of three treatment groups. Table 1 describes the clinical characteristics of patients in each group. The average age was 54.4 ± 10.6 years, and 71.6% of the patients were male. The incidence of hypertension, hyperlipidemia, diabetes mellitus, coronary artery disease, and peripheral vascular diseases did not differ statistically among the three groups. Most of the patients underwent cerebrovascular DSA examination because of TIA or stroke (80%, 70%, and 76.7% in the three groups, respectively) without statistical difference between the groups (P = 0.431). Other reasons for cerebrovascular DSA examination included symptoms of ischemic stroke and cerebral vascular malformations. However, there was a significant difference in perioperative antiplatelet therapy among the three groups. In addition, a higher proportion of patients in the microdose group were taking oral hypoglycemic drugs (48.3% in the microdose group compared to 21.7% in the regular group and 31.7% in the no-heparinization group, P = 0.008).

Table 1.

Clinical characteristics of patients enrolled in the study

	Systemic heparinization (regular dose), n (%)	Systemic heparinization (micro-dose), n (%)	No heparinization	P
n	60	60	60
Age, years	55.15±11.07	55.88±9.62	52.18±11.07	0.132
Sex
Female	15 (25.0)	16 (26.7)	20 (33.3)	0.563
Male	45 (75.0)	44 (73.3)	40 (66.7)
BMI (kg/m2)	25.66±3.31	26.74±3.57	25.40±2.91	0.063
TIA/stroke	48 (80.0)	42 (70.0)	46 (76.7)	0.431
Hypertension	41 (68.3)	38 (63.3)	43 (71.7)	0.617
Hyperlipidemia	20 (33.3)	9 (15.0)	15 (25.0)	0.065
Diabetes melitus	20 (33.3)	28 (46.7)	23 (38.3)	0.320
CAD	12 (20.0)	6 (10.0)	5 (8.3)	0.117
Peripheral vascular diseases	3 (5.0)	2 (3.3)	3 (5.0)	0.877
Smoke	32 (53.3)	30 (50.0)	35 (58.3)	0.654
Alcohol consumption	12 (20.0)	14 (23.3)	17 (28.3)	0.560
Family history of cerebrovascular disease	8 (13.3)	2 (3.3)	5 (8.3)	0.14
Antiplatelet
None	0	7 (11.7)	8 (13.3)	<0.001*
Single	14 (23.3)	28 (46.7)	37 (61.7)
Dual	46 (76.7)	25 (41.7)	15 (25.0)
Statin	59 (98.3)	55 (91.7)	55 (91.7)	0.212
Antihypertensive	38 (63.3)	39 (65.0)	42 (70.0)	0.724
Insulin	8 (13.3)	4 (6.7)	7 (11.7)	0.465
Oral hypoglycemic drug	13 (21.7)	29 (48.3)	19 (31.7)	0.008*

*Marked significant differences. TIA: Transient ischemic attack, CAD: Coronary artery disease

Laboratory test before and after angiography

Laboratory test results, including coagulation tests, were collected before and after angiography [Table 2]. Before angiography, the number of red blood cells (RBCs) and platelets did not differ significantly among the three groups. However, after angiography, the number of RBCs was significantly lower in the no-heparinization group compared to the regular-dose and microdose groups (4.14 ± 0.53 × 10¹²/L vs. 4.06 ± 0.36 × 10¹²/L vs. 3.89 ± 0.24 × 10¹²/L, P = 0.001). Nonetheless, there was no significant difference in hemoglobin levels in any of the three groups before and after angiography. After angiography, the thrombin time of patients in the systemic heparinization (regular- and microdose) groups was more prolonged than that of patients without heparin. However, this difference did not reach statistical significance (16.34 ± 1.12s vs. 16.12 ± 1.19s vs. 15.76 ± 1.61s, P = 0.055). Meanwhile, the fibrinogen level was significantly higher in the no-heparinization group (3.25 ± 0.74 g/L vs. 3.19 ± 0.68 g/L vs. 3.81 ± 1.53 g/L, P = 0.002). Venous thrombosis was not found in any patient, whereas there was one case of intrathecal thrombosis of the catheter in the low-dose heparin group, which was detected by careful catheter examination of the surgeons after the operation.

Table 2.

Laboratory tests of patients enrolled in the study

	Systemic heparinization (regular dose)	Systemic heparinization (microdose)	No heparinization	P
Preangiography
RBC (×1012/L)	4.52±0.58	4.47±0.39	4.56±0.67	0.631
Hemoglobin (g/L)	137.32±15.50	134.38±15.08	139.70±17.18	0.190
Platelets (×109/L)	217.61±61.82	214.91±55.75	235.43±74.36	0.169
INR	0.95±0.07	1.14±1.27	0.98±0.07	0.331
PT (s)	13.05 (12.5–13.5)	13.1 (12.7–13.5)	13.2 (12.6–13.6)	0.157
TT (s)	16.2 (15.5–16.9)	16.3 (15.5–16.8)	16.2 (15.4–16.6)	0.362
APTT (s)	39.88±17.45	37.38±4.49	36.71±3.64	0.229
Fibrinogen (g/L)	3.16±0.70	3.07±0.74	3.23±0.97	0.556
Postangiography
RBC (×1012/L)	4.14±0.53	4.06±0.36	3.89±0.24	0.001*
Hemoglobin (g/L)	135.25±16.66	135.85±16.38	140.47±17.30	0.179
Platelets (×109/L)	219.49±62.14	214.28±49.46	231.33±74.26	0.315
INR	0.98±0.07	1.15±1.30	0.98±0.12	0.359
PT (s)	13.06±0.74	13.17±0.73	13.21±0.80	0.534
TT (s)	16.34±1.12	16.12±1.19	15.76±1.61	0.055
APTT (s)	40.15±14.47	36.80±6.00	37.48±5.67	0.134
Fibrinogen (g/L)	3.25±0.74	3.19±0.68	3.81±1.53	0.002*

*Marked significant differences. RBC: Red blood cell, INR: International normalized ratio, PT: Prothrombin time, TT: Thrombin time, APTT: Activated partial thromboplastin time

Safety assessment in the three groups

To further compare the outcomes of the three groups, information on patient care and common complications during the postoperative period was collected [Table 3]. A multivariable analysis that included antiplatelet therapy, oral hypoglycemic agents, age, and gender was conducted to eliminate any risks of bias due to differences in baseline. Bleeding at the puncture site was more common in the regular-dose group of patients compared to the microdose and no-heparinization groups but did not reach statistical significance. However, patients in the no-heparinization group had significantly less bleeding at the puncture site than those in the regular-dose group (regular dose vs. no heparinization: 11.7% vs. 3.3%, P = 0.025). Moreover, patients receiving a regular dose of heparin were more likely to develop subcutaneous hematomas than the other two groups. Pseudoaneurysms during the postoperative period were only observed in patients in the regular-dose group (regular-dose vs. micro-dose vs. no-heparinization: 5.0% vs. 0% vs. 0%, P = 0.047). Among the three groups, there was no significant difference in the incidence of postoperative thrombotic or ischemic events (regular-dose vs. micro-dose vs. no-heparinization: 1.7% vs. 3.3% vs. 1.7%, P = 0.774).

Table 3.

Clinical outcomes of patients enrolled in the study

	Systemic heparinization (regular dose), n (%)	Systemic heparinization (microdose), n (%)	No heparinization, n (%)	P a	P b	P c	P d
Safety endpoints
Bleeding at the puncture site	7 (11.7)	3 (5.0)	2 (3.3)	0.089	0.103	0.025*	0.730
Subcutaneous hematoma	9 (15.0)	2 (3.3)	0	0.002*	0.043*	0.875	0.997
Pseudoaneurysm	3 (5.0)	0	0	0.047*	0.566	0.997	-
Postoperative ischemia	0	0	0	-	-	-	-
New cerebral infarction	1 (1.7)	2 (3.3)	1 (1.7)	0.774	0.566	0.997	0.430
Arterial embolism (operated limb)	0	0	0	-	-	-	-
Intracatheter thrombosis	0	0	0	-	-	-	-
Intrathecal thrombosis	0	1 (1.7)	0	0.366	-	-	-
Efficacy endpoints
NRS of back pain					-	-	-
None	23 (38.3)	29 (48.3)	44 (73.3)	<0.001*	0.511	0.997	0.003*
1~3 points	24 (40.0)	28 (46.7)	15 (25.0)		0.439	<0.001*	0.596
4~6 points	13 (21.7)	3 (5.0)	1 (1.7)		0.027*	0.035*	0.785
Paralysis of the operated limb	25 (41.7)	19 (31.7)	13 (21.7)	0.062	0.257	0.011*	0.483
Pain of the operated limb	15 (25.0)	11 (18.3)	9 (15.0)	0.370	0.377	0.177	0.683
Urination off bed	7 (11.7)	36 (60.0)	59 (98.3)	<0.001*	<0.001*	<0.001*	0.002*
Urinary catheterization	16 (26.7)	9 (15.0)	6 (3.3)	0.046*	0.12	0.184	0.511

*Marked significant differences, ^aComparison of patient outcomes between 3 groups, ^bAdjusted P value of comparison of regular- and micro-dose systemic heparinization, ^cAdjusted P value of comparison of regular-dose systemic heparinization and no heparinization, ^dAdjusted P value of comparison of micro-dose systemic heparinization and no heparinization. NRS: Numerical rating scale

Efficacy assessment in the three groups

It was also observed that as the dose of heparin was reduced, the postoperative low back pain in patients decreased significantly [Table 3]. The low proportion of patients in the microdose group (5.0%) and no-heparinization group (1.7%) reported severe low back pain (4–6 points) after DSA, whereas 21.7% of patients in the regular-dose group experienced severe low back pain. There was a significant difference in the rate of postoperative low back pain between microdose or heparin-free group and the regular-dose group (regular-dose vs. micro-dose: 21.7% vs. 5.0%, P = 0.027; regular-dose vs. no-heparinization: 21.7% vs. 1.7%, P = 0.035). Moreover, patients in the no-heparinization group had significantly less paralysis of operated limbs than those in the regular-dose group (regular-dose vs. no-heparinization: 41.7% vs. 21.7%, P = 0.011). Conversely, a significantly higher proportion of patients experienced urination on bed after the operation as the dose of heparin was reduced (regular dose vs. microdose vs. no-heparinization: 11.7% vs. 60.0% vs. 98.3%, P < 0.001). Correspondingly, the proportion of patients with urinary catheterization in the regular-dose group was significantly higher (regular dose vs. microdose vs. no-heparinization: 26.7% vs. 15.0% vs. 3.3%, P = 0.046).

Discussion

The current study was first conducted to investigate and analyze the effects of different doses of heparin on cerebral angiography. Specifically, the study aimed to compare the differences in the effects of regular dose, microdose systemic heparinization, and heparin-free cerebral angiography. Our data suggested that reducing the use of heparin did not increase the incidence of perioperative ischemic events but significantly improved patient comfort.

Cerebral angiography is considered the gold standard in the diagnosis and endovascular treatment of cerebrovascular disease.[15] Heparin is one of the most commonly used anticoagulants during angiography.[16] The anticoagulant effect of heparin reduces thrombosis during angiography, and thus, embolism-related complications, but it may also increase the risk of bleeding and lead to bleeding events.[17] Moreover, the life-threatening complication of heparin-induced thrombocytopenia can induce the use of heparin.[18,19] Recently, several previous studies on acute ischemic stroke have found that heparin free did not increase perioperative risks of complications compared with conventional doses of heparin during intervention.[20,21,22] In the coronary study, the low risk of heparin-free or low-dose heparin was also found without significant difference in the incidence of serious adverse events such as death, myocardial infarction, or acute occlusion of the target vessel compared to the conventional dose of heparin during the intervention.[23] However, few studies reported on the dose of heparin in cerebral DSA.

We verified the safety and efficacy of microdose or heparin-free cerebral angiography in this study. Regarding safety in reducing heparin during cerebral angiography, a significant concern in reducing the use of heparin is the potential risk of embolism during angiography. Although cerebral angiography procedures may increase the risk of thrombosis formation, the hemostatic and procoagulant systems in the body are in a dynamic balance with the anticoagulant and fibrinolytic systems to maintain the continuous circulation of blood under physiological conditions. Even if there is minor damage to the blood vessel, there would not be excessive bleeding or widespread thrombosis or embolism due to local hemostasis.[24,25] In addition, previous studies found that the shorter the operation time, the fewer thrombosis formations occur, and the lower the risk of perioperative complications.[26] With the maturation of technology, the operating time for cerebral angiography has significantly reduced. Therefore, this evidence supported the theory of using low dose or no heparin during DSA. Ari et al. revealed that low-dose local heparinization is safer with lower perioperative complications compared with conventional-dose heparinization in coronary angiography.[23] In cerebral DSA, our data suggested that microdose or no heparin did not increase the incidence of postoperative ischemia and new intracranial infarction compared to the regular-dose group instead of reducing the incidence of subcutaneous hematomas and pseudoaneurysms. In terms of efficacy, patients in the microdose or no-heparin group suffered significantly lower levels of low back pain compared to those in the conventional systemic heparinization group. In addition, the reduced dose of heparin has significantly reduced the postoperative resting time and enabled the patient to get out of bed and urinate early, all of which has helped the patient to recover quickly, shorten the length of hospital stay, and reduce medical costs.

Limitation

There are several limitations to our study. This is a preliminary study conducted at a single center, where we excluded high-risk patients and included a relatively low-risk controlled population. Moreover, the relatively small sample size from a single center might have introduced some bias in the comparison results, further studies with large sample sizes are warranted for verification. In addition, other types of heparin were not considered, and the safety and efficacy of using other types of heparin, such as low-molecular-weight heparin, could not be assessed. Finally, this prospective cohort study only examined changes in the perioperative period, and longer-term postoperative effects were not evaluated.

Conclusions

This study is the first to investigate the safety and efficacy of microdose or heparin-free cerebral DSA. Compared to conventional systemic heparinization, microdose systemic heparinization and heparin-free cerebral angiography did not increase perioperative ischemic events instead reducing local complications of the puncture site and accelerating patient recovery. Further validation of these findings is warranted.

Author contributions

ZW and JL contributed to the preparation of the manuscript and data collection. QQ, HT, HY, and WL contributed to the data collection. TW and FF contributed to data analysis and interpretation. LJ contributed to the experimental design and manuscript revision. All authors contributed to the article and approved the submitted version.

Ethical policy and institutional review board statement

The procedure of this study was performed in accordance with the Declaration of Helsinki and was approved by the Ethics Committee of Xuanwu Hospital, Capital Medical University (approval number: 2018-120, dated on 29 March, 2019), written informed consent was obtained from all patients.

Data availability statement

The raw data supporting the conclusions of this article will be made available by the corresponding author to any qualified researcher.

Conflicts of interest

Dr. Tao Wang is an Editorial Board member of Brain Circulation. The article was subject to the journal’s standard procedures, with peer review handled independently of this Editorial Board member and their research groups.

Funding Statement

This study was funded by the special projects of Xuanwu Hospital, Capital Medical University (XWHL-2018010).