Effects of Deep Venous Thrombosis Treatments on Early and Long-term Quality of Life: Medical Therapy vs. Systemic Thrombolysis vs. Pharmacomechanical Thrombolysis

Abstract

Objectives

The present study aimed to compare the effects of medical therapy (MT), systemic thrombolysis (ST), and pharmacomechanical thrombolysis (PMT) methods used in our clinic for the treatment of deep venous thrombosis (DVT) on symptom reduction, the incidence of post-thrombotic syndrome (PTS) development, and quality of life.

Methods

Data from160 patients diagnosed with acute DVT between January 2012 and May 2021 and treated and followed up in our clinic were retrospectively analyzed. The patients were divided into three groups according to treatment method. The patients who received MT treatment were defined as Group 1, anticoagulant treatment after ST as Group 2, and anticoagulant treatment after PMT as Group 3. The patients were called to the outpatient clinic, informed consent was obtained, EuroQol-5D-3 L (EQ-5D-3 L) scoring and Villalta scoring were performed, and anamnesis was taken.

Results

A total of 160 patients were included, with 71 (44.4%) patients in Group 1, 45 (28.1%) in Group 2, and 44 (27.5%) in Group 3. The mean age was 48.9 ± 14.9 years for Group 1, 42.2 ± 10.8 for Group 2, and 29.0 ± 7.2 for Group 3. When the time to return to normal life and the EQ-5D-3 L score index were compared, the differences between Groups 1 and 2 and between Groups 1 and 3 were statistically significant (P = .000 and P = .000, respectively). However, the differences between Groups 2 and 3 were statistically insignificant (P = .213 andp = .074, respectively). When Villalta scores and EQ Visual Analogue Scale (EQ-VAS) scores were compared between groups, the difference between all groups was statistically significant (P = .000).

Conclusions

The medical treatment alone was observed to be insufficient in terms of symptomatic improvement, development of PTS, quality of life, and long-term complications. When the ST and PMT groups were compared, it was determined that PMT treatment was more advantageous in terms of EQ-VAS score and PTS development, although there was no statistical difference regarding complications, such as return to normal life and long-term quality of life, the incidence of recurrent DVT development, and pulmonary thromboembolism incidence.

Keywords

deep venous thrombosis pharmachomechanical cathater base

Introduction

Deep venous thrombosis (DVT) is a common disease that can be life threatening in the event of pulmonary embolism (PE) and has adverse effects on quality of life due to recurrent DVT and post-thrombotic syndrome (PTS) in the long term, despite appropriate treatment. The conventional treatment for DVT is long-term oral anticoagulation therapy, in addition to heparin. Recently, however, low molecular weight heparin (DMWH) has become increasingly preferred and has started to be considered a standard treatment.¹ Different treatment options, such as pharmacological thrombolysis, surgical thrombectomy, percutaneous mechanical thrombectomy, venous angioplasty, and stenting, have also been used, and some of these methods have gained great popularity. The main goals in DVT treatment can be listed as relief of symptoms, prevention of PE, and prevention of recurrent DVT and PTS² Anticoagulation treatment alone inhibits the spread of thrombus formation, relieves symptoms, and reduces the development of PE. However, since it does not provide fibrinolysis, it cannot eliminate the existing venous obstruction in the early period. It is thought that this may cause PTS in the long term.^3,4 Therefore, eliminating thrombosis in the early period would reduce the incidence of PTS⁵ Thus, treatment methods using pharmacological and mechanical thrombolysis have begun to be used more and more.

The present study aimed to compare the effects of medical therapy (MT), systemic thrombolysis (ST), and pharmacomechanical thrombolysis (PMT) methods used in our clinic for the treatment of DVT on symptom reduction, the incidence of PTS development, and quality of life.

Materials and Methods

Patient Population

With the approval of the ethics committee of the institution (20.12.21- 2021/22-273), data from 160 patients diagnosed with acute DVT between January 2012 and May 2021 and treated and followed up in our clinic were retrospectively analyzed. The demographic data of the patients and the treatment methods used were evaluated by examining the patients’ anamnesis forms, clinical follow-up notes, and Doppler ultrasound reports performed before and after the treatment. Acute DVT was defined as DVT detected on Doppler ultrasound (CDUS) with symptoms of swelling, pain, or bruising in the leg for less than 10 days. “Proximal DVT″was defined as the DVTs occurring in the popliteal vein and proximal. DVTs distal to the popliteal vein were determined as distal DVTs. The patients were called to the outpatient clinic, informed consents were obtained, EuroQol-5D-3 L scorings and Villalta scorings were made, and anamneses were taken.

Treatment groups

The treatment method to be used in our clinic is made according to the surgeon’s preference. In our clinic, MT is preferred in case of contraindication to ST, in elderly patients, in patients with comorbidity, and in patients with distal DVT. Thrombolytic therapy is not administered in cases with a recent stroke, intracranial bleeding, gastrointestinal bleeding, major surgery within the last three months, coagulopathy, or central nervous system malignancy. The patients were divided into three groups according to the treatment methods they received. The patients who received MT treatment were defined as Group 1, those who received anticoagulant treatment after ST as Group 2, and those who received anticoagulant treatment after PMT as Group 3.

In our clinic, for medical treatment, patients are hospitalized in the early period of acute DVT, DMWH is initiated. When they are discharged a new oral anticoagulant (NOAC) (rivaroxaban, apixaban, edoxaban) is started for oral anticoagulant treatment.

For ST, patients are hospitalized, intravenous access is opened, preferably in the leg that develops DVT, and alteplase is initiated at a dose of 50 mg/day for 24 hours. Then, control CDUS is performed, and recanalization is checked. Treatment is continued for one more day in patients who do not develop recanalization in control CDUS. Then, alteplase is stopped, DMWH is started, and NOAC (rivaroxaban, apixaban, edoxaban) is initiated for oral anticoagulant therapy when being discharged.

For PMT, patients are taken to the angiography unit, a vena cava filter (Incaven; Invamed, Ankara, Turkey) is inserted under local anesthesia, and thrombolysis is completed using a pharmacomechanical thrombolysis device (Mantis Curved; Invamed, Ankara, Turkey). A dose of 50 mg alteplase is administered through the catheter to the DVT developing vein during the procedure, guided by fluoroscopy. After recanalization is achieved, alteplase treatment is continued for 1day through the catheter at 50 mg/day. Filter washing is performed using 2500 IU heparin twice a day. Then, alteplase is stopped, DMWH is started, and NOAC (rivaroxaban, apixaban, edoxaban) is initiated for oral anticoagulant therapy when being discharged.

Complete blood count control is performed four times a day in patients receiving alteplase. Control CDUS is applied on the 10^th day after discharge, and then monthly CDUS controls are performed. Treatment is continued for 6 months if DVT is not detected.

Endpoints

To evaluate the speed of symptomatic improvement, our study questioned the time required to return to normal life. For the working patient group, our study considered the time to start a normal life as the time that elapsed from the moment of diagnosis to the date when swelling and pain in the leg resolved and the patient resumed working. For the non-working patient population, the time from the diagnosis to when swelling and pain in the leg subsided and they started to do their daily activities and housework was considered the time to start a normal life.

Villalta scoring was used to evaluate the severity of PTS⁶ Patient-related symptoms, such as pain, cramps, heaviness, numbness, and pruritis, and clinician-rated symptoms, such as edema, skin induration, hyperpigmentation, pain during calf compression, venous ectasia, and redness, were scored as mild (0), moderate,¹ and severe.²

The EuroQol-5D-3 L scoring system and EQ Visual Analogue Scale (EQ-VAS) were used to evaluate the quality of life.⁷ The patients completed the questionnaire forms during the outpatient clinic examination. In this questionnaire, patients’ mobility, self-care, usual activities, pain/discomfort, and anxiety/depression statuses were questioned, and their quality of life was scored as problem-free, moderately problematic, or severely problematic, according to the response. An index value between 0 and 1 was calculated after proportioning to the general population. The value “1” indicates an excellent quality of life, and as it approaches “0,” the quality of life decreases. In the EQ-VAS system, patients are asked to indicate their current health status between 0 and 100. Since the value sets of EuroQol-5D-3 L are not available for Turkey, we selected value sets for Germany to calculate index values.

Statistical Analysis

Data were evaluated using IBM SPSS version 22. One-way ANOVA and post hoc Tukey analysis compared number, percentage, mean, and more than two variables. Independent groups were evaluated using the t-test, Mann-Whitney U. The statistical significance was considered as P < .05.

Results

Demographics

One hundred sixty patients were included in the study. There were 71 (44.4%) patients in Group 1, 45 (28.1%) in Group 2, and 44 (27.5%) in Group 3. The mean follow-up period of the patients was 81 ± 16.44 months, being 84 ± 18.64 months in Group 1, 78.3 ± 17.1 months in Group 2, and 80.74 ± 13.27 months in Group 3.

The mean age of the patients was 41.6 ± 14.56 years, and the mean weight was 77.2 ± 13.4 kg. One hundred eight (67.5%) of the patients were male. While 104 (65%) patients had proximal DVT, the remaining 56 (35%) patients had distal DVT.

The mean age of Group 1 was 48.9 ± 14.9, Group 2 was 42.2 ± 10.8, and Group 3 was 29.0 ± 7.2. There was a statistically significant difference in age between Groups 1 and 2, Groups 1 and 3, and Groups 2 and 3 (P = .032, P = .012, and P = .016, respectively). When the gender distribution within the groups was examined, the rate of male patients in Group 1 was lower than in Group 2 (P = .05). There was no statistically significant difference between the groups regarding body weight (P = .244, P = .132, and P = .186, respectively).

The proximal DVT rate in Group 1 was lower than in the other two groups (P = .04 and P = .005, respectively). The rate of proximal DVT was 49.3% in Group 1, 62.2% in Group 2, and 93.2% in Group 3 (Table 1).

Table 1.

Demography.

						All Patients	P
			Group 1	Group 2	Group 3	All Patients	Group1-2	Group 1-3	Group 2-3
			Mean, SD	Mean, SD	Mean, SD	Mean, SD	P Values
Age (mean,years)			48,94 ± 14,901	42,29 ± 10,818	29,05 ± 7,23	41,6 ± 14,56	0,032	0,012	0,016
Weight (mean kilograms)			80,13 ± 13,25	77,51 ± 13,64	72,2 ± 12,16	77,2 ± 13,4	0,244	0,132	0,186
			n, %	n, %	n, %	n, %
Gender	Male		45 (63,3)	31 (75,5)	32 (72,7)	108 (67,5)	0,050	0,142	0,458
Gender	Female		26 (36,7)	14 (24,5)	12 (27,3)	52 (32,5)	0,062	0,156	0,245
Smoking			39 (54,9)	29 (64,4)	26 (59,1)	94 (58,8)	0,206	0,404	0,382
Canser			1 (1,4)	0	0	1 (0,6)	0,612	0,617	-
CHF			9 (12,7)	0	0	9 (5,6)	0,010	0,011	-
COPD			10 (14,1)	0	0	10 (6,3)	0,006	0,006	-
Obesity			20 (28,2)	14 (31,1)	6 (13,6)	40 (25,0)	0,446	0,055	0,042
Orthopedic surgery			4 (5,6)	3 (6,7)	0	7 (4,4)	0,557	0,141	0,125
Other major surgery			3 (4,2)	0	0	3 (1,9)	0,225	0,231	-
Postpartum DVT			4 (5,6)	0	0	4 (2,5)	0,136	0,141	-
İmmobilisation (hospital stay)			1 (1,4)	0	0	1 (0,6)	0,612	0,617	-
Oral contraseptive Usage			0	3 6,7)	1 (2,3)	4 (2,5)	0,056	0,383	0,317
Venous ulceration			1 (1,4)	0	0	1 (0,6)	0,025	0,025	-
Side		Right	42 (59,2)	29 (64,4)	26 (59,1)	97 (60,6)	0,238	0,682	0,156
Side		Left	29 (40,8)	16 (35,6)	18 (40,9)	63 (39,4)	0,142	0,586	0,250
Level		Proximal	35 (49,3)	28 (62,2)	41 (93,2)	104 (65,0)	0,040	0,005	0,106
Level		Distal	36 (50,7)	17 (37,8)	3 (6,8)	56 (35,0)	0,078	0,048	0,036

CHF: Congestive Heart Failure COPD; Chronic Obstructive Pulmonary Disease, DVT: Deep venous thrombosis.

Time to Symptomatic Recovery, PTS, and Quality of Life Data

A one-way ANOVA test was used to compare more than two variables. Our study determined the mean time to return to normal life as 11.52 ± 3.906 days in Group 1, 5.27 ± 2.178 days in Group 2, and 4.23 ± 1.054 days in Group 3. The difference between groups was statistically significant (F = 108.673, P = .000).

The mean EQ-5D-3 L score index was .839 ± .2 in Group 1, .982 ± .04 in Group 2, and .997 ± .01 in Group 3. It was observed that the difference between the groups was statistically significant (F = 12.114, P = .00).

The mean EQ-VAS score was 68.02 ± 19.90 in Group 1, 78.33 ± 10.44 in Group 2, and 88.52 ± 7.59 in Group 3. The difference between the groups was statistically significant (F = 26.029, P = .000).

The mean Villalta score was 7.73 ± 3.45 in Group 1, 5,60 ± 1,97 in Group 2, and 3.77 ± 1.89 in Group 3, and the difference between the groups was statistically significant (F = 29.749, P = .000) (Table 2).

Table 2.

Comparison of groups according to endpoints.

		n	Mean	SD	SE	Min	Max	Test and P Value
EQ-5D-3 L index	Group 1	71	0,8386	0,28543	0,03387	0,06	1,00	F: 12.114, p:0.00
	Group 2	45	0,9825	0,04524	0,00674	0,80	1,00
	Group 3	44	0,9972	0,01721	0,00263	0,89	1,00
VAS score	Group 1	71	68,0282	19,90116	2,36183	25,00	95,00	F: 26.029, p: .000
	Group 2	45	78,3333	10,44466	1,55700	50,00	95,00
	Group 3	44	88,5227	7,59280	1,14466	70,00	100,00
Villalta score	Group 1	71	7,73	3456	0,410	4	18	F: 29.749, p: .000
	Group 2	45	5,60	1947	0,290	2	10
	Group 3	44	3,77	1891	0,285	1	11
Time to return to normal life (days)	Group 1	71	11,52	3906	0,464	7	30	F:108, 673, p:0.000
	Group 2	45	5,27	2178	0,325	2	14
	Group 3	44	4,23	1054	0,159	2	7

VAS: Visual analogue scale.

A post hoc Tukey test was used after the ANOVA test to determine which group caused statistical differences between the groups. When the groups were compared, the differences between Groups 1 and 2 and Groups 1 and 3 were statistically significant in the further analysis of the Tukey test when the time to return to normal life and the EQ-5D-3 L score index were compared. However, the difference between Groups 2 and 3 was statistically insignificant (P = .213 and P = .074, respectively). When the Villalta and EQ-VAS scores were compared, the differences between all groups were statistically significant (Table 3).

Table 3.

Post-Hoc Tukey test results after one-way variance analysis (ANOVA).

	Group 1-2			Group 1-3			Group 2-3
	P Values	Mean Difference	SE	P Values	Mean Difference	SE	P Values	Mean Difference	SE
EQ-5D-3 L index	0,000	1420*	0,315	0,000	2192*	0,317	0,074	0,772	0,350
VAS score	0,001	−10,30516*	2,84509	0,000	−20,49456*	2,86481	0,004	−10,18939*	3,16566
Villalta score	0,000	2132*	0,517	0,000	3960*	0,521	0,005	1827*	0,575
Time to return to normal life (days)	0,000	6254*	0,553	0,000	7294*	0,557	0,213	1039	0,616

VAS: Visual analogue scale.

Complications

The length of hospital stay was 4 ± 2.4 days in Group 1, 4 ± 1.7 days in Group 2, and 4 ± 2.7 days in Group 3, and no statistically significant difference was observed between the groups (P = .71). While readmission was observed in 2 (2.8%) patients in Group 1, it was not observed in other groups. The number of recurrent DVTs was observed in eight (11.3%) patients in Group 1, one(2.2%) in Group 2, and one (2.3%) patient in Group 3. A higher incidence of recurrent DVT was observed in Group 1 compared to the other groups, and the differences between the groups were statistically significant (P = .022 and P = .028, respectively). Pulmonary embolism was determined in only one (1.4%) patient in Group 1. The rates for the use of compression stockings (P = .045 and P = .042, respectively) and anticoagulant use (P = .036 and P = .030, respectively) were higher in Group 1 than in the other groups (Table 4).

Table 4.

Complications in long-term follow-up.

Complications				All	P Value
Complications	Group1	Group 2	Group 3	All	Group1-2	Group 1-3	Gorup 2-3
	n, %	n, %	n, %	n, %
Recurrent DVT	8 (11,3)	1 (2,2)	1 (2,3)	10 (6,3)	0,022	0,028	0,432
Anticoagulants usage	63 (88,7)	32 (71,1)	31(70,5)	126 (78,8)	0,036	0,030	0,342
Mechanical compression stockings usage	42 (59,2)	19 (42,2)	25 (56,8)	86 (53,8)	0,045	0,042	0,402
Pulmonary embolism	1 (1,4)	0	0	1 (0,6)	0,025	0,025	—

DVT: Deep venous thrombosis.

Discussion

The primary goals in DVT treatment can be specified as relief of symptoms, prevention of PE, and prevention of recurrent DVT and PTS² Anticoagulation alone prevents the spread of thrombus formation, relieves symptoms, and reduces the development of PE. However, since it does not provide fibrinolysis, anticoagulants cannot eliminate the existing venous obstruction in the early period. It is thought that this may result in PTS in the long term.^3,4 Therefore, eliminating thrombosis in the early period would reduce the incidence of PTS⁵ MT, ST, and PMT methods are still widely used in DVT treatment. Our study aimed to examine the effects of these treatment methods on early symptomatic improvement, complication development, long-term development of PTS, and quality of life. As a result, it was observed that MT alone was insufficient in both the early and long term. Thrombolytic therapy and PMT were determined to be equally effective in terms of symptomatic recovery rate, EQ-5D-3 L score index, the incidence of recurrent DVT development, and PE. However, ST was not as effective as PMT on the long-term development of PTS and EQ-VAS score.

Symptomatic Improvement

If medical treatment alone is administered, thrombus regression and venous recanalization become insufficient.^8,9 To evaluate the speed of symptomatic improvement, our study questioned the time required to return to normal life. This period was the longest in the group receiving medical treatment (11.5 ± 3.9 days). We believe that MT alone is insufficient in terms of symptomatic recovery rate. This period was 5.2 ± 2.1 days in the ST group and 4.2 ± 1.05 days in the PMT group. However, the mean age of the MT group was 48.9 ± 14.9 years, the ST group was 42.2 ± 10.8 years, and the PMT group was 29.0 ± 7.2 years. We think that the difference between the mean age of the groups may also affect the rate of symptomatic improvement.

PTE and Recurrent DVT

PTE occurs in approximately 50% of DVT patients, and only a minority of patients are symptomatic^10-12. It has been reported that thrombolytic therapy reduces the incidence of PTE.^13,14 The incidence of PTE during catheter-directed thrombolysis (CDT) has been stated to be approximately 1%, and the incidence of fatal PTE to be between 0% and .2%^15-17. In our study, while PTE was observed in 1 (1.4%) patient in the medical treatment group, there was no PTE in the other groups.

Recurrent DVT is another factor that develops after DVT and reduces quality of life. It has been reported that recurrent DVT develops in approximately 2% to 25% of patients despite MT^18-21. Lichtenberg et al. demonstrated that recurrent DVT was higher in the PMT group in their meta-analysis, in which they compared the groups using PMT with ST or CDT.²² In our study the incidence of recurrent DVT was higher in the medical treatment group than in the other groups. However, there was no difference in the incidence of recurrent DVT between the ST and PMT groups.

PTS Incidence

The development of PTS is one of the long-term complications of DVT. It is thought that PTS develops in approximately 20% to 50% of DVT patients.^23-25 In the case of recurrent DVT, the risk of PTS development increases.^23,26 Discussions about whether early thrombectomy with MT or ST reduces the incidence of PTS development continue.^27,28 In their meta-analysis, Xing et al. indicated that catheter-based treatments do not reduce the risk of PTS development.²⁹ On the other hand, Vedantham et al. examined 692 patients in their randomized clinical trial (ATTRACT trial) and reported that catheter-based treatments did not reduce the incidence of PTS development.³⁰ Again, Park et al. determined no statistical difference between PMT and CDT groups regarding the Villalta score.³¹ A multicenter randomized clinical study performed by Notten et al., in which 184 patients were examined, revealed that CDT alone could not be superior to medical treatment in terms of the incidence of PTS development.²⁸ In contrast, Enden et al. stated that CDT is superior to medical treatment in PTS development.²⁵ Nevertheless, Du et al. demonstrated in another meta-analysis that CDT was superior to medical treatment alone in terms of the long-term development of PTS. In their study comparing PMT and CDT, Huang et al. reported that PMT was superior to CDT in PTS development.³² In their meta-analysis, Lichtenberg et al. concluded that the incidence of moderate and advanced PTS was higher in the PMT group than in the systemic thrombolysis or CDT group.²² However, our study revealed that the highest Villalta score was observed in the group that received MT. It was also observed that the mean Villalta score of the ST group was higher than that of the PMT group. Again, we believe that the mean age of the groups may affect the development of PTS.

Quality of Life

PTS is the leading factor affecting quality of life (QoL) after DVT.^33-36 Furthermore, factors such as age, comorbidity, and obesity affect QoL.^33-36 There are various studies in the literature on QoL after DVT. Huang et al. used venous-disease-specific QoL scoring to evaluate the quality of life in a study in which PMT and CDT groups were compared. Their study determined that the group receiving PMT had better long-term QoL scores.³⁷ The ATTRACT study concluded that catheter-based interventions were not superior to MT in terms of QoL.³⁰ Comerota et al., on the other hand, reported that PMT was superior to MT in terms of improving QoL in their study where they used the Venous Insufficiency Epidemiological and Economic Study Quality of Life scoring system in patients with iliofemoral DVT.³⁸ Again, Kahn et al. revealed that PMT is superior to MT in improving QoL.³⁹ Our study observed that PMT and ST were superior to MT in terms of the EQ-5D-3 L score index and the EQ-VAS score. However, although there was no statistically significant difference between the PMT and ST groups in terms of the EQ-5D-3 L score index, we observed that the EQ-VAS scores of the PMT group were higher. But we believe that the mean age of the groups may have affected these findings.

Since endovenous stenting has been used in DVT patients in our clinic in recent years, there is no patient who has undergone endovenous stenting in our patient population. However, endovenous stenting has also started to gain popularity in the treatment of DVT. It may be preferred in patients with acute illiofemoral DVT, in cases of residual thrombosis despite ST. In chronic DVT patients, it may be preferred in case of venous stenosis or presence of severe PTS symptoms.⁴⁰ It is reported that better results are obtained when used with PMT compared to PMT alone, and it also does not increase the incidence of adverse events.^41-43

Limitations

The most critical limitation of our study is that it was a single-center retrospective study. The low number of patients makes it difficult to compare the three groups, and we believe that retrospective or randomized clinical studies using larger patient populations are needed. Additionally, the fact that demographic data cannot be similar between the groups would impact the study results, especially on quality of life scores. Incidence of some complications such as PE was low in our patient population. The incidence of distal DVT was higher in the MT group. This makes it difficult to compare groups, especially in terms of quality of life and PTS development.

Conclusions

Medical treatment alone was observed to be insufficient in terms of symptomatic improvements, development of PTS, QoL, and long-term complications. When the ST and PMT groups were compared, it was determined that PMT treatment was more advantageous in terms of EQ-VAS score and PTS development, although there was no statistical difference in terms of complications such as return to normal life, long-term quality of life, the incidence of recurrent DVT development, and PTE incidence.

Footnotes

Author Contributions

ZY: Conception or design of the work, Drafting the work, Final approval of the version to be published, any part of the work are appropriately investigated and resolved. MAK: Revising the work, Final approval of the version to be published, any part of the work are appropriately investigated and resolved. TÖ: Revising the work, Final approval of the version to be published, any part of the work are appropriately investigated and resolved. HKL: Conception or design of the work, Revising the work, Final approval of the version to be published, any part of the work are appropriately investigated and resolved. MSD: Revising the work, Final approval of the version to be published, any part of the work are appropriately investigated and resolved. HIÇD: Acquisition and analysis, Final approval of the version to be published, any part of the work are appropriately investigated and resolved. SE: Drafting the work, Final approval of the version to be published, any part of the work are appropriately investigated and resolved. ÖD: Revising the work, Final approval of the version to be published, any part of the work are appropriately investigated and resolved

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

Servet Ergün

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