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Original Article

J Pharmacopuncture 2021; 24(4): 196-205

Published online December 31, 2021 https://doi.org/10.3831/KPI.2021.24.4.196

Copyright © The Korean Pharmacopuncture Institute.

The Effect of Comfrey on Enoxaparin-Induced Bruise in Patients with Acute Coronary Syndrome: A Randomised Clinical Trial

Zahra Bagheri1 , Azim Azizi2 , Khodayar Oshvandi1 , Younes Mohammadi3 , Amir Larki-Harchegani4,5*

1Department of Medical Surgical Nursing, School of Nursing and Midwifery, Hamadan University of Medical Sciences, Hamadan, Iran
2Chronic Diseases (Home Care) Research Center, Malayer School of Nursing, Hamadan University of Medical Sciences, Hamadan, Iran
3Department of Epidemiology, School of Public Health, Hamadan University of Medical Sciences, Hamadan, Iran
4Department of Pharmacology and Toxicology, School of Pharmacy, Hamadan University of Medical Sciences, Hamadan, Iran
5Medicinal Plants and Natural Products Research Center, Hamadan University of Medical Sciences, Hamadan, Iran

Correspondence to:Amir Larki-Harchegani
Department of Pharmacology and Toxicology, School of Pharmacy, Hamadan University of Medical Sciences, Hamadan, Iran
Tel: +98-81-3838-1591
E-mail: dr.amir.larki@gmail.com

Received: July 29, 2021; Revised: October 24, 2021; Accepted: November 26, 2021

This is an Open-Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Objectives: Bruising is an important side effect of enoxaparin injection. Comfrey (Symphytum officinale) is used to treat different types of wounds, bone fractures, and bruising in traditional medicine in many countries for centuries. This study aimed to determine the effects of the Comfrey ointment on the bruise size and color following enoxaparin injection.
Methods: This double-blind randomized clinical trial was conducted on 80 patients with acute coronary syndrome (ACS). The participants were randomly divided into two groups of 40, namely Comfrey and Placebo. Changes in bruise size and color in both groups were assessed daily before and after the intervention.
Results: The Comfrey and Placebo groups were homogeneous in demographic and clinical variables. A downward trend was observed in the bruise size in both groups throughout the study. However, the bruise size was smaller in the Comfrey group than the Placebo group on day 2-5 of the intervention. Moreover, there was a significant difference in bruise color between the groups, with a shorter healing course in the Comfrey group.
Conclusion: The Comfrey ointment accelerated the healing process of enoxaparin injection-induced bruising in patients with ACS. It is recommended as a safe and simple approach for these patients.

Keywords: bruise, enoxaparin, comfrey, acute coronary syndrome, patient, ointment

INTRODUCTION

Acute Coronary Syndrome (ACS) is a general term for the signs and symptoms of myocardial ischemia [1]. Patients with ACS take many drugs, specifically enoxaparin, to control symptoms and complications [2]. Enoxaparin is a low molecular weight anticoagulant administered as a subcutaneous injection [3].

Despite many advantages, enoxaparin has side effects such as pain, anemia, hematoma, thrombocytopenia, and injection site bruising [4, 5]. Bruising is defined as skin color change in a surface area of equal or larger than 2 mm2 [6]. This side effect is the result of bleeding from damaged vessels into the subcutaneous tissue. The bruise maximizes over 48 hours and then slowly starts resolving after 60 to 72 hours. However, complete healing typically occurs between two to three weeks [7, 8].

One of the most important responsibilities of a nurse towards patients is to prevent injury and discomfort and maintain safety [9]. Nevertheless, despite following standard patient care protocols, there are different degrees of discomfort and bruising with injections [10]. Enoxaparin injection-induced bruising occurs in 53.6% of patients with ACS [11]. A bruise can also disrupt physical and psychological comfort, impair mental self-image, and reduce self-confidence [12].

Nurses must reduce the fear and concern of patients regarding nursing interventions and care delivery. As a result, nurses should look for new methods to reduce such issues through professional development and research [13]. A literature review showed that different methods can be used to reduce the bruise size at the injection site, such as using cold and warm compresses [10], changing the needle length and diameter [14], cooling the injection site [15], and changing the injection angle [16] and speed [13]. Almost all of these methods can prevent bruising. According to databases such as Google Scholar and PubMed, there are no studies examining bruise size reduction and bruise healing in patients with ACS.

Comfrey (Symphytum officinale) is a medicinal plant used in traditional medicine to cure bruises. As a member of the Boraginaceae family, Comfrey is native to Europe and tropical regions in Asia. It has anti-inflammatory and pain-relieving effects, stimulates granulation, accelerates fractures, tissue regeneration, wound healing, and bruise, and improves rheumatic disorders, muscular pain, and sport-induced sprain [17-23]. The beneficial effects of this plant on cellular metabolism and cell survival of human skin fibroblasts have been proven [21]. Researchers attributed the medicinal effects of Comfrey to three major compounds, namely phenolic acids (rosmarinic acid, caffeic acid, and salicylic acid), amine (allantoin), glycopeptides, and mucilage polysaccharides [24]. Allantoins stimulate cellular metabolism and growth in subcutaneous tissue as well as bone, tendon, and ligament. On the other hand, rosmarinic acid has antioxidant and anti-inflammatory effects and inhibits the synthesis of prostaglandins [25].

Given the inevitable side effects of drugs such as enoxaparin injection-induced bruises in some patients [10, 13], the anti-bruise and anti-inflammatory effects of Comfrey in traditional medicine [26], and the lack of a comprehensive scientific study into the effect of Comfrey on bruises, this study aimed to determine the effect of Comfrey on the size and color of enoxaparin injection-induced bruises in patients with ACS.

MATERIALS AND METHODS

1. Study design

This randomized clinical trial was conducted on two homogeneous groups in the CCU and Heart Department of Farshchian Heart Hospital of Hamadan from July 2020 to July 2021.

97 participants enrolled in the study. 13 patients were excluded from the study due to non-compliance with the inclusion criteria, and the remaining 84 participants were randomly assigned to the Comfrey or Placebo groups, in a parallel-group scheme (1:1 ratio) using a permuted block randomization with a block size of four. Two participants in each group refused to continue with the study. 40 patients in each group were present until the end of the study (Fig. 1).

Figure 1. Flow diagram of the patients in the Comfrey and Placebo groups throughout the different phases of the trial.

2. Participants and study setting

The research sample included eligible patients with ACS who received enoxaparin (1 mg/kg with a maximum dose of 90 mg twice a day). The inclusion criteria were bruising (at least 1 cm2) caused by enoxaparin injection, age group of 30-85 years, no food and drug allergy, no coagulation problem, consciousness, not taking warfarin, heparin, and anti-inflammatory drugs (Glucocorticosteroids and NSAIDs), the injection site on the abdomen, and bruising less than 12 hours old. The exclusion criteria were allergy to employed ointments, early discharge, the occurrence of acute coagulation disorders, repeated injection into the bruising area, enoxaparin withdrawal, and not taking the drug twice a day.

3. Ethics statements

All procedures in this study were done in agreement with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration. The research was approved by the Ethics Committee of Hamadan University of Medical Sciences (IR.UMSHA.REC.1397.471). The study objectives were explained to the patients and all patients signed a written informed consent form to declare their agreement to participate in this study. This trial was registered in the Iranian Registry of Clinical Trials (http://www.irct.ir; IRCT2015062822956N1).

4. Sample size

Following a previously published trial (Jeffrey et al., 2015), the equation for calculating the sample size in randomized clinical trials was used in the present study, where type one error (α) was 0.05, type two errors (β) was 0.10 (power = 0.90), the difference in mean (d) of bruise size was 10 mm, and the standard deviation (SD) was 10.

Assuming the probable loss to follow-up of 20% in each group, a total of 40 participants was considered as the final sample size for each group [27].

5. Randomization and blinding

The eligible participants were assigned to the Comfrey and placebo groups using permuted block randomization technique with a block size of four and an equal allocation ratio. Microsoft Excel 2016 software (Microsoft Corp., Redmond, WA, USA) was used to create random sequences of block sizes. To blind the study, the Comfrey and placebo groups were denoted by letters A and B, respectively. The researcher, patients, and statisticians were blinded to the groups until the end of the data analysis stage.

6. Plant materials

The plant (Symphytum officinale) was purchased from the Avicenna Herb Garden in Hamadan in early summer 2018 and then approved by a botanical specialist in Hamadan University of Medical Sciences. The herbal specimen was deposited in the herbarium (voucher number PMP-1329).

7. Preparation of Comfrey hydro-alcoholic extract

A total of 200 g of the dried plant was first ground and then suspended in ethanol 70% and subjected to continuous ultrasonic vibrations (USV) for three days. The suspension was stirred gently several times during this period. The obtained extract was then filtered using the Whatman® filter paper No. 30 and condensed using a rotary evaporator. The solution was then placed in a 30-40℃ oven to obtain the dry extract [28]. After weighing, the percent of extraction from the plant sample was calculated as 18.5% (w/w).

8. Preparation of Comfrey ointment

The dried smoothed powder of Comfrey hydro-alcoholic extract was mixed with eucerin as the base of ointment to prepare the Comfrey ointment 10% (w/w). A homogenizer was used to achieve a uniform ointment with acceptable appearance characteristics [29].

9. Preparation of placebo ointment

The placebo ointment was also eucerin-based, to which appropriate neutral food dye was added to achieve the same color as the Comfrey ointment and then placed in similar tubes.

The Comfrey and placebo ointments were prepared by a pharmacist in the laboratory of biopharmaceutical products, school of pharmacy, Hamadan University of Medical Sciences, Hamadan, Iran.

10. Data collection instruments

Demographic and clinical information of all participants was recorded and assessed by designing a questionnaire. Moreover, the bruise size and color in both groups were determined before the intervention and the days 1 to 5 of the intervention. To reduce the error rate in reporting the results, all bruise size and color measurements were taken at a fixed time (9 am) during the research period. The bruise size was recorded by placing a transparent paper strip on the bruise and coloring the spot with a fine-tip permanent marker. The measurement was replicated three times. Then, the paper was scanned by a scanner and the accurate bruise size was obtained in mm2 in ImageJ software version 1.52n. The bruise color was determined using a bruising color chart, reflecting four key bruise color changes from the onset to healing, and the dominant color was recorded. To investigate the reliability of the observers, the size and color of the bruise complication in ten patients were measured separately by the main researcher (the assessor) and three trained nurses at the same time, and the intraclass correlation coefficient (ICC) of 0.93 and 0.90 were obtained, respectively, indicating very good reliability [17]. After the initial evaluation of the bruise size and color, the participants in Group A received Comfrey ointment on the enoxaparin injection-induced bruising site. The ointment was administered four times per day with 6-hour intervals for five consecutive days. The participants in Group B underwent the same procedure, except that they received the Placebo ointment instead of Comfrey ointment. The amount of ointment used varied from patient to patient, depending on the size of the bruised area. Approximately 0.3 g of ointment was applied per cm2 of the bruised area to create a proper coverage of the ointment.

11. Statistical analysis

Data were analyzed with ANOVA. Then, Tukey’s post hoc test, and paired/unpaired t-test and their nonparametric equations were used if needed. The nonparametric assessment of the bruise color of each patient at different times was done using the Mann-Whitney U test. The statistical analysis was done in SPSS20 at the significance level of p < 0.05. Data were presented in the form of means ± SEM for all 40 patients in each group.

RESULTS

There was no significant difference between the groups in demographic information (sex, marital status, job, education, monthly income, place of residence, health-care insurance, smoking, age, BMI, INR, PT, PTT, and serum platelet counts (Tables 1-3).

Table 1

Distribution of participants’ qualitative demographic characteristics between the two study groups.

VariablesSub groupsComfrey groupN = 40Placebo groupN = 40p value


NumberPercentNumberPercent
GenderFemale16401947.50.435
Male24602152.5
Marital statusMarried348538950.311
Single2500
Widow41025
Employment statusEmployee410717.50.054
Housewife10251640
Retired1025717.5
Unemployed0037.5
Freelance job1640717.5
Education levelIlliterate20501537.50.611
Middle school6151015
Diploma922.5922.5
University education512.5615
Monthly incomeUnder 100 USD205014350.09
100-500 USD16401640
More than 500 USD4101025
Living placeCity266528700.633
Village14351230
Health insuranceInsured389536900.675
Non-insured25410
Smoking statusSmoker2357.516400.174
Non-smoker1742.52460


Table 2

Distribution of participants’ quantitative demographic variables between the two study groups.

VariablesExperimental group (N = 40)Placebo group (N = 40)p value


Mean ± SDMaximumMinimumMean ± SDMaximumMinimum
Age (years)64.13 ± 8.97794363.85 ± 10.4980410.900
Weight (kg)72.79 ± 9.27915875.95 ± 9.0990530.131
Height (cm)168.93 ± 9.95189144168.53 ± 9.971881550.858
BMI (kg/m2)25.58 ± 3.2132.8117.0826.85 ± 3.535.7020.960.097


Table 3

Distribution of participants’ clinical data between the Comfrey and placebo groups.

VariablesExperimental group (N = 40)Placebo group (N = 40)Means comparison



Mean ± SDMean ± SDp value
PT before intervention13.29 ± 0.8213.22 ± 0.870.722
PT 1 day after intervention13.83 ± 1.1913.32 ± 0.760.080
PT 3 days after intervention13.45 ± 0.8913.30 ± 0.700.426
PT 5 days after intervention13.56 ± 1.0213.60 ± 0.650.936
PTT before intervention28.28 ± 5.1331.68 ± 9.140.141
PTT 1 day after intervention31.20 ± 16.0531.06 ± 6.300.543
PTT 3 days after intervention31.15 ± 9.0432.82 ± 15.120.661
PTT 5 days after intervention31.13 ± 4.9734.20 ± 7.660.416
INR before intervention1.09 ± 0.101.09 ± 0.130.503
INR 1 day after intervention1.14 ± 0.181.10 ± 0.100.256
INR 3 days after intervention1.13 ± 0.131.09 ± 0.100.480
INR 5 days after intervention1.14 ± 0.151.15 ± 0.100.934
Platelet before intervention199423 ± 46309201750 ± 407030.813
Platelet 1 day after intervention200684 ± 25177194632 ± 299840.640
Platelet 3 days after intervention204568 ± 35715196050 ± 322330.342
Platelet 5 days after intervention180666 ± 39525194200 ± 211820.511


Fig. 2 shows no significant difference between the groups in the mean bruise size before the intervention (p = 0.494). On the first day after the intervention, the mean bruise size in the Comfrey group was lower than in the Placebo group. However, based on the independent t-test, there was no significant difference between the groups in the mean bruise size (p = 0.274). A significant difference was observed between the groups in the mean bruise size in the second to fifth days of the intervention (Fig. 2) (p > 0.05) with lower mean bruise size in the Comfrey group. Friedman’s test showed a significant difference between the groups in the mean bruise size at the observation times (p < 0.001). According to Fig. 2, there is a downward trend in the bruise size at the observation point in both groups, specifically in the Comfrey group.

Figure 2. Comparison of bruising size-reduction trend in Comfrey and Placebo groups. There was no significant difference between the Comfrey group and the placebo group in the mean size of bruising before the intervention (p = 0.494). Data are presented as mean ± SEM.

In Table 4 the non-parametric Friedman’s test was used to investigate the intervention effect on the bruise size and perform intra-group comparisons before and five days after the intervention. There was a significant difference within both groups in terms of bruise color at all six observation points (p < 0.001). The bruise color distribution was similar in both groups before the intervention. Comparison of bruise color in the first-to-fifth-day post-intervention showed a significant difference in the bruise color distribution in all five days of the intervention (p > 0.001). In that, the color of the bruised area indicated a faster healing course in the Comfrey group (Fig. 3).

T1, Before intervention; T2, First day after intervention; T3, Second day after intervention; T4, Third intervention day after intervention; T5, Fourth day after intervention; T6, Fifth day after intervention. *Chi-square test, **Fisher exact test..

&md=tbl&idx=4' data-target="#file-modal"">Table 4

Comparison of bruise color before and after intervention between the groups.

GroupsBruise colorT1n (%)T2n (%)T3n (%)T4n (%)T5n (%)T6n (%)Friedman test statisticp value
Intervention groupPink and red40 (100)20 (50)0000184.37< 0.001
Blue and dark purple020 (50)37 (92.5)17 (42.50)4 (10)0
Pale green003 (7.5)22 (55)28 (70)19 (47.5)
Yellow and brown0001 (2.5)8 (2)21 (52.5)
Placebo groupPink and red40 (100)40 (100)34 (85)19 (47.50)8 (20)2 (5)140.65< 0.001
Blue and dark purple006 (15)21 (52.5)32 (80)34 (85)
Pale green000004 (10)
Yellow and brown000000
Statistic-26.57*69.91**51.25**76.05**80.78*zz*
p value-< 0.001< 0.001< 0.001< 0.001< 0.001

T1, Before intervention; T2, First day after intervention; T3, Second day after intervention; T4, Third intervention day after intervention; T5, Fourth day after intervention; T6, Fifth day after intervention. *Chi-square test, **Fisher exact test..



Figure 3. Bruising healing in one patient in the intervention group for the first to fifth days after the intervention (left to right, respectively).

Table 5 shows the probability of bruise color change (Kaplan–Meier) in both groups after the intervention. According to the results, the probability of change in bruise color was 50% after the first day of the intervention, which reached 100% after the second day of intervention in the Comfrey group. This bruise color change was observed in all participants until the second day of intervention in this group. The bruise color change was not observed in any of the placebo control participants one day post-intervention. The probabilities of a change in the bruise color in the second, third, fourth, and fifth days after the intervention were 25%, 52%, 80%, and 95%, respectively.

T1, Before intervention; T2, First day after intervention; T3, Second day after intervention; T4, Third intervention day after intervention; T5, Fourth day after intervention; T6, Fifth day after intervention. *Bruise color change..

&md=tbl&idx=5' data-target="#file-modal"">Table 5

Bruise color change probability (Kaplan–Meier estimator) after intervention in the Comfrey and placebo groups.

GroupsTime of eventNumber of events*Number of risksNumber of censored casesProbability of not happeningProbability of happening
Comfrey groupT1040010
T2204000.500.50
T32020001
>T3-----
Placebo groupT1040010
T2040010
T364000.850.25
T4153400.480.52
T5111900.200.80
T66820.050.95

T1, Before intervention; T2, First day after intervention; T3, Second day after intervention; T4, Third intervention day after intervention; T5, Fourth day after intervention; T6, Fifth day after intervention. *Bruise color change..


DISCUSSION

There was a significant difference between the groups in the mean bruise size at the assessment times. In addition, a downward trend was observed in the bruise size at different time points in both groups. To establish whether there is a difference between the groups in the bruise size reduction, the Comfrey and Placebo groups were compared at different time points and the results showed that the groups were homogeneous in this regard before the intervention. Although the mean bruise size in the Comfrey group was smaller than the Placebo group on the first day after the intervention, this difference between the groups was not significant. However, the difference between the groups in the mean bruise size was significant at 2-5 days with a smaller mean bruise size in the Comfrey group. As a result, the use of Comfrey ointment can reduce the size of enoxaparin injection-induced bruises. This finding confirmed the research hypothesis that Comfrey ointment affects the size of enoxaparin injection-induced bruises.

Inconsistent with this study, Barna et al. [30] showed no significant difference in wound healing of the control group before and after the intervention. Moreover, Chaiet et al. [31] showed no significant difference in the bruise size in the placebo group, which can be due to the short duration of these two studies, specifically with respect to the wound type.

Consistent with the current study, Frost et al. [25], Sowa et al. [21], Miškulin et al. [19], Gilca et al. [32], Alamgir [33], and Jarić et al. [34] highlighted the anti-bruising effects of Comfrey. However, these studies only addressed the properties of Comfrey or its effects on variables other than bruising and neglected its anti-bruising effects.

It seems that the anti-inflammatory effects of Comfrey play a role in its anti-bruising effects seen in the Comfrey group. Anders et al. [35] showed that cutaneous medications containing Comfrey root (5% and 10%) were as effective as or even more effective than diclofenac, in healing ultraviolet-induced erythema. Moreover, these anti-bruising effects can be due to the plant compounds including allantoin, ellagic acid, and rosmarinic acid [21, 25]. Smith et al. [26] and Staiger [36] highlighted the anti-inflammatory and stimulatory effects of Comfrey on granulation, tissue regeneration, and rapid healing.

Change in bruise color took place sooner in the Comfrey group than the control. Results showed that the bruise color change occurred one day after the intervention in the Comfrey group and 2-3 days after the intervention in the control. The difference in the onset of bruise color change between the groups was significant. As a result, the application of Comfrey ointment could facilitate the bruise color change following enoxaparin injection in the Comfrey group.

Bruising at the injection site is the undesirable result of enoxaparin subcutaneous injection, which can cause physical discomfort [27, 37]. According to the results, Comfrey ointment can be used to reduce these impacts. Consistent with our findings, different studies mentioned the effectiveness of Comfrey ointment in the rapid healing of trauma-induced bruises. However, these studies only provided a descriptive explanation of Comfrey properties and did not scientifically investigate the effect of Comfrey on bruising [38].

According to a study in the Medical University of Lublin, Poland, the Comfrey plant root can facilitate the growth and proliferation of skin fibroblasts [26]. This plant has been effective in improving cutaneous inflammation and skin redness caused by overexposure to ultraviolet (UV) rays, which confirms the findings of the current study [24, 39, 40].

CONCLUSIONS

The results showed that comfrey ointment accelerated the healing of enoxaparin injection-induced bruise (size and color) in patients with ACS. Therefore, Comfrey is recommended to be used as a safe, non-aggressive, and simple method to facilitate bruise improvement caused by enoxaparin injection.

Fig 1.

Figure 1.Flow diagram of the patients in the Comfrey and Placebo groups throughout the different phases of the trial.
Journal of Pharmacopuncture 2021; 24: 196-205https://doi.org/10.3831/KPI.2021.24.4.196

Fig 2.

Figure 2.Comparison of bruising size-reduction trend in Comfrey and Placebo groups. There was no significant difference between the Comfrey group and the placebo group in the mean size of bruising before the intervention (p = 0.494). Data are presented as mean ± SEM.
Journal of Pharmacopuncture 2021; 24: 196-205https://doi.org/10.3831/KPI.2021.24.4.196

Fig 3.

Figure 3.Bruising healing in one patient in the intervention group for the first to fifth days after the intervention (left to right, respectively).
Journal of Pharmacopuncture 2021; 24: 196-205https://doi.org/10.3831/KPI.2021.24.4.196

Table 1 . Distribution of participants’ qualitative demographic characteristics between the two study groups.

VariablesSub groupsComfrey groupN = 40Placebo groupN = 40p value


NumberPercentNumberPercent
GenderFemale16401947.50.435
Male24602152.5
Marital statusMarried348538950.311
Single2500
Widow41025
Employment statusEmployee410717.50.054
Housewife10251640
Retired1025717.5
Unemployed0037.5
Freelance job1640717.5
Education levelIlliterate20501537.50.611
Middle school6151015
Diploma922.5922.5
University education512.5615
Monthly incomeUnder 100 USD205014350.09
100-500 USD16401640
More than 500 USD4101025
Living placeCity266528700.633
Village14351230
Health insuranceInsured389536900.675
Non-insured25410
Smoking statusSmoker2357.516400.174
Non-smoker1742.52460

Table 2 . Distribution of participants’ quantitative demographic variables between the two study groups.

VariablesExperimental group (N = 40)Placebo group (N = 40)p value


Mean ± SDMaximumMinimumMean ± SDMaximumMinimum
Age (years)64.13 ± 8.97794363.85 ± 10.4980410.900
Weight (kg)72.79 ± 9.27915875.95 ± 9.0990530.131
Height (cm)168.93 ± 9.95189144168.53 ± 9.971881550.858
BMI (kg/m2)25.58 ± 3.2132.8117.0826.85 ± 3.535.7020.960.097

Table 3 . Distribution of participants’ clinical data between the Comfrey and placebo groups.

VariablesExperimental group (N = 40)Placebo group (N = 40)Means comparison



Mean ± SDMean ± SDp value
PT before intervention13.29 ± 0.8213.22 ± 0.870.722
PT 1 day after intervention13.83 ± 1.1913.32 ± 0.760.080
PT 3 days after intervention13.45 ± 0.8913.30 ± 0.700.426
PT 5 days after intervention13.56 ± 1.0213.60 ± 0.650.936
PTT before intervention28.28 ± 5.1331.68 ± 9.140.141
PTT 1 day after intervention31.20 ± 16.0531.06 ± 6.300.543
PTT 3 days after intervention31.15 ± 9.0432.82 ± 15.120.661
PTT 5 days after intervention31.13 ± 4.9734.20 ± 7.660.416
INR before intervention1.09 ± 0.101.09 ± 0.130.503
INR 1 day after intervention1.14 ± 0.181.10 ± 0.100.256
INR 3 days after intervention1.13 ± 0.131.09 ± 0.100.480
INR 5 days after intervention1.14 ± 0.151.15 ± 0.100.934
Platelet before intervention199423 ± 46309201750 ± 407030.813
Platelet 1 day after intervention200684 ± 25177194632 ± 299840.640
Platelet 3 days after intervention204568 ± 35715196050 ± 322330.342
Platelet 5 days after intervention180666 ± 39525194200 ± 211820.511

Table 4 . Comparison of bruise color before and after intervention between the groups.

GroupsBruise colorT1n (%)T2n (%)T3n (%)T4n (%)T5n (%)T6n (%)Friedman test statisticp value
Intervention groupPink and red40 (100)20 (50)0000184.37< 0.001
Blue and dark purple020 (50)37 (92.5)17 (42.50)4 (10)0
Pale green003 (7.5)22 (55)28 (70)19 (47.5)
Yellow and brown0001 (2.5)8 (2)21 (52.5)
Placebo groupPink and red40 (100)40 (100)34 (85)19 (47.50)8 (20)2 (5)140.65< 0.001
Blue and dark purple006 (15)21 (52.5)32 (80)34 (85)
Pale green000004 (10)
Yellow and brown000000
Statistic-26.57*69.91**51.25**76.05**80.78*zz*
p value-< 0.001< 0.001< 0.001< 0.001< 0.001

T1, Before intervention; T2, First day after intervention; T3, Second day after intervention; T4, Third intervention day after intervention; T5, Fourth day after intervention; T6, Fifth day after intervention. *Chi-square test, **Fisher exact test..


Table 5 . Bruise color change probability (Kaplan–Meier estimator) after intervention in the Comfrey and placebo groups.

GroupsTime of eventNumber of events*Number of risksNumber of censored casesProbability of not happeningProbability of happening
Comfrey groupT1040010
T2204000.500.50
T32020001
>T3-----
Placebo groupT1040010
T2040010
T364000.850.25
T4153400.480.52
T5111900.200.80
T66820.050.95

T1, Before intervention; T2, First day after intervention; T3, Second day after intervention; T4, Third intervention day after intervention; T5, Fourth day after intervention; T6, Fifth day after intervention. *Bruise color change..


References

  1. Zipes DP, Libby P, Bonow RO, Mann DL, Tomaselli GF. Braunwald's heart disease e-book: a textbook of cardiovascular medicine. 11th ed. Philadelphia: Elsevier; 2018.
  2. Galli M, Andreotti F, D'Amario D, Vergallo R, Vescovo GM, Giraldi L, et al. Antithrombotic therapy in the early phase of non-ST-elevation acute coronary syndromes: a systematic review and meta-analysis. Eur Heart J Cardiovasc Pharmacother. 2020;6(1):43-56.
    Pubmed CrossRef
  3. Martinez BK, White CM. Pharmacologic considerations in the management of acute coronary syndrome in elderly patients. Expert Opin Pharmacother. 2019;20(15):1787-90.
    Pubmed CrossRef
  4. Jupalli A, Iqbal AM. Enoxaparin. Treasure Island: StatPearls Publishing; 2019.
  5. Zeitouni M, Kerneis M, Nafee T, Collet JP, Silvain J, Montalescot G. Anticoagulation in acute coronary syndrome-state of the art. Prog Cardiovasc Dis. 2018;60(4-5):508-13.
    Pubmed CrossRef
  6. Jameson JL, Fauci A, Kasper DL, Hauser SL, Longo DL, Loscalzo J. Harrison's principles of internal medicine. 20th ed. New York: McGraw-Hill Education; 2018.
  7. Hess CT. Clinical guide to skin and wound care. 7th ed. Philadelphia: Lippincott Williams and Wilkins; 2012.
  8. Zaybak A, Khorshid L. A study on the effect of the duration of subcutaneous heparin injection on bruising and pain. J Clin Nurs. 2008;17(3):378-85.
  9. Bindon SL. Professional development strategies to enhance nurses' knowledge and maintain safe practice. AORN J. 2017;106(2):99-110.
    Pubmed CrossRef
  10. Amaniyan S, Varaei S, Vaismoradi M, Haghani H, Sieloff C. Effect of local cold and hot pack on the bruising of enoxaparin sodium injection site: a randomized controlled trial. Contemp Nurse. 2016;52(1):30-41.
    Pubmed CrossRef
  11. Poursafar Z, Jafroudi S, Baghaei M, Kazemnezhad Leyli E, Zarrizei M. Incidence and extent of bruising after subcutaneous injection of enoxaparin sodium in patients hospitalized at coronary care units. J Holist Nurs Midwifery. 2019;29(2):90-6.
    CrossRef
  12. Chan H. Effects of injection duration on site-pain intensity and bruising associated with subcutaneous heparin. J Adv Nurs. 2001;35(6):882-92.
    Pubmed CrossRef
  13. Chenicek TE. Effects of injection duration on site-pain intensity and bruising associated with subcutaneous administration of Lovenox (enoxaparin sodium) [master's thesis]. [Tallahassee (FL)]: Florida State University; 2004. 70 p.
  14. Taylor CR, Lillis C, Lemone P, Lynn P, Lebon M. Study guide for Fundamentals of nursing: the art and science of nursing care. 7th ed. Philadelphia: Lippincott Williams & Wilkins; 2011.
  15. Bartell JC, Roberts KA, Schutte NJ, Sherman KC, Muller D, Hayney MS. Needle temperature effect on pain ratings after injection. Clin J Pain. 2008;24(3):260-4.
    Pubmed CrossRef
  16. Candiotti K, Rodriguez Y, Koyyalamudi P, Curia L, Arheart KL, Birnbach DJ. The effect of needle bevel position on pain for subcutaneous lidocaine injection. J Perianesth Nurs. 2009;24(4):241-3.
    Pubmed CrossRef
  17. Chen S, Shang H, Yang J, Li R, Wu H. Effects of different extraction techniques on physicochemical properties and activities of polysaccharides from comfrey (Symphytum officinale L.) root. Ind Crops Prod. 2018;121:18-25.
    CrossRef
  18. Jedlinszki N, Balazs B, Csanyi E, Csupor D. Penetration of lycopsamine from a comfrey ointment through human epidermis. Regul Toxicol Pharmacol. 2017;83:1-4.
    Pubmed CrossRef
  19. Mi?kulin I, Lali? Z, Mi?kulin M, Dumi? A, ?ebo D, V?ev A, editors. Efficacy of ointment containing comfrey and propolis in the treatment of mild acute sports injuries. In: Mi?kulin I, Lali? Z, Mi?kulin M, Dumi? A, ?ebo D, V?ev A, editors. Proceedings of World Congress Integrative Medicine & Health 2017; 2017 May 3-5; Berlin. Germany. London (UK): BioMedCentral; c2017.
  20. Nossa GDL, Talero PYV, Rozo NEW. Determination of polyphenols and antioxidant activity of polar extracts of comfrey (Symphytum officinale L). Rev Cubana Plant Med. 2016;21(2):125-32.
  21. Sowa I, Paduch R, Strzemski M, Zieli?ska S, Rydzik-Strzemska E, Sawicki J, et al. Proliferative and antioxidant activity of Symphytum officinale root extract. Nat Prod Res. 2018;32(5):605-9.
    Pubmed CrossRef
  22. Staiger C. Comfrey root: from tradition to modern clinical trials. Wien Med Wochenschr. 2013;163(3-4):58-64.
    Pubmed KoreaMed CrossRef
  23. Trifan A, Opitz SEW, Josuran R, Grubelnik A, Esslinger N, Peter S, et al. Is comfrey root more than toxic pyrrolizidine alkaloids? Salvianolic acids among antioxidant polyphenols in comfrey (Symphytum officinale L.) roots. Food Chem Toxicol. 2018;112:178-87.
    Pubmed CrossRef
  24. European Scientific Cooperative on Phytotherapy. ESCOP monographs. 2nd ed. Exeter: ESCOP; 2003.
  25. Frost R, O'Meara S, MacPherson H. The external use of comfrey: a practitioner survey. Complement Ther Clin Pract. 2014;20(4):347-55.
    Pubmed CrossRef
  26. Smith DB, Jacobson BH. Effect of a blend of comfrey root extract (Symphytum officinale L.) and tannic acid creams in the treatment of osteoarthritis of the knee: randomized, placebo-controlled, double-blind, multiclinical trials. J Chiropr Med. 2011;10(3):147-56.
    Pubmed KoreaMed CrossRef
  27. Jafroudi S. Study of effect of subcutaneous enoxaparin sodium injection duration on incidence and extent of bruising at injection site in hospitalized patient [master's thesis]. [Rasht]: Shahid Beheshti Nursing and Midwifery College; 2015.
  28. Amidi N, Moradkhani S, Sedaghat M, Khiripour N, Larki-Harchegani A, Zadkhosh N, et al. Effect of green tea on inflammation and oxidative stress in cisplatin-induced experimental liver function. J HerbMed Pharmacol. 2016;5(3):99-102.
  29. Hemmati AA, Larki-Harchegani A, Shabib S, Jalali A, Rezaei A, Housmand G. Wound healing property of milk in full thickness wound model of rabbit. Int J Surg. 2018;54(Pt A):133-40.
    Pubmed CrossRef
  30. Barna M, Kucera A, Hlad?cova M, Kucera M. [Wound healing effects of a Symphytum herb extract cream (Symphytum x uplandicum NYMAN): results of a randomized, controlled double-blind study]. Wien Med Wochenschr. 2007;157(21-22):569-74. German.
    Pubmed CrossRef
  31. Chaiet SR, Marcus BC. Perioperative Arnica montana for reduction of ecchymosis in rhinoplasty surgery. Ann Plast Surg. 2016;76(5):477-82.
    Pubmed CrossRef
  32. Gilca M, Tiplica GS, Salavastru CM. Traditional and ethnobotanical dermatology practices in Romania and other Eastern European countries. Clin Dermatol. 2018;36(3):338-52.
    Pubmed CrossRef
  33. Alamgir A. Therapeutic use of medicinal plants and their extracts: volume 2: phytochemistry and bioactive compounds. Cham: Springer; 2018.
    KoreaMed CrossRef
  34. Jari? S, Kosti? O, Mataruga Z, Pavlovi? D, Pavlovi? M, Mitrovi? M, et al. Traditional wound-healing plants used in the Balkan region (Southeast Europe). J Ethnopharmacol. 2018;211:311-28.
    Pubmed CrossRef
  35. Andres R, Brenneisen R, Clerc J. Relating antiphlogistic efficacy of dermatics containing extracts of Symphytum officinale to chemical profiles. Planta Med. 1989;55(7):643-4.
    CrossRef
  36. Staiger C. Comfrey: a clinical overview. Phytother Res. 2012;26(10):1441-8.
    Pubmed KoreaMed CrossRef
  37. Dehghani K, Najari Z, Dehghani H. Effect of subcutaneous Enoxaparin injection duration on bruising size in acute coronary syndrome patients. Iran J Nurs Midwifery Res. 2014;19(6):564-8.
  38. Duke JA. Handbook of medicinal herbs: herbal reference library. Boca Raton: CRC Press; 2018.
    CrossRef
  39. Weiss R, Fintelmann V. Herbal medicine. 2nd ed. Stuttgart: Thieme; 2000.
  40. Kora? RR, Khambholja KM. Potential of herbs in skin protection from ultraviolet radiation. Pharmacogn Rev. 2011;5(10):164-73.
    Pubmed KoreaMed CrossRef