NOVEL TOPICAL QUICK PENETRATING SOLUTION OF HEPARIN IN MANAGEMENT OF SUPERFICIAL THROMBOPHLEBITIS: RESULTS OF RANDOMIZED ACTIVE CONTROLLED TRIALHTML Full Text
NOVEL TOPICAL QUICK PENETRATING SOLUTION OF HEPARIN IN MANAGEMENT OF SUPERFICIAL THROMBOPHLEBITIS: RESULTS OF RANDOMIZED ACTIVE CONTROLLED TRIAL
Avinash Supe 1, B.M. Subnis 2, M. Rajeev Rao 3, Vasantray H. Panchal 4, R. J. Lakhani 5, Bhavin Mehtalia 6, Sanjay Kumar H. Maroo*7, Ketan R. Patel 7, Rakesh U. Ojha 7 and Dixit D. Patel 7
Department of Gastro - Surgery, Seth GS Medical College and KEM Hospital 1, Mumbai, Maharashtra, India
Department of Surgery, D.Y. Patil Medical College 2, Pimpri, Pune-411018, Maharashtra, India
Department of Orthopedics, Jubilee Mission Medical College Hospital 3, Thrissur, Kerala, India
Department of Anesthesia, Panchal Pain Clinic 4, Surat, Gujarat, India
Department of Surgery, Shrey Hospital Pvt. Ltd. 5, Ahmedabad, Gujarat, India
Department of Nephrology, Siddhi Vinayak Hospital 6, Ahmadabad Gujarat, India
Medical Services Department, Troikaa Pharmaceuticals Ltd. 7, Ahmedabad, Gujarat, India
Aim: To compare safety and efficacy of topical quick penetrating solution (QPS) of heparin 1000 IU/ml versus heparin gel 200 IU/g in the management of post infusion superficial thrombophlebitis.
Methods: Total 202 patients of early, medium and advance stage ofsuperficial thrombophlebitis were randomized to receive either treatment. Treatments were applied 3 times daily until healing or for a maximum of 7 days. Primary efficacy endpoints were change in length of the venous lesion, proportion of patients with complete healing; while secondary efficacy endpoints included local symptoms, change in the grade of the lesion, global assessment by patients and investigator. Safety of treatment in all patients was evaluated.
Results: Mean change in length of the venous lesion from baseline was significantly higher in heparin QPS group as compared to heparin gel on day 3 (P =0.0144). 90.0% patients in heparin QPS group were healed at day 7 which was significantly higher as compared to 65.7% patients in heparin gel group (P=0.00001). Heparin QPS was also found better in secondary efficacy endpoints. No adverse events were reported in either group.
Conclusions: Heparin QPS was found more effective in treatment of post infusion superficial thrombophlebitis with similar safety profile to heparin gel.
Heparin, Quick penetrating topical solution, Superficial thrombophlebitis
INTRODUCTION:Superficial thrombophlebitis is a common complication of continuous intra-venous infusion 1.
It is a pathological condition characterized by presence of a thrombus in the lumen of a superficial vein, followed by inflammatory reaction of its wall and adjacent tissues. It presents with a palpable, hot, painful and hyperemic cord through a superficial vein.
This thrombosis has variable amplitude, reaching from small tributaries until large extension of saphenous trunks in the lower limbs.
In more severe cases, it can be extended to the deep venous system (DVS); it can also cause pulmonary embolism, and there are indications of an association with recurrent episodes of venous thromboembolism 1, 2.
The association of superficial thrombophlebitis with deep venous thrombosis (DVT) according to different publications ranges between 6-44% of affected subjects 3. The goals of treatment of superficial thrombophlebitis are to reduce pain and other symptoms and also to prevent complications.
Effective treatment of superficial thrombophlebitis is important not only for resolution of local symptoms but also for preventing the development of systemic conditions such as deep vein thrombosis4. Topical heparins are widely used for the prevention and treatment of local symptoms associated with peripheral vascular disorders including infusion induced superficial venous thrombophlebitis.
Topical formulation allows heparin to penetrate through the skin at the site of application, with a lack of systemic exposure at clinically relevant doses, hence reducing the risk of adverse bleeding effects4. Several line of clinical evidences suggest that higher concentration of topical heparin 1000 IU/g gel may be more effective than other topical preparations of heparin in treating superficial thrombophlebitis, possibly because of the relatively high heparin levels in this formulation and is generally well tolerated 4.
In India, topical heparin gel of lower strength (200 IU/g) is available and most commonly used in management of superficial thrombophlebitis.
Troikaa Pharmaceuticals Limited has developed novel topical Quick Penetrating Solution (QPS) of heparin sodium 1000 IU/ml, which contains non aqueous and non-volatile solvents with added permeability enhancers to increase penetration of the heparin across the skin.
Increased penetration of heparin may improve efficacy compared to conventional heparin gel. We hypothesize that QPS of heparin sodium 1000 IU/ml in the form of spray is more effective than available heparin gel and equally safe in management of superficial thrombophlebitis.
Heparin QPS will also offer a hands free usage which may facilitate ease of application and improve compliance of patients as well as nursing staff.
The present study was conducted to compare the safety and efficacy of topical quick penetrating solution of heparin 1000 IU/ml versus heparin gel 200 IU/g in the management of post infusion superficial thrombophlebitis.
MATERIAL AND METHODS: This prospective, randomized, two arm, open label, active controlled phase III clinical study was conducted at six different hospitals across India. The study protocol was approved by office of Drug Controller General of India and Ethics Committees of each participating study centre before initiation of study. The study was also registered to clinical trial registry-India (CTRI) prior to initiation of the study (CTRI Registration No: CTRI/2010/091/002947). The study was conducted in accordance with the Good Clinical Practice (GCP) guidelines issued by the Central Drugs Standard Control Organization (CDSCO), Ministry of Health, Government of India, and the ethical standards laid down in declaration of Helsinki 1964 and its later amendments; and Ethical guidelines for biomedical research on human participants issued by Indian Council of Medical Research (2006), New Delhi.
Patients of either sex aged 18-60 years, having early, medium and advance stage ofsuperficial thrombophlebitis based on phlebitis scale (grade 2-4) were selected during January 2011 to June, 2012.
All patients were explained the procedure clearly and written informed consent was obtained from each patients before their participation in the study. During screening, medical history was obtained; physical examination and laboratory investigations were performed.
Patients with known hypersensitivity or contraindications to heparin were excluded. Patients who are on anticoagulants and required topical anti-inflammatory agent were also excluded. The women of child bearing age underwent the urine pregnancy test; the pregnant and lactating women were excluded in the present study.
The patients were enrolled after verification of eligibility criteria. Enrolled patients were equally randomized using computer generated simple randomization sheet to receive either heparin QPS 1000 IU/ml (manufactured by Troikaa Pharmaceuticals Ltd, Ahemedabad, India) or topical gel containing Heparin Sodium Gel 200 IU/g (Thrombophob gel, Zydus Cadila India).
At the time of enrollment, study medications were dispensed to the patients. Patients were instructed to apply a thin layer in an amount sufficient to cover the phlebitis lesion 3 times daily (morning, noon and evening). Treatment was continued daily until healing or for a maximum of 7 days. Patients were instructed to visit study centre on day 3 and day 7 after initiating the study medication to evaluate the efficacy and safety of both the treatments.
Length of venous lesion in millimeter was measured using pre calibrated stainless steel scale before the start of study drug (at baseline) and on day 3 after initiation of treatment. Also the grade of the lesion using Phlebitis Scale as per “Standards for Infusion Therapy” by Royal College of Nursing IV Therapy Forum, July 2003 was noted at baseline and on day 3 after initiation of treatment. In this phlebitis scale, Grade 0 indicates no sign of phlebitis; Grade 1 indicates possibly the first sign of phlebitis; Grade 2 indicates early stage of phlebitis; Grade 3 indicates medium stage of phlebitis; Grade 4 indicates advance stage of phlebitis or stage of thrombophlebitis; Grade 5 indicates advanced stage of thrombophlebitis 5.
Local symptoms like pain, tenderness, redness, raised local temperature and venous induration were also recorded at baseline and on day 3 after initiation of study drugs. All the local symptoms were measured on 4 point severity scale (0- None, 1- Light, 2- Moderate, 3- Severe). Proportion of patients with complete healing was noted on day 3 and day 7 day after initiation of treatment.
Medications considered necessary for any concomitant illness and which will not interfere with the study drugs were allowed. At the end of study period, global assessment of treatments based on efficacy and safety was assessed by investigators and patients.
Primary efficacy endpoints were change in length of the venous lesion on day 3, proportion of patients with complete healing on day 3 and 7; while secondary efficacy endpoints included local symptoms on day 3, change in the grade of the lesion on day 3, global assessment by patients and investigator at the end of study.
Safety of each patient was evaluated throughout the study period. Complete monitoring of all the vital data were done before (baseline) and after the study on day 3 and day 7. In addition, complete physical (general and systemic) examination of each patient was performed. Any other local as well as systemic adverse events observed/reported during the study period were noted in the case record form.
Sample size calculation was performed using software, PS Power and Sample Size Calculations Program, version no.3. Based on the study6, a sample size of 174 patients, 87 in each arm, is required to detect a clinically significant difference of 20 % between groups in proportion of patients healed on day 7 using a two-tailed Chi square test with 80% power and a 5% level of significance. Considering dropout rate of 15 %, total adjusted sample size will be 204 patients (102 patients in each group).
Quantitative data are presented as mean ± standard deviation (SD), whereas categorical data are expressed as absolute number/proportion of patients. Quantitative data of both the treatments groups were analyzed by unpaired “t” test or Mann Whitney test based on the distribution of data. Chi-square test or fisher exact test was used to compare the categorical data of both the treatment groups. P value of less than 0.05 was considered as statistically significant difference between both the treatment groups. All statistical analyses were performed using software, GraphPad prism, version no. 5.
RESULTS: Total 220 patients with were screened. Among them 16 patients did not fulfill the eligibility criteria, hence 204 patients were enrolled. Out of 204, two patients were discontinued in Heparin QPS group. The data obtained from 202 patients were subjected to statistical analysis. Demography (age, gender, height and weight) and baseline characteristics (mean length of the venous lesion, local symptoms, and grade of phlebitis) were comparable between both the treatment groups (Table 1). All the enrolled patients have unilateral superficial thrombophlebitis on upper limb.
TABLE 1: DEMOGRAPHIC AND BASELINE CHARACTERISTICS
|Characteristics||Heparin QPS (N=100)||Heparin Gel (N=102)||P value|
|Age (Years)||41.45 ± 12.29||38.22 ± 13.59||0.079*|
|Weight (Kg)||64.20 ± 12.41||63.24 ± 13.47||0.601*|
|Height (Cm)||161.47 ± 07.39||160.33 ± 08.15||0.302*|
|Length of the venous lesion (mm)||31.95 ± 14.98||32.67 ± 17.16||0.7509*|
|Pain||01.88 + 00.57||01.88 + 00.69||1.000*|
|Tenderness||01.90 + 00.59||01.87 + 00.71||0.744*|
|Redness||01.06 + 00.69||01.12 + 00.69||0.537*|
|Local temperature||00.91 + 00.67||00.80 + 00.70||0.255*|
|Venous induration||00.71 + 00.81||00.75 + 00.74||0.715*|
|Grade of phlebitis|
|Early stage of
phlebitis (Grade 2)
|Medium stage of phlebitis (Grade 3)||35||39|
|Advanced stage of phlebitis (Grade 4)||09||11|
Values are expressed in Mean ± SD for age and absolute numbers for gender and grade of phlebitis, N = number of patients. *Data analyzed by Unpaired t test; # Data analyzed byChi-Square test.
On day 3 after study drug administration, mean length of the venous lesion (mm) was 15.94 + 09.92 in heparin QPS group while in heparin gel group it was 20.43 + 13.92. Significant reduction in length of the venous lesion from baseline was observed in both the treatment groups (P< 0.001, Wilcoxan test). However, change in length of the venous lesion from baseline was higher in heparin QPS group (16.01 + 12.11 mm) as compared to heparin gel (12.24 + 9.40 mm), and the difference was statistically significant (P =0.0144, Mann Whitney test).
On day 3, more number of patients in heparin QPS group had healed as compared to heparin gel group. However, difference was not statistically significant between both the treatment groups. Whereas on day 7, there was significantly more number of patients healed in heparin QPS group as compared to heparin gel group. 90.0% of patients in heparin QPS group were healed at day 7 which was significantly higher as compared to 65.7% of patients in heparin gel group (Table 2).
Table 2. Proportion of patients with complete healing on day 3 and day 7
TABLE 2: PROPORTION OF PATIENTS WITH COMPLETE HEALING ON DAY 3 AND DAY 7
|Healing||Heparin QPS (N=100)||Heparin Gel (N=102)||P value|
|Yes||22 (22%)||18 (17.6%)||0.4376|
|No||78 (78 %)||84 (82.4%)|
|Yes||90 (90%)||67 (65.7%)||<0.00001|
|No||10 (10%)||35 (34.3%)|
N = Number of subjects in treatment group. Numerical represent number and proportion of patients for particular assessment. Data were analyzed byChi-Square test.
On day 3, there was significantly more number of patients in heparin QPS group experienced significant improvement from baseline phlebitis grade as compared to Heparin gel group (Table 3).
TABLE 3: PROPORTION OF PATIENTS WITH CHANGE IN THE GRADE OF PHLEBITIS ON DAY 3
|Grade of Phlebitis||Heparin QPS (N=100)||Heparin Gel (N=102)||P value|
|No signs of phlebitis (Grade 0)||11 (11%)||12 (11.8 %)||0.0133|
|Possibly the first signs of phlebitis (Grade 1)||45 (45%)||23 (22.5%)|
|Early stage of phlebitis (Grade 2)||33 (33%)||46 (45.1%)|
|Medium stage of phlebitis (Grade 3)||10 (10%)||20 (19.6%)|
|Advanced stage of phlebitis (Grade 4)||01 (1%)||01 (0.98%)|
N = Number of subjects in treatment group. Numerical represent number and proportion of patients for particular assessment. Data were analyzed byChi-Square test.
On day 3, Mean score of pain, redness and venous induration was decreased from the baseline in both the treatment groups. However, no statistically significant difference was found between both the treatment groups. Mean score of tenderness and raised local temperature was also decreased from the baseline in both the treatment groups. Reduction in severity of tenderness and raised local temperature was statistically more in Heparin gel group as compared to heparin QPS group; however, the difference was not clinically significant (Table 4).
TABLE 4: CHANGES IN LOCAL SYMPTOMS FROM BASELINE ON DAY 3
|Symptoms||Heparin QPS (N=100)||Heparin Gel (N=102)||P value|
|Pain||0.77 ± 00.68||0.61 ± 00.62||0.082|
|Tenderness||0.91 ± 00.65||0.69 ± 00.67||0.019|
|Redness||0.66 ± 00.71||0.60 ± 00.69||0.543|
|Raised Local temperature||0.64 ± 00.66||0.42 ± 00.60||0.014|
|Venous induration||0.42 ± 00.65||0.40 ± 00.68||0.831|
Values are expressed in Mean ± SD, N = number of patients. *Data were analyzed by Mann Whitney U test.
In heparin QPS group, there was significantly more number of patients rated treatment as excellent when compared to heparin gel group. Based upon the observation of data, patients global assessment was more favorable towards heparin QPS than heparin gel (Table 5). Similarly, based upon the observation of data, investigator global assessment was more favorable towards heparin QPS than heparin gel (Table 5).
TABLE 5: GLOBAL ASSESSMENT BY PATIENTS AND INVESTIGATORS AT END OF STUDY
|Global Assessment rating||Patient’s global assessment||Investigator’s global assessment|
|Excellent||61 (61%)||26 (25.5%)||63 (63%)||32 (31.4%)|
|Good||35 (35% )||44 (43.1 %)||34 (34%)||41 (40.2%)|
|Fair||04 (4%)||26 (25.5 %)||03 (3%)||29 (28.4%)|
|Poor||0 (0%)||06 (5.9 %)||0 (0%)||0 (0%)|
|P value||< 0.00001||< 0.00001|
N = Number of subjects in treatment group. Numerical represent number and proportion of patients for particular assessment .Data were analyzed by Chi-Square test.
No case of any abnormality in the vital data as well as in physical examination was found during study period.
No cases of any other expected and unexpected local as well as systemic adverse events were reported/observed during study period.
DISCUSSION: In our study, both the study drugs were effective and safe in management of post infusion superficial thrombophlebitis. However, heparin QPS is more effective than heparin gel as heparin QPS significantly reduced the length of venous lesion.
Also heparin QPS was found to have an excellent clinical response in term of healing as 90% of the patients experienced complete resolution of the lesion and local symptoms compared to 65.7% of the patients treated with heparin gel. These favorable results were found may be due to novel patented QPS technology used in formulation which allows higher penetration of heparin through the skin. Our finding was consistent with the line of evidences suggest that heparin 1000 IU/g topical gel is more effective than other topical preparations of heparin in treating superficial thrombophlebitis, possibly because of the relatively high heparin levels in such formulation4. Moreover, more number of patients who were treated with heparin QPS experienced significant better improvement from baseline phlebitis as compared to Heparin gel.
In our study, no case of any adverse events was recorded with either study drug. Safety results suggested that, while improving the efficacy of heparin through quick penetrating solution, safety of the patients was not vitiated. In safety endpoint, our result was consistent with the several clinical studies which have shown that heparin 1000 IU gel was well tolerated4.
Based upon the overall efficacy and safety of both the study drugs, patients and investigator global assessment was more favorable towards heparin QPS than heparin gel. Further, greater improvement in efficacy of heparin with similar safety profile may have contributed to the higher preference of heparin QPS. As in India, currently topical formulations of heparin are available as gels, ointments and creams, which need to be applied manually. Based on the results of this study, Indian drug regulatory authority has approved Heparin QPS for clinical use in India.
CONCLUSION: Heparin QPS was found to more effective in treatment of post infusion superficial thrombophlebitis with similar safety profile to heparin gel. Hands free usage of Heparin QPS would facilitate ease of application and improve compliance of patients as well as nursing staff. Therefore, heparin QPS can be a better and convenient alternative in the management of post infusion superficial thrombophlebitis.
ACKNOWLEDGEMENTS: We thank all the participating patients, study nurses, and members of the data management team for making the trial possible. This study was sponsored by Troikaa Pharmaceuticals Ltd., India and all the study related materials including study drugs were provided by Troikaa Pharmaceuticals Ltd. Ahemdabad, India. Authors would like to thanks all the study subjects for their valuable participation in this study.
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How to cite this article:
Supe , Subnis BM, Rao MR, Panchal VH, Lakhani RJ, Mehtalia B, Maroo SKH, Patel KR, Ojha RU and Patel DD: Novel topical quick penetrating solution of Heparin in management of superficial thrombophlebitis: Results of randomized active controlled trial. Int J Pharm Sci Res 2013; 4(11): 4442-47. doi: 10.13040/IJPSR. 0975-8232.4(11).4442-47
All © 2013 are reserved by International Journal of Pharmaceutical Sciences and Research. This Journal licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License.
Avinash Supe , B.M. Subnis , M. Rajeev Rao , Vasantray H. Panchal , R. J. Lakhani , Bhavin Mehtalia , Sanjay Kumar H. Maroo*, Ketan R. Patel , Rakesh U. Ojha and Dixit D. Patel
Sr. General Manager, Medical Services Department, Troikaa Pharmaceuticals Ltd., Commerce House 1, Opp.Rajvansh Apartment, Satya Marg, Bodakdev, Ahmedabad - 380054 Gujarat, India
25 June, 2013
29 July, 2013
25 October, 2013
01 November, 2013