Journal of Clinical and Diagnostic Research, ISSN - 0973 - 709X

Users Online : 52581

AbstractMaterial and MethodsResultsDiscussionConclusionReferencesDOI and Others
Article in PDF How to Cite Citation Manager Readers' Comments (0) Audio Visual Article Statistics Link to PUBMED Print this Article Send to a Friend
Advertisers Access Statistics Resources

Dr Mohan Z Mani

"Thank you very much for having published my article in record time.I would like to compliment you and your entire staff for your promptness, courtesy, and willingness to be customer friendly, which is quite unusual.I was given your reference by a colleague in pathology,and was able to directly phone your editorial office for clarifications.I would particularly like to thank the publication managers and the Assistant Editor who were following up my article. I would also like to thank you for adjusting the money I paid initially into payment for my modified article,and refunding the balance.
I wish all success to your journal and look forward to sending you any suitable similar article in future"



Dr Mohan Z Mani,
Professor & Head,
Department of Dermatolgy,
Believers Church Medical College,
Thiruvalla, Kerala
On Sep 2018




Prof. Somashekhar Nimbalkar

"Over the last few years, we have published our research regularly in Journal of Clinical and Diagnostic Research. Having published in more than 20 high impact journals over the last five years including several high impact ones and reviewing articles for even more journals across my fields of interest, we value our published work in JCDR for their high standards in publishing scientific articles. The ease of submission, the rapid reviews in under a month, the high quality of their reviewers and keen attention to the final process of proofs and publication, ensure that there are no mistakes in the final article. We have been asked clarifications on several occasions and have been happy to provide them and it exemplifies the commitment to quality of the team at JCDR."



Prof. Somashekhar Nimbalkar
Head, Department of Pediatrics, Pramukhswami Medical College, Karamsad
Chairman, Research Group, Charutar Arogya Mandal, Karamsad
National Joint Coordinator - Advanced IAP NNF NRP Program
Ex-Member, Governing Body, National Neonatology Forum, New Delhi
Ex-President - National Neonatology Forum Gujarat State Chapter
Department of Pediatrics, Pramukhswami Medical College, Karamsad, Anand, Gujarat.
On Sep 2018




Dr. Kalyani R

"Journal of Clinical and Diagnostic Research is at present a well-known Indian originated scientific journal which started with a humble beginning. I have been associated with this journal since many years. I appreciate the Editor, Dr. Hemant Jain, for his constant effort in bringing up this journal to the present status right from the scratch. The journal is multidisciplinary. It encourages in publishing the scientific articles from postgraduates and also the beginners who start their career. At the same time the journal also caters for the high quality articles from specialty and super-specialty researchers. Hence it provides a platform for the scientist and researchers to publish. The other aspect of it is, the readers get the information regarding the most recent developments in science which can be used for teaching, research, treating patients and to some extent take preventive measures against certain diseases. The journal is contributing immensely to the society at national and international level."



Dr Kalyani R
Professor and Head
Department of Pathology
Sri Devaraj Urs Medical College
Sri Devaraj Urs Academy of Higher Education and Research , Kolar, Karnataka
On Sep 2018




Dr. Saumya Navit

"As a peer-reviewed journal, the Journal of Clinical and Diagnostic Research provides an opportunity to researchers, scientists and budding professionals to explore the developments in the field of medicine and dentistry and their varied specialities, thus extending our view on biological diversities of living species in relation to medicine.
Knowledge is treasure of a wise man. The free access of this journal provides an immense scope of learning for the both the old and the young in field of medicine and dentistry as well. The multidisciplinary nature of the journal makes it a better platform to absorb all that is being researched and developed. The publication process is systematic and professional. Online submission, publication and peer reviewing makes it a user-friendly journal.
As an experienced dentist and an academician, I proudly recommend this journal to the dental fraternity as a good quality open access platform for rapid communication of their cutting-edge research progress and discovery.
I wish JCDR a great success and I hope that journal will soar higher with the passing time."



Dr Saumya Navit
Professor and Head
Department of Pediatric Dentistry
Saraswati Dental College
Lucknow
On Sep 2018




Dr. Arunava Biswas

"My sincere attachment with JCDR as an author as well as reviewer is a learning experience . Their systematic approach in publication of article in various categories is really praiseworthy.
Their prompt and timely response to review's query and the manner in which they have set the reviewing process helps in extracting the best possible scientific writings for publication.
It's a honour and pride to be a part of the JCDR team. My very best wishes to JCDR and hope it will sparkle up above the sky as a high indexed journal in near future."



Dr. Arunava Biswas
MD, DM (Clinical Pharmacology)
Assistant Professor
Department of Pharmacology
Calcutta National Medical College & Hospital , Kolkata




Dr. C.S. Ramesh Babu
" Journal of Clinical and Diagnostic Research (JCDR) is a multi-specialty medical and dental journal publishing high quality research articles in almost all branches of medicine. The quality of printing of figures and tables is excellent and comparable to any International journal. An added advantage is nominal publication charges and monthly issue of the journal and more chances of an article being accepted for publication. Moreover being a multi-specialty journal an article concerning a particular specialty has a wider reach of readers of other related specialties also. As an author and reviewer for several years I find this Journal most suitable and highly recommend this Journal."
Best regards,
C.S. Ramesh Babu,
Associate Professor of Anatomy,
Muzaffarnagar Medical College,
Muzaffarnagar.
On Aug 2018




Dr. Arundhathi. S
"Journal of Clinical and Diagnostic Research (JCDR) is a reputed peer reviewed journal and is constantly involved in publishing high quality research articles related to medicine. Its been a great pleasure to be associated with this esteemed journal as a reviewer and as an author for a couple of years. The editorial board consists of many dedicated and reputed experts as its members and they are doing an appreciable work in guiding budding researchers. JCDR is doing a commendable job in scientific research by promoting excellent quality research & review articles and case reports & series. The reviewers provide appropriate suggestions that improve the quality of articles. I strongly recommend my fraternity to encourage JCDR by contributing their valuable research work in this widely accepted, user friendly journal. I hope my collaboration with JCDR will continue for a long time".



Dr. Arundhathi. S
MBBS, MD (Pathology),
Sanjay Gandhi institute of trauma and orthopedics,
Bengaluru.
On Aug 2018




Dr. Mamta Gupta,
"It gives me great pleasure to be associated with JCDR, since last 2-3 years. Since then I have authored, co-authored and reviewed about 25 articles in JCDR. I thank JCDR for giving me an opportunity to improve my own skills as an author and a reviewer.
It 's a multispecialty journal, publishing high quality articles. It gives a platform to the authors to publish their research work which can be available for everyone across the globe to read. The best thing about JCDR is that the full articles of all medical specialties are available as pdf/html for reading free of cost or without institutional subscription, which is not there for other journals. For those who have problem in writing manuscript or do statistical work, JCDR comes for their rescue.
The journal has a monthly publication and the articles are published quite fast. In time compared to other journals. The on-line first publication is also a great advantage and facility to review one's own articles before going to print. The response to any query and permission if required, is quite fast; this is quite commendable. I have a very good experience about seeking quick permission for quoting a photograph (Fig.) from a JCDR article for my chapter authored in an E book. I never thought it would be so easy. No hassles.
Reviewing articles is no less a pain staking process and requires in depth perception, knowledge about the topic for review. It requires time and concentration, yet I enjoy doing it. The JCDR website especially for the reviewers is quite user friendly. My suggestions for improving the journal is, more strict review process, so that only high quality articles are published. I find a a good number of articles in Obst. Gynae, hence, a new journal for this specialty titled JCDR-OG can be started. May be a bimonthly or quarterly publication to begin with. Only selected articles should find a place in it.
An yearly reward for the best article authored can also incentivize the authors. Though the process of finding the best article will be not be very easy. I do not know how reviewing process can be improved. If an article is being reviewed by two reviewers, then opinion of one can be communicated to the other or the final opinion of the editor can be communicated to the reviewer if requested for. This will help ones reviewing skills.
My best wishes to Dr. Hemant Jain and all the editorial staff of JCDR for their untiring efforts to bring out this journal. I strongly recommend medical fraternity to publish their valuable research work in this esteemed journal, JCDR".



Dr. Mamta Gupta
Consultant
(Ex HOD Obs &Gynae, Hindu Rao Hospital and associated NDMC Medical College, Delhi)
Aug 2018




Dr. Rajendra Kumar Ghritlaharey

"I wish to thank Dr. Hemant Jain, Editor-in-Chief Journal of Clinical and Diagnostic Research (JCDR), for asking me to write up few words.
Writing is the representation of language in a textual medium i e; into the words and sentences on paper. Quality medical manuscript writing in particular, demands not only a high-quality research, but also requires accurate and concise communication of findings and conclusions, with adherence to particular journal guidelines. In medical field whether working in teaching, private, or in corporate institution, everyone wants to excel in his / her own field and get recognised by making manuscripts publication.


Authors are the souls of any journal, and deserve much respect. To publish a journal manuscripts are needed from authors. Authors have a great responsibility for producing facts of their work in terms of number and results truthfully and an individual honesty is expected from authors in this regards. Both ways its true "No authors-No manuscripts-No journals" and "No journalsNo manuscriptsNo authors". Reviewing a manuscript is also a very responsible and important task of any peer-reviewed journal and to be taken seriously. It needs knowledge on the subject, sincerity, honesty and determination. Although the process of reviewing a manuscript is a time consuming task butit is expected to give one's best remarks within the time frame of the journal.
Salient features of the JCDR: It is a biomedical, multidisciplinary (including all medical and dental specialities), e-journal, with wide scope and extensive author support. At the same time, a free text of manuscript is available in HTML and PDF format. There is fast growing authorship and readership with JCDR as this can be judged by the number of articles published in it i e; in Feb 2007 of its first issue, it contained 5 articles only, and now in its recent volume published in April 2011, it contained 67 manuscripts. This e-journal is fulfilling the commitments and objectives sincerely, (as stated by Editor-in-chief in his preface to first edition) i e; to encourage physicians through the internet, especially from the developing countries who witness a spectrum of disease and acquire a wealth of knowledge to publish their experiences to benefit the medical community in patients care. I also feel that many of us have work of substance, newer ideas, adequate clinical materials but poor in medical writing and hesitation to submit the work and need help. JCDR provides authors help in this regards.
Timely publication of journal: Publication of manuscripts and bringing out the issue in time is one of the positive aspects of JCDR and is possible with strong support team in terms of peer reviewers, proof reading, language check, computer operators, etc. This is one of the great reasons for authors to submit their work with JCDR. Another best part of JCDR is "Online first Publications" facilities available for the authors. This facility not only provides the prompt publications of the manuscripts but at the same time also early availability of the manuscripts for the readers.
Indexation and online availability: Indexation transforms the journal in some sense from its local ownership to the worldwide professional community and to the public.JCDR is indexed with Embase & EMbiology, Google Scholar, Index Copernicus, Chemical Abstracts Service, Journal seek Database, Indian Science Abstracts, to name few of them. Manuscriptspublished in JCDR are available on major search engines ie; google, yahoo, msn.
In the era of fast growing newer technologies, and in computer and internet friendly environment the manuscripts preparation, submission, review, revision, etc and all can be done and checked with a click from all corer of the world, at any time. Of course there is always a scope for improvement in every field and none is perfect. To progress, one needs to identify the areas of one's weakness and to strengthen them.
It is well said that "happy beginning is half done" and it fits perfectly with JCDR. It has grown considerably and I feel it has already grown up from its infancy to adolescence, achieving the status of standard online e-journal form Indian continent since its inception in Feb 2007. This had been made possible due to the efforts and the hard work put in it. The way the JCDR is improving with every new volume, with good quality original manuscripts, makes it a quality journal for readers. I must thank and congratulate Dr Hemant Jain, Editor-in-Chief JCDR and his team for their sincere efforts, dedication, and determination for making JCDR a fast growing journal.
Every one of us: authors, reviewers, editors, and publisher are responsible for enhancing the stature of the journal. I wish for a great success for JCDR."



Thanking you
With sincere regards
Dr. Rajendra Kumar Ghritlaharey, M.S., M. Ch., FAIS
Associate Professor,
Department of Paediatric Surgery, Gandhi Medical College & Associated
Kamla Nehru & Hamidia Hospitals Bhopal, Madhya Pradesh 462 001 (India)
E-mail: drrajendrak1@rediffmail.com
On May 11,2011




Dr. Shankar P.R.

"On looking back through my Gmail archives after being requested by the journal to write a short editorial about my experiences of publishing with the Journal of Clinical and Diagnostic Research (JCDR), I came across an e-mail from Dr. Hemant Jain, Editor, in March 2007, which introduced the new electronic journal. The main features of the journal which were outlined in the e-mail were extensive author support, cash rewards, the peer review process, and other salient features of the journal.
Over a span of over four years, we (I and my colleagues) have published around 25 articles in the journal. In this editorial, I plan to briefly discuss my experiences of publishing with JCDR and the strengths of the journal and to finally address the areas for improvement.
My experiences of publishing with JCDR: Overall, my experiences of publishing withJCDR have been positive. The best point about the journal is that it responds to queries from the author. This may seem to be simple and not too much to ask for, but unfortunately, many journals in the subcontinent and from many developing countries do not respond or they respond with a long delay to the queries from the authors 1. The reasons could be many, including lack of optimal secretarial and other support. Another problem with many journals is the slowness of the review process. Editorial processing and peer review can take anywhere between a year to two years with some journals. Also, some journals do not keep the contributors informed about the progress of the review process. Due to the long review process, the articles can lose their relevance and topicality. A major benefit with JCDR is the timeliness and promptness of its response. In Dr Jain's e-mail which was sent to me in 2007, before the introduction of the Pre-publishing system, he had stated that he had received my submission and that he would get back to me within seven days and he did!
Most of the manuscripts are published within 3 to 4 months of their submission if they are found to be suitable after the review process. JCDR is published bimonthly and the accepted articles were usually published in the next issue. Recently, due to the increased volume of the submissions, the review process has become slower and it ?? Section can take from 4 to 6 months for the articles to be reviewed. The journal has an extensive author support system and it has recently introduced a paid expedited review process. The journal also mentions the average time for processing the manuscript under different submission systems - regular submission and expedited review.
Strengths of the journal: The journal has an online first facility in which the accepted manuscripts may be published on the website before being included in a regular issue of the journal. This cuts down the time between their acceptance and the publication. The journal is indexed in many databases, though not in PubMed. The editorial board should now take steps to index the journal in PubMed. The journal has a system of notifying readers through e-mail when a new issue is released. Also, the articles are available in both the HTML and the PDF formats. I especially like the new and colorful page format of the journal. Also, the access statistics of the articles are available. The prepublication and the manuscript tracking system are also helpful for the authors.
Areas for improvement: In certain cases, I felt that the peer review process of the manuscripts was not up to international standards and that it should be strengthened. Also, the number of manuscripts in an issue is high and it may be difficult for readers to go through all of them. The journal can consider tightening of the peer review process and increasing the quality standards for the acceptance of the manuscripts. I faced occasional problems with the online manuscript submission (Pre-publishing) system, which have to be addressed.
Overall, the publishing process with JCDR has been smooth, quick and relatively hassle free and I can recommend other authors to consider the journal as an outlet for their work."



Dr. P. Ravi Shankar
KIST Medical College, P.O. Box 14142, Kathmandu, Nepal.
E-mail: ravi.dr.shankar@gmail.com
On April 2011
Anuradha

Dear team JCDR, I would like to thank you for the very professional and polite service provided by everyone at JCDR. While i have been in the field of writing and editing for sometime, this has been my first attempt in publishing a scientific paper.Thank you for hand-holding me through the process.


Dr. Anuradha
E-mail: anuradha2nittur@gmail.com
On Jan 2020

Important Notice

Original article / research
Year : 2022 | Month : April | Volume : 16 | Issue : 4 | Page : NC09 - NC12 Full Version

Comparison of Long-term Efficacy of Intravitreal Ranibizumab in Diabetic Retinopathy following Monthly vs Pro Re Nata vs Treat and Extend Protocol


Published: April 1, 2022 | DOI: https://doi.org/10.7860/JCDR/2022/52668.16288
Avik Dey Sarkar, Sanjay Kumar Daulat Thakur, Rupam Roy, Ajoy Dey Sarkar

1. Fellow, Department of Vitreo-Retinal Services, Aravind Eye Hospital, Madurai, Tamil Nadu, India. 2. Professor, Department of Ophthalmology, Midnapore Medical College and Hospital, West Bengal, India. 3. Associate Professor, Department of Ophthalmology, Midnapore Medical College and Hospital, West Bengal, India. 4. Professor and Head, Department of Ophthalmology, Nilratan Sircar Medical College and Hospital, Kolkata, West Bengal, India.

Correspondence Address :
Dr. Avik Dey Sarkar,
48, JK Mitra Road, Kolkata, West Bengal, India.
E-mail: avikds24@gmail.com

Abstract

Introduction: Diabetic Retinopathy (DR) is a major complication of Diabetes Mellitus (DM), which remains a leading cause of visual loss in working age populations. The most common cause of vision loss in patients with DR is Diabetic Macular Oedema (DME). Intravitreal administration of anti-Vascular Endothelial Growth Factor (anti-VEGF) agents is currently the mainstay of therapy for both early and advanced stages of DR.

Aim: To compare long-term change in Central Macular Thickness (CMT) and Best Corrected Visual Acuity (BCVA) in patients with Non Proliferative Diabetic Retinopathy (NPDR) with Clinically Significant Macular Oedema (CSME) after receiving Intravitreal Ranibizumab (IVR) following monthly, Pro Re Nata (PRN) protocol and Treat and Extend (T&E) protocol.

Materials and Methods: This is a hospital based longitudinal prospective cohort study conducted on patients attending the Out Patient Department (OPD) of the Opthalmology Department at Midnapore Medical College and Hospital, West Bengal, India. from October 2018 to February 2021. Institutional Ethical clearance was obtained prior to the initiation of the study. Among 93 patients, 31 were chosen each for IVR PRN Monthly (Group A), (Group B) and T&E protocol (Group C) over a period of nine months. CMT and BCVA were measured at baseline and followed-up monthly for 12 months after last injection using Spectral Domain Optical Coherence Tomography (SD-OCT), while Glycated Haemoglobin (HbA1c) level was maintained below 7.4. Statistical analyses were performed using Statistical Package of Social Sciences (SPSS) statistics version 20 software. Chi-square test was used to find out the association between categorical variables. Pre and post comparisons were done using Wilcoxon sign rank test. A p-value less than 0.05 were considered as statistically significant.

Results: There was significant decrease in CMT and betterment of BCVA in all groups at the end of treatment compared to baseline. At six months and one year of last injection there was no significant change in CMT in group A and C while group B at one year (p=0.0487) showed significant increase. There was no significant worsening of BCVA in group A and group C while group B (p=0.01) showed significant worsening at one year long-term follow-up.

Conclusion: Thus, the present study concludes that, even though monthly protocol T&E protocol are equally good compared to PRN protocol on the basis of long-term beneficial effect, T&E protocol needed comparatively fewer doses of IVR compared to monthly protocol making it the choice of protocol for long-term control in NPDR with DME patients.

Keywords

Diabetic macular oedema, Glycosylated haemoglobin, Optical coherence tomography, Vascular endothelial growth factor

Diabetic Retinopathy is a major complication of DM, which remains a leading cause of visual loss in working age populations. The diagnosis of DR is made by clinical manifestations of vascular abnormalities in the retina. Clinically, DR is divided into two stages: NPDR and Proliferative Diabetic Retinopathy (PDR). The most common cause of vision loss in patients with DR is DME. DME is characterised by swelling or thickening of the macula due to sub-retinal and intraretinal accumulation of fluid in the macula triggered by the breakdown of the Blood-Retinal Barrier (BRB) (1). DME can occur at any stage of DR and cause distortion of visual images and a decrease in visual acuity. Current treatment strategies for DR aim at managing the microvascular complications, including intravitreal pharmacologic agents, laser photocoagulation and vitreous surgery. Intravitreal administration of anti-VEGF agents is currently the mainstay of therapy for both early and advanced stages of DR (2).

The IVR injection has been approved for the treatment of macular oedema following DME in 2015 (3). There have been various protocols widely accepted in the IVR therapy worldwide, namely Monthly protocol, PRN protocol and T&E protocol. In monthly protocol, monthly administration of IVR is used until the disease activity terminates. While in PRN protocol, after three initial doses of monthly IVR the therapy is readministered only when the disease requires retreatment detected during monthly follow-ups. In T&E protocol initially the IVR therapy is continued till the macula goes dry and then the monthly follow-up schedules are deferred for definite interval usually for two weeks for decreasing hospital visits of the patient and IVR therapy is administered as per need (4).

Previous studies have shown reduced Glycosylated haemoglobin (HbA1c) level has a significant positive correlation with resolution of DME (4),(5). But according to the best knowledge, this study is first of its type where all the protocols have been compared together for their efficacy in maintaining long-term effect of IVR therapy in DR patients. Hence the objective of the study was to compare long-term change in CMT, BCVA in patients NPDR with CSME after receiving IVR following monthly, PRN protocol and T&E protocol, keeping adequate HbA1c control (HbA1c <7.4).

Material and Methods

The study design was a longitudinal prospective cohort study. It included the final diagnosis codes E11.311 encompassing Type 2 DM with unspecified DR with macular oedema according to the International Classification of Diseases, Tenth Revision (ICD-10), on patients attending Ophthalmology Department at Midnapore Medical College and Hospital, West Bengal, India. The hospital-based study was performed from October 2018 to February 2021.

The protocol of the study followed the provisions of the Declaration of Helsinki. It was approved by the Local Bioethics Committee at the Midnapore Medical College as a quality assurance project (Reference number-IEC/21/06).

Inclusion criteria: Any patient over 18 years of age coming to the department with diagnosis of Type 2 DM with NPDR and DME requiring IVR without any retinal disease or significant cataract and willing to take part in the study was included in the study.

Based on the incidence of the disease and the attendance of DR patients in the institution, 93 patients of NPDR with CSME were included in the study.

Exclusion criteria: Patients who received previous intravitreal injections of anti-VEGF medications or corticosteroids within the previous 12 weeks or had any previous focal macular laser photocoagulation treatment were excluded prior to grouping.

Study Procedure

An informed consent was obtained from the patients prior to the study. They were well informed about the complete process of the study with possible risks and hazards.

Visual acuity of the patients was recorded at baseline and on subsequent follow-ups using Snellen’s Chart and then converted to LogMar equivalent for analysis purpose. Detailed anterior segment and fundus examination was performed using Slit lamp with +90D Double Aspheric Lens (6),(7).

Then all the patients underwent baseline CMT measurement to confirm the diagnosis of CSME using a Special Domain-Optical Coherence Tomography (SD-OCT) machine. HbA1c was measured at baseline and then at every three months till conclusion of the follow-up period.

All the patients were divided into three groups (A, B and C) of 31 patients each using systemic random sampling.

• Group A was posted for receiving monthly dosing IVR 0.5 mg for consecutive nine months or till the DME resolves whichever is earlier.
• Group B was posted to be given the same according to PRN Protocol.
• Group C received T&E protocol.

The group receiving IVR according to PRN protocol, after receiving initial three monthly doses, was followed by four weekly assessments in which retreatment was given as and when required if visual acuity dropped by 10 or more letters from baseline, if OCT central subfield thickness was greater than 250 μm, or if DME was judged to be the cause of visual acuity loss (8).

In T&E protocol, injection Ranibizumab was given till macula was dry. Then the next treatment was given at an increment of two weeks of each visit if the macula remained dry and a decrement of two weeks of each visit if there was new subretinal or intraretinal fluid on OCT (9).

Subsequent CMT and visual acuity was measured on each monthly follow-up for one year after last injection. Patients receiving retreatment with in the follow-up period by the means of additional intravitreal anti-VEGF injections or laser therapy were excluded from the study. Any patient not being able to maintain proper diabetic control assessed by HbA1c >7.4 were also excluded even if not requiring retreatment. Submitted scans were assessed for signal strength and image centration. Scans with signal strength below five or visibly decentred, if any, were excluded from the analysis. Finally group A had 26 patients, group B had 23 patients and group C had 25 patients each.

The primary outcome measured was change in mean CMT from baseline (at end of IVR therapy for nine months) and at six months after the last injection and one year of the last injection. Secondary outcome measures included comparison of mean change in BCVA and average number of intravitreal injections in all the protocols.

Every patient received 0.5 mg of IVR (Accentrix®; manufactured in India by Novartis) intravitreally for the treatment purpose. All the injections were given following adequate aseptic measures in the Ophthalmology Operation Theatre (OT). After dressing and draping, with the help of callipers the exact area of injection site was located at the pars plana region depending upon the phakic status of the patient. Then 0.5 mg of IVR was introduced intravitreally with the help of a 30G needle directed towards the centre of the globe. After delivering the adequate dose of IVR the needle was withdrawn carefully and the injection site was supported by a cotton pellet for a minute. Lastly, the eye was closed after instillation of 0.2 mL preservative free moxifloxacin eye drop at the site of injection. No serious postoperative complication was noted in any of the patients.

Statistical Analysis

Statistical analyses were performed using SPSS Statistics version 20 software (IBM Corp., Armonk, NY, USA). Results of descriptive analyses were expressed as means±standard deviations for quantitative variables, and as counts and percentages for categorical variables. A Chi-square test was used to find out the association between categorical variables. Pre and post comparisons were done using Wilcoxon sign rank test. Intergroup variability of outcome was compared using F test for equal variances. A p-value less than 0.05 was considered as statistically significant.

Results

A total of 93 patients with NPDR of different grades with CSME were enrolled randomly in the present study. The basic characteristics of the study population have been described in (Table/Fig 1).

After end of treatment, all the patients were adequately controlled for HbA1c (HbA1c <7.4) level for next one year. During this period five patients from group A, eight from group B and six from group C were unable to maintain HbA1c (HbA1c <7.4) level at any point or needed retreatment due to re-appearance of oedema. These patients were excluded from the study. So, the final calculations reflect results on 74 individuals.

In this study, there was significant decrease in CMT in all three groups at the end of treatment compared to baseline (p<0.01). On subsequent follow-up at six months there was no significant change in CMT noted in group A, B and C signifying good short-term control. At one year long-term follow-up, all three groups show increased CMT from end of treatment, though non significant, while group B showed maximum increment which was statistically significant (p=0.0487). None of the patients from group A and C required retreatment afterwards on follow-up due to good visual acuity maintenance and not meeting retreatment criteria while six patients from group B required retreatment meeting up the criteria after one year of last injection (Table/Fig 2).

In the present study, there was significant betterment of BCVA in all three groups at the end of treatment compared to baseline. On subsequent follow-up at six months there was no significant worsening of BCVA noted in group A, group B and group C. At one year long-term follow-up, all three groups showed BCVA worsening from end of treatment, of which Group B (p=0.01) showed statistical significance (Table/Fig 3).

While comparing intergroup control of CMT and maintenance of BCVA it has been seen that group A and group C had no statistically significant difference between them with respect to control of CMT and maintenance of BCVA in one year long-term follow-up.

But statistically group A and group C both were superior to group B in terms of control of BCVA (A vs B: p=0.04; C vs B: p=0.04). On intergroup comparison of CMT, group B and C and A and B, non significant results were obtained (Table/Fig 4).

Discussion

The recommended dose of DME for Ranibizumab is 0.5 mg (0.05 mL) administered once a month by an intravitreal injection. The phase III RISE and RIDE clinical trials and the phase III VIVID and VISTA trials established the superiority of anti-VEGF drugs over focal laser for the treatment of eyes with DME (9). For eyes with centre-involving DME, monthly treatment leads to rapid visual acuity improvement that is maintained for at least three years. As and when needed (PRN) treatment protocol injections are administered based on the presence of DME compared to monthly injection protocol. The decision of treatment depends on factors such as changes in visual acuity or persistent or worsening centre-involving DME on clinical examination or Optical Coherence Tomography (OCT) imaging. A T&E regimen inherits qualities of both monthly and PRN treatment regimens (4). Here, instead of a fixed four week follow-up interval, the length of the interval varied based on disease activity. The treatment interval was extended by one to two weeks at a time on controlling the DME, as long as vision and macular oedema remain stable. If macular oedema recurs or the visual acuity decreases, the interval was shortened by one to two weeks until the eyes return to their baseline (10).

In this study, all the groups had mean age of the patients in a comparable range >49 years with male preponderance. There was no bias over laterality. Baseline CMT and baseline BCVA in Log MAR scale in group A, group B, group C were comparable.

In the present study average number of injections required for the completion of 12 months follow-up after last injection in group A, group B, group C were respectively 7±1.68, 6.35±1.13, 5.28±1.34. A study by Lai K et al., in the population of mainland China showed that a 1+PRN protocol over 12 months required 6.83 injections on average (10). Gedar Totuk OM et al., conducted a study in which they have seen a requirement of 6.1 injections were needed over 24 months (11). Prunte C et al., in their “RETAIN study” showed the mean number of injections was 12.4 and 12.8 in the T&E + laser and T&E groups and 10.7 in the PRN group (8). A study by Ziemssen F et al., in Germany needed 4.42 injections over first year under T&E protocol (12).

In the present study, after patients receiving treatment with IVR in various protocols over nine months had shown significant reduction of CMT irrespective of the protocol type. On subsequent follow-up at six months and one year since end of therapy had shown varied picture. In monthly protocol and T&E protocol there was no significant change in CMT from the end of the treatment keeping adequate HbA1c control (HbA1c<7.4) over next one year. While patients receiving IVR under PRN guideline had experienced significant bounce back of CMT after stoppage of treatment at one yearly follow-up (p=0.0487 at one year follow-up). In all the cases, HbA1c level was adequately controlled. Lai K et al., in their study showed decreased CMT from 478.23±172.31 μm at baseline to 349.74±82.21 μm, 313.52±69.62 μm, 292.59±61.07 μ μm, 284.67±69.85 μm, 268.33±43.03 μm, and 270.39±49.27 μm at time point of 1, 2, 3, 6, 9, and 12 months respectively (p<0.05) (10). The study by Gedar Totuk OM et al., observed significant improvements in CMT at six months (p=0.036), at 12 months (p=0.013), at 18 months (p=0.021), and 24 months (p=0.021) in non vitrectomised eyes, respectively (11). Prünte C et al., found similar results in both one year and second year follow-up (8).

In this study, all three groups experienced significant improvement of BCVA at end of treatment from baseline (p<0.001). On six month and one year follow-up after end of treatment group A and group C show the best results without any significant deterioration of BCVA from final achieved value. In group B at 12 monthly follow-up following commencement of treatment, worsening of BCVA was statistically significant. Although the net effect of betterment of BCVA from baseline have been maintained even after one year of stoppage of therapy irrespective of the protocol keeping adequate HbA1c control (HbA1c <7.4). Ziemssen F et al., described that mean baseline VA was 60.6 (95% CI: 59.7; 61.5) early treatment DR study letters. VA improved by C 15 letters in 21.5% and 23.5% of the participants at 12 months and 24 months, respectively. It was concluded that despite fewer injections given compared to randomised controlled trials, with a consequently reduced overall mean visual gain, a profound functional improvement (C 15 letters) was achieved over two years in 23.5% of eyes with DME (12). Prünte C et al., observed T&E regimens were non inferior to PRN based on mean average BCVA change from baseline to 1-12 months (T&E + laser: +5.9 and T&E: +6.1 vs PRN: +6.2 letters; both p<0.0001). Mean BCVA change at 24 months was similar across groups (+8.3, +6.5 and +8.1 letters, respectively. The T&E regimens showed 46% reduction in the number of clinic visits. Over 70% of patients maintained their BCVA, with treatment intervals of ≥2 months over 24 months (8). Gedar Totuk OM et al., revealed mean BCVA improved significantly during the 24 month period (11). Lai K et al., in their study have published that logarithm of minimal angle of resolution (LogMAR) BCVA improved from 0.64±0.23 at baseline to 0.56±0.27, 0.53±0.26, 0.47±0.25, 0.44±0.32, 0.47±0.26 and 0.46±0.26 at 1, 2, 3, 6, 9, and 12 months respectively (p<0.05 for any follow-up time point except first month). It was concluded that older age, lower baseline BCVA, VMT, and disruption of ellipsoid zone are predictors for final poor BCVA while Posterior Vitreous Detachment (PVD) is a positive predictive factor for good final BCVA (10).

Limitation(s)

The main limitation of this study is the smaller sample size. A larger study sample in each group would have provided a more holistic view on the scenario. Other than that, a longer study with further follow-up would provide better results.

Conclusion

In this detailed study, there has been focus on the practical scenario as long-term effect of IVR given under different protocols keeping adequate HbA1c control (HbA1c <7.4). In this study, the results were evident that in spite of requiring maximum numbers of injections in PRN protocol, the long-term efficacy was inferior among all. The results clearly indicate that the T&E protocol is as good as monthly protocol and both are superior to PRN protocol when all the protocols were continued for nine months for maintaining long-term benefit.

But keeping in mind the socio-economic scenario in our population the burden of regular monthly affordability of injection Ranibizumab is quite difficult and here comes the importance of T&E protocol protocols. Comparing the cost burden for requirement of injections, T&E protocol require significantly least amount of injections for maintaining apparently acceptable long-term treatment outcome comparing from baseline only by keeping adequate HbA1c control (HbA1c <7.4). Hence, it was concluded that T&E protocol of IVR given over nine months may be a good choice for treatment of NPDR with DME in India.

References

1.
Romero-Aroca P, Baget-Bernaldiz M, Pareja-Rios A, Lopez-Galvez M, Navarro-Gil R, Verges R. Diabetic macular edema pathophysiology: Vasogenic versus inflammatory. J Diabetes Res. 2016;2016:2156273. Doi: 10.1155/2016/2156273. Epub 2016 Sep 28. [crossref] [PubMed]
2.
Brownlee M. The pathobiology of diabetic complications: A unifying mechanism. Diabetes. 2005;54(6):1615-25. Doi: 10.2337/diabetes.54.6.1615. [crossref] [PubMed]
3.
Lucentis (ranibizumab). FDA Approval History- Drugs.com. (n.d.). Retrieved June 23, 2020. Available from: https://www.drugs.com/history/lucentis.html.
4.
Aderman CM, Garg SJ. Intravitreal Anti-VEGF Injection Treatment Algorithms for DME. Retina Today. 2017:53-55.
5.
Chou TH, Wu PC, Kuo JZ, Lai CH, Kuo CN. Relationship of diabetic macular oedema with glycosylated haemoglobin. Eye (Lond). 2009;23(6):1360-63. Doi: 10.1038/eye.2008.279. Epub 2008 Sep 12. [crossref] [PubMed]
6.
Ferris FL, Kassoff A, Bresnick GH, Bailey L. New visual acuity charts for clinical research. American Journal of Ophthalmology. 1982:94(1):91-96. [crossref]
7.
Schulze-Bonsel K, Feltgen N, Burau H, Hansen L, Bach M. Visual acuities “hand motion” and gcounting fingersh can be quantified with the freiburg visual acuity test. Investigative Ophthalmology and Visual Science. 2006;47(3):1236-40. [crossref] [PubMed]
8.
Prunte C, Fajnkuchen F, Mahmood S, Ricci F, Hatz K, Studnic. ka J, et al; RETAIN Study Group. Ranibizumab 0.5 mg treat-and-extend regimen for diabetic macular oedema: the RETAIN study. Br J Ophthalmol. 2016;100(6):787-95. Doi: 10.1136/bjophthalmol-2015-307249. Epub 2015 Oct 9. [crossref] [PubMed]
9.
Nguyen QD, Brown DM, Marcus DM, Boyer DS, Patel S, Feiner L, et al. RISE and RIDE Research Group. Ranibizumab for diabetic macular edema: results from 2 phase III randomized trials: RISE and RIDE. Ophthalmology. 2012;119(4):789-801. Doi: 10.1016/j.ophtha.2011.12.039. [crossref] [PubMed]
10.
Lai K, Huang C, Li L, Gong Y, Xu F, Zhong X, et al. Anatomical and functional responses in eyes with diabetic macular edema treated with “1 + PRN” ranibizumab: One-year outcomes in population of mainland China. BMC Ophthalmol. 2020;20:229. [crossref] [PubMed]
11.
Gedar Totuk OM, Kanra AY, Bromand MN, Kilic Tezanlayan G, Ari Yaylal. S, Turkmen I, et al. Effectiveness of intravitreal ranibizumab in nonvitrectomised and vitrectomised eyes with diabetic macular edema: a two-year retrospective analysis. J Ophthalmol. 2020;2020:2561251. Doi: 10.1155/2020/2561251. [crossref] [PubMed]
12.
Ziemssen F, Wachtlin J, Kuehlewein L, Gamulescu MA, Bertelmann T, Feucht N, et al; OCEAN study group. Intravitreal Ranibizumab Therapy for Diabetic Macular Edema in Routine Practice: Two-Year Real-life data from a non interventional, multicenter study in Germany. Diabetes Ther. 2018;9(6):2271-89. Doi: 10.1007/s13300-018-0513-2. Epub 2018 Oct 4. [crossref] [PubMed]

DOI and Others

DOI: 10.7860/JCDR/2022/52668.16288

Date of Submission: Oct 01, 2021
Date of Peer Review: Dec 09, 2021
Date of Acceptance: Jan 27, 2022
Date of Publishing: Apr 01, 2022

AUTHOR DECLARATION:
• Financial or Other Competing Interests: None
• Was Ethics Committee Approval obtained for this study? Yes
• Was informed consent obtained from the subjects involved in the study? Yes
• For any images presented appropriate consent has been obtained from the subjects. NA

PLAGIARISM CHECKING METHODS:
• Plagiarism X-checker: Oct 06, 2021
• Manual Googling: Dec 08, 2021
• iThenticate Software: Jan 27, 2022 (19%)

ETYMOLOGY: Author Origin

JCDR is now Monthly and more widely Indexed .
  • Emerging Sources Citation Index (Web of Science, thomsonreuters)
  • Index Copernicus ICV 2017: 134.54
  • Academic Search Complete Database
  • Directory of Open Access Journals (DOAJ)
  • Embase
  • EBSCOhost
  • Google Scholar
  • HINARI Access to Research in Health Programme
  • Indian Science Abstracts (ISA)
  • Journal seek Database
  • Google
  • Popline (reproductive health literature)
  • www.omnimedicalsearch.com