This is a HIPAA de-identified open-online-patient-record with initial information in patient's voice, posted here after collecting informed patient consent (form downloadable Click Here) by BMJ Elective Student.
Our patient-centered case discussion started on WhatsApp group and opened-up the discussion with the following message:
Dr Aarti our student doctor from the 6th semester is evaluating this patient of suspected macular edema and we have asked her to look at the planned intervention namely VEGF vs laser. We have asked Aarti to share the patient details in a sequential timeline here along with images etc that can help us gain a better understanding of the patient's requirements and research the role of participatory action in EBM decision making, particularly it's role in improving student learning outcomes and it's correlation with improving patient healthcare outcomes. Over to Aarti for sharing the case presentation around this patient first followed by a discussion in PICO format around this patient's planned intervention.
Case Story:
This patient is a 50-year-old woman from west bengal who was evaluated in West Bengal for the heaviness of head during reading and detailed fundoscopic evaluation revealed macular edema for which possibly the doctors at West Bengal advised anti-VEGF and/or Laser or be prepared to lose her vision.
The patient has come for a second opinion before embarking on an expensive procedure to tackle something that was incidentally detected just because she chose to show an ophthalmologist for the heaviness of her head. I guess we need to begin by first evaluating the entire patient data in detail.
She is also a diabetic for the last 18 years and RB has seen her at 5 different time points in his career, in 4 different medical colleges in Bhopal (2), Durgapur, KIMs and once exclusively through asynchronous Telemedicine discussion.
The next step here would be to repeat the tests to see the current status of the macular edema. Once macular edema is confirmed, we need to revisit the evidence around available interventions before she takes the plunge into utilizing them.
Case-based conversational Learning:
VP: Wonderful. Very eager to learn about Laser and VEGF in the treatment of diabetic retinopathy which I have personally experienced and eager to know about their role.
MS: When was the last time she has visited the Ophthalmologist, sir?? Redoing the tests may cost her more money, why aren't we using her previous reports??
RB: She's visiting our ophthalmology along with Aarti today and getting all the tests repeated free of cost. AS, please share the tests here and let this group interpret it.
AS: I have the reports of this patient with me. Should I post them here right away, or do I need to de-identify them?
RB: Yes deidentify always. I think PB already has taken their signatures on a consent form but it would be good for you to take it again on both the UDHC and BMJ forms
AS: OCT shows there is vitro-retinal traction, that occurs when vitreous tries to pull fovea towards itself. Macular edema is confirmed( more, or less). The patient is a known diabetic, so non- progressive diabetic retinopathy was diagnosed.
RB: Why non-progressive? 🤔
AS: ETDRS shows increased thickness around the macular area, than usual, hence macular edema confirmed.
RB: Please share the Image of her retinoscopy finding report asap or ask Vishnu to do that.
Dr VS:
RB:
RB: VP, AKG, MS, can you search and find out how these images were obtained using what tools and what is their sensitivity and specificity? As you may note the diagnosis of CSME (clinically significant macular edema) was done using only the tool presented here.
VP: It is OCT. Found a good study from Cochrane evaluating its diagnostic efficacy.
EBM input:
"In nine studies providing data on CSMO (759 participants, 1303 eyes), pooled sensitivity was 0.78 (95% confidence interval (CI) 0.72 to 0.83) and specificity was 0.86 (95% CI 0.76 to 0.93). The median central retinal thickness cut-off we selected for data extraction was 250 µm (range 230 µm to 300 µm). Using retinal thickness thresholds lower than 300 µm and ophthalmologist’s fundus assessment as reference standard, central retinal thickness measured with OCT was not sufficiently accurate to diagnose the central type of CSMO in patients with DR referred to retina clinics. However, at least OCT false positives are generally cases of subclinical DMO that cannot be detected clinically but still suffer from increased risk of disease progression. Therefore, the increasing availability of OCT devices, together with their precision and the ability to inform on retinal layer structure, now make OCT widely recognized as the new reference standard for assessment of DMO, even in some screening settings.
However, researchers have found that disagreements between OCT and clinical examination occur because OCT can detect early, subclinical retinal thickening in people without CSMO and more advanced retinopathy. They suggested that such cases of subclinical macular oedema are followed more closely, since they are at increased risk of progression to CSMO. Furthermore, OCT is an essential tool to manage antiangiogenic therapy in patients with DMO and is believed by many to be a new reference standard for its diagnosis.
Our systematic review of 10 studies found that central retinal thickness measured with OCT is not sensitive enough (0.81) nor specific enough (0.85) to detect the central type of CSMO defined using fundus examination or photography according to the conventional ETDRS definition, which has guided for decades the use of laser photocoagulation, until antiangiogenic therapy became available.
In plain summary-
We found that OCT retinal thickness measurement is not sufficiently accurate to detect CSMO, involving the centre of the macula, using clinical fundus examination as the reference standard. Of 10 patients with diabetic retinopathy, 5 of whom have CSMO, 1 of 5 with no CSMO would be wrongly diagnosed as having CSMO, and about 1 of 5 with CSMO would be missed.
RB: Excellent inputs around her diagnostics Vivek. Now would you like to provide some inputs on the therapeutic strategy in such patients? Particularly with a critical appraisal of this paper https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5328320/ to enable us to make this crucial decision about what therapeutic strategy would be beneficial for her.
VP:
EBM Input:
Purpose- to evaluate the efficacy, safety, and injection frequency of vascular endothelial growth factor (VEGF) inhibitors as used in clinical practice for the treatment of diabetic macular edema. They collected data for ≥6 months after the first injection included Snellen best-corrected visual acuity (BCVA) and central retinal thickness (CRT) by OCT.
The mean age of the study population was 63.4 years, Glycated hemoglobin (HbA1c) data were available in the charts for approximately half the patients; most of the patients with available HbA1c data had good glycemic control (HbA1c ≤8%).
The primary endpoint was a combined endpoint of visual acuity and anatomic response, and patients had to have both BCVA and CRT data from the same visit to be included in the analysis. After most injections, ~1 in 5 patients with analyzable data met the primary endpoint of BCVA 20/40 or better and CRT ≤250 μm on TD-OCT or ≤300 μm on SD-OCT at the same visit. The percentage of patients who achieved the primary endpoint was 16.4% (17/104) after the first anti-VEGF injection and reached a maximum of 38.9% (7/18) after the tenth anti-VEGF injection
Conclusion:
The results of this study confirm that patients with DME treated with intravitreal anti-VEGF in the clinical practice setting receive injections less frequently than in reported clinical trials. Many patients treated with ranibizumab and bevacizumab did not achieve 20/40 or better visual acuity and/or a dry macula after anti-VEGF injection. The results indicate that a substantial number of patients with DME do not respond optimally to anti-VEGF therapy. Patients who are suboptimal responders to anti-VEGF treatment may need additional therapies, including intravitreal corticosteroid and laser therapy.
RB: So the conclusion as well as numbers are not in favor of anti-VEGF? Dr. Sumana, Dr. Vishnu how do we communicate this to the Ophthalmology people tomorrow? Also Vivek what happens to the suboptimal responders if they receive the other therapy that you mentioned?
VP: Not in favor because the frequency at which it was suggested is not followed sir.
RB: So can we look at trial outcomes where the frequency at which it was suggested was followed?
VP: In this study, they haven't said what happened to the suboptimal responders, but they concluded since DME improvement is not very promising with VEGF, so in suboptimal responders drugs that work beyond the point of VEGF in the pathogenesis should be considered. But I am sure there will study to reflect that.
RB: Yes we need to look at the efficacy of those drugs that work beyond the point of VEGF.
VP: One was corticosteroids.
RB: Yes we need to search steroids efficacy dme.
VP:
EBM Input
Injection of 4 mg of triamcinolone acetonide produces a rapid reduction in macular thickness, often within days, and with a several line gain in visual acuity [93-98]. However, the treatment response in diabetic ME is transient. As a result, repeated injections are necessary, but these responses are also transient and adverse effects may be seen.
These outcomes were illustrated by the results of a two-year trial of intravitreal triamcinolone injection versus focal photocoagulation in which the following findings were noted:
●Mean visual acuity was significantly better in the photocoagulation group at two years [98] and in the subset of patients who completed three years of follow-up [99].
●At least 50 per cent of patients treated with intravitreal triamcinolone injection developed glaucoma and/or significant cataracts [98].
Larger clinical trials are required to clarify whether there is a role for intravitreal triamcinolone injection with photocoagulation for the management of diabetic ME.
VEGF inhibitors versus intravitreal triamcinolone injection — In randomized trials of a single intravitreal injection of triamcinolone (4 mg) versus bevacizumab (1.25 or 1.5 mg) in patients with refractory diabetic ME, there was a greater reduction in macular thickness and better visual acuity (20/100 versus 20/160) at 12 weeks with intravitreal triamcinolone injection [105,106]. However, the improvements were transient in both treatment groups. In one trial, macular thickness and visual acuity returned to baseline within 12 weeks after injection of bevacizumab [106]. The beneficial effects of intravitreal triamcinolone injection lasted longer but were approaching baseline by 24 weeks. In addition, intravitreal triamcinolone injection increased intraocular pressure more than bevacizumab.
Source: UpToDate
RB: This is an amazing paper Vivek. Then what is the point of using expensive bevacizumab at all??!! Our patient on repeated history taking clarified that other than having heaviness of head she also had reduced visual acquity for distant vision and even at age 56 her near vision remains good. Will need to clarify if how she noticed the reduction of visual acquity in a gradual manner
VP: Yes sir. This drug is very expensive. When I took my dad the FDA approved drug was 36K taka (30K rupees) and non-FDA approved one was 6K. Such a costly drug with this much of efficacy!!
RB: Thanks Vivek. Let's now check out what would be her chances of having a better and less transient outcome with laser alone. Can you help us with the literature?
VP:
EBM Input
The efficacy of panretinal photocoagulation has been demonstrated in several randomized trials [28-30] and summarized in a 2007 systematic review [5]. In the Diabetic Retinopathy Study, where 1758 diabetic patients with advanced retinopathy were assigned to panretinal photocoagulation in one eye (with the other eye being the control), the cumulative risk of developing severe visual loss at six years was reduced by more than 50 percent in the treated eyes (figure 4) [28]. A similar magnitude of benefit was noted in the systematic review [5]. In addition, regression of neovascularization occurs in 30 to 55 percent of eyes after panretinal photocoagulation and may correlate with visual prognosis [28,31].
Regression of proliferative retinopathy following panretinal photocoagulation is affected by the level of glycemic control during the pretreatment, treatment, and posttreatment periods. In an observational study of 76 type 2 diabetic patients undergoing photocoagulation (115 eyes treated), 57 percent had a successful response at 12 weeks [32]. The probability of having a satisfactory response to panretinal photocoagulation was greater in those with lower glycated hemoglobin (A1C) values (odds ratio [OR] of response to panretinal photocoagulation among subjects with A1C >8.0 compared with A1C <8.0 0.28, 95% CI 0.13-0.62).
RB: Very valuable inputs Vivek. This lady has an hba1c of 9.4 so this may be a barrier but nothing that cannot be tackled although I guess the hba1c values in the study you cited actually reflects the metabolic disease activity of the patients in that group who may have fared badly due to the disease activity and that may not be reversible by just controlling the hyperglycemia. Risk reduction of 50% appears too huge and merits a detailed look at the actual study. Vivek can you share the study and Pranab can we discuss how it reached the 50% risk reduction mark.
RB has taken a detailed history of this patient.................
I took some time yesterday to gather her history in detail. She's a 63-year-old woman who looks 40 and has had diabetes for 10 years. She was a headmaster of a school in her town.
She had no problems with vision till a year back and could even read comfortably.
A year back she gradually started noticing that she was unable to recognize the faces of people from a distance and had to guess their identity from their silhouettes and body language. The local ophthalmology prescribed her glasses for myopia and she was OK. Later 6 months back she started having a problem with near vision and reading and she was asked to get a fundoscopy followed by an OCT and this is where we come into our discussion around what best intervention would match her requirements.
Going by Vivek's inputs so far I have passively decided that she doesn't need any emergent intervention with injections (anti VEGF or steroids) as the expected visual recovery would be minimal now and she may benefit long term with laser therapy.
Another interesting anecdote she shared was about the cost of the medicines.
She was informed by her doctors that there were two varieties, one was 5000/- and another was 25,000 and the 25,000 was touted to be more efficacious.
There was a man in her town she knew who related that he had gone for the 25,000 and after repeated injection sessions each costing 25,000 he didn't notice any improvement and turned bitter against his health care providers. This was one of the reasons she decided to make this 2000 km journey to us
[10:02 AM, 8/25/2018] Prof. Rakesh Sir: Here's an interesting paper on the costs of this drug in India although for a slightly different indication (even as the market dynamics remain the same)
RB: Advice from the vitreoretinal surgeon here-
VP: They finally advised the injection?
RB: Yes and even more interestingly they said if VEGF doesn't work we can try steroids after that.
VP: Nicely and inversely aligning with our discussion above.
RB: Any role of these NSAID eye drops? Vivek?
VP: Sir the eye drops are temporarily indicated for pain and inflammation relief?
RB: She doesn't have any pain or inflammation in the eye. The macular edema is supposed to be due to indolent inflammation in the retina due to metabolic syndrome but again what role would NSAID eye drops have there?
VP: That's interesting. How would these drugs reach inside the retina from the surface of the eye? Need to look up.
EBM Inputs
"This study was conducted to evaluate the efficacy of prophylactic administration of topical NSAIDs on macular edema following cataract surgery in diabetic patients and to compare between types of NSAIDs (ketorolac tromethamine 0.4% and nepafenac 0.1%) in preventing macular edema in diabetic patients undergoing phacoemulsification cataract surgery." In conclusion, this study revealed the prophylactic effect of topical NSAIDs in reducing the frequency and severity of CME in diabetic patients undergoing cataract surgery; and showed insignificant difference between ketrolac and nepafenac eye drops in the prevention of macular edema."
"This is a case series: The results from these 6 eyes suggest that nepafenac 0.1% may have activity against diabetic macular edema and warrants further investigation"
"This phase II trial may provide proof of concept evidence that topical NSAID treatment can have a beneficial effect on DME and possibly prevent increases in retinal volume or progression of non central-involved DME into the central subfield of the macula. Since effective treatments, including laser photocoagulation and intravitreal injections, already exist for DME treatment, topical NSAIDs would have to demonstrate a substantial effect on DME progression in order to be of sufficient clinical interest for further investigation. If a beneficial effect is apparent in this trial, which utilizes a relatively small sample size and short follow-up period, results from this phase II study might be utilized in planning future phase III trials. These future phase III trials could definitively answer whether or not NSAIDs are an efficacious novel therapeutic approach to the treatment of DME or preventing the progression of DME from extending into the central subfield of the macula."
"The benefits of topical NSAID therapy for DR control are mainly reported anecdotally or in uncontrolled retrospective case studies. Pseudophakic DME showed improvement in retinal thickness and visual acuity after treatment with nepafenac 0.1% for 6 months in a case report [84]. Similarly, in a case series of 6 eyes with DME that were treated with nepafenac 0.1%, the average foveal thickness decreased significantly from 417 μm to 267 μm after a mean of 178 days. Authors moreover reported that four eyes gained vision and two eyes maintained vision, with a statistically significant mean visual acuity improvement from 0.78 logMAR to 0.67 logMAR [125]. Such results suggest that nepafenac 0.1% may exhibit activity against diabetic macular edema and warrant further investigation in larger, controlled studies, possibly with and without associated anti-VEGF therapy."
"Expert opinion: A growing body of evidence suggests that NSAIDs may be beneficial in the treatment of age-related macular degeneration, diabetic retinopathy, and ocular tumors. Recent studies from our group and other authors have shown that the vitreous levels of NSAID exceed the median inhibitory concentration, which can significantly decrease vitreous PGE2levels"
Reference: https://www.researchgate.net/publication/280103710_Efficacy_and_vitreous_levels_of_topical_NSAIDs
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