Lecture: Trials to Treatment: A Case-Based Expedition to the Lessons from the Landmark Glaucoma Trials

DR DIKSHIT: Yeah. Hello, everyone. This is Dr. Siddharth, from Hyderabad. I’m from the LV Prasad Eye Institute, and it’s a pleasure to be in front of you. I hope you can make out who I am. And please believe me, the person in the photographs is the same. Well, I’m going to talk about something that’s very close to the hearts of all the glaucoma specialists, and I’ll tell you why the Landmark trials on glaucoma are so important, and how you can extract the juice to drink it for yourself. How you can use it for your patients. I’ll try to use as many case examples as possible to get my point across, and I hope this makes it a little more interesting and easy to remember. We’ll evaluate some clinical situations in open-angle glaucoma, look at the Landmark clinical trials with similar situations, and implement evidence-based decision making for these scenarios, which will serve as examples for you to carry on. For the sake of simplicity, all patients will have one eye. We will not be talking about the other eye. There’s no other pathology from those mentioned, and the visual acuity is also good. We are not discussing the specifics of medical therapy, which is another ballgame and probably another webinar. And please do remember that I can change my own rules, and there’s no political connections here. Just kind of a symbol for power. So the spectrum of trials for open-angle glaucoma is spread across many varieties, but we will be concentrating on the ocular hypertension treatment study, which is the OHTS, the early manifest glaucoma trial, EMGT, and the collaborative initial glaucoma treatment study, CIGTS. The ocular hypertension treatment study was a study that dealt with patients with ocular hypertension and not glaucoma, and compared what happens with treatment and without treatment. And looked at progression based on visual fields and disc photos. The same thing for early glaucoma was done in the early manifest glaucoma trial. When they looked at primary open-angle glaucomas, normal tension glaucomas, and pseudoexfoliation glaucomas in a similar way. The collaborative initial glaucoma treatment study was a study that looked at the impact of initial treatment in the ways of medicine or surgery in patients with all the primary and secondary open-angle glaucomas. So we will be doing it by finding whether the patient is similar to the patient included in a particular trial, or find a group which is similar to our patient. We will try to guess what the likely outcome in the patient is going to be, given we know what has happened in the trial, and we know what the characteristics of the patient are. We will consider the benefit and harm with either option. And we will also have to see if the intervention is suitable in your practice. So if I am someone who is sitting in a tertiary center, I probably have a lot of ammunition in my pocket. It will be lesser than what probably people would have in a lot of hospitals in the US. But if I go to one of my secondary centers, which is like a thousand kilometers or 500 miles from here, in a village, I would hardly have any instruments, and just my eyes and applanation to assess what the open-angle glaucoma is going to do. And the memory and probably the mobile data. But I hope you get what I’m talking about. Let us look at this case, case 0. To begin with. So if you see here, this is a 62-year-old male, who comes and the intraocular pressure is 24 millimeters of mercury. The angles are of course open, like all the patients we’ll have in this presentation. If you look at the disc, it looks like a large disc, cup to disc ratio of 0.5. The rims look healthy. There is mild peripapillary atrophy on the temporal side, good striations. There’s some nerve fiber layer which is very thin, but otherwise essentially a normal-looking disc. The visual field also is quite okay. With visual field index of 99% no difference, as such, and with very good mean deviation and pattern standard deviation. So clearly the diagnosis here is not glaucoma but ocular hypertension. So the question is: What should be the treatment? We should observe, follow up monthly, observe, follow-up 4 to 6 monthly, treat medically, or do you need more information? I’ve provided you a significant amount of information. You can choose any of the above options. The poll will close in a few seconds. Right. So most of you have chosen to observe and follow up six monthly. Some of you want to follow up on a monthly basis. Some of you want to treat. And 22% want more information. All right. Let’s go ahead and see where the answer lays in the ocular hypertension treatment study. Quite clearly, because this is not glaucoma, but OHT, or ocular hypertension, in this patient, we are going to find our answer in the ocular hypertension treatment study. Hopefully. So let’s look at what this study was. Before we go ahead, I will just share one thought that is very close to my heart. About this study. The OHTS. Which is very close to my heart. This study is one of the most public randomized controlled trials that has ever been held. Every document related to the protocol is there in the public, if you search the web. There’s a website for this study. Most of the articles which have been published are available for everyone to see. The number of papers that they have published out of the study is enormous, and the data which they provide to the reader is amazing. If you ever want to conduct a randomized controlled trial please go to the OHTS website, look deep into it, and you will know what to do without any doubt. And that is why this is my favorite study, and as you would know, that I’ll be talking a lot about OHTS, because not only about ocular hypertension. You get to know a lot of things about how to interpret evidence. What data is required to interpret and learn more from the study. So this study included patients with ocular hypertension. Which had pressures of 24 to 32. The fellow eye might be a little lower. They needed to have at least two consecutive normal visual fields. They were obviously branched into observation and treatment arms. Treatment was to reduce the intraocular pressure by at least 20%. And less than 24 millimeters of mercury. Whichever was lower. And follow them up every six months for a period of five years. And look at visual fields and flicker chronoscopy for progression. And what was the result at the end of five years? In the treatment arm, progression was seen in 4.4% of the patients. And in the observation arm, 9.5% of patients progressed. So it was quite a significant difference, with double the number of patients developing open-angle glaucoma in the observation arm. What is very interesting to see here is: Even in the observation arm, over five years, 90% of patients did not develop glaucoma. So the authors were not just satisfied. So they did something more. This is the baseline factors. You will see CCT is the major risk factor that comes out. To a lesser extent, the cup to disc ratio, the age. But CCT is the major thing that stands out here as a risk factor. So the authors were not satisfied with this study. So they did something called OHTS2, in which the arm which was under treatment — they were continued on treatment. And patients who were under observation were also started on treatment. So from a treated and an observed group, you now have an early treatment group and a delayed treatment group. So what this did was: It told us what happens when you treat ocular hypertension for 13 years consecutively. Compared to observed for 7.5 years and treated for only the remaining 6 years. So it was seen that there was a difference between the two groups. And the difference was that of 22% and 16%. Now, what they also did was they developed a scale where they could predict the risk factors or the risk of developing open-angle glaucoma in patients with ocular hypertension. Based on the data from the European glaucoma prevention study and the ocular hypertension treatment study, and they just arranged these in a line and took the topmost 1/3, middle 1/3, and the lowest 1/3. So the lowest 1/3 were found to have a 6% risk, middle 1/3, a 6 to 13%, and highest was more than 13%. Now, quite interestingly, at the end of 13 years, these two groups — and especially these three columns — behaved very differently. In the lowest risk group, there was hardly any difference in the mean risk or the confidence intervals. The p-value was also not significant. The middle risk group, 6 to 13%, the difference was around 5%, or 1/3 of the mean risk in the medication group. But the confidence intervals were quite overlapping. The p-value also was not significant. So a statistically significant difference was found only in the highest risk group, where the p-value was 0.09. But here also the confidence intervals were just overlapping. In another way to put it, if you look at the number needed to treat, it was vastly different between the two groups. The lowest risk group had an NNT of 98, which meant that to benefit one person with therapy, you had to treat 98 patients without any benefit at all. So if you start treating everyone with lowest risk, we would be unnecessarily exposing 98 patients with the risks of medication, with the cost of medication, with the burden of putting the medication… For the benefit of one person. The same number, the number needed to treat in the highest group, is 7. So here it makes some sense for the highest risk group. So basically, the decision to treat a patient with ocular hypertension will depend on the decision of: Where do you place these patients within these three groups? And if you place them in the highest risk group, probably you should treat. If you place them in the lowest risk group, probably you should just observe. Middle would be a middling ground, and not everyone will agree on this, but we’ll look at it through examples. So this is just to show how the lowest, middle, and highest risk patients were classified. They were divided into three groups, based on an ascending order of risk, and that is how they got the numbers, less than 6, 6 to 13, and greater than 13. This is the baseline predictor from the OHT and the European Glaucoma Study groups. And here if you see they have included all the risk factors, which were supposed to affect the outcomes, risk factors that were significant in multivariate analysis. The age, the mean intraocular pressure, mean central corneal thickness, the vertical cup to disc ratio, and the mean pattern standard deviation. These are all the baseline factors. And they have scoring for the present — they give a point for each of these present. And the score would be zero in the first group, one in the second group, and three in the third group. And the more they score, the more is the risk. So it is very clear that most ocular hypertension patients are at low risk. They can be followed up without medication. And delaying the treatment for 7.5 years also did not result in any significant risk of primary open-angle glaucoma. Treatment should be started on high risk patients, and these patients may have needed a greater intraocular pressure reduction, which will come later. I’ve deliberately hidden this thing. Now, coming back to our patient, whether we should observe or follow up… This is what the patient was, and if we look at the risk factors here… We cannot, because we don’t have information. So we need more information, specifically related to the CCT. If we assume that the CCT or the central corneal thickness was 580 microns, what would the treatment be now? This is an information that I had not shared earlier. So if we have this twist, of the CCT being 580, would you want to observe and follow up monthly? Observe and follow up once every four to six months? Treat medically? Or you would want still more information? Remember that there is no other ocular pathology already in any of these patients. Right. I’m very happy that most of you agree with me. And if you look at the chart here, most of the pointers here point out towards a low risk. So until there’s some other ocular pathology, which is not the case with this patient, I don’t feel that there is a need for treatment, because the risk of developing open-angle glaucoma in this patient is very low. Also, if you see the rate of progression of — or change of visual field in the treatment and even in the control group of these patients — has been very low, over five years, so whether you treat or you observe, very little change is expected, within the matter of a few months. So there’s really no point in doing a visual field every month or four to six months. These are patients you can observe, and observe on a relaxed basis. Do a visual field once every year. And that is what the recommendation from the American Academy and many other societies also suggest, that these patients should be observed on a four to six monthly basis, with visual fields performed annually. Right. Now, what if we change the central corneal thickness to 470? What would we do now? Same options. No difference at all. What would you choose to do if the central corneal thickness is 470 from 580? These questions are good, because they give me the time to sip some water. Okay, so some of you want to observe and follow up monthly. Some of you, 13%, want to observe and follow up 6 monthly. Treat medically, 52%. So how do we decide? We go back to this chart here, and what happens here is that there is one high risk factor. Two factors which are somewhere down the middle. And if we recall the chart seen earlier, the central corneal thickness was the factor with the highest hazard ratio and the most significant importance. So if the cornea is really thin, I would not really want to wait to treat the patient. Also given the patient’s age. So the patient has to live for a long time. If you look at the patient’s age, again, in most countries of the world, he would have 20, 30, or even more years to live. It’s not a very good idea, given the fact that we have agents which can be used once daily with ease, and they have very few systemic side effects, to not treat here. Let’s give the patient an advantage to treat, because we would want to be not at 40% risk, if the risk is high. With significant reduction. So ocular hypertension treatment study involved reduction of the intraocular pressure by 20%. Now, you can achieve much more than this. You can achieve a 30% reduction with just a single prostaglandin analog molecule. And this is something that I think would benefit the patient. And in my clinic, I won’t deprive the patient of this. Now, this is again to show that the central corneal thickness is far ahead of other criteria, when it comes to the hazard ratio, and the risk of — risk prediction for the development into primary open-angle glaucoma. So this is the single most important factor. So here I would really like to treat medically, and not just observe without treatment. Observation with monthly follow-up won’t be really bad, but I don’t think CCT or central corneal thickness of 470 warrants just observation. All right. Just as we discussed. Now let us see what would you do if the intraocular pressure was 28 millimeters of mercury, and the CCT was 520. We will have this same question again. With the CCT now becoming 520, and the intraocular pressure becoming 28 millimeters of mercury. See, we can have the poll question. For the C twist. C reminds me of waves. The waves remind me of water. Okay. 83% of you want to treat this. Now I will agree with you. Because if you look at the risk factors here, intraocular pressure more than 28 is in the highest category. So if one of these goes into the highest category, especially intraocular pressure, and the CCT, irrespective of what the others say, I would consider the chances of progression to be significantly more. Now, why others are not important? The cup to disc ratio? Because when you look at the cup to disc ratio here, we’re not considering the disc size. The disc size, if it’s large, even a cup to disc ratio of 0.6 is quite good. And mean deviation is something that may vary between 1 to 0.5 decibels from visit to visit. The age, while the risk of developing glaucoma — our field defects would decrease, you also have a risk of significant blindness or blindness that can affect a person’s life as the person goes older. So if the intraocular pressure is 28, we are entering the zone where the risk of vascular occlusion starts becoming great. Not really at this pressure, but something more than 30. So you would want to reduce this pressure and treat this medically. Now let us move to case 1, from case 0. So the 0 there was not really 0, but O, and it stood for ocular hypertension. Not a mistake in numbering. So we’ll look at this simple, straightforward case. Where a 65-year-old female homemaker comes to you with open angles, intraocular pressures of 28 millimeters of mercury, an average sized disc with a disc hemorrhage, and nerve fiber layer defects superiorly, along with an excavation. Inferiorly, probably there is a resolving disc hemorrhage. And with this superior defect, she has an inferior defect in the nasal aspect, which is typical of early glaucomas. So this is a disc with correlating visual field defect. The site of the inferior disc hemorrhage is a likely site where an NFLD and excavation will develop in the future. But let’s see. We don’t have it right now. So what will your decision be? For this patient? And how closely do you want to follow this patient up? Do you want to observe or treat? If you want to treat, do you want to follow up and do fields annually, do visual fields every 6 to 8 months, or do a 4 monthly visual field for this patient? Oh, wow, I love to see a divided opinion. So 24% want annual fields. 56% want a visual field 6 to 8 monthly, and 16% want a 4 monthly visual field. Right. Now, we have to pick up one study here which would be representative or very likely to find patients similar to what you have in that particular study. And that study would be… Early manifest glaucoma trial. Early manifest glaucoma trial is really another favorite of mine, because you’re never going to have another trial like this, where you do not treat glaucoma patients and observe over five years. So the people who did the study were genius in the way of developing a visual field protocol which could make all kinds of health authorities certain of the fact that their patients were being taken care of, and in no manner, even if the glaucoma progresses, are they going to lose any significant vision that is going to cost them in their life. So the early manifest glaucoma trial is the second study that we’re going to look at. And it was performed in Sweden. And all the newly diagnosed glaucomas were picked up from a screening of the general population. These were of various etiologies, like the primary open-angle glaucoma, exfoliation glaucoma, and normotension glaucoma. Patients were either observed without treatment or treated to achieve a 25% reduction in intraocular pressure, with an absolute maximum of 25 millimeters of mercury being acceptable by a combination of betaxolol and trabeculoplasty. They were observed for four years, and very closely monitored on visual fields, as well as disc photographs. And that is how the outcome was achieved. It was realized that the treatment reduced the pressures from 20.6 to start with to 15.5, so a single agent with trabeculoplasty was able to achieve this reduction, and maintain it throughout, and greater reduction was achieved in patients with higher intraocular pressures. In the control group also, the pressure did not go on rising, and it was maintained to less than 35 millimeters of mercury. There is some lacunae of data in the study group, but what it does tell us is that older age worse mean deviation, lateral eligibility, presence of pseudoexfoliation, increase in intraocular pressure, and disc hemorrhage on follow-up are all risk factors for progression of glaucoma. So in this patient that we have, we have quite a few risk factors which were present. With the age, very close to being eligible. So that is why this yellow color. And presence of disc hemorrhage and intraocular pressure being high. Risk factors that are present. Now, this is a graph from the sum total of patients from the EMGT study. And what we see here, from the hypertension glaucoma — this is a graph of the progression of disease, how the mean deviation is likely to change, and the patients are likely to go from near normal eyes to blindness within 10 to 12 years. So it’s difficult to say what this number is, but something like 10 to 12 years is what will be required for these people to lose entire vision. A lot less will be required for them to be symptomatic and significantly affect their lives. But yes, total blindness will take around 10 to 12 years. The patient that we have in question here belongs to this, but if you see mean deviation is close to 1, less than 2, so this patient is starting really high. So you don’t see that this patient has a significant likelihood of progressing on to blindness or significant loss if you start on treatment, and that is why you will start on treatment. At this early stage, you would do something like 6 to 8 monthly visual fields, especially because there has been two disc hemorrhages. Annual fields won’t have been a bad choice, but in the presence of disc hemorrhage, which usually is a predictor of progression in visual field, you would rather do a visual field extra, rather than doing something annually. So having three to four visual fields over a period of two years is something that you would want, and then look closely at the progression. So it’s been known that disc hemorrhages can be a precursor for a visual field defect and an NFLD, coming within the next 3 to 6 months. So if we give some time for it to settle, and then we take that through a visual field. A slightly more complex case of glaucoma. Well, how complex can primary open-angle glaucoma be? So you have a 70-year-old person with a pressure of 28 millimeters of mercury. The disc here shows a cup to disc ratio of 7.8, almost, with there being a notch here, and a nerve fiber layer defect that is developing. Still not fully developed. There’s a diffused nerve fiber layer, rather than a specific one. So you see this dark-light pattern is no longer the case. This looks dull, and there is no stark contrast between the central nerve fiber layer near the vessels. So the visual field shows a superior defect very well matching to the clear cut NFL defect and excavation inferiorly. The same in the 24-2 and 10-2. Some defects were there on 24-2 earlier. So the risk factors that are present here are older age and increased intraocular pressure. We will assume that the CCT if not mentioned is quite okay here. So again, this is a patient who has high tension glaucoma, but is slightly lower down on the scale of damage. So you would want to do a little more visual field, because this is a disease that has actually progressed to this level on its own. Compared to what you saw in the other patient. Now, while age is always a risk factor across studies for developing glaucoma, we need to look at the age in a way that probably the studies cannot capture. You need to use your common sense. So let’s see the story of this person, who is an 85-year-old retired professor, intraocular pressure of 24 millimeters of mercury. Pseudophakic, open angles. He shows a cup to disc… It’s difficult to guess. An average disc with a cup to disc ratio of say 0.5. Superior rim is excavated, and early nerve fiber layer defect is seen, which is matched and correlates well with the scotoma that you see in the nasal and the arcuate area here, encroaching very close to the center. So what would you want to do here? Given that there is a risk factor of increased age, and 20 millimeters of mercury. Now, what do we see here? Despite having a little more number of risk factors, the fact is that the mean deviation is very close to 1 decibel. Even if you allow this patient to progress completely, without treatment, and without any observation, he is very, very unlikely to go blind even over 12, 13 years. So treatment, yes. Especially in view of the safe drugs, as far as the systemic health is concerned, of being available, the prostaglandin analogs, and the ease of use on a once daily basis. But this is not a patient where you would want to do visual fields too regularly. Let the man have rest in his old age. Enjoy the retired life. So here probably I would consider doing fields on an annual basis, and look at him after initial intraocular pressure control once every six months, not to trouble the grandpa so much. Being an educated person, I think he is someone who will come to your office and not miss appointments. At least, that’s the hope. Look at another extreme. So this is a patient with pseudoexfoliation, with a significantly high intraocular pressure, 64-year-old male, who shows bipolar excavation, almost a notch superiorly, yes, a notch superiorly, wide nerve fiber layer defects, which are seen even better in the black and white photograph. In the red field photograph, you see that the dark and light part is completely reversed, which is evident of dense nerve fiber layer defect, and you see bilateral scotoma as well as inferior defects on the 10-2. So what should the treatment be here? We have all the possible risk factors. Quite a few risk factors here. Old age, worse mean deviation, quite a significant loss here, presence of intraocular pressure greater than 20 millimeters of mercury. And the most important thing, presence of pseudoexfoliation. In my experience, pseudoexfoliation even within India varies from place to place. So pseudoexfoliation in some parts of India might not be that bad a prognostic factor, but in certain populations it really has a very poor prognosis. Let’s leave it at that, because this is neither evidence-based nor something that has come up at other places. Just something that I can say on the webinar. I hope without any controversies. But yes, significant risk factor shown by many other studies, including the EMGT. The time that the pseudoexfoliation glaucoma will take to develop blindness from a near normal field is just over five years. So that is the kind of danger that pseudoexfoliation glaucoma carries. So that is why these patients should be observed very closely, do visual fields frequently, and if you have any suspicion, rule out fluctuations by diagonal exfoliation. And do a surgery, because the fluctuations will be taken care of. There’s something which is amazing about both these studies, the OHTS and EMGT. I would like you to comment on what is common between the ocular hypertension treatment study and the early manifest glaucoma trial. They both included glaucoma patients. Both of them showed pseudoexfoliation as a risk factor. The treatment in both studies in the treatment arm could have been more aggressive, or the mean rate of progression on visual fields in both studies was around 0.5 decibels per year. I have a feeling that I have already let the answer out. Hopefully you won’t remember what I said earlier. And the answer has probably been let out earlier, at least to a partial extent. Let’s see if you do remember. I wonder if I can also answer these questions, and is there a prize. Okay, so ocular hypertension study did not include glaucoma patients. At the baseline, they were patients with ocular hypertension. They did not comment if pseudoexfoliation was present in the population or not. The mean progression was something like 0.3 decibels, which is probably not important. So the common factor was the treatment in both these studies should have been more aggressive in the treatment arm. Let’s look at why. So it is amazing that a single medication in EMGT would reduce the intraocular pressure by 25%. But at the same time, we can see that even in the treatment arm, there was a significant number of people who progressed. 45% over time. And even in the control arm, there were 38% of patients who did not progress. So is the treatment actually doing much here? Of course, characteristically, it did enough to be proven as a protective factor, but would this much lowering of intraocular pressure be sufficient? Probably not, and that is why the reason — that is the reason why we saw progression. Not all glaucoma patients who started at the same point in time are equal. There will be patients with ocular hypertension who will never go on to develop glaucoma. There will be patients with ocular hypertension who will go on to develop glaucoma over time. Many, many years. There will be patients with ocular hypertension, again, who will develop glaucoma more rapidly than other people. There will be patients with open-angle glaucoma who will progress rapidly. There will be patients with open-angle glaucoma who will progress so rapidly that they are kind of jumping towards blindness until a major intervention is performed. So the rate of progression, as you see in the curve here, the lines here, which are made by joining the visual field indices over time, in the GP analysis that you can get now in the Humphrey machine, is different for different patients. What it means is that there might be a patient whose disease is very mild. And these are patients who probably did not progress within the four-year study period of even being in the control group of EMGT. On the other hand, there might have been patients who were rapid progressers, and who required more than just 25% reduction of intraocular pressure. Even in the ocular hypertension treatment study, there were 79 patients who developed glaucoma out of a patient total of 1,000 patients, despite being on treatment for 13 years. So the 20% reduction in OHTS, the 25% reduction in the EMGT, may not have been sufficient, and we probably need to treat some patients who show signs of early progression especially now that the imaging is there, a little more aggressively than just reducing the intraocular pressures by 20% to 25%, and that is what we usually look at or desire in the patients in our clinic. So treatment in both the studies, in the treatment arm, could have been more aggressive. The other thing that is very important here, as far as you’re looking at the Humphrey visual field printouts, you may be looking at a lot of other things, but here is a patient who has three visual field printouts in what is called the overview layout of a 10-2 field. Here you can see that there is a deepening of the scotoma in gray scale, and at the same time, there is some enlargement here, and if you carefully look at the numbers, the numbers are also worsening. They are increasing from single digits to 10s to 20s to something that is all 0. So there is deepening and enlargement of scotoma. And you can make this out by looking at just three visual fields. However, if you depend on the trend-based software, you will not get the answers until you have three follow-up fields, after the two baselines. So if you want to catch the progression early, you have to look at each individual field in an overview layout. 10-2 visual fields are likely to catch progression earlier than 24-2. So these are some things which are not there in the EMGT, but probably were worth pointing out, and has been proven through various other trials. So you have to determine the aggressiveness of the disease in the initial few years by looking at the amount of pressure control you can get through medications and by performing for visual fields. The target intraocular pressure is neither universal, because the patients can have different severities of the disease, nor a single number, which can be — has to be dynamic. And you have to be following up patients more closely when required, and repeated visual field can prevent a significant visual loss in these patients. Looking at a slightly more complex patient, you see a patient who is a 58-year-old male. The intraocular pressure is 31. There is a large disc with inferior notch, and a superonasal notch. What a place to have a notch. And a significantly depressed superior and inferior hemifield in the 10-2 and bilateral arcuate scotoma in 24-2. The mean deviation in 24-2 is 23.57 minus. So what would you think should be the way this patient should be treated? Medical management with 4 to 6 monthly visual fields? You don’t know what the trials on the basis of what the EMGT says… Medical management, close follow-up, 4 to 6 monthly fields, not from these trials, medical management, close follow up, 3 to 6 monthly fields, and I’m very happy that everybody has chosen trabeculectomy. Not that I agree with the answer. So quite obviously, the collaborative initial glaucoma treatment study is the one that included advanced glaucomas, and that’s what we looked at. These were all newly developed glaucomas, and in patients with open-angle glaucoma, exfoliation glaucoma, and pigmentary glaucoma, these were randomizing two medication groups, where they were treated with medications, trabeculoplasty, and trabeculectomy in sequence if one step failed. And in the surgical group, it was trabeculectomy, medication if the trabeculectomy failed, and follow up for five years. The great thing was that there was significantly reduced progression in both arms. The average intraocular pressure levels that were achieved were slightly lower in the surgical group. Or that was statistically significant. And there was not much difference in the total symptoms here. So a lot of people believe, including this recent article, that the CIGTS has actually shown that the advanced glaucomas are likely to progress if treated initially with surgery, and that this would apply to the patient that we discussed. We very often missed the point that the review articles have not looked at this — the numbers from the original article — that the progression is significantly associated with the same effect in both treatment groups if intraocular pressure levels were achieved that were the same in both groups. If you achieve an intraocular pressure level of 14 to 16 with medications or with surgery, it is not going to make any difference. Now, the second most important thing is: If you look at the fields, individual fields, in the upper row, and the lower row, all of these are advanced glaucomas. But if you look carefully, the mean deviations are greater than around -16 decibels in the upper row, compared to what you see in the lower row, means that these patients were not included in the study population for the CIGTS. And CIGTS definitely cannot comment upon patients which were not included, so a patient with advanced glaucoma who has visual fields like this — a 10-2 visual field like this, and a split on a macular program, probably cannot be commented upon through the CIGTS, and definitely they did not have the sample size with the number of patients included with these advanced fields — were not much. So both the medications and the trabeculectomy group can have significantly lower intraocular pressure, and aggressive lowering of intraocular pressure leads to lower progression, and the risk of progression is related to intraocular pressure levels. What is true is that you are more likely to achieve a lower intraocular pressure through surgery. But 14 on surgery is very likely to be 14 on medications. And the quality of life does not improve with surgical therapy. Something that people really believe that they’re doing a great job, by reducing the medications that the patients are using. And surgery was associated with more complications. And it does not apply to a patient whose visual field score was more than 16.0, which can somewhat be correlated or be considered close to the mean decibels. The mean deviation on decibels. So for this patient, even the CIGTS showed that you would probably treat this patient medically, manage with close follow-up, and then look at the response as far as the intraocular pressure is concerned. Do visual fields at the earliest sign of medical failure. Do not hesitate in going further. The initial treatment may be trabeculoplasty for this patient, and then start on medications, but either of them alone may not be sufficient. So that is what my plan would be, to treat on medications, to lower the intraocular pressure. Mid teens preferably, or low teens, and surgery if treatment fails, by doing a very closely based visual field. So the lessons to take home is, again, that the medications are first line of therapy, and the patient always has to be a participant, and you should not assume that the quality of life becomes better by reducing the number of medications. And it’s been proven in the randomized controlled trial. So this was just a brief overview of the trials on open-angle glaucoma, which mimic our situations most commonly. And there is much more to learn, but I hope this gives you an idea of how you can take these messages from trials to your patients by following these steps of looking for a similar group. Predicting the likely outcome in the patient. Measuring the benefit versus harm in either options, applied to your particular patient, and is this intervention suitable to your practice? So just because someone recommends a trabeculoplasty, I may not be able to do a trabeculoplasty, if it’s not available here, and I would go beyond that particular trial. Similarly, if we have imaging available, there is no doubt that you should involve imaging now, in the light of evidence that we have seen beyond these landmark trials. So a lot will depend on not just you, but also the choices that the patient would make. I would like to stop here and dedicate some time for questions and answers. So what you see here are the photographs of the beautiful campuses that we have, and I’m really proud of the greenery that we see here.

>> Thank you, Doctor. So far we have three Q and A questions, so if you want, you can stop your screen share and open up the Q and A.

DR DIKSHIT: Okay, I have to stop my screen share. I didn’t figure that out. Okay. I’m unable to actually stop the screen share. Lawrence, can you do something to stop my screen share?

>> Sure, one moment. It looks like it’s stopped now.

DR DIKSHIT: Yeah, it has. So I’ll go to the Q and A. Okay. So I see the question on how about SLT for ocular hypertension. Right. So SLT is a very good option for treating these patients as the initial modality of treatment. But that is not something that ocular hypertension treatment study showed, so it was not relevant here, so I didn’t speak of it, but of course, SLT is definitely a good option when you want to reduce the intraocular pressure in a patient with ocular hypertension or early glaucoma. The next question is: If I can move this out of my way… Yeah. When to treat high myopes with OHT or suspicion of glaucoma? Ocular hypertension in any patient should be treated the way it is treated. Imaging especially is not a very good option in patients who are high myopes, and have nerve fiber layer changes, just because of the myopia that they have. And if the visual field is good, which again may not be the situation, you have to depend on the visual fields more than the imaging in these patients. Do not treat just on the suspicion of glaucoma. When all is said and done, there are situations — like if you see a patient with coloboma, where you cannot make out the disc at all, if you see a patient with a gross posterior scotoma, you end up treating the intraocular pressure, and I don’t think this is something really wrong. So with these questions, the next two questions are related to imaging. And the question is: What is the best indicator for diagnosis of glaucoma? And whether the OCT is being used excessively or not. Now, there is no denying the evidence that OCT catches glaucoma early. There is no denying the evidence that the GCC or GCA, depending on which machine you are using, the ganglion cellular analysis, catches glaucoma earlier. Now, what is the problem with this is… You can be so early in catching things, if you’re catching extra things also. So a fish net which catches a lot of fishes is going to catch a lot of other stuff also. So what I need to say here is: Not all patients who have abnormalities on OCT with GCA or GCC are likely to have glaucoma. Patients with early glaucoma are likely to show glaucoma earlier on GCC, but that cannot be the sole criterion for treating patients with glaucoma. There’s this landmark paper, which talks about progression on OCT from a famous group in the US, which has been quoted very often by many people for proving that the OCT will catch progression early. Now, in that paper, 50% of patients who were under treatment in the clinic have shown progression over four years. Can you imagine that that can happen? It clearly means there are a lot of false positives being caught by the OCT for diagnosis of glaucoma, and for the diagnosis of progression. So use OCT. It’s a very important tool in glaucoma management. But don’t use OCT in isolation. And just because there is a thinning of 0.1 microns on the OCT, it does not mean that the patient is going to go blind. So use the OCT, but use it wisely. It’s a sword which can damage people around if you don’t use it properly. I hope I’ve answered the question in the most appropriate manner that I can think of.

>> So that looks like all of the questions, and we’re at an hour now, so that might be a good place to stop.

DR DIKSHIT: Right. Thank you, Lawrence. Thanks to all the audience who have taken time to be here. And thanks to Orbis and Cybersight. Thank you so much. And have a good day.