Reducing Intraocular Pressure: Is Surgery Better than Drugs?1

It is irreversible because it results from the degeneration of retinal ganglion cells, and to date there is no cure for neuronal central nervous system degeneration, or means of regenerating lost neurons.

After more than a century of active research in the management of glaucoma, the Holy Grail of glaucoma treatment is still elusive and we have to be pragmatically content with our attempts to prevent further progression of glaucomatous damage, rather than curing the disease.

Glaucoma progression is strongly associated with a number of risk factors.^7-14 Some of these factors are unmanageable like ethnicity and age, while others can be manipulated, with varying degrees of success, in an attempt to slow or arrest progression, like IOP and possibly vascular dysregulation.

Reducing IOP is presently the evidence based, most accepted, and most practised therapeutical approach of glaucoma patients.^12,15 Currently topical ocular hypotensive medications, with its different classes, as well as filtering surgery (trabeculectomy and non-penetrating surgery) are in the forefront of therapeutic modalities to reduce IOP.^{15, 16-22}

This review article looks at the potential advantages and disadvantages of topical medications versus filtering surgery and vice versa. It does not directly address the question of initial treatment of glaucoma,^{19, 20, 23-28} or what is the better treatment²⁹ of glaucoma, as other review articles had, but rather looks in a more specific fashion on the pros and cons of each in relation to IOP reduction. In other words this review article deals with the situation once the decision has been made to reduce IOP.

Last but by any means not least, in a world exceedingly aware of the heavy medical care expenses³⁰ an ideal treatment to reduce IOP should be economically sound.

In the Advanced Glaucoma Intervention Study (AGIS),³² eyes were randomized to laser trabeculoplasty or filtering surgery when medical therapy failed. In the roughly one quarter of eyes in the study in which the IOP was always lower than 18 mm Hg (mean IOP, 12.3 mm Hg) during 6 years of follow-up, there was no net change in the mean visual field score. While 15 percent of such eyes were said to have worsened by 4 AGIS visual field units, an equal percentage “improved” by the same criterion, perhaps providing an estimate of the false-positive rate of progression. In contrast, in those eyes in which the IOP was greater than 17 mm Hg more than half the time (average IOP, 20.2 mm Hg), eyes lost an average of approximately 3 AGIS units during 8 years of follow-up. A clear dose-response relationship between IOP and risk of progressive field loss was evidenced for intermediate categories.

With surgery levels of IOP in the low teens, or even lower, are technically achievable,^19,20,33-36 and that is independent of the IOP values prior to surgery. What determines IOP levels postoperatively are mainly the degree of surgical precision intraoperatively, the resistance to outflow posed by the scleral flap in trabeculectomy, at least initially. On the long run the degree of wound scarring²⁹ postoperatively and whether this has been manipulated by antimetabolites,^20,34 plays a role of paramount importance.

In topical medications IOP in the low teens is less likely to be achieved³⁷ but never the less possible specially with newer classes of medications¹⁸ and with the use of combination topical medical therapies, while the level of IOP is largely dependent on IOP values before commencing therapy. Topical medications depending on their mechanisms of action, whether reducing production or increasing outflow, tend to knock down percentages of prior levels.

It is fair though to acknowledge that not every patient requires an IOP in the low teens in order to halt his glaucoma progression. In the collaborative initial glaucoma treatment study²³ it would seem that patients with mild, initial damage can do well at pressures in the mid-to-upper teens, while those with more advanced damage indeed do better when pressure is reduced to the lower teens.

Long-term IOP reduction capabilities of other newer classes of medications are still not fully determined.^{39, 40} One study¹⁸ with a two-year follow-up found that latanoprost significantly reduced IOP from pretreatment values, and this reduction was maintained over the 24-month treatment period with no sign of upward drift.

Surgery also shows deterioration of its results with time. Chen and coworkers⁴¹ studied the long-term outcomes of primary trabeculectomies that were successful at 1 year. This was retrospective study of patients with various types of glaucoma who had trabeculectomies that were successful at 1 year and who had a follow-up of at least 10 years. Forty patients (40 eyes) were enrolled, who had primary trabeculectomies that were successful at 1 year and who had a follow-up range of 10 to 21 years. Control of IOP was evaluated at 5, 10 and 15 years and at the last obtainable follow-up. Successful control of IOP was defined as IOP less than 21 mm Hg or a reduction of 33 percent if preoperative IOP was less than 21 mm Hg. These results show that if an eye was considered successful by IOP at 1 year, the probability of successful control of IOP was 82 percent at 5 years and 67 percent at 10 and 15 years. If an eye did not require further glaucoma surgery at 1 year, the probability that it still would not need further surgery at 5 years was 90 percent, at 10 years 75 percent, and at 15 years 67 percent. They concluded that loss of IOP control and progression of glaucomatous damage occurs over time despite initial success at 1 year.

Another study⁴² examined the long-term results (1 to 14 years) of trabeculectomies with 5-fluorouracil injections that were successful at 1 year. In a retrospective non-comparative case series the authors identified 87 3patients (87 eyes) who had trabeculectomies with 5-fluorouracil injections that were successful at 1 year and had a follow-up range of 1.0 to 14.7 years (mean, 8.1, standard deviation of 4.4 years). All patients had previously failed glaucoma surgery (66.7%), cataract surgery (47.1%), or other diagnoses making them at high risk for failure. Successful control of IOP was defined as IOP less than 21 mm Hg or a reduction of 33 percent if preoperative pressure was less than 21 mm Hg. Statistical analysis was performed using Kaplan-Meier life table analysis. If an eye is considered successful by IOP at 1 year, the probability of successful control is 61 percent at 5 years, 44 percent at 10 years, and 41 percent at 14 years. They concluded that despite successful IOP control at 1 year, trabeculectomies with 5-fluorouracil injections show a continual loss of IOP control over time.

Asrani and coworkers⁴⁵ have demonstrated that the diurnal IOP range and the IOP range over multiple days were significant risk factors for glaucomatous progression, even after adjusting for office IOP, age, race, gender, and visual field damage at baseline. This implies that we can no longer rely on an IOP in the statistically normal levels under treatment in office visits. Patients could still suffer from glaucomatous progression because of high fluctuations. What remains to be identified is the risk of this progression in large “within statistically normal” fluctuations compared to fluctuations outside of what is statistically normal.

Migdal and coworkers³⁷ compared the long-term functional outcome in POAG in medically treated patients versus surgically treated patients. Among many results from this study they observed that patients in the surgery treated group had the lowest mean IOPs and with fewer peaks and troughs. The maximum mean IOP was 15.5 mm Hg and the minimum mean IOP was 13.1 mm Hg for surgery compared with 22.1 mm Hg and 15.9 mm Hg for medicine.

Another study⁴⁶ was designed specifically to compare the IOP fluctuations in glaucoma patients under ocular hypotensive therapy with those of patients previously submitted to trabeculectomy. The IOP peaks and fluctuations for the same patients in response to the water-drinking test (WDT) were also examined. The study included 30 primary open-angle glaucoma (POAG) patients using ocular hypotensive medications and with no history of previous intraocular surgery (medical group), and 30 POAG patients previously submitted to one or more trabeculectomies though taking no medication at the time of the study (surgical group). All patients were submitted to a diurnal tension curve (DTC) followed by the WDT. The IOP peak and IOP fluctuation during the diurnal tension curve were significantly greater in the medical group than in the surgical group. The same was observed following the WDT. From an overall baseline IOP of 10.6 mm Hg, the mean IOP change following the WDT was 13 percent in the surgical group and 40 percent in the medical group. The study concluded that patients submitted to trabeculectomy have less IOP fluctuations during the diurnal tension curve and following a water-drinking provocative test.

This observation does constitute a definite advantage of surgery over medical treatment in that respect, thus potentially offering better potential chance of stabilization or retardation of the glaucomatous disease process. One criticism to these two studies though, was the inclusion of patients under different classes of ocular hypotensive 4medications under the medical group. Different classes have different effects on IOP diurnal curves as has been demonstrated by Orzalesi and coworkers.⁴⁷ They compared the round-the-clock intraocular pressure (IOP) reduction induced by timolol (0.5%), latanoprost (0.005%), and dorzolamide in patients with primary open-angle glaucoma (POAG) or ocular hypertension (OHT). This was a crossover trial, 20 patients with POAG or OHT were treated with timolol, latanoprost, and dorzolamide for 1 month. The treatment sequence was randomized. All patients underwent measurements for four 24-hour tonometric curves: at baseline and after each 1-month period of treatment. The between-group differences were tested for significance by means of parametric analysis of variance. To compare the circadian IOP rhythms in the POAG-OHT and control groups, the acrophases for each subject were calculated. All the drugs significantly reduced IOP in comparison with baseline at all times, except for timolol at 3 AM. Latanoprost was more effective in lowering IOP than timolol at 3, 6, and 9 AM (P = 0.03), noon (P = 0.01), 9 PM, and midnight (P = 0.05) and was more effective than dorzolamide at 9 AM, noon (P = 0.03), and 3 and 6 PM (P = 0.04). Timolol was more effective than dorzolamide at 3 PM (P = 0.05), whereas dorzolamide performed better than timolol at midnight and 3 AM (P = 0.05). In this study latanoprost seemed to lead to a fairly uniform circadian reduction in IOP, whereas timolol seemed to be less effective during the night-time hours. Dorzolamide was less effective than latanoprost but led to a significant reduction in nocturnal IOP. Although the study compares IOP lowering effect of the medications over a diurnal curve, the study lacks, or does not report, information on the differences in fluctuations in the diurnal curve between the different medications. In fact if one compares different diurnal curves of different medications, latanaprost seems to have its curve in the lowest level, but if one examines the IOP diurnal curves presented in this study, it appears that latanaprost provides similar range of fluctuations to timolol. Another concern in that we are judging mean IOPs and not individual curves, theoretically single individuals might be at higher risk of glaucomatous progression due to high fluctuations, which would not be apparent from mean IOP curves, this is of special concern in an era where individualized therapeutic decisions are stressed.

Medication class specific or even medication specific studies comparing IOP fluctuations in surgically versus medically controlled glaucomatous patients are in dire need, if this point is to be resolved. Though the bulk of evidence, for the time being, seems to point to a relative advantage of surgery over medications in that respect.

Clinically significant non-compliance with glaucoma medications has been well documented. One study⁵⁵ documented the prevalence of non-compliance in a Greek cohort. Clinically significant non-compliance (more than two doses missed per week) was established in 44 percent of patients examined. Men and those using eyedrops more than 4 times a day were more likely to default. Non-compliant patients exhibited higher mean IOP (22.9 vs. 18.5 mm Hg; p > 0.001) and worse visual field loss (10.8 vs. 7.0 dB; p = 0.008) compared with compliant patients. Involuntary non-compliance was also common in this group, with only 53 percent instilling their eyedrops accurately.

Another study⁵¹ was designed to assess levels of compliance in elderly glaucoma patients on timolol eyedrops. Twenty-four percent of patients admitted to omitting eyedrops either occasionally or frequently. Fifty-one percent were found to have had insufficient drops dispensed to comply with treatment as prescribed. In non-complaint patients the mean period without drops was 85 days of the year, with a maximum of 165 days.

Compliance could theoretically, but safely be assumed to be much worse in developing countries compared to developed ones, for obvious reasons. It could be assumed to improve with fewer medications and fewer doses per day, more easily tolerated side effects, as well as with better understanding of the nature and gravity of the disease process.5

One study⁵⁶ examined the causes of non-compliance with drug regimens in glaucoma patients. The results showed that forgetfulness was the number one reported reason for non-compliance. In the literature^48-56 rates of non-compliance range between 23 percent and 51 percent, whatever the rate may be in different communities and age groups surgery has a clear advantage over medications in this respect.

One useful way in assessing compliance with eyedrop medications is the miniature compliance monitor as purposed by Kass and coworkers.⁵⁷ The medication monitor resembles commercially available 30 ml eyedrop bottles in size, shape and weight. It electronically records the date and time of each medication administration over a six-week period.

Glaucoma patients’ persistence with long-term pharamcotherapy is also an issue of concern when discussing ocular hypotensive medications. Two studies^58,59 have identified persistency as a significant factor that may influence not only health outcomes, but also long-term costs and health planning. One study compared persistency (time on initial therapy) of latanoprost versus beta-blocker monotherapy. The authors reported that patients receiving a beta-blocker as initial therapy were 3.8 times more likely to change therapy than those initially treated with latanoprost.

Another much dreaded, but fortunately a rare complication is expulsive hemorrhage. One study⁷¹ reported an incidence of 0.57 percent after trabeculectomy. Another study⁷² examined delayed suprachoroidal hemorrhage (DSCH) after glaucoma filtration procedures. Of a total of 1863 trabeculectomy procedures, DSCH developed in 9 of 615 (1.5%) trabeculectomies without antimetabolite, 30 of 1248 (2.4%) trabeculectomies with antimetabolite.

Other complications that do occur more commonly include hypotonic maculopathy (8.9%), bleb leaks (8 −14.6%), hyphema (24.6%), and choroidal detachment (14.1%).⁷³

Of special interest is cataract incidence after trabeculectomy. This complication, apart from its deleterious effect on vision, often necessitates another intraoperative surgery, which could adversely affect the initial trabeculectomy results. The cataractogenic effect of surgery has been well documented.^23,74 Cataract incidence post-trabeculectomy has been reported to be as high as 20.2 percent in a follow-up of 12 months.⁷³ It is worth mentioning that such complication rates are not reported with non-penetrating surgery.^75-82 The vast majority of studies in the literature report significantly lower early postoperative complications compared to trabeculectomy. It also reports lower incidence of postoperative cataract formation. It is necessary though to acknowledge that the randomized controlled trials reporting on cataract incidence after non-penetrating surgery do not have the same long-term follow-ups as in the case of trabeculectomy.

Ocular hypotensive medications are not devoid of ocular side effects and complications. For one, the early manifest glaucoma trial¹⁵ reported increases in clinical nuclear lens opacity gradings with medical treatment (P =0.002). Similar observation, but not statistically significant was observed in the ocular hypertensive treatment study,⁸³ where 6.4 percent of the treatment group had cataract surgeries compared to 4.3 percent of the observation group (p=0.06).

It is worth mentioning that the last two studies medication groups were under different medications. We have no information about which ocular hypotensive medication would put a patient under a higher risk of cataract occurrence.

The noxious effect of ocular hypotensive medications on the ocular surface has been long identified. One study⁸⁴ reported that administration of a single topical medication 6preserved with benzalkonium chloride, irrespective of type, for 3 months or more induced a significant degree of subclinical inflammation detected as increased expression of HLA-DR on conjunctival epithelial cells. Another study⁸⁵ reported that latanoprost treatment induces ocular surface changes which are more evident in POAG patients who are also affected by allergic conjunctivitis. The authors hypothesized that these findings are probably related to the very high latanoprost concentration of benzalkonium chloride and to its bedtime administration, which further amplifies the toxicity.

An increasing number of studies^23,37,86,87 both experimental and epidemiological, have provided evidence that filtering glaucoma surgery maybe less effective than initially described. Of a number of risk factors for failure, duration and number of antiglaucoma drugs prior to surgery seem to play a critical role and highly accumulated antiglaucoma topical treatments significantly reduce success rates.⁸⁸ Inversely trabeculectomies performed as a primary procedure do offer higher success rates than trabeculctomies performed after a history of ocular hypotensive medications.

Again very little is known about which medication, in which patient is associated with which adverse effects, and if that is clinically relevant.

Among others, pulmonary effects of beta-blockers are exceptionally worrisome. Two drops of 0.5 percent timolol equates to a 10 mg oral dose. This is not enough to cause symptoms in many patients, but unfortunately glaucoma and airways disease frequently coexist. Glaucoma affects 5 percent of people over 65 years⁹⁶ and incidence⁹⁷ of asthma in elderly patients (above 65 years old) is 4 percent in males and 7 percent in females. This should not be understood in the sense that beta-blockers are contraindicated in patients above 65 years, only patients with a clinically relevant bronchial asthma does run a risk with beta-blockers.

Attempts have been made though to offer better safety profile ocular hypotensive medications. Betaxolol [Betoptic] is cardioselective beta-blocker but is associated with poorer IOP control.⁹⁸ Carbonic anhydrase inhibitors^30,47,99-105 applied topically are associated with less serious systemic side effects, but are also less potent than if orally administered. Prostaglandins^18,40,47,95 are however very effective at lowering intraocular pressure with are however very effective at lowering intraocular pressure with, as far as we know, minimal systemic side effects and have become the treatment of first choice in many cases.

The advantage of beta-blockers still is that it has been tried and tested, we know a lot about beta-blockers and we probably do not know the same amount of information about newer classes of ocular hypotensive medications. This makes beta-blockers still a very valid option.

The cost of medication^106,107 for a latanaprost treated patient per year is $ 337, while it is $ 336 and $ 288 for betaxolol and dorzolamide, respectively. The daily cost of latanaprost is $ 0.87, this should be put in context with the fact that according to the United Nations and the World Bank, more than one billion to 1.3 billion people live on a daily income of less than $ 1 (one dollar) a day. This makes glaucoma a surgical disease in most of the developing countries. Developing countries have the majority of glaucoma patents, and thus surgery is the treatment of choice to the majority of glaucoma patients. Unfortunately very little industry research funding is being allocated for research in glaucoma surgery, which the majority of glaucoma patients are poised to benefit from.

There is evident lack of studies related to economic evaluation in glaucoma. Kobelt¹⁰⁸ states that the genuine lack of a useful outcome measure, and the impossibility to calculate the absolute annual risk of vision loss at given levels of the one parameter that is being treated, IOP, has essentially limited the research to resource utilization. One other limitation is that economical studies usually take in consideration data from industrialized countries which could be misleading if applied to developing countries circumstances.

Although surgery is usually the first line treatment in developing countries, it is still resorted to as a final attempt to reduce IOP in developed countries. The possibility of employing surgery as a first line treatment is limited by the high incidence of potential ocular complications.

Beta-blockers are effective and relatively safe ocular hypotensive medications, but have a well established list of side effects, it has been tried and tested over long-term follow-ups. The real advantage lies in the fact that the amount of information that we possess about beta-blockers is relatively large. Prostaglandins may offer certain advantages of limited side effects and effective IOP reduction, but longer follow-ups are in dire need to provide evidence of efficacy and safety.

There is evidence that non-penetrating surgery could offer a safer option to trabeculectomy, but the wide-spread practice is hindered by its surgical complexity, which results in long learning curves. Being technically demanding, it is very difficult to employ in mass surgical treatment, specially in developing countries. The use of implants with non-penetrating surgery is an extraconsiderable cost. Another disadvantage is that non-penetrating surgery does not seem to achieve its previously defined target IOP, in a significant percentage, without the postoperative use of goniopuncturing, which necessitates the access to laser equipment.¹⁰⁹

There is an urgent need to improve our surgical options in order to reduce related ocular complications. If possible safer and simpler surgical procedures should be developed to tackle the bulk of our glaucoma problem in developing countries.

Reducing IOP, is surgery better than drugs? As is the case in many aspects of glaucoma, indeed as in life itself, there are no easy answers to such questions. What could be at a clear advantage for one patient could be an absolute contraindication for another. In fact many patients, specially in the developing world, do not have the luxury of an option.

We look forward to the day when effectively reducing IOP would not be such an important matter. When we can manipulate other risk factors, as vascular autoregulation, and neuronal damage, to the advantage of our glaucoma patients.8