Medical treatment of open-angle glaucoma can induce undesirable changes within the conjunctiva and Tenon’s capsule. In addition to the transient conjunctival changes related to allergy and toxicity that most topically applied eye drops can induce, the parasympathomimetics and sympathomimetics can be associated with cicatricial pemphigoid.6–8
Early developed beta blockers such as practolol commonly caused scarring of the conjunctiva, and even commercially available timolol has been associated with drug-induced ocular pemphigoid in at least two cases.7,8
Furthermore, carbonic anhydrase inhibitors are known to occasionally induce Stevens-Johnson syndrome with severe conjunctival scarring.9,10
Finally, investigators have reported that exposure to topical antiglaucoma medications for more than 3 years is associated with a significant foreshortening of the inferior fornix secondary to conjunctival fibrosis.11
These clinical observations suggest that a possibility for enhanced postoperative scarring of surgically created filtering blebs might be more likely in patients receiving long-term antiglaucoma medications. In fact, many believe that the continuing use of miotics prior to filtering surgery increases the likelihood of surgical failure.12
In spite of these reports and studies, there has been general agreement that surgical treatment of open-angle glaucoma is indicated only after maximally tolerated medical treatment has failed.
However, in recent years studies of conjunctiva and Tenon’s capsule have demonstrated increased inflammatory cells in patients receiving long-term open-angle glaucoma therapy as described above.1,2
These results suggest that extensive medical therapy before surgery may enhance the risk of external bleb scarring and filtration surgery failure. Therefore, investigators and clinicians have awaited a well-designed clinical study to support this speculation. Such an investigation might link the laboratory finding of subclinical inflammation within the conjunctiva to an enhanced scarring of the surgical bleb with failure of filtering surgery. This would change the approach to the medical treatment of open-angle glaucoma.
During the past 10 years, the results of clinical studies have been referenced with authority as good evidence that long-term medical therapy of open-angle glaucoma (>1 year) can adversely affect the results of fistulizing surgery.3–5
The suggestion that medical therapy for open-angle glaucoma patients may be counterproductive and encourage the failure of filtering procedures represents a major change in thinking that essentially redefines conservative treatment of open-angle glaucoma patients. This dramatic change in therapeutic attitude requires a rigorous, properly controlled, well-designed clinical study as support. However, this study does not exist.
The most commonly quoted clinical study that concludes that long-term treatment can adversely affect the results of fistulizing surgery is not randomized, prospective, or masked.3
Therefore, the potential for bias has not been properly controlled. In fact, there is clear evidence for bias within this study because the subjects within the PT group, patients with minimal medical treatment, were selected from a group of subjects reported within a prior study. More specifically, the 47 subjects used in this pivotal study as the minimally treated control are selected from a group of 57 subjects that were reported in a prior study.5
It remains unclear how and why the 10 subjects present within the initial study but absent from the subsequent study were eliminated.
In addition to potential subject-selection bias, this pivotal study is weakened because there is evidence that the two groups being compared in terms of postoperative IOP after 18 months are not comparable at baseline in several important ways. As summarized in , the MT group demonstrates more advanced visual field defects and a greater duration of disease and has more subjects with a history of laser surgery than does the PT group. Furthermore, all of the subjects in the MT group are by definition medical treatment failures. The PT group, which consists of newly diagnosed open-angle glaucoma, may have, at best, only 20% of its subjects that will ultimately become treatment failures.3
These differences suggest that open-angle glaucoma is present in a more advanced form in the MT group compared with the PT group. In addition, the presence of subjects with a history of laser treatment within the MT group may influence the results of trabeculectomy surgery in these patients, because eyes treated with laser trabeculoplasty before filtration surgery have been reported to have a decreased probability of successful surgery.13
Preoperative comparability of primary trabeculectomy (PT) and multiple treatment (MT) groups*
Although these important differences between the two groups significantly weaken the integrity of the study, an even more critical consideration is whether all of the subjects within the PT group really have open-angle glaucoma. The likelihood that this disease is not present is greater in subjects having had the diagnosis for 8 or fewer weeks than in subjects having had the diagnosis for 1 to 17 years. This possibility seems particularly reasonable in light of recent studies showing that visual field defects observed in open-angle glaucoma patients require confirmation to ensure their presence.14
This diagnostic requirement is much more likely to have been fulfilled within the MT group than the PT group, because the subjects within the PT group, by definition, had their diagnosis of open-angle glaucoma for only 8 or fewer weeks prior to their surgery. This limited time period is hardly sufficient to confirm visual field defects in potential open-angle glaucoma patients on three separate occasions.
It is recognized that preoperative use of miotics can influence the success of glaucoma filtering procedures.12
Although the anticholinesterase agents are most clearly implicated, all of the parasympathomimetics are capable of disrupting the blood-aqueous barrier and changing the chemical composition of the aqueous humor. It is possible that more of the filtering procedures within the medically treated group would have been successful if the miotics had been discontinued at least 3 days prior to surgery, as some have recommended.12
In addition to concerns about the comparability of the two groups prior to surgery, it appears that the surgeries provided the two groups might not be comparable. The presenting IOPs are higher in the PT group. Furthermore, consultants performed more than twice as many of the surgeries in the MT group. Finally, there were almost four times as many shallow chambers following surgery in the PT group, compared with the MT group (). These differences may have influenced the long-term results of surgery, including the number of failures observed 18 months following surgery.
Preoperative, operative, and postoperative comparability of surgical procedures in primary trabeculectomy (PT) and multiple treatment (MT) groups*
A final consideration is whether the results of this study and its subsequent conclusions can be extrapolated to the current treatment of open-angle glaucoma patients. summarizes the medications used in the MT group and, in particular, the medical treatment that the surgical failures received prior to trabeculectomy. Pilocarpine and epinephrine were used in 100% and 89%, respectively, of the surgical failures in this study. These parasympathomimetic and sympathomimetic drugs are used much less extensively as part of the current medical treatment of open-angle glaucoma. Furthermore, the guanethidine-epinephrine combination, which was used in 56% of the surgical failures, has never been used in the United States. Therefore, it is clear that the current medical therapy for open-angle glaucoma is different from the medical treatments used within this study.
Glaucoma medications used by subjects in multiple treatment (MT) group*
A subsequent study of 124 patients was published in support of the findings of the pivotal study discussed above.4
This study concludes that its results show that topical therapy has an adverse effect on the conjunctiva and that these changes correlate with the failure of trabeculectomies. However, this investigation has the most worrisome of the shortcomings within the previously published study.3
In addition, the more recent study has fewer subjects in the minimal treatment group, has a shorter follow-up period, and includes a group with minimal treatment that is even more highly selected than the previous study. Therefore, it is difficult to accept the publication’s conclusion that good evidence exists showing that early surgery is more likely to be successful and more likely to reduce disease progression in open-angle glaucoma patients.4
In summary, there is no convincing evidence that long-term medical treatment as used today influences the success of contemporary trabeculectomy surgery. Existing evidence makes it appropriate to agree with investigators who believe that preoperative use of topical medication does not influence the outcome of surgery.13
The studies that attempt to justify early surgery are all potentially biased, based on postoperative comparisons of groups that are not comparable at baseline, and include medical treatments that do not reflect current treatment regimens. Therefore, it seems only prudent to employ long-term medical treatment of open-angle glaucoma in our open-angle glaucoma patients, delaying filtering surgery until maximal tolerated medical treatment fails.