‘Alphabet soup’ expands clinical knowledge

Randomised controlled studies with clinically relevant outcome criteria have a crucial role in determining appropriate management.

Roibeard O’hEineachain

Posted: Saturday, May 1, 2021

Randomised controlled trials (RCTs) have transformed the understanding of nature of glaucoma and changed the goal of treating the condition, said Prof Anders Heijl MD, Malmö University Hospital, Lund University, Sweden, in the inaugural Jules François lecture delivered at the 14th European Glaucoma Society Congress.
Prof Heijl noted that in particular, RCTs published over the last few decades have greatly cleared up the confusion regarding the role of intraocular pressure (IOP) in glaucoma pathology. The normal values for IOP were first determined in the 1950s following a large population study, which showed that normal IOP had an upper limit of around 20mmHg. From this finding, many assumed that patients with higher levels either had glaucoma or would develop the condition in a relatively short amount of time.
However, subsequent studies in the 1960s showed that, to the contrary, patients with ocular hypertension generally had a good prognosis most of them not developing manifest glaucoma, while at the same time, many glaucoma patients had IOP within the normal range. These findings raised important questions about who should be treated, when they should be treated and how they should be treated.
To address those questions researchers at several centres around the world conducted randomised studies in the 1980s to evaluate whether IOP reduction was useful in glaucoma by investigating whether it could reduce the incidence of glaucoma damage in patients with ocular hypertension. However, the studies had contradictory results, and some had design flaws, leaving the questions unanswered. This triggered several crucial studies that started in the 1990s.
Knowledge increased dramatically with the publication of the “alphabet soup” of RCTs published in the early years of this century, including the collaborative normal tension glaucoma study (CNTGS), the early manifest glaucoma trial (EMGT), the ocular hypertension study (OHTS), Collaborative Initial Glaucoma Treatment Study (CIGTS), the advanced Glaucoma Intervention Study (AGIS) and, later, the UK Glaucoma Treatment Study (UKGTS).
The EMGT showed that IOP reduction reduced the risk of progression of open-angle glaucoma, including normal tension glaucoma. The OHTS study showed that timolol reduced the risk of progression to glaucoma in eyes with ocular hypertension. The CIGTS trial showed that initial surgery was more effective than medication in eyes with advanced glaucoma and the UKGTS study showed that latanoprost reduced the risk of progression in eyes with open-angle glaucoma, including normal-tension glaucoma (NTG).
The studies also revealed important risk factors for glaucoma such as higher IOP, exfoliation, older age and worse glaucoma status as expressed by the mean deviation value. The OHTS study showed similar risk factors, but also showed thinner central corneas to be an independent risk factor for progression to glaucoma.
“The large glaucoma RCTs dramatically increased our knowledge about glaucoma, showing that IOP lowering actually works, that 21mmHg is not low enough, but pressure sensitivity varies a lot among eyes. Some progression occurs in the majority of glaucoma patients, even if IOP is always “normal”. Rates of progression vary a lot among patients – even with identical IOP levels.
“Nobody discussed rate of progression before the results of these large RCTs. But, since progression is the rule, we no longer consider any progression a failure and a reason to step up treatment. Now we instead consider whether the observed progression is acceptable, or whether it poses a threat to the patient’s visual function and quality of life,” Prof Heijl said.
The clinical implications of this were quickly understood by the EGS, Prof Heijl noted. For example, the third edition of the EGS guidelines introduced the recommendation that all newly diagnosed glaucoma patients should be tested with standard automated perimetry (SAP) three times per year during the first two years after diagnosis. In this way, rate of progression can be determined early, and rapidly progressing eyes be revealed with great certainty.
Several subsequent RCTs have also provided valuable information regarding glaucoma management. For example, at the beginning of this century, it was generally believed among glaucoma specialists that short-wave automated perimetry (SWAP) could detect glaucomatous field loss earlier than SAP. However, a Dutch study published in 2010 proved definitively that SWAP was actually inferior to SAP in that regard.
Similarly, much hope was placed in the neuroprotective potential of memantine as a means of protecting the optic nerve from glaucomatous damage. However, despite a wealth of non-clinical data supporting that conjecture, two 48-month prospective RCTs involving 2,298 patients showed that treatment did not prevent glaucoma progression.
“These study results clearly demonstrate one of the really great advantages of RCTs – they give us the right answer even if we do not understand the mechanisms. RCTs, therefore, almost always give results that are clinically relevant,” Prof Heijl said.
The EGS introduced the Jules François lecture at its 14th Congress to mark the 40th anniversary of the society’s founding and is named in honour of the founding president of the society.