Incorporating glaucoma risk factors in clinical trials (Dr Marcelo Nicolela)

26Jun2010 1145hrs presented at the COS Annual Meeting in Quebec City by Marcelo Nicolela

In this talk, Dr Nicolela sets out to discuss how to incorporate risk factors into our clinical decisions about patients with glaucoma. He starts by defining risk factors, prognostic factors and modifiable risk factors. We tend to use risk and prognostic factors interchangeably; is there really a difference when it comes to glaucoma [as a continuum]? This topic is discussed in greater detail with Dr Nicolela and myself in an episode of Talking About Glaucoma found on, in iTunes, and the EyeHandbook app for iOS and Android.

Our understanding of risk factors

Our understanding of risk factors is influenced by many randomized clinical trials (RCTs) and population studies. He shows what he admists to be a ‘busy table’ using term risk factor loosely as some are actually related to the disease itself:

- IOP, disc heme, worse damage, PXF, low BP or PP, Thinner CCT, female, older age, Black race, Family Hx, others eg ACA

Gender is interesting in that some studies show male higher prevalence but females may be more prone to progression. [Editorial note: perhaps this is because women tend to live longer than men and are therefore more likely to show progression in their lifetime?]

One of the Collaborative Normal Tension Glaucoma studies (CNTGS) graph shows the Mean Deviation (MD) slope (on Visual Field testing) in untreated patients some showed significant progression, even early on, and others not changing over time, with slope ranging from -0.2 to 2.0 dB progression per year

Making sense of these risk factors

There are only a few modifiable factors such as intraocular pressure (IOP) and for a select few patients with low blood pressure, changing their BP medication dosing so avoid nocturnal dips on perfusion of the optic nerve head.

Most risk factors are non-modifiable and some of these represent early disease [such as increased vertical cupping of the optic nerve.] Some subsets of glaucoma patients respond less well to intervention because they have mostly non modifiable risk factors.

Are risk factors for onset different from those for progression?

Intuitively, risk factors for converting to glaucoma are probably the same as those for progression of the disease if really part of a continuum. However, there are really no studies to confirm this yet. That being said, several large clinical trials looking for the onset of glaucoma such as the Ocular Hypertension Treatment Study (OHTS), Early Manifest Glaucoma Trial (EMGT), and Malmoe studies to look for IOPs association with glaucoma onset. If look at these studies and CNTGS, all but the NTG study shows correlation with IOP and progression Although we suspect IOP fluctuations between visits to be important, no association has been found between inter-visit IOP fluctuation and progression. IOP is a risk factor for both onset and progression.

Now looking at central corneal thickness (CCT) and its relationship to onset and progression, things look a bit different. CCT in OHTS was strongly associated with conversion to glaucoma but not with progression of disease but this may be based on study design.

IOP independent risk factors

- females, migraine, and disc hemorrhage were the risk factors in CNTGS

Just remember there may be subgroups of normal tension glaucoma patients who are less likely to benefit from IOP reduction. Therefore you need to weigh the non-IOP dependent (IOP independent) risk factors with IOP when assessing patients. In an NTG patient, many will benefit from further IOP reduction in terms of preventing progression but some may be completely IOP independent for whom we still have no ideal treatment for preventing progressive glaucoma damage.

For these patients, you may need to investigate other factors such as IOP spikes, low BP, poor compliance, CV disease, ACA.