CATT at 2 Years: The Facts

Charles C. Wykoff, MD, PhD; David M. Brown, MD

Disclosures

August 13, 2012

In This Article

Comparison of AMD Treatment Trial (CATT)

Age-related macular degeneration (AMD) is the leading cause of severe vision loss in older adults in the developed world.[1] Most profound visual loss associated with AMD is due to the neovascular form, with approximately 200,000 new cases diagnosed each year in the United States.[2,3]

Vascular endothelial growth factor (VEGF)-A is a diffusible cytokine that stimulates angiogenesis and vascular permeability.[4] Clinical blockade of VEGF has revolutionized the management of neovascular AMD since its clinical introduction in the early 2000s.[5,6,7,8]

Intravitreal injection of the related biologic agents bevacizumab and ranibizumab has proven exceptionally effective against choroidal neovascularization (CNV) in AMD. Bevacizumab is a full-length humanized antibody that is approved by the US Food and Drug Administration (FDA) for the treatment of metastatic colon cancer[9] and is used off-label for the treatment of neovascular AMD. Ranibizumab is a modified antibody fragment that was approved by the FDA in 2006 after the landmark ANCHOR and MARINA trials in which, for the first time, patients with neovascular AMD experienced on average visual improvement. Approximately 30% of eyes gained significant vision, and more than 90% of eyes had reductions of visual acuity scores by fewer than 15 letters.[6,7]

The prospective, multicenter CATT enrolled 1107 patients and addressed 2 key questions[10]:

  • Are monthly and as-needed treatment approaches clinically equivalent? and

  • Are bevacizumab and ranibizumab clinically equivalent?

Impressively, CATT was performed without financial support from the pharmaceutical industry -- a rarity for prospective trials of this size. Another key issue was treatment burden, reflected by both number of treatments required and drug cost.

Monthly vs As-Needed Treatment

Both MARINA and ANCHOR evaluated monthly ranibizumab dosing.[6,7] Although this approach yielded exceptional results, with sustained visual gains over 2 years, monthly physician visits are often impractical and very difficult for patients and their caregivers to achieve. Therefore, trials have evaluated 2 main alternative approaches in an attempt to reduce the treatment burden while maintaining visual gains: fixed-interval treatments with less-than-monthly dosing and as-needed treatment.

Fixed-interval schedules with treatments less frequent than monthly have resulted in disappointing visual outcomes.[11,12,13] The PIER study,[12] a phase 3b, multicenter, randomized, controlled trial, compared sham injections with ranibizumab monthly injections for 3 months and then quarterly. Visual outcomes were statistically better with ranibizumab than the sham treatment, but the improvement in visual acuity observed at month 3 was lost by month 12.

As-needed treatment approaches have yielded mixed results. In PrONTO,[14] a 2-year, prospective, open-label (nonrandomized) single-arm study of 40 eyes, patients received 3 consecutive monthly intravitreal injections of ranibizumab followed by monthly evaluation and retreatment if certain clinical criteria were fulfilled. At month 24, mean visual acuity had improved by 11.1 letters with an average of 9.9 injections.

In contrast, as-needed therapy was found to be statistically inferior to monthly therapy at 2 years in the much larger CATT.[10] Specifically, fixed monthly dosing with either ranibizumab or bevacizumab resulted in a mean improvement of about one-half line of visual acuity compared with as-needed treatment (difference, -2.4 letters; P = .046). With respect to avoiding vision loss, 7% of patients in the best-performing group (monthly ranibizumab) lost 3 lines of visual acuity from baseline compared with 12% of patients in the worst-performing group (as-needed bevacizumab). Although at first glance these data may appear similar, they demonstrate that 5% of patients (1 in 20) will experience a 3-line loss in visual acuity if they are treated with as-needed bevacizumab compared with monthly ranibizumab.

The losses in visual acuity with as-needed therapy are probably secondary to the regimen's reduced anatomic efficacy. Patients in the as-needed groups had more persistent retinal fluid (75% of baseline levels with as-needed ranibizumab and 85% with as-needed bevacizumab vs 52% with monthly ranibizumab and 67% with monthly bevacizumab; P < .001) and larger CNV lesions (mean sizes compared with baseline, +1.9 mm2 with as-needed ranibizumab and +3 mm2 with as-needed bevacizumab vs -0.4 mm2 with monthly ranibizumab and +1.6 mm2 with monthly bevacizumab; P < .001). Finally, one half of patients initially assigned to monthly treatment were reassigned to as-needed treatment after 1 year; the visual acuity of the eyes reassigned to as-needed dosing decreased by a mean of 1.5-3 letters compared with eyes maintained on monthly dosing (P = .03).

Results from HARBOR,[15] a large prospective trial involving 1097 patients that compared monthly ranibizumab with as-needed treatment, further emphasize the challenges of the latter dosing schedule. At 1 year of follow-up, as-needed treatment did not meet the prespecified noninferiority criterion of a 4-letter difference compared with monthly dosing.

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