Bevacizumab vs Triamcinolone for Diabetic Macular Edema

Look before you leap.

MARK GILLIES, PhD, FRANZCO

With a handle on the treatment of exudative age-related macular degeneration (AMD), retinal physicians and scientists are wondering how best to treat the second major retinal cause of vision loss, diabetic macular edema (DME) (Figure). DME is less common than with wet AMD, but its significance is magnified because DME affects a younger population and even more commonly affects both eyes. Two treatments for DME have recently emerged: steroids and anti-vascular endothelial growth factor (VEGF) drugs. Of these, triamcinolone acetonide and bevacizumab (Avastin, Genentech) are the most readily accessible, but neither has been developed conventionally. Limited evidence exists for the former and less for the latter, yet it appears that both can be efficacious in selected cases. Despite the paucity of good quality data for these drugs, the "miraculous" properties of triamcinolone and bevacizumab for DME are splashed across the Web, so physicians in general practice are required to give advice and make recommendations daily in what can sometimes be highly charged circumstances.

STUDIES THUS FAR

Whether intravitreally injected triamcinolone acetonide (IVTA) is effective in wet AMD is debatable, but there is little doubt that it can settle many cases of DME and improve visual acuity (VA), at least in the short to medium term. Following anecdotal reports,^1,2 a small (n=69 eyes) but otherwise well-conducted randomized, placebo-controlled trial found that patients assigned to IVTA had twice the chance of improved vision (5 or more letters) and half the risk of further loss compared with placebo over 2 years.^3,4 This was associated with a significant reduction in mean central macular thickness (CMT) throughout the 2-year study. However, a clear risk of steroid-related adverse events existed, with 55% of eyes eventually requiring cataract surgery (almost all in the second year of the study), and 44% needing medication for elevated intraocular pressure (IOP). Trabeculectomy was performed on 6% of treated eyes. The results of the much larger Diabetic Retinopathy Clinical Research Network (DRCR.net) randomized clinical trial of preservative-free IVTA for DME to be reported soon are expected to be similar, with additional welcome information provided on the safety and efficacy of a lower dose of triamcinolone.

Because increased VEGF levels have been detected in the retina and vitreous of human eyes with diabetic retinopathy, anti-VEGF drugs are an attractive therapeutic option for DME. The best evidence for this class of drug comes from a phase 2 study of pegaptanib sodium (Macugen, OSI/Pfizer) involving 172 patients with DME, in which pegaptanib was administered every 6 weeks for 12 weeks with the option of continuing for 18 more weeks or undergoing laser treatment. Patients receiving 0.3 mg had better VA at the end of the study compared with those receiving placebo (P=.04), as well as a reduction in retinal thickness of 68 μm compared to a slight increase under sham treatment (P=.021).⁵ Given the apparent superiority of ranibizumab (Lucentis, Genentech) over pegaptanib for wet AMD, the question now is how safe and efficacious for DME are ranibizumab and bevacizumab? These drugs are not as similar as many people think, but they do work by attaching to VEGF at the same site.

Few data exist for ranibizumab for DME. In a dose-escalation study of 10 patients, Chun et al.⁶ found the VA of half the eyes improved by ≥10 letters after 3 months of dosing with ranibizumab. A more marked reduction of CMT was seen in the group receiving 0.5 mg than 0.3 mg. No doubt more studies on ranibizumab will appear; however, this would be an expensive intervention for patients with DME, many of whom may need lifelong treatment.

Bevacizumab, by contrast, is available for off-label use at a fraction of the price. At this writing, there are concerns about the ongoing supply of bevacizumab; with hope, these concerns will be overcome with time. The manufacturer should recognize that this is an unprecedented occurrence in drug development that is unlikely to be repeated and that they cannot wholly absolve themselves from blame because they were the ones who drew the wrong conclusions from their preclinical testing.

Figure. A common problem: cystic DME persisting despite extensive laser treatment.

Many studies on the use of bevacizumab for DME have appeared over the last year. Aravelo and colleagues⁷ performed a retrospective analysis of 78 eyes of 64 patients treated for DME with bevacizumab (0.25 mg or 2.5 mg) and followed for 6 to 9 months in 6 US centers. The majority of eyes had a single injection. An improvement of ≥2 lines of VA was found in 55% and was accompanied by a reduction in CMT. No ocular or systemic adverse events were reported; however, systemic adverse events are likely to be substantially underreported by a retrospective chart review. In a 6-month, prospective, randomized, placebocontrolled trial of 115 eyes of 101 patients with refractory DME, patients were treated with 3 x 6 weekly injections of bevacizumab (1.25 mg), bevacizumab plus IVTA (2 mg), or placebo.⁸ Clinical improvement in CMT and best-corrected visual acuity (BCVA) occurred more rapidly in the combination group; however, the group treated with IVTA plus bevacizumab ultimately did no better than the group treated with only bevacizumab. No detailed comments were made on the incidence of systemic adverse effects in this study. Other studies have reported a modest but significant clinical effect of bevacizumab for DME.^9,10

The only study that has made a direct comparison between IVTA and bevacizumab comes from Pacola et al.¹¹ While randomization and masking procedures were not fully described, this was a reasonably well-planned study in which 24 eyes with recalcitrant DME were randomized to receive a single dose of 1.5 mg bevacizumab or 4 mg IVTA and then followed for 24 weeks. Eyes receiving IVTA did better, with both CMT and VA improving compared with baseline from 4 weeks through 16 weeks. Significant improvement in CMT of bevacizumab-treated eyes was only found at weeks 4 and 8, and VA only at week 4. Reduction in CMT was significantly greater in the IVTA compared to the bevacizumab-treated eyes throughout the study, and VA was better at weeks 8 and 12. This study does not provide information on how bevacizumab-treated eyes would have fared had they received multiple injections, as would usually be the case in clinical practice — it might have been better; however, it may be significant that eyes treated with IVTA had a better CMT response even after 4 weeks, at which point one would expect bevacizumab to still be working.

NEW WORK FROM THE DRCR.NET

A start has been made by the DRCR.net to appraise more thoroughly the utility of intravitreal bevacizumab for DME. In a phase 2 study of 121 patients, eligibility criteria included loss of vision from DME involving the center of the macula.¹² Unlike some studies of DME, cases could be included that had not previously been treated by another modalities. Efficacy was reported for the first 12 weeks of the study and safety was studied for 24 weeks. Patients were randomized into 5 groups including laser alone and single and multiple injections of 1.25 and 2.5 mg bevacizumab. Modest improvements in both LogMAR BCVA and CMT were seen after 12 weeks in all groups except the group that had received just 1 injection of bevacizumab at baseline. Only about half the eyes receiving bevacizumab had a significant reduction in CMT, and this was not significantly better than eyes receiving laser alone. Eyes receiving bevacizumab had in general a 1-line better response in VA compared with laser alone throughout the study. The short-term effect of 2.5 mg bevacizumab did not appear superior to 1.25 mg, and the effect of both doses appeared to wane between the 3- and 6-week visits, suggesting that 6 weeks may be too long between injections for a sustained effect. Although laser therapy combined with bevacizumab did not produce superior short-term results, the investigators felt that further research was still warranted on combination treatment with laser, particularly to determine whether laser can reduce the number of doses of bevacizumab required.

While local adverse events were rare in the DRCR.net study, there were some significant systemic adverse events. For example, 2 patients suffered myocardial infarcts, 1 of whom died, and 1 developed congestive cardiac failure in the 24-week period of follow-up. This would be equivalent to around a 5% annual risk of severe cardiovascular adverse events. These numbers are of course very small; however, they need to be interpreted in the light of the significant increase in risk of nonocular hemorrhage found in the ranibizumab-treated group in the combined results from the MARINA and ANCHOR studies for AMD (7.8% for ranibizumab vs 4.2% for sham; P=.01).¹³ It is well known that people with diabetes have an increased risk of developing cardiovascular disease, and this may be increased further in the population with advanced retinopathy who might be considered for treatment with bevacizumab, the serum half-life of which is 30 times greater than that of ranibizumab

These results from the DRCR.net provide a strong foundation for further research in this area. One might expect a more marked beneficial effect compared with laser treatment if enrollment in future studies were restricted to patients who had already received conventional treatment (because this is the group in which intravitreal therapy will be used in the first instance, and some treatment-naïve patients may actually respond to photocoagulation quite well, particularly where central leak is emanating from a clear, focal extrafoveal source). Future research on bevacizumab will need to identify the lowest dose that is effective and how practical the intervention is when given over a long term. The risk of severe cardiovascular side effects will need to be addressed somehow, even if studies need to be designed to pick up a risk as low as 2%, which many patients may find unacceptable. DME may cause loss of reading and driving vision, but there may not be as much at stake as there is in a patient losing vision in her second eye from wet AMD, in which untreated cases usually (but not always) progress to legal blindness within a few months.

CONCLUSION

On the basis of the existing evidence as outlined above, I continue to use triamcinolone as first-line therapy for cases of advanced DME that have failed medical treatment unless there are clear contraindications, eg, glaucoma. Six monthly, rather than 6 weekly, injections are attractive, although we are all, patients included, getting used to the latter. Cataract eventually occurs in the majority of IVTA-treated eyes, but this has not stopped us performing vitrectomies. The effect of cataract removal from eyes requiring IVTA has not been well studied — our own research suggests that a small proportion may do badly even under cover of a repeated injection shortly before surgery. IOP requires constant vigilance and prompt referral to a glaucoma specialist if elevation does not respond immediately to monotherapy.

These steroid-induced local adverse events are, nevertheless, a major problem associated with IVTA therapy that is not seen with anti-VEGF drugs. But there are no data yet that examine the efficacy and safety of bevacizumab in patients with DME for more than 3 doses; it may be wishful thinking to presume that there will not be any problems. In our 2-year study of IVTA for DME, half the treated eyes only required 1 or 2 doses; however, 20% required 4 or 5,⁴ which is equivalent to approximately 15 doses of bevacizumab. Just as we have tested IVTA as rigorously as we could for DME, the onus is now on those who propose bevacizumab for DME to prove its long-term efficacy and safety; this responsibility is not abrogated by the requirement for the more extensive studies that will be required to rule out a small but significant increase in severe systemic adverse events that may not be picked up by an ophthalmologist in routine clinical practice. Time should tell whether bevacizumab or IVTA is safer and more efficacious and, indeed, which of the inevitable improved anti-VEGF agents and improved steroidal agents, are superior, but only if good-quality clinical research studies are instituted now. RP

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