CATT, Meet IVAN

What have we learned from the ongoing ranibizumab vs bevacizumab trials?

Andrew Lotery, MD

In May, two landmark studies, IVAN and CATT, reported their respective one- and two-year findings in their comparisons of bevacizumab vs ranibizumab as a treatment for neovascular age-related macular degeneration.

THE IVAN ONE-YEAR RESULTS

The alternative treatments to Inhibit VEGF in Age-related choroidal Neovascularisation (IVAN) randomized trial compared monthly or “as needed” ranibizumab or bevacizumab. It was undertaken by the UK National Health Service (NHS). IVAN is a multicenter, factorial, noninferiority randomized trial.

Study Design

The participants were patients older than 50 years with untreated neovascular AMD in the study eye who read ≥25 letters on the ETDRS chart. These participants were randomized to four groups, comprising ranibizumab or bevacizumab, given either every month (continuous) or as needed (discontinuous), with monthly reviews.

Diagnoses were confirmed by fluorescein angiography. Participants without a subfoveal (within 200 µm) neovascular component were eligible if subretinal fluid or serous pigment epithelial detachment was subfoveal.

To avoid including inactive or advanced disease, lesions comprising >50% fibrosis or blood were excluded. Only one eye was studied per patient. The participants were from 23 teaching and general hospitals in the NHS.

As in CATT, the drug doses were 0.5 mg ranibizumab and 1.25 mg bevacizumab. All of the participants were treated at visits 0, 1 and 2. Participants randomized to the continuous regimen were treated monthly thereafter, while participants randomized to the discontinuous regimen were not retreated after visit 2, unless prespecified clinical and optical coherence tomography criteria for active disease were met.

If retreatment was needed, a further cycle of three doses delivered monthly was required. The retreatment criteria were any subretinal fluid, increasing intraretinal fluid, or fresh blood. If there was uncertainty about these criteria, and visual acuity had dropped by ≥10 letters, retreatment could be initiated. In the absence of fluid on OCT or visual acuity deterioration, fluorescein leakage >25% of the lesion circumference or expansion of choroidal neovascularization was required to initiate retreatment.

The primary outcome for IVAN is at two years (follow-up is ongoing), but the protocol specifies an interim analysis at one year. The primary outcome measurement is best-corrected distance visual acuity measured in ETDRS letters. The secondary outcome measurements include: (1) adverse effects; (2) EQ-5D (generic health-related quality of life); (3) cumulative resource use and costs; (4) contrast sensitivity, near visual acuity, and reading index; (5) lesion morphology and metrics from angiograms and OCTs; and (6) serum VEGF levels.

All outcomes, except for EQ-5D and serum VEGF, were measured at baseline and at visits 3, 6, and 12. EQ-5D was measured at baseline and at visits 3 and 12, and serum VEGF was measured at baseline and at visits 1, 11 and 12.

Adverse events were recorded at each visit. The primary safety outcome measurement was the occurrence of an arteriothrombotic event or heart failure. A target sample size of 600 patients was planned, giving 90% power to detect non-inferiority (significance 2.5% one-sided). In total, IVAN has recruited and treated 610 patients.

Results

The differences in total one-year costs between continuous and discontinuous dosing regimens were estimated for each drug. One result of IVAN was that one year after randomization, the comparison between bevacizumab and ranibizumab was inconclusive (bevacizumab minus ranibizumab = -1.99 letters, 95% confidence interval [CI] -4.04 to 0.06). The mean difference between the drugs was two letters in favor of ranibizumab, a small difference from a clinical perspective. The difference in visual acuity between continuous and discontinuous regimens was negligible, showing that the treatment regimens were equivalent.

Figure 1. The above flow chart illustrates the enrollment and follow-up process of the IVAN study. Reprinted with permission from Elsevier, originally published by Ophthalmology.

Discontinuous treatment was equivalent to continuous treatment (discontinuous minus continuous = -0.35 letters, -2.40 to 1.70). Foveal total thickness did not differ by drug but was 9% less with continuous treatment (geometric mean ratio [GMR] 0.91, 0.86 to 0.97, P = .005). Fewer participants receiving bevacizumab had arteriothrombotic events or heart failure (odds ratio 0.23, 0.05 to 1.07, P = .03). There was no difference between drugs in the proportion of patients experiencing serious systemic adverse events (odds ratio 1.35, 0.80 to 2.27, P = .25). Serum VEGF was lower with bevacizumab (GMR 0.47, 0.41 to 0.54, P <.0001) and higher with discontinuous treatment (GMR 1.23, 1.07 to 1.42, P = .004).

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TWO-YEAR CATT RESULTS

The Comparison of AMD Treatment Trials (CATT) study has just reported its two-year results. In this US-based study, 1,107 patients were followed for the second year of the trial. The CATT team reported the effects of ranibizumab and bevacizumab when administered monthly or as needed for two years in the treatment of neovascular AMD. In addition, at one year, patients initially assigned to monthly treatment were reassigned randomly to monthly or as-needed treatment, without changing the drug assignment.

The results were that among patients following the same regimen for two years, the mean gain in visual acuity was similar for both drugs (bevacizumab-ranibizumab difference, 1.4 letters; 95% CI, 3.7 to 0.8; P = .21). The mean gain was greater for monthly treatment than for as-needed treatment (difference, -2.4 letters; 95% CI, -4.8 to -0.1; P = .046). The proportion of patients without fluid ranged from 13.9% in the bevacizumab as-needed group to 45.5% in the ranibizumab monthly group (drug, P = .0003; regimen, P <.0001).

Switching from monthly to as-needed treatment resulted in a greater mean decrease in vision during year 2 (-2.2 letters; P = .03) and a lower proportion without fluid (-19%; P < .0001).="" the="" rates="" of="" death="" and="" arteriothrombotic="" events="" were="" similar="" for="" both="" drugs="">P > 0.60). The proportion of patients with one or more systemic serious adverse events was higher with bevacizumab than ranibizumab (39.9% vs 31.7%; adjusted risk ratio, 1.30; 95% CI, 1.07-1.57; P = .009). The sample size of approximately 300 patients in each of the treatment groups was sufficient to provide two-sided 99.2% confidence limits that would exclude a difference of five letters (the noninferiority limit) if the true difference were zero letters.

Treatment decisions by ophthalmologists in year 2 were consistent with the identification of fluid on OCT scans by the reading center for 68.5% in the ranibizumab as-needed group and 69.6% in the bevacizumab as-needed group. Ninety-five percent of inconsistencies were instances of missed treatments in which the OCT reading center detected fluid, but the patient was not treated. This error occurred at a similar frequency for spectral-domain OCT scans (70%) to time-domain OCT scans (69%; P = .22).

The estimated two-year drug cost per patient varied from $705 in the bevacizumab as-needed group to $44,800 in the ranibizumab monthly group. The proportion of study eyes with geographic atrophy at two years among eyes without apparent geographic atrophy at enrollment, ranging from 25.8% in the ranibizumab monthly group to 12.9% in the bevacizumab as-needed group, was greater among patients treated monthly (P = .007).

DISCUSSION

Collectively, the IVAN and CATT studies demonstrate that bevacizumab and ranibizumab have equivalent efficacy in terms of their visual benefits. These two high-quality randomized trials were conducted independently of the drugs' manufacturer and recruited one-and-a-half times as many patients as the original licensing trials for ranibizumab, ANCHOR (n=423) and MARINA (n=716).

Reassuringly, there is no evidence of any difference in mortality between the drugs.

The IVAN trial observed more arteriothromboembolic events or heart failure with ranibizumab than with bevacizumab; this finding became nonsignificant when combined with the CATT one-year data (which were available at the time of the IVAN meta-analysis) but was still 24% higher.

There does appear to be a difference in the frequency of other serious adverse events between the drugs — approximately a 30% increase in the risk of any systematic serious adverse events. However, the interpretation of these events is not straightforward; they appear to cause hospitalization but not deaths. They were more frequent in the PRN arms of the studies compared to continuous treatment and included a variety of causes for hospitalization that, for example, included hernias.

It is difficult to think of a causal mechanism for how intravitreal bevacizumab could induce a hernia. Therefore, as the CATT investigators state it is it “uncertain whether this difference was the result of chance, imbalances at baseline not captured in multivariate modeling, or truly higher risk.”

In IVAN, the comparison of visual acuity at one year between bevacizumab and ranibizumab was inconclusive. Therefore, the IVAN investigators cannot rule out either that the drugs are equivalent or that the drugs are different, based on the estimate of the difference between the drugs that was observed. This was mainly because they set a narrower margin than the CATT investigators for testing equivalence. Based on the CATT margin for equivalence, they would have concluded that the drugs were equivalent.

The IVAN study also showed that serum VEGF decreased more with bevacizumab than ranibizumab. This finding implies that intravitreal drugs can egress into the circulation. The clinical importance of this finding is difficult to judge given that other outcomes were similar for the two drugs and regimens. It is possible that the consequences of differential suppression of circulating VEGF will only become apparent after longer follow-up.

Interestingly, in a separate presentation at the 2012 annual meeting of the Association for Research in Vision and Ophthalmology, the CATT investigators reported a trend toward a reduced rate of CNV in the fellow eyes of treated with bevacizumab vs ranibizumab. Among 1,185 CATT patients, 727 (61%) had no signs of CNV in the fellow eye at enrollment. At one year, CNV had developed in 29 (8.0%) of 365 eyes of patients treated with ranibizumab and 26 (7.2%) of 362 patients treated with bevacizumab (P = .76; log rank test).

After adjusting for known risk factors for CNV and for the drug-dosing regimen, the estimated hazard ratio associated with treatment for bevacizumab was 0.92 (95% CI 0.54-1.56). This finding might relate to greater systemic suppression of VEGF in the bevacizumab-treated patients. If so, it is a helpful effect.

The CATT study concerningly showed more geographic atrophy at two years in patients treated with ranibizumab. It also showed that the modest gain in visual acuity for patients receiving continuous monthly treatment in year 1 was lost if they switched to PRN dosing in year 2. The difference in letters gain that was noted between continuous monthly and PRN dosing seen in CATT at year 1 was not seen in IVAN between PRN and continuous dosing.

This finding could be related to the mandated three injections given in IVAN in the PRN arm whenever retreatment was initiated (compared to a single retreatment in CATT). However, the number of injections needed in the PRN arm of IVAN was similar to CATT, at just more than seven injections per annum.

CONCLUSIONS

After the one-year IVAN and two-year CATT results, most physicians would agree that both drugs yield similar visual outcomes with no difference in mortality for either drug. All would agree that ranibizumab is significantly more expensive than bevacizumab.

Extrapolating the results for discontinuous treatment suggests that switching from ranibizumab to bevacizumab could save the NHS £84.5 million (more than $130 million) based on the 17,295 eyes being treated in the United Kingdom annually. In the United States, ranibizumab costs the healthcare economy billions of dollars more by using it instead of bevacizumab.

There is still controversy over whether an unlicensed drug (bevacizumab), which has not been approved by normal regulatory agencies, should be used when a licensed drug (ranibizumab) is available. This is a topic for regulatory agencies to consider. CATT and IVAN have now provided robust clinical trial data on the similar visual outcomes, relative safety and cost implications of these two drugs to guide regulators in such evaluations. RP