Bevacizumab helpful in BRVO

7 12 2009

The SCORE study showed that intravitreal triamcinolone was no more helpful than standard therapy (macular laser) in improving vision in patients with branch retinal vein occlusions (BRVO), and thus the SCORE study concluded to continue using standard therapy to treat BRVO.  The question is, might another agent, say a VEGF inhibitor like bevacizumab (Avastin) be helpful in treating BRVO?

We get some indirect answers in a study published in the November/December issue of Retina.  The study (Comparison of two doses of intravitereal bevacizumab as primary treatment for macular edema secondary to branch retinal vein occlusion:  results of the pan american collaborative retina study group at 24 months) by Wu et al and the Pan-American Collaborative Retina Study Group was a retrtospective multicenter study looking at results from 63 eyes treated with two different doses of bevacizumab:  1.25 mg and 2.5 mg.  Other studies had shown benefit in visual acuity and central macular thickness (CMT) with bevacizumab in BRVO, and the authors wondered if an increased dose may improve the visual outcome or decrease the frequency of injections.  Patients with macular edema were given bevacizumab at one of the two doses (depending on the center they visited) and were examined on a monthly basis.  OCT’s were performed at months 1, 3, 6, 12 and 24.  If at any time the OCT measured CMT > 250 microns, they were classified as “recurrent” or “persistent” macular edema, and were re-injected.  Re-injections were also given if visual acuity decreased by more than 5 letters (1 line).

Their study found that there was no additional benefit from the higher dose, and that both groups experienced improved vision and decreased CMT.  The results showed that on average, CMT improved from about 450 mic at the first visit, to 250 mic at 3 months, and ended up at the 240 mic range at 24 months.  Furthermore, the mean time for repeat injections was in the 10-13 week range.

But is this better than laser?  Well, the study doesn’t directly look at this question, but it does state that among its small sample size of 63 eyes, of those receiving 1.25 mg, 68% experienced improvement in vision by 3 or more lines of vision (72% in the 2.5 mg group).  That’s pretty significant percentage of improved vision.  You’ll recall that the SCORE Study patients had improved vision in the 26-29% range for IVTA and laser.  So bevacizumab seems to give better results than laser for BRVO.  I realize I’m mixing studies — not really a meta-analysis (maybe a “mini”-analysis), and clearly this needs to be studied further.  But the authors seem to lay out a reasonable approach for treating BRVO with bevacizumab, and their results seem to be significantly better than best results we have available with laser or IVTA.  Check vision monthly, and if worse by 5 letters, treat with bevacizumab;  check OCT at 3, 6 12 and 24 mo, and if CMT > 250 treat with bevacizumab.  Expect about 70% to improve 3 or more lines of vision.


Early Treatment for Retinopathy of Prematurity (ETROP)

2 12 2009

I have a patient in the NICU that I’ve been following for the past couple of weeks with ROP, so it’s given me the opportunity to review the ETROP results, the final results of which were published in 2004 by William V. Good on behalf of the ETROP Cooperative Group.

The CRYO-ROP trial had given us the “threshold” of treatment for ROP.  Threshold was defined by the CRYO-ROP as at least five clock hours of contiguous, or eight cumulative clock hours of stage 3 ROP in zone I or II in the presence of plus disease.  When I was a resident, a quick trick we were taught was to look at the posterior pole for plus disease.  If there was no plus disease, no matter how extensive the ROP might be, you weren’t at threshold.  And I still do this now, looking first at the posterior pole for plus disease, before heading off into the periphery to determine zones and stages.

The ETROP study came about because of a sense that treating some patients sooner than these threshold definitions could be beneficial, and in fact the ETROP proved it to be so, effectively changing the threshold for treatment.  The most important change is that treatment can now be considered sooner without regard to the number of clock hours involved.  The new criteria defined by ETROP are:

1.  Zone I ROP with plus disease (doesn’t matter what stage)

2.  Zone I ROP with stage 3 disease (don’t need plus disease)

3.  Zone II ROP, stage 2 or 3, with plus disease.

These three criteria are defined as “Type I” ROP.

Treating these eyes instead of waiting for CRYO-ROP threshold criteria resulted in reduction in unfavorable visual acuity outcomes from 19.8% to 14.3%, and a reduction in unfavorable structural outcomes from 15.6% to 9.0% (both at 9 months).  Bear in mind that these results are not comparing “treated” to “untreated”, but are comparing “treating earlier” to “waiting for CRYO-ROP threshold”.  Treating these Type I eyes resulted in treatment on average 2 weeks earlier than waiting for CRYO-ROP threshold.

Looking at these numbers, there is a definite clinical benefit to treating earlier, but you can spin the numbers in a couple of ways.  You can say that unfavorable visual acuity outcomes were reduced by 25% (from 19.8 down to 14.3%), but I think it’s more meaningful to look at the absolute percentage reduction, which is about 5%.  A 5% decrease means that for every 20 eyes you treat early, you see a benefit in one of them.  Not great, but given that you’re only changing the timing of the treatment in most cases, (66% of control eyes went on to need treatment by CRYO-ROP criteria anyway), it’s pretty good.  The question though is, what risk was involved in treating these infants two weeks earlier?  The study showed that there was a definite increase in morbidity in the early treatment group (but not mortality) — bradycardia, re-intubation, etc.  How often did this occur?  If you treat two patients early, one had a potentially serious systemic side effect.  So, the decision regarding the timing of treatment is not so cut and dried as the study numbers might suggest.  On the other hand, it does support treating ROP at “pre-threshold” levels, and that should be taken into account.  Furthermore it points to the need to follow pre-threshold eyes more closely, and to be prepared to treat within 48 hours of reaching threshold.

Is Avastin the new laser for diabetic macular edema?

19 11 2009

In the June 2009 issue of Ophthalmology Soheilian et al, out of Tehran, published an important paper comparing intravitreal bevacizumab (IVB) alone or in combination with triamcinolone (+IVTA) to macular photocoagulation for treatment of diabetic macular edema.  They randomized a total of 150 eyes with clinically significant macular edema (CSME) into three treatment groups, and followed them for up to 36 weeks (which is about 9 months).   If CSME persisted at 12 week (3 mo) intervals, the eye were retreated with the same intervention.  Their study showed that intravitreal bevacizumab yielded better visual acuity results at 36 weeks than did laser treatment.  Specifically, vision improved by > 2 Snellen lines of acuity in 37% of the IVB group, 25% of the IVB+IVTA group, and 15% of the laser group.  On the other hand, retreatment was required in 28%, 20% and 6% of the three groups respectively.  IVB improves vision more, but needs to be used more often.

One of the things that the study did not do, was differentiate the patients with CSME into those with cystic edema and those with non-cystic edema.  My hunch is that we would find that in the group with cystic edema, the difference between the effectiveness in bevacizumab and laser would be even greater.  Will bevacizumab become a replacement for laser in treating CSME?  It’s too soon to say.  My hope is that the Sohelian et al will continue to follow these patients and report on results as they reach the 1 year and 2 year marks.

In clinical practice, this paper seems to support what many of us are currently doing:  using bevacizumab as first line treatment for diabetic macular edema to decrease the edema and improve the vision, and following it up with laser treatment for long term control.  I’d like to see a study that looks at this situation.  I use the sequential approach with greatest success in patients with massive or cystic macular edema.

Here is the abstract:

Ophthalmology. 2009 Jun;116(6):1142-50. Epub 2009 Apr 19.

Randomized trial of intravitreal bevacizumab alone or combined with triamcinolone versus macular photocoagulation in diabetic macular edema.

Soheilian MRamezani AObudi ABijanzadeh BSalehipour MYaseri MAhmadieh HDehghan MHAzarmina MMoradian SPeyman GA.

Ophthalmology Department, Labbafinejad Medical Center, Shaheed Beheshti Medical University, Tehran, Iran.

PURPOSE: To compare the results of intravitreal bevacizumab (IVB) injection alone or in combination with intravitreal triamcinolone acetonide (IVT) versus macular laser photocoagulation (MPC) as a primary treatment of diabetic macular edema (DME). DESIGN: Randomized 3-arm clinical trial. PARTICIPANTS: A total of 150 eyes of 129 patients with clinically significant DME and no previous treatment.

METHODS: The eyes were randomly assigned to 1 of the 3 study arms: the IVB group, patients who received 1.25 mg IVB (50 eyes); the IVB/IVT group, patients who received 1.25 mg of IVB and 2 mg of IVT (50 eyes); and the MPC group, patients who underwent focal or modified grid laser (50 eyes). Retreatment was performed at 12-week intervals whenever indicated. MAIN OUTCOME MEASURES: Change in best-corrected visual acuity (VA) at week 24.

RESULTS: VA changes among the groups were statistically significant at 6 (P<0.001) and 24 (P = 0.012) weeks. The significant treatment effect was demonstrated in the IVB group at all follow-up visits and in the IVB/IVT group at 6 and 12 weeks. VA changes +/- standard deviation at 36 weeks were -0.28+/-0.25, -0.04+/-0.33, and +0.01+/-0.27 logarithm of minimum angle of resolution in the IVB, IVB/IVT, and MPC groups, respectively (P = 0.053). Significant central macular thickness (CMT) reduction was observed in all groups only up to 6 weeks; however, CMT changes were not significant among the groups in all visits. Overall, retreatment was required for 27 eyes up to 36 weeks (14 in the IVB group, 10 in the IVB/IVT group, and 3 in the MPC group). In the IVB group, in which a greater VA improvement was observed, only 1 injection was required in 72% of the cases. VA improvement >2 Snellen lines at 36 weeks was detected in 37%, 25%, and 14.8% of patients in the IVB, IVB/IVT, and MPC groups, respectively.

CONCLUSIONS: Intravitreal bevacizumab injection in patients with DME yielded a better visual outcome at 24 weeks compared with macular photocoagulation. A change in CMT beyond the 6-week time point that corresponded to the vision change was not detected. No adjunctive effect of IVT was demonstrated.

SCORE (not!): Air-ball for IVTA in BRVO

7 11 2009

The one-year results of the SCORE study were published in September.  The studies (two really, one comparing standard of care vs. intravitreal triamcinolone (IVTA) injections in central retinal vein occlusion (CRVO), and the other in branch retinal vein occlusion (BRVO).  Here I’ll discuss the results in the BRVO study.  Standard of care for BRVO with macular edema is laser.  The study compared visual results for patients with BRVO who received either laser, IVTA 1 mg or IVTA 4 mg.  The results showed no significant difference if visual outcome among the three groups.  Vision improved by 3 lines or more in 29%, 26% and 27% respectively.  Because IVTA carries the risk of increased IOP and cataract, the study recommends that laser treatment remain standard of care for treating macular edema in BRVO.  It’s interesting that in the SCORE CRVO study, IVTA proved to be more effective than standard care (observation), whereas in the BRVO study, standard care (laser) proved to be more effective than IVTA.  Here’s the abstract.

Arch Ophthalmol. 2009 Sep;127(9):1115-28.
A randomized trial comparing the efficacy and safety of intravitreal triamcinolone with standard care to treat vision loss associated with macular Edema secondary to branch retinal vein occlusion: the Standard Care vs Corticosteroid for Retinal Vein Occlusion (SCORE) study report 6.
Scott IU, Ip MS, VanVeldhuisen PC, Oden NL, Blodi BA, Fisher M, Chan CK, Gonzalez VH, Singerman LJ, Tolentino M; SCORE Study Research Group.

OBJECTIVE: To compare the efficacy and safety of 1-mg and 4-mg doses of preservative-free intravitreal triamcinolone with standard care (grid photocoagulation in eyes without dense macular hemorrhage and deferral of photocoagulation until hemorrhage clears in eyes with dense macular hemorrhage) for eyes with vision loss associated with macular edema secondary to branch retinal vein occlusion (BRVO). METHODS: Multicenter, randomized clinical trial of 411 participants. Main Outcome Measure Gain in visual acuity letter score of 15 or more from baseline to month 12.

RESULTS: Twenty-nine percent, 26%, and 27% of participants achieved the primary outcome in the standard care, 1-mg, and 4-mg groups, respectively. None of the pairwise comparisons between the 3 groups was statistically significant at month 12. The rates of elevated intraocular pressure and cataract were similar for the standard care and 1-mg groups, but higher in the 4-mg group.

CONCLUSIONS: There was no difference identified in visual acuity at 12 months for the standard care group compared with the triamcinolone groups; however, rates of adverse events (particularly elevated intraocular pressure and cataract) were highest in the 4-mg group. Application to Clinical Practice Grid photocoagulation as applied in the SCORE Study remains the standard care for patients with vision loss associated with macular edema secondary to BRVO who have characteristics similar to participants in the SCORE-BRVO trial. Grid photocoagulation should remain the benchmark against which other treatments are compared in clinical trials for eyes with vision loss associated with macular edema secondary to BRVO.

SCORE! A win for IVTA in CRVO

7 11 2009

The one-year results of the SCORE study were published in September.  The studies (two really, one comparing standard of care vs. intravitreal triamcinolone (IVTA) injections in central retinal vein occlusion (CRVO), and the other in branch retinal vein occlusion (BRVO).  Here I’ll discuss the results in the CRVO study.  Standard of care for CRVO with macular edema is observation.  No effective treatment has been available, to reduce the macular edema and improve vision.  The SCORE study has shown that IVTA at a 1 mg dose is indeed effective at improving vision in CRVO with macular edema.  How effective?  Those who were in the observation group had a 7% rate of improvement in vision, whereas those in the IVTA group had 26% improvement in vision.  Although this is nearly a five-fold increase in the rate of improvement, it bears mentioning that nearly 3/4 of patients who did receive IVTA did not gain the levels of vision defined as the endpoint of the study.  The study compared 1 mg and 4 mg doses of preservative free triamcinolone, and found that the success rate was essentially the same (27% and 26% respectively), but that the higher dose had increased risk of cataracts and IOP.  271 patients were enrolled in the study.

Bottom line:  A single 1 mg dose of IVTA results in 26% of patients with CRVO and ME gaining 3 or more lines of vision, vs. 7% with observation.  The shortcoming of the data is that we only have 1 year results.  Time will tell whether the improvement will hold.

Here are links to the NIH/NEI press release, the article on Medscape.  The abstract is below.

Arch Ophthalmol. 2009 Sep;127(9):1101-14.
A randomized trial comparing the efficacy and safety of intravitreal triamcinolone with observation to treat vision loss associated with macular edema secondary to central retinal vein occlusion: the Standard Care vs Corticosteroid for Retinal Vein Occlusion (SCORE) study report 5.
Ip MS, Scott IU, VanVeldhuisen PC, Oden NL, Blodi BA, Fisher M, Singerman LJ, Tolentino M, Chan CK, Gonzalez VH; SCORE Study Research Group.
OBJECTIVE: To compare the efficacy and safety of 1-mg and 4-mg doses of preservative-free intravitreal triamcinolone with observation for eyes with vision loss associated with macular edema secondary to perfused central retinal vein occlusion (CRVO).

METHODS: Multicenter, randomized, clinical trial of 271 participants. MAIN OUTCOME MEASURE: Gain in visual acuity letter score of 15 or more from baseline to month 12.

RESULTS: Seven percent, 27%, and 26% of participants achieved the primary outcome in the observation, 1-mg, and 4-mg groups, respectively. The odds of achieving the primary outcome were 5.0 times greater in the 1-mg group than the observation group (odds ratio [OR], 5.0; 95% confidence interval [CI], 1.8-14.1; P = .001) and 5.0 times greater in 4-mg group than the observation group (OR, 5.0; 95% CI, 1.8-14.4; P = .001); there was no difference identified between the 1-mg and 4-mg groups (OR, 1.0; 95% CI, 0.5-2.1; P = .97). The rates of elevated intraocular pressure and cataract were similar for the observation and 1-mg groups, but higher in the 4-mg group.

CONCLUSIONS: Intravitreal triamcinolone is superior to observation for treating vision loss associated with macular edema secondary to CRVO in patients who have characteristics similar to those in the SCORE-CRVO trial. The 1-mg dose has a safety profile superior to that of the 4-mg dose. Application to Clinical Practice Intravitreal triamcinolone in a 1-mg dose, following the retreatment criteria applied in the SCORE Study, should be considered for up to 1 year, and possibly 2 years, for patients with characteristics similar to those in the SCORE-CRVO trial.

ANCHOR Study: Lucentis is better than Photodynamic Therapy for Classic ARMD

29 10 2009

Here’s the abstract for the two-year study results.  There are a few key points:  Ranibizumab patients maintained vision better (90%) vs. PDT patients (65%).  More ranibizumab patients gained vision (about 35-40%) than PDT patients (6%).  Injections were monthly.

Ophthalmology. 2009 Jan;116(1):57-65.e5.
Ranibizumab versus verteporfin photodynamic therapy for neovascular age-related macular degeneration: Two-year results of the ANCHOR study.
Brown DM, Michels M, Kaiser PK, Heier JS, Sy JP, Ianchulev T; ANCHOR Study Group.

Collaborators (87)
Vitreoretinal Consultants, Methodist Hospital, Houston, Texas 77030, USA.
Comment in:

Ophthalmology. 2009 Aug;116(8):1593.
OBJECTIVE: The 2-year, phase III trial designated Anti-vascular endothelial growth factor (VEGF) Antibody for the Treatment of Predominantly Classic Choroidal Neovascularization (CNV) in Age-related Macular Degeneration (ANCHOR) compared ranibizumab with verteporfin photodynamic therapy (PDT) in treating predominantly classic CNV. DESIGN: Multicenter, international, randomized, double-masked, active-treatment-controlled clinical trial. PARTICIPANTS: Patients with predominantly classic, subfoveal CNV not previously treated with PDT or antiangiogenic drugs.

INTERVENTION: Patients were randomized 1:1:1 to verteporfin PDT plus monthly sham intraocular injection or to sham verteporfin PDT plus monthly intravitreal ranibizumab (0.3 mg or 0.5 mg) injection. The need for PDT (active or sham) retreatment was evaluated every 3 months using fluorescein angiography (FA). MAIN OUTCOME MEASURES: The primary, intent-to-treat efficacy analysis was at 12 months, with continued measurements to month 24. Key measures included the percentage losing <15 letters from baseline visual acuity (VA) score (month 12 primary efficacy outcome measure), percentage gaining >or=15 letters from baseline, and mean change over time in VA score and FA-assessed lesion characteristics. Adverse events were monitored.

RESULTS: Of 423 patients (143 PDT, 140 each in the 2 ranibizumab groups), the majority (>or=77% in each group) completed the 2-year study. Consistent with results at month 12, at month 24 the VA benefit from ranibizumab was statistically significant (P<0.0001 vs. PDT) and clinically meaningful: 89.9% to 90.0% of ranibizumab-treated patients had lost <15 letters from baseline (vs. 65.7% of PDT patients); 34% to 41.0% had gained >or=15 letters (vs. 6.3% of PDT group); and, on average, VA was improved from baseline by 8.1 to 10.7 letters (vs. a mean decline of 9.8 letters in PDT group). Changes in lesion anatomic characteristics on FA also favored ranibizumab (all comparisons P<0.0001 vs. PDT). Overall, there was no imbalance among groups in rates of serious ocular and nonocular adverse events. In the pooled ranibizumab groups, 3 of 277 (1.1%) patients developed presumed endophthalmitis in the study eye (rate per injection = 3/5921 [0.05%]).

CONCLUSIONS: In this 2-year study, ranibizumab provided greater clinical benefit than verteporfin PDT in patients with age-related macular degeneration with new-onset, predominantly classic CNV. Rates of serious adverse events were low. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Bevacizumab speeds resolution of vitreous hemorrhage

27 10 2009

A study in the September 2009 issue of Retina by Huang et al. out of Taiwan is titled “Intravitreal Bevacizumab and Panretinal Photocoagulation for Proliferative Diabetic Retinopathy Associated with Vitreous Hemorrhage.”  In this important study, they took 40 patients with vitreous hemorrhage (VH) too dense to treat with PRP, and if the VH  did not clear within two weeks, they treated them with bevacizumab (Avastin).  If the VH did not clear, they treated again in 4-6 weeks.  If the VH heme had not cleared by 12 weeks, they performed a pars plana vitrectomy (PPV).  They compared this to a group of 40 patients who did not receive bevacizumab.  When the vitreous was clear enough in either group, they received PRP.

The results showed that patients receiving bevacizumab cleared anywhere from 2-20 weeks (avg 12 weeks), whereas the patients who did not receive bevacizumab required 6-30 weeks (avg 18 weeks) to clear.  Only 10% of those receiving bevacizumab required PPV, whereas 40% of those who did not receive the drug required PPV.

So, clearly, intravitreal bevacizumab is helpful in the initial treatment of VH from proliferative diabetic retinopathy.  It improves the rate of resolution of VH, and decreases the need for surgery.  Two points were of interest to me.  Neither was specifically studied in the paper, but the authors raise the issues in their study design .  First, they remind us that bevacizumab can induce a fibrous response (“Avastin crunch”) and lead to tractional retinal detachments, and so they excluded patients whose ultrasounds showed the presence of tractional detachments or fibrous responses.  They repeated the B-scans as they followed the injected patients to watch for tractional detachments.  Second, they chose 4-6 weeks as the interval for re-injection of bevacizumab. They based this on two previous papers.  One by Jorge et al. which showed that peak regression of NV in diabetic retinopathy occured at 6 weeks, and that by 12 weeks, leakage had resumed; and the other by Arevalo et al. which showed that regression of NV could occur as quickly as 7-15 days after injection of bevacizumab.

Pearls to take away:  Inject bevacizumab for dense vitreous hemorrhages, get a baseline B-scan and follow the B-scans after injection for tractional detachments, and consider re-injections at 4-6 weeks.