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.

Phases of Clinical Trials

26 10 2009

In my previous post, I referred to phases of clinical trials for the injectable sustained release steroids to treat diabetic macular edema.  There are four phases to clinical trials.  This description is taken from the National Institutes of Health website:

Clinical trials are conducted in a series of steps, called phases – each phase is designed to answer a separate research question.

  • Phase I: Researchers test a new drug or treatment in a small group of people for the first time to evaluate its safety, determine a safe dosage range, and identify side effects.
  • Phase II: The drug or treatment is given to a larger group of people to see if it is effective and to further evaluate its safety.
  • Phase III: The drug or treatment is given to large groups of people to confirm its effectiveness, monitor side effects, compare it to commonly used treatments, and collect information that will allow the drug or treatment to be used safely.
  • Phase IV: Studies are done after the drug or treatment has been marketed to gather information on the drug’s effect in various populations and any side effects associated with long-term use.

Steroid Implants for Diabetic Macular Edema

26 10 2009

A presentation yesterday at the American Academy of Ophthalmology caught my interest.  There are two sustained-release steroid implants that are injectable, making it possible to use these within the office setting.  The two that I’m watching are the Alimera Iluvien fluocinolone acetonide resevoir implant, which contains half the drug as the Retisert implant to decrease the side-effects seen with Retisert.  It’s implantable with a 25-gauge needle and floats in the vitreous.  The phase 3 clinical trial results for DME may be out by the end of this year.

The other product is Allergan’s Ozurdex (called Posurdex everywhere except in the US).  It’s also an injectible implant that floats in the vitreous through a 22 gauge system, but contains dexamethasone.  It has been FDA approved as of June 2009 for persistent macular edema due to vein occlusion.  The phase 2 trials reported at the AAO meeting involving DME patients showed “35 percent of eyes receiving 700 micrograms improved 10 letters or more by Day 90, compared with 24 percent of those receiving 350 micrograms, and 13 percent in the observation group.”  (from Academy Live email from the AAO)

I like the Alimera product because it is implantable through a 25 gauge system.  The 22 gauge system required to implant the Allergan product is likely to require sutures more frequently to close to wound.  However, the advantage of the Allergan product is that it is completely biodegradable, whereas the Alimera product leaves behind the core which contained the drug.  This floats around in the vitreous, presumably forever.

Improving intravitreal injections

25 10 2009

Have you ever noticed that when you give an intravitreal injection of bevacizumab, or some other drug, a bleb seems to rise on the conjunctiva immediately after injection?  Presumably, that bleb is reflux of the drug (or vitreous).  One way to avoid this, is to simply start the injection at a 30 degree angle to the tangent to the globe.  Just as the needle enters the sclera, turn the needle so it is going straight in (90 degrees to the tangent), and then enter the vitreous.  This effectively creates a “bi-planar” path of the needle, and reduces reflux of the drug.

The technique is described briefly in the September 2009 issue of Retina in an article by Pascal Knecht et al. out of Switzerland.  In their study, they compared the straight ahead injection to the “bi-planar” injection (which they call “tunneled”, but they’re both tunneled, aren’t they?).  They looked at three parameters after injection 0.05 mL of bevacizumab: rise in intraocular pressure, amount of vitreous reflux, and patient discomfort.  The IOP increased more in the tunnelled group (avg 35 mmHg) vs. the straight group (avg 30 mmHg), but after 5 minutes there was no IOP difference between the two groups.  After 15 minutes, both groups were less than 30 mmHg.  Good news on that front.

The amount of vitreous reflux was measured by documenting the width of the broadest conjunctival elevation at the injection site, i.e. the width of the bleb.  They were graded as either 1mm, 2mm, and >2mm.  Not surprisingly, the straight technique had more reflux.  20/30 patients in the straight group had reflux, whereas only 8/30 in the tunneled group had reflux.  The amount of reflux was also more in the straight group.

Finally, there was no difference in pain between the two groups.

Since reading this article, I’ve started the bi-planar “tunneled” technique.  The key is to turn the needle from 30 degrees to 90 degrees while the needle is only partially through the sclera.  I’ve also found it helps prevent reflux to withdraw the needle slowly after the injection, and I actually turn the needle back to the 30 degree angle as the tip emerges from the globe.

Head-to-head Lucentis vs. Avastin Trials

25 10 2009

This bit of news just came in from the annual meeting of the American Academy of Ophthalmology, which is being held right now in San Francisco. There is a lot happening in terms of these two drugs. The results will be important, both clinically and economically. Lucentis costs $2,000 per dose. Avastin costs less than 10% per dose. Both drugs are made by Genentech — that’s a whole different story. Here is a list of current clinical trials as described in the article from “Academy Live” email from Friday October, 23, 2009, a service of the American Academy of Ophthalmology.

Bevacizumab vs. ranibizumab: Initial results expected in 2011
Bevacizumab (Avastin) and ranibizumab (Lucentis) are competing in a hefty schedule of six head-to-head randomized clinical trials directly comparing their use in AMD patients, said Daniel F. Martin, MD. This year, researchers hope to complete enrollment in the studies, which compare varying doses and treatment schedules of the drugs. Initial study results are expected to be available in early 2011, Dr. Martin said.

Here’s the status of each of the studies:

  • The NEI-sponsored CATT (Comparison of AMD Treatments Trial) study began enrolling an estimated 1,200 wet AMD patients at 44 sites in the United States in February 2008. The four-arm study comparing bevacizumab and ranibizumab on fixed and variable schedules is proceeding well, according to Dr. Martin, with one-year results targeted for 2011.
  • In April 2008, researchers in the United Kingdom began enrolling an anticipated 600 patients at 17 sites in the IVAN (Inhibit VEGF in Age-related choroidal Neovascularization) study. This four-armed study compares monthly bevacizumab 1.25 mg and ranibizumab 0.5 mg injections given over two years with three monthly injections followed by PRN dosing.
  • The four-site German VIBERA study started enrolling 360 AMD patients in 2008 to receive three monthly bevacizumab 2.0 mg or ranibizumab 0.5 mg injections and additional injections as needed.
  • The Austrian MANTA study began assigning an anticipated 320 AMD patients in June 2008 to three monthly bevacizumab or ranibizumab injections, with additional treatment as needed.
  • Researchers in Norway began enrolling an anticipated 450 patients in the 12-site LUCAS study in March. Subjects receive bevacizumab 1.25 mg or ranibizumab 0.5 mg monthly as needed until dry, with intervals between doses decreasing over time.
  • French investigators opened enrollment this fall in the 600-patient, 20-site GEFAL study. Subjects are randomized to receive three initial monthly injections of one of the two drugs.

Risk of Stroke with Lucentis vs. Avastin

25 10 2009

In the February 2009 issue of Ophthalmology, a meta-analysis was reported in a letter to the editor pointing out some risks associated with intravitreal injection of ranibizumab (Lucentis). The letter looked at pooled data from the MARINA, ANCHOR and FOCUS studies which were done to determine effectiveness and adverse effects of Lucentis. The authors of the letter point out that when pooling all the data, the ranibizumab group had a 2.2% incidence of stroke, whereas the control group had a 0.7% incidence of stroke. They conclude that the risk of stroke rises as a result of ranibizumab treatment. When they look at the incidence of myocaridal infarction (MI), the ranibizumab group had a 1.9% incidence whereas the control group had a 3.0% incidence. They did not “conclude” that intravitreal injection was protective for MI, but the incidence is lower in the group receiving the drug vs. the control group.

Since the letter was published, there has been some discussion regarding the implications of this meta-analysis for those of us using Avastin. At the current time the feeling is that this data cannot be extrapolated to Avastin, in part because Avastin is a larger molecule (the entire globulin, vs. the immune arms as with ranibizumab). This molecular characteristic is felt to result in less egress of Avastin into the systemic circulation, and it is to this characteristic that the longer-acting effect of Avastin has been attributed. There is currently an NIH sponsored head-to-head clinical trial comparing Lucentis and Avastin underway. The results are due in 2012. The study is ongoing, and the fact that it has not been stopped is some solace to those of us who prefer Avastin that the study has not to date shown that Avastin is either hugely inferior or has significantly higher side-effects that Lucentis.