Avastin Lucentis Update 49 A Follow up on Infections from Intravitreal Injections

In my last posting (Avastin/Lucentis Update 48), I wrote about the problems with Avastin injections, that appeared to be caused by non-sterile/non-aseptic techniques during re-packaging Avastin from 4 ml bottles into much smaller doses (0.05ml) in tuberculin syringes.

A colleague, who is a compounding pharmacist, pointed out to me that other things can cause contamination of the eye during intravitreal injections besides using non-aseptic techniques during aliquoting and re-packaging of Avastin into injectable syringes.

He sent me a copy of a report from Medscape Medical News that was published online following a meeting of the American Academy of Ophthalmology and Middle East Africa Council of Ophthalmology 2010 Joint Annual Meeting, held during last year’s AAO Meeting.

Here are excerpts from that report:

Intravitreal Injections Expose Patients to Streptococcus More Often Than Eye Surgery

Kathleen Louden
October 20, 2010
Medscape Medical News

Streptococcus is isolated much more frequently from endophthalmitis cultures after intravitreal injection (IVI) of antivascular endothelial growth-factor agents than after ocular surgery, results of a meta-analysis show.

Ophthalmologists should consider using additional sterile techniques during these injections to prevent exposing patients to the sight-threatening complication of streptococcal endophthalmitis, said study author Colin McCannel, MD, associate professor of ophthalmology from the Jules Stein Eye Institute at the University of California at Los Angeles.

"If we can prevent some of the worst cases of endophthalmitis, I think it's worth the effort," Dr. McCannel told Medscape Medical News.

To confirm his impression that reports of Streptococcus organisms seemed more frequent than should be expected after IVI, Dr. McCannel analyzed the American medical literature from 2005 through 2009. He found 16 articles that reported the causative organism in post-IVI endophthalmitis. As expected, endophthalmitis was rare, occurring in 54 of 105,531 injections. Only 26 were culture-positive, according to the abstract. Most of the causative organisms were coagulase-negative Staphylococcus, he said.

However, cultures yielded Streptococcus organisms 30.8% of the time (8 of 26), which Dr. McCannel said is "3- or 4-fold higher" than the incidence reported in the literature for acute postoperative endophthalmitis. The postoperative incidence of streptococcal endophthalmitis ranges from 0% after vitrectomy to 8.2% to 9% after cataract surgery, he reported.

Likely Source of Infection

This finding led him, he said during an interview, to do "some detective work" to try to find the possible source of these streptococcal infections. He found several studies in the anesthesia literature reporting streptococcal meningitis after dural puncture, a procedure that, according to Dr. McCannel, has a working distance between physician and patient similar to that of IVI. Analysis found that the causative organisms in most of those cases came from the treating physician's oral flora, which was aerosolized during talking.

Consequently, the Centers for Disease Control and Prevention in Atlanta, Georgia, recommended in 2007 that spinal procedure operators wear a surgical mask during the procedure (MMWR Morb Mortal Wkly Rep. 2010;59:65-69).

Ophthalmologists "often have to give directions to the patient during injections, and sometimes there is small talk," Dr. McCannel said. "The patient's eye is probably being showered with these microscopic droplets. We may be contaminating the injection field or the needle."

Recommendations

If other studies validate his findings, the ophthalmic community should decide whether to recommend wearing a surgical mask during IVI, he said. He told the audience that he does not wear a mask because "it would be burdensome to take it on and off" during the brief injections.

Another precautionary strategy that Dr. McCannel suggested was to avoid talking, coughing, or sneezing during the injections. He said he asks his ophthalmic technicians to instruct the patient before the procedure that "the injection is not the time to ask questions" and to refrain from talking. If he needs to instruct the patient, he said he speaks away from the patient.

A panelist at the session who did not participate in the study, Joan W. Miller, MD, said in an interview that the study findings have the potential to change clinical practice. Dr. Miller, professor and chair of ophthalmology at Harvard Medical School in Boston, Massachusetts, said she will consider changing her IVI techniques to try to prevent the spread of Streptococcus.

"Not talking on the [injection] field is probably sufficient precaution," she told Medscape Medical News.



My friend, the compounding pharmacist, went on to say,  “I wish we had more visibility into what [really] happened in TN and FL and the pharmacies that prepared those compounds. It is even more critical that physicians look to do their diligence when choosing a pharmacy to provide these sterile compounds to patients. Because of our strict quality control and assurance procedures we have created an environment that focuses on quality.”

“As you may be aware OMIC, the ophthalmology insurance carrier, has been recommending to physicians that the best practice is to seek out compounding pharmacies that have been accredited by PCAB, the Pharmacy Compounding Accreditation Board.  Being accredited by PCAB gives confidence to physicians and consumers that products are prepared in accordance with the United States Pharmacopeial Convention's standards. Chapter 797 of the USP clearly outlines the facility, environment and testing necessary to provide sterile compounded products.  Without an accreditation body like PCAB, there is no reliable third-party verification that a pharmacy meets the USP 797 standard.”

Avastin Lucentis Update 12 The Controversy Makes the Front Page of the WSJ

On February 22nd, Marilyn Chase of the Wall Street Journal’s staff, in a front page article, reported on the controversy both within Genentech and outside, between retinal specialists, on the use of either the high-priced, FDA approved for AMD Lucentis, and the much lower-priced but off-label use of the FDA approved (for colorectal cancer) Avastin for treating "wet" age-related macular degeneration. I would like to claim at least a little credit for the story, as I urged Ms. Chase (and a number of other investigative reporters) to take a look behind the rumors that some medical and pharmaceutical companies were trying to stop the upcoming NEI/NIH trial to compare the effectiveness of Avastin versus Lucentis, after posting my Update No. 9: A Disturbing Report... on December 2nd.

Following Ms. Chase’s story on Genentech that appeared in the Journal on January 11th, I wrote her with a link to my posting above. Then following the posting of the White Paper, Why Avastin vs Lucentis Matters, prepared by a group of retinal specialists alarmed by the public health implications of the high cost of Lucentis to society (Update No. 11 – published February 10th), I again urged Ms. Chase to pursue the cause. The result was yesterday’s story.

Because of Copyright laws, I will only publish excerpts of Ms. Chase’s story. Anyone wishing to see the complete article can go to http://www.wsj.com/ (if you are a subscriber to the online edition of the Journal), or send me an email and I will be happy to respond with a copy of the story.

BLIND AMBITION

Genentech's Big Drug For Eyes Faces a Rival

Intended for Other Use, Cheaper Injection Is One of Its Own Products

By MARILYN CHASE (February 22, 2007; [WSJ] Page A1)

SAN FRANCISCO -- For some of her patients at risk of blindness, retinal specialist Anne Fung injects the drug Lucentis, which costs nearly $2,000 a shot. For those who have less health coverage, she offers a shot of another drug, Avastin, that costs around $40.

The two drugs are both made by Genentech Inc. They work similarly. Doctors say both can be effective in preventing or even reversing vision loss. But only Lucentis is approved by the Food and Drug Administration to treat eye problems.

...The Lucentis-Avastin showdown has thrown the pharmaceutical world into a tizzy. Genentech, fearful that a potential billion-dollar-a-year product could be headed down the tubes, is urging doctors to stick to Lucentis and its proven efficacy in treating age-related macular degeneration. Doctors are weighing benefit and cost -- and often choosing to roll the dice with Avastin, although it is approved only as a cancer treatment, to ensure that less well-off patients get treatment.

Now the federal government is hoping to settle the dispute by funding a head-to-head comparison of the two biotechnology drugs, the first such trial by the National Institutes of Health. If Avastin works as well as Lucentis, the government's Medicare program for the elderly could save $1 billion or more a year, officials say.

The mutiny by doctors nationwide against a high-priced drug -- and Washington's willingness to go to bat for them -- is triggering alarms in the drug industry. "Industry doesn't want an equivalency trial where there could be decisions on coverage. They are terrified," says William L. Rich, director of health policy at the American Academy of Ophthalmology, which backs the NIH trial.

...For Genentech, the world's second-largest biotechnology company by revenue after Amgen Inc., the stakes are high. Lucentis was a surprise hit after its June 30 launch, logging $10 million in sales on its first day and $371 million in the second half of 2006. Eric Schmidt, an analyst at Cowen & Co., estimates the figure could reach $900 million this year and rise to $1.3 billion by 2011.

Genentech has refused to provide any funding or drugs for the NIH trial, scheduled to start in April. The Biotech Industry Organization says the NIH should be studying cutting-edge science, not comparing two approved drugs. Genentech's head of business development, Joseph McCracken, adds: "If I were trying to decide how to spend NIH's money, I might not think this is the best way."

...Doctors are using Lucentis and Avastin to treat "wet AMD," a type of the disease in which overgrowth of blood vessels and leakage of fluid cause gross swelling of the macula, a part of the retina.

...Avastin fights cancer by halting the growth of blood vessels that sustain tumors. The FDA approved it as a cancer treatment (for colorectal cancer) in 2004.

More than a decade ago, research suggested that taming vessel overgrowth might also be used to treat diseases of the eye. But based on early tests in monkeys using a similarly sized molecule, Genentech thought the Avastin molecule was too big to penetrate the retina. Its scientists spent two years re-engineering it to create Lucentis, which then underwent seven years of testing.

...In July 2005, Genentech reported the results of a big Phase III study of Lucentis before a hushed crowd of 2,000 at a medical meeting in Montreal. The studies showed it halted blindness in 90% of people with AMD and improved vision in 30%.

"There was an audible gasp," recalls George Williams, chairman of ophthalmology at the Beaumont Eye Institute in Royal Oak, Mich. Lucentis "was so much better than anything else." Previously the disease was treated with less-effective drugs, photodynamic therapy and lasers -- "like using a blowtorch to stop weeds," says Dr. Fung in San Francisco.

The only problem: Approval would take another year.

Then came an apparent solution: At the same meeting, Philip Rosenfeld, a professor at the Bascom Palmer Eye Institute of the University of Miami Medical School, presented a case of a patient who had been going blind and was injected with Avastin. The patient's retinal scans dramatically improved a week after treatment and vision began to regain sharpness over six months.

It was a review of this meeting, the July 2005 American Society of Retina Specialists held in Montreal, by Lynne Peterson in her Trends-in-Medicine newsletter, that piqued my interest, and started my journey in reporting on the Avastin (and later Lucentis) phenomenon, beginning with my posting of January 31, 2006, Avastin: A New Hope for Treating AMD.

Over the following year plus, that initial posting was followed by an additional 12 reports on the status of the two drugs in treating wet AMD. See the Author’s Notes at the end of this posting for a complete listing and links to each story.

...Rather than wait until Lucentis was approved by the FDA, many doctors grasped at the next best thing. With the help of compounding pharmacists who siphoned tiny doses of Avastin into small syringes, eye doctors tried it in thousands of patients. In large doses for cancer, Avastin costs $55,000 a year. The dose used in the eye costs just $20 to $100.

"People thought we were cowboys, but we were doing it in our patients' interests," says Robert Avery, an ophthalmologist in Santa Barbara, Calif. "When people are going blind, they're willing to take risks."

Even after Lucentis received FDA approval last year (June 30, 2006), many doctors stuck to Avastin because a comparable Lucentis injection costs $1,950. "This is a public-health issue," says Dr. Rosenfeld of Miami. "I believe in profit but things are out of proportion."

See also the above mentioned White Paper: Why Avastin vs Lucentis Matters, for more discussion on the public health issues on the costs to society of the continued use of the high-priced Lucentis.

...Last month, the American Society of Retina Specialists found in a survey that doctors preferred Avastin over Lucentis 76% to 9% for their Medicare patients. Even when patients had supplemental insurance policies that covered the patient's cost, the margin was 51% to 43%.

Genentech argues Lucentis is the only product shown to safely restore vision and Avastin remains unproven as an eye treatment. "I've seen anecdotal reports. They're impressive. But they're still single-case reports," says Susan Desmond-Hellmann, the company's president of product development. She cites the mom test: "If my mom had [AMD], I'd want her to get the drug that is safe and effective."

...Genentech, in justifying the cost of Lucentis, says its trials of the drug included more than 6,000 patients who received vision tests, retinal scans and monthly doctor checkups. It was "one of the more expensive clinical trials we've run," says Ronald Park, team leader for pricing. He notes that older drugs for AMD cost nearly $1,000 a dose without improving vision. Lucentis "is a breakthrough drug for a very bad disease," says Dr. Park.

The company also reasons that Lucentis could prevent disability, falls, broken hips and depression associated with blindness. The elderly blind "become more dependent on those they love to drive, get food, help around the house. Until you've seen someone who was independent go blind -- and I've treated these folks -- you don't understand how terrible this can be," Dr. Park says. The American Academy of Ophthalmology this month said blindness costs the health-care system more than $2 billion a year including nursing-home care.

Finally, Genentech says it is happy to help those who can't afford Lucentis. Since Lucentis's approval last summer, 15,000 patients have called the company's assistance programs asking about the drug, a spokeswoman says.

...With billions of dollars at stake and medical questions unanswered, the National Eye Institute plans to start a two-year trial in May or June to compare safety and efficacy of Avastin versus Lucentis. While the NIH has previously run tests comparing newer brand-name drugs against older and cheaper generics, this is the first time it is pitting two brand-name biotech drugs against each other, says Dr. Ferris, the eye institute's clinical director. He says the government must conduct the study because it needs to ensure that the widespread use of Avastin is safe.

Daniel Martin, chair of ophthalmology at Emory University School of Medicine, is leading the NIH trial and has selected 45 test sites for it. He offers his own mom test. "If I were treating your mom, you'd want me to know which drug is better," he says. "And if they're equal, why not use the less-expensive one?"

However, funding for the trial remains uncertain. In part because the government has to purchase all of its Lucentis and Avastin supplies, the eye institute says it can't afford to fund the trial on its own and is seeking help from Medicare.

Barry Straube, chief medical officer of the Center for Medicare and Medicaid Services, says he welcomes the trial as a guide for reimbursement policy, but lawyers for the agency have said it lacks legal authority to use the Medicare trust fund for such research expenses. Dr. Martin says the NIH has awarded $16.2 million for the trial and he'll seek additional funds elsewhere if needed.

Officials at the center, which administers Medicare, project that Lucentis could over time cost taxpayers more than $1 billion a year and possibly as much as $3 billion annually. Dr. Straube says he would be pleased if that figure can be reduced. "Not only are we interested in preserving the Medicare trust fund, but we're sensitive to the higher co-insurance payment Medicare beneficiaries would have to pay," he says.

Genentech says some of the projections of the Medicare impact are too high, noting analysts' estimates that this year's total sales will fall short of $1 billion.

For the moment, the company's data suggest Lucentis has captured about 55% of the market in new cases of AMD. Doctors' surveys suggest Avastin has captured much of the rest. That "unique situation," Executive Vice President Ian Clark recently told analysts, "will challenge our rate of growth of Lucentis in 2007."

Author’s Note on Avastin

Since posting the original article on January 31, 2006, I have now added twelve updates on this important drug for treating age-related macular degeneration. In addition to the posting you are reading, here is a listing (with links) to the others:

Avastin: A New Hope for Treating AMD (January 2006)

Avastin Update: Medicare not Likely to Cover its Use (March 2006)

Avastin Update II: AAO supports Medicare Coverage for Off-label Avastin Use (April 2006)

ARVO 2006: A Further Update on Both Avastin and Lucentis for Treating AMD (May 2006)

Avastin/Lucentis Update 4: FDA Approves Lucentis for Treating Wet AMD (July 2006)

Avastin Update 5: NIH Considers Comparing Lucentis and Avastin (August 2006)

Avastin/Lucentis Update 6: Latest Results Published in NEJM and Another Call for a Trial Between Them (October 2006)

Avastin/Lucentis Update 7: BREAKING NEWS – NEI/NIH Will Fund Comparative Study (October 2006)

Avastin/Lucentis Update 8: A Report of the Latest News from the 2006 AAO Meeting (November 2006)

Avastin/Lucentis Update 9: A Disturbing Report about the Upcoming Trial Between Avastin and Lucentis (December 2006)

Avastin/Lucentis Update 10: A Review of the Current Status of These Drugs for Treating AMD (January 2007)

Avastin/Lucentis Update 11: A White Paper on Why Avastin vs Lucentis Matters (February 2007)

Avastin Lucentis Update 50 A Possible Break in the Dam

News has just come out of England that Novartis may discount the price of Lucentis to off-set the gains made by Avastin in the treatment of wet AMD. As Nick Smith of APM Health Europe wrote yesterday, Novartis is considering cutting the price of Lucentis because of the gains being made by doctors using Avastin to treat AMD.

Here is Nick’s story...and as we hear more, we will bring you the news:

Novartis UK may cut Lucentis price to compete with off-label Avastin in AMD
by Nick Smith, APM Health Europe

LONDON, Oct 4 (APM) - Novartis on Tuesday indicated it may discount Lucentis (ranibizumab) in age-related macular degeneration (AMD) to curb the off-label use of Roche's Avastin (bevacizumab) in the UK.

In a statement to APM following earlier press reports that Novartis may take such a step, the company said: "We recognize the cost pressure within the National Health Service" adding it was "working with the Department of Health and NICE ... exploring all options, to help make Lucentis available for as many as possible of the patients who could benefit from this treatment."

Novartis gave no further indication of what steps it might be prepared to take to boost sales volume but did highlight that NICE had found the drug cost-effective in AMD.

PATIENT ACCESS SCHEME

It did not mention the patient access scheme, then known as a 'risk-sharing' scheme, which was used to discount the drug to gain approval.

The company agreed to pay the cost of the drug beyond 14 injections in August 2008, (APMHE 12490) but this did not stop the UK government undermining the agreement by asking NICE if it could examine Avastin for cost-effectiveness in the indication, despite the fact it is not licensed for the use.

Early take up of Lucentis seemed slow, leading to some sales figures coming below analysts' expectations.

However, an ever-wider global market, ageing population and innovative pricing schemes has helped the company turn this around and second quarter sales reached the equivalent of 310 million euros.

ns/ra

CATT Study Update 14 One Year Study Results Show Equivalency Between Avastin and Lucentis

The Comparison of AMD Treatment Trials (CATT Study) one-year results were released today in the New England Journal of Medicine (NEJM). As anticipated, the two anti-VEGF drugs, Avastin and Lucentis, both produced by Genentech, showed equivalent results in the four-arm head to head study. The 43-center, single-blind, noninferiority trial of 1208 patients with neovascular age-related macular degeneration, showed no significant difference either on a monthly injection schedule, or on an as needed injection schedule.

The National Eye Institute (NEI) launched the CATT Study in 2008 to compare Lucentis and Avastin for treatment of wet AMD. The study has now reported the one-year results for 1,185 patients treated at the 43 clinical centers in the United States. Patients were randomly assigned and treated with one of four regimens for a year. They received Lucentis monthly or as needed, or Avastin monthly or as needed. Enrollment criteria required that study participants had active disease.

Patients in the monthly dosing groups received an initial treatment and then had an injection every 28 days. Patients in the as needed groups received an initial treatment and were then examined every 28 days to determine medical need for additional treatment. As needed groups received subsequent treatment when there were signs of disease activity, such as fluid in the retina. Ophthalmologists involved in patient care did not know which study drug a patient was getting, to make sure that the data was not affected by how anyone felt about the treatment.

Change in visual acuity served as the primary outcome measure for CATT. Thus far, visual acuity improvement was virtually identical (within one letter difference on an eye chart) for either drug when given monthly. In addition, no difference was found in the percentage of patients who had an important gain or loss in visual function. Also, when each drug was given on an as needed schedule, there also was no difference (within one letter) between drugs. As needed dosing required four to five fewer injections per year than monthly treatment. Visual gains were about two letters less with as needed than with monthly treatment but overall visual results were still excellent.

In the monthly treatment arms, Avastin was equivalent to Lucentis, with 8.0 and 8.5 visual acuity letters gained, respectively, and in the as-needed arms, Avastin was equivalent to Lucentis with 5.9 and 6.8 letters gained.

Lucentis as needed was equivalent to monthly Lucentis treatments, although the comparison between Avastin as needed and monthly treatments was inconclusive.  The mean decrease in central retinal thickness was greater in the Lucentis-monthly group (196 μm) than in the other groups (152 to 168 μm, P=0.03 by analysis of variance).

Rates of death, myocardial infarction, and stroke were similar for patients receiving either Lucentis or Avastin (P>0.20). The proportion of patients with serious systemic adverse events (primarily hospitalizations) was higher with Avastin than with Luentis (24.1% vs. 19.0%; risk ratio, 1.29; 95% confidence interval, 1.01 to 1.66), with excess events broadly distributed in disease categories not identified in previous studies as areas of concern.

It should be noted that the median age of patients in the CATT Study was over 80 years, and a high rate of hospitalizations might be anticipated as a result of chronic or acute medical conditions more common to older populations.

In conclusion, the CATT Research Group reported that at 1 year, Avastin and Lucentis had equivalent effects on visual acuity when administered according to the same schedule. Lucentis  given as needed with monthly evaluation had effects on vision that were equivalent to those of Lucentis administered monthly. Differences in rates of serious adverse events require further study.

Or to put it another way, Avastin and Lucentis are equivalent in treating wet AMD, as needed dosing is nearly as effective as monthly injections and, there are no major safety differences between the two drugs.

I have chosen two graphics to illustrate the study results.

Graph 1 shows the changes in visual acuity over the course of the study and illustrates the equivalency of the four arms of the study.

Graph 1

The part of Table 2 that I have chosen, again shows how close the results were for the four arms of the study, and in addition, shows the number of treatments for each arm, as well as the average annual cost to the patients, with Lucentis costing as much as 40 times the cost of Avastin. This will have an important impact on national health care costs when extrapolated to the more than 250,000 patients who are treated for neovascular AMD annually in the United States.

Table 2

(By clicking on the table, an enlarged version will become visible.)

Another important observation was made concerning adverse effects. The CATT Research Group noted that "Clinical trials of intravenous Avastin in patients with cancer have identified associations with arteriothrombotic events, venous thrombotic events, gastrointestinal perforation and hemorrhage, wound-healing complications, and hypertension. With a limited statistical power to detect important adverse events, we found no significant differences between the two drugs in rates of death, arteriothrombotic events, or venous thrombotic events, findings that are consistent with the results of a study of Medicare claims involving more than 145,000 treated patients.However, in our study, the rate of serious systemic adverse events, primarily hospitalizations, was higher among Avastin-treated patients than among Lucentis-treated patients (24.1% vs. 19.0%, P=0.04). The excess numbers of these events were distributed over many different types of conditions, most of which were not identified in cancer trials involving patients who were receiving intravenous doses of Avastin that were 500 times those used in intravitreal injections. We also did not observe increased rates of adverse events with increased exposure to the study drugs; rates were higher for the two drugs when given as needed than when given monthly. The difference in rates may be attributable to chance, imbalances in baseline health status that were not included in the medical history or multivariate models, or a true difference in risk. Resolving this issue will require many more patients than were available for this study. Results from the second year of this study and from other comparative trials will provide more information regarding the relative risks of serious adverse events."


Dr. Philip Rosenfeld (the father of Avastin) provided an editorial to accompany the CATT Study results in the NEJM. Here is the full text of his editorial:

Editorial

Bevacizumab versus Ranibizumab - The Verdict

Philip J. Rosenfeld, M.D., Ph.D.

April 28, 2011 (10.1056/NEJMe1103334)

For 5 years, patients and clinicians have wrestled with the choice between two drugs for the treatment of neovascular age-related macular degeneration (AMD), a common cause of irreversible blindness among the elderly worldwide. Vision loss results from the abnormal growth and leakage of blood vessels in the macula, a specialized portion of the retina responsible for the best visual acuity. Without this macular vision, patients become legally blind. Vascular endothelial growth factor (VEGF), the cytokine primarily responsible for blood-vessel growth, is inhibited when anti-VEGF drugs are injected repeatedly into the eye, and blindness is prevented in most patients. The majority of treated patients go on to have some improvement in vision.

The two anti-VEGF drugs most commonly used are bevacizumab (Avastin) and ranibizumab (Lucentis), both developed by Genentech. Bevacizumab, a full-length humanized monoclonal antibody, has been approved by the Food and Drug Administration (FDA) for the systemic treatment of certain cancers. Ranibizumab, an antigen-binding fragment, is a smaller molecule that was specifically developed and approved to treat eye diseases and is derived from the same anti-VEGF mouse monoclonal antibody as bevacizumab. Both ranibizumab and bevacizumab bind VEGF at the same position; however, they differ in size, affinity for VEGF, speed of clearance from the eye, and cost. Ranibizumab, the FDA-approved treatment for neovascular AMD, costs approximately $2,000 per dose, whereas bevacizumab, the off-label treatment, costs approximately $50. This cost difference, along with the perceived clinical similarities between these two drugs, has led to the widespread use of bevacizumab in the absence of level I evidence.

Editors Note: According to various sources, approximately 65% of ophthalmologists in the U.S. currently use Avastin over Lucentis as their primary treatment for neovascular AMD.

In this issue of the Journal, Martin and colleagues provide such evidence in their findings from the first year of the Comparison of AMD Treatment Trials (CATT), a large, prospective, multicenter, randomized clinical trial comparing bevacizumab and ranibizumab. Despite formidable obstacles, the investigators successfully compared the two drugs and two different dosing regimens: a monthly regimen versus an as-needed regimen (i.e., drug administration only when signs of exudation are present). A monthly regimen is considered the standard for treatment. An as-needed regimen is used less frequently and relies on clinical judgment and imaging techniques to determine when to reinject the drug. The most common imaging method that is used is optical coherence tomography (OCT), a noninvasive technique that identifies fluid leakage from blood vessels. This VEGF-mediated exudate resolves after the injection of ranibizumab or bevacizumab. An OCT-guided as-needed regimen has been shown to result in improved visual acuity, but CATT is the first prospective approach to directly compare a monthly regimen with an as-needed regimen.

Martin et al. found that the monthly use of either bevacizumab or ranibizumab results in the same visual acuity outcome. This finding holds true for the mean visual acuity and the proportion of patients who gain 15 letters (which represents a doubling of the visual acuity), lose 15 letters, or remain stable. Critics will argue that the OCT outcomes suggest differences between these two drugs. Although the OCT retinal thickness measurements favor ranibizumab, this difference is not reflected in any of the visual-acuity or angiographic outcomes. Whether this difference is associated with changes in vision should become clear during the second year of follow-up.

In addition, Martin et al. observed equivalent visual-acuity outcomes with both the monthly and the as-needed regimens of ranibizumab. This result is particularly good news for patients. The success of the as-needed regimen in a multicenter clinical trial cannot be overstated, given the intrinsic difficulties associated with the training of investigators to agree on OCT interpretation and retreatment guidelines. Given deficiencies that were reported by the reading center, it is likely that visual acuity and anatomic outcomes would have been even better with improved investigator compliance. Other strategies to improve overall treatment outcomes might include the use of newer OCT techniques with improved image resolution to help with retreatment decisions and the use of three mandated monthly injections at the start of the study.

Although the as-needed regimen with bevacizumab appeared similar to the as-needed regimen with ranibizumab, the as-needed bevacizumab regimen compared less favorably with monthly regimens for either bevacizumab or ranibizumab. One possibility may be that bevacizumab has a less durable treatment effect in a subgroup of patients and thus more frequent administration may be required. If the frequency of administration were increased, then the outcomes in such patients should approach the outcomes observed with monthly treatments.

Although CATT addresses the question of efficacy, the study was insufficiently powered to identify differences in drug-related adverse events. Although bevacizumab persists longer than ranibizumab in the systemic circulation after an intravitreal injection, Martin et al. observed none of the expected adverse events associated with systemic anti-VEGF therapy. Although more patients receiving bevacizumab had multiple systemic serious adverse events and hospitalizations than those receiving ranibizumab, these events were not associated with organ systems typically identified with systemic anti-VEGF therapy. The results from the second year of CATT and from five other large, ongoing, multicenter comparative clinical trials in Europe should help to clarify whether these adverse events are related to intravitreal anti-VEGF therapy.

The CATT results, together with the totality of global experience, support the use of either bevacizumab or ranibizumab for the treatment of neovascular AMD. An as-needed regimen is an acceptable alternative to a monthly regimen, but strict compliance on the part of both the clinician and the patient is required. Health care providers and payers worldwide will now have to justify the cost of using ranibizumab. Regulators in certain countries will be forced to reconsider their policies that make it illegal to use drugs off-label, particularly when so many of their citizens cannot afford ranibizumab. The CATT data support the continued global use of intravitreal bevacizumab as an effective, low-cost alternative to ranibizumab.

Avastin Lucentis Update 22 Recent Avastin Study Compared to Use of Lucentis in PrONTO

Dr. James Folk, writing in his Medical Rounds Blog, commented on a recent study done by Bashshur and colleagues and published in the American Journal of Ophthalmology. In the Bashshur study, the doctor and his colleagues treated 60 patients with Avastin only, but at a higher than normal dosage – 2.5 mg vs 1.25 mg. They gave one injection and then observed the results one month later using OCT.

If the OCT was dry, the authors didn’t give an injection but asked the patient to return one month later for a re-examination. The treatment paradigm was similar to the PrONTO study except in PrONTO, Lucentis at 0.5mg was used instead of Avastin and the patient first received three monthly injections followed by additional injections as needed.

The other difference was that Bashshur and colleagues would not reinject if the eye showed persistent subretinal or intraretinal fluid after three injections. They believe that these eyes often remain stable. Therefore they would follow them and only reinject if they worsened. In the PrONTO study, any fluid on OCT was an indication for another injection.

As Dr. Folk noted, the Bashshur study was small, only 60 patients (with 9 lost to followup), but the Comparison of AMD Treatment Trials (CATT) is starting and will be the definitive study comparing Avastin to Lucentis for the treatment of wet AMD. The results of Bashshur and colleagues however predict that at most, we’ll probably only find a modest difference between the two drugs.