The Promise and Perils of Combination Therapy

A discussion of off-label treatments for age-related macular degeneration.

The Promise and Perils of Combination Therapy
A discussion of off-label treatments for age-related macular degeneration.

The past decade has witnessed seminal breakthroughs in our understanding of the pathogenesis of neovascular age-related macular degeneration (AMD). The elucidation of the role of vascular endothelial growth factor (VEGF) in particular provides a specific target for therapeutic intervention. At present, only pegaptanib sodium (Macugen, Eyetech/Pfizer) is FDA approved, but it seems likely other anti-VEGF treatments will be online within the next 24 months. These therapies, along with photodynamic therapy (PDT), with verteporfin (Visudyne,VQLT/Novartis Ophthalmics) provide retinal physicians with a variety of treatment options. Despite these options, the treatment of neovascular AMD remains a frustrating process for both the retinal physician and patient.

There is a strong scientific rationale for combination therapy. Along with our improved understanding of the pathogenesis of neovascular AMD has come the realization that neovascularization is a complex process involving multiple cytokines, growth factors, and cell types intertwined in intricate pathways with multiple redundancies.

Combination therapy is common and often routine in the management of diseases such as hypertension, ischemic heart disease, asthma, and cancer. Why should neovascular AMD differ?


Currently, the 4 available treatments for neovascular AMD are: thermal ablative photocoagulation as described by the Macular Photocoagulation Study (MPS),1 PDT with verteporfin,2,3 intravitreal pegaptanib sodium4, and intravitreal triamcinolone.5 The likely availability of ranibizumab (Lucentis, Genentech) and perhaps anecortave acetate (Retaane, Alcon) will soon add to the possible treatment permutations. Because these therapies have different effects on neovascularization and none are individually optimal, it seems reasonable and even compelling to consider combination therapy. The goal of combination therapy is both to enhance efficacy and to diminish the disadvantages of the respective treatments, such as recurrence and treatment frequency.

Today, the most frequently employed combination therapy is PDT with verteporfin and intravitreal triamcinolone acetamide. Based on the initial report of Richard Spaide, MD, many retinal physicians have tried this combination.5 The 2004 Practice and Trends survey of the American Society of Retina Specialists indicates 60% of retinal physicians use this combination. The rationale for combining PDT and triamcinolone is strong. Photodynamic therapy closes neovascular perfusion via thrombosis and has been shown to decrease the growth of the neovascular lesion. Unfortunately, reperfusion occurs in nearly all cases, necessitating retreatment. Animal studies demonstrate that despite its short-term thrombotic effects, PDT also increases VEGF expression, which may contribute to the reperfusion and leakage seen on post-PDT fluorescein angiography. Intravitreal steroids, such as triamcinolone, may decrease VEGF expression and thereby ameliorate post-PDT phenomena.

Although there is an increasing clinical consensus that this combination improves efficacy and decreases retreatment frequency, there are no definitive data from randomized clinical trials to support these contentions. Furthermore, the potential toxicity of routine intravitreal triamcinolone acetamide such as glaucoma, cataract, and endophthalmitis must be addressed.

Combination therapy with pegaptanib sodium and PDT was allowed for predominantly classic lesions at individual investigator discretion in the VISION trial.4 Approximately 22% of patients received combination therapy with PDT and pegaptanib sodium. The VISION trial suggests there are no safety concerns with this combination therapy. However, patients were not randomized to PDT and the criteria for PDT treatment were not standardized. No definitive conclusions can be made concerning the benefits of combining pegaptanib sodium with PDT.

Combination therapy with pegaptanib and triamcinolone also deserves consideration. Theoretically, one could expect synergy because of the different mechanisms of action of pegaptanib sodium and triamcinolone. However, the clinical experience to date is limited and there are no published reports on this combination.

Although fewer than 20% of patients with neovascular AMD present with MPS-eligible extrafoveal or juxtafoveal well-defined lesions, thermal laser is often effective in the short-term ablation of these lesions.1 Unfortunately, the high incidence of recurrent neovascularization limits the long-term visual benefit. Combination therapy with pegaptanib sodium or triamcinolone to prevent recurrence is an obvious option. Again, the clinical experience with this combination is limited. Furthermore, the low incidence of MPS-eligible lesions will make clinical trials difficult.


As newer treatments become available, the possible therapeutic combinations increase. The obvious question is how can we determine the safety and efficacy of all possible combination therapies in the absence of confirmatory clinical trials? The answer is that we cannot. The rapid development of new therapies makes it increasingly difficult to design clinical trials that will be relevant at the time of their completion. Furthermore, as multiple treatments are approved, how do we determine which treatment or combination of treatments is the appropriate standard of care against which new treatments are to be evaluated? In the current era of limited resources, we cannot answer all the questions. We must therefore come to a consensus to determine the most important questions. Although this requires the participation of retinal physicians in conjunction with industry and government, it is the retinal physicians as patient advocates who must drive this process.

Combination therapy also raises ethical issues. Patients with neovascular AMD are desperate and vulnerable. They fear blindness as much or more than stroke, myocardial infarction, or AIDS.6,7 Retinal physicians who suggest combination therapy are obligated to take the time to explain the known benefits as well as the limitations of monotherapy, the rationale for combination therapy and the uncertainties concerning efficacy and risk. The Ophthalmic Mutual Insurance Corporation also suggests for risk management reasons that patients be informed when drugs such as triamcinolone are used off-label.8 Some retinal physicians and, in my experience, many patients are uncomfortable with the uncertainties of combination therapy, and off-label drug use. If so, they should be confident that monotherapy according to current coverage criteria with either PDT or pegaptanib sodium are the only proven treatments.


The substantial cost (See "The Economic Impact of Combination Therapy and AMD", page 48) of treating neovascular AMD demands that ophthalmologists use evidence-based treatment criteria to determine which patients will benefit from which treatment and, just as importantly, which patients will not. Well-executed case series and single-center trials can provide useful and important information. They are the genesis of medical progress. Only retinal physicians skilled in the diagnosis and treatment of neovascular AMD are capable of critically evaluating and applying treatment results from a variety of sources to a specific patient. Retinal physicians therefore need flexibility in the coverage criteria for the treatment of neovascular AMD to pursue optimal treatments.

The Economic Impact of Combination Therapy and AMD

Visual loss from AMD is a demographic time bomb. The Eye Disease Prevalence Research Group estimates that in the United States in 2000 there were 1.75 million people with advanced AMD defined as neovascular or central geographic atrophy.9 Perhaps even more ominously, 7.3 million people are estimated to be at high risk for developing advanced AMD. By 2020, nearly 3 million people are projected to have advanced AMD with the majority having neovascular AMD.10 Prior to the introduction of verteporfin therapy in 2000, less than 20% of eyes with neovascular AMD were treatable. Today, with therapeutic options including verteporfin, pegaptanib sodium, and triamcinolone virtually all de novo cases of neovascular AMD can be treated. As a result, the treatment of neovascular AMD will consume an increasing amount of healthcare resources and is likely to become 1 of the leading line items in Medicare expenditures.

The costs associated with the treatment of AMD are driven primarily by 2 factors: the allowable reimbursement of the drugs and the increase in physician services, which are necessary for the diagnosis, drug administration, and treatment follow-up. At present, both of these factors have an adverse effect on the calculation of the sustainable growth rate (SGR), which is used to determine the yearly update to the conversion factor. The conversion factor translates the Resource Based Relative Value Scale valuation of all combination therapy procedures into dollars. It is projected that if the current SGR methodology remains in effect, there will be a 40% decrease in Medicare physician payment rates by 2013. The net effect is that in 2013, physician payment rates will be 20% lower than they were in 1990 when the SGR process began. Therefore, there is a consensus among policy makers that the SGR process requires revision or replacement. However, there is no consensus on how to change the present system or how to pay for any change. Since 2002, yearly congressional action has superseded the SGR mandated cuts at the cost of over $60 billion. In the absence of a permanent fix to the SGR process, it is unknown whether Congress will continue to choose to override the projected cuts.

In 2005, projected total Medicare expenditures will be approximately $325 billion. Of that total, physicians receive approximately $80 billion and ophthalmologists about $5 billion. Therefore, the net effect of ophthalmology-related increases in general and AMD-related increases in particular on the SGR calculation are minimal. However, within ophthalmology the treatment costs of AMD will become a substantial portion of overall ophthalmology-related expenditures. At present, protocol treatment costs range between approximately $8000 for PDT and $12,000 for pegaptanib sodium per new case of neovascular AMD. These costs include the drugs and subsequent necessary physician services such as treatment, imaging studies, and office visits. Although it is too soon to know the relative use of PDT versus pegaptanib sodium, in 2003 approximately 40000 patients received PDT. The broader FDA label and coverage criteria for pegaptanib sodium will result in substantially greater utilization. If one conservatively assumes that only 50% of the estimated 200000 new cases of CNV/year are treated with either modality at an average cost of $10,000 per patient, the total cost is approximately $1 billion/year. Furthermore, since all of these patients require follow-up and some require additional treatment beyond 1 year, the cumulative costs are even greater.

With these costs for monotherapy as a baseline, it is apparent why payers are concerned about the costs of combination therapy. Obviously, if patients receive per protocol treatment with both PDT and pegaptanib sodium, the increased costs are substantial. However, combination therapy also has the potential to lower costs. For example, if the combination of intravitreal triamcinolone and PDT decreases the frequency of PDT retreatment, drug costs would decrease.

George A. Williams, MD, is chair of the Department of Ophthalmology at Williams Beaumont Hospital and director at Beaumont Eye Institute located in Royal Oak, Mich.. Dr. Williams has no financial interest in the information contained in this article. He can be reached by e-mail at


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