To: Administrative File: [CAG #00066R4]
From: Louis Jacques, MD
Director, Coverage and Analysis Group
Tamara Syrek Jensen, JD
Deputy Director, Coverage and Analysis Group
James Rollins, MD, PhD
Division Director; Medical Officer
Chuck Shih, PhD
Subject: Final Decision Memorandum for Ocular Photodynamic Therapy (OPT) with Verteporfin for Macular Degeneration
Date: April 3, 2013
I. Final Decision
The Centers for Medicare & Medicaid Services (CMS) will expand coverage of ocular photodynamic therapy (OPT) with verteporfin for “wet” age-related macular edema (AMD). Currently, fluorescein angiography (FA) testing is required for coverage of follow-up treatments. We will revise the requirements for testing to permit either optical coherence tomography (OCT) or FA to assess treatment response. All other coverage criteria would continue to apply.
We note for the readers’ convenience that the acronyms OPT and PDT (photodynamic therapy) are used by various authors to identify ocular photodynamic therapy (i.e., these two terms are used synonymously). When citing the works of these authors we use the author’s terminology. The term FA refers in context to fluorescein angiography or to a fluorescein angiogram. In the context of this reconsideration the use of a test to assess response to prior therapy is
intended to inform subsequent treatment, i.e. whether or not additional therapy may be indicated.
AMD is the leading cause of vision loss in Americans aged 60 and older (NEI, 2012). The prevalence of AMD increases dramatically with age. The prevalence of AMD among women increases from 0.70% in those ages 65-69 to 16.39% for women over the age of 80; similarly, the prevalence of AMD increases from 1.08% for men ages 65-69 to 11.90% for men over the age of 80 (Eye Disease Group, 2004). While the exact etiology of AMD is not completely understood, it is thought to be a multi-factorial disease. In addition to genetic predisposition, at least four additional physiological factors are involved with the disease: lipofuscinogenesis, drusogenesis, local inflammation and neovascularization (in the case of the wet form) (Nowak, 2006). In addition to age, several other risk factors are associated with AMD. These include a family history of AMD, smoking, and light eye color.
AMD involves the destruction of normal macular function. In AMD, acellular debris called drusen accumulates within Bruch’s membrane. Bruch’s membrane is a tissue layer between the outer edge of the retina and the choroid. This key layer keeps the blood vessels of the choroid from leaking fluid into the retina. There are two basic types of AMD: dry and wet. Dry AMD is the most common form, accounting for 90% of all cases. In dry AMD, the accumulation of drusen and the resulting effect on macular function leads to central vision deterioration. In wet AMD, breaks in Bruch’s membrane allow vessels from the choroid to grow, leak, and bleed into the subretinal space; this is termed choroidal neovascularization (CNV). CNV can cause large distortions of the macula and can progress quickly (over the course of days or weeks), effectively destroying central vision. While AMD is the most common condition associated with CNV, other retinal disorders such as pathologic myopia, presumed ocular histoplasmosis syndrome, angloid streaks, and retinal hamartomas can be complicated by CNV formation. Wet AMD accounts for 10% of cases of CNV, and poses a higher risk of severe central vision loss.
In recent years, intravitreal anti-vascular endothelial growth factor (anti-VEGF) therapy has become the standard treatment for neovascular AMD. These agents have been shown to cause a reversal of the growth of abnormal blood vessels as well as improvements in vision (Brown, 2009). For patients who do not benefit from anti-VEGF treatment, however, OPT with verteporfin remains a treatment alternative.
OPT with verteporfin for the treatment of CNV involves the intravenous injection of a photosensitive drug, verteporfin. A laser, which emits light only at verteporfin’s absorption peak of 689nm, is then directed into the eye. It is thought that the excitation of verteporfin generates singlet oxygen and other reactive intermediates that result in temporary closure of leaking blood vessels. The laser is non-thermal; thus it does not produce a heat effect on the retina and thus causes no damage to the retinal tissue. OPT with verteporfin is neither a cure nor a preventative measure for CNV in AMD; it is meant to slow down progression of the disease. Its effect is generally not permanent. The closure of leaking blood vessels caused by OPT is often temporary, and these vessels may re-open. Additional OPT therapy, therefore, may be needed.
At the time of Medicare’s last reconsideration of the topic in 2004, monitoring of the treatment effect of OPT with verteporfin in patients with CNV secondary to AMD involved the use of FA. Leakage of dye from lesions during FA procedures was taken to be an indication of bulk fluid flow from the lesion. There are two patterns of fluorescein leakage in wet AMD: classic and occult. In pure classic CNV, the choriocapillaris plexuses from which fluid leaks can be seen distinctly. In pure occult lesions, the location of the offending vessels responsible for the leakage is not seen. Many CNV lesions are a combination of both the occult and classic forms, with a portion showing a defined site of leakage and another portion being obscured. CNV in AMD is further characterized by one of three locations: subfoveal, juxtafoveal, or extrafoveal. Subfoveal, as the name implies, is CNV that lies directly below the fovea. Juxtafoveal and extrafoveal CNV lie progressively further away from the fovea (but still in the macula).
Since CMS last considered this topic, optical coherence tomography (OCT) has become a common diagnostic technique for the imaging of the retinal structure. OCT is a non-invasive, medical diagnostic imaging technique that can obtain cross-sectional images of biological tissue and is now commonly used for evaluating macular pathology. OCT can be used to measure foveal thickness and to assess possible subfoveal neovascularization. It has also been used to assess the presence of subretinal or intraretinal fluid, though dynamic changes in lesion activity cannot be shown. Whereas FA visualizes the distribution of fluorescein molecules within vessels and fluid-filled spaces, OCT visualizes the arrangement of different layers and distribution of pathologic fluid or tissue within and below the retina. Recent studies have reported on the use of OCT to study patients with CNV after OPT and have also compared the findings of OCT with that of FA. These studies indicate that classic CNV tends to be subretinal while occult CNV appears as pigment epithelial detachment (PED) (Sadda, 2010).
III. History of Medicare Coverage
CMS’s current policy provides coverage for OPT with verteporfin for patients with a diagnosis of neovascular AMD with:
- Predominately classic CNV lesions (where the area of classic CNV occupies ≥ 50% of the area of the entire lesion) at the initial visit as determined by a FA. (CNV lesions are comprised of classic and/or occult components.) Subsequent follow-up visits require a FA prior to treatment.
There are no requirements regarding visual acuity, lesion size, and number of retreatments when treating predominantly classic lesions.
- Subfoveal occult with no classic associated with AMD.
- Subfoveal minimally classic CNV (where the area of classic CNV occupies < 50% of the area of the entire lesion) associated with AMD.
The above 2 indications are considered reasonable and necessary only when:
The lesions are small (4 disk areas or less in size) at the time of initial treatment or within the 3 months prior to initial treatment; and,
The lesions have shown evidence of progression within the 3 months prior to initial treatment. Evidence of progression must be documented by deterioration of visual acuity (at least 5 letters on a standard eye examination chart), lesion growth (an increase in at least 1 disk area), or the appearance of blood associated with the lesion.
A. Current Request
CMS received a formal written request from the American Academy of Ophthalmology (AAO) for review and rescission of section 80.3.1 of the NCD manual. The requestor notes that the current coverage decision for OPT with verteporfin is from 2004, prior to the emergence of targeted anti-VEGF intravitreal treatments. The requestor states that these newer therapies have largely supplanted OPT with verteporfin as initial management of AMD and that OPT with verteporfin is largely relegated to patients in whom the newer therapies have failed. When the policy was written, an initial FA was ordered to determine if the lesions were considered classic CNV lesions. Then the patients were followed monthly with additional FA to determine the need for retreatment. The requestor believes that the current NCD requirement for follow-up FA for continued use of OPT with verteporfin is no longer supportable for these “end-stage” patients.
CMS conducted a follow-up phone call with the AAO to seek clarification on their request to “review and rescind” the NCD. The AAO clarified their intent was to have the requirement for the follow-up only by FA removed, not the NCD itself.
(We note that the request specifies section 80.3.1 of the NCD manual but the requirement for follow-up FA also appears in sections 80.2, 80.2.1, and 8.3 of the NCD manual).
B. Benefit Category
Medicare is a defined benefit program. An item or service must fall within a benefit category as a prerequisite to Medicare coverage §1812 (Scope of Part A); §1832 (Scope of Part B) and §1861(s) (Definition of Medical and Other Health Services) of the Act. OPT with verteporfin is considered to be within the following benefit category: §1861(s) (2) (O); (drugs and biologics) and 1861(s) (1); (physician services). This may not be an exhaustive list of all applicable Medicare benefit categories for this item or service.
IV. Timeline of Recent Activities
|July 24, 2012||CMS accepts a formal request for Ocular Photodynamic Therapy (OPT) with verteporfin for macular degeneration. A tracking sheet was posted on the web site and the initial 30 day public comment period commenced.|
| August 23, 2012||The initial 30 day public comment period ended. Twelve comments were received. |
| October 23, 2012|| CMS conducted a follow-up phone call with the AAO to seek clarification on their request to “review and rescind” the NCD. The AAO clarified their intent was to have the requirement for the follow-up only by fluorescein angiography (FA) removed, not the NCD itself.|
| January 17, 2013||Proposed decision memorandum posted on the CMS website.|
| February 16, 2013|| The second 30 day public comment period ended. Four comments were received.|
V. FDA Status
On April 12, 2000, the Food and Drug Administration (FDA) approved the use of verteporfin in AMD-related subfoveal CNV in which more than 50% of the lesion is classic (i.e. predominantly classic) as determined on fluorescein angiogram. On August 22, 2001, FDA approved verteporfin for the treatment of predominantly classic subfoveal CNV related to pathologic myopia as well as ocular histoplasmosis. The use of OPT with verteporfin for subfoveal occult with no classic CNV in AMD is an unlabeled use.
VI. General Methodological Principles
When making national coverage determinations, CMS generally evaluates relevant clinical evidence to determine whether or not the evidence is of sufficient quality to support a finding that an item or service falling within a benefit category is reasonable and necessary for the diagnosis or treatment of illness or injury or to improve the functioning of a malformed body member. The critical appraisal of the evidence enables us to determine to what degree we are confident that: 1) the specific assessment questions can be answered conclusively; and 2) the intervention will improve health outcomes for beneficiaries. An improved health outcome is one of several considerations in determining whether an item or service is reasonable and necessary.
A detailed account of the methodological principles of study design that the Agency utilizes to assess the relevant literature on a therapeutic or diagnostic item or service for specific conditions can be found in Appendix A.
Public commenters sometimes cite the published clinical evidence and provide CMS with useful information. Public comments that provide information based on unpublished evidence, such as the results of individual practitioners
or patients, are less rigorous and, therefore, less useful for making a coverage determination. CMS uses the initial comment period to inform its proposed decision. CMS responds in detail to the public comments that were received in response to the proposed decision when it issues the final decision memorandum.
The purpose of this evidence review is to summarize the published literature on whether AMD patients with the types/indications that CMS currently covers receiving OPT with verteporfin after having been initially diagnosed by a FA experience improved health outcomes if OCT is used to assess the response to subsequent treatment with OPT with verteporfin. We have not limited our review to studies examining the accuracy of OCT compared to that of FA. Studies in which OCT was used for patient assessment following treatment with PDT and verteporfin have also been reviewed to determine whether response to treatment can be assessed with OCT.
B. Discussion of Evidence Reviewed
Is the evidence adequate to conclude that the use of OPT with verteporfin improves health outcomes in patients with AMD whose response to treatment is assessed with OCT after having been initially diagnosed using FA?
2. External Technology Assessments
CMS did not request an external technology assessment (TA) on this issue.
3. Internal technology assessment
Literature search methods
The evidence reviewed in this assessment was gathered from articles submitted by the requester and from a literature search of PubMed, the Cochrane Library, EMBASE, and other sources such as TRIP Database, performed by the CMS staff. Search terms included the following: macular degeneration, age related macular degeneration, fluorescein angiogram, fundus fluorescein angiography, optical coherence tomography, ocular photodynamic therapy (OPT), and photodynamic therapy (PDT) (these two latter terms are used synonymously).
From the PubMed search results, CMS then excluded non-English language articles, studies with fewer than 10 cases and those not involving human subjects. Using these terms and exceptions, CMS identify a number of other articles in addition to those provided by the requestor.
Published studies described below are organized into four categories:
- Cross-sectional Comparison of OCT and FA CNV Assessment Performance
- Cross-sectional Comparisons of OCT Morphologic and FA Angiographic Findings
- Single-Arm Studies of OPT with Verteporfin Using OCT for Follow-up
- Comparative Studies of OPT with Verteporfin Using OCT for Follow-up
No studies were found that directly compared follow-up of AMD patients with OCT to other assessment modalities after they received OPT with verteporfin. We did, however, find several studies, including comparative trials, in which patients were assessed with OCT following treatment strategies that included PDT with verteporfin. These studies were used to demonstrate whether response to treatment could be evaluated with OCT. Studies comparing the diagnostic accuracy of OCT and FA were also reviewed to determine whether the information provided by OCT is reliable and valid for assessment of AMD patients after treatment with OPT and verteporfin compared to the assessment modality currently required following treatment with OPT and verteporfin.
Cross-sectional Comparison of OCT and FA CNV Assessment Performance
Henschel A, Spital G, Lommatzcsh A, Pauleikhoff D. Optical coherence tomography in neovascular age-related macular degeneration compared to fluorescein angiography and visual acuity. European Journal of Ophthalmology.
The aim of this prospective study was to assess the sensitivity and specificity of OCT for monitoring patients with CNV after PDT compared to FA. Fourteen (14) patients with CNV secondary to age-related macular degeneration (5 predominantly classic and 9 occult) were enrolled in this study. PDT was applied according to VIP/TAP study treatment standards, and fluorescein angiography and OCT studies were again applied at 2, 6, 12, and 24 weeks after treatment. OCT sensitivity and specificity for identifying vessel leakage observed with FA was assessed along with the correlation between retinal thickness and visual acuity.
Mean follow-up time per participant was 14.1 weeks, and in all, 61 pairs of OCT and FA examinations were obtained and used in the analysis. Angiographic leakage was present in 31 examinations (51%). OCT scans showed intraretinal fluid in 46 cases (75%) and subretinal fluid in 30 cases (49%). In 49 cases (80%), either intraretinal or subretinal fluid was present. The sensitivity of detecting intraretinal fluid by OCT as compared to angiographic leakage was 90%, with a specificity of 40%; for subretinal fluid, sensitivity was 71%, with a specificity of 73%. The combination of both OCT criteria (presence of either intraretinal or subretinal fluid) compared to FA leakage yielded a sensitivity of 97% and a specificity of 37%. The authors also found that increased central subfoveal thickness was significantly correlated with decreased visual acuity (p < 0.05).
Salinas-Alaman A, Garcia-Layana A, Maldonado MJ, Sainz-Gomez C, Alvarez-Vidal A. Using Optical Coherence Tomography to Monitor Photodynamic Therapy in Age Related Macular Degeneration. American Journal of Ophthalmology. 2005;140(1):23-8.
The aim of this prospective observational case study was to assess the sensitivity and specificity of OCT in determining CNV activity before and after PDT. A total of 53 consecutive patients (62 eyes) who presented with signs of exudative age-related macular degeneration (ARMD) with predominant classic CNV were enrolled in the study (nine patients had CNV caused by ARMD in both eyes). Of those that participated in the study, 42 participants were evaluated at the 12-month follow-up examination; the other 20 were evaluated at least at the 6-month follow-up visit. All patients underwent a complete ophthalmic evaluation every 3 months, and FA and OCT images were obtained with dilated pupils. The main outcome being explored in this study was the presence or absence of leakage on fluorescein angiography, presence of intraretinal or sub-retinal fluid on OCT, and macular and choroidal neovascular complex thickness on OCT. FA leakage was considered the standard reference for these two findings in OCT.
Fifty-three consecutive patients (26 males, 27 females with an average age of 76.50 (7.5 SD years) were enrolled in the study. A total of 62 eyes were analyzed; 32 were right eyes and 30 were left eyes. The mean number of PDT treatments was 2.5 (1.2 SD, range, 1 to 3) in the group of eyes (n = 62) followed for 6 months, and 2.9 (1.1 SD, range, 1 to 5) in the group followed for 12 months (n = 42). All sets of FA and OCT scans (n = 62) were obtained before treatment. After the first treatment of the 208 sets of FA and OCT that were expected, 176 (84.6%) were obtained. As a result of intolerance to FA, 12 cases (5.8%) were unavailable, and in 20 cases (9.6%) the OCT technician was unavailable at that particular visit for the examination.
Results of the study revealed that the macular thickness decreased significantly after PDT (p < .001) though no significant changes in CNV thickness were measured after PDT (p = .567). Once the diagnosis of ARMD was established before treatment, OCT had a sensitivity of 97% for detecting CNV activity. After treatment, OCT had a sensitivity of 96% and a specificity of 59.01% in determining CNV activity, thus resulting in an overall diagnostic efficiency (proportion of correct results) of 82.95%.
The authors concluded that OCT could be a good complementary imaging technique in the decision-making process when considering treatment or re-treatment of CNV in ARMD with PDT. They note that compared to FA, OCT has high sensitivity and moderate specificity in detecting CNV activity before and after PDT. Lastly, the authors note if no intraretinal or sub-retinal fluid is observed in OCT, it would be unlikely that CNV activity exists.
Khurana R, Dupas B, Bressler N. Agreement of time-domain and spectral-domain optical coherence tomography with fluorescein leakage from choroidal neovascularization. Ophthalmology. 2010;117(7):1376-80. Epub 2010 May 7.
The purpose of this retrospective consecutive case series study was to compare fluorescein leakage from CNV with signs of intraretinal or subretinal fluid on time-domain optical coherence tomography (TD-OCT) and spectral-domain optical coherence tomography (SD-OCT) in patients receiving anti-vascular endothelial growth factor (anti-VEGF) therapy for CNV caused by AMD. The study involved 59 eyes of 56 patients with neovascular AMD receiving anti-VEGF therapy. All participants were imaged using FA, TD-OCT, and SD-OCT. Fluorescein leakage from CNV and OCT abnormalities (presence of interstitial fluid, retinal cystoid abnormalities, and subretinal fluid) were documented for each visit, and the main outcome of interest was agreement of OCT findings with presence or absence of fluorescein leakage from CNV as seen in FA. The mean age of participants was 78 years; median visual acuity was 20/80.
Results of the study revealed that for TD-OCT, the sensitivity, specificity, positive predictive value, and negative predicative value (and 95% confidence intervals) for OCT abnormalities were 59% (46-72), 63% (50-75%), 61% (49-73), and 61% (48-74), respectively. For SD-OCT, the sensitivity, specificity, positive predictive value, and negative predictive value (and 95% confidence intervals) for OCT abnormalities were 90% (82-98), 47% (34-60), 62% (49-75), and 82% (72-92), respectively. The authors concluded that spectral-domain optical coherence tomography was more likely than TD-OCT to detect abnormalities when fluorescein leakage from CNV is detected after anti-VEGF therapy. The authors also noted that SD-OCT also seemed to detect abnormalities frequently in the absence of fluorescein leakage from CNV.
Eter N, Spaide RF. Comparison of fluorescein angiography and optical coherence tomography for patients with choroidal neovascularization after photodynamic therapy. Retina. 2005;25(6):691-6.
The purpose of this retrospective, nonrandomized, two-center investigational study was to investigate retinal morphology by means of FA and OCT in patients who had undergone PDT with verteporfin at their 3-month-interval examination. In the study, 60 eyes of 60 patients with predominantly classic CNV secondary to age-related macular degeneration received PDT with verteporfin according to the TAP study protocol. Twenty-nine patients had been treated with PDT for the first time, while 18 patients had received their second PDT, 7 received their third PDT, 2 received their fourth PDT, 1 patient his sixth PDT, and 1 his ninth PDT. The patients were then examined 3 months later, and best distant visual acuity was determined. The eyes were then examined by FA and OCT. The median age of the 60 patients (29 females and 31 males) was 78 years, and the median visual acuity was 20/100.
Results of the study revealed that fluorescein staining was seen in 57 eyes (95%), and fluorescein leakage was noted in 50 eyes (83%), and cystoid loculation of fluorescein was seen in 21 eyes (35%). By OCT, cystoids spaces in the macula were seen in 42 patients (70%), and subretinal fluid was seen in 15 patients (25%). The authors note that of the 22 eyes with cystoid spaces seen during FA, 20 (91%) had cystoid spaces seen during OCT, while 22 (57.9%) of the 38 eyes with no cystoids spaces seen during FA had cystoid spaces seen during OCT. The authors concluded that this difference in proportions was significant (P < 0.016), because there were a large number of eyes with cystoid spaces detected by OCT that were not seen during FA. The authors also noted that leakage seen shown by FA was correlated with the OCT finding of cystoids spaces but not with the OCT finding of subretinal fluid.
van Velthoven M, de Smet M, Schlingemann R, Magnani M, Verbraak F. Added value of OCT in evaluating the presence of leakage in patients with age-related macular degeneration treated with PDT. Graefes Archive for
Clinical and Experimental Ophthalmology. 2006;244(9):1119-1123.
In this study the authors used OCT and FA to assess the presence or absence of leakage in 30 AMD patients with subfoveal CNV scheduled for PDT retreatment. Interobserver agreement [kappa (κ) coefficient] on the presence of leakage for FA raters was calculated as was interobserver agreement for OCT raters. Agreement between FA and OCT was also calculated. The decision to retreat was based on leakage found using FA, and follow-up data at 9 months was obtained from the patient’s medical records, which data on a follow-up FA three month after treatment.
Results of the study revealed that agreement between observers on the presence of leakage was moderate for FA (κ = 0.51) and good for OCT (κ = 0.85). Agreement between FA and OCT for the presence of leakage was poor (κ = 0.16). Based on FA results, 23 patients were retreated. Eight of these patients did not show leakage on OCT, and five of these patients (62%) remained stable without additional treatment. The analysis also revealed that only three out of 15 patients (20%) with leakage on both FA and OCT remained stable during follow-up. Of the seven patients who were not retreated, four patients (57%) remained stable in follow-up. Authors also report that both
modalities are capable of detecting leakage with some cases only detected by one modality, and they ultimately concluded that OCT could be used in decision-making regarding PDT retreatment.
Krebs I, Ansari-Shahrezaei S, Goll A, Binder S. Activity of neovascular lesions treated with bevacizumab: comparison between optical coherence tomography and fluorescein angiography. Graefes Archive for Clinical and Experimental Ophthalmology. 2008;246:811–815.
This study’s purpose was to investigate whether examination with OCT alone was sufficient to ascertain the need of re-treatment with bevacizumab for exudative AMD or if a FA was needed. In the study, two independent examiners reviewed FA and OCT images and performed assessments using Weighted Kappa indices to calculate the concordance between OCT and FA. Disease activity was based on a semi-quantitative assessment (no activity, mild activity, moderate activity, or advanced activity).
During the study a total of 153 OCT and FA examinations were performed and evaluated on 69 patients (mean age was 77.1±7.9 (55–89) years; 29.0% were male, 71.0% female); analysis revealed that there were on average 2.2 examinations per patient. Results of the study revealed that there was agreement concerning the presence of lesion activity after treatment in 71% of cases. In 4% of cases, activity was detected in only FA; and in 25% of cases, activity was detected only with OCT. In comparisons of level activity detected using FA compared to OCT, ratings were the same in 47.7% of cases; in 31.4% higher scores were found in the OCT, and in 19.6% of cases, higher scores were detected with FA.
Higher grades of activity in the OCT were found in lesions with detachment of the RPE and fibrotic lesions, higher grades of activity in FA were found in classic lesions and lesions including retinal angiomatous proliferation (RAP). The weighted Kappa index showed concordance for activity in OCT and FA weak during the first investigation 4–6 weeks after initial treatment (0.3847), and the second investigation period 8-10 weeks after initial treatment revealed a concordance of 0.4170. The authors note that if PED was excluded in the assessment, OCT examinations showed strong concordance between the measurement for the first and second investigation (0.6761, 0.6756, respectively). The study did reveal higher values of activity with the OCT compared to FA. They noted that the most frequent reasons for discrepancies were detachment of the pigment epithelium and fibrosis.
The authors concluded that there was evidence of agreement between both examinations, and that OCT was even more sensitive to detect activity of a lesion. But they also noted that in conducting studies based on OCT as the single examination, it should be clearly defined how long fibrotic lesions or lesions with pigment epithelial detachment should be re-treated.
Cross-sectional Comparisons of OCT Morphologic and FA Angiographic Findings
Sadda SR, Liakopoulos S, Pearse K, Ongchin S, Msutta S, Chang K, Walsh A. Relationship between angiographic and optical coherence tomographic (OCT) parameters for quantifying choroidal neovascular lesions. Graefes
Archive for Clinical and Experimental Ophthalmology. 2010;248:175–184.
The purpose of this retrospective study was to correlate volume measurements of various OCT features with planimetric FA measures of CNV lesion components in a consecutive series of eyes with neovascular AMD. FAs were first reviewed to verify that the disease etiology was AMD only and that CNV itself was present under the foveal center. Area and greatest linear dimension of CNV lesion components were calculated on FAs, which were viewed and graded using DIRC FA grading software equipped with standard planimetric tools. CNV lesions were graded according to the modified Macular Photocoagulation Study (MPS) grading protocol utilized in the treatment of AMD with photodynamic therapy (TAP) and verteporfin in photodynamic therapy (VIP) studies. The software used for OCT analysis (termed OCTOR) was designed to facilitate viewing and manual grading. The grader used a computer mouse to draw various boundaries in the retinal cross-sectional images showing the calculated thickness and volume values for the nine Early Treatment Diabetic Retinopathy Study (ETDRS) macular subfields, and the mean and standard deviation of the foveal center point (FCP) thickness. This allowed the measurement of the volume of the neurosensory retina, subretinal fluid, subretinal tissue, and pigment epithelial detachment (PED).
In the study 65 consecutive cases of active subfoveal CNV associated with AMD were collected. Angiographic classification revealed predominantly classic CNV in 11 cases, minimally classic CNV in 22 cases, and occult with no classic CNV in 32 eyes. In eight cases, retinal angiomatous proliferation (RAP) was identified additionally. Analysis revealed that the inner retinal height from choroid volume on OCT correlated with the total area of the CNV lesion on FA (p < 0.0001, R = 0.59) as well as with the total area of CNV leakage on FA (p < 0.0001, R = 0.61). The volume of subretinal tissue on OCT correlated well with the area of classic CNV (p < 0.0001, R = 0.6), and additionally with the area of staining scar (p < 0.003, R = 0.37) and the area of thick hemorrhage (p < 0.005, R = 0.34) on FA. The volume of PED on OCT correlated with the area of occult CNV (p < 0.0001, R = 0.62), as well as the area of CNV lesion (p < 0.0001, R = 0.55) and the area of CNV leakage (p < 0.0001, R = 0.62) on FA. Retinal volume and subretinal fluid on OCT showed generally weaker correlations with FA parameters than subretinal tissue and PED volumes. Significant correlations were observed between neurosensory retinal volume on OCT and area of classic CNV (p < 0.002, R = 0.38) and total CNV lesion (p < 0.05, R = 0.24) on FA. Also, subretinal fluid volume on OCT was correlated with the area of occult CNV (p < 0.027, R = 0.28) as well as area of CNV leakage on FA (p < 0.024, R = 0.28).
The authors reported that OCT volume measures of CNV lesions, as determined by the manual OCT grading software, were found to correlate with CNV area measurements obtained by FA. The study also revealed that the FA area of classic CNV showed the highest positive correlation with the volume of subretinal tissue (R = 0.60, p < 0.0001). The area of occult CNV showed the highest positive correlation with PED volume (R = 0.62, p < 0.0001), and was negatively correlated with subretinal tissue volume (R = −0.26, p < 0.03).
Moutray T, Alarbi M, Mahon G, Stevenson M, Chakravarthy U. Relationships between clinical measures of visual function, fluorescein angiographic and optical coherence tomography features in patients with subfoveal choroidal neovascularisation. British Journal of Ophthalmology. 2008;92:361–364. doi:10.1136/bjo.2007.123976.
The purpose of this retrospective study was to examine the relationships between measures of vision, OCT and fundus fluorescein angiography (FFA) characteristics in patients with exudative AMD. In the study the FFA parameters included greatest linear diameter of lesion (GLD), area of CNV and area of leakage while the OCT parameters included maximum retinal thickness (Retmax), central foveal thickness, maximum thickness of the CNV (CNVmax), and the distances from the foveal depression to Retmax and CNVmax. The authors emphasized that the study was designed to systematically examine the relationships between three commonly used clinical measures of vision, namely distance visual acuity (DVA), near visual acuity (NVA) and contrast sensitivity and a variety of widely accepted FA and OCT parameters. The study enrolled 74 patients; the mean age of participants was 77 years (range 45 to 93). DVA, NVA and contrast sensitivity along with angiographic and tomographic features of the CNV were analyzed.
Results of the study revealed that correlations were highly statistically significant for both NVA and contrast sensitivity with GLD, along with CNV area and leakage (p < 0.01 for all combinations). With DVA, modest statistically significant correlations were seen with CNV area and GLD (p < 0.05). Also noted was a statistically significant correlation between CNV leakage and the distance of CNVmax to the fovea (p < 0.05). But the correlation between the measures of vision and OCT parameters were weak and did not reach significance. Regression analysis was performed and revealed that the combination of Retmax, GLD, and CNVmax to fovea had the highest coefficient (r2 = 0.27).
The authors concluded that both FFA and OCT measurements complement each other, but felt that OCT alone cannot be used as a substitute for, or replace of FFA in the management of AMD, and that in the management of AMD, OCT measurements by themselves are not robust markers for visual function.
Coscas F, Coscas G, Souied E, Tick S, Soubrane G. Optical coherence tomography identification of occult choroidal neovascularization in age-related macular degeneration. American Journal of Ophthalmology. 2007;144(4):592-599.
The purpose of this prospective, consecutive, observational case series study was to evaluate and describe the different characteristics of occult choroidal neovascularization in AMD patients as seen using OCT at various stages of diagnosis. The study included 153 eyes of 130 consecutive patients, followed in a university eye clinic, aged of 55 years or older, with subfoveal occult CNV resulting from AMD. Baseline studies performed on scanning laser ophthalmoscope (SLO), FA and SLO indocyanine green angiography (ICGA) were included and compared with OCT. Diagnostic criteria for occult CNV on angiography were: heterogeneous hyperfluorescence with late leakage in the macular region associated with PED, stippled hyperfluorescent dots, and signs of deterioration (recent changes in visual acuity, subretinal hemorrhages, or both, and exudates and serous retinal detachment). The mean age of patients included in the study was 78 years, with a female predominance (69 females, 34 males).
Results of the study revealed that PED was observed on OCT in 98% (150 eyes) either as a limited retinal pigment epithelium (RPE) elevation (54 eyes [35.3%]) or a complete detachment (96 eyes [62.7%]). Occult CNV corresponded to zones of hyperreflectivity in contact with the RPE band and was detected in 62.7% of eyes. In fibrovascular PED (63 eyes [65.5%]), the elevated RPE was highlighted posteriorly by a moderately reflective band overlying a hyporeflective cavity. In serous PED, the cavity remained optically empty. The RPE in the detached zone showed changes such as fragmentation (137 eyes [89.5%]). OCT also showed intraretinal (122 eyes [79.7%]) and subretinal (64 eyes [41.8%]) fluid.
The authors concluded that OCT features correlated with the appearance of the ocular fundus on biomicroscopy and fundus camera retinography, as well as features observed on angiography (FA and ICGA), the best established and most conventional method for the analysis of retinal and choroidal blood supply. They also concluded that OCT use provides valuable information in confirming features of subepithelial occult CNV.
Sato T, Iida T, Hagimura N, Kishi S. Correlation of Optical Coherence Tomography with angiography in retinal pigment epithelial detachment associated with age-related macular degeneration. Retina 2004;24:910–914.
The purpose of this prospective cross-sectional study was to correlate OCT with angiographic signs of CNV in retinal pigment epithelial detachment (PED) associated with age-related macular degeneration (ARMD), using fluorescein or indocyanine green angiography. The tomographic features of CNV beneath serous PED in 35 consecutive eyes of 35 patients (30 men and 5 women) with ARMD were studied. Participants’ ages ranged from 56 to 87 years (mean 71.6 +/- 8.0 years). During the study, fluorescein and indocyanine green angiography was used in all 35 eyes. Inclusion criteria consisted of patients with serous PED in the macular area and CNV at the margin of or within the PED. Fluorescein or indocyanine green angiography showed CNV at the margin of the PED in 18 eyes and within it in 17 eyes. OCT was performed in all 35 eyes with horizontal, vertical, or oblique planes through the CNV and PED under a monitoring camera.
Results of the study revealed that 10 (56%) of 18 eyes in which the CNV was at the margin of the PED, a small PED was adjacent to the central, dome-shaped PED, and there was a notch between the central and small mounds of PED. In 13 (76%) of 17 eyes in which the CNV was within the PED, a notch was seen in the dome-shaped PED, resulting in a contour with 2 mounds. One of the 2 mounds contained a highly reflective mass immediately beneath the detached retinal pigment epithelium in 8 (62%) of the 13 eyes. The OCT findings indicated that CNV was present not only in the area of the notch but also within one of the two mounds of PED. The authors noted that OCT and angiographic studies showed that tomographic and angiographic notches had a close correspondence, and concluded that a tomographic notch in the PED may be diagnostically important as an indication of the presence of CNV beneath the detached RPE in eyes with ARMD.
Malamos P, Sacu S, Georgopoulos M, Kiss C, Pruente C, Schmidt-Erfurth U. Correlation of high-definition optical coherence tomography and fluorescein angiography imaging in neovascular macular degeneration. Investigative Ophthalmology and Visual Science. 2009; 50:4926-4933.
The purpose of the study was to evaluate the diagnostic capacity of raster scanning high-definition optical coherence tomography (HD-OCT) in cases of early and late neovascular AMD, and to correlate the findings with the features distinguished by conventional FA. Inclusion criteria were based on the Age-Related Eye Disease Study (AREDS) classification for early AMD and advanced neovascular AMD with recent-onset exudative CNV. Exclusion criteria were a history of any other retinal disease, significant media opacities, previous intraocular surgery or pharmacologic intervention or laser treatment, and amblyopia. The study was restricted to the July 2007 to October 2007 time period, and included 60 patients that met the inclusion criteria. Baseline examination included a full ophthalmologic examination which consisted of best corrected visual acuity (BCVA) and a dilated fundus examination. HD-OCT imaging was then conducted.
Patients identified as having AMD underwent fluorescein angiography procedure. After the injection, images were taken during the early phase (10–20 seconds) and late phase (10 minutes) using a confocal scanning laser ophthalmoscope. From each series, one representative early-phase angiogram and one from the late phase were selected for analysis. The 60 participants were then placed into five patient groups as follows:
- early AMD patients with maculopathy consisting of hard and/or soft drusen accompanied with retinal pigment epithelium (RPE) alterations, according to AREDS categories 3 and 4 (n = 13),
- patients showing classic CNV (n = 16),
- patients with minimally classic lesions (defined as occult lesions with a classic component occupying less than 50% of the entire lesion area by FA (n = 5),
- patients with an occult-only CNV (n = 16), and
- age-matched control group with conditions unrelated to macular disease, and had at least one normal eye. There was documentation of a normal fovea reflex and macular area, as well as clear visualization of all retinal layers (n = 10).
Results of the test revealed that with HD-OCT imaging used to delineate the lesion morphology, early AMD was detected as having a normal foveal contour and minimal alteration in the macular area; classic CNV as a well-defined lesion with steep margins and a craterlike configuration; occult CNV as an ill-defined, flat lesion with a convex surface; and minimally classic CNV as having classic and occult components. FA-OCT overlay images provided a significant correlation between FA patterns and OCT features such as retinal thickness (RT).
The authors concluded that 3D-OCT provided realistic anatomic maps of the retina, RPE, and RT in patients with AMD. They noted that discrimination between the predominant CNV lesion types was achieved, and their precise shape was identified, together with information about the lesion’s localization and leakage activity.
Liakopoulos S, Ongchin S, Bansa A, Msutta S, Walsh AC, Updike PG, Sadda S. Quantitative Optical Coherence Tomography Findings in Various Subtypes of Neovascular Age-Related Macular Degeneration. Investigative Ophthalmology and Visual Science. 2008;49(11):5048-54. Epub 2008 Jun 19.
The purpose of this prospective observational case study was to analyze OCT images of eyes with neovascular AMD using computer-assisted manual grading software to quantify various spaces visible on OCT images for a more precise comparison of the characteristics of different angiographic CNV lesion subtypes. The study was based on retrospectively collected data from 66 eyes of 66 consecutive patients who received therapy for neovascular AMD. Eligibility criteria included documentation of previously untreated, active subfoveal CNV due to AMD and OCT imaging, as well as FA imaging performed on the same date. In addition, in order to be eligible for the study, the entire CNV lesion as defined on FA had to fall within a 6-mm-diameter circle centered on the fovea. Active CNV was defined as the presence of hemorrhage or evidence of vision loss or lesion growth within the prior 3 months.
Results of the study revealed that lesions that were identified as minimally and predominantly classic CNV membranes had subretinal tissue on OCT in all cases and appeared to show a significantly greater volume of subretinal tissue than did the occult membranes. Also subretinal fluid was present in all the predominantly classic cases. A PED was visible in all the occult CNV cases in the study, indicating less retinal thickening and significantly greater PED volumes than minimally and predominantly classic CNV lesions. The authors also found lesions associated with RAP showed significant thickening, and the highest percentage of cystoids spaces.
The authors concluded that angiography and OCT represent complementary imaging modalities, both of which displayed different information. FA imaging revealed information about the integrity of the inner and outer retinal barrier as well as the presence of pathologic vessels. OCT imaging demonstrated the arrangement and reflectivity of retinal and subretinal layers as well as the axial distribution of pathologic fluid or tissue within the retina, the subretinal or sub-RPE space.
Single-Arm Studies of OPT with Verteporfin Using OCT for Follow-up
Jin C, Ge J, Zhou S, Chen H, Zhong X, Jiang R, Chen L, et al. Photodynamic Therapy for age-related macular degeneration. Eye Science. 2004;20:158-162.
Jin et al. (2004) performed a retrospective study to evaluate the short-term effects of a single PDT session for AMD patients with CNV. Participants included 20 patients (20 eyes; 13 males, 7 females, aged 50-78 with a mean age of 56.8 years) with subfoveal or juxtafoveal CNV as determined by FA and OCT. Visual acuity (which ranged from 0.1 to 0.5), FA, and OCT were examined 1 week before PDT as well as 1 week and 3 months after PDT. Results of the study revealed that, by the end of the study (3 month follow-up), five eyes had vision progress, 15 eyes had vision stabilization, and no eyes had vision deterioration. FA post 1 week PDT showed cessation of fluorescein leakage in eight eyes (patients with prominent classic CNV) and reduction in fluorescein leakage in 12 eyes (patients with minimal classic CNV or occult CNV without a classic component). At three months following PDT, FA showed fluorescein leakage reappeared in four of eight eyes with prominent classic CNV. Among 12 eyes with minimal classic CNV or occult CNV without a classic component, nine eyes showed a decrease or unchanged fluorescein leakage, while 3 eyes had a progression of fluorescein leakage. The study also reported that OCT demonstrated recovery of serous sensory retinal detachment after PDT and that the thickness of sensory retina gradually became normal after treatment.
Fackler T, Reddy S, Bearelly S, Stinnett S, Fekrat S, Cooney M. Retrospective Review of Eyes with Neovascular Age-related Macular Degeneration Treated with Photodynamic Therapy with Verteporfin and Intravitreal Triamcinolone. Annals Academy of Medicine. 2006;35:701-5.
This retrospective study described the use of intravitreal triamcinolone in combination with PDT and verteporfin, for the initial treatment of subfoveal CNV in patients with AMD. Visual outcomes, complications, and OCT data were reviewed for all eyes that received this therapy, over a 12 month follow-up. Eyes with choroidal neovascularization from any other cause were excluded. Baseline data collected included age, gender, greatest linear diameter (GLD) of the CNV, and lesion type as noted on FA. Subsequent data collected at each visit included visual acuity, intraocular pressure, lens clarity, and complications. Central foveal thickness and total macular volume using OCT measurements were also analyzed. For all eyes, triamcinolone was injected within 1 week of the initial PDT treatment. Eyes were evaluated at baseline, 3 months, 6 months, 9 months, and 12 months after therapy. Eyes received additional PDT if angiographic leakage was present, and/or intravitreal triamcinolone at 3-month intervals at the discretion of the retinal specialist.
According to the authors, therapy using OCT findings as retreatment criteria, resulted in short term visual benefit that was maintained over 12 months, though mean visual acuity did not change in any significant way at the 3-, 6-, 9-, and 12-month follow-up. Additionally, all eyes treated with PDT, verteporfin, and triamcinolone required fewer than expected repeat treatments during follow-up as compared to PDT and verteporfin alone. The authors found that OCT measurements demonstrated a statistically significant decrease in foveal thickness and total macular volume at 3 months, though the difference was not maintained at the 9- and 12-month follow up visits. The authors concluded that OCT appeared to be useful in evaluating and documenting the change in disease state before and after therapy.
Spielberg L, Leys A. Treatment of Neovascular age-related macular degeneration with variable ranibizumab dosing regimen and one-time reduced-fluence photodynamic therapy: the TORPEDO trial at 2 years. Graefes Archives for Clinical and Experimental Ophthalmology. 2010;248:943-956.
The purpose of the prospective, non-randomized, open-label, single-center study was to demonstrate the prevention of vision loss and improvement of best corrected visual acuity (BVCA) in patients with neovascular AMD (Spielberg et al. 2010). The study was designed to last for 24 months; therapy included one-time reduced-fluence-rate verteporfin PDT followed by a variable regimen of intravitreal ranibizumab. Initial patient screening was performed with FA to determine CNV characteristics and OCT to define retinal morphology. Subsequent ranibizumab injections were placed at 4 and 8 weeks after the initial therapy. Follow up examination consisted of BCVA measurement and a complete anterior and dilated ocular examination by the same examiner at each visit. Retreatment with ranibizumab was based on meeting any of the following criteria: (1) presence of subretinal fluid intraretinal edema, or sub-retinal pigment epithelial fluid as seen on OCT, (2) increase of central macular thickness (CMT) by > 100mm on OCT, (3) signs of active CNV leakage seen on fluorescein angiography, (4) new sub- or intraretinal hemorrhage, or (5) best-corrected visual acuity (BCVA) decreased of ≥ 5 letters on the Early Treatment Diabetic Retinopathy Study (ETDRS) chart.
Results of the study revealed that using OCT findings as retreatment criteria, short term visual improvement was maintained over 24 months, and mean visual acuity improved by 7.2 letters (p < 0.05), and the mean CMT decreased by 146 micrometers. Also 84% of patients had stable or improved vision, and no systemic side-effects were noted, including uveitis, or choroidal collateral vascular damage. The authors concluded that OCT appeared to be useful in evaluating and documenting the change in disease state before and during therapy.
Augustin A, Puls S, Offerman I. Triple Therapy for Choroidal Neovascularization due to Age-Related macular Degeneration: Verteporfin PDT, Bevacizumab, and Dexamethasone. Retina. 2007;27( 2):133-140.
The purpose of this prospective, non-comparative case series study was to investigate the preliminary efficacy and safety of triple therapy using verteporfin PDT, intravitreal bevacizumab, and intravitreal dexamethasone in patients with wet AMD (Augustin et al. 2007). The primary efficacy variable was defined as change in visual acuity (VA) from baseline to the last visit as measured using Snellen VA charts. The study consisted of 104 participants. Verteporfin PDT was administered initially, and approximately 16 hours later, dexamethasone and bevacizumab were injected intravitreally. All patients attended follow-up visits every 6 weeks, undergoing visual acuity and intraocular pressure measurement, slit-lamp and ophthalmoscopic examination, and OCT. Fluorescein angiography was performed every 3 months or earlier if OCT showed significant edema. In the study, the mean follow-up period was 40 weeks (range, 22-60 weeks). Baseline mean VA was 20/126 (8.7% of the patients had a VA of 20/40 or better at baseline).
Results of the study revealed that during the study, visual acuity improved in most patients, with a mean increase of 1.8 lines (P < 0.01), and the mean follow-up VA score was 20/85 (28.8% of the patients had a VA of 20/40 or better at last follow up). A total of 39.4% of the patients gained 3 or more lines of vision, while a total of 3.8% lost 3 or more lines. A mean decrease in retinal thickness of 182 µm (P < 0.01) was
Rogers A, Martidis A, Greenberg P, Puliafito C. Optical Coherence Tomography findings following Photodynamic Therapy of Choroidal Neovascularization. American Journal of Ophthalmology. 2002;134(4):566-76.
Rogers and associates performed a retrospective analysis to develop an OCT classification system that would be helpful in monitoring the response of eyes treated with PDT with verteporfin for CNV from AMD (Rogers et al. 2002). Ninety eyes (88 patients) with predominantly classic subfoveal CNV AMD were treated with PDT using verteporfin. OCT and FA were performed before treatment and at subsequent follow-up examinations in all eyes, and OCT findings were evaluated and compared with corresponding FA. During the study, eleven of 90 eyes (11 patients) were excluded, because the OCT could not be accurately interpreted or scanned during a portion of the follow-up period, or other limitations with OCT were encountered. The final number of participants in the study used to determine the OCT classification system was a total of 79 eyes of 77 patients.
In the study the authors noted that OCT provides cross-sectional images and reproducible measurements of the macula. They also noted that OCT is useful for observing changes that occur in the retina following PDT. After retrospectively reviewing the OCT and FA of 90 eyes treated with PDT for subfoveal CNV based on TAP study group criteria, consistent patterns emerged that allowed for the development of an OCT classification system.
Results of the analysis were reported in a five-stage OCT classification system. Stage I (n = two eyes) was recognized within the first week of treatment and demonstrates an acute inflammatory response with increased subretinal fluid. Stage II (n = 28 eyes) represents the restoration of a near-normal fovea contour with diminished subretinal fluid occurring 1 to 4 weeks after treatment. Stage III (n = 79 eyes) occurs between 4 to 12 weeks following treatment and is subdivided into two categories based on the amount of subretinal fibrosis and fluid present. Stage IIIa (n = 15 eyes) contains a greater subretinal fluid to fibrosis ratio indicating an active CNV process. Lesions in stage IIIb (n = 64 eyes) less actively leak and have more prominent fibrosis with minimal intraretinal fluid. Cystoid macular edema defines a stage IV lesion (n = 11 eyes). In stage V lesions (n = 19 eyes) the subretinal fluid resolves with thinning of the retina as well as fibrosis merging with the retinal pigment epithelial layer (RPE).
The authors concluded that OCT was useful in evaluating the response of the retina and RPE to PDT. They note that OCT alone cannot replace FA, but the two technologies enhance one another and have allowed the development of a useful classification system for CNV treated with PDT.
Ozdemir H, Arf Karacorlu S, Murat Karacorlu M. Early Optical Coherence Tomography Changes After Photodynamic Therapy in Patients With Age-Related Macular Degeneration. American Journal of Ophthalmology. 2006;141(3):574-6.
The purpose of this prospective interventional case series study was to evaluate early changes after PDT in patients with AMD by optical OCT. Enrolled in the study were 20 patients with 20 eyes that underwent PDT for subfoveal CNV attributable to AMD. Enrollees in the study were 58 to 79 years of age (mean 67.85), and patient selection criteria included the presence of classic or predominantly classic CNV involving the foveal avascular zone. Before therapy, at 2 and 12 hours , at 1, 3, 7, and 15 days, and at 1 month after therapy, patients were examined with OCT, noting changes in intra-retinal fluid, sub-retinal fluid, retinal pigment epithelium, and CNV noted on images. Pretherapy FA findings indicated classic CNV in 15 patients (75%) and predominantly classic CNV in five patients (25%).
After treatment sub-retinal fluid increase was observed in all patients by day 1, appearing in two patients (10%) at 2 hours, in an additional eight patients (40%) by 12 hours, and in the remaining 10 patients (50%) by 24 hours. Intra-retinal fluid increase was observed in 13 patients (65%) by day 1, appearing in five patients (25%) at 12 hours, and eight patients (40%) at 24 hours. By the third day, OCT showed a decrease in sub-retinal fluid in three patients (15%) and a decrease in intra-retinal fluid in four patients (20%). On the seventh day, sub-retinal fluid had regressed in eight patients (40%), and intra-retinal fluid had regressed in seven (35%). On the fifteenth day, seven patients (35%) presented with a decrease in sub-retinal fluid and one (5%) with a decrease in intra-retinal fluid, whereas in one patient (5%) the size of the retinal pigment epithelium detachment had decreased.
One month after therapy, OCT images revealed regression in sub-retinal fluid in two (10%) patients and in intra-retinal fluid in one (5%) patient, whereas no changes were observed in either CNV or retinal pigment epithelium detachment. The authors found that the serial OCT evaluation of patients with subfoveal CNV attributable to AMD demonstrated that the initial response after PDT was an increase in SF and IF. They also noted that OCT changes after PDT were similar to other studies that explored this feature. The authors felt that this study was more informative than previous studies because post-therapy OCT images of all cases were repeated at identical intervals in the early period, as oppose to other studies where unplanned follow-up intervals occurred in the early period after PDT was implemented.
Comparative Studies of OPT with Verteporfin Using OCT for Follow-up
Arias L, Garcia-Arumi J, Ramon J, Badia M, Rubio M, Pujol O. Optical coherence tomography analysis of a randomized study combining photodynamic therapy with intravitreal triamcinolone. Graefes Archives for Clinical and Experimental Ophthalmology. 2008;246:245–254.
Arias and colleagues (2006) conducted a prospective, randomized study and its purpose was to analyze OCT scan differences between patients with predominantly classic subfoveal CNV secondary to AMD treated with only PDT and patients treated with PDT combined with intravitreal triamcinolone acetonide (IVTA). In the study, 61 patients were randomized to receive PDT (n = 30) or PDT combined with IVTA (n = 31). Study participants were evaluated every 3 months with a refraction protocol for best-corrected visual acuity (VA), FA, and OCT. The primary endpoint of the study was to determine the mean change from baseline in neuroretinal foveal thickness (NFT) and outer high reflectivity band thickness (OHRBT) at the 12-month follow-up. Secondary endpoints were to evaluate the correlation between: VA and NFT; VA and OHRBT; angiographic area of the lesion and NFT; and angiographic area and OHRBT. Study duration was 12 months
Results of the study revealed that the mean change in NFT was not significantly reduced (P = 0.9), but the mean change in OHRBT was significantly lower (P = 0.004) in the group of patients who received PDT combined with IVTA. The analysis failed to find a significant association between final VA and NFT in either patient group (P = 0.2), and the final VA was significantly worse in eyes with a thicker OHRBT (P = 0.04) in the group of patients treated with only PDT. The analysis also failed to demonstrate an association between angiographic area and NFT and OHRBT in either patient group (P > 0.3), though there was a statistically significant difference between the pre-treatment angiographic area of the lesion and VA at the 12-month follow-up in the combined therapy group (P = 0.01), and more eyes treated with only PDT presented with intraretinal fluid at the last follow-up (P = 0.01). The authors concluded that combined therapy with PDT+IVTA was more effective than PDT alone at reducing OHRBT, and that OHRBT seemed to be have a greater effect on VA than NFT.
Lim J, Lee S, Kim J, Lee J, Chung H, Yoon Y. Intravitreal bevacizumab alone versus in combination with photodynamic therapy for the treatment of neovascular maculopathy in patients aged 50 years or older: 1-year results of a prospective clinical study. Acta Ophthalmologica. 2012: 90: 61–67.
Lim et al. performed a randomized, prospective study to compare the outcomes of treatment with intravitreal bevacizumab alone (BEVA group) or in combination with PDT (COMB group), in patients aged 50 or more with neovascular maculopathy (Lim et al. 2012). After meeting inclusion criteria, 41 patients with AMD were randomized to either the BEVA group (n = 18) or the COMB group (n = 23). After screening, all subjects underwent a complete ophthalmologic examination including biomicroscopy, FA, and ICGA to identify areas of leakage, and CFT (central focal thickness) was measured using OCT. A total of three intravitreal bevacizumab injections were given at 6-week intervals. In the COMB group, PDT was included near the time of one injection. The primary outcome of interest was BCVA and CFT. Changes from baseline were measured at each of six visits (screening, and at weeks 6, 12, 18, 32 and 48).
The final analysis only included 18 patients in the BEVA group and 23 patients in the COMB group; remainder patients were lost to follow-up. Analysis revealed that overall, both BCVA improved (p = 0.001) and central foveal thickness (CFT) improved (p < 0.001) measured by OCT at 12 months in the study, but there was no between-group difference in BCVA or CFT between the BEVA and COMB groups. The authors concluded that intravitreal bevacizumab alone was similar in efficacy and safety to bevacizumab plus PDT for treatment of patients with neovascular AMD.
Weigert G, Michels S, Sacu S, Varga A, Prager F, Geitzenauer W, Schmidt-Erfurth U. Intravitreal bevacizumab (Avastin) therapy versus photodynamic therapy plus intravitreal triamcinolone for neovascular age-related macular degeneration: 6- month results of a prospective, randomised, controlled clinical study. British Journal of Ophthalmology. 2008;92:356–360. doi:10.1136/bjo.2007.125823.
This open-label, single center, randomized control clinical trial was performed to compare functional and anatomical outcomes of intravitreal bevacizumab (Avastin) and verteporfin (photodynamic) therapy (PDT) combined with intravitreal triamcinolone (IVTA) in patients with neovascular AMD. The primary outcome measures used in this study was change in mean visual acuity, and central retinal thickness. Patients were randomly assigned 1:1 to 1mg intravitreal bevacizumab or standard PDT plus IVTA. All patients were evaluated at baseline, day one, day seven, months one, three, and six. FA as well as ICGA was also performed at baseline, three and six months. Patients randomly assigned to intravitreal bevacizumab also were seen at months two, four, and five. Retreatment was based on FA at 3-month intervals. Twenty eight patients (19 female and 9 males) were enrolled in the study. The mean age of participants were 78 (SD 8), ranging from 58 to 88 years of age.
Results of the study revealed that in the bevacizumab-treated group mean visual acuity (VA) improved to a 2.2 line gain at 6 months follow-up. Also the eyes treated in the PDT plus IVTA group had a stable mean VA at month 6 compared with baseline. The analysis showed that there was a statistically significant difference (p < 0.03) between both groups as early as one day after initial treatment, though the reduction in central retinal thickness (CRT) did not show a statistical difference between both groups (p = 0.3). Mean CRT was reduced from 357 micrometers at baseline to 239 micrometers at month 6 in bevacizumab-treated patients and from 326 micrometers to 222 micrometers in PDT plus IVTA-treated
A Medicare Evidence Development and Coverage Advisory Committee (MEDCAC) meeting was not convened on this issue.
5. Evidence-based guidelines
The AAO Preferred Practice Pattern Guidelines for Age-Related Macular Degeneration are published as a service to members of the Academy and to the public and are considered guidelines rather than definite standards of practice. For follow-up after treatment for neovascular AMD, the guidelines identify OCT, FA, and fundus photography as potentially helpful tools to detect signs of exudation. These guidelines can be found at http://one.aao.org/CE/PracticeGuidelines/PPP.aspx.
6. Professional Society Position Statements
The American Society of Retina Specialists (ASRS) submitted public comment and stated that while OPT with verteporfin remains a viable treatment for some second-line wet-AMD patients and other patients with associated retinal diseases, the standard for assessing the treatment of these patients has changed significantly. They stated that the use of OCT is now the standard imaging modality used to follow the disease and to make treatment choices.
7. Expert Opinion
We did not receive any expert opinions during the comment periods.
8. Public Comments
Initial Comment Period: [7/24/12 – 8/23/12]
CMS received 12 timely public comments during the initial comment period. Ten of these comments supported the request to review the current policy supporting the requestor’s position that the policy is outdated and does not reflect current practice for treating wet AMD. They support that the current NCD requirement for follow-up fluorescein angiography with OPT with verteporfin is no longer necessary.
One comment supported the treatment of OPT with verteporfin and provided a testimonial of how it provided benefit for a family member. This comment did not mention the requirement for follow-up FA.
One comment neither agreed nor disagreed with the proposed decision. It was a comment regarding uveitis, which is not relevant to this proposed decision.
Of these public comments received, seven were from physicians, one of whom is a retina specialist and one of whom is a vitreoretinal surgeon, two were from professional societies; one of whom is the requestor, one was from a clinical assistant professor of surgery, one from a consultant, and one from a family member of a Medicare beneficiary. None of the comments included any references for review.
Second Comment Period: January 17, 2013 – February 16, 2013
CMS received four timely comments during the proposed decision comment period. All of the comments supported the proposed decision to revise the requirements for testing to permit either OCT or FA to assess treatment response. Of these public comments received, one was from a retina specialist, two were from professional associations; the American Optometric Association (AOA) and AHIP, and one commenter did not disclose an affiliation. No new evidence was provided through the comments received. The comments are summarized below:
A retina specialist who has been in practice for 33 years and was part of the Visudyne Clinical Trial supports the proposed decision and points out although it is important in most cases to obtain a preoperative FA; it is not always necessary post operatively. The commenter further states that OCT is sufficient if the purpose of the test is to determine leakage, which is better accomplished with OCT than a FA and if there is persistent leakage then a FA should be considered to determine where the leakage site is to decide on a treatment plan.
The American Optometric Association (AOA) supports the proposed decision to revise the requirements for testing to permit either OCT or FA to assess treatment and response. The AOA further states that physicians should be given the authority to determine which approach is most appropriate for a patient.
AHIP supports the proposed decision to revise the requirements for testing to permit either OCT or FA to assess treatment response. They further suggest CMS provide guidelines on when OCT or FA is more appropriate in monitoring treatment of macular degeneration.
The fourth comment also supports the proposed decision to revise the requirements for testing to permit either OCT or FA to assess treatment response. The commenter further states that a FA is essential in making the initial diagnosis of wet AMD, but serial OCTs are more valuable in monitoring response to treatment, and believes that the choice should be left at the discretion of the treating physician.
CMS appreciates the supportive comments. Based on our review of the evidence, we believe that OCT and FA are acceptable options for the assessment of a beneficiary’s response to covered verteporfin treatment. Thus, we anticipate that treating physicians will discuss options with their patients. We note, however, that CMS does not develop physician practice guidelines.
Full text public comments without personal health information can be viewed at http://www.cms.gov/medicare-coverage-database/details/nca-view-public-comments.aspx?NCAId=262.
VIII. CMS Analysis
National coverage determinations (NCDs) are determinations by the Secretary with respect to whether or not a particular item or service is covered nationally by Medicare (§1862(l) of the Act).
In order to be covered by Medicare, an item or service must fall within one or more benefit categories contained within Part A or Part B, and must not be otherwise excluded from coverage. Moreover, section 1862(a)(1) of the Social Security Act in part states that, with limited exceptions, no payment may be made under part A or part B for any expenses incurred for items or services:
- which, are not reasonable and necessary for the diagnosis or treatment of illness or injury or to improve the functioning of a malformed body member (§1862(a)(1)(A)).
Is the evidence adequate to conclude that the use of OPT with verteporfin improves health outcomes in patients with AMD whose response to treatment is assessed with OCT after having been initially diagnosed using FA?
As described above, evidence in this evaluation includes cross-sectional analyses comparing OCT and FA as well longitudinal studies (both single-arm and comparative) examining the ability of OCT to assess response to PDT with verteporfin. As noted earlier in the Background section, the use here of a test to assess response to prior therapy is intended to inform subsequent treatment, i.e. whether or not additional OPT with verteporfin therapy may be indicated. The included cross-sectional studies comparing OCT and FA have been reviewed to determine whether information provided by OCT is similar to that provided by FA as well as to determine whether information provided by OCT, when not consistent with FA findings, is clinically useful for the assessment of patients following treatment.
Longitudinal studies following patients after treatment with verteporfin OPT are highlighted in order to assess whether it is possible to use OCT to assess patients’ response to treatment. We have previously determined that OPT with verteporfin is a beneficial treatment for some AMD patients. Data reviewed in this analysis is not meant re-examine this issue; rather, our goal is to establish whether OCT can be used in patient follow-up. Studies are evaluated to determine whether information provided after treatment with verteporfin OPT can subsequently be used to assess treatment response.
Our review identified five cross-sectional studies comparing the diagnostic performance of OCT and FA (Eter, 2005; Salinas-Alaman, 2005; Krebs, 2008; van Velthoven, 2006; Henschel, 2009; Khurana, 2010). These comparisons of OCT to FA indicate that OCT has high sensitivity and moderate to low specificity compared to a FA reference standard. An explanation for these phenomena is that OCT findings may lag FA findings showing remnants of intraretinal fluid not previously resorbed. Conversely, it has been stated that OCT may also be more accurate than FA and show signs of CNV leakage not being captured with FA (Krebs, 2008; Henschel, 2009; Khurana, 2010). Two of the studies identified above in fact demonstrated that OCT was able to identify CNV leakage that was otherwise missed by FA (Krebs, 2008; van Velthoven, 2006). Our review also indicates that OCT has higher inter-rater reliability than FA (van Velthoven, 2006). One challenge of FA cited in the literature is that its raters often disagree on FA findings, including lesion type and the presence of leakage (Salinas-Alaman, 2005).
We believe the evidence demonstrates that the use of OCT for patient assessment after OPT with verteporfin, therefore, is a reliable complement to FA. There are circumstances in which FA would be determined, based on clinical judgment, to be the preferred assessment modality. For example, when clinicians suspect new vessel growth, a confirmatory FA may be appropriate. Nevertheless, there are situations when an OCT alone would suffice. For example, due to high sensitivity for identifying CNV leakage compared to a FA reference standard, OCT results that indicate the presence of intraretinal or sub-retinal fluid would eliminate the need for a confirmatory FA (Henschel, 2009, Salinas-Alaman, 2005).
We also identified and described six studies that examined OCT findings and FA findings in cross-sectional populations of AMD patients (Moutray, 2008; Sadda, 2010; Sato, 2004; Coscas, 2007; Liakopoulos, 2008; Malamos, 2009). Studies indicate that volume measures determined by OCT are correlated to CNV area measurements determined with FA (Moutray, 2008; Sadda, 2010). Studies also indicate that tomographic and angiographic CNV features observed with OCT and FA, respectively, correspond with one another (Sato, 2004; Coscas, 2007, Liakopoulos, 2008).
A total of six single-arm longitudinal studies in which patients receiving treatment that included OPT with verteporfin and assessed over time with OCT have been described above (Jin, 2004; Fackler, 2006; Spielberg, 2010; Augustin, 2007; Rogers, 2002; Ozdemir, 2006) . All of these studies reported OCT findings, and 4 also reported changes in patient visual functioning (i.e., visual acuity). Study authors for the two studies only reporting changes in OCT findings concluded that OCT could be used to monitor retinal morphologic response to treatment with PDT and verteporfin (Ozdemir, 2006; Rogers, 2002). These two studies reported statistically significant changes in OCT findings following treatment.
Four of these studies collected data on OCT findings and visual acuity. Formal patient-level correlative analyses comparing OCT measurements and visual acuity measures were not performed in all studies (Jin, 2004; Fackler, 2006; Spielberg, 2010; Augustin, 2007). Nevertheless, trends in visual acuity changes and OCT findings over time provide evidence of the ability of OCT to assess the impact treatment with verteporfin OPT. These studies demonstrate a correlation between vision improvement and stabilization and changes in retinal structure determined with OCT.
Jin et al (2004) report that 20 of 20 eyes reported vision progress or stabilization after treatment with OPT with verteporfin. These investigators also commented that the sensory retina thickness, as determined with OCT, gradually became normal after treatment. Fackler et al (2006) reported that after treatment with intravitreal triamcinolone in combination with PDT and verteporfin, there was not a statistically significant improvement in visual acuity at 12 months. Consistent with these results, the authors also reported that though there was significant decrease in foveal thickness at three months, this difference was not maintained at 12 months. This result indicates that OCT is also an effective tool for identifying non-response to treatment.
Spielberg et al (2010) also reported significant improvements in visual acuity and mean central macular thickness as measured with OCT after treatment with verteporfin PDT and intravitreal ranibizumab. Lastly, Augustin and colleagues (2007) examined the impact of a triple therapy of verteporfin PDT, intravitreal bevacizumab, and intravitreal dexamethasone in patients with wet AMD. Patients experienced improvements in visual acuity and a significant decrease in retinal thickness. Overall, results of these single-arm studies indicate that OCT can provide meaningful information during patient follow-up after treatment with OPT and verteporfin.
Three comparative studies examined treatment strategies that included the use of PDT with verteporfin for patients with AMD (Arias, 2008; Lim, 2012; Weigert, 2008). One study compared the effect of OPT with verteporfin against OPT with verteporfin combined with intravitreal triamcinolone acetonide (Arias, 2008). Another assessed the use of intravitreal bevacizumab alone compared to in combination with OPT with verteporfin (Lim, 2012). A third study evaluated the use of OPT and verteporfin with intravitreal triamcinolone compared to intravitreal bevacizumab alone (Weigert, 2008). All three utilized OCT to assess morphologic response to treatment and also evaluated changes in visual functioning.
All three studies found that after treatment with of PDT and verteporfin, used alone or in combination with other therapies, OCT findings could show changes in retinal morphology during follow-up. OHRBT, determined with OCT, was also shown to be associated with changes in visual acuity (Arias, 2008). It was also observed that patients who experienced improvements in visual acuity, exhibited decreases in central retinal thickness (Weigert, 2008) and decreases in central foveal thickness (Lim, 2012).
These comparative studies demonstrate that follow-up assessment with OCT for AMD patients who have received PDT with verteporfin can be used as a management tool to assess the effect of treatment. The published literature indicate that OCT can provide information on the impact of PDT with verteporfin on retinal morphology, including retinal thickness and the presence of subretinal fluid.
No comparative studies assessing patient outcomes compared the use of OCT to other assessment tools after treatment with OPT and verteporfin. Thus no data are available to directly assess the impact of OCT on patient outcomes such as improved visual functioning. Nevertheless, we believe the studies reviewed and summarized above provide sufficient evidence that AMD patients can be effectively assessed with OPT and/or FA following treatment with OPT and verteporfin. Published literature demonstrates that though FA and OCT provide different information on a patient’s response to therapy, they both can be used for patient management and follow-up assessment.
We believe that the evidence leads to an affirmative answer to our question. As noted above, we have already determined that OPT with verteporfin is reasonable and necessary for certain patients with wet AMD. The issue before us is whether that determination should be extended if one diagnostic test (OCT) is used as an alternative to another (FA) for the assessment of response to treatment.
The literature indicates that OCT has high sensitivity and moderate to low specificity compared to the reference standard of FA for identifying CNV leakage (Eter, 2005; Salinas-Alaman, 2005; Krebs, 2008; van Velthoven, 2006; Henschel, 2009; Khurana, 2010). This finding is consistent across studies and has led investigators to conclude that OCT is not a replacement for FA in all circumstances. However, researchers have also recognized that there are scenarios in which one of the respective tests may be more appropriate than the other, including situations in which it would be appropriate to perform only an OCT. For example, due to its high sensitivity, OCT can be used alone without the need for a follow-up confirmatory FA when no intraretinal or sub-retinal fluid is observed. Use of OCT alone in this circumstance would thus eliminate the risks associated with intravenous fluorescein dye injections. Research also indicates that OCT is capable of identifying CNV leakage that is not captured by FA (Krebs, 2008) and that OCT has better inter-rater reliability than FA (van Velthoven, 2006).
OCT has also been used to assess patient response to PDT with verteporfin. The evidence described above includes studies reporting changes in OCT measures of retinal and subretinal morphology following treatment with PDT and verteporfin. Studies have also found that changes in retinal morphology as measured by OCT are associated with improvements in visual functioning (Augustin, 2007; Spielberg, 2010). While OCT cannot be used to determine the presence of CNV leakage, we believe the use of OCT to assess patients after treatment with OPT is appropriate and provides clinically useful information for patient management after PDT with verteporfin.
Therefore, we believe that OPT with verteporfin is reasonable and necessary in patients with AMD whose response to treatment is assessed with OCT after having been initially diagnosed using FA
A review of the studies discussed above in this decision memorandum revealed one article where all of the participants were of one particular ethnic group (Byun, 2010). The decision to use this group of enrollees may have been based on the convenient acquisition of data from a retrospective source. A further review of the literature failed to reveal an ethnic predisposition to AMD, though we will continue to search to see if any exist. But at this time any inference about relative benefits of OCT in specific racial or ethnic groups would be, at best, speculative. CMS also notes the absence of evidence about benefits or harms related to other population classifiers that have been associated historically with healthcare access or outcome disparities, such as gender, sexual orientation, religion, and age, and encourages additional studies in which such associations might be studied.
We have previously determined that ocular photodynamic therapy (OPT) with verteporfin is a beneficial treatment for some age-related macular degeneration (AMD) patients. Data reviewed in this analysis are not meant re-examine this issue; rather, our goal is to establish whether ocular photodynamic therapy (OCT) can be used in patient follow-up to inform subsequent ocular photodynamic therapy (OPT) with verteporfin treatment.
We will expand coverage of ocular photodynamic therapy (OPT) with verteporfin for “wet” age-related macular edema (AMD). Currently, fluorescein angiography (FA) testing is required for coverage of follow-up treatment. We will revise the requirements for testing to permit either optical coherence tomography (OCT) or FA to assess treatment response. All other coverage criteria would continue to apply.
General Methodological Principles of Study Design
(Section VI of the Decision Memorandum)
When making national coverage determinations, CMS evaluates relevant clinical evidence to determine whether or not the evidence is of sufficient quality to support a finding that an item or service falling within a benefit category is reasonable and necessary for the diagnosis or treatment of an illness or injury or to improve the functioning of a malformed body member. The overall objective for the critical appraisal of the evidence is to determine to what degree we are confident that: 1) the specific assessment questions can be answered conclusively; and 2) the intervention will improve health outcomes for patients.
We divide the assessment of clinical evidence into three stages: 1) the quality of the individual studies; 2) the generalizability of findings from individual studies to the Medicare population; and 3) overarching conclusions that can be drawn from the body of the evidence on the direction and magnitude of the intervention’s potential risks and benefits.
The methodological principles described below represent a broad discussion of the issues we consider when reviewing clinical evidence. However, it should be noted that each coverage determination has its unique methodological aspects.
Assessing Individual Studies
Methodologists have developed criteria to determine weaknesses and strengths of clinical research. Strength of evidence generally refers to: 1) the scientific validity underlying study findings regarding causal relationships between health care interventions and health outcomes; and 2) the reduction of bias. In general, some of the methodological attributes associated with stronger evidence include those listed below:
- Use of randomization
(allocation of patients to either intervention or control group) in order
to minimize bias.
- Use of contemporaneous
control groups (rather than historical controls) in order to ensure
comparability between the intervention and control groups.
- Prospective (rather than
retrospective) studies to ensure a more thorough and systematical
assessment of factors related to outcomes.
- Larger sample sizes in
studies to help ensure adequate numbers of patients are enrolled to
demonstrate both statistically significant as well as clinically
significant outcomes that can be extrapolated to the Medicare population.
Sample size should be large enough to make chance an unlikely explanation
for what was found.
- Masking (blinding) to
ensure patients and investigators do not know to which group patients were
assigned (intervention or control). This is important especially in
subjective outcomes, such as pain or quality of life, where enthusiasm and
psychological factors may lead to an improved perceived outcome by either
the patient or assessor.
Regardless of whether the design of a study is a randomized controlled trial, a non-randomized controlled trial, a cohort study or a case-control study, the primary criterion for methodological strength or quality is the extent to which differences between intervention and control groups can be attributed to the intervention studied. This is known as internal validity. Various types of bias can undermine internal validity. These include:
characteristics between patients participating and those theoretically
eligible for study but not participating (selection bias).
- Co-interventions or
provision of care apart from the intervention under evaluation
- Differential assessment
of outcome (detection bias).
- Occurrence and reporting
of patients who do not complete the study (attrition bias).
In principle, rankings of research design have been based on the ability of each study design category to minimize these biases. A randomized controlled trial minimizes systematic bias (in theory) by selecting a sample of participants from a particular population and allocating them randomly to the intervention and control groups. Thus, in general, randomized controlled studies have been typically assigned the greatest strength, followed by non-randomized clinical trials and controlled observational studies. The design, conduct and analysis of trials are important factors as well. For example, a well designed and conducted observational study with a large sample size may provide stronger evidence than a poorly designed and conducted randomized controlled trial with a small sample size. The following is a representative list of study designs (some of which have alternative names) ranked from most to least methodologically rigorous in their potential ability to minimize systematic bias:
- Randomized controlled
- Prospective cohort
- Retrospective case
- Cross-sectional studies
- Surveillance studies
(e.g., using registries or surveys)
- Consecutive case series
- Single case reports
When there are merely associations but not causal relationships between a study’s variables and outcomes, it is important not to draw causal inferences. Confounding refers to independent variables that systematically vary with the causal variable. This distorts measurement of the outcome of interest because its effect size is mixed with the effects of other extraneous factors. For observational, and in some cases randomized controlled trials, the method in which confounding factors are handled (either through stratification or appropriate statistical modeling) are of particular concern. For example, in order to interpret and generalize conclusions to our population of Medicare patients, it may be necessary for studies to match or stratify their intervention and control groups by patient age or co-morbidities.
Methodological strength is, therefore, a multidimensional concept that relates to the design, implementation and analysis of a clinical study. In addition, thorough documentation of the conduct of the research, particularly study selection criteria, rate of attrition and process for data collection, is essential for CMS to adequately assess and consider the evidence.
Generalizability of Clinical Evidence to the Medicare Population
The applicability of the results of a study to other populations, settings, treatment regimens and outcomes assessed is known as external validity. Even well-designed and well-conducted trials may not supply the evidence needed if the results of a study are not applicable to the Medicare population. Evidence that provides accurate information about a population or setting not well represented in the Medicare program would be considered but would suffer from limited generalizability.
The extent to which the results of a trial are applicable to other circumstances is often a matter of judgment that depends on specific study characteristics, primarily the patient population studied (age, sex, severity of disease and presence of co-morbidities) and the care setting (primary to tertiary level of care, as well as the experience and specialization of the care provider). Additional relevant variables are treatment regimens (dosage, timing and route of administration), co-interventions or concomitant therapies, and type of outcome and length of follow-up.
The level of care and the experience of the providers in the study are other crucial elements in assessing a study’s external validity. Trial participants in an academic medical center may receive more or different attention than is typically available in non-tertiary settings. For example, an investigator’s lengthy and detailed explanations of the potential benefits of the intervention and/or the use of new equipment provided to the academic center by the study sponsor may raise doubts about the applicability of study findings to community practice.
Given the evidence available in the research literature, some degree of generalization about an intervention’s potential benefits and harms is invariably required in making coverage determinations for the Medicare population. Conditions that assist us in making reasonable generalizations are biologic plausibility, similarities between the populations studied and Medicare patients (age, sex, ethnicity and clinical presentation) and similarities of the intervention studied to those that would be routinely available in community practice.
A study’s selected outcomes are an important consideration in generalizing available clinical evidence to Medicare coverage determinations. One of the goals of our determination process is to assess health outcomes. We are interested in the results of changed patient management not just altered management. These outcomes include resultant risks and benefits such as increased or decreased morbidity and mortality. In order to make this determination, it is often necessary to evaluate whether the strength of the evidence is adequate to draw conclusions about the direction and magnitude of each individual outcome relevant to the intervention under study. In addition, it is important that an intervention’s benefits are clinically significant and durable, rather than marginal or short-lived. Generally, an intervention is not reasonable and necessary if its risks outweigh its benefits.
If key health outcomes have not been studied or the direction of clinical effect is inconclusive, we may also evaluate the strength and adequacy of indirect evidence linking intermediate or surrogate outcomes to our outcomes of interest.
Assessing the Relative Magnitude of Risks and Benefits
Generally, an intervention is not reasonable and necessary if its risks outweigh its benefits. Health outcomes are one of several considerations in determining whether an item or service is reasonable and necessary. For most determinations, CMS evaluates whether reported benefits translate into improved health outcomes. CMS places greater emphasis on health outcomes actually experienced by patients, such as quality of life, functional status, duration of disability, morbidity and mortality, and less emphasis on outcomes that patients do not directly experience, such as intermediate outcomes, surrogate outcomes, and laboratory or radiographic responses. The direction, magnitude and consistency of the risks and benefits across studies are also important considerations. Based on the analysis of the strength of the evidence, CMS assesses the relative magnitude of an intervention or technology’s benefits and risk of harm to Medicare beneficiaries.