National Medical Policy

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1 National Medical Policy Subject: Policy Number: Endothelial Keratoplasty NMP534 Effective Date*: June 2014 Updated: June 2016 This National Medical Policy is subject to the terms in the IMPORTANT NOTICE at the end of this document For Medicaid Plans: Please refer to the appropriate State s Medicaid manual(s), publication(s), citation(s), and documented guidance for coverage criteria and benefit guidelines prior to applying Health Net Medical Policies The Centers for Medicare & Medicaid Services (CMS) For Medicare Advantage members please refer to the following for coverage guidelines first: Use Source Reference/Website Link National Coverage Determination (NCD) National Coverage Manual Citation Local Coverage Determination (LCD)* Article (Local)* X Other MLN Matters Number: MM9486. January 2016 Update of the Hospital Outpatient Prospective Payment System (OPPS): Education/Medicare-Learning-Network- MLN/MLNMattersArticles/downloads/MM9486.pdf MLN Matters Number: MM9484. January 2016 Update of the Ambulatory Surgical Center (ASC) Payment System: Education/Medicare-Learning-Network- MLN/MLNMattersArticles/Downloads/MM9484.pd f Medicare B Connection. Emergency update to the 2016 Medicare physician fee schedule database. January 2016: 63.pdf Palmetto GBA. Jurisdiction 11 Part B. Endothelial Endothelial Keratoplasty Jun 16 1

2 None Keratoplasty. Updated 2/27/2014: nsf/docscat/providers~jm%20part%20b~brows e%20by%20specialty~optometry%20ophthalm ology~8eeljh6113?open Use Health Net Policy Instructions Medicare NCDs and National Coverage Manuals apply to ALL Medicare members in ALL regions. Medicare LCDs and Articles apply to members in specific regions. To access your specific region, select the link provided under Reference/Website and follow the search instructions. Enter the topic and your specific state to find the coverage determinations for your region. *Note: Health Net must follow local coverage determinations (LCDs) of Medicare Administration Contractors (MACs) located outside their service area when those MACs have exclusive coverage of an item or service. (CMS Manual Chapter 4 Section 90.2) If more than one source is checked, you need to access all sources as, on occasion; an LCD or article contains additional coverage information than contained in the NCD or National Coverage Manual. If there is no NCD, National Coverage Manual or region specific LCD/Article, follow the Health Net Hierarchy of Medical Resources for guidance. Current Policy Statement Please see Health Net National Medical Policy on Refractive Surgery (LASIK, LASEK, PRK, PARK and PRK-A) Health Net, Inc. considers endothelial keratoplasty* using Descemet s stripping endothelial keratoplasty (DSEK), Descemet s stripping automated endothelial keratoplasty (DSAEK), Descemet s membrane endothelial keratoplasty (DMEK), or Descemet s membrane automated endothelial keratoplasty (DMAEK) medically necessary for the treatment of endothelial dysfunction, in individuals with endothelial failure and otherwise healthy corneas, including but not limited to any of the following: 1. Ruptures in Descemet s membrane; or 2. Fuch s endothelial corneal dystrophy; or 3. Aphakic and pseudophakic bullous keratopathy; or 4. Iridocorneal endothelial (ICE) syndrome; or 5. Corneal edema attributed to endothelial failure; or 6. Failure or rejection of a previous corneal transplant. *NOTE: Endothelial keratoplasty should not be used in place of penetrating keratoplasty (PK) for conditions with concurrent endothelial disease and anterior corneal dystrophies. These situations would include anterior corneal scars from trauma or prior infection, and ectasia after previous laser vision correction surgery. (AAO recommendation) Health Net, Inc. considers femtosecond laser-assisted corneal endothelial keratoplasty (FLEK) or femtosecond and excimer laser-assisted endothelial keratoplasty (FELEK) investigational, since although there have been studies, additional, larger, peer-reviewed studies are necessary to demonstrate the efficacy and long-term outcomes of these procedures. Endothelial Keratoplasty Jun 16 2

3 Key Words Definitions ALK BSCVA BK DALK DLEF DLEK DLKP DMAEK DMEK DSAK DSAEK EBAA EK FECD FELK FELEK PK PTK Anterior lamellar keratoplasty Best spectacle corrected visual acuity Bulbous keratopathy Deep anterior lamellar keratoplasty Deep lamellar endothelial keratoplasty Deep lamellar endothelial keratoplasty Deep lamellar keratoplasty Descemet's membrane automated endothelial keratoplasty Descemet's membrane endothelial keratoplasty Descemet's stripping automated keratoplasty Descemet's stripping automated endothelial keratoplasty Eye Bank Association of America Endothelial Keratoplasty Fuchs endothelial corneal dystrophy Femtosecond laser-assisted corneal endothelial keratoplasty Femtosecond and excimer laser-assisted endothelial keratoplasty Penetrating keratoplasty Phototherapeutic keratectomy Codes Related To This Policy NOTE: The codes listed in this policy are for reference purposes only. Listing of a code in this policy does not imply that the service described by this code is a covered or noncovered health service. Coverage is determined by the benefit documents and medical necessity criteria. This list of codes may not be all inclusive. On October 1, 2015, the ICD-9 code sets used to report medical diagnoses and inpatient procedures have been replaced by ICD-10 code sets. ICD-9 Codes Corneal edema, unspecified Idiopathic corneal edema Secondary corneal edema Bullous keratopathy Corneal edema due to wearing of contact lenses Rupture in Descemet's membrane Endothelial corneal dystrophy (Fuchs' endothelial dystrophy) Other posterior corneal dystrophies Mechanical complication due to corneal graft Mechanical complication due to ocular lens prosthesis ICD-10 Codes H Bullous keratopathy H18.13 H Other and unspecified corneal edema H H Rupture in Descemet's membrane H H18.51 Endothelial corneal dystrophy (Fuchs' endothelial dystrophy) H18.59 Other hereditary corneal dystrophies 08R83KZ Replacement of right cornea with nonautologous tissue substitute, percutaneous approach Endothelial Keratoplasty Jun 16 3

4 08R93KZ Replacement of left cornea with nonautologous tissue substitute, percutaneous approach T85.29XA- Other mechanical complication of intraocular lens T85.29XS T Corneal transplant rejection T Corneal transplant failure T Other complications of corneal transplant CPT Codes Keratoplasty (corneal transplant); endothelial Backbench preparation of corneal endothelial allograft prior to transplantation HCPCS Codes N/A Scientific Rationale Update June 2016 Iridocorneal Endothelial Syndrome (ICE) is a unique ophthalmic disorder that involves an irregular corneal endothelium that can lead to varying degrees of corneal edema, iris atrophy, and secondary angle-closure glaucoma. Per the American Academy of Ophthalmology (2015) corneal decompensation, resulting from ICE, can be treated with surgery when medical management fails. Penetrating keratoplasy (PKP) or endothelial keratoplasty (commonly DSEK or DSAEK) can be implemented to replace the abnormal corneal endothelial cells and improve corneal function. At times, both a filtering and corneal transplant procedure are necessary. Concomitant control of intraocular pressure (IOP) is vital for maintenance of corneal graft clarity. Droutsas et al. (2016) completed a study to compare visual rehabilitation after Descemet membrane endothelial keratoplasty (DMEK) and Descemet stripping automated endothelial keratoplasty (DSAEK) for Fuchs endothelial dystrophy. The medical records of patients undergoing endothelial keratoplasty were retrospectively evaluated. A DMEK (n = 25 eyes) and a DSAEK (n = 25 eyes) group were formed. Specific matched pairs consisting of 1 DMEK and 1 DSAEK eye with the same preoperative best spectacle-corrected visual acuity (BSCVA) were built and compared with regard to visual rehabilitation, subjective refraction, central corneal thickness, and endothelial cell density. Preoperative median BSCVA (logarithm of the minimal angle of resolution) was for both groups 0.7 (range, ). At 12 months, median BSCVA was 0.0 (range, to 0.7) after DMEK and 0.3 (range, ) after DSAEK (P < 0.001). The spherical equivalent changed after DMEK from 0.0 D (range, to 4.63 D) to 0.5 D (range, -1 to 2.5 D) and after DSAEK from D (range, to 1 D) to 0.63 D (range, to 2 D). Central corneal thickness decreased from 718 μm (range, μm) to 533 μm (range, μm) after DMEK and from 650 μm (range, μm) to 605 μm (range, μm) after DSAEK. Endothelial cell density decreased from 2448 cells/mm (range, cells/mm) to 1263 cells/mm (range, cells/mm) after DMEK and from 2348 cells/mm (range, cells/mm) to 1327 cells/mm (range, cells/mm) after DSAEK. DMEK patients showed faster rehabilitation and higher BSCVA at all postoperative visits; however, the decline in graft's endothelial cell count and change in the spherical equivalent were similar for both procedures. Scientific Rationale Update June 2015 Kasbekar et al. (2014) completed a multicenter cohort study, to investigate graft survival and surgical experience on clinical outcome following deep anterior lamellar keratoplasty (DALK). The United Kingdom Transplant Database was used to identify patients who had undergone a first DALK or penetrating keratoplasty (PKP) for Endothelial Keratoplasty Jun 16 4

5 keratoconus. Data were collected at the time of surgery and at 1, 2, and 5 years postoperatively. Graft survival, best-corrected visual acuity, and refractive error were analyzed for 3 consecutive time periods. DALK outcomes were analyzed according to surgeon experience. A total of 4521 patients were included. Graft survival was 92% (95% CI: 90-92) for PKP and 90% (95% CI: 88-92) for DALK (P =.09). For corneal transplants undertaken in the periods , , and , graft survival was 90%, 92%, and 88% following DALK, and 93%, 91%, and 92% following PKP, respectively. There was no evidence of a difference between surgeons in terms of case mix (P =.4) or outcome (P =.2). Surgeon experience, in terms of the number of previous DALK undertaken, had no significant effect on outcome. A donor recipient trephine size disparity of 0.5 mm was associated with an increased risk of graft failure for both DALK (P =.03) and PKP (P =.002), whereas ocular surface disease was a significant risk factor for DALK (P =.04) but not PKP. Therefore, there has been little change in graft survival for DALK and PKP over the past decade. Ocular surface disease is an important risk factor for graft failure following DALK. A surgical learning curve for DALK could not be demonstrated in terms of clinical outcome. Keane et al. (2014) identified two completed studies, with a total of 111 participants (n = 30 and n = 81), that met the author s inclusion criteria. Participants had moderate to severe keratoconus pre-operatively and were randomly allocated to receive either DALK or penetrating keratoplasty. Only one eye of each participant was treated as part of the trials. The smaller study had 12 month follow-up data for all participants. For the larger study, four DALK surgeries had to be abandoned due to technical failure and visual and refractive outcomes were not measured in these participants. Follow-up length for the remaining 77 participants ranged from 6.8 to 36.4 months, with all 77 followed for at least three months post-suture removal. Details of the randomisation procedure were unavailable for the smaller study and so sensitivity analyses were conducted to determine if the results from this study had affected the overall results of the review. Neither of the included studies reported a difference between groups on any of the measures of post-graft visual achievement, keratometric astigmatism or spherical equivalent. A single case of graft failure in a penetrating keratoplasty was reported. No postoperative graft failures were reported in the DALK group of either study. Instances of graft rejection were reported in both groups, in both studies. The majority of these cases were successfully treated with steroids. The data, which related to all cases in each study - given that the four cases that did not go ahead as planned had already technically failed without presence of rejection - showed that rejection was less likely to occur in DALK (odds ratio (OR): 0.33, 95% confidence interval (CI) 0.14 to 0.81, GRADE rating: moderate). Results of the sensitivity analysis indicated that inclusion of the Razmju 2011 study did not bias the results with regards to rejection episodes. While sensitivity analysis showed altered results with regards to failure rates, the data available from the Javadi 2010 study alone had a very wide 95% CI, suggesting an imprecise estimate. Therefore, even after removal of the Razmju 2011 data, it is still difficult to draw conclusions regarding superiority of one technique over another with regards to graft failure.dalk was unable to be completed as planned in four cases and in a further three cases, complications during dissection required further intervention. In recipients of DALK, one participant had interface neovascularisation (a proliferation of blood vessels where the host and donor cornea come together) and one had wrinkling of Descemet's membrane, the basement membrane separating the corneal stroma from the corneal endothelium. In the penetrating keratoplasty groups, one participant required graft resuturing and one had an atonic pupil, a condition in which the pupil dilates and is non-reactive.overall, the quality of the evidence was rated as very low to moderate, with methodological limitations, incomplete data analysis and imprecision of findings, as well as high risk of bias in several areas for both studies. The authors found no evidence to support a difference Endothelial Keratoplasty Jun 16 5

6 in outcomes with regards to BCVA at three months post-graft or at any of the other time points analysed (GRADE rating: very low). The authors also found no evidence of a difference in outcomes with regards to graft survival, final UCVA or keratometric outcomes. Some evidence that rejection is more likely to occur following penetrating keratoplasty than DALK (GRADE rating: moderate), was noted. The small number of studies included in the review and methodological issues relating to the two, mean that the overall quality of the evidence in this review is low. There is currently insufficient evidence to determine which technique may offer better overall outcomes, final visual acuity and time to attain this, keratometric stabilisation, risk of rejection or failure, or both, and risk of other adverse events, for patients with keratoconus. Large randomised trials comparing the outcomes of penetrating keratoplasty and DALK in the treatment of keratoconus are needed. (Cochrane Database Review 2014). Scientific Rationale Initial Penetrating keratoplasty (PK) was the primary corneal transplant technique and has evolved over the years from the early 1900s, when this procedure was first performed. At one time, conventional penetrating keratoplasty was the standard of care. However, these techniques were accompanied by slower wound healing time and decreased wound stability requiring tighter suture placement, which can lead to decreased best spectacle corrected visual acuity (BSCVA) and significant postoperative astigmatism. Over the past 10 years, PK has been challenged by endothelial keratoplasty (EK) also referred to as posterior lamellar keratoplasty, a procedure in which only the abnormal part of the diseased cornea needs to be replaced, leaving the cornea surface relatively untouched. Therefore, if the cornea has an endothelial problem, then only the posterior cornea would need to be replaced. If it is a stromal problem, the stroma is replaced and no surgery is necessary for the Descemet and endothelium. This procedure is the preferred way to restore vision when the inner cell layer of the cornea stops working properly, with bullous keratopathy, iridocorneal endothelial (ICE) syndrome, or other endothelial disorders. Dr. Price, founder and president of the Cornea Research Foundation, was an early pioneer of this procedure, since The endothelium or the diseased inner layer of the cornea is replaced with healthy donor tissue, through a small incision, as part of the EK procedure. The healthy area of the cornea is left intact. An air bubble is used to unfold and position the donor tissue against the patient s cornea. The small incision is either self-sealing or may be closed with a few sutures. Specific techniques of endothelial keratoplasty include Descemet s stripping endothelial keratoplasty (DSEK), Descemet s stripping automated endothelial keratoplasty (DSAEK), Descemet s membrane endothelial keratoplasty (DMEK), or Descemet s membrane automated endothelial keratoplasty (DMAEK). The most common types of EK procedures are DSEK and DSAEK, which are proposed to leave the eye much stronger and less prone to injury than full-thickness transplants. During DSEK hand-dissected donor tissue is used and diseased or opacified corneal endothelial cells are stripped away. Grafts are applied to the posterior 1/4 to 1/3 donor cornea thickness to the inner surface of the recipient cornea. This technique is proposed to offer certain clinical advantages while achieving the goal of penetrating keratoplasty in patients with disease largely related to endothelial dysfunction. Patients without other eye problems usually achieve average vision of 20/30 or better within a couple of months. This procedure is not indicated for elective refractive surgery. Endothelial Keratoplasty Jun 16 6

7 The donor corneal tissue and an artificial chamber on the individual s eye are prepared prior to the DSAEK procedure. The donor tissue is cut with a microkeratome, with a small incision from the temporal side of the cornea in order to provide the greatest manual access and visualization. Two clear corneal incisions are also placed about 5 clock hours apart to be used as access points to the anterior chamber during the operation. This incision is a depth of microns. The cut donor tissue is then punched with a trephine to 9 mm in size for the transplant. A big-bubble technique is then used to detach the central 6.0 to 7.0 mm of Descemet membrane. The scleral rim is again mounted on an artificial anterior chamber. This leaves a bare central Descemet membrane with an attached peripheral rim of stroma. The graft is inserted and the graft's stromal rim allows it to spontaneously unfold once inside the eye. The previously-prepared donor tissue is then folded with a pair of special folding forceps and implanted into the anterior chamber of the eye. After manipulations to center the donor tissue inside the eye and to remove the fluid between the donor tissue and the host, the anterior chamber is then completely filled with air to help with the adherence of the donor tissue to the endothelial side of the cornea. During the DMEK procedure, the endothelium and attached Descemet s membrane has to be peeled off the back of the donor cornea. The ultra-thin DMEK grafts are so fragile that sometimes the precious donor tissue tears while separating the layers and it cannot be salvaged. The preparation of the donor tissue is usually the biggest issue with this procedure. Descemet s membrane is only about 15 microns thick, so the preparation has to be done very carefully. Once a DMEK graft is placed into the patient s eye, it usually curls up into a scroll. The scroll has to be unrolled and the surgeon has to determine which side should face the recipient cornea and which side should face the inside of the eye. Some techniques have been developed to help with this, but it is still a complex surgery for the surgeon. The main advantage of DMEK over DSEK/DSAEK is that the visual outcomes are better. After DMEK surgery about 75% of eyes may achieve a best corrected visual acuity of 20/25 or better within the first 6 months after surgery. This difference may be explained by the near-anatomic restoration with DMEK. In DMAEK the donor graft just has the thin Descemet s membrane and endothelium in the center, with an outer rim of extra supporting tissue which is the thickness of a DSEK / DSAEK graft. The outer ring of thicker tissue prevents the graft from curling into a scroll and allows easier placement of the tissue in the patient s eye. In the DMAEK technique, the anterior stromal tissue is removed from the donor with a Microkeratome, similar to what is done in DSAEK surgery. Next the donor tissue is turned over and air is injected into the tissue to separate Descemet s membrane from the rest of the donor over the central 5 to 7 mm of the cornea. The endothelium is then coated with a special viscoelastic material to protect it, remount it on an artificial anterior chamber and remove the stromal tissue over the area where the Descemet s membrane was removed by the air. The DMAEK graft is now ready to be cut with a round trephine to the sized needed for the patients eye, just as is done for a standard penetrating keratoplasty or DSEK / DSAEK. More reinjections of air is done to keep the thin donor tissue up against the back of the patient s cornea during the first few days to weeks after surgery comparable to DSEK / DSAEK. Fuchs endothelial corneal dystrophy (FECD) is an inherited autosomal dominant degenerative progressive disease of the endothelial cells of the cornea, which has been mapped to chromosome 13. There is often no known family history because affected family members may have had mild or undiagnosed disease. It often results in the development of corneal edema, and is estimated to have a prevalence of approximately 4% in the United States. FECD is a leading cause for corneal Endothelial Keratoplasty Jun 16 7

8 transplantation, with 13,107 of the 61,741 (21%) keratoplasties (penetrating or endothelial) in 2012 performed for this condition according to the Eye Bank Association of America. While clinical studies have led to a remarkable replacement of penetrating keratoplasty by endothelial keratoplasty for the surgical management of FECD over the last 5 years, efforts to determine the genetic risk factors underlying FECD have been pursued concurrently. However, despite the prevalence of FECD, only recently has research focused on examining disease characteristics and comorbidities within the general population. Keratoplasty for FECD had been typically reserved until a patient experienced a significant, persistent decrease in vision throughout the day, not simply in the morning, when the cornea is most swollen. Originally this was thought to occur when FECD reached a threshold where compensatory mechanisms, such as the up-regulation of endothelial cell pumping action with remaining normal endothelial cells, were insufficient to offset the declining barrier function of the endothelium with FECD-affected diseased cells. However, it was demonstrated from our cohort of cases and controls that an increase in central corneal thickness occurs progressively with increasing severity of FECD, including at stages of FECD where stromal and/or epithelial edema was not evident on slitlamp examination (below grade 5). This suggests there may be clinical benefit to measuring corneal thickness even at early stages of the disease to monitor progression and subsequent timing of surgical intervention, particularly now that endothelial keratoplasty is recommended at an earlier stage, before structural damage to the stroma occurs from chronic edema. This approach may prove particularly useful given the individual variation in baseline corneal thickness in normal and FECD patients, even prior to any disease related changes. Tracking changes in corneal thickness over time may better identify surgical candidates than use of preoperative thresholds and could change standards of care. Eyes with combined Fuchs dystrophy and keratoconus or a perforated herpes simplex virus corneal ulcer or a central scar from a large full-thickness corneal laceration are not great candidates for endothelial keratoplasty and are probably best served by a PK. Some eyes with bullous keratopathy have significant anterior stromal haze from the long-standing edema. While an EK and subsequent excimer laser phototherapeutic keratectomy (PTK) or even a partial thickness anterior lamellar keratoplasty could be performed after the EK healed, a single PK procedure is often a better option. Anterior lamellar keratoplasty was performed on a very limited basis until the concept of baring the Descemet membrane and transplanting a full-thickness cornea, minus the Descemet and endothelium, was developed. This deep anterior lamellar keratoplasty (DALK) technique simplified the procedure in many ways and resulted in better visual outcomes with much less interface haze. While the refractive and visual results were typically no better than PK, the procedure had some advantages. The primary advantage was no endothelial rejection, allowing for less postoperative steroid use and potentially a longer lifespan of the graft. The primary reasons DALK hasn t caught on are that it is much more time consuming than performing a PK, involves numerous technical and visual outcome issues, and high rate of intraoperative perforation of the Descemet membrane, often leading to conversion to PK. The fact that it has a long learning curve, didn t help. Therefore, anterior lamellar keratoplasties make up only a small percentage of the grafts performed in the United States at this time. In cases of anterior corneal disease such as a central corneal opacity, keratoconus, or anterior pigmentation of cornea, a penetrating keratoplasty may be preferred. Femtosecond laser-assisted corneal endothelial keratoplasty (FLEK) and femtosecond and excimer lasers-assisted endothelial keratoplasty (FELEK), are procedures that were introduced in 2006 and utilize a laser. The femtosecond laser is an infrared Endothelial Keratoplasty Jun 16 8

9 laser that delivers very short pulses of energy, on the order of femtoseconds or seconds, to make corneal cuts. With the use of software, the laser is preprogrammed to make cuts at specific depths, thereby creating the desired corneal shape. These procedures include some donor stroma along with the endothelium and Descemet s membrane, which results in a thickened stromal layer after transplantation. These techniques are a modification of traditional full-thickness penetrating keratoplasty. FLEK and FELEK have not been shown to have improved outcomes compared to existing techniques in peer reviewed studies. Position Statements The American Academy of Ophthalmology (Lee et al., 2009) notes that endothelial keratoplasty procedures offer an alternative to penetrating keratoplasty to replace diseased endothelium with healthy donor tissue, without the need to remove the entire cornea. Descemet's stripping endothelial keratoplasty (DSEK) was introduced in 2005, and Descemet's stripping automated endothelial keratoplasty (DSAEK) was introduced in These procedures have replaced deep lamellar endothelial keratoplasty (DLEK). These methods for endothelial keratoplasty (EK) involve removal of Descemet's membrane and endothelium and replacement with donor tissue. When donor tissue is comprised of Descemet's membrane and endothelium alone, the technique is known as Descemet's membrane endothelial keratoplasty (DMEK). The AAO position paper states that endothelial keratoplasty procedures are associated with a smaller incision and faster visual rehabilitation than penetrating keratoplasty. The AAO paper states that there remain concerns about potential complications and long-term efficacy of endothelial keratoplasty, including concerns about graft dislocations, endothelial cell loss, and failed grafts. The AAO position paper cites the conclusions of an AAO Technology Assessment, which acknowledge the relatively short-term follow up and varying surgical techniques in the literature, but states "there is no evidence that DSAEK carries unacceptable risks for surgical treatment of endothelial corneal disease. In comparison to PK, DSAEK appears at least equivalent in terms of safety, efficacy, surgical risks, and complications rates and superior to PK in terms of refractive stability, postoperative refractive outcomes, wound and suture-related complications, and intraoperative choroidal hemorrhage risk". The AAO position paper was based in large part on a comprehensive review of the literature on Descemet s stripping automated endothelial keratoplasty (DSAEK) by the American Academy of Ophthalmology s Ophthalmic Technology Assessment Committee. The Technology Assessment Committee concluded that the evidence reviewed suggests DSAEK appears safe and efficacious for the treatment of endothelial diseases of the cornea. Evidence from retrospective and prospective DSAEK reports described a variety of complications from the procedure, but these complications do not appear to be permanently sight threatening or detrimental to the ultimate vision recovery in the majority of cases. Long-term data on endothelial cell survival and the risk of late endothelial rejection cannot be determined with this review. DSAEK should not be used in lieu of PK for conditions with concurrent endothelial disease and anterior corneal disease. These situations would include concurrent anterior corneal dystrophies, anterior corneal scars from trauma or prior infection, and ectasia after previous laser vision correction surgery. The National Institute for Health and Clinical Excellence (NICE, 2008) found adequate evidence to support the use of this procedure. The NICE assessment cited comparative studies which found better visual acuity and a lower incidence of astigmatism with endothelial keratoplasty compared with penetrating keratoplasty. The specialist advisors to NICE listed adverse events of endothelial keratoplasty reported in the literature or anecdotally as graft dislocation, graft failure and rejection, interface opacification, and loss of best spectacle corrected visual acuity. Endothelial Keratoplasty Jun 16 9

10 Eye Bank Association of America (EBAA) statistics show the number of EK cases in the United States increased from 1,429 in 2005 to 23,409 in The EBAA report estimates that approximately 1/2 of corneal transplants performed in the U.S. were endothelial grafts. As with any new surgical technique, questions have been posed about long-term efficacy and the risk of complications. EK-specific complications include graft dislocations, endothelial cell loss, and rate of failed grafts. Long-term complications include increased intraocular pressure, graft rejection, and late endothelial failure. Also of interest is the impact of the surgeon s learning curve on the risk of complications. Studies Price et al. (2010) completed a multicenter, prospective, nonrandomized clinical trial, the Cornea Donor Study which compared Descemet's stripping endothelial keratoplasty (DSEK) with penetrating keratoplasty (PKP). Two surgeons performed DSEK on 173 patients, with the following findings at 3 years: 111 patients (64%) were examined and found to have clear grafts; 44 patients (25%) had clear grafts when last examined but withdrew or were lost to follow-up before the 3-year evaluation; 11 patients (6.4%) had died; and 7 patients (4%) had graft failure. The investigators calculated a cumulative probability of a DSEK graft survival of 94% at 3 years. The 3-year graft survival rate was 96% for both the DSEK and PKP eyes with Fuchs dystrophy, and 86% for the DSEK eyes verses 84% for the PKP eyes with other preoperative diagnoses. Statistically significantly fewer immunologic graft rejection episodes occurred in the DSEK group (6.4%) vs the PKP group (20%) at 3 years (P =.0005). At 3 years, the median endothelial cell loss was similar for the DSEK and PKP groups (48% vs 53%, respectively, P =.17). Eyes with Fuchs dystrophy had less endothelial cell loss than eyes with other preoperative diagnoses, but it was similar for the DSEK and PKP eyes. Of interest, DSEK eyes had more endothelial cell loss than the PKP eyes at 1 year but less cell loss over the subsequent 2 years. The 2 sites in this study used different incision lengths: 3.2 mm and 5.0 mm. The significantly greater cell loss observed in the 3.2-mm-incision eyes compared with the 5.0-mm-incision eyes at 1 year persisted at 3 years (60% vs 33%, P =.0007). The 5.0-mm incision showed significantly less cell loss in the DSEK eyes than in the PKP eyes at 3 years (33% vs 53%, P =.0017). Compared with PK, DSAEK resulted in lower EC loss with comparable cumulative graft survival rates for up to 3 years in patients with Fuchs' dystrophy and bulbous keratopathy (BK). Straiko et al. (2011) completed a retrospective analysis of a prospectively collected dataset. All 17 eyes with a preoperative diagnosis of failed penetrating keratoplasty graft were identified out of a total pool of 793 eyes that had received DSAEK for endothelial dysfunction in a prospective Institutional Review Board approved study of endothelial keratoplasty. A standard surgical strategy of careful slit-lamp examination and preoperative optical coherence tomography (OCT) to determine optimal DSAEK graft diameter was combined with undersized Descemet stripping and peripheral bed scraping. A total of 17 eyes in 16 patients were identified. The DSAEK graft size ranged from 7.0 to 8.0 mm, with all DSAEK graft diameters less than or equal to the PK diameter. The average follow-up was 16 months (range 2-38 months). All PK grafts cleared and the visual acuity improved in all patients. There were no cases of pupillary block or primary graft failure. There was 1 dislocation Endothelial Keratoplasty Jun 16 10

11 (5.9%). The dislocation occurred in an eye with aniridia, prior trabeculectomy, and scleromalacia with postoperative hypotony from a wound leak. DSAEK for failed PK using DSAEK grafts with a diameter less than or equal to the PK diameter allowed improved vision with a low complication rate. Preoperative OCT of posterior PK contour can aid in graft diameter selection. Nanavaty et al. (2014, Cochrane Database) Two authors independently screened the search results, that included 3 RCTs comparing EK versus PKP for people, of any age and gender, who had been clinically diagnosed with Fuchs endothelial dystrophy (FED). This included a total of 139 eyes of 136 participants and analyzed 123 (88%) eyes. Two RCTs randomised eyes into either the endothelial keratoplasty (EK) group or penetrating keratoplasty (PKP) group and one RCT randomised eyes into either the femtosecond laser-assisted endothelial keratoplasty (FLEK) group or PKP group. The RCTs comparing EK with PKP did not show any significant differences between procedures with respect to best corrected visual acuity (BCVA) at two years (mean difference (MD) 0.14 logmar; 95% confidence interval (CI) to 0.36; P = 0.23) or at one year (MD 0.09 logmar; 95% CI to 0.23; P = 0.22), whereas the trial comparing FLEK with PKP showed significantly better BCVA after PKP (MD 0.20 logmar; 95% CI 0.10 to 0.30; P = ). Only one RCT reported on irregular astigmatism (higher-order aberration), which was less with EK than PKP (MD µm; 95% CI to -0.87; P < 0.001). Only one RCT reported on endothelial cell counts (lower after FLEK than PKP: MD -969 cells/mm²; 95% CI to -777; P < 0.001), primary graft failure (higher after FLEK than PKP: RR 7.76; 95% CI 0.41 to ; P = 0.10), and graft rejection (more after FLEK than PKP: RR 1.11; 95% CI 0.07 to 17.12; P = 0.94). Only one RCT reported that 27.8% of participants had graft dislocation, 2.8% had epithelial ingrowth and postoperative pupillary block, and 13.9% had intraocular pressure (IOP)-related problems in the FLEK group compared with the PKP group, in whom 10% had suture-related problems, 5% had wound dehiscence and 10% had suture revision to correct astigmatism. Overall, the adverse events in the FLEK group appeared to be more frequent than in the PKP group. No trials reported information about quality of life or economic data. The overall methodological quality of the three trials was not satisfactory as most did not perform allocation concealment or masking of participants and outcome assessors, and all trials had a small sample size. The rapid growth of endothelial keratoplasty as the treatment of choice for FED is based upon the belief that visual recovery is more rapid, surgically induced astigmatism, regular and irregular, is less and rates of transplant rejection are lower with EK. This change in practice also assumes that the rates of long term transplant survival are equal for the two procedures. The practical differences between the surgical procedures mean that visual recovery is inherently more rapid following EK, but this review found no strong evidence from RCTs of any difference in the final visual outcome between EK and PKP for people with FED. This review also found that higher order aberrations are fewer following EK but endothelial cell loss is greater following EK. The RCTs that we included employed different EK techniques, which may have a bearing on these findings. EK procedures have evolved over the years and can be performed using different techniques, for example deep lamellar endothelial keratoplasty, Descemets stripping endothelial keratoplasty (DSEK), Descemets stripping automated endothelial keratoplasty (DSAEK), femtosecond laser-assisted endothelial keratoplasty and Descemet membrane endothelial keratoplasty (DMEK). More RCTs are needed to compare PKP with commonly performed EK procedures such as DSEK, DSAEK and DMEK in order to determine the answers to two key questions, whether there is any difference in the final visual outcome between these techniques and whether there are differences in the rates of graft survival in the long term. There are a number of ongoing Clinical Trials. There is one that is currently recruiting participants Outcome After Descemet Membrane Endothelial Keratoplasty (DMEK) Endothelial Keratoplasty Jun 16 11

12 and Ultra-thin Descemet Stripping Automated Endothelial Keratoplasty (DSAEK). The ClinicalTrials.gov Identifier is NCT , and it was last verified in December The purpose of this study is to evaluate the outcome after posterior lamellar keratoplasty (DMEK and Ultra-thin DSAEK) for corneal transplantation. The estimated primary completion date is December Another Clinical trial on Study of Endothelial Keratoplasty Outcomes, also currently recruiting participants. The ClinicalTrials.gov Identifier is NCT , and it was last updated November Endothelial keratoplasty is undergoing rapid and widespread adoption. Between 2005 and 2007, the number of corneas placed by US eye banks for endothelial keratoplasty increased ten-fold (i.e., 2007 Eye Bank Association of America Annual Report). However, the procedure is less than 10 years old, and little is known about long term outcomes. Endothelial keratoplasty candidates at our center are invited to participate in an open enrollment, prospective study of the long-term outcomes of this procedure. The estimated primary completion date is February Chamberlain et al. (2013) completed a non-randomized retrospective comparative study involving 100 subjects, in which FLEK (n=50) was compared to PK (n=50). Significantly lower topographic astigmatism was achieved in the FLEK group over the PK group in the 4 to 6 month follow-up period (p=0.0324). However, this difference was not present in any other follow-up period up to 24 months postoperatively. A subset analysis of subjects with keratoconus or post-lasik ectasia did not show any difference in either astigmatism or visual acuity at any time. No significant improvement in BSCVA was noted at any time point. Vetter et al. (2013) completed a small (n=22) retrospective cohort study and reported a reduction in visual acuity when the endothelial transplant was prepared with FLEK vs. DSAEK. There was also greater surface irregularity with the laserassisted EK. Given this data, it is unclear that there is any benefit to FLEK, and it may be deduced by the available evidence that PK may be superior to FLEK with regard to postoperative visual acuity. Cheng et al. (2011) reported a prospective, randomized clinical trial involving 80 subjects (80 eyes) with corneal endothelial dysfunction randomized to undergo FLEK or PK. At the end of 12 months, only 29 (72.5%) FLEK subjects were available for analysis vs. 39 (97.5%) in the PK group. In the FLEK group, postoperative refractive and topographic astigmatism values were not significantly different from preoperative values. In the PK group, all postoperative refractive and topographic astigmatism values were significantly higher compared with those before surgery. At twelve months after surgery, the percentage of subjects with a refractive astigmatism of 3.0 D was significantly higher in the FLEK group compared with the PK group (86.2% vs. 51.3%, p=0.004). Post-operatively, the mean BSCVA in the PK group was significantly better when compared with the FLEK group at all follow-up visits. The mean gain in BSCVA at 12 months was not significantly different between the FLEK and PK groups (p=0.103). Cheng et al. (2009) completed a randomized trial comparing FLEK with PK for 80 subjects (80 eyes) with Fuchs' endothelial dystrophy, pseudophakic bullous keratopathy, or posterior polymorphous dystrophy, and best spectacle-corrected visual acuity less than 20/50. Subjects were randomly assigned in a 1:1 manner. In the FLEK group, 4 of the 40 eyes which did not receive the procedure were excluded from the analysis. Eight eyes failed (22% of 36), and 2 participants were lost to follow-up due to death. In the PK group only 1 participant was lost to follow-up. At 12 months postoperatively, refractive astigmatism was lower in the FLEK group than the PK group (86% vs. 51%), but there was greater hyperopic shift. Mean BCVA was Endothelial Keratoplasty Jun 16 12

13 better following PK than FLEK at 3-, 6-, and 12-month follow-up. Endothelial cell loss was reported as greater in the FLEK group (65%) vs. the PK group (23%). With the exception of dislocation and need for repositioning of the FLEK grafts in 28% of eyes, the percentage of complications were similar in the 2 groups. Complications in the FLEK group were due to pupillary block, graft failure, epithelial ingrowth, and elevated intraocular pressure, whereas complications in the PK group were related to the sutures and elevated intraocular pressure. The authors concluded that FLEK effectively reduced postoperative astigmatism and eliminated wound healing related problems compared to PK. However, they note that visual acuity is lower compared with conventional PK, and the rate of endothelial cell loss warrants further investigation. In summary, although the majority of the studies on endothelial keratoplasty (EK) are not RCTs, they seem to have promising results at this time. In addition, this procedure is less invasive than penetrating keratoplasty since only the diseased part of the cornea needs to be replaced. The studies indicate potential advantages of the procedure in terms of more rapid recovery of visual acuity than penetrating keratoplasty (PK) without causing significant refractive errors. ions. There are two ongoing Clinical Trials to evaluate the outcomes of endothelial keratoplasty but they will not be completed until 2015 and Per the American Academy of Ophthalmology (2013) the ongoing development of endothelial keratoplasty from DLEK to DSEK/DSAEK to DMEK/DMAEK, and possibly DMET, indicates that there has a decreasing number of penetrating keratoplasties. The number of EKs has now surpassed the number of PKs performed in the United States. There are many reasons for this rapid conversion, including faster surgery, less change in corneal curvature, fewer suture-related complications, and a stronger wound. Longer-term graft survival with these new techniques is presently unknown. However, current procedures result in acceptable short-term survival, and additional surgical intervention can be performed with a low risk of vision loss. Due to the marked reduction in serious complications compared to the alternative, DSEK/DSAEK has become the preferable approach for endothelial dysfunction among corneal surgeons. DMEK/DMAEK have also become accepted approaches to EK, due to a reduction in stromal haze and improvement in visual acuity. Review History June 2014 Medical Advisory Council, initial approval June 2015 Update no revisions. Codes updated. June 2016 Update no revisions. Codes updated. This policy is based on the following evidence-based guidelines: 1. American Academy of Ophthalmology (AAO). Cornea Through the Looking Glass Where We Are, Where We re Headed. 2. American Academy of Ophthalmology Health Policy Committee Position Paper on Endothelial Keratoplasty, (2009 January 29). 3. Lee WB, Jacobs DS, Musch DC, et al. Descemet's stripping endothelial keratoplasty: Safety and outcomes: A report by the American Academy of Ophthalmology. Ophthalmology. 2009;116(9): Hayes. Health Technology Brief. Descemet Stripping with Manual or Automated Endothelial Keratoplasty for Corneal Endothelial Degeneration. March 2, Archived March 9, National Institute for Health and Clinical Excellence (NICE). Corneal endothelial transplantation. December Updated June Available at: Endothelial Keratoplasty Jun 16 13

14 References Update June Droutsas K, Lazaridis A, Papaconstantinou D, et al. Visual Outcomes After Descemet Membrane Endothelial Keratoplasty Versus Descemet Stripping Automated Endothelial Keratoplasty-Comparison of Specific Matched Pairs. Cornea Jun;35(6): doi: /ICO Huang GF, Gao Y, Charlotte Aimee XJ, et al. Preliminary results of femtosecond laser-assisted Descemet stripping endothelial keratoplasty for bullous keratopathy. Zhonghua Yan Ke Za Zhi Mar 11;52(3): doi: /cma.j.issn Oldham GW. Iridocorneal Endothelial Syndrome and Secondary Glaucoma. American Academy of Ophthalmology (AAO). May References Update June Coster DJ, Lowe MT, Keane MC, et al. A comparison of lamellar and penetrating keratoplasty outcomes: a registry study. Ophthalmology. 2014; 121(5): Fan Gaskin JC, Patel DV, McGhee CN. Acute corneal hydrops in keratoconus - new perspectives. Am J Ophthalmol 2014; 157: Kasbekar SA, Jones MN, Ahmad S, et al. Corneal transplant surgery for keratoconus and the effect of surgeon experience on deep anterior lamellar keratoplasty outcomes. Am J Ophthalmol 2014; 158: Keane M, Coster D, Ziaei M, et al. Deep anterior lamellar keratoplasty versus penetrating keratoplasty for treating keratoconus. Cochrane Database Syst Rev 2014; 7:CD Lockington D, Fan Gaskin JC, McGhee CN, et al. A prospective study of acute corneal hydrops by in vivo confocal microscopy in a New Zealand population with keratoconus. Br J Ophthalmol 2014; 98: Mitry D, Bhogal M, Patel AK, et al. Descemet stripping automated endothelial keratoplasty after failed penetrating keratoplasty: survival, rejection risk, and visual outcome. JAMA Ophthalmol. 2014; 132(6): Perez JF, Valero MA, Martínez PFJ. Early diagnosis of keratoconus: what difference is it making? Br J Ophthalmol 2014; 98: Stem M, Webster LS, Mian SI, et al. Descemet Membrane Endothelial Keratoplasty for Graft Failure After Descemet Stripping Endothelial Keratoplasty: Clinical Results and Histopathologic. JAMA Ophthalmology. References Initial 1. Allan B, Terry MA, Price FW, et al. Corneal transplant rejection rate and severity after endothelial keratoplasty. Cornea 2007; 26: Ang M, Mehta JS, Lim F, et al. Endothelial cell loss and graft survival after Descemet's stripping automated endothelial keratoplasty and penetrating keratoplasty. Ophthalmology Nov;119 (11): doi: /j.ophtha Epub 2012 Aug Chen ES, Terry MA, et al. Endothelial keratoplasty: vision, endothelial survival, and complications in a comparative case series of fellows vs. attending surgeons. Am J Ophthalmol (2009) 148(1):26-31.e2. 4. Chen ES, Terry MA, Shamie, N et al. Descemet-stripping automated endothelial keratoplasty: insertion using novel 40/60 underfold technique for preservation of donor endothelium. Cornea 2008; 27: Chen ES, Terry MA, Shamie N, et al. Descemet-stripping automated endothelial keratoplasty: six-month results in a prospective study of 100 eyes. Corneal. 2008; 27(5): Cheng YY, van den Berg TJ, Schouten JS, et al. Quality of vision after femtosecond laser-assisted descemet stripping endothelial keratoplasty and Endothelial Keratoplasty Jun 16 14

15 penetrating keratoplasty: a randomized, multicenter clinical trial. Am J Ophthalmol. 2011; 152(4): Cheng YY, Schouten JS, et al. Efficacy and safety of femtosecond laser-assisted corneal endothelial keratoplasty: a randomized multicenter clinical trial. Transplantation (2009) 88(11): Chih A, Lugo M, Kowinqo D. Descemet stripping and automated endothelial keratoplasty: an alternative to penetrating keratoplasty. Optom Vis Sci. 2008; 85(3): Clinicaltrials.gov. Outcome After Descemet Membrane Endothelial Keratoplasty (DMEK) and Ultra-thin Descemet Stripping Automated Endothelial Keratoplasty (DSAEK). ClinicalTrials.gov Identifier:NCT December Available at: lasty&rank=1 10. Clinicaltrials.gov. Study of Endothelial Keratoplasty Outcomes. ClinicalTrials.gov Identifier: NCT November Available at: lasty&rank=2 11. Clinicaltrials.gov. Descemet Stripping (Automated) Endothelial Keratoplasty (DSEK or DSAEK). ClinicalTrials.gov Identifier: NCT Covert DJ, Koenig SB. Descemet stripping and automated endothelial keratoplasty (DSAEK) in eyes with failed penetrating keratoplasty. Cornea. 2007; 26(6): Dapena I, Ham L, Melles GR. Endothelial keratoplasty: DSEK/DSAEK or DMEKthe thinner the better? Curr Opin Ophthalmol 2009; 20(4): Den S, Shimmura S, et al. Impact of the Descemet membrane perforation on surgical outcomes after deep lamellar keratoplasty. American Journal of Ophthalmology (2007 May) 143(5): Ehlers JP, Shah CP, eds. The Wills Eye Manual. 5th ed. Philadelphia: Lippincott Williams & Wilkins; Feng MT, Price MO, Price FW Jr. Update on Descemet membrane endothelial keratoplasty. Int Ophthalmol Clin. 2013; 53(2): Fontana L, Parente G, et al. Clinical outcomes after deep anterior lamellar keratoplasty using the big-bubble technique in patients with keratoconus. American Journal of Ophthalmology (2007 January) 143(1): Guerra FP, Anshu A, Price MO, et al. Descemet's membrane endothelial keratoplasty: prospective study of 1-year visual outcomes, graft survival, and endothelial cell loss. Ophthalmology. 2011; 118(12): Ham L, Dapena I, van Luijk C, et al. Descemet membrane endothelial keratoplasty (DMEK) for Fuchs endothelial dystrophy: review of the first 50 consecutive cases. Eye Jan 30. [Epub ahead of print] 20. Ho C, Cunningham J. Descemet stripping automated endothelial keratoplasty: A review of the clinical and cost-effectiveness. Ottawa, ON: Canadian Agency for Drugs and Technologies in Health (CADTH) Hyams M, Segev F, et al. Early postoperative complications of deep lamellar endothelial keratoplasty. Cornea (2007 July) 26(6): Jordan CS, Price MO, Trespalacios R, et al. Graft rejection episodes after Descemet stripping with endothelial keratoplasty: part one: clinical signs and symptoms. Br J Ophthalmol 2009;93: Koenig SB, Covert DJ. Early results of small-incision Descemet's stripping and automated endothelial keratoplasty. Ophthalmology. 2007;114(2): Kosker M, Suri K, Duman F, et al. Long-term outcomes of penetrating keratoplasty and Descemet stripping endothelial keratoplasty for Fuchs endothelial dystrophy: fellow eye comparison. Cornea. Epub ahead of print 2013 Apr 30. Endothelial Keratoplasty Jun 16 15