Corneal Transplantation Studies
By Loretta B. Szczotka - Flynn, OD, PHD, MS, FAAO
The National Eye Institute (NEI), one of the National Institutes of Health of the U.S. Department of Health and Human Services, has sponsored three major clinical trials on corneal transplantation. Collectively, these studies have sought to answer questions surrounding the associations between graft success and tissue matching, donor age, and donor preservation time.
Collaborative Corneal Transplantation Studies
Between 1986 and 1989, the Collaborative Corneal Transplantation Studies (CCTS) Group conducted two controlled, double-masked studies addressing distinct scientific questions about donor-recipient histocompatibility matching.
The CCTS Crossmatch Study was a randomized study assessing the effectiveness of crossmatching in preventing graft rejection among high-risk patients who had lymphocytotoxic antibodies. The CCTS Antigen Matching Study was a prospective, doublemasked, observational study of the effectiveness of HLA-A, -B, and -DR donor-recipient matching in high-risk patients who had no lymphocytotoxic antibodies.
After three years of patient follow up, CCTS researchers found that patients who received corneal transplants with well-matched antigens did not fare significantly better compared to those with a poor match. Each patient group had similar rates of initial immune reactions, graft rejection, and graft failure due to rejection or other causes. However, the researchers did note that CCTS patients who were compatible with the donor's blood type had a better outcome compared to unmatched patients.
In short, CCTS data indicated that matching patient and donor blood types (combined with treating patients with high-dose topical steroids after surgery) may be potentially effective in improving high-risk corneal transplantation. This had significant impact as these two inexpensive strategies were much more economical compared to more expensive donor-recipient tissue typing.
Cornea Donor Study
The Cornea Donor Study (CDS) was a prospective cohort study to determine whether the graft-failure rate is the same when using corneal tissue from donors older than 65 years old compared with tissue from younger donors. Through July 2002, the study enrolled 1,101 patients between the ages of 40 years to 80 years, with corneal disease associated with endothelial dysfunction. Approximately one-half of the patients received a cornea from donors older than 65 years and one-half from donors younger than 65 years.
The CDS also assessed the relationship between donor/recipient ABO blood type compatibility and graft failure due to rejection, because the CCTS indicated that matching patient and donor blood types was potentially an effective strategy. Lastly, the CDS assessed corneal endothelial cell density as an indicator of the health of the cornea and as a surrogate outcome measure.
The CDS was conceived in 1997 when a real threat to the donor pool was present based on the concerns of an emerging HIV and hepatitis epidemic, the impact of refractive surgery procedures, an aging population with an increase in the number of Fuchs' endothelial corneal dystrophy (FECD) and pseudophakic bullous keratopathy (PBK) cases in the United States, and a worldwide demand for corneal tissue. This simple, but powerful, evidence-based prospective, masked clinical trial showed 86 percent graft success following penetrating keratoplasty for endothelial dysfunction conditions at five years in both the 65 year old to 75 year old donor group and in the younger than 65 years old donor group. The study demonstrated that older donor tissue (greater than 65 years old to 75 years old) is as suitable and successful when used in keratoplasty as younger tissue is for the management of FECD and PBK cases.
The study had significant public health impact because the use of older donor tissue has resulted in opening up a whole new pool of tissue that would not have been used by many surgeons in the United States.
The CDS also has shown that other donor factors such as method of retrieval, processing factors, timing of the donor cornea usage (Sugar et al, October 2009), and ABO incompatibility have no effect on graft survival five years postoperatively (Dunn et al, 2009). On the other hand, the risk for graft failure was approximately four-fold higher in eyes that had pseudophakic/aphakic corneal edema than in eyes with FECD (Sugar et al, June 2009).
Additionally, prior glaucoma surgery and/or preoperative glaucoma medication use also substantially increased the graft failure rate (Sugar et al, June 2009).
Endothelial cell density (ECD) was assessed in a subset of subjects in an ancillary study of the CDS, the Specular Microscopy Ancillary Study (SMAS). The CDS noted a slight association between increasing donor age and greater post-PKP corneal endothelial cell loss by five years, even though graft success was the same.
Cornea Preservation Time Study
The Effect of Corneal Preservation Time on Long-Term Graft Success, or Cornea Preservation Time Study (CPTS) for short, is the most recent study funded by the NEI. The CPTS study is now enrolling up to 1,330 patients across about 35 sites in the United States.
Several factors that had the potential to impact the donor supply in 1997 still remain today. New issues including emerging infections also have arisen, which may impact the U.S. donor supply. One way to expand the U.S. donor pool is the routine domestic use of longer-preserved tissue. Currently, most surgeons request tissue that has been preserved seven days or less, even though the FDA has approved tissue to be stored in approved media for up to 14 days. The excess, predominantly longer-preserved tissue is being exported to the international community where the tissue is routinely transplanted after up to 14 days of storage.
The goals of the CPTS are to determine whether the three-year graft failure rate after endothelial keratoplasty (EK) performed with donor corneas that have a preservation time of eight to 14 days is non-inferior to the failure rate when donor corneas that have a preservation time of seven or fewer days are used (Figure 1). It will also determine whether the central corneal endothelial cell density three years after EK is related to preservation time.
Figure 1. Successful endothelial keratoplasty with a clear recipient stroma. COURTESY OF GEORGE ROSSENWASSER, MD.
Although other studies have been performed that indirectly examined the question of preservation time, the CPTS is the first prospective masked trial that is randomizing participant eyes on this basis. By and large, the previous studies on this topic have not found increasing preservation time to be associated with graft success or endothelial cell loss, although none of these studies were designed with preservation time as the primary variable of interest (Chang et al, 1996; Abbott et al, 1979; for a complete reference list visit www.clspectrum.com).
A lack of well-run studies on a preservation time of more than seven days has contributed to a bias against using corneal tissue beyond this time. If the CPTS determines that donor corneas preserved longer than seven days are non-inferior to those preserved seven days or less, this bias will be addressed, which will facilitate an increase in the U.S. domestic donor supply.
Patients and practitioners interested in enrolling in the study can visit www.clinicaltrials.gov (NCT 01537393) to find recruiting locations. CLS
For references, please visit www.clspectrum.com/references.asp and click on document #199.
|Dr. Szczotka-Flynn is the director of the Coordinating Center for the CPTS Study. She is also a professor in the Departments of Ophthalmology & Visual Sciences and Epidemiology & Biostatistics at Case Western Reserve University and senior optometrist at University Hospitals Case Medical Center Eye Institute. She has received research funding from Alcon, CooperVision, and Vistakon.|