Verteporfin photodynamic therapy for neovascular age-related ...

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66 Discussion of resultsStrengths and weaknesses of the verteporfin photodynamictherapy cohort studyDespite its observational nature, the VPDT cohort study has many strengths. These includeits size, pragmatic nature, and systematic collection of standardised data on acuity and lesioncharacteristics. This was the largest study of its kind to date, giving new insights into the HRQoLof people with nAMD and new data that will be pivotal to future studies of effectiveness inthis population. Many aspects of the data collected in this study were robust. Protocol-basedBCVA and CS were measured and HRQoL instruments administered at multiple time points,which allowed us to investigate in detail the relationships between clinical measures of visionand HRQoL. The large sample gave us reasonable power to test secondary hypotheses about theshape of the relationships and adaptation to vision loss over a 2-year period, even though theproportion of patients with data for more than three visits was small.The VPDT cohort study was the first with concurrent concurrent collection of data on HRQoLand patient-level data on HSS resource use, and, hence, first to have undertaken a systematicCEA using data acquired during treatment rather than data stipulated by a trial protocol. OurCEA also tackled three major methodological concerns not previously addressed in CEAs ofinterventions for nAMD. Thus, our work extends the literature on the costs and cost-effectivenessof interventions for nAMD, and its findings will assist future CEA.Set against these strengths, there were a number of limitations. These include the observationalnature of the study, the loss to follow-up of large proportions of the original sample, missingdata and the lack of a BSC comparison group of current relevance. There were major logisticalchallenges in establishing the study, which were discussed at a project review meeting about18 months after the contract for the study started; key observations and recommendations fromthis meeting are set out in Appendix 3.Unlike the pivotal trials, in which almost all patients were followed up for 24 months, 3,4,30 abouthalf of the patients included in our analyses did not have 1-year follow-up. Because poor dataquality is a well-recognised limitation of observational studies, we undertook computeriseddata validation checks on an on-going basis and when compiling the final data set. We checkedwhether or not data were missing for some visits by (a) matching records from paper andelectronic systems for collecting BCVA and (b) requesting that centres should check explicitlywhether or not additional visits had taken place for selected patients. The results from thesechecks implied that data had been submitted for > 95% of completed visits.The exact reasons for loss to follow-up are not known. We attempted to collect informationabout reasons for completing a treatment episode early or for patients being lost to follow-up,but participating centres did not report reasons reliably. Anecdotally, we became aware thatsome hospitals had a policy of not rebooking appointments for patients who missed a visit,and some ophthalmologists were put under pressure to discharge patients who did not requireactive treatment rather than to continue to review them. The context for these policies was theextremely overstretched nature of macular clinics. It should be remembered that providingVPDT required hospitals to make regular appointments (up to four per year) to review a largenumber of patients who had previously had fewer than one; reviewing a patient required FA and,if treatment was required, administration of VPDT. Irrespective of whether or not funding wasavailable to pay for these resources, the expert workforce needed to provide VPDT could not beexpanded rapidly.
DOI: 10.3310/hta16060Health Technology Assessment 2012; Vol. 16: No. 667Patients who were not followed lost the opportunity to be retreated if reactivation occurred; thiscould have led to worse BCVA outcomes with treatment in everyday practice than with treatmentin the licensing trials. However, the BCVA outcome in the VPDT cohort study was generallysimilar to that observed in the treatment arm of the TAP trials.The loss to follow-up introduced uncertainty to the data analyses, which was taken into accountby using a mixed regression model to predict BCVA at 1 year in different subgroups. Thisapproach allows all of the available data to be modelled but does not prevent attrition bias.We observed that patients who were lost to follow-up tended to have poorer BCVA at baseline(data available from the authors). Because follow-up data were more likely to be missing withincreasing duration after first treatment, and patients with a poor outcome were more likely tobe lost to follow-up, the model may have tended to underestimate deterioration in BCVA overtime. The regression model for BCVA trajectory assumed that BCVA deteriorated steadily (on theprinciples of parsimony and ‘best fit’); this assumption is unlikely to be valid when BCVA is poorbecause the neovascular process burns out, causing a ‘floor’ effect. Attrition bias and a floor effectwould have affected the results in opposite directions. Consequently, it is uncertain whether ornot the BCVA deterioration over time in the study was truly similar to that observed in the TAPtrials or underestimated because of selective attrition.Although loss to follow-up is a scientific limitation, our experience also demonstrates vividly thedifficulties associated with follow-up when treatments requiring multiple visits over an extendedperiod of time in an older age group are introduced into routine clinical practice. Such dataare invaluable to health service planners and are rarely available. We believe that patients andophthalmologists became disheartened with eyes that experienced deterioration of vision duringtreatment and follow-up, causing treatment to be discontinued before the recommended timepoint of 2 years. We did not attempt to predict outcome at 2 years because the data were sparse.A further limitation of the study was the inability to classify 40% of the lesions at baselinewith respect to TAP eligibility (eyes classified as UNC), either because an angiogram was notsubmitted or because the submitted angiogram could not be graded. This group was retainedin the model and had parameter estimates which tended to lie between those for EFT and IFTgroups and between those for predominantly and minimally classic lesions. Thus, there was noreason to believe that these eyes represented a biased selection with respect to eligibility for theTAP trials or their lesion composition.In the CEA, we were unable to use a direct control group, instead we relied on the controlgroup in the TAP trials. Extrapolating relative effects across different populations is potentiallyproblematic; for example, trials often report different estimates of effect from those given byobservational studies. 58 Nevertheless, in this cohort study, BCVA at first treatment and at 1 and2 years were similar to the predominantly classic subgroup studied in the TAP trials.InterpretationComparison of outcomes in the verteporfin photodynamic therapy cohortstudy versus TAPVisual acuity outcomeThe effectiveness of VPDT in reducing deterioration in BCVA in the context of RCTs has beenconfirmed by a systematic review in which the chosen outcomes were step changes in BCVAover 24 months, for example loss of three or more lines of visual acuity. 59 VPDT was estimated toreduce the risk of losing more than three lines by 20% (risk ratio 0.80, 95% CI 0.73 to 0.88).© Queen’s Printer and Controller of HMSO 2012. This work was produced by Reeves et al. under the terms of a commissioning contract issued by theSecretary of State for Health.
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DOI: 10.3310/hta16060Health Technol
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xExecutive summaryretreat on criter
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xiiExecutive summaryof data, with i
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2 Introductionon-going or new clini
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4 Introductionof VPDT in routine cl
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Page 34 and 35: 20 Key changes to the protocolThese
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Page 52 and 53: 38 Results (1) - study cohortTABLE
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Page 82 and 83: 68 Discussion of resultsThe VPDT st
Page 84 and 85: 70 Discussion of resultsOur analyse
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Page 88 and 89: 74 Discussion of resultsVPDT. It is
Page 98 and 99: 84 References16. Stelmack J. Qualit
Page 100 and 101: 86 References49. Guymer RH, Chiu AW
Page 102 and 103: 88 References83. Margrain TH. Minim
Page 104 and 105: 90 Appendix 1THE VERTEPORFIN PHOTOD
Page 106 and 107: 92 Appendix 11. Overview of Manual
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116 Appendix 1level of benefit from
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122 Appendix 112. Data issues12.1 D
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128 Appendix 1Barnes RM, Gee L, Tay
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130 Appendix 1Appendix 1: Classifyi
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132 Appendix 1Liverpool re-treatmen
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136 Appendix 1Has your photographer
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138 Appendix 1There are many differ
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140 Appendix 1testing on vision tes
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144 Appendix 1College of Ophthalmol
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146 Appendix 1Appendix 5:Protocol f
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152 Appendix 1Appendix 6:Protocol f
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158 Appendix 1
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170 Appendix 1Dos and Don’tsDosDo
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176 Appendix 1ADVERSE REACTION AND
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180 Appendix 1Ophthalmologistrespon
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FeedbackThe HTA programme and the a
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