Zdenka Haskova

Vascular Safety of Ranibizumab in Patients With Diabetic Macular Edema: A Pooled Analysis of Patient-Level Data From Randomized Clinical Trials

Importance Patients with diabetic macular edema (DME) are at high risk of vascular complications, including stroke and myocardial infarction (MI). Concerns have been raised that intravitreal dosing of vascular endothelial growth factor inhibitors in DME could be associated with an increase in cardiovascular and cerebrovascular adverse events. Objective To evaluate the cardiovascular and cerebrovascular safety of ranibizumab, 0.5 mg and 0.3 mg, compared with sham with and without laser in DME. Data Sources Patient-level data from 6 randomized, double-masked, sham- and laser-controlled clinical trials. Study Selection Company-sponsored (Genentech or Novartis) studies in DME completed as of December 31, 2013. Data Extraction and Synthesis Pairwise comparisons (ranibizumab, 0.5 mg, vs sham and laser; ranibizumab, 0.3 mg, vs sham) were performed using Cox proportional hazard regression (hazard ratios, 95% CIs) and rates per 100 person-years. Data analysis was conducted from June 1 to July 15, 2015. Main Outcomes and Measures Standardized Medical Dictionary for Regulatory Activities queries and extended searches were prospectively defined to identify relevant safety end points, including arterial thromboembolic events, MI, stroke or transient ischemic attack, vascular deaths, and major vascular events as defined by the Antiplatelet Trialists’ Collaboration (APTC). Results Overall, 936 patients were treated with ranibizumab, 0.5 mg; 250 patients with ranibizumab, 0.3 mg; and 581 patients with sham/laser. The hazard ratios associated with all pairwise comparisons included 1 for all key cardiovascular and cerebrovascular safety end points. For ranibizumab, 0.5 mg, vs sham/laser and ranibizumab, 0.3 mg, vs sham, the hazard ratios were, respectively, arterial thromboembolic events, 1.05 (95% CI, 0.66-1.68) and 0.78 (95% CI, 0.43-1.40); MI, 0.84 (95% CI, 0.41-1.72) and 0.94 (95% CI, 0.43-2.06); stroke or transient ischemic attack, 0.94 (95% CI, 0.44-1.99) and 0.53 (95% CI, 0.19-1.42); stroke (excluding transient ischemic attack), 1.63 (95% CI, 0.65-4.07) and 0.59 (95% CI, 0.14-2.46); vascular death, 2.17 (95% CI, 0.57-8.29) and 2.51 (95% CI, 0.49-12.94); and APTC-defined events, 1.09 (95% CI, 0.63-1.88) and 1.00 (95% CI, 0.51-1.96). Conclusions and Relevance This pooled analysis includes 1 of the largest patient-level data sets on treatment of DME with ranibizumab. Although still underpowered to detect small differences for infrequent events, such as stroke, the findings suggest that intravitreous ranibizumab does not increase the risk of systemic vascular events. However, uncertainty remains for patients with DME who are at high risk for vascular disease and were not included in these trials.

Vision-related functional burden of diabetic retinopathy across severity levels in the United States

Importance Among adults with diabetes in the United States, severe forms of diabetic retinopathy (DR) are significantly associated with a greater vision-related functional burden. Objective To assess the functional burden of DR across severity levels in the United States. Design, Setting, and Participants This cross-sectional study was based on 1004 participants 40 years or older with diabetes and valid ocular and sociodemographic outcomes in the National Health and Nutrition Examination Surveys (NHANES) (2005-2006 and 2007-2008). Diabetic retinopathy was based on fundus photograph grading, using the Early Treatment Diabetic Retinopathy Study severity scale. The analysis was performed from October 15, 2016, to June 15, 2017. Main Outcomes and Measures Functional difficulties secondary to vision were assessed during a household questionnaire in which participants self-reported difficulty with reading, visuospatial tasks (ie, close-up work or finding things on a crowded shelf), mobility (ie, walking down steps, stairs, or curbs), and driving. The main outcome measure was vision-related functional burden, which was defined as present for individuals reporting moderate or greater difficulty in any of the aforementioned tasks. Results Of the 1004 persons with diabetes analyzed for this study (mean age, 65.7 years [95% CI, 64.0-67.3 years]; 51.1% male [95% CI, 47.1-55.2] and 48.9% female [95% CI, 44.8-52.9]), the prevalence was 72.3% for no retinopathy, 25.4% for mild and moderate nonproliferative diabetic retinopathy (NPDR), and 2.3% for severe NPDR or proliferative diabetic retinopathy (PDR). The prevalence of vision-related functional burden was 20.2% (95% CI, 16.3%-24.1%) for those with no retinopathy, 20.4% (95% CI, 15.3%-27.8%) for those with mild and moderate NPDR, and 48.5% (95% CI, 25.6%-71.5%) for those with severe NPDR or PDR (P = .02). In multivariable analysis, the odds of vision-related functional burden were significantly greater among those with severe NPDR or PDR relative to those with no retinopathy (adjusted odds ratio [aOR], 3.59; 95% CI, 1.29-10.05; P = .02). Those with severe NPDR or PDR did not have a statistically significant greater odds of vision-related functional burden than did those with mild or moderate NPDR (aOR, 2.70; 95% CI, 0.93-7.78; P = .07). Conclusions and Relevance Among US adults with diabetes, approximately half of those with severe NPDR or PDR had difficulty with at least one visual function task. Moreover, vision-related functional burden was significantly greater among those with severe NPDR or PDR than among those with no retinopathy. These data suggest the importance of preventing severe forms of DR to mitigate the vision-related functional burden among US adults with diabetes. Future studies should complement our study by assessing the association of worsening retinopathy with objectively measured functional outcomes.

Usability of the Ranibizumab 0.5-mg Prefilled Syringe: Human Factors Studies to Evaluate Critical Task Completion by Healthcare Professionals

Purpose: A ranibizumab prefilled syringe (PFS) has been approved by the U.S. Food and Drug Administration. Here we evaluate the use of the ranibizumab PFS for intravitreal injection by assessing whether the PFS enables healthcare providers to successfully prepare and administer an injection without prior training. Design: Simulated-use and actual-use human factors usability studies. Participants: Retina specialists and ophthalmic medical personnel. Methods: In a simulated-use summative usability study, retina specialists (n = 15) and ophthalmic medical personnel (n = 15) prepared the ranibizumab PFS and performed injections into a model eye. In an actual-use formative usability study (ClinicalTrials.gov identifier: NCT02698566), three assistants and three retina specialists prepared the PFS and performed intravitreal injections, respectively, in study eyes of patients with retinal diseases (n = 35). Main Outcome Measures: Twelve tasks specific to the unpacking, preparing, and properly administering the PFS for intravitreal injection were evaluated by a study assessor. Task performances were evaluated for use errors, close calls, and operational difficulties. Post-injection subjective user evaluations were performed to assess ease of use. Results: All participants successfully performed all essential and safety-critical tasks without use error in both the simulated-use and actual-use human factors usability studies. The majority of participants rated the tasks required to use the ranibizumab PFS as “Easy” or “Very Easy.” Conclusions: Both the simulated-use and actual-use usability studies yielded consistent data, showing that healthcare professionals are able to use the ranibizumab PFS by successfully performing all critical tasks involved in preparing and delivering an intravitreal injection. The simulated-use usability testing was sufficiently realistic and representative of real-world use, and was appropriate and preferred over actual-use usability testing for proper evaluation of the product user interface. LAY ABSTRACT: Ranibizumab is approved in the United States to treat various eye conditions, including neovascular (wet) age-related macular degeneration, macular edema following retinal vein occlusion, diabetic macular edema, diabetic retinopathy, and myopic choroidal neovascularization. It is administered as an injection into the eye once a month, and is available in a vial from which medication needs to be withdrawn using a standard syringe with a 19-gauge filter needle. The filter needle is then replaced by a smaller gauge needle for the intravitreal injection. The recent U.S. Food and Drug Administration approval of a 0.5 mg ranibizumab prefilled syringe eliminates the need for withdrawing medication from a vial and changing needles prior to use. The studies described in this report assessed the usability of the ranibizumab prefilled syringe by retina specialists and ophthalmic medical personnel in simulated- and actual-use settings. Twelve tasks that included unpacking, preparing, and properly administering the prefilled syringe for intravitreal injection were evaluated by a study assessor. Task performances were evaluated for use errors, close calls, and operational difficulties. Participants successfully performed all the tasks without any critical errors in both simulated-use and actual-use human factors usability studies, and most participants found the syringe to be “Easy” or “Very Easy” to use.

Self-reported healthcare utilization by adults with diabetic retinopathy in the United States

ABSTRACT Purpose: To assess healthcare utilization patterns across diabetic retinopathy (DR) severity levels in the United States (US). Design: Cross-sectional study of 699 adults, participating in the 2005–2008 National Health and Nutritional Examination Surveys. Methods: Diagnosis of DR was based on fundus photographs and categorized as: (1) no DR; (2) mild/moderate nonproliferative DR (NPDR); and (3) severe NPDR/proliferative DR (PDR). Healthcare utilization patterns were assessed during a household questionnaire where survey participants self-reported: (1) awareness that diabetes had affected their eyes; (2) pupil-dilation during the past year; and (3) visits to a diabetes education/nutrition specialist during the past year. Results: Among adults with self-reported diabetes, the proportion of those that were aware that diabetes had affected their eye was 15.3% [95% confidence interval (C.I.)] 10.9–19.6%), 21.7% (95% C.I. 14.6–28.7%), and 81.5% (95% C.I. 66.5–96.5%) across those with no retinopathy, mild/moderate NPDR, and severe NPDR/PDR, respectively (p < 0.01). The utilization of a diabetic education/nutrition specialist during the past year was 30.4% (95% C.I. 24.8–36.0%), 31.8% (95% C.I 23.4–40.2%), and 55.9% (95% C.I. 32.3–79.6%) across those with no retinopathy, mild/moderate NPDR, and severe NPDR/PDR, respectively (p = 0.13). Pupil dilation within the past year was 62.2% (95% C.I. 56.3–68.1%), 62.1% (95% C.I. 53.4–70.8%), and 93.8% (95% C.I. 87.3–100.0%) across those with no DR, mild/moderate NPDR, and severe NPDR/PDR, respectively (p = 0.01). Conclusions: Adults with diabetes in the United States, even those with the most severe forms of DR, do not fully utilize healthcare services for diabetic eye disease. Future studies should aim to address barriers to appropriate diabetes care.