Diagnostic role of head-up tilt test in patients with cough syncope.

AIMS: The aim of this study was to describe the head-up tilt (HUT) test and carotid sinus massage (CSM) responses, and the occurrence of syncope with coughing during HUT in a large cohort of patients. METHODS AND RESULTS: A total of 5133 HUT were retrospectively analysed to identify patients with cough syncope. Head-up tilt followed by CSM were performed. Patients were made to cough on two separate occasions in an attempt to reproduce typical clinical symptoms on HUT. Patients with cough syncope were compared with 29 age-matched control patients with syncope unrelated to coughing. A total of 29 patients (26 male, age 49 ± 14 years) with cough syncope were identified. Coughing during HUT reproduced typical prodromal symptoms of syncope in 16 (55%) patients and complete loss of consciousness in 2 (7%) patients, with a mean systolic blood pressure reduction of 45 ± 26 mmHg, and a mean increase in heart rate of 13 ± 8 b.p.m. No syncope or symptoms after coughing were observed in the control group. The HUT result was positive in 13 (48%) patients with the majority of positive HUT responses being vasodepressor (70% of positive HUT). Carotid sinus massage was performed in 18 patients being positive with a vasodepressor response causing mild pre-syncopal symptoms in only 1 patient. CONCLUSION: Syncope during coughing is a result of hypotension, rather than bradycardia. Coughing during HUT is a useful test in patients suspected to have cough syncope but in whom the history is not conclusive.

Multicenter Evaluation of Diagnostic Circulating Biomarkers to Detect Sight-Threatening Diabetic Retinopathy.

Importance: It is a global challenge to provide regular retinal screening for all people with diabetes to detect sight-threatening diabetic retinopathy (STDR). Objective: To determine if circulating biomarkers could be used to prioritize people with type 2 diabetes for retinal screening to detect STDR. Design, Setting, and Participants: This cross-sectional study collected data from October 22, 2018, to December 31, 2021. All laboratory staff were masked to the clinical diagnosis, assigned a study cohort, and provided with the database containing the clinical data. This was a multicenter study conducted in parallel in 3 outpatient ophthalmology clinics in the UK and 2 centers in India. Adults 40 years and older were categorized into 4 groups: (1) no history of diabetes, (2) type 2 diabetes of at least 5 years' duration with no evidence of DR, (3) nonproliferative DR with diabetic macular edema (DME), or (4) proliferative DR. STDR comprised groups 3 and 4. Exposures: Thirteen previously verified biomarkers were measured using enzyme-linked immunosorbent assay. Main Outcomes and Measures: Severity of DR and presence of DME were diagnosed using fundus photographs and optical coherence tomography. Weighted logistic regression and receiver operating characteristic curve analysis (ROC) were performed to identify biomarkers that discriminate STDR from no DR beyond the standard clinical parameters of age, disease duration, ethnicity (in the UK) and hemoglobin A1c. Results: A total of 538 participants (mean [SD] age, 60.8 [9.8] years; 319 men [59.3%]) were recruited into the study. A total of 264 participants (49.1%) were from India (group 1, 54 [20.5%]; group 2, 53 [20.1%]; group 3, 52 [19.7%]; group 4, 105 [39.8%]), and 274 participants (50.9%) were from the UK (group 1, 50 [18.2%]; group 2, 70 [25.5%]; group 3, 55 [20.1%]; group 4, 99 [36.1%]). ROC analysis (no DR vs STDR) showed that in addition to age, disease duration, ethnicity (in the UK) and hemoglobin A1c, inclusion of cystatin C had near-acceptable discrimination power in both countries (area under the receiver operating characteristic curve [AUC], 0.779; 95% CI, 0.700-0.857 in 215 patients in the UK with complete data; AUC, 0.696; 95% CI, 0.602-0.791 in 208 patients in India with complete data). Conclusions and Relevance: Results of this cross-sectional study suggest that serum cystatin C had good discrimination power in the UK and India. Circulating cystatin-C levels may be considered as a test to identify those who require prioritization for retinal screening for STDR.

Topographical Response of Retinal Neovascularization to Aflibercept or Panretinal Photocoagulation in Proliferative Diabetic Retinopathy: Post Hoc Analysis of the CLARITY Randomized Clinical Trial.

IMPORTANCE: Eyes with proliferative diabetic retinopathy have a variable response to treatment with panretinal photocoagulation (PRP) or anti-vascular endothelial growth factor agents. The location of neovascularization (NV) is associated with outcomes (eg, patients with disc NV [NVD] have poorer visual prognosis than those with NV elsewhere [NVE]). OBJECTIVE: To investigate the distribution of NV in patients with proliferative diabetic retinopathy and the topographical response of NV to treatment with aflibercept or PRP. DESIGN, SETTING, AND PARTICIPANTS: This post hoc analysis of the phase 2b randomized clinical single-masked multicenter noninferiority Clinical Efficacy and Mechanistic Evaluation of Aflibercept for Proliferative Diabetic Retinopathy (CLARITY) trial was conducted from November 1, 2019, to September 1, 2020, among 120 treatment-naive patients with proliferative diabetic retinopathy to evaluate the topography of NVD and NVE in 4 quadrants of the retina on color fundus photography at baseline and at 12 and 52 weeks after treatment. EXPOSURES: In the CLARITY trial, patients were randomized to receive intravitreal aflibercept (2 mg/0.05 mL at baseline, 4 weeks, and 8 weeks, and as needed from 12 weeks onward) or PRP (completed in initial fractionated sessions and then on an as-needed basis when reviewed every 8 weeks). MAIN OUTCOMES AND MEASURES: Main outcomes were per-retinal quadrant frequencies of NV at baseline and frequencies of patterns of regression, recurrence, and new occurrence at 12-week and 52-week unmasked follow-up. RESULTS: The study included 120 treatment-naive patients (75 men; mean [SD] age, 54.8 [14.6] years) with proliferative diabetic retinopathy (there was a 1:1 ratio of eyes to patients). At baseline, NVD with or without NVE was observed in 42 eyes (35.0%), and NVE only was found in 78 eyes (65.0%); NVE had a predilection for the nasal quadrant (64 [53.3%]). Rates of regression with treatment were higher among eyes with NVE (89 of 102 [87.3%]) compared with eyes with NVD (23 of 43 [53.5%]) by 52 weeks, with NVD being more resistant to either treatment with higher rates of persistence than NVE (20 of 39 [51.3%] vs 29 of 100 [29.0%]). Considering NVE, the regression rate in the temporal quadrant was lowest (32 of 42 [76.2%]). Eyes treated with aflibercept showed higher rates of regression of NVE compared with those treated with PRP (50 of 52 [96.2%] vs 39 of 50 [78.0%]; difference, 18.2% [95% CI, 5.5%-30.8%]; P = .01), but no difference was found for NVD (11 of 17 [64.7%] vs 12 of 26 [46.2%]; difference, 18.6% [95% CI, -11.2% to 48.3%]; P = .23). CONCLUSIONS AND RELEVANCE: This post hoc analysis found that NVD is less frequent but is associated with more resistance to currently available treatments than NVE. Aflibercept was superior to PRP for treating NVE, but neither treatment was particularly effective against NVD by 52 weeks. Future treatments are needed to better target NVD, which has poorer visual prognosis. TRIAL REGISTRATION: isrctn.org Identifier: ISRCTN32207582.

Evaluation of real-world early response of DMO to aflibercept therapy to inform future clinical trial design of novel investigational agents.

New clinical trials for diabetic macular oedema (DMO) are being designed to prove superiority over aflibercept when this agent is already very effective in improving visual acuity (VA) and DMO. The aim of this study was to determine the optimal inclusion-exclusion criteria for trials to aim for superiority in visual outcomes with newer agents. As Phase 1 studies are short duration, we aimed to evaluate the early response of aflibercept in a real-world cohort initiated on monthly aflibercept for 3 consecutive injections and observed the effects at 4 months. The sub-optimal responders were pre-defined based on different cut-offs for VA and central sub-field thickness (CST). 200 patients with treatment naïve DMO treated with 3 loading doses of aflibercept were included in the study. We found that those presenting with baseline VA of 35-54 ETDRS letters (n = 43) had higher proportion of sub-optimal responders compared to other categories (p < 0.001). Patients with baseline CST of less than 400 µm (n = 96) responded less well functionally and anatomically to loading dose than eyes with baseline CST of 400 µm or more (n = 104, p = 0.02), indicating that eyes with CST ≥ 400 µm is another inclusion criteria. There was minimal correlation between change in CST and change in VA at 4 months (r = - 0.27), suggesting that both these inclusion criteria are non-exclusive. However, for maximal efficacy, patients that meet both these inclusion criteria are more likely to show benefit from an alternative intervention. New trials should aim to include patients with treatment naïve DMO with VA between 35-54 letters and CST of 400 µm or more when aflibercept is used as the comparator.