Anti-vascular endothelial growth factor (anti-VEGF) drugs are used to treat eye diseases, and are administered directly into the eyes. Doctors have recently become aware that anti-VEGF administered into the eye might have side effects in other parts of the body. These side effects include high blood pressure, urine protein leak and/or decline in kidney function. Over time, these effects could lead to kidney failure, requiring dialysis or a kidney transplant. However, doctors do not yet know how common or severe these problems might be.
We will use electronic health records from GP practices linked to hospital records to determine whether anti-VEGF administered directly into the eye are associated with side effects in other parts of the body in patients with eye disease. We will also assess whether anti-VEGF administered into the eye increases the risk of heart problems and/or death. We think it is important to inform patients about the risks of anti-VEGF treatment (especially kidney failure) as well as the benefits (preventing blindness) to inform decisions about their treatment. With help from our kidney and eye disease patient group, we will quantify these risks and summarise them in a way that is meaningful for patients. We will also use this information to inform doctors about how best to monitor patients who have been treated with anti-VEGF for eye disease.
Anti-vascular endothelial growth factor (anti-VEGF) drugs block the development of new blood vessels and are increasingly used through intravitreal injection to treat age-related macular degeneration, diabetic macular oedema and other eye diseases. There is known to be systemic absorption of anti-VEGF from intravitreal injection, and there are several case-reports of systemic side effects including development of proteinuria and decline in kidney function. Analysis of adverse events from the original clinical trials for ophthalmic indications shows a signal of harm but these trials were small, of limited duration and did not have adjudicated cardio-renal end points.
We will use data from the clinical practice research datalink (CPRD) linked to hospital episode statistics (HES) to carry out a cohort study and self-controlled risk interval study to measure the association between anti-VEGF intravitreal injections and kidney related adverse events. We will use two study populations: 1) people without diabetes who have anti-VEGF intravitreal injections (exposed) versus cataract surgery (comparator), and 2) people with diabetes who have anti-VEGF intravitreal injections (exposed) versus laser photocoagulation (comparator), exposure and comparator status will be determined through OPCS codes in linked HES data. The primary outcome will be ≥40% reduction in estimated glomerular filtration rate (eGFR) determined through blood tests in the primary care record. In the cohort study we will use a propensity score weighted Cox proportional hazards regression model. The self-controlled risk interval approach uses cases only. We will compare the risk of the outcome during the year after first anti-VEGF intravitreal injection to the risk in the year prior, using a conditional Poisson regression model.
We will provide definitive information to patients and clinicians about the potential benefits and risks of treatment, to develop adequate monitoring if needed, and to prompt consideration of whether further randomised trials of enhanced vascular prevention during treatment are needed.
Primary outcome: ≥40% reduction in estimated glomerular filtration rate (eGFR)
Secondary outcomes: progression of albuminuria stage (A0 to A1 or 2, or A1 to A2); change in slope of eGFR progression; kidney failure defined as dialysis or kidney transplantation; development of coded nephrotic syndrome; a new diagnosis of hypertension; atrial fibrillation/flutter; myocardial infarction; peripheral arterial ischaemia identified through coded revascularisation procedures or diagnosis of deep vein thrombosis (DVT) or pulmonary embolism (PE); ischaemic or haemorrhagic stroke; heart failure; cardiovascular death; all-cause mortality.
Control outcomes: diagnosis of herpes zoster; hip fracture
Laurie Tomlinson - Chief Investigator - London School of Hygiene & Tropical Medicine ( LSHTM )
Ruth Costello - Corresponding Applicant - London School of Hygiene & Tropical Medicine ( LSHTM )
Emily Herrett - Collaborator - London School of Hygiene & Tropical Medicine ( LSHTM )
Ian Douglas - Collaborator - London School of Hygiene & Tropical Medicine ( LSHTM )
John Buchan - Collaborator - London School of Hygiene & Tropical Medicine ( LSHTM )
Qing Wen - Collaborator - London School of Hygiene & Tropical Medicine ( LSHTM )
HES Admitted Patient Care;HES Outpatient;ONS Death Registration Data;Patient Level Index of Multiple Deprivation