Risk of stroke associated with intravitreal ranibizumab injections in age-related macular degeneration: a nationwide case-crossover study

Abstract

Objective To evaluate the risk of stroke associated with intravitreal ranibizumab in age-related macular degeneration (AMD). Methods A nationwide retrospective case-crossover study was performed using data from the Korean National Health Insurance Service (KNHIS) database, which included patients with exudative AMD in South Korea (n = 41,860). The index date was the date of hospitalization for stroke. We defined the case period as 60 days and four control periods before the index date. A pharmacy prescription database was searched for ranibizumab use during the case and control periods. We calculated adjusted odds ratios (ORs) and 95% confidence intervals (CIs) with a conditional logistic regression model. Results A total of 865 patients with AMD and incident stroke were included. Of all the patients, 12.02% had been treated during the preceding 60-day case period, compared with 9.25-10.29% during control periods. The adjusted OR of stroke associated with intravitreal ranibizumab during the case period was 1.285 (95% CI 0.979-1.686) (p = 0.07). In the subgroup analysis, the risk of hemorrhagic stroke had an OR of 2.252 (95% CI 1.068-4.749, p = 0.033). Further analyses based on patient gender, age, and different risk periods of 15 and 30 days yielded no increase in the risk of stroke associated with intravitreal ranibizumab. Conclusions This case-crossover analysis revealed no evidence of increased risk of hospitalization for stroke within 60 days of intravitreal ranibizumab injection in AMD patients. A secondary analysis indicated the possibility of an increased risk of hemorrhagic stroke, with borderline significance. Further research is needed regarding the underlying biological mechanisms and drug safety.

Risk analysis for patients with arterial thromboembolic events after intravitreal ranibizumab or aflibercept injections

“…Patients with chronic retinal diseases require multiple injections over a certain period, and the risk of major ATEs must be considered in patients with systemic diseases. Although some studies demonstrated that intravitreal anti-VEGF agents did not increase the risks of ATEs comparing to the non-IVI groups, patients with cardiovascular diseases, or patients with an AMI/IS history were excluded in those studies 41 , 42 , which the included cases were less than those in real world situation. While some clinical trials demonstrated that IVI did not increase the risk of ATEs compared to the non-IVI groups, patients with cardiovascular diseases, or recent AI or IS were excluded from previous clinical trials 24 , 41 , 42 .…”

“…Although some studies demonstrated that intravitreal anti-VEGF agents did not increase the risks of ATEs comparing to the non-IVI groups, patients with cardiovascular diseases, or patients with an AMI/IS history were excluded in those studies 41 , 42 , which the included cases were less than those in real world situation. While some clinical trials demonstrated that IVI did not increase the risk of ATEs compared to the non-IVI groups, patients with cardiovascular diseases, or recent AI or IS were excluded from previous clinical trials 24 , 41 , 42 . Malony et al evaluated the risk of ATEs in DME patients with prior strokes or AMI; the risk of ATEs was not increased in these patients 43 .…”

Individual trigger factors for hemorrhagic stroke: Evidence from case-crossover and self-controlled case series studies

“…Two studies were conducted in Korea to determine the association between ranibizumab injection and HS in patients with age-related macular degeneration. 23,24 The CCOS showed that ranibizumab treatment was associated with the onset of HS within 2 months (OR, 2.25; 95% CI, 1.07-4.75), 23 while the SCCS did not report a positive result (OR, 1.05; 95% CI, 0.80-1.38). 24 Hsu et al 25 studied 77,797 Chinese patients and found that the use of short-acting antihypertensive drugs, such as nifedipine, labetalol, and captopril, was associated with the risk of developing ICH (ORs range, 1.99-3.24).…”

“…Sixteen studies examined whether medication use could trigger the onset of HS, including non-steroidal anti-inflammatory drugs (NSAIDs), antiplatelets, anticoagulants, ranibizumab, mood stabilizers/antipsychotics, antihypertensive and hypoglycemic drugs, hospitalization for psychiatric disorders, and percutaneous coronary intervention. [13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28] Among them, 14 studies were CCOSs and two were SCCSs (Supplemental Table S1 and Figure S1).…”

Risk of Myocardial Infarction, Stroke, or Death in New Users of Intravitreal Aflibercept Versus Ranibizumab: A Nationwide Cohort Study

“…The risk of thromboembolic events has not been established in randomized clinical trials, which are generally based on selected populations and are not sufficiently powered to detect rare side effects [4]. The vast majority of observational studies conducted on the topic have found that IVT anti-VEGF treatment is safe [5][6][7][8][9][10][11][12][13][14][15]. However, most of these studies lacked the statistical power to assess the risk in subgroups of patients with risk factors and may have been subject to bias, particularly related to the choice of a comparative group not exposed to IVT anti-VEGF.…”