To describe the rates of myocardial infarction (MI), stroke, and mortality in patients who have treatment with intravitreal anti–vascular endothelial growth factor (anti-VEGF) injections for age-related macular degeneration (AMD).
A retrospective population linkage study.
We identified patients aged 40 years and above who received treatment with intravitreal anti-VEGF injections for AMD from January 1, 2008 to December 31, 2011 at the Singapore National Eye Centre. We used a national record linkage database to identify patients who developed MI, stroke, and all-cause mortality after the first injection, excluding those with previous MI or stroke at baseline from the respective analysis. We compared rates of MI, stroke, and mortality to that of the total Singapore population.
A total of 1182 individuals had an intravitreal anti-VEGF injection included in this analysis, with the majority receiving bevacizumab (n = 1011). Overall, 19 patients developed MI, 16 developed stroke, and there were 43 mortalities, giving an age-adjusted incidence rate of 350.2 per 100 000 person-years for MI, 299.3 per 100 000 person-years for stroke, and 778.9 per 100 000 person-years for mortality. This is comparable to the weighted incidence rates of the Singapore population (427.1 per 100 000 person-years for MI, 340.4 per 100 000 person-years for stroke, and 921.3 per 100 000 person-years for mortality).
The incidence rate of MI, stroke, and death in this cohort of AMD patients treated with anti-VEGF was low, and was not significantly higher than the age-adjusted incidence rate of these events in the Singapore population.
Intravitreal anti–vascular endothelial growth factor (VEGF) treatment has revolutionized the management of major retinal diseases, including age-related macular degeneration (AMD), diabetic macular edema, and retinal vein occlusion. While reported complication rates have been low, there are lingering concerns over the potential systemic side effects of anti-VEGF therapy, particularly with regard to the potential risk of cardiovascular and thromboembolic events. Of the 3 most commonly used anti-VEGF agents, most major clinical trials on ranibizumab or aflibercept have not found significant signals in these events. There are, however, fewer studies on the safety of bevacizumab, a full-length monoclonal antibody structure with longer half-life, with the fragment crystallizable portion of the molecule thought to increase systemic exposure. In this regard, several studies have demonstrated reduced systemic VEGF levels in patients receiving intravitreal anti-VEGF, but the systemic effect appears to be most obvious with bevacizumab and lowest with ranibizumab. Another line of evidence came from studies that used Medicare case records. Gower and associates reported increased risk of stroke and mortality in patients receiving bevacizumab as compared to ranibizumab (Gower EW, et al. IOVS 2011; 52:ARVO E-Abstract 6644). In the CATT study, the 2-year results demonstrated higher adverse event rates in patients treated with bevacizumab as compared to those treated with ranibizumab. Other studies, however, have not found bevacizumab to confer an increased risk of systemic side effects.
In this study, we report the incidence of myocardial infarction (MI), stroke, and death from any cause among individuals who have been treated with intravitreal anti-VEGF therapy for AMD at a major tertiary eye hospital in Singapore. We compared the rates of these events with the national population data.
This is a population linkage study that used the anti-VEGF database at the Singapore National Eye Center and the National Registry of Diseases Office of Singapore. The Singapore National Eye Center is the largest eye department in Singapore, managing more than 50% of outpatient ophthalmology visits and surgery in the country. Approval for this study was obtained from the Singhealth Centralised Institutional Review Board prior to the start of the research. Further, we obtained approval from the Ministry of Health of Singapore for accessing the National Registry of Diseases Office database.
We identified all AMD patients who were Singapore citizens or permanent residents who received treatment with intravitreal anti-VEGF over a 4-year period from January 1, 2008 to December 31, 2011 from the center. We then matched the patients’ unique national identity number (National Registration Identity Card) against the National Registry of Diseases Office database, which recorded all incident MI, stroke, and deaths after the first injection. Patients with history of MI or stroke before the first anti-VEGF therapy were excluded. Patients below the age of 40 years at the initial treatment were also excluded from this study.
Assessment of Incident Adverse Events
Incident MI, stroke, and death from all causes that occurred after a patient’s first anti-VEGF injection during the study period from January 1, 2008 to December 31, 2011 was obtained by linking the cases that received intravitreal anti-VEGF for AMD to the database registered by National Registry of Diseases Office. The register electronically captures new cases of these events via the unique national identity number. Incident cases are identified by the Registry through multiple sources, including notifications by healthcare professionals, hospital data for cases admitted to hospitals, and necropsy, radiology, and laboratory reports. These national data have been published in the official website of the Registry. The main source of data on diagnosis was from electronic medical records and hard copy hospital in-patient case notes. In these cases, the diagnosis was confirmed by a team of trained nurses who reviewed the relevant electronic or hard copy documents before entering into the national registry. Where available, radiology reports were also examined to validate the diagnosis for stroke in patients who had neuroimaging. For patients who died before arriving at the emergency department or in the emergency department, the diagnosis of MI in the majority of cases was validated by necropsy listing. The Registry manages the database with quality assurance to ensure that all data collected for the registries have been validated and are properly anonymized before analysis. We have previously used the database for other studies.
MI was defined as either (1) definitive or clinical MI; or (2) death cases signed up by pathologists or physicians as MI, with or without necropsy done. Incident MI was identified by linkage with a subset of the National Registry of Diseases Office database: the Singapore Myocardial Infarction Registry, which captures all MI diagnosed and coded with International Classification of Diseases 9th Revision (ICD-9) 410 in all hospitals. Stroke data were obtained from another subset of the National Registry of Diseases Office database: the Singapore Stroke Registry, which used ICD-9 codes 430–433 and 436–437, while excluding 432.0, 432.1, and 435 (extradural hemorrhage, subdural hemorrhage, and transient cerebral ischemia, respectively).
Mean (standard deviation [SD]) for continuous variables or number (percentages) of participants for categorical variables were used to describe characteristics of the study population. Independent t test or χ 2 were used to examine differences in baseline characteristics between subjects that experience stroke/MI/mortality and those without. Cox proportional hazards regression was used to examine the relation of number and type of injections (bevacizumab or ranibizumab) for age/sex-adjusted models. Proportional hazard assumption was confirmed for all predictors with Schoenfeld’s residuals ( P value >.05).
We used direct method to calculate age-standardized and sex-specific age-standardized incidence rates (IR) via the R function age-adjust direct in the package epitools based on the following: agestandardizedIR=∑jRjwjagestandardizedIR=∑jRjwj
a g e s t a n d a r d i z e d I R = ∑ j R j w j
, where RjRj
denotes the incidence in the j th age interval and Nj
denotes the number of people in the j th age interval of the standard population. The standard weights for the j th age interval are written as wj=Nj∑iNi.
w j = N j ∑ i N i .
. We used the 2011 Singapore Population as the standard population for comparison. Specifically, we used the Singapore Male population (consisting of 48.8% of the total Singapore population) for standardizing the male participants, and the Singapore Female population (consisting of 52.2% of the total Singapore population) for standardizing the female participants. Age strata-specific (5-year age group) IR were calculated by weighing the proportions of the corresponding age strata in the population census. A Gamma (γ) confidence interval (CI) was used to estimates CIs.
We regarded P values of <.05 from 2-sided tests to indicate statistical significance. Statistical analyses were performed using both R version 2.15.3 ( R Development Core Team, 2013, Vienna, Austria) and STATA version 12.