Ophthalmic Surgery, Lasers and Imaging Retina

Clinical Science 

Classification of Strokes in Patients Receiving Intravitreal Anti-Vascular Endothelial Growth Factor

Matthew R. Starr, MD; Lauren A. Dalvin, MD; Jackson E. AbouChehade, MD; Gena M. Damento, MD; Maria D. Garcia, MD; Saumya M. Shah, BS; David O. Hodge, MS; Irene Meissner, MD; Raymond Iezzi, MD; Sophie J. Bakri, MD

Abstract

BACKGROUND AND OBJECTIVE:

The purpose of this study was to identify the differences in the types of strokes seen in patients receiving intravitreal anti-vascular endothelial growth factor (VEGF) compared with normal control populations.

PATIENTS AND METHODS:

We performed a retrospective consecutive review of all patients receiving intravitreal anti-VEGF injections in Olmsted County, Minnesota, from January 1, 2004, to December 31, 2013, for exudative age-related macular degeneration (AMD), diabetic macular edema (DME), proliferative diabetic retinopathy (PDR), or retinal vein occlusion (RVO). A 2-year follow-up period was required for study inclusion. Three age- and sex-matched cohorts were identified.

RESULTS:

A total of 2,541 patients were examined. There were 690 patients identified during the study period as receiving an intravitreal injection for AMD, DME, PDR, or RVO. Of these patients, 38 (5.8%) suffered a stroke after starting intravitreal injection therapy. Of these strokes, 27 (71.1%) were ischemic, six (15.8%) were embolic, and five (13.2%) were hemorrhagic. There were no differences in the types of strokes identified among the patients receiving intravitreal injections between the case cohort and the control cohorts (P > .05 for all).

CONCLUSION:

The authors' data suggest there is no predilection to the development of ischemic infarcts or hemorrhagic strokes in those patients receiving intravitreal anti-VEGF compared with control populations.

[Ophthalmic Surg Lasers Imaging Retina. 2019;50:e140–e157.]

Abstract

BACKGROUND AND OBJECTIVE:

The purpose of this study was to identify the differences in the types of strokes seen in patients receiving intravitreal anti-vascular endothelial growth factor (VEGF) compared with normal control populations.

PATIENTS AND METHODS:

We performed a retrospective consecutive review of all patients receiving intravitreal anti-VEGF injections in Olmsted County, Minnesota, from January 1, 2004, to December 31, 2013, for exudative age-related macular degeneration (AMD), diabetic macular edema (DME), proliferative diabetic retinopathy (PDR), or retinal vein occlusion (RVO). A 2-year follow-up period was required for study inclusion. Three age- and sex-matched cohorts were identified.

RESULTS:

A total of 2,541 patients were examined. There were 690 patients identified during the study period as receiving an intravitreal injection for AMD, DME, PDR, or RVO. Of these patients, 38 (5.8%) suffered a stroke after starting intravitreal injection therapy. Of these strokes, 27 (71.1%) were ischemic, six (15.8%) were embolic, and five (13.2%) were hemorrhagic. There were no differences in the types of strokes identified among the patients receiving intravitreal injections between the case cohort and the control cohorts (P > .05 for all).

CONCLUSION:

The authors' data suggest there is no predilection to the development of ischemic infarcts or hemorrhagic strokes in those patients receiving intravitreal anti-VEGF compared with control populations.

[Ophthalmic Surg Lasers Imaging Retina. 2019;50:e140–e157.]

Introduction

Age-related macular degeneration (AMD) is the leading cause of blindness in the developing world in people older than 50 years of age.1 Along with AMD, patients with diabetic macular edema (DME), proliferative diabetic retinopathy (PDR), and retinal vein occlusions (RVO) suffer from significant vision loss. The management of these four conditions has drastically changed with the advent of intravitreal anti-vascular endothelial growth factor (VEGF) injections.2–7

Despite the proven success of intravitreal anti-VEGF agents in treating these conditions, there is theoretical concern that these agents increase the risk of stroke. Scappaticci et al. in 2007 showed an increase in systemic arterial thromboembolic events in patients with metastatic colorectal, breast, or non–small-cell lung carcinoma being treated with chemotherapy plus bevacizumab (Avastin; Genentech, South San Francisco, CA) versus chemotherapy alone.8 This study defined arterial thromboembolic events as angina pectoris, arterial thrombosis, cerebral infarct, cerebral ischemia, cerebrovascular accident, myocardial infarction, and myocardial ischemia. The study also included transient ischemic attacks (TIAs) in its analysis. The incidence of thromboembolic events was 1.7% in the control population versus 3.8% in the cohort receiving bevacizumab.8 Ranpura et al. found overall incidence of fatal adverse events of 2.9% in patients with advanced solid tumors (colorectal, prostate, non-small cell lung, renal cell, and prostate cancers) treated with systemic bevacizumab versus 2.2% in chemotherapy patients alone.9

It is widely accepted that the systemic use of bevacizumab results in an increased risk of arterial thromboembolic events.8,9 Although given in much smaller doses to the eye, there is concern that intravitreal anti-VEGF could be associated with an increase in the risk of stroke. The two main types of strokes, ischemic and hemorrhagic, can be further subdivided based on etiology. Hemorrhagic strokes consist predominantly of intracerebral hemorrhages and subarachnoid hemorrhages, whereas ischemic strokes are most commonly attributed to thrombosis, embolism, and hypoperfusion, although other etiologies such as dissection and inflammation may play a role.10 Additionally, thrombotic strokes can be further divided into large vessel (carotid and vertebrobasilar) and small vessel (lacunar) disease.10 It is important to distinguish between different types of strokes because the etiology and management vary between different subtypes. Transient ischemic attacks (TIAs) differ from strokes in that there is no visible end-organ damage.11 The purpose of this study is to identify any difference in the types and distribution of strokes seen in patients receiving intravitreal anti-VEGF compared with two control populations.

Patients and Methods

This study is in compliance with the Health Insurance Portability and Accountability Act, received approval from Mayo Clinic and Olmsted County institutional review boards, and adhered to the tenets of the Declaration of Helsinki. We performed a retrospective consecutive review of all patients receiving intravitreal anti-VEGF injections in Olmsted County from January 1, 2004, through December 31, 2013. We utilized the Rochester Epidemiology Project (REP) records to identify all patients who received at least one anti-VEGF injection for exudative AMD, DME, PDR, or RVO. A 2-year follow-up period was required for study inclusion. If the patient passed away before 2 years of follow-up, they were still included in the study. The REP records include epidemiologic as well as health care data among the residents of Olmsted County, Minnesota. The predominant care to patients in Olmsted County is provided by Mayo Clinic and Olmsted Medical Center as well as several smaller, private clinics, all of which participate in the REP database, a widely validated research tool minimizing bias, allowing capture of almost all of the residents in Olmsted County.12,13 Demographic data among this population is similar to that of the Upper Midwest. Although it is a less diverse population compared with the entire United States population, mortality rates are similar. The database meticulously tracks the date of last patient contact across the clinics and date of death.14,15 Three age- and sex-matched control groups were identified from the REP: two cohorts of patients with AMD, DME, PDR, or RVO, with one cohort from the pre-anti-VEGF era (1990–2003) and one concurrent cohort of patients from 2004 through 2013 that did not receive anti-VEGF intravitreal injections. The last cohort of patients was drawn from a concurrent 2004 through 2013 time period that underwent a general ophthalmological examination documenting no AMD and was created by searching the REP database for patients diagnosed with cataracts. After initial evaluation of all patients with AMD, DME, PDR, and RVO, these respective diseases were then separated for analysis based on disease pathology: macular degeneration, diabetes, and vein occlusion.

Injection Cohort

All patients who received at least one intravitreal injection from January 1, 2004, through December 31, 2013, were included in this cohort. Intravitreal anti-VEGF agents were pegaptanib (Macugen; Bausch + Lomb, Rochester, NY), ranibizumab (Lucentis; Genentech, South San Francisco, CA), bevacizumab, and aflibercept (Eylea; Regeneron, Tarrytown, NY). Only patients with AMD, DME, PDR, and RVO were included. Patients receiving intravitreal injections for other indications, such as presumed ocular histoplasmosis or rubeosis iridis, were excluded. The records were manually reviewed for the type of anti-VEGF agent used, its frequency, and total number of injections; patient age, race, sex, body mass index, and smoking status; patient family history of heart disease, strokes, or macular degeneration; and patient medical history. If a patient suffered a stroke after receiving any intravitreal anti-VEGF injections, both pre- and post-stroke medications were documented. Patients who suffered a stroke before receiving intravitreal anti-VEGF injections were included. The prior stroke was noted but was not included in the stroke analysis unless they suffered another stroke.

Non-Injection Cohorts

To control for the possibility that the diseases necessitating anti-VEGF therapy could be associated with a higher risk of thromboembolic events, we matched a prior time period cohort from 1990 through 2003 using age and sex to the already collected case cohort. In order to control for the possibility that the risk of cardiovascular events may have increased from the pre-anti-VEGF era to the present cohort, we created a concurrent time period cohort. These patients, matched for age, sex, and ocular disease from 2004 through 2013, were not receiving anti-VEGF to manage their AMD, DME, PDR, or RVO. The last cohort was age- and sex-matched against the exudative AMD patients only. This cohort included any patient with a documented ophthalmological examination who did not have AMD (dry or wet) from 2004 through 2013. We labeled this cohort the cataract cohort as it was populated by searching the REP database for patients diagnosed with cataracts during this time period.

Stroke Analysis

The location, type, and age of the patient at the time of the stroke through December 31, 2015, were recorded. The type of stroke was classified as embolic, ischemic, hemorrhagic (intraparenchymal or subarachnoid), or hemorrhagic conversion of an ischemic stroke. Determination of the type of stroke was made based on review of the medical record. Stroke location was divided into the distributions of the three large intracranial vessels (anterior, middle, and posterior cerebral arteries) and adjudicated as to whether it was cortical or lacunar in distribution. Nearly all patients had computed tomography or magnetic resonance imaging of the brain and were managed by neurologists at Mayo Clinic. We categorized the strokes based on the classification the neurologists made after the patients underwent a thorough stroke evaluation. In addition to head imaging, the stroke workup typically included echocardiography, carotid ultrasonography, and laboratory data. If any reviewer noted a discrepancy in the stroke classifications after reviewing the imaging and neurology notes, the chart was further reviewed by MRS or LAD to determine stroke etiology. If, after reviewing the medical records, we were unable to determine the type and distribution of the stroke based on the neurology records, or if there were no neurology records and it was not clear, based on other medical records, we marked the mechanism of the event as indeterminate.

A separate analysis based on number of injections prior to the development of a stroke was also performed. Patients were divided into number of injections per year: less than three per year, between three and nine injections per year, and more than nine injections per year. The types of strokes were then examined between these cohorts of patients.

The data were collected and entered into Microsoft Excel 2010 (Microsoft Corporation, Redmond, WA). For statistical analysis, SAS software (SAS Institute, Cary, NC) was used. A rank-sum test was performed for the continuous data. Categorical data was analyzed using chi-square analysis. A P value less than .05 was considered to be statistically significant. Analyses were carried out comparing all cohorts together. Subsequently, the cohorts were then divided based on their separate disease processes and separate analyses were performed. Logistic models controlling for atrial fibrillation, carotid stenosis, malignancy, and blood thinners were performed for all patients as well as the cohorts separated out by disease type.

Results

We identified 841 patients with exudative AMD, DME, PDR, or RVO who received at least one intravitreal injection during the 10-year time frame examined. Of these, 151 patients were excluded after examination of the medical records for insufficient follow-up, receiving intravitreal injections of other agents without receiving any anti-VEGF, or receiving anti-VEGF injections for disease processes other than AMD, DME, PDR, or RVO. Of the 690 patients included in the study, 504 (73.0%) had wet AMD, 86 (12.5%) had DME or PDR, and 100 (14.5%) had RVO. There were 419 females (60.7%) and 271 males (39.3%) with a mean age of 74.1 years ± 12.0 years. Mean body mass index was 27.6 ± 6.4. About half of these patients, 335 (48.6%), were either current smokers or had a history of smoking. Mean number of injections was 17 ± 16.5 for all patients and 10.5 ± 12.1 for the patients suffering a stroke. There was no difference in the number of injections between these patients (P = .22). The most common anti-VEGF agent used was bevacizumab, but more than half of the patients received more than one type of anti-VEGF injection, limiting any statistical analysis comparing different injections that could be performed. Seven patients received pegaptanib only, without exposure to any of the currently used anti-VEGF agents. Of the 38 patients suffering a stroke, the median time from last injection to stroke was 40 days (range: 9 days to 5 years). There were 10 stroke patients that had not received an injection in more than 1 year prior to their infarct. The baseline medical history and medication use data for all patients are presented in Tables 14.

Baseline Characteristics, Medical History, and Medication Use for All Patients in the Case Cohort and Both Control CohortsBaseline Characteristics, Medical History, and Medication Use for All Patients in the Case Cohort and Both Control Cohorts

Table 1:

Baseline Characteristics, Medical History, and Medication Use for All Patients in the Case Cohort and Both Control Cohorts

Comparison of Baseline Characteristics, Medical History, and Medication Use for Patients With Exudative AMD Who Received Intravitreal Anti-VEGF InjectionsComparison of Baseline Characteristics, Medical History, and Medication Use for Patients With Exudative AMD Who Received Intravitreal Anti-VEGF Injections

Table 2:

Comparison of Baseline Characteristics, Medical History, and Medication Use for Patients With Exudative AMD Who Received Intravitreal Anti-VEGF Injections

Comparison of Baseline Characteristics, Medical History, and Medication Use for Patients With DME or PDR Who Received Intravitreal Anti-VEGF InjectionsComparison of Baseline Characteristics, Medical History, and Medication Use for Patients With DME or PDR Who Received Intravitreal Anti-VEGF Injections

Table 3:

Comparison of Baseline Characteristics, Medical History, and Medication Use for Patients With DME or PDR Who Received Intravitreal Anti-VEGF Injections

Comparison of Baseline Characteristics, Medical History, and Medication Use for Patients With RVO Who Received Intravitreal Anti-VEGF InjectionsComparison of Baseline Characteristics, Medical History, and Medication Use for Patients With RVO Who Received Intravitreal Anti-VEGF Injections

Table 4:

Comparison of Baseline Characteristics, Medical History, and Medication Use for Patients With RVO Who Received Intravitreal Anti-VEGF Injections

Stroke Characteristics (All Patients)

In the case cohort, there were 38 patients (5.5%) who suffered a stroke after beginning treatment with intravitreal anti-VEGF injections. Of these, 27 (71.1%) were ischemic strokes, five (13.2%) were hemorrhagic, and six (15.8%) were cardioembolic. No strokes were hemorrhagic conversions. The pre-anti-VEGF cohort showed 78 patients (11.5%) suffered a stroke after the initial diagnosis of AMD, DME, PDR, or RVO. Of these, 57 (73.1%) were ischemic, 10 (12.8%) were hemorrhagic, nine (11.5%) were cardioembolic, and two (2.6%) were indeterminate. There were also no hemorrhagic conversions in this cohort. There was no significant difference between the distribution of strokes seen between the cases and the pre-anti-VEGF cohort(P = .72). The concurrent time period cohort had 26 patients (3.8%) suffer a stroke after the initial diagnosis of AMD, DME, PDR, or RVO. Of these strokes, 20 (76.9%) were ischemic, two (7.7%) were hemorrhagic, and four (15.4%) were cardioembolic. None were hemorrhagic conversions. There was no significant difference between this cohort and the case cohort (P = .78) (Table 5). No significant differences were found when logistic models were performed controlling for incidence of atrial fibrillation, carotid stenosis, malignancy history, and anti-coagulation status. When analyzed by anatomical location, there were no significant differences in the cerebral artery distribution of strokes (P > .05 for all) (Table 5).

Stroke Characteristics for All Patients Based on Type and Distribution of Stroke

Table 5:

Stroke Characteristics for All Patients Based on Type and Distribution of Stroke

Cohorts Analyzed by Ocular Disease Stroke Characteristics

The cohorts were analyzed by intravitreal anti-VEGF indication and subsequently compared for stroke type and distribution. There were no differences in either stroke type or stroke distribution when comparing AMD patients, DME/PDR patients, or RVO patients from the case cohort to the concurrent or past time period controls (P > .05 for all) (Tables 68). There was a significant difference between the AMD case cohort and the concurrent cataract control group regarding types of strokes. The cataract control cohort had an increased number of cardioembolic strokes (13.3% vs. 46.3%), whereas the AMD case cohort had a much higher percentage of ischemic infarctions (70.0% vs. 46.3%; P = .01). There was a trend toward anterior cerebral artery distribution strokes in the cataract cohort (10.0% vs. 48.8%), but the difference was not significant (P = .11) (Table 6).

Stroke Characteristics for the Macular Degeneration Patients Based on Type and Distribution of Stroke

Table 6:

Stroke Characteristics for the Macular Degeneration Patients Based on Type and Distribution of Stroke

Stroke Characteristics for the Diabetic Patients Based on Type and Distribution of Stroke

Table 7:

Stroke Characteristics for the Diabetic Patients Based on Type and Distribution of Stroke

Stroke Characteristics for Patients With RVO Based on Type and Distribution of Stroke

Table 8:

Stroke Characteristics for Patients With RVO Based on Type and Distribution of Stroke

Injection Data

Mean number of injections prior to a stroke was 10.5 ± 12.1 in all patients, 10.0 ± 11.7 for AMD patients, 12.0 ± 19.9 for diabetic patients, and 12.8 ± 12.9 for RVO patients. Median time from last injection to stroke was 40 days (25th percentile, 19 days; 75th percentile, 476 days) for all patients, 36.5 days (25th percentile, 19 days; 75th percentile, 320 days) for AMD patients, 153 days (25th percentile, 48 days; 75th percentile, 1,358 days) for diabetic patients, and 22 days (25th percentile, 18 days; 75th percentile, 648 days) for RVO patients. When dividing the patients based on stroke frequency, there were 258 patients with less than three injections per year, 237 patients with three to nine injections per year, and 195 patients with greater than nine injections per year prior to having a stroke. There was no statistical difference in stroke type when analyzed by injection frequency prior to the patient suffering a cerebrovascular infarction (P = .97).

Discussion

It is well-known that VEGF plays a pivotal role in disease progression in patients with exudative AMD, DME, PDR, and RVO. Our results indicate that there is no statistically significant difference in the types of strokes nor was there any difference in the distribution of the strokes between the patients receiving anti-VEGF injections and the age- and sex-matched controls.

Studies by Ng et al., Semeraro et al., Schlenker et al., Cleary et al., and Campbell et al. examined patients with AMD treated with intravitreal anti-VEGF.16–20 The only study to suggest an increased risk of cerebrovascular ischemic events was the study by Schlenker et al., but this study examined only the risk of ischemic events and did not examine hemorrhagic strokes.19 None of these studies analyzed the types of strokes suffered by patients receiving anti-VEGF, and each of them analyzed only patients with exudative AMD. Given the proposed mechanisms for how anti-VEGF agents may cause a stroke, it is important to include not only ischemic events but also hemorrhagic events that could be related to the use of intravitreal anti-VEGF agents.

Several large studies have examined the use of intravitreal anti-VEGF for exudative AMD, including the Comparison of AMD Treatment Trials (CATT), Minimally Classic/Occult Trial of the Anti-VEGF Antibody Ranibizumab in the Treatment of Neovascular AMD (MARINA),6 Anti-VEGF Antibody for the Treatment of Predominantly Classic Choroidal Neovascularization in AMD (ANCHOR),4,21 RhuFab V2 Ocular Treatment Combining the Use of Visudyne to Evaluate Safety (FOCUS),22 Open-label Extension Trial of Ranibizumab for Choroidal Neovascularization Secondary to AMD (HORIZON),23 and Seven-year Outcomes in Ranibizumab-Treated Patients in ANCHOR, MARINA, and HORIZON (SEVEN-UP)24 trials. These trials analyzed thromboembolic adverse events as a secondary analysis in their respective studies. All studies focused on nonfatal strokes and did not include fatal strokes in their analysis. Some studies did mention vascular causes of death but did not note the specific vascular event. None of these studies compared the types of strokes seen by the patients in the trials, although some did mention ischemic and hemorrhagic events in the analysis (Table 9).

Comparison of the CATT, ANCHOR, MARINA, FOCUS, HORIZON, and SEVEN-UP Trials With Regard to Stroke DataComparison of the CATT, ANCHOR, MARINA, FOCUS, HORIZON, and SEVEN-UP Trials With Regard to Stroke Data

Table 9:

Comparison of the CATT, ANCHOR, MARINA, FOCUS, HORIZON, and SEVEN-UP Trials With Regard to Stroke Data

The longest follow-up available from these studies was 7.3 years in the SEVEN-UP trial, but this study did not include cerebrovascular events in its report. The HORIZON trial was the longest trial at 4 years that included stroke data. In our study, the minimum follow-up time was 2 years with an average follow-up time of 4.4 years for the case cohort, 6.0 years for the concurrent cohort, 9.7 years for the past time period cohort, and 6.3 years for the cataract cohort. This might explain why the past time period had more strokes seen, but there was no difference in the types or location of the strokes, thus, making it unlikely that there was any change in the characteristics of the strokes seen further from the initial intravitreal anti-VEGF injection.

These studies used arterial thromboembolic events (ATEs) as defined by the Antiplatelet Trialists' Collaboration (APTC) when examining the ocular safety profile of intravitreal anti-VEGF agents. The APTC defined vascular events as nonfatal myocardial infarctions, strokes, and vascular deaths,25 while the study by Scappaticci et al. included TIAs, angina, and arterial emboli.8 Scappaticci noted an increased risk for ATEs, whereas the MARINA, ANCHOR, and HORIZON studies noted no difference in ATEs, and the FOCUS trial actually showed an increase in ATEs.6,21–23

In our study, we identified that the majority of the cerebrovascular events were ischemic, with a significant proportion being hemorrhagic. There was no difference between the case cohort versus either of the control cohorts in regard to stroke type. A study published by the American Heart Association in 2014 reported the proportion of strokes in the United States as being 87% ischemic, 10% due to intraparenchymal hemorrhage, and 3% due to subarachnoid bleeding.26 These numbers are similar to our study. A few variables could explain the difference found in the subgroup analysis between the exudative AMD cohort and the cataract cohort. The cataract cohort had more patients with estrogen use, potentially leading to an increase in embolic events.27

Regarding the number of injections prior to stroke, there was no difference in injection frequency in the year leading up to the stroke. The frequency of injections did not influence the type of strokes these patients suffered. The type of injection was not analyzed owing to the variety of agents patients received. About half of the patients received different types of injections, making it difficult to draw any meaningful conclusions about the different types of intravitreal anti-VEGF agents.

The primary goal of this study was to highlight the characteristics of cerebrovascular ischemic or hemorrhagic events seen in patients receiving intravitreal anti-VEGF agents in the treatment of AMD, DME, PDR, and RVO. There are limitations to this study. It was a retrospective study, which is limited by its design. There were no metrics in the medical history that were significantly different between the case cohort and both control cohorts. There were, however, significant differences between several high-risk metrics between the case cohort and either the concurrent or past time period cohorts. Of the four major non-modifiable risk factors for strokes, age, sex, race, and family history of stroke,28 there were no differences between any of the cohorts. Still, there were differences in hypertension, hyperlipidemia, coronary heart disease, and atrial fibrillation between some of the cohorts, which could confound the types of strokes seen in our patients. The same can be said for medication use including anti-coagulation and estrogen use. It is also important to note that 10 of the 38 patients who suffered a stroke while receiving intravitreal anti-VEGF injections had not received an injection in more than a year prior to suffering their stroke, making it plausible anti-VEGF did not influence the type of stroke seen in these 10 patients.

The difference in stroke type seen when comparing the cataract control cohort and the exudative cohort was potentially related to anti-VEGF use, but there were no similar findings among the two other control cohorts, making it difficult to draw any conclusion from this finding. It is clear, though, that there are no differences in type or anatomic distribution of strokes seen in patients who received intravitreal anti-VEGF compared with patients with similar disease processes who did not receive intravitreal anti-VEGF.

References

  1. Mehta S. Age-related macular degeneration. Prim Care. 2015;42(3):377–391. doi:10.1016/j.pop.2015.05.009 [CrossRef]
  2. Ashraf M, Souka AA, Singh RP. Central retinal vein occlusion: Modifying current treatment protocols. Eye (Lond). 2016;30(4):505–514. doi:10.1038/eye.2016.10 [CrossRef]
  3. Bandello F, Cunha-Vaz J, Chong NV, et al. New approaches for the treatment of diabetic macular oedema: Recommendations by an expert panel. Eye (Lond). 2012;26(4):485–493. doi:10.1038/eye.2011.337 [CrossRef]
  4. Brown DM, Kaiser PK, Michels M, et al. ANCHOR Study Group. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl J Med. 2006;355(14):1432–1444. doi:10.1056/NEJMoa062655 [CrossRef]
  5. Martin DF, Maguire MG, CATT Research Group et al. Ranibizumab and bevacizumab for neovascular age-related macular degeneration. N Engl J Med. 2011;364(20):1897–1908. doi:10.1056/NEJMoa1102673 [CrossRef]
  6. Rosenfeld PJ, Brown DM, Heier JS, et al. MARINA Study Group. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med. 2006;355(14):1419–1431. doi:10.1056/NEJMoa054481 [CrossRef]
  7. Simó R, Sundstrom JM, Antonetti DA. Ocular anti-VEGF therapy for diabetic retinopathy: The role of VEGF in the pathogenesis of diabetic retinopathy. Diabetes Care. 2014;37(4):893–899. doi:10.2337/dc13-2002 [CrossRef]
  8. Scappaticci FA, Skillings JR, Holden SN, et al. Arterial thromboembolic events in patients with metastatic carcinoma treated with chemotherapy and bevacizumab. J Natl Cancer Inst. 2007;99(16):1232–1239. doi:10.1093/jnci/djm086 [CrossRef]
  9. Ranpura V, Hapani S, Wu S. Treatment-related mortality with bevacizumab in cancer patients: A meta-analysis. JAMA. 2011;305(5):487–494. doi:10.1001/jama.2011.51 [CrossRef]
  10. Frizzell JP. Acute stroke: Pathophysiology, diagnosis, and treatment. AACN Clin Issues. 2005;16(4):421–440; quiz 597–598. doi:10.1097/00044067-200510000-00002 [CrossRef]
  11. Easton JD, Saver JL, Albers GW, et al. Definition and evaluation of transient ischemic attack: A scientific statement for healthcare professionals from the American Heart Association/American Stroke Association Stroke Council; Council on Cardiovascular Surgery and Anesthesia; Council on Cardiovascular Radiology and Intervention; Council on Cardiovascular Nursing; and the Interdisciplinary Council on Peripheral Vascular Disease. The American Academy of Neurology affirms the value of this statement as an educational tool for neurologists. Stroke. 2009;40(6):2276–2293. doi:10.1161/STROKEAHA.108.192218 [CrossRef]
  12. Kurland LT, Molgaard CA. The patient record in epidemiology. Sci Am. 1981;245(4):54–63. doi:10.1038/scientificamerican1081-54 [CrossRef]
  13. Melton LJ 3rd, . History of the Rochester Epidemiology Project. Mayo Clin Proc. 1996;71(3):266–274. doi:10.4065/71.3.266 [CrossRef]
  14. St Sauver JL, Grossardt BR, Leibson CL, Yawn BP, Melton LJ 3rd, Rocca WA. Generalizability of epidemiological findings and public health decisions: An illustration from the Rochester Epidemiology Project. Mayo Clin Proc. 2012;87(2):151–160. doi:10.1016/j.mayocp.2011.11.009 [CrossRef]
  15. Campion ME, Naessens JM, Leibson CL, Shaller D, Ballard DJ. The Olmsted County Benchmark Project: Primary study findings and potential implications for corporate America. Mayo Clin Proc. 1992;67(1):5–14. doi:10.1016/S0025-6196(12)60270-5 [CrossRef]
  16. Campbell RJ, Bell CM, Paterson JM, et al. Stroke rates after introduction of vascular endothelial growth factor inhibitors for macular degeneration: A time series analysis. Ophthalmology. 2012;119(8):1604–1608. doi:10.1016/j.ophtha.2012.05.028 [CrossRef]
  17. Cleary CA, Sharaznayan D, Hickey-Dwyer M. Intravitreal anti-VEGF therapy for neovascular age-related macular degeneration and the risk of stroke. Ir Med J. 2011;104(5):146–149.
  18. Ng WY, Tan GS, Ong PG, et al. Incidence of myocardial infarction, stroke, and death in patients with age-related macular degeneration treated with intravitreal anti-vascular endothelial growth factor therapy. Am J Ophthalmol. 2015;159(3):557–564.e1. doi:10.1016/j.ajo.2014.12.005 [CrossRef]
  19. Schlenker MB, Thiruchelvam D, Redelmeier DA. Intravitreal anti-vascular endothelial growth factor treatment and the risk of thromboembolism. Am J Ophthalmol. 2015;160(3):569–580.e5. doi:10.1016/j.ajo.2015.06.011 [CrossRef]
  20. Semeraro F, Morescalchi F, Duse S, Gambicorti E, Romano MR, Costagliola C. Systemic thromboembolic adverse events in patients treated with intravitreal anti-VEGF drugs for neovascular age-related macular degeneration: An overview. Expert Opin Drug Saf. 2014;13(6):785–802.
  21. Brown DM, Michels M, Kaiser PK, Heier JS, Sy JP, Ianchulev TANCHOR Study Group. Ranibizumab versus verteporfin photodynamic therapy for neovascular age-related macular degeneration: Two-year results of the ANCHOR study. Ophthalmology. 2009;116(1):57–65.e5. doi:10.1016/j.ophtha.2008.10.018 [CrossRef]
  22. Antoszyk AN, Tuomi L, Chung CY, Singh AFOCUS Study Group. Ranibizumab combined with verteporfin photodynamic therapy in neovascular age-related macular degeneration (FOCUS): Year 2 results. Am J Ophthalmol. 2008;145(5):862–874. doi:10.1016/j.ajo.2007.12.029 [CrossRef]
  23. Singer MA, Awh CC, Sadda S, et al. HORIZON: An open-label extension trial of ranibizumab for choroidal neovascularization secondary to age-related macular degeneration. Ophthalmology. 2012;119(6):1175–1183. doi:10.1016/j.ophtha.2011.12.016 [CrossRef]
  24. Rofagha S, Bhisitkul RB, Boyer DS, Sadda SR, Zhang KSEVEN-UP Study Group. Seven-year outcomes in ranibizumab-treated patients in ANCHOR, MARINA, and HORIZON: A multicenter cohort study (SEVEN-UP). Ophthalmology. 2013;120(11):2292–2299. doi:10.1016/j.ophtha.2013.03.046 [CrossRef]
  25. Collaborative overview of randomised trials of antiplatelet therapy--I: Prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. Antiplatelet Trialists' Collaboration. BMJ. 1994;308(6921):81–106. doi:10.1136/bmj.308.6921.81 [CrossRef]
  26. Go AS, Mozaffarian D, Roger VL, et al. American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics--2014 update: A report from the American Heart Association. Circulation. 2014;129(3):e28–e292.
  27. Grady D, Wenger NK, Herrington D, et al. Postmenopausal hormone therapy increases risk for venous thromboembolic disease. The Heart and Estrogen/progestin Replacement Study. Ann Intern Med. 2000;132(9):689–696. doi:10.7326/0003-4819-132-9-200005020-00002 [CrossRef]
  28. Grysiewicz RA, Thomas K, Pandey DK. Epidemiology of ischemic and hemorrhagic stroke: Incidence, prevalence, mortality, and risk factors. Neurol Clin. 2008;26(4):871–895, vii. doi:10.1016/j.ncl.2008.07.003 [CrossRef]

Baseline Characteristics, Medical History, and Medication Use for All Patients in the Case Cohort and Both Control Cohorts

Cases vs. Past Time PeriodCases vs. Concurrent Time Period
Baseline DataCase Cohort (n = 690)Past Time Cohort (n = 659)P ValueCase Cohort (n = 690)Concurrent Time Cohort (n = 688)P Value
Mean age (standard deviation)74.1 (12.0)74.5 (12.4).270174.1 (12.0)73.7 (12.0).5453
Female (count)419 (60.7%)412 (62.5%).4982419 (60.7%)418 (60.8%).9905
Mean body mass index (standard deviation)27.6 (6.4)27.3 (7.1).080227.6 (6.4)28.0 (6.3).1835
Family history of stroke (count)268 (48.4%)218 (43.0%).0791268 (48.4%)271 (51.1%).3642
Medical History
Hypertension628 (91.0%)584 (88.6%).1454628 (91.0%)598 (86.9%).0152*
Coronary artery disease347 (50.3%)294 (44.6%).0369*347 (50.3%)374 (54.4%).1304
Transient ischemic attacks98 (14.2%)120 (18.2%).0457*98 (14.2%)100 (14.5%).8606
Carotid stenosis107 (15.5%)108 (16.4%).6585107 (15.5%)75 (10.9%).0116*
Diabetes272 (39.4%)255 (38.7%).7849272 (39.4%)249 (36.2%).2166
Atrial fibrillation201 (29.2%)239 (36.3%).0055*201 (29.2%)186 (27.0%).3776
Venousthromboembolism94 (13.6%)94 (14.3%).734194 (13.6%)78 (11.3%).1992
Pulmonary embolism51 (7.4%)48 (7.3%).939651 (7.4%)36 (5.2%).0995
Congestive heart failure185 (26.8%)276 (41.9%)< .0001*185 (26.8%)184 (26.7%).9775
Peripheral vascular disease92 (13.3%)111 (16.8%).071592 (13.3%)53 (7.7%).0007*
Hyperlipidemia544 (78.8%)386 (58.6%)< .0001*544 (78.8%)530 (77.0%).4189
Hypertriglyceridemia105 (15.2%)90 (13.7%).4153105 (15.2%)81 (11.8%).0614
Obstructive sleep apnea140 (20.3%)105 (15.9%).038*140 (20.3%)159 (23.1%).204
Glaucoma167 (24.2%)166 (25.2%).6855167 (24.2%)110 (16.0%).0001*
Chronic kidney disease245 (35.5%)232 (35.2%).9076245 (35.5%)225 (32.7%).2723
Malignancy323 (46.9%)331 (50.5%).2319323 (46.9%)270 (39.2%).0108*
Smoking history327 (49.4%)253 (49.3%).9788327 (49.4%)335 (53.0%).194
Medications
Antihypertensives513 (74.5%)448 (68.0%).0086*513 (74.5%)474 (68.9%).022*
Beta blockers405 (58.7%)310 (47.0%)< .0001*405 (58.7%)347 (50.4%).0021*
Calcium channel blockers259 (37.5%)212 (32.2%).0388*259 (37.5%)210 (30.5%).006*
Statins414 (60.0%)205 (31.1%)< .0001*414 (60.0%)350 (50.9%).0007*
Insulin103 (14.9%)113 (17.1%).2665103 (14.9%)107 (15.6%).747
Warfarin132 (19.1%)112 (17.0%).3085132 (19.1%)109 (15.8%).1082
Aspirin365 (52.9%)319 (48.4%).099365 (52.9%)346 (50.3%).3328
Clopidogrel78 (11.3%)44 (6.7%).0031*78 (11.3%)74 (10.8%).7452
Direct factor inhibitors5 (0.7%)3 (0.5%).51955 (0.7%)0 (0.0%).0253*
Estrogen60 (8.7%)55 (8.3%).818260 (8.7%)27 (3.9%).0003*

Comparison of Baseline Characteristics, Medical History, and Medication Use for Patients With Exudative AMD Who Received Intravitreal Anti-VEGF Injections

Exudative AMD Case Cohort vs. Non-Exudative AMD Concurrent CohortExudative AMD Case Cohort vs. Past Time Period CohortExudative AMD Case Cohort vs. CataractCohort
Baseline DataExudative AMD Case Cohort (n = 504)Non-Exudative AMD Concurrent Cohort (n = 504)P ValueExudative AMD Case Cohort (n = 504)Exudative AMD Past Time Cohort (n = 473)P ValueExudative AMD Case Cohort (n = 504)Cataract Cohort (n = 504)P Value
Mean age (standard deviation)76.5 (10.0)76.4 (10.0).955576.5 (10.0)77.9 (9.4).0125*76.5 (10.0)76.4 (10.1).9872
Female (count)321 (63.7%)321 (63.7%)1321 (63.7%)314 (66.4%).3776321 (63.7%)321 (63.7%)1
Mean body mass index (standard deviation)26.9 (6.1)27.4 (5.7).086526.9 (6.1)26.6 (6.6).394426.9 (6.1)27.6 (6.8).0464*
Family history of stroke (count)199 (50.0%)202 (52.2%).5382199 (50.0%)168 (50.0%)1199 (50.0%)211 (42.6%).0280*
Medical History
Hypertension455 (90.3%)439 (87.1%).1116455 (90.3%)421 (89.0%).5142455 (90.3%)427 (84.7%).0077*
Coronary artery disease266 (52.8%)268 (53.2%).8996266 (52.8%)223 (47.1%).0785266 (52.8%)255 (50.6%).4881
Transient ischemic attacks83 (16.5%)81 (16.1%).864583 (16.5%)94 (19.9%).167383 (16.5%)89 (17.7%).6054
Carotid stenosis71 (14.1%)54 (10.7%).104271 (14.1%)77 (16.3%).339671 (14.1%)68 (13.5%).784
Diabetes157 (31.2%)140 (27.8%).2402157 (31.2%)142 (30.0%).7018157 (31.2%)157 (31.2%)1
Atrial fibrillation152 (30.2%)143 (28.4%).5199152 (30.2%)179 (37.8%).0119*152 (30.2%)158 (31.3%).6976
Venous thromboembolism61 (12.1%)54 (10.7%).48861 (12.1%)58 (12.3%).939561 (12.1%)60 (11.9%).9228
Pulmonary embolism31 (6.2%)24 (4.8%).331731 (6.2%)34 (7.2%).515531 (6.2%)38 (7.5%).3826
Congestive heart failure136 (27.0%)142 (28.2%).6724136 (27.0%)198 (41.9%)< .0001*136 (27.0%)146 (29.0%).4829
Peripheral vascular disease64 (12.7%)40 (7.9%).013*64 (12.7%)63 (13.3%).773164 (12.7%)85 (16.9%).0624
Hyperlipidemia389 (77.2%)382 (75.8%).6031389 (77.2%)255 (53.9%)< .0001*389 (77.2%)327 (64.9%)< .0001*
Hypertriglyceridemia68 (13.5%)57 (11.3%).293268 (13.5%)62 (13.1%).859768 (13.5%)59 (11.7%).393
Obstructive sleep apnea89 (17.7%)101 (20.0%).333889 (17.7%)54 (11.4%).0058*89 (17.7%)109 (21.6%).1682
Glaucoma107 (21.3%)82 (16.3%).0421*107 (21.3%)118 (24.9%).1731107 (21.3%)115 (22.8%).5543
Chronic kidney disease164 (32.5%)157 (31.2%).636164 (32.5%)155 (32.8%).939164 (32.5%)133 (26.4%).0322*
Malignancy266 (52.9%)220 (43.7%).0034*266 (52.9%)243 (51.6%).687266 (52.9%)178 (35.5%)< .0001*
Smoking history253 (52.4%)263 (56.1%).252253 (52.4%)167 (49.3%).3786253 (52.4%)230 (46.2%).0523
Medications
Antihypertensives361 (71.6%)347 (68.8%).3348361 (71.6%)304 (64.3%).0137*361 (71.6%)341 (67.8%).1856
Beta blockers290 (57.5%)250 (49.6%).0115*290 (57.5%)216 (45.7%).0002*290 (57.5%)268 (53.2%).163
Calcium channel blockers192 (38.1%)157 (31.2%).0205*192 (38.1%)142 (30.0%).0078*192 (38.1%)152 (30.2%).0079*
Statins280 (55.6%)240 (47.6%).0117*280 (55.6%)116 (24.5%)< .0001*280 (55.6%)267 (53.0%).4111
Insulin28 (5.6%)36 (7.1%).301428 (5.6%)36 (7.6%).194428 (5.6%)32 (6.3%).5944
Warfarin93 (18.5%)81 (16.1%).317393 (18.5%)71 (15.0%).150393 (18.5%)102 (20.2%).473
Aspirin252 (50.0%)244 (48.4%).6143252 (50.0%)208 (44.0%).0593252 (50.0%)278 (55.2%).101
Clopidogrel50 (9.9%)47 (9.3%).748750 (9.9%)31 (6.6%).056550 (9.9%)42 (8.3%).3816
Direct factor inhibitors5 (1.0%)0 (0.0%).0250*5 (1.0%)0 (0.0%).0299*5 (1.0%)4 (0.8%).7378
Estrogen56 (11.1%)23 (4.6%).0001*56 (11.1%)22 (4.7%).0002*56 (11.1%)78 (15.5%).0412*

Comparison of Baseline Characteristics, Medical History, and Medication Use for Patients With DME or PDR Who Received Intravitreal Anti-VEGF Injections

Diabetic Case Cohort vs. Diabetic Past Time CohortDiabetic Case Cohort vs. Diabetic Concurrent Cohort
Baseline DataDiabetic Case Cohort (n = 86)Diabetic Past Time Cohort (n = 86)P ValueDiabetic Case Cohort (n = 86)Diabetic Concurrent Cohort (n = 86)P Value
Mean age (standard deviation)62.7 (13.4)60.0 (13.4).137362.7 (13.4)60.1 (13.1).1381
Female (count)42 (48.8%)42 (48.8%)142 (48.8%)42 (48.8%)1
Mean body mass index (standard deviation)31.4 (6.9)30.7 (9.2).149331.4 (6.9)32.1 (7.6).4553
Family history of stroke (count)28 (39.4%)20 (26.0%).080528 (39.4%)32 (51.6%).1592
Medical History
Hypertension82 (95.3%)76 (88.4%).094382 (95.3%)79 (91.9%).3498
Coronary artery disease32 (37.2%)33 (38.4%).87532 (37.2%)49 (57.0%).0094*
Transient ischemic attacks8 (9.3%)11 (12.8%).46568 (9.3%)10 (11.6%).6183
Carotid stenosis19 (22.1%)11 (12.8%).107919 (22.1%)9 (10.5%).0389*
Diabetes86 (100.0%)86 (100.0%)186 (100.0%)86 (100.0%)1
Atrial fibrillation25 (29.1%)22 (25.6%).607725 (29.1%)18 (20.9%).2177
Venous thromboembolism18 (20.9%)16 (18.6%).701818 (20.9%)7 (8.1%).0173*
Pulmonary embolism12 (14.0%)3 (3.5%).015*12 (14.0%)5 (5.8%).737
Congestive heart failure30 (34.9%)39 (45.3%).161530 (34.9%)23 (26.7%).2477
Peripheral vascular disease17 (19.8%)23 (26.7%).278817 (19.8%)8 (9.3%).0515
Hyperlipidemia79 (91.9%)67 (77.9%).0106*79 (91.9%)75 (87.2%).3191
Hypertriglyceridemia23 (26.7%)20 (23.3%).597323 (26.7%)14 (16.3%).0949
Obstructive sleep apnea29 (33.7%)26 (30.2%).623829 (33.7%)33 (38.4%).5253
Glaucoma20 (23.3%)14 (16.3%).250620 (23.3%)11 (12.8%).0742
Chronic kidney disease55 (64.0%)49 (57.0%).349455 (64.0%)43 (50.0%).0646
Malignancy22 (25.6%)37 (44.0%).0114*22 (25.6%)19 (22.1%).5914
Smoking history33 (40.7%)43 (55.1%).069433 (40.7%)42 (57.5%).0374*
Medications
Antihypertensives78 (91.8%)70 (81.4%).0469*78 (91.8%)67 (77.9%).0116*
Beta blockers58 (67.4%)48 (55.8%).116958 (67.4%)49 (57.0%).157
Calcium channel blockers36 (41.9%)33 (38.4%).640736 (41.9%)22 (25.6%).0239*
Statins71 (82.6%)49 (57.0%).0003*71 (82.6%)65 (75.6%).2608
Insulin69 (80.2%)68 (79.1%).849869 (80.2%)65 (75.6%).4622
Warfarin20 (23.3%)16 (18.6%).453420 (23.3%)12 (14.0%).117
Aspirin63 (73.3%)53 (61.6%).103763 (73.3%)53 (61.6%).1037
Clopidogrel18 (20.9%)3 (3.5%).0005*18 (20.9%)18 (20.9%)1
Direct factor inhibitors0 (0.0%)2 (2.3%).15490 (0.0%)0 (0.0%)1
Estrogen1 (1.2%)11 (12.8%).0028*1 (1.2%)0 (0.0%).3159

Comparison of Baseline Characteristics, Medical History, and Medication Use for Patients With RVO Who Received Intravitreal Anti-VEGF Injections

Vein Occlusion Cases vs. Vein Occlusion Past Time PeriodVein Occlusion Cases vs. Vein Occlusion Concurrent Cohort
Baseline DataVein Occlusion Case Cohort (n = 100)Vein Occlusion Past Time Cohort (n = 100)P ValueVein Occlusion Case Cohort (n = 100)Vein Occlusion Concurrent Time Cohort (n = 98)P Value
Mean age (standard deviation)72.2 (14.0)71.0 (13.8).445772.2 (14.0)71.9 (12.2).5741
Female (count)56 (56.0%)56 (56.0%)156 (56.0%)55 (56.1%).9862
Mean body mass index (standard deviation)28.3 (6.0)27.3 (6.6).126328.3 (6.0)27.9 (6.6).489
Family history of stroke (count)41 (48.2%)30 (31.9%).0258*41 (48.2%)37 (45.7%).7415
Medical History
Hypertension91 (91.0%)87 (87.0%).36691 (91.0%)80 (81.6%).0548
Coronary artery disease49 (49.0%)38 (38.0%).116749 (49.0%)57 (58.2%).1962
Transient ischemic attacks7 (7.0%)15 (15.0%).07067 (7.0%)9 (9.2%).573
Carotid stenosis17 (17.0%)20 (20.0%).584917 (17.0%)12 (12.2%).3441
Diabetes30 (30.0%)27 (27.0%).638430 (30.0%)23 (23.5%).2994
Atrial fibrillation24 (24.0%)38 (38.0%).032324 (24.0%)25 (25.5%).8055
Venous thromboembolism15 (15.0%)20 (20.0%).352115 (15.0%)17 (17.3%).6538
Pulmonary embolism8 (8.0%)11 (11.0%).46948 (8.0%)7 (7.1%).8197
Congestive heart failure19 (19.0%)39 (39.0%).0018*19 (19.0%)19 (19.4%).9448
Peripheral vascular disease11 (11.0%)25 (25.0%).01*11 (11.0%)5 (5.1%).1279
Hyperlipidemia76 (76.0%)64 (64.0%).064176 (76.0%)73 (74.5%).8055
Hypertriglyceridemia14 (14.0%)8 (8.0%).175114 (14.0%)10 (10.2%).4132
Obstructive sleep apnea22 (22.0%025 (25.00%).494922 (22.0%025 (25.5%).5616
Glaucoma40 (40.0%)34 (34.0%).379540 (40.0%)17 (17.3%).0004*
Chronic kidney disease26 (26.0%)28 (28.0%).750126 (26.0%)25 (25.5%).9372
Malignancy35 (35.0%)51 (51.0%).0381*35 (35.0%)32 (32.7%).7271
Smoking history41 (41.8%)43 (44.8%).677941 (41.8%)30 (33.3%).2296
Medications
Anti-hypertensives74 (74.0%)74 (74.0%)174 (74.0%)60 (61.2%).0546
Beta blockers57 (57.0%)46 (46.0%).119657 (57.0%)48 (49.0%).2582
Calcium channel blockers31 (31.0%)37 (37.0%).370531 (31.0%)31 (31.6%).9235
Statins63 (63.0%)40 (40.0%).0011*63 (63.0%)45 (45.9%).0158*
Insulin6 (6.0%)9 (9.0%).42066 (6.0%)6 (6.1%).9712
Warfarin19 (19.0%)25 (25.0%).350719 (19.0%)16 (16.3%).622
Aspirin50 (50.0%)58 (58.0%).256450 (50.0%)49 (50.0%)1
Clopidogrel10 (10.0%)10 (10.0%)110 (10.0%)9 (9.2%).8454
Direct factor inhibitors0 (0.0%)1 (1.0%).31610 (0.0%)0 (0.0%)1
Estrogen3 (3.0%)22 (22.0%)< .0001*3 (3.0%)4 (4.1%).6803

Stroke Characteristics for All Patients Based on Type and Distribution of Stroke

Cases vs. Past Time PeriodCases vs. Concurrent Time Period
Baseline DataCase Cohort (n = 690)Past Time Cohort (n = 659)P ValueCase Cohort (n = 690)Concurrent Time Cohort (n = 688)P Value
Total Number of Strokes38783826
Cerebral Hemispheric Location
  Right22 (47.9%)34 (43.6%).216322 (47.9%)16 (61.5%).6994
  Left14 (36.8%)38 (48.7%).216314 (36.8%)10 (38.5%).6994
  Both2 (5.3%)6 (7.7%).21632 (5.3%)0 (0%).6994
Stroke Distribution
  Indeterminate0 (0.0%)0 (0.0%).27680 (0.0%)0 (0.0%).6086
  Posterior Cerebral Artery Distribution6 (15.8%)7 (9.0%).27686 (15.8%)2 (7.7%).6086
  Lacunar12 (31.6%)36 (46.2%).276812 (31.6%)12 (46.2%).6086
  Middle Cerebral Artery Distribution17 (44.7%)25 (32.1%).276817 (44.7%)10 (38.5%).6086
  Anterior Cerebral Artery Distribution3 (7.9%)10 (12.8%).27683 (7.9%)2 (7.7%).6086
Type of Stroke
  Indeterminate0 (0.0%)2 (2.6%).71770 (0.0%)0 (0.0%).7805
  Ischemic27 (71.1%)57 (73.1%).717727 (71.1%)20 (76.9%).7805
  Hemorrhagic5 (13.2%)10 (12.8%).71775 (13.2%)2 (7.7%).7805
  Hemorrhagic Conversion0 (0.0%)0 (0.0%).71770 (0.0%)0 (0.0%).7805
  Embolic6 (15.8%)9 (11.5%).71776 (15.8%)4 (15.4%).7805

Stroke Characteristics for the Macular Degeneration Patients Based on Type and Distribution of Stroke

Exudative AMD Case Cohort vs. Non-Exudative AMD Concurrent CohortExudative AMD Case Cohort vs. Past Time Period CohortExudative AMD Case Cohort vs. Cataract Cohort
Baseline DataExudative AMD Case Cohort (n = 504)Non-Exudative AMD Concurrent Cohort (n = 504)P ValueExudative AMD Case Cohort (n = 504)Exudative AMD Past Time Cohort (n = 473)P ValueExudative AMD Case Cohort (n = 504)Cataract Cohort (n = 504)P Value
Total Number of Strokes301730463041
Cerebral Hemispheric Location
  Right17 (56.7%)10 (58.8%).989217 (56.7%)21 (45.7%).215117 (56.7%)18 (43.9%).29
  Left12 (40.0%)7 (41.2%).989212 (40.0%)20 (43.5%).215112 (40.0%)22 (53.7%).29
  Both1 (3.3%)0 (0.0%).98921 (3.3%)5 (10.9%).21511 (3.3%)1 (2.4%).29
Stroke Distribution
  Indeterminate0 (0.0%)0 (0.0%).27180 (0.0%)2 (4.3%).40320 (0.0%)1 (2.4%).1072
  Posterior cerebral artery distribution6 (20.0%)0 (0.0%).27186 (20.0%)4 (8.7%).40326 (20.0%)4 (9.8%).1072
  Lacunar10 (33.3%)7 (41.2%).271810 (33.3%)21 (45.7%).403210 (33.3%)0 (0.0%).1072
  Middle cerebral artery distribution11 (36.7%)8 (47.1%).271811 (36.7%)13 (28.2%).403211 (36.7%)16 (39.0%).1072
  Anterior cerebral artery distribution3 (10.0%)2 (11.8%).27183 (10.0%)6 (13.0%).40323 (10.0%)20 (48.8%).1072
Type of Stroke
  Indeterminate0 (0.0%)0 (0.0%).36310 (0.0%)0 (0.0%).57440 (0.0%)0 (0.0%).0117*
  Ischemic21 (70.0%)15 (88.2%).363121 (70.0%)36 (75.0%).574421 (70.0%)19 (46.3%).0117*
  Hemorrhagic5 (16.7%)1 (5.9%).36315 (16.7%)6 (12.5%).57445 (16.7%)3 (7.3%).0117*
  Hemorrhagic conversion0 (0.0%)0 (0.0%).36310 (0.0%)0 (0.0%).57440 (0.0%)0 (0.0%).0117*
  Embolic4 (13.3%)1 (5.9%).36314 (13.3%)4 (8.3%).57444 (13.3%)19 (46.3%).0177*

Stroke Characteristics for the Diabetic Patients Based on Type and Distribution of Stroke

Diabetic Case Cohort vs. Diabetic Past Time CohortDiabetic Case Cohort vs. Diabetic ConcurrentCohort
Baseline DataDiabetic Case Cohort (n = 86)Diabetic Past Time Cohort (n = 86)P ValueDiabetic Case Cohort (n = 86)Diabetic Concurrent Cohort (n = 86)P Value
Total Number of Strokes31735
Cerebral Hemispheric Location
  Right2 (66.7%)6 (35.3%).57552 (66.7%)4 (80.0%).6733
  Left1 (33.3%)10 (58.8%).57551 (33.3%)1 (20.0%).6733
  Both0 (0.0%)1 (5.9%).57550 (0.0%)0 (0.0%).6733
Stroke Distribution
  Indeterminate0 (0.0%)0 (0.0%).75870 (0.0%)0 (0.0%).6733
  Posterior cerebral artery distribution0 (0.0%)3 (17.6%).75870 (0.0%)0 (0.0%).6733
  Lacunar2 (66.7%)8 (47.1%).75872 (66.7%)4 (80.0%).6733
  Middle cerebral artery distribution1 (33.3%)4 (23.5%).75871 (33.3%)1 (20.0%).6733
  Anterior cerebral artery distribution0 (0.0%)2 (11.8%).75870 (0.0%)0 (0.0%).6733
Type of Stroke
  Indeterminate0 (0.0%)1 (5.9%).79910 (0.0%)0 (0.0%).6884
  Ischemic2 (66.7%)10 (58.9%).79912 (66.7%)3 (60.0%).6884
  Hemorrhagic0 (0.0%)2 (11.8%).79910 (0.0%)1 (20.0%).6884
  Hemorrhagic Cconversion0 (0.0%)0 (0.0%).79910 (0.0%)0 (0.0%).6884
  Embolic1 (33.3%)4 (23.5%).79911 (33.3%)1 (20.0%).6884

Stroke Characteristics for Patients With RVO Based on Type and Distribution of Stroke

Vein Occlusion Cases vs. Vein Occlusion Past Time PeriodVein Occlusion Cases vs. Vein Occlusion Concurrent Cohort
Baseline DataVein Occlusion Case Cohort (n = 100)Vein Occlusion Past Time Cohort (n = 100)P ValueVein Occlusion Case Cohort (n = 100)Vein Occlusion Concurrent Time Cohort (n = 98)P Value
Total Number of Strokes51454
Cerebral Hemispheric Location
  Right3 (60.0%)6 (42.9%).71773 (60.0%)2 (50.0%).7642
  Left2 (40.0%)7 (50.0%).71772 (40.0%)2 (50.0%).7642
  Both0 (0.0%)1 (7.1%).71770 (0.0%)0 (0.0%).7642
Stroke Distribution
  Indeterminate0 (0.0%)0 (0.0%).13820 (0.0%)0 (0.0%).0601
  Posterior cerebral artery distribution0 (0.0%)0 (0.0%).13820 (0.0%)2 (50.0%).0601
  Lacunar0 (0.0%)5 (35.7%).13820 (0.0%)1 (25.0%).0601
  Middle cerebral artery distribution5 (100.0%)7 (50.0%).13825 (100.0%)1 (25.0%).0601
  Anterior cerebral artery distribution0 (0.0%)2 (14.3%).13820 (0.0%)0 (0.0%).0601
Type of Stroke
  Indeterminate0 (0.0%)0 (0.0%).52370 (0.0%)0 (0.0%).3428
  Ischemic4 (80.0%)11 (78.6%).52374 (80.0%)2 (50.0%).3428
  Hemorrhagic0 (0.0%)2 (14.3%).52370 (0.0%)0 (0.0%).3428
  Hemorrhagic conversion0 (0.0%)0 (0.0%).52370 (0.0%)0 (0.0%).3428
  Embolic1 (20.0%)1 (7.1%).52371 (20.0%)2 (50.0%).3428

Comparison of the CATT, ANCHOR, MARINA, FOCUS, HORIZON, and SEVEN-UP Trials With Regard to Stroke Data

Study DesignNumber of PatientsLength of Follow-UpNumber of StrokesIschemic StrokesHemorrhagic StrokesIndeterminate StrokesStroke Details
CATTFour cohorts divided into receiving bevacizumab monthly or as needed and ranibizumab monthly or as needed, crossover at 1 year (did not change drug assignment)1,107 total patients; 599 ranibizumab and 586 bevacizumab2 years16Did not classify strokesDid not classify strokesDid not classify strokes16 nonfatal strokes, 8 for ranibizumab and 8 for bevacizumab; 26 vascular deaths
MARINAThree cohorts divided into monthly injections of either a sham, 0.3, or 0.5 mg ranibizumab for 2 years716 total patients; 238 sham, 238 0.3 mg, 240 0.5 mg2 years1121811 nonfatal strokes, 2 in the sham injection (1 subsequently died of a stroke), 3 in the 0.3 mg cohort, 6 in the 0.5 mg cohort; one of the patients who suffered stroke in sham cohort actually did receive one intravitreal 0.5 mg ranibizumab accidently; 10 vascular deaths
ANCHORThree cohorts divided into verteporfin PDT plus monthly sham injection or sham PDT plus monthly ranibizumab, PDT as needed every 3 months423 total patients; 143 PDT, 140 0.3 mg ranibizumab, 140 0.5 mg ranibizumab2 years5Did not classify strokesNo nonfatal hemorrhagic strokesDid not classify strokes5 nonfatal cerebrovascular accidents including 1 non-serious eventof cerebral ischemia, 2 in the PDTgroup, 3 in the 0.3mg ranibizumab cohort, none in the 0.5 mg cohort; 7 vascular deaths
FOCUSTwo cohorts, one receiving monthly injections of 0.5 mg ranibizumab, the other, sham injections. Both cohorts received PDT on day 0 and then quarterly as needed162 total patients; 106 ranibizumab, 56 sham injections2 years5Did not classify strokesNo nonfatal hemorrhagic strokesDid not classify strokes5 nonfatal ischemicor indeterminate strokes; higher rate of arterial thromboembolic events in PDT group (7.1%) vs ranibizumab group (4.8%)
HORIZON2 year extension of the ANCHOR, MARINA, and FOCUS trials853 total patients, 600 ranibizumab only, 190 ranibizumab crossover, and 63 ranibizumab naïve2 years after study (4 total)1913 nonfatal (12 in ranibizumab only, 1 in ranibizumab crossover) and 1 fatal in ranibizumab only cohort3 nonfatal (2 in ranibizumab only, 1 in ranibizumab crossover)1 nonfatal in ranibizumab naïve cohort and 1 fatal in ranibizumab only cohort19 total strokes, 17 nonfatal, 2 fatal; 18 vascular deaths (none were in the ranibizumab naïve cohort)
SEVEN-UP7.3 year follow-up study to the ANCHOR, MARINA, and HORIZON trials; FOCUS study excluded65 total patients7–8 yearsDid not report stroke dataDid not report stroke dataDid not report stroke dataDid not report stroke dataDid not report stroke data
Authors

From the Department of Ophthalmology, Mayo Clinic, Rochester, Minnesota (MRS, LAD, JEAC, RI, SJB); Mayo Clinic School of Medicine, Rochester, Minnesota (GMD, MDG, SMS); the Department of Health Sciences Research/Biomedical Statistics and Informatics, Mayo Clinic, Jacksonville, Florida (DOH); and the Department of Neurology, Mayo Clinic, Rochester, Minnesota (IM).

This paper was presented in part at the Association for Research in Vision and Ophthalmology meeting, May 7, 2017, Baltimore; the American Society of Retinal Specialists meeting, August 15, 2017, Boston; and the Retina Society meeting, October 7, 2017, Boston.

This study was made possible using the resources of the Rochester Epidemiology Project, which is supported by the National Institute on Aging of the National Institutes of Health under Award Number R01AG034676. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. This work was also supported by Research to Prevent Blindness, New York, and the VitreoRetinal Surgery Foundation, Minneapolis. None of the funding sources had any involvement in study design; collection, analysis, or interpretation of the data; writing the report; or the decision to submit for publication.

Dr. Iezzi is a consultant to and receives non-financial support from Alcon outside the submitted work. Dr. Bakri is a consultant to and receives non-financial support from Allergan, Genentech, Novartis, Roche, and Zeiss outside the submitted work. The remaining authors report no relevant financial disclosures.

Address correspondence to Sophie J. Bakri, MD, or Raymond Iezzi, MD, Mayo Clinic, Department of Ophthalmology, 200 First Street SW, Rochester, MN 55905; email: bakri.sophie@mayo.edu or iezzi.raymond@mayo.edu.

Received: March 22, 2018
Accepted: June 04, 2018

10.3928/23258160-20190503-14

Sign up to receive

Journal E-contents