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Table 1 Characteristics of included studies

From: A meta-analysis of stroke risk following herpes zoster infection

  Breuer Kang Kwon Langan Lin Minassian Sreenivasan Sundström Yawn
Year 2014 2009 2016 2014 2010 2015 2013 2015 2016
Design Retrospective Matched Cohort Retrospective Matched Cohort Retrospective Matched Cohort Self-Controlled Case Series Retrospective Matched Cohort Self-Controlled Case Series Retrospective Cohort Retrospective Cohort Retrospective Matched Cohort
Data Source, Country The Health Improvement Network (THIN) general practice database, United Kingdom Taiwan National Health Insurance Research Database (NHIRD), Taiwan Korea Health Insurance Database, Korea UK Clinical Practice Research Datalink (CPRD) general practice database, United Kingdom Taiwan National Health Insurance Research Database (NHIRD), Taiwan Medicare administrative data claims, USA Danish Civil Registration System (CRS), Denmark Västra Götaland County Primary Health Care Register and the Swedish Patient Register, Sweden Rochester Epidemiology Project, USA
HZ diagnosis period 2002–2010 1997–2001 2003–2013 1987–2012 2003–2004 2006–2011 1995–2008 2008–2010 1986–2011
Number of Cases (HZ and HZO) 106,601 7,760 70,424 6,584 658 42,954 117,926 13,296 4,478
Number of Controls 213,202 23,280 695,755 0 1,974 0 4,503,054 ~1,500,000 16,800
Follow-Up Period 24 years 1 year 11 years 1 year 1 year 1 year 14 years 1 year 3 years
Gender, % female 59 52 49 57 51 71 51 60 62
Mean age at zoster diagnosis, years 59 47 41 Median age at stroke onset 77 years 57 80 Not reported 59 68
% Receiving AV Therapy Not reported Not reported Not reported 55% 24% of cases 100% 50% Not reported Not reported
Case Inclusion Criteria Adults 18 years of age or older diagnosed with incident HZ or HZO (index date as recorded in database) Adults 18 years of age or older presenting to ambulatory clinic with incident HZ or HZO (index date as recorded in database) Adults 18 years of age or older with incident HZ Adults 18 years of age or older with incident HZ or HZO and incident stroke Adults 18 years of age or older presenting to ambulatory clinic with incident HZO (index date as recorded in database) Adults 65 years of age or older with evidence of incident HZ or HZO and an incident ischemic/nonspecific stroke Adults 18 years of age or older who received acyclovir 800 mg in packs of 35 All individuals recorded in either of the two databases with incident HZ Adults 50 years and older with incident HZ
Case Exclusion Criteria Patients who experienced cardiovascular/stroke event (MI, TIA, stroke) before index date and those with recurrent HZ Patients who had been diagnosed with stroke before the index date Patients who had been diagnosed with stroke before HZ Patients with evidence of HZ, postherpetic neuralgia, or stroke before the study period. Patients with incident episodes of TIA and subarachnoid hemorrhage or risk factors for subarachnoid hemorrhage. Patients with encephalitis 12 months after stroke. Patients with nonspecific cerebral aneurysms. Patients diagnosed with HZO during the previous 1-year period. Patients diagnosed with any type of stroke prior to index ambulatory care visit. Patients with systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, HIV, malignancy, and use of steroids or immunosuppressants for more than 1 month within 1 year prior to index date. Individuals with evidence of vascular events or HZ before observation period. Secondary inpatient diagnosis of zoster or cardiovascular events. Individuals with subarachnoid hemorrhage (or established risk factors of) or encephalitis diagnosed up to 12 months after stroke Patients who received a second acyclovir prescription of same strength and pack size. Patients with a stroke or TIA diagnoses before the start of the follow up period as per the ICD10 codes below as well as ICD8 codes 430-438 Patients diagnosed with HZ during the previous 1-year Recurrent herpes simplex infection, history of stroke great than 1 month before index date, MI before index date
HZ Definition Read codes corresponding to diagnoses of incident HZ (index date as recorded in database) Incident HZ diagnosis using ICD9 codes 053x (index date as recorded in database) ICD10 codes corresponding to diagnoses of incident HZ (index date as recorded in database) Read or ICD10 codes corresponding to diagnoses of incident HZ N/A HZ diagnosis using ICD-9 codes 053x
AND antiviral therapy 7 days before or after diagnosis
Patients who filled a single prescription of acyclovir 800 mg for 35 tablets Incident HZ diagnosis using ICD-10 code B02.X Incident HZ diagnosis using ICD-9 codes, and confirmed by medical record review
HZO Definition Read codes corresponding to diagnoses of incident HZO Incident HZO diagnosis using ICD9 code 053 N/A Read codes corresponding to diagnoses of incident HZO Incident HZO diagnosis based on the ICD9 code 053.2 HZO diagnosis using ICD-9 codes
AND antiviral therapy 7 days before or after diagnosis
N/A N/A N/A
Stroke Definition Read codes corresponding to stroke, diagnosis Stroke/TIA diagnosis as per ICD9 codes 430-438 Stroke/TIA diagnosis as per ICD10 codes Read or ICD10 codes corresponding to stroke diagnosis Stroke/TIA diagnosis as per ICD9 codes 430-438 Ischemic/nonspecific stroke diagnosis as per ICD9 codes 436, 433x1, or 434x1 Diagnosis in hospital of stroke/TIA as per ICD10 I60-64 and G45 Stroke diagnosis as per ICD-10 codes I61-I64 (excluding I62) Stroke diagnosis using ICD-9 codes
Control selection Patients who had no record of HZ, matched (2:1) by age (+/−2 years), sex, and general practice Patients with no HZ or stroke before 2001, matched (3:1) on age and sex, and defined their index date as their first ambulatory care visit in 2001 Patients without HZ, matched on age group Self controlled Selected from remaining patients, matched (3:1) on age group and gender, and defined their index date as their first ambulatory care visit in 2004 Self controlled Patients who had no prior history of acyclovir, valacyclovir, or famciclovir use (as a proxy for unexposed) Total remaining population without HZ Matching each patient with HZ with up to 4 patients whose birthday was +/− 1 year, who were the same sex, and no HZ in the past 5 years
Confounders (Adjusted for) Age, sex, obesity, smoking, high cholesterol recording, hypertension, diabetes, ischemic heart disease, atrial fibrillation, intermittent arterial claudication, carotid stenosis, and valvular heart disease Age, sex, hypertension, diabetes, coronary heart disease, hyperlipidemia, renal disease, atrial fibrillation, heart failure, heart valve/myocardium disease, carotid/peripheral vascular disease, monthly income, urbanization level, and geographical region Age, male gender, hypertension, hyperlipidaemia, ischaemic heart disease, diabetes,
heart failure, peripheral vascular disease, arterial fibrillation or atrial flutter, renal disease and valvular
heart disease
Confounders are implicitly controlled for due to study design Age, sex, hypertension, diabetes, hyperlipidemia, coronary heart disease, chronic rheumatic heart disease, other forms of heart disease, and medication habits Confounders are implicitly controlled for due to study design Age, sex, calendar period, acute MI, atrial fibrillation, education, cancer, medications (antihypertensives, drugs used to treat dyslipidemia and atrial fibrillation, immunosuppressive drugs) Age and sex Age, sex, hypertension, dyslipidemia, coronary artery disease (including MI), arrhythmias, congestive heart failure, diabetes, depression, chronic obstructive pulmonary disorder, vasculopathies, stroke, and anxiety
Relevant study outcomes Stroke HR after >1 year follow up, with analyses stratified by age <40 and ≥40 years, and by HZO. Stroke HR after 1 year follow up since HZ, with analyses stratified by age (<45 and ≥ 45 years), gender and by HZO Stroke HR after 11 years of follow up, stratified by age 18–30, 30–40, 40–50, 50–60, 60–70, and >70 years Stroke IR 1–4, 5–12, 13–26, and 27–52 weeks after HZ or HZO +/−head and
neck involvement, with analyses stratified by those
who received antiviral therapy and by HZO
Stroke HR after 1 year follow up since HZO, with analyses stratified by those
who received antiviral therapy
Stroke IR at 1, 2–4, 5–12, 13–26, and 27–52 weeks since HZ diagnosis, with analyses stratified by gender, HZO Stroke IRR after <2 weeks, 2–52 weeks, and >1 year follow up since HZ, with analyses stratified by age <40, 40–59, and ≥60 years and by gender Stroke IRR after 1 year follow up, with analyses stratified by age <40, 40–49, 50–59, 60–69, 70–79, and ≥80 years and gender Stroke OR 3 and 6 months and 1 and 3 years after zoster.
  1. HZ herpes zoster, HZO herpes zoster ophthalmicus, MI myocardial infarction, TIA transient ischemic attack, HIV human immunodeficiency virus, BMI body mass index, IQR interquartile range, ICD International Classification of Diseases, HR hazard ratio, IR incidence ratio, OR odds ratio