Study population and data source
The study was conducted and is reported based on recommendations of the STROBE statement.16
The study population was derived from the General Practice Research Database (GPRD), a medical records database in the United Kingdom (UK) that was established for epidemiologic research in 1987. Details of the GPRD, including validation of psoriasis, cardiovascular risk factors and cardiovascular disease, have been published elsewhere.3, 7, 17
Time period and age eligibility
Data were obtained between 1987–2002 for patients who were 18 years or older at the date their person-time began. For the primary analysis, patients with a history of cardiovascular disease, defined as a code of ischemic heart disease, myocardial infarction, transient ischemic attack, stroke or peripheral arterial disease on or before the start date, were excluded.
Definition of exposure
We defined patients with severe psoriasis as those with a diagnostic code of psoriasis and history of systemic therapy consistent with severe psoriasis, including phototherapy, PUVA, methotrexate, azathioprine, cyclosporine, oral retinoids (etretinate, acitretin), hydroxyurea, and mycophenolate mofetil. Of note, during the time period in which this study was conducted, biologic therapies were not approved for treatment of psoriasis in the UK and therefore are not represented in this dataset. The unexposed population (controls) was composed of patients with no history of a psoriasis diagnostic code.
Sampling of exposed and unexposed cohorts
All patients with severe psoriasis (as defined above) who were 18 years or older at their index date, and had at least 1 day of observation time, were included. For patients with severe psoriasis, their index date was the first date on or after the first diagnosis of psoriasis in which the patient received a code for treatment consistent with severe disease. For patients without psoriasis, their index date was the date of a medical record entry which was within 60 days of the psoriasis index date. Up to 4 unexposed subjects who were 18 years or older at their index date were randomly selected for each patient with psoriasis, matched on practice, date of registration in the practice, and psoriasis index date (corresponding to a medical record date of the unexposed patient).
For patients with severe psoriasis, follow-up started at the latest date when the patient could first be defined as having severe psoriasis (e.g. received a treatment code consistent with severe disease), was registered with the practice, or the practice was deemed up to standard (UTS), defined as having sufficient data meeting audit requirements to participate in research. For unexposed subjects, follow-up started at the latest date when the patient was registered in the practice, the index date (matched to the psoriasis index date), and the date that the practice was deemed UTS. For all groups, follow-up ended at the date of death, development of an outcome of interest, transfer out of the practice, or end of UTS.
Outcome of interest
The outcome of interest was first recorded major adverse cardiac event, defined as occurrence of non-fatal myocardial infarction, non-fatal stroke, or death due to cardiovascular etiology. Outcomes were determined by diagnostic codes consistent with acute myocardial infarction, acute ischemic stroke, or mortality secondary to myocardial infarction, stroke, or arrhythmia. These outcomes have been previously validated for research in the GPRD17–19
and have been demonstrated by our group and others.4, 7, 20–22
Co-variables of interest
We identified traditional cardiovascular risk factors including age, sex, hypertension, diabetes, hyperlipidemia, and smoking (current, former, never) by the presence of diagnostic codes. BMI was extracted from patient charts in 69% of the cohort.
The sample size was determined by including the maximum eligible number of patients with severe psoriasis based on age criteria. We randomly selected up to 4 unexposed subjects per patient with psoriasis, as additional matching yields minimal increases in statistical power. Data were summarized descriptively and differences in dichotomous and continuous variables were examined between patients with and without psoriasis. Dichotomous variables were tested with Fisher’s exact test. Continuous variables were tested with a T-test if they were normally distributed, or with the Wilcoxon test if the data were not normally distributed. We fit age- and sex-adjusted Cox proportional hazards models to determine the overall hazard ratio (HR) of major adverse cardiac events comparing psoriasis patients to those without psoriasis. The primary model included major cardiovascular risk factors. Multiple sensitivity analyses were performed to test the underlying assumptions of our primary analysis and to test the robustness of our findings. All analyses were performed using STATA 10.0, and a two-sided p-value <0.05 was the threshold for statistical significance.
We applied the adjusted HR of psoriasis obtained from the primary model to the following formula to estimate 10-year incidence of major adverse cardiac events: adjusted HR for major adverse cardiac events in psoriasis × baseline incidence of major adverse cardiac events in the unexposed population resulted in an adjusted incidence rate (IR) for major adverse cardiac events in the psoriasis group. We subtracted the baseline incidence of major adverse cardiac events in the unexposed population from this adjusted IR of major adverse cardiac events in psoriasis to obtain the excess attributable risk of psoriasis. The attributable risk of psoriasis was multiplied by ten to obtain 10-year risk of major adverse cardiac events due to psoriasis.
Protection of Human Subjects
This study was approved by the University of Pennsylvania Institutional Review Board and by the Independent Scientific Advisory Committee of the Medicines and Healthcare Products Regulatory Agency of the United Kingdom Department of Health. The study was conducted in accordance with the Declaration of Helsinki.