Safety of Apremilast in Patients with Psoriasis and Psoriatic Arthritis: Findings from the UK Clinical Practice Research Datalink

Data Sources

This study was conducted using the UK Clinical Practice Research Datalink (CPRD), which is the largest research database in the UK with longitudinal, representative primary care data linked to data from other healthcare settings (Fig. 1). The CPRD supports international pharmacovigilance by providing a large, anonymized, representative general population database and is the basis of over 2900 published research studies. The UK CPRD encompasses two large population-based electronic medical databases: CPRD GOLD and CPRD Aurum. CPRD Aurum, which is newly available to researchers and continues to undergo validation assessments, was found to have an incomplete capture of apremilast prescriptions. See the Electronic Supplementary Material (ESM) for a summary of CPRD Aurum methods and findings. Methods and results for the CPRD GOLD study are described here. The CPRD GOLD contains electronic patient records of over 3 million currently registered patients from 397 general practices [14] and includes demographics, diagnoses, prescriptions, and lifestyle factors recorded by general practitioners (GPs) as well as clinical information sent to GPs from hospitalizations and specialist encounters [15]. Validation studies have repeatedly demonstrated the high quality and completeness of CPRD GOLD data [16,17,18]. The study protocol was approved by the Independent Scientific Advisory Committee for MHRA Database Research. The study was conducted in accordance with the principles of the Declaration of Helsinki of 1975, and its later amendments.

Fig. 1figure 1

Study design. AESI adverse events of special interest, GP general practitioner, Rx prescription

Cohort Definitions

The study population was selected from all adults with research quality data and a prescription for a systemic PsO or PsA treatment (see ESM) recorded between January 2015 and June 2020. There were four exposure groups: apremilast-exposed (with or without other concomitant non-apremilast treatments) and three non-apremilast groups (oral treatment only exposed, injectable treatment only exposed, and oral and injectable treatment [concomitant or sequential] exposed). Non-apremilast treatments included those prescribed for PsO or PsA at the time of the initial protocol approval in 2015 as well as new treatments approved thereafter. These drugs included tumor necrosis factor inhibitor biologics, non-tumor necrosis factor inhibitor biologics, DMARDs, oral or injectable steroids, and azathioprine. Each patient in the apremilast-exposed cohort was matched, with replacement, to up to ten patients in each non-apremilast cohort for age (± 3 years), sex, year of record start (± 3 years or a longer history for the matches than the apremilast-exposed patient), and calendar time (the non-apremilast patient was required to be present in the database on the date of the first apremilast prescription of the matched apremilast-exposed patient). Matched patients were required to have a diagnosis code for PsO and/or PsA recorded at any time and at least one prescription for a non-apremilast comparison treatment within 6 months or any time after the apremilast-exposed patient’s first apremilast prescription.

For patients in the apremilast-exposed cohort, the cohort entry date was the first apremilast prescription. For patients in the non-apremilast cohorts, the cohort entry date was the matched date (date of apremilast user’s first apremilast prescription) unless their last prescription was recorded before the matched date. In these instances (2%), the cohort entry date was the date of the first prescription received in the 6 months before the matched date. While matched non-apremilast patients were required to have at least 1 year of registration before the cohort entry date, 19 (6%) apremilast-exposed patients had < 1 year of registration prior to cohort entry. This was done to capture as many apremilast-exposed patients as possible, given the small number of these patients available in the database (Table 1).

Table 1 Description of patients at cohort entry in the apremilast and matched non-apremilast treatment cohorts: CPRD GOLD (2015–20)Outcomes

Adverse events of special interest were identified a priori based on those observed in apremilast clinical trial programs [5,6,7,8,9, 19], the mechanism of action of apremilast, apremilast non-clinical data, possible class effects, known comorbidities in patients with PsO or PsA, and safety issues identified with currently marketed compounds in the proposed indications. These events were identified using Read codes (see ESM) and included cancers, opportunistic and serious infections, major adverse cardiac events (MACE), vasculitis, tachyarrhythmia, hypersensitivity reactions, suicidal behaviors, treated depression, and treated anxiety/nervousness. All-cause mortality was also included to capture important potentially drug-related events resulting in death.

All AESIs were required to be incident (i.e., first recorded after cohort entry) with the exception of episodic AESIs (opportunistic and serious infections and hypersensitivity reactions). That is, analyses for a specific AESI excluded patients with a history of that outcome on or before cohort entry. Treated depression required at least one prescription for an antidepressant recorded within 60 days of a depression diagnosis and analyses excluded patients with the treated condition at any time before cohort entry or who received an antidepressant without a recorded depression diagnosis in the year before cohort entry. Treated anxiety was defined similarly, using records for anti-anxiety treatments and anxiety diagnoses. Major adverse cardiac events included myocardial infarction, non-traumatic stroke, and sudden cardiac death. Tachyarrhythmias included atrial fibrillation and flutter, supraventricular tachyarrhythmia and tachycardia, and ventricular tachycardia, fibrillation, and flutter. Opportunistic and serious infections included pneumocystis pneumonia, cryptosporidiosis, mycobacterial infections (including tuberculosis), bartonellosis, leukoencephalopathy, candidiasis, cryptococcosis, other mycoses, cytomegaloviral disease, herpes simplex, herpes zoster, human papilloma virus, viral hepatitis, Epstein–Barr virus infection, histoplasmosis, and toxoplasmosis, and infections that required hospitalization, were life threatening, or resulted in death. We reviewed the electronic record of each case of MACE, cancer, vasculitis, and tachyarrhythmia to confirm that the records contained additional clinical evidence for the diagnosis and a sample of cases of depression, anxiety, infection, and hypersensitivity reaction to ensure that these conditions were appropriately coded. No cases were excluded as potential rule-outs or miscoded diagnoses.

Analysis

Person-days were accumulated for each patient from the first study drug prescription on or after cohort entry until the first of the following: (1) study outcome occurred (separately for each outcome), (2) end of study drug filled use and outcome-specific lag time, (3) end of patient record, (4) death, or (5) end of data collection. Lag times were set a priori to reflect the amount of time it could take for the outcome to manifest after exposure; 90 days for all-cause mortality, MACE, and vasculitis; 30 days for infections, suicidal behaviors, depression, and anxiety; and 14 days for tachyarrhythmia and hypersensitivity reactions. Cases of malignancy were assessed starting 1 year after the date of the first study drug after cohort entry through the end of the patient record. The electronic record of each case of an AESI was reviewed to confirm that the patient was exposed to a study drug (including lag times) at the time of the event.

We estimated IRs per 1000 patient-years with 95% confidence intervals (CIs) for each AESI by cohort. For AESIs with more than five events in the apremilast-exposed cohort, we calculated crude incidence rate ratios (IRRs) with 95% CIs using Poisson regression for each non-apremilast cohort versus the apremilast-exposed cohort (i.e., apremilast was used as the common reference for all IRR estimates). For outcomes with more than five events in the apremilast-exposed cohort, we also provided cumulative incidence functions for each AESI by cohort using the Kaplan–Meier method. Statistical analyses were carried out using Stata 15 (StataCorp LLC, College Station, TX, USA).

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