This retrospective cohort study was performed in accordance with the Declaration of Helsinki and the STROBE guideline11. It has been approved by the Joint Chinese University of Hong Kong – New Territories East Cluster Clinical Research Ethics Committee. The requirement for patient consent has been waived because of the use of retrospective data. All data underlying this study is available on reasonable request to the corresponding author.
Source of data
All data used were retrieved from the Clinical Data Analysis and Reporting System (CDARS), a territory-wide electronic health records database documenting key demographics, diagnoses, procedures, and medication records of all patients that attend public healthcare institutions in Hong Kong. The International Classification of Diseases, Ninth Revision (ICD-9) codes were used to code all diagnoses. CDARS is linked to the Hong Kong Death Registry, a population-wide governmental registry of all Hong Kong citizens’ death records, from which mortality data may be obtained and linked to CDARS records. Causes of mortality were encoded using either ICD-9 or ICD-10, depending on the year of death. CDARS and its associated mortality data have been used extensively for research12, 13.
The inclusion criteria were adult patients (18 years old or above) who had a diagnosis of PCa and were receiving any ADT in Hong Kong between December 1999 and March 2021. Diagnosis of prostate cancer was determined by ICD-9 codes (Supplementary Table 1). ADT included bilateral orchidectomy, gonadotrophin-releasing hormone agonists, and gonadotrophin-releasing hormone antagonists.
The following patients were excluded: (a) with less than 180 days of medical castration without subsequent bilateral orchidectomy, (b) with less than 180 days of concurrent statin use and ADT, and (c) with missing baseline total cholesterol level.
Definition of statin users and non-users
Statin users were defined as patients who had at least 180 days of concurrent statin and ADT use. Statin non-users were defined as patients who never used statin.
Follow-up and outcomes
All patients were followed up from the day of ADT initiation (baseline date) up until 30 September 2021. The primary outcome was PCa-related mortality. The secondary outcome was all-cause mortality. The duration between ADT initiation and mortality was recorded, and all causes of death were ascertained by ICD codes (Supplementary Table 2).
All included patients’ age at baseline, type of ADT received, other comorbidities at baseline as determined by ICD-9 codes (hypertension, ischaemic heart disease, myocardial infarction, heart failure, stroke, diabetes mellitus, chronic kidney disease, anaemia, atrial fibrillation, chronic liver disease, chronic obstructive pulmonary disease, hyperlipidaemia, any malignancy; codes detailed in Supplementary Table 1), use of other medications (angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker, beta-blocker, dihydropyridine calcium channel blocker, metformin, sulfonylurea, dipeptidyl peptidase-4 inhibitor, glucagon-like peptide 1 receptor agonist, insulin, corticosteroid, antiplatelet, anticoagulant, and androgen receptor antagonists (abiraterone, enzalutamide, and bicalutamide)), ever underwent radiotherapy, ever underwent radical prostatectomy, prior chemotherapy (docetaxel, cabazitaxel, mitoxantrone, and estramustine), chemotherapy concurrent with ADT, and total cholesterol level at baseline were recorded.
Due to the nature of our data source, cancer staging is unavailable. To mitigate this limitation, we considered the use of androgen receptor antagonists or chemotherapy, typical treatments of metastatic PCa, as a surrogate marker of metastatic PCa14. An a priori subgroup analysis was performed, comparing patients with and without the use of these medications, to explore whether the associations between statin use and mortality risks would apply to patients with metastatic PCa. A second a priori subgroup analysis was performed for each type of ADT given to investigate whether the associations between statin use and mortality risks remained significant for different types of ADT.
To investigate the effects of statin use at the time of ADT initiation on the observations, a sensitivity analysis was performed where patients who were not using statin at the time of ADT initiation were excluded from the statin user group, such that only statin users who had statin use at the time of ADT initiation were compared against patients who never used statin.
Whilst the present study included a mix of hydrophilic and lipophilic statins, a sensitivity analysis was performed by excluding patients who had any hydrophilic statin exposure from the user group in order to investigate the mortality effects of lipophilic statin use.
Continuous variables were expressed as mean ± standard deviation. Logistic regression-based inverse probability treatment weighting (IPTW) using the aforementioned covariates was used to balance the treatment groups. Standardized mean difference (SMD) was used to examine the balance of covariates between treatment groups, with values < 0.1 considered to represent good balance.
IPTW-weighted univariable Cox regression was used to assess the association of statin treatment with the risks of the outcomes. Weighted hazard ratios (wHR) with 95% confidence intervals (CI) were used as the summary statistics. Kaplan-Meier curves were used to visualize the cumulative freedom from the outcomes.
All p values were two-sided, with values < 0.05 considered statistically significant. All statistical analyses were performed on SPSS (version 25.0, IBM Corp, USA) or Stata (Version 13.0, StataCorp LLC, USA).