Long‐term prognostic impact of cardiovascular comorbidities in patients with prostate cancer receiving androgen deprivation therapy: A population‐based competing risk analysis

Our study investigated how adverse cardiovascular outcomes are impacted by cardiovascular comorbidities in patients with prostate cancer treated by androgen deprivation therapy (ADT). Using prospective, population‐based data, all Hong Kong patients with prostate cancer who received ADT during 1 January 1993 to 3 March 2021 were identified and followed up for the endpoint of cardiovascular hospitalization/mortality until 31 September 2021, whichever earlier. Multivariable competing risk regression was used to compare the endpoint's cumulative incidence between different combinations of major cardiovascular comorbidities (heart failure [HF], myocardial infarction [MI], stroke and/or arrhythmia), with noncardiovascular death as competing event. Altogether, 13 537 patients were included (median age 75.9 [interquartile range 70.0‐81.5] years old; median follow‐up 3.3 [1.5‐6.7] years). Compared to those with none of prior HF/MI/stroke/arrhythmia, the incidence of the endpoint was not different in those with only stroke (subhazard ratio [SHR] 1.06 [95% confidence interval (CI): 0.92‐1.23], P = .391), but was higher in those with only HF (SHR 1.67 [1.37‐2.02], P < .001), arrhythmia (SHR 1.63 [1.35‐1.98], P < .001) or MI (SHR 1.43 [1.14‐1.79], P = .002). Those with ≥2 of HF/MI/stroke/arrhythmia had the highest incidence of the endpoint (SHR 1.94 [1.62‐2.33], P < .001), among whom different major cardiovascular comorbidities had similar prognostic impacts, with the number of comorbidities present being significantly prognostic instead. In conclusion, in patients with prostate cancer receiving ADT, the sole presence of HF, MI or arrhythmia, but not stroke, may be associated with elevated cardiovascular risks. In those with ≥2 of HF/MI/stroke/arrhythmia, the number of major cardiovascular comorbidities may be prognostically more important than the type of comorbidities.

cardiovascular comorbidities may be prognostically more important than the type of comorbidities.

K E Y W O R D S
androgen deprivation therapy, cardio-oncology, comorbidity, hospitalization, mortality, prostate cancer What's new?
While androgen deprivation therapy has been associated with adverse cardiovascular outcomes in patients with prostate cancer, how adverse cardiovascular outcomes are impacted by cardiovascular comorbidities remains unclear. In this Hong Kong population-based study of 13 537 patients covering the 1993 to 2021 period, a history of heart failure, myocardial infarction and arrhythmia, but not stroke, was associated with co-existing cardiovascular conditions, as well as a higher risk of cardiovascular events on follow-up. However, in patients with more than two major co-existing cardiovascular conditions, the number of cardiovascular comorbidities may have greater prognostic importance than the type of comorbidities.

| INTRODUCTION
Androgen deprivation therapy (ADT) involves pharmacological or surgical suppression of androgen activity, and has long been a cornerstone of prostate cancer (PCa) treatment. 1 While the efficacy of ADT for treating PCa is undoubted, the past decade has seen studies demonstrating an association between ADT and adverse cardiovascular outcomes. Ever since the landmark study by Keating et al, 2 ADT has been shown to be associated with increased risks of myocardial infarction, arrhythmia, stroke, heart failure and cardiovascular mortality, with many also demonstrating other aspects of adverse cardiometabolic outcomes. 3 Given the rising prevalence of PCa and the important role played by ADT in PCa treatment, increasing attention has been given to the adverse cardiovascular effects of ADT. In the 2022 European Society of Cardiology Guidelines on cardio-oncology, one of the first major societal guidelines in cardio-oncology, a separate section was dedicated to the surveillance for ADT-related cardiotoxicity. 4 The same guideline recommended the use of the Heart Failure Association-International Cardio-Oncology Society (HFA-ICOS) risk assessment tool for cardiovascular risk stratification of cardio-oncology patients, in which numerous cardiovascular risk factors were designated categories that reflect their relative prognostic significance for cardiotoxicity related to a specific class of anticancer medications. 4,5 However, this important risk assessment tool did not include such designations for ADT. Indeed, little is known about the relative impact of different cardiovascular risk factors on adverse cardiovascular outcomes. Similarly, studies of relationships between different cardiovascular risk factors in patients receiving ADT are lacking. These represent important gaps in the understanding and stratification of cardiovascular risk and burden in these patients. Therefore, we aimed to investigate the interrelationship between different major cardiovascular comorbidities, and their impact on cardiovascular outcomes in patients with PCa receiving ADT.

| MATERIALS AND METHODS
Our study was conducted in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology guideline. ADT included medical castration and bilateral orchiectomy (BO).

| Follow-up and outcomes
All patients were followed up from the date of ADT initiation until 31 September 2021, death or the primary endpoint, whichever occurred earlier. The primary endpoint was a composite of cardiovascular hospitalization and cardiovascular mortality. Cardiovascular hospitalizations were identified by ICD-9 codes listed in Table S1, while cardiovascular mortality was identified by ICD-9 or ICD-10 codes listed in Table S2.

| Major cardiovascular comorbidities and their relative impact
We focused on prior history of HF, MI, stroke and arrhythmia as the major cardiovascular comorbidities of interest. These comorbidities were chosen among broader cardiometabolic conditions, such as hypertension and diabetes mellitus, as (a) we had shown that these accounted for >75% of cardiovascular hospitalizations in patients with PCa receiving ADT, 14  As these comorbidities commonly overlap, we further explored the relative impact of each major cardiovascular comorbidity in those with overlapping comorbidities (ie, with ≥2 major cardiovascular comorbidities). This was done by comparing patients with both a condition of focus and any of the "nonfocus" conditions against patients with ≥2 of the "nonfocus" conditions. For instance, to explore the relative impact of HF, we compared patients with HF and any of MI/stroke/arrhythmia against those with ≥2 of MI/stroke/arrhythmia.

| Statistical analyses
Continuous variables were expressed as medians with interquartile ranges (IQRs). There was no missing value due to the nature of database and variables used. All variables used for multivariable adjustments were determined based on clinical expertise. The number of major cardiovascular comorbidities was compared between groups using multivariable Poisson regression adjusting for all recorded baseline variables, with the ratio of cardiovascular comorbidity counts and corresponding 95% confidence intervals (CIs) as summary statistics.
Noncardiovascular mortality constituted a competing event for the primary outcome. As Kaplan-Meier curves over-estimate cumulative incidences in the presence of competing events, 14,15 the causespecific cumulative incidence of the primary endpoint was estimated and visualized using the Aalen-Johansen estimator. 14,15 The 3-, 5-and 10-year cause-specific cumulative incidences were estimated for each group (none of HF/MI/stroke/arrhythmia, HF only, MI only, stroke only, arrhythmia only and at least two of HF/MI/stroke/arrhythmia).
The cumulative incidence of the primary endpoint was quantitatively compared between groups using multivariable Fine-Gray competing risk regression, with subhazard ratios (SHRs) and 95% CIs as summary statistics and adjusting for all collected baseline variables. All reported SHRs and corresponding CIs are adjusted estimates.
As the exploratory analysis for the relative impact of each major cardiovascular comorbidity focused on patients with ≥2 of these comorbidities, the corresponding Fine-Gray regressions were additionally adjusted for the number of major cardiovascular comorbidities present to account for potential imbalances in the number of comorbidities between groups. Furthermore, in view of the results from the exploratory analysis, a post hoc analysis was conducted to explore the prognostic effects of the number of major cardiovascular comorbidities on the primary endpoint among patients with ≥2 of these comorbidities. Because very few patients had all four of these comorbidities, this post hoc analysis compared those with two of these comorbidities against those with ≥3 of these comorbidities.
Fine-Gray regression was separately performed in two prespecified and one post hoc subgroup analyses. First, to clarify any impact that heterogeneity in the type of ADT may have on the observed effects, subgroup analysis was performed for each type of ADT (medical castration, bilateral orchidectomy and both; all patients received bilateral orchidectomy after medication castration, mostly because, until recently, the local reimbursement system did not subsidize medical castration and bilateral orchidectomy was often performed as a cost-saving long-term alternative to medical castration). On the other hand, as cancer staging and histology were not available from the database used, we used ever-prescription of ARSI or chemotherapy as a surrogate for metastatic disease, as these were only indicated in metastatic PCa. 16,17 The second subgroup analysis thus stratified patients by whether they were ever prescribed ARSI or chemotherapy, as a surrogate of whether they had metastatic disease. The third, post hoc subgroup analysis explored the effects of metabolic dysfunction or hypertension on our findings, with stratification for the presence of hypertension, diabetes mellitus or dyslipidemia. Due to the small sample sizes for each risk category, interactions between subgroups were not tested. Additionally, due to the relatively small number of patients with ≥2 major cardiovascular comorbidities, these subgroup analyses were not performed for the exploratory analysis of the relative impact of each comorbidity in those with overlapping comorbidities.
Two-sided P < .05 were considered statistically significant. All analyses were performed on Stata version 16 Among patients who had one to three of the four major cardiovascular comorbidities, patients who had HF, MI or arrhythmia had significantly more major cardiovascular comorbidities than those who did not have each of these conditions (P < .001 for all; Table 2), but not for those who had stroke (P = .303). The number of patients with each possible combination of major cardiovascular comorbidities are shown in Table S3.  Table S4. Compared to patients who had none of prior HF/MI/ T A B L E 1 Characteristics of included patients.

| Impact of cardiovascular comorbidities
T A B L E 2 Comparison of the number of major cardiovascular comorbidities among those who had one to three of such these conditions.

| Subgroup analysis
Subgroup analysis by the type of ADT (

| Relative impact of each comorbidity in patients with overlapping comorbidities
The relative impact of each specified major cardiovascular comorbidity were explored among the 494 patients with ≥2 of HF/MI/stroke/arrhythmia, with cumulative incidences of the primary endpoint stratified by different combinations of cardiovascular comorbidities (Figure 2   conferred similarly elevated cardiovascular risks compared to those without any of these conditions, but stroke was not associated with any significant increase in cardiovascular risks, regardless of the type of stroke. Third, in those with ≥2 of HF/MI/stroke/arrhythmia, these conditions may have similar impact on cardiovascular risks, and the overall number of comorbidities was likely a significant prognosticator for cardiovascular events. It is less clear why patients with stroke only did not have significantly different incidence of the primary endpoint compared to those without any of the major cardiovascular comorbidities, regardless of the type of stroke. A probable explanation may be that significant physical disability and immobility are not uncommon in patients with major stroke, which are likely to deter clinicians from initiating ADT in these patients. Therefore, the observed patients with only stroke likely had relatively mild stroke, implying a less prominent association with underlying atherosclerotic burden and inflammatory activity which thus did not confer any significant increase in the risk of adverse cardiovascular outcomes. This was further supported by our finding that patients with a history of stroke did not have significantly different number of major cardiovascular comorbidities than those without stroke ( However, CDARS has been demonstrated to have good data completeness and accuracy, 7 and all data were input by treating clinicians independent of the authors.

| CONCLUSIONS
In patients with PCa receiving ADT, the sole presence of a history of HF, MI and arrhythmia, but not stroke, were associated with the presence of more major cardiovascular comorbidities. The sole presence of HF, MI or arrhythmia, but not stroke, may be associated with significantly elevated cardiovascular risks. In those with ≥2 of prior HF/MI/ stroke/arrhythmia, the number of cardiovascular comorbidities may be prognostically more important than the type of comorbidities present.

CONFLICT OF INTEREST STATEMENT
The authors declare no conflicts of interest.

DATA AVAILABILITY STATEMENT
The data that support the findings of our study are available from the corresponding author upon reasonable request.

ETHICS STATEMENT
Our study was approved by Joint Chinese University of Hong Kong-