Androgen-Deprivation Therapy and the Risk of Stroke in Patients With Prostate Cancer

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1 EUROPEAN UROLOGY 60 (2011) available at journal homepage: Prostate Cancer Androgen-Deprivation Therapy and the Risk of Stroke in Patients With Prostate Cancer Laurent Azoulay a,b, *, Hui Yin a, Serge Benayoun c, Christel Renoux a, Jean-François Boivin a,d, Samy Suissa a,d a Centre for Clinical Epidemiology and Community Studies, Sir Mortimer B. Davis Jewish General Hospital, Montreal, Quebec, Canada; b Department of Oncology, McGill University, Montreal, Quebec, Canada; c Department of Urology, Hôpital Maisonneuve-Rosemont, Montreal, Quebec; d Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, Quebec, Canada Article info Article history: Accepted August 18, 2011 Published online ahead of print on August 27, 2011 Keywords: Prostate Androgen-deprivation therapy Population based Stroke Cerebrovascular Abstract Background: Some evidence indicates that androgen-deprivation therapy (ADT) increases the risk of diabetes and cardiovascular disease. To date, few studies have investigated whether this therapy also increases the risk of cerebrovascular events. Objective: To determine whether different types of ADT increase the risk of stroke/ transient ischaemic attacks (TIAs) in patients with prostate cancer. Design, setting, and participants: We conducted a population-based cohort study using a nested case-control analysis within the United Kingdom s General Practice Research Database population. The cohort included all patients at least 40 yr of age newly diagnosed with prostate cancer between January 1, 1988, and December 31, 2008, and followed until December 31, Cases consisted of those who experienced a firstever stroke/tia during follow-up. Up to 10 controls were matched to each case on age, year of cohort entry, and duration of follow-up. Measurements: Adjusted rate ratios (RRs) of stroke/tia associated with the use of different ADTs (gonadotropin-releasing hormone [GnRH] agonists, oral antiandrogens, combined androgen blockade, bilateral orchiectomy, and others) were estimated using conditional logistic regression. Results and limitations: The cohort included patients with prostate cancer, followed for a mean of 3.9 yr, where 938 patients experienced a first-ever stroke/tia (rate: 10.7 per 1000/yr). Compared with nonusers of ADT, current users of GnRH agonists (adjusted RR: 1.18; 95% confidence interval [CI], ), oral antiandrogens (adjusted RR: 1.47; 95% CI, ), and those who underwent bilateral orchiectomy (adjusted RR: 1.77; 95% CI, ) were at an increased risk of stroke/tia. No statistically significant increased risks were observed for patients on combined androgen blockade and other ADTs, but the small numbers do not rule out a possible association. Conclusions: The results of this large population-based study provide additional evidence that different forms of ADT may increase the risk of stroke/tia. # 2011 European Association of Urology. Published by Elsevier B.V. All rights reserved. * Corresponding author. Sir Mortimer B. Davis Jewish General Hospital, Centre for Clinical Epidemiology and Community Studies, 3755 Côte Sainte-Catherine, H-425.1, Montreal, Quebec, Canada, H3T 1E2. Tel ext 8396; Fax: address: laurent.azoulay@mcgill.ca (L. Azoulay) /$ see back matter # 2011 European Association of Urology. Published by Elsevier B.V. All rights reserved. doi: /j.eururo

2 EUROPEAN UROLOGY 60 (2011) Introduction Androgen-deprivation therapy (ADT) has been the mainstay of treatment for advanced prostate cancer since first described by Huggins and Hodges in 1941 [1]. However, ADT is not an innocuous therapy. Beyond the quality-of-life side effects, the suppression of testosterone levels has been associated with several adverse effects often called the androgen-deprivation syndrome. This hypogonadal condition is characterised by metabolic changes such as dyslipidemia [2 4], insulin resistance [5], and modification of body composition towards an increase of fat mass [4,6]. All these metabolic changes put patients at an increased risk of cerebrovascular events, such as ischaemic strokes and transient ischaemic attacks (TIAs). Evidence for these potential adverse events is limited and conflicting, with just three studies published on the subject [7 9]. Given the increasing use of ADT, particularly in men with earlier stage disease [10], it is imperative to adequately assess the cerebrovascular risks associated with this therapy. Thus the objective of this large population-based study was to determine whether different types of ADT increase the risk of stroke and TIA in patients newly diagnosed with prostate cancer. 2. Materials and methods 2.1. Data source This study was conducted using the General Practice Research Database (GPRD), a large primary care database from the United Kingdom [11]. The geographic distribution of the practices participating in the GPRD has been shown to be representative of the UK population, and age and sex distributions of patients in the GPRD are similar to those reported by the National Population Census [12]. Participating general practitioners have been trained to record medical information including demographic data and medical diagnoses using a standardised form. Prescriptions written by GPRD physicians are automatically transcribed into the computer record. In addition, the GPRD collects information regarding lifestyle variables such as body mass index (BMI) and quantitative and qualitative data pertaining to smoking and excessive alcohol use. The Read classification is used to enter medical diagnoses and procedures, and a coded drug dictionary based on the UK Prescription Pricing Authority Dictionary is used for recording prescriptions. The recorded information on drug exposures and diagnoses has been validated and proven to be of high quality [13 16]. The study protocol was approved by the Independent Scientific Advisory Committee of the GPRD and the Ethics Committee of the Jewish General Hospital, Montreal, Canada Study population A population-based cohort study was conducted within the GPRD population, consisting of all male patients, at least 40 yr of age, diagnosed for the first time with prostate cancer between January 1, 1988, and December 31, 2008, with follow-up until December 31, The cohort was restricted to patients with at least 1 yr of medical history in the GPRD before diagnosis (cohort entry). Patients with a history of stroke/tia at any time before cohort entry were excluded, as were those with evidence of metastases at diagnosis. Thus all cohort members were followed from their diagnosis of prostate cancer until a first-ever diagnosis of stroke/tia, death from any cause, end of registration with the general practice, or end of the study period (December 31, 2009), whichever came first. Cancer diagnoses have been shown to be highly valid in the GPRD [17] Study design A nested case-control analysis was conducted within the cohort previously defined. Cases consisted of all patients who experienced a first-ever stroke/tia, identified on the basis of Read codes, during followup. The GPRD has been used in several previous studies on stroke, and a study in 2004 showed that approximately 90% of computerised diagnoses of stroke were in agreement with the original medical file [18]. The calendar date of each patient s stroke/tia diagnosis was defined as their index date. Up to 10 controls were randomly selected from the case s risk set (ie, subset of patients in the cohort still at risk at the time when the case experienced the outcome), after matching on year of birth, year of cohort entry, and duration of follow-up Androgen-deprivation therapy exposure We considered all ADTs available on the UK market during the study period. Exposure was assessed using two different approaches. In the first, patients were classified into one of seven mutually exclusive groups based on their current exposure at the index date: (1) gonadotropin-releasing hormone (GnRH) agonists (leuprolide, goserelin, triptorelin) monotherapy (which may have included up to 4 wk of an oral antiandrogen treatment at start of therapy), (2) oral antiandrogens (cyproterone acetate, flutamide, bicalutamide, nilutamide) monotherapy, (3) combined androgen blockade (use of both GnRH agonists and >4 wk of an oral antiandrogen), (4) bilateral orchiectomy, (5) other therapies (such as estrogens) or combinations of the above, (6) past use of any ADT, and (7) no use of any ADT for at least 1 yr before the index date. Patients were deemed currently exposed to an ADT pharmacologic agent if the duration of the last prescription plus a residual effect period overlapped the index date. It was necessary to consider a residual effect period because hypogonadism may persist after discontinuation of therapy [19,20]. Thus we considered a residual effect period of 3 mo for GnRH agonists and 30 d for oral antiandrogens. Sensitivity analyses were conducted by varying the length of these time periods (GnRH agonists: 6 mo; oral antiandrogens: 60 d). In the second approach, patients deemed currently exposed to GnRH agonists were further categorised according to duration of continuous use. Continuous use was defined as when the duration of a prescription overlapped with the date of the next prescription, allowing for a 3-mo grace period between any two prescriptions. Duration was then categorised according to the following: 4, 5 12, 13 24, or 25 mo. For both the approaches described, the reference category consisted of patients not exposed to any ADT for at least 1 yr before the index date Statistical analysis Conditional logistic regression was used to estimate rate ratios (RRs) along with 95% confidence intervals (CIs) of stroke/tia in relation to ADT use. In a first model, we determined whether current use of the different ADTs increased the risk of stroke/tia. In a second model, we assessed whether there was a dose response relationship in terms of GnRH duration of use in relation to stroke/tia. In addition to year of birth, year of cohort entry, and duration of follow-up on which the logistic regression was conditioned, all models were adjusted for the following potential confounders measured at baseline: obesity (BMI 30), excessive alcohol use, smoking status, atrial fibrillation, congestive heart failure, myocardial infarction, hypertension, diabetes, thromboembolic disorders, previous cancer (other than nonmelanoma cancer), and use of aspirin, warfarin, antiplatelet agents, antipsychotics, selective serotonin reuptake inhibitors, and statins.

3 1246 EUROPEAN UROLOGY 60 (2011) We conducted two secondary analyses to determine whether the presence of cardiovascular risk factors and age (<65 yr, yr, 75 yr) at baseline modified the association between ADT and the risk of stroke/tia. The cardiovascular risk factors considered consisted of at least one of the following comorbid conditions: atrial fibrillation, thromboembolic disorders, congestive heart failure, hypertension, myocardial infarction, and diabetes. The effect modification of these variables was assessed by including interaction terms in the models between ADT exposure status and the relevant variable. All analyses were conducted with SAS v.9.2 software (SAS Institute, Cary, NC, USA). 3. Results The cohort consisted of patients newly diagnosed with prostate cancer (Fig. 1). The mean (standard deviation [SD]) age at cohort entry was 72.3 (3.9) yr, and the mean duration of follow-up was 3.9 (3.0) yr. At cohort entry, the median prostate-specific antigen (PSA) was 15.2 ng/ml. Overall, (68.9%) of the cohort received ADT at some point during follow-up, of which (83.0%) received it within 6 mo of diagnosis. A total of 938 patients experienced a first-ever stroke/tia during person-years of follow-up, yielding an overall rate of 10.7 per 1000 persons per year (95% CI, ). As expected, a number of differences were observed between cases and matched controls, particularly in terms of comorbidity and drug use at baseline (Table 1). [(Fig._1)TD$FIG] Table 2 presents the results of the primary analysis. Current use of GnRH agonists was associated with an 18% (RR: 1.18; 95% CI, ) increased risk of stroke/tia. Increased risks were also observed for patients currently on oral antiandrogens (47% increased risk; RR: 1.47; 95% CI, ), and patients who underwent bilateral orchiectomy had the highest risk (77% increased risk; RR: 1.77; 95% CI, ) (Table 2). No statistically significant association was observed for patients on combined androgen blockade and those who used other ADTs or combinations (Table 2). Similar results were obtained by varying the residual effect period for GnRH agonists to 6 mo and for oral antiandrogens to 60 d (data not shown). Table 3 presents the effects of duration of GnRH agonist use among patients exposed to this therapy. Although no increased risk was observed for patients exposed < 4 mo, a >40% increased risk was observed in patients exposed between 5 and 24 mo. The risk then returned to null in patients exposed >25 mo (Table 3). The results of the secondary analyses indicate that the presence of cardiovascular risk factors at baseline did not modify the association between current use of any ADT and stroke/tia risk ( p value for interaction: 0.32), although the point estimate for those without cardiovascular risk factors was numerically elevated (Fig. 2). Overall, age did not significantly modify the association ( p value for interaction: 0.49); however, patients <65 yr of age appeared to be at a significantly increased risk of stroke/tia (Fig. 2). Male pa ents diagnosed with prostate cancer between January 1, 1998, and December 31, 2008 (n = ) Prostate cancer cohort (n = ) Exclusions: Less than 40 yr of age at cohort entry (n =37) Less than 1 yr of medical history in the GPRD before cohort entry (n =14179) Presence of metastases at me of diagnosis (n = 278) Exclusion: Strokes or TIAs before cohort entry (n =2803) Study cohort (n = ) Incident cases of stroke or TIA (n = 938) Fig. 1 Study flow chart. GPRD = General Practice Research Database; TIA = transient ischaemic attack.

4 EUROPEAN UROLOGY 60 (2011) Table 1 Characteristics of cases and controls at baseline Cases (n = 938) Controls (n = 8007) Crude RR (95% CI) Age, yr, mean (SD) *,y 78.5 (7.6) 78.5 (7.0) Excessive alcohol use, n (%) 13 (1.4) 78 (1.0) 1.43 ( ) Body mass index, n (%) < (75.4) 6017 (75.2) 1.00 (reference) (10.7) 916 (11.4) 1.06 ( ) Unknown 121 (12.9) 1074 (13.4) 0.86 ( ) Smoking status, n (%) Ever 429 (45.7) 3336 (41.7) 1.30 ( ) Never 383 (40.8) 3566 (44.5) 1.00 (reference) Unknown 126 (13.4) 1105 (13.8) 0.86 ( ) Oral anticoagulants, n (%) 47 (5.0) 308 (3.9) 1.38 ( ) Aspirin, n (%) 259 (27.6) 1644 (20.5) 1.65 ( ) Other antiplatelets, n (%) 18 (1.9) 114 (1.4) 1.49 ( ) Other nonsteroidal anti-inflammatory drugs, n (%) 172 (18.3) 1228 (15.3) 1.24 ( ) Antipsychotics, n (%) 8 (0.9) 24 (0.3) 3.07 ( ) Selective serotonin reuptake inhibitors, n (%) 31 (3.3) 186 (2.3) 1.55 ( ) Statins, n (%) 119 (12.7) 1076 (12.4) 1.11 ( ) Atrial fibrillation or atrial flutter, n (%) 76 (8.1) 472 (5.9) 1.44 ( ) Thromboembolic disorders, n (%) 52 (5.6) 364 (4.6) 1.19 ( ) Previous cancer, n (%) 131 (14.0) 1187 (14.8) 0.95 ( ) Congestive heart failure, n (%) 58 (6.2) 359 (4.5) 1.30 ( ) Hypertension, n (%) 349 (37.2) 2632 (32.9) 1.32 ( ) Myocardial infarction, n (%) 8 (0.9) 41 (0.5) 1.58 ( ) Diabetes, n (%) 93 (9.9) 555 (6.9) 1.58 ( ) RR = rate ratio; CI = confidence interval. * One of the matching variables (along with year of cohort entry and duration of follow-up). y Measured at index date. Table 2 Androgen-deprivation therapy and the risk of stroke/transient ischaemic attacks Cases (n = 938) Controls (n = 8007) Crude RR Adjusted RR (95% CI) y No use of androgen-deprivation therapy, n (%) 361 (38.5) 3599 (45.0) (reference) Current use of GnRH agonists only, n (%) 348 (37.1) 2926 (36.5) ( ) Current use of oral antiandrogens only, n (%) 58 (6.2) 399 (5.0) ( ) Current use of combined androgen blockade z, n (%) 55 (5.9) 426 (5.3) ( ) Bilateral orchiectomy, n (%) 47 (5.0) 248 (3.1) ( ) Current use of other therapies or combinations, n (%) 18 (1.9) 124 (1.6) ( ) RR = rate ratio; CI = confidence interval; GnRH = gonadotropin-releasing hormone. y Adjusted for the variables listed in Table 1. z Composed of patients prescribed GnRH with >4 wk of an oral antiandrogen. Note: Past users of androgen-deprivation therapy are not displayed in the table but were considered in the regression model. Table 3 Gonadotropin-releasing hormone agonist duration of use and the risk of stroke/transient ischaemic attacks Cases (n = 938) Controls (n = 8007) Crude RR Adjusted RR (95% CI) y No use of androgen-deprivation therapy, n (%) 361 (38.5) 3599 (45.0) (reference) Months of GnRH agonist use among current users, n (%) 4 59 (6.3) 574 (7.2) ( ) (9.8) 748 (9.3) ( ) (8.4) 606 (7.6) ( ) (12.6) 998 (12.5) ( ) RR = rate ratio; CI = confidence interval; GnRH = gonadotropin-releasing hormone. y Adjusted for the variables listed in Table 1. Note: Current and past users of other androgen-deprivation therapies are not displayed in the table but were considered in the regression model. 4. Discussion The results of this large population-based study indicate that different types of ADTs may increase the risk of stroke/ TIA in patients with prostate cancer. Increased risks were observed with all ADTs, with the highest in patients who underwent bilateral orchiectomy. No increased risk was observed for those on combined androgen blockade, but this analysis may have been limited by the few cases exposed. For patients on GnRH agonists, the risk was

5 1248 [(Fig._2)TD$FIG] EUROPEAN UROLOGY 60 (2011) Fig. 2 Current use of any androgen-deprivation therapy in relation to stroke/transient ischaemic attack (TIA) risk stratified by presence of cardiovascular risk factors and age at baseline. CI = confidence interval; RR = rate ratio. observed early in the treatment but then declined after longer periods of use. Finally, the presence of cardiovascular risk factors did not appear to modify the association between use of any ADT and risk of stroke/tia, although a potential risk may exist for patients <65 yr of age. Although our results are in line with those of two of the three studies that have investigated stroke as an outcome, some differences are noteworthy. In the first study, an increased risk of stroke/tia was limited to GnRH agonists, whereas no statistically significant associations were observed with other ADTs [8], although bilateral orchiectomy and combined androgen blockade were uncommon during that study period ( %, respectively) [8]. In contrast, all ADTs were associated with an increased risk of stroke in the second study [9]. Finally, in one study, the use of any ADT was associated with a decreased risk of stroke (hazard ratio [HR]: 0.88; 95% CI, ) [7]. This surprising finding can be due to the way the exposure groups were selected, which likely introduced immortal-time bias. Specifically, ADT users were required to be exposed for at least 6 mo after their first prescription. Thus by design, it was not possible for events to occur during this 6-mo immortal-time period, whereas events could have occurred in the unexposed group immediately after cohort entry. This bias can also explain the lack of a previously reported association with acute myocardial infarction and sudden cardiac death. An interesting finding of this study was that patients who underwent bilateral orchiectomy had the highest increased risk, followed by patients on oral antiandrogens and GnRH agonists. Similar increased risks would have been expected between orchiectomy and GnRH agonists because they achieve comparable castration levels; however, orchiectomy represents the only definitive and permanent treatment. Compliance issues or intermittent treatment might be responsible for the discrepancies observed. It is also possible that such differences are related to statistical power and not a biologic effect because the number of patients who underwent bilateral orchiectomy (47 cases) and those exposed to oral antiandrogens (58 cases) were relatively few during the study period. Although statistically significant, the CIs for these ADTs were wide and overlapping, indicating they are not statistically different from each other. Another finding was that a decreasing risk was observed after an initial period of increased risk with GnRH agonist duration of use. This noncumulative effect may be related to the depletion of susceptible phenomenon, where patients who remained on GnRH agonists >25 mo were those who tolerated it, whereas those susceptible to experiencing a stroke/tia selected themselves out of the exposure group in the early phase of treatment. Interestingly, a similar effect was observed in another study with sudden cardiac death [21]. Our study should prompt additional research to evaluate the timing of cardiovascular events in relation to the use of GnRH agonists. The timing of ADT initiation remains one of the most debated areas in prostate cancer management [22]. Although there is no question that early ADT delays biochemical and clinical disease progression, its effects on survival remain unclear [23]. The present study, which demonstrates an additional serious deleterious vascular effect, argues in favour of limiting ADT exposure. With an increased risk observed as early as after 5 mo of GnRH agonist use, even patients undergoing intermittent ADT or patients with a short course of adjuvant ADT along with radiation therapy may be at an increased risk. With risks associated with ADT becoming more defined, clinicians should prescribe ADT with caution, and they should temper enthusiasm to apply this therapy indiscriminately to all men with progressive prostate cancer. This population-based study has a number of strengths. First, we assembled a large population-based cohort of patients with prostate cancer, followed for up to 22 yr. Second, because the GPRD uses prerecorded exposure histories, the possibility of recall bias was eliminated. Third, our exposure definition was time dependent, thus taking into account changes in this variable over time. Finally, the GPRD database contains information on a number of important confounders, such as BMI, excessive alcohol use, and

6 EUROPEAN UROLOGY 60 (2011) smoking. Therefore, we were able to adjust for a number of important confounders often absent in administrative databases. This study does have some limitations. Drug information in the GPRD represents prescriptions written by general practitioners. Thus it is unknown whether prescriptions were actually filled at the pharmacy. However, for GnRH agonists, these are often injected at the physician s office, and thus it is reasonable to assume a high concordance between prescriptions and receipt of these agents. Another limitation is that the GPRD does not capture prescriptions written by specialists (such as urologists or oncologists), and therefore some patients may have been misclassified as unexposed. Although a high proportion of patients were ever exposed to ADT (68.9%), suggesting that general practitioners play an important role in ADT treatment, the observed increased risks may have been underestimated because of such misclassifications. The GPRD does not collect information on tumour stage or grade; however, our results are consistent with those of other studies that adjusted for such variables [8], suggesting that these variables are not strong confounders. Finally, our stroke definition may have included haemorrhagic events because the stroke subtype (ischaemic vs haemorrhagic) was not always specified in the GPRD files. However, the vast majority (>80%) of strokes are ischaemic, and inclusion of haemorrhagic strokes would have diluted the observed association. This potential bias is likely to have been minimal because our overall stroke/tia rate was very similar to the one reported in a previous study [8] (10.7 of 1000 vs 10.8 of 1000 persons per year, respectively). 5. Conclusions This study provides additional evidence that ADT may increase the risk of stroke/tia. Although ADT remains the mainstay of treatment for advanced disease, it is increasingly being prescribed to men with earlier stage disease [10]. As such, treating physicians and patients should be aware of this potential risk when considering this therapy. Author contributions: Laurent Azoulay had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Azoulay, Benayoun, Renoux, Boivin, Suissa. Acquisition of data: Azoulay, Suissa. Analysis and interpretation of data: Azoulay, Yin, Benayoun, Renoux, Boivin, Suissa. Drafting of the manuscript: Azoulay. Critical revision of the manuscript for important intellectual content: Azoulay, Yin, Benayoun, Renoux, Boivin, Suissa. Statistical analysis: Azoulay, Yin. Obtaining funding: Azoulay. Administrative, technical, or material support: Yin. Supervision: Azoulay. Other (specify): None. Financial disclosures: I certify that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/ affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Dr. Laurent Azoulay is the recipient of a Chercheur-Boursier Award from the Fonds de la recherche en santé du Québec. Dr. Samy Suissa is the recipient of a Distinguished Investigator Award from the Canadian Institutes of Health Research. The remaining authors have nothing to disclose. Funding/Support and role of the sponsor: Prostate Cancer Canada. The sponsor had no role in the analysis, interpretation of the results, and drafting of the manuscript. References [1] Huggins C, Hodges C. 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