Antihypertensive drug use and prostate cancer-specific mortality in Finnish men

RESEARCH ARTICLE Antihypertensive drug use and prostate cancer-specific mortality in Finnish men Aino SiltariID 1,2☯ *, Teemu J. Murtola 1,3☯ , Kirsi Talala 4 , Kimmo Taari 5 , Teuvo L. J. Tammela 1,3 , Anssi Auvinen 6 1Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland, 2Department of Pharmacology, Faculty of Medicine, University of Helsinki, Helsinki, Finland, 3Department of Urology, TAYS Cancer Center, Tampere, Finland, 4Finnish Cancer Registry, Helsinki, Finland, 5Department of Urology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland, 6School of Health Sciences, Tampere University, Tampere, Finland ☯These authors contributed equally to this work. *[email protected] Abstract The aim of this study was to investigate preand post-diagnostic use of antihypertensive drugs on prostate cancer (PCa)-specific survival and the initiation of androgen deprivation therapy (ADT). The cohort investigated 8,253 PCa patients with 837 PCa-specific deaths during the median follow-up of 7.6 years after diagnosis. Information on drug use, cancer incidence, clinical features of PCa, and causes of death was collected from Finnish registries. Hazard ratios with 95% confidence intervals were calculated using Cox regression with antihypertensive drug use as a time-dependent variable. Separate analyses were performed on PCa survival related to preand post-diagnostic use of drugs and on the initiation of ADT. Antihypertensive drug use overall was associated with an increased risk of PCaspecific death (Pre-PCa: 1.21 (1.04–1.4), Post-PCa: 1.2 (1.02–1.41)). With respect to the separate drug groups, angiotensin II type 1 receptor (ATr) blockers, were associated with improved survival (Post-PCa: 0.81 (0.67–0.99)) and diuretics with an increased risk (PostPCa: 1.25 (1.05–1.49)). The risk of ADT initiation was slightly higher among antihypertensive drug users as compared to non-users. In conclusion, this study supports anti-cancer effect of ATr blockers on PCa prognosis and this should be investigated further in controlled clinical trials. Introduction Prostate cancer (PCa) is the most common cancer in men [1]. Known risk factors for PCa are age, race, and a family history of PCa. Hypertension has been suggested as a risk factor for PCa progression [2–4]. However, hypertension is linked to other factors such as metabolic syndrome—thus, it is difficult to distinguish the impacts of underlying risk factors, hypertension and its medication on PCa development and progression. As in many other cancers, PCa involves re-programmed normal cellular functions, such as glucoseand cholesterol metabolism, in cancer progression [5]. Thus, commonly used drugs affecting normal cellular PLOS ONE PLOS ONE | https://doi.org/10.1371/journal.pone.0234269 June 29, 2020 1 / 15 a1111111111 a1111111111 a1111111111 a1111111111 a1111111111 OPEN ACCESS Citation: Siltari A, Murtola TJ, Talala K, Taari K, Tammela TLJ, Auvinen A (2020) Antihypertensive drug use and prostate cancer-specific mortality in Finnish men. PLoS ONE 15(6): e0234269. https:// doi.org/10.1371/journal.pone.0234269 Editor: Jian Gu, The University of Texas MD Anderson Cancer Center, UNITED STATES Received: March 17, 2020 Accepted: May 21, 2020 Published: June 29, 2020 Peer Review History: PLOS recognizes the benefits of transparency in the peer review process; therefore, we enable the publication of all of the content of peer review and author responses alongside final, published articles. The editorial history of this article is available here: https://doi.org/10.1371/journal.pone.0234269 Copyright: ©2020 Siltari et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability Statement: Sharing individuallevel data, even in pseudonymized form is not possible according to the current Finnish regulation regarding privacy, data protection and EU-level GDPR. Full anonymization of the data is not functions such as drugs targeting the renin-angiotensin system (RAS), fluid homeostasis, and the sympathetic nervous system may influence PCa progression. In particular, the role of RAS in cancer development and progression has been under investigation [6,7]. In mice, treatment with angiotensin II receptor blockers decreased the volume of a prostate tumor. However, administration of angiotensin II had no effect on tumor size [8]. On the other hand, angiotensin II has increased prostate cell viability in different cell models [9,10]. Results on antihypertensive drug use and PCa-specific mortality are controversial [11–18]. In general, the evaluation of use of different antihypertensive drug groups is challenging due to the heterogeneity of drug users. Furthermore, differentially acting drug groups are commonly used in parallel to achieve blood pressure control. Recently, we showed that the use of antihypertensive drugs is moderately associated with an increased risk for prostate cancer in a comprehensive population-based cohort study based on the Finnish Randomized Study of Screening for Prostate Cancer (FinRSPC). The risk increase was not related to any specific drug group [19]. Here we have investigated whether preand post-diagnostic use of any antihypertensive drug group associates with PCa-specific survival. Furthermore, we evaluated the risk of PCa progression by using initiation of androgen-deprivation therapy (ADT) as a surrogate. Materials and methods Study cohort The original study cohort, FinRSPC, involved 80,458 men aged 55–67 years old at study entry from Tampere and Helsinki areas in Finland [20]. All men were free of PCa at baseline. By the end of 2016, 8,253 men were diagnosed with prostate cancer and information was available on their drug use. These men formed our study population. The Finnish Cancer Registry, which covers 96% of all solid tumor cases, provided information on cancer diagnoses [21]. Data on Gleason scores, TNM stage, and prostate cancer-specific antigen (PSA) level at the time of diagnosis was obtained from medical records. The Cause of Death registry in Statistics Finland houses information on causes of death (TK-53-1330-18) and the Care Register for Health Care provided information on diagnoses and medical procedures in secondary and tertiary health care units. Unique personal identification number, assigned to all Finnish citizens, was used in a deterministic linkage to combine information from the registries and medical records. Causes of death were classified using the International Classification of Diseases (ICD-10) codes; PCa was considered the cause of death when the underlying cause was C61 and deaths from cardiovascular disease (CVD) included codes I20-I25, I30-I52, and I70-I79. During 2004–2008, a questionnaire about height, weight, and use of non-prescription drugs, such aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) was mailed to participants still in the study. Originally, information on Body Mass Index (BMI) was collected from 11,698 subjects [22], and in the current study population, this was available for 805 men. Information on medication use The prescription database of Social Insurance Institution (SII) of Finland was used to collect information on the use of antihypertensive drugs from 1996 to 2016. As a part of the national health insurance, SII provides reimbursements for purchases of physician-prescribed drugs to all Finnish citizens. All reimbursements are recorded in the database including the purchase date, drug dose, number of doses in the package, and number of drug packages for each purchase. In Finland, all antihypertensive drugs are available only by prescription, thus all purchases, except drugs for hospital patients, are recorded. PLOS ONE Antihypertensive drugs and prostate cancer-specific mortality PLOS ONE | https://doi.org/10.1371/journal.pone.0234269 June 29, 2020 2 / 15 feasible, because at individual level, there would be numerous unique records if all variables used in the analyses were to be retained (even if collapsing discrete variables and categorizing continuous variables). Permission for data access was applied from Finnish institute of health and welfare and data access can be applied from there ([email protected]). Funding: This work was supported by Pirkanmaa Hospital District in the form of a grant awarded to TM (9T036), Cancer Foundation Finland in the form of a grant awarded to TM (25024194), and FinnishNorwegian Medical Foundation in the form of a grant awarded to AS (201900067). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing interests: The authors have declared that no competing interests exist. Drug-specific Anatomic Therapeutic Chemical (ATC) codes were used to identify the medications and were divided according to mechanism of action into angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor (ATr) blockers, beta-blockers, calcium channel blockers, and diuretics. Additional information on purchases of statins, antidiabetic drugs, 5-alpha-reductase inhibitors, and prescription aspirin and other NSAIDs was also collected. The diuretics analyzed included only those drugs used for hypertension. Thus, loop-diuretics and spironolactone, commonly used for edema and fluid retention problems, were excluded. Defined Daily Dose (DDD) [23] was used to calculate standardized cumulative doses by dividing annual amount of purchased drug by drug-specific DDD-values. All DDDs in each group were calculated together and value presented as annual cumulative doses of each drug group. The number of years with recorded drug purchases was used to calculate cumulative years of drug use. By dividing cumulative doses by cumulative years, average annual doses, i.e. average intensities of the drug use were calculated. Risk trends were analyzed by stratifying the study population by tertiles of intensity, DDD-values, and years of the drug use (termed low, medium and high use). Statistical analysis Hazard ratios (HR) and their 95% confidence intervals (CI) for prostate cancer-specific mortality were estimated using Cox regression models. The time metric was months and years from diagnosis. Each antihypertensive drug group was analyzed as a time-dependent variable, except pre-diagnostic use which was analyzed as a time-fixed variable (thus subjects were classified as either ever-users or never-users before the diagnosis). Purchases were used to determine annually cumulative use for each follow-up year for each drug group. Subjects stayed as non-users until the first antihypertensive drug purchase and after that, they remained as everusers for the whole follow-up period. This minimized bias due to selective discontinuation of medication in the terminal phase of cancer. Analysis of overall antihypertensive drug use was conducted separately. Different drug groups were included into models simultaneously as separate time-dependent variables, to enable modelling of mutually adjusted simultaneous use of several antihypertensive drugs. Lag-time analysis was conducted by lagging the diagnosis of PCa by one or three years from different drug use. To evaluate whether antihypertensive drug use exerted any impact on the progression of cancer, the risk for initiation of androgen deprivation therapy (ADT) was analyzed using a Cox regression model, where follow-up started at PCa diagnosis and continued until ADT initiation, death/emigration, or the end of 2016. The analysis was limited only for long-term ADT treatment, participants who also had radiation therapy as primary management in addition to ADT were excluded. Analyses were performed for risk overall and separately for subgroups of Gleason grade 7 and 8–10, risk group 2 (for definition see below), and metastatic cancers. The risk for all-cause mortality was calculated without subgroup analyses. All analyses were adjusted for age, FinRSPC trial arm (screening arm and control arm), year of diagnosis, cancer clinical characteristics (T stage, metastasis, and Gleason grade), Charlson comorbidity index, use of statins, antidiabetic drugs, anticoagulants, 5-alpha-reductase inhibitors, aspirin and other NSAIDs. Sensitivity analysis by adjusting the model by marital and socioeconomical status, and BMI were conducted with subgroup in whom information was available. We also conducted sensitivity analysis by number of used drugs (one, two, or three or more) and combination of different drug groups (e.g. ATr blockers + diuretics). PCa risk groups were created based on Gleason grade, clinical characteristics and tumor extent: risk group 0 included cases where Gleason grade was 6, T-stage was 1 or 2, or PSA was less than 10 μg/l, risk group 1 included PLOS ONE Antihypertensive drugs and prostate cancer-specific mortality PLOS ONE | https://doi.org/10.1371/journal.pone.0234269 June 29, 2020 3 / 15 cases where Gleason grade was 7, T-stage was 3, or PSA was 10–20 μg/l and risk group 2 included cases where Gleason grade was 8 or more, T-stage was 4, cancer was metastatic, or PSA was more than 20 μg/l. Charlson comorbidity index was calculated as explained previously [24]. All analyses were performed using IBM SPSS statistical software (version 24). We performed competing risks analysis to estimate association between antihypertensive drug groups and PCa-specific death, with deaths from cardiovascular disease (CVD) as the competing risk. Deaths due to non-cancer and non-CVD causes were censored. The model was adjusted for age, FinRSPC trial arm, year of diagnosis, PCa risk group, Charlson comorbidity index, use of statins, antidiabetic drugs, anticoagulants, 5-alpha-reductase inhibitors, aspirin, and other NSAIDs. The analysis was done using StataCorp Stata Statistics (version 14.0). Results Population characteristics The majority (79%) of the study population had at least one antihypertensive drug purchase during the follow-up (Table 1). Of the 8,253 prostate cancer cases, 2,479 had Gleason grade 7 and 1,379 Gleason 8 or above, 2284 patients belonged to risk group 2, and 589 had metastatic cancer. The median follow-up time was 7.6 years after diagnosis. The median age at diagnosis was 68 years. In total, 2,765 subjects died during the follow-up, including 837 deaths from PCa (Table 1). The overall PCa-specific death rate after diagnosis was 13.3 per 1000 person-years. It was 12.0 among users and 20.2 in non-users (Table 1). Of the specific drug groups, PCa-specific mortality after diagnosis was highest among users of diuretics (11.7 deaths per 1000 person-years) and lowest among users of ATr blockers (8 per 1000) (Table 1). The users of antihypertensive drugs also had been prescribed other drugs more often than non-users (p<0.001) (Table 1). Non-users had slightly lower BMI values. There was no difference in the distribution of FinRSPC study arms or age at diagnosis between the groups (68 or 69 years in all groups). The follow-up time was slightly shorter in the group of non-users, however, it was similar between all other groups (Table 1). Risk of prostate cancer-specific death by antihypertensive drug use Both preand post-diagnostic use of antihypertensive drugs was associated with an increased risk for PCa-specific death compared to non-users in multivariable-adjusted analysis (HR 1.21, 95% CI 1.04–1.4 and HR 1.2, 95% CI 1.02–1.41, respectively) (Fig 1,Table 2). In addition, the risk for all-cause mortality was higher among users of antihypertensive drugs (Pre: HR 1.38, 95% CI 1.27–1.5, Post: HR 1.33, 95% CI 1.21–1.47) (Table 3A). As expected, the risk of CVD-specific deaths was elevated in users of antihypertensive drugs (Pre: HR 1.96 95% CI 1.61–2.39, Post: HR 2.57, 95% CI 1.97–3.36) (Table 3B). When antihypertensive drug groups were analyzed separately, post-diagnostic use of ATr blockers was associated with a decreased risk for PCa death (HR 0.81, 95% CI 0.67–0.99) (Fig 1,Table 2). The risk decrease was observed also for pre-diagnostic use (HR 0.74, 95% CI 0.58– 0.96). Preand post-diagnostic use of diuretics was associated with an increased risk of death from PCa (Pre: HR 1.31, 95% CI 1.07–1.6, Post: HR 1.25, 95% CI 1.05–1.49) (Fig 1,Table 2). Tumor characteristics did not modify the risk associations by the use of ATr blockers or diuretics (Fig 2,Table 2). Furthermore, pre-diagnostic use of ATr blockers was associated with a decreased all-cause mortality (Table 3A). On the other hand, the use of beta-blockers and ACE inhibitors was associated with increased all-cause mortality (Table 3A). Other investigated antihypertensive drug group did not associate with the risk of PCa-specific or all-cause mortality (Fig 1, PLOS ONE Antihypertensive drugs and prostate cancer-specific mortality PLOS ONE | https://doi.org/10.1371/journal.pone.0234269 June 29, 2020 4 / 15 Tables 2&3A). The use of beta-blockers and ACE inhibitors also associated with elevated CVD mortality (Table 3B). Diuretics and calcium channel blockers displayed no association with deaths from CVD. Adjustments of the model by socioeconomical and marital status, and BMI did not modify the risk associations. Lagging the PCa diagnosis by one or three years after drug use did not reveal any statistically meaningful association with prostate cancer-specific mortality (S3 Table). Table 1. Population characteristics. Cohort of 8253 men with prostate cancer (PCa) from the Finnish Randomized Study of Screening for Prostate Cancer. ACE inhibitors = angiotensin-converting enzyme inhibitors; ATr blockers = angiotensin II receptor type. All Non-users Users ACE inbitors ATr blockers Beta-blockers Calcium channel blockers Diuretics NO. of PCa cases 8253 1875 (22.7) 6378 (77.3) 3297 (39.9) 2316 (28.1) 4467 (54.1) 3172 (38.4) 2397 (29) Gleason 7 n (%) 2479 (30) 539 (28.7) 1940 (30.5) 990 (30.0) 694 (30.0) 1355 (30.3) 958 (30.2) 705 (29.4) Gleason 8–10 n (%) 1379 (16.7) 345 (18.4) 1034 (16.2) 510 (15.5) 352 (15.2) 705 (15.8) 464 (14.6) 361 (15.1) Risk group 2 n (%) 2284 (27.7) 559 (29.8) 1725 (27) 877 (26.6) 560 (24.2) 1211 (27.1) 811 (25.6) 627 (26.2) Metastatic ceses n (%) 589 (7.1) 180 (9.6) 409 (6.4) 208 (6.3) 99 (4.3) 277 (6.2) 173 (5.5) 141 (5.9) Hormonal therapy n (%) (excluded cases where radiation therapy was combined with ADT) 2120 (25.7) 483 (25.8) 1637 (25.7) 872 (26.4) 469 (20.3) 1149 (25.7) 764 (24.1) 581 (24.2) Median age at time of randomization (IQR) 63 (59–63) 59 (55–63) 63 (59–67) 63 (59–67) 59 (59–63) 63 (59–67) 63 (59–67) 63 (59–67) Median age at time of diagnosis (IQR) 68 (64–72) 68 (64–72) 69 (65–72) 68 (64–72) 68 (64–72) 69 (65–73) 68 (65–72) 68 (64–72) Follow-up time after randomization, median (IQR) 12 (11–13) 12 (11–13) 12 (11–13) 12 (11–13) 12 (11–13.4) 12 (11–13) 12 (11–13) 12 (11–13) Follow-up time after diagnosis, median (IQR) 7.6 (3.8– 11.1) 5.9 (2.8– 10.3) 8 (4.2–11.3) 8.4 (4.6–11.8) 8.7 (4.8–11.8) 8.1 (4.3–11.5) 8.5 (4.7–11.7) 8.9 (5–12) Deaths n (%) 2765 (33.5) 622 (33.2) 2143 (33.6) 1148 (34.8) 663 (28.6) 1587 (35.5) 1042 (32.8) 805 (33.6) PCa-specifin deaths n (% from all deaths) 837 (30.2) 224 (36) 613 (28.6) 308 (26.8) 162 (24.4) 415 (26.1) 271 (26) 249 (30.9) PCa-specifin deaths per 1000 personyears after diagnosis 13.3 20.2 12.0 11.1 8.0 11.5 10.1 11.7 CVD-specific deaths n (% from all deaths) 586 (21.2) 66 (10.6) 520 (8.2) 328 (28.6) 175 (26.4) 420 (26.5) 259 (24.9) 197 (24.4) Median BMI (IQR) (n) 26.24 (24.22– 28.67) (805) 25.06 (23.54– 27.17) (197) 26.59 (24.55– 28.73) (608)� � � 26.6 (24.4– 29.0) (277)� � � 27.1 (25.0– 29.1) (242)� � � 27.0 (24.9– 29.1) (391)� � � 26.9 (24.9– 29.1) (299)� � � 27.74 (25.42– 30.05) (202) FinRSPC arm Screening n (%) 3425 (41.5) 797 (42.5) 2628 (41.2) 1391 (42.2) 934 (40.3) 1855 (41.5) 1318 (41.6) 962 (40.1) Control n (%) 4828 (58.5) 1078 (57.5) 3750 (58.8) 1906 (57.8) 1382 (59.7) 2612 (58.5) 1854 (58.4) 1435 (59.9) Use of other drugs Statins n (%) 3870 (46.9) 408 (21.8) 3462 (54.3)� � � 1913 (58.0)� � � 1383 (59.7)� � � 2604 (58.3)� � � 1825 (57.5)� � � 1382 (57.7)� � � Antidiabetic drugs n (%) 1599 (19.4) 118 (6.3) 1481 (23.3)� � � 915 (27.8)� � � 608 (26.2)� � � 1130 (25.3)� � � 853 (26.9)� � � 617 (25.7)� � � NSAIDs n (%) 7065 (85.6) 1534 (81.8) 5531 (86.7)� � � 2821 (85.6)� � � 2058 (88.9)� � � 3881 (86.9)� � � 2771 (87.4)� � � 2107 (87.9)� � � Aspirin n (%) 1143 (13.8) 139 (7.4) 1004 (15.7)� � � 522 (15.8)� � � 404 (17.4)� � � 760 (17.0)� � � 528 (16.6)� � � 374 (15.6)� � � 5-alpha-reductase inhibitors n (%) 1229 (14.9) 224 (11.9) 1005 (15.8)� � � 495 (15.0)� � � 381 (16.5)� � � 717 (16.1)� � � 499 (15.7)� � � 390 (16.3)� � � Anticoagulants n (%) 4275 (51.8) 585 (31.2) 3690 (57.9)� � � 2050 (62.2)� � � 1370 (59.2)� � � 2895 (64.8)� � � 1867 (58.9)� � � 1388 (57.9)� � � https://doi.org/10.1371/journal.pone.0234269.t001 PLOS ONE Antihypertensive drugs and prostate cancer-specific mortality PLOS ONE | https://doi.org/10.1371/journal.pone.0234269 June 29, 2020 5 / 15 Sensitivity analysis by number of used drugs did not modify the results as risk for PCa-specific death was increased similarly despite number of drug groups in use (S5 Table). Some drug combinations showed slightly different survival associations compared to main analysis; combination of beta-blockers and diuretics were associated with lowered risk of PCa death compared non-users (HR 0.74, 95% CI 0.57–0.96) whereas diuretics and beta-blockers in combination were associated with increased risk (HR 2.36, 95% CI 1.89–2.94). Other drug group combination did not show significant associations with PCa-specific survival (S5 Table). Risk trends by cumulative antihypertensive drug use In the risk trend analysis for the post-diagnostic use of ACE inhibitors, the risk for PCa death tended to decrease with the amount of use, but the trend was not statistically significant (Table 4). Among ATr blocker users, the strongest risk decrease was observed in the tertile of highest intensity of use (over 559.2 DDDs annually) regardless of cancer grade and stage (Table 4). No clear dose-dependent risk trends were observed by pre-diagnostic use for either drug group (S1 Table). Risk trend analyses for tertiles of post-diagnostic DDD-values and years of use can be found in the supplemental material (S2 Table). Risk for initiation of androgen deprivation therapy Any use of antihypertensive drugs was associated with a slightly increased risk for initiation of ADT as compared to non-users (HR 1.15, 95% CI 1.05–1.27) (Table 4). The risk increase was seen also in Gleason 8–10 and risk group 2 tumors (Table 5). When different drug groups were compared, only use of ACE inhibitors and beta blockers showed increased risks (HR 1.21, 95% CI 1.09–1.35, and HR 1.1, 95% CI 1–1.21, respectively). Such associations were not seen in the subgroups of clinical tumor characteristics (Table 5). Drug groups did not reveal any meaningful dose-dependent association with the risk of initiation of ADT (S4 Table). Competing risk analysis The risk association for the pre-diagnostic use antihypertensive drug use was similar in competing risk analysis as in the main analysis; use of ATr blockers continued to be associated with improved disease-specific survival (HR 0.74, 95% CI 0.57–0.98) and the use of diuretics slightly increased the risk (HR 1.25, 95% CI 1.01–1.54). Fig 1. Association of prostate cancer (PCa)-specific mortality and preand post-diagnostic use of different antihypertensive drugs. Data is presented as hazard ratios (HR) with 95% confidence intervals (CI). https://doi.org/10.1371/journal.pone.0234269.g001 PLOS ONE Antihypertensive drugs and prostate cancer-specific mortality PLOS ONE | https://doi.org/10.1371/journal.pone.0234269 June 29, 2020 6 / 15 Discussion We evaluated prostate cancer-specific and all-cause mortality by preand post-diagnostic antihypertensive drug use in a Finnish cohort study consisting of men living in metropolitan areas Table 2. Risk for prostate cancer (PCa)-specific mortality of preand post-diagnostic use of antihypertensive drugs compared to non-users after PCa diagnosis. Cox regression hazard model was adjusted with age, FinRSPC trial arm (screening arm and control arm), year of diagnosis, cancer clinical characteristics (T stage, metastasis, and Gleason grade), Charlson comorbidity index, use of statins, antidiabetic drugs, anticoagulants, 5-alpha-reductase inhibitors, aspirin and other NSAIDs. ACE inhibitors = angiotensin-converting enzyme inhibitors; ATr blockers = angiotensin II receptor type 1 blockers; HR (95% CI) = hazard ratio and 95% confidence intervals. PCa-specific death Pre-diagnostic use Post-diagnostic use Overall risk n of men n of PCa deaths (%) HR (95% CI) HR (95% CI) Non-users 1875 224 (11.9) ref. ref. Users 6378 613 (9.6) 1.21 (1.04–1.4) 1.2 (1.02–1.41) ACE inhibitors 3297 308 (9.3) 1.11 (0.93–1.33) 1.04 (0.88–1.22) ATr blockers 2316 162 (7) 0.74 (0.58–0.96) 0.81 (0.67–0.99) Beta-blockers 4467 415 (9.3) 1.18 (1.0–1.39) 1.15 (0.99–1.33) Calcium channel blockers 3172 271 (8.5) 0.93 (0.78–1.12) 1.01 (0.86–1.19) Diuretics 2397 249 (10.4) 1.31 (1.07–1.6) 1.25 (1.05–1.49) Gleason 7 Non-users 539 50 ref. ref. Users 1940 178 1.69 (1.28–2.26) 1.39 (1–1.94) ACE inhibitors 1489 130 1.26 (0.89–1.78) 1.26 (0.97–1.76) ATr blockers 1785 179 0.89 (0.56–1.43) 0.76 (0.53–1.09) Beta-blockers 1124 111 1.31 (0.96–1.8) 1.07 (0.79–1.44) Calcium channel blockers 1521 141 0.86 (0.6–1.23) 1.05 (0.78–1.41) Diuretics 1774 145 1.48 (1.1–2.16) 1.55 (1.13–2.15) Gleason 8–10 Non-users 345 115 ref. ref. Users 1034 288 1.05 (0.84–1.31) 1.11 (0.88–1.41) ACE inhibitors 510 134 1.1 (0.85–1.42) 0.91 (0.72–1.15) ATr blockers 352 81 0.72 (0.51–1.02) 0.9 (0.68–1.2) Beta-blockers 705 195 1.14 (0.9–1.45) 1.12 (0.96–1.48) Calcium channel blockers 464 119 0.98 (0.76–1.26) 1.01 (0.8–1.28) Diuretics 361 103 1.24 (0.94–1.65) 1.08 (0.8–1.28) Risk group 2 Non-users 559 179 ref. ref. Users 1725 426 1.12 (0.94–1.33) 1.1 (0.91–1.33) ACE inhibitors 1407 214 1.18 (0.95–1.45) 1.1 (0.91–1.33) ATr blockers 1724 106 0.7 (0.52–0.94) 0.82 (0.65–1.05) Beta-blockers 1073 282 1.13 (0.94–1.38) 1.08 (0.9–1.23) Calcium channel blockers 1473 181 0.93 (0.76–1.15) 0.99 (0.82–1.2) Diuretics 1657 163 1.31 (1.03–1.66) 1.15 (0.93–1.42) Metastatic disease Non-users 180 112 ref. ref. Users 409 213 1.04 (0.82–1.32) 0.95 (0.74–1.22) ACE inhibitors 381 106 1.38 (1.02–1.85) 1.1 (0.83–1.45) ATr blockers 490 41 0.73 (0.48–1.12) 0.83 (0.57–1.22) Beta-blockers 312 131 0.95 (0.73–1.24) 0.93 (0.73–1.19) Calcium channel blockers 416 87 1 (0.75–1.34) 1.08 (0.82–1.42) Diuretics 448 67 1.01 (0.73–1.41) 0.89 (0.64–1.23) https://doi.org/10.1371/journal.pone.0234269.t002 PLOS ONE Antihypertensive drugs and prostate cancer-specific mortality PLOS ONE | https://doi.org/10.1371/journal.pone.0234269 June 29, 2020 7 / 15 of Helsinki and Tampere. In general, the use of antihypertensive drugs was associated with increased PCa-specific and all-cause mortality as compared to non-users. When we evaluated the different antihypertensive drug groups, post-diagnostic use of RAS-inhibiting drugs, ACE inhibitors, and AT-receptor blockers were associated with improved survival, whereas diuretics were associated with poorer survival. The reduction in risk was more pronounced for AT-receptor blockers than for ACE inhibitors. However, only post-diagnostic use of ACE inhibitors showed a dose-dependent risk trend. Similarly, in a UK population-based cohort, Cardwell et al. [13] revealed that users of ACE inhibitors and ATr blockers had a slightly decreased PCa-specific mortality and concluded that it was safe to use these antihypertensive drugs after PCa diagnosis. Furthermore, Ronquist et al. [25] observed that the post-operative captopril users had less biochemical Table 3. Risk for all-cause mortality (A), and cardiovascular diseases (CVD) mortality of preand post-diagnostic use of antihypertensive drugs compared to nonusers after PCa diagnosis. Cox regression hazard model was adjusted with age, FinRSPC trial arm (screening arm and control arm), year of diagnosis, cancer clinical characteristics (T stage, metastasis, and Gleason grade), Charlson comorbidity index, use of statins, antidiabetic drugs, anticoagulants, 5-alpha-reductase inhibitors, aspirin and other NSAIDs. ACE inhibitors = angiotensin-converting enzyme inhibitors; ATr blockers = angiotensin II receptor type 1 blockers; HR (95% CI) = hazard ratio and 95% confidence intervals. A) All-cause death Pre-diagnostic use Post-diagnostic use Overall risk n of men n of deaths HR (95% CI) HR (95% CI) Non-users 1875 622 ref. ref. Users 6378 2143 1.38 (1.27–1.5) 1.33 (1.21–1.47) ACE inhibitors 3297 1148 1.22 (1.11–1.34) 1.19 (1.09–1.29) ATr blockers 2316 663 0.88 (0.77–1) 0.98 (0.89–1.08) Beta-blockers 4467 1587 1.22 (1.12–1.33) 1.4 (1.28–1.52) Calcium channel blockers 3172 1024 1.05 (0.96–1.16) 1.07 (0.99–1.17) Diuretics 2397 805 1.16 (1.05–1.29) 0.97 (0.88–1.07) B) CVD death Pre-diagnostic use Post-diagnostic use Overall risk n of men n of CVD deaths HR (95% CI) HR (95% CI) Non-users 1875 66 ref. ref. Users 6378 520 1.96 (1.61–2.39) 2.57 (1.97–3.36) ACE inhibitors 3297 328 1.52 (1.25–1.85) 1.85 (1.54–2.22) ATr blockers 2316 175 0.83 (0.64–1.08) 1.26 (1.03–1.54) Beta-blockers 4467 420 1.67 (1.39–2.02) 2.07 (1.7–2.53) Calcium channel blockers 3172 259 1.12 (0.92–1.36) 0.88 (0.72–1.06) Diuretics 2397 197 1.11 (0.9–1.37) 1.13 (0.95–1.36) https://doi.org/10.1371/journal.pone.0234269.t003 Fig 2. Role of tumor clinical characteristics on PCa mortality among users of any antihypertensive drug, and separately for angiotensin II receptor blockers (ATr blockers) and diuretics. Data is presented as hazard ratios (HR) with 95% confidence intervals (CI). https://doi.org/10.1371/journal.pone.0234269.g002 PLOS ONE Antihypertensive drugs and prostate cancer-specific mortality PLOS ONE | https://doi.org/10.1371/journal.pone.0234269 June 29, 2020 8 / 15 Table 4. Risk of prostate cancer (PCa)-specific mortality by the post-diagnostic use of antihypertensive drugs after diagnosis of PCa. Users stratified into tertiles by cumulative intensity of the use (DDD values/years of the use). Cox regression model was adjusted with age, FinRSPC trial arm (screening arm and control arm), year of diagnosis, cancer clinical characteristics (T stage, metastasis, and Gleason grade), Charlson comorbidity index, use of statins, antidiabetic drugs, anticoagulants, 5-alphareductase inhibitors, aspirin and other NSAIDs. ACE inhibitors = angiotensin-converting enzyme inhibitors; ATr blockers = angiotensin II receptor type 1 blockers; HR (95% CI) = hazard ratio with 95% confidence intervals. ACE inhibitors ATr blockers Beta-blockers Calcium channel blockers Diuretics Limits Low <336 <303.2 <100 <261.3 <148.3 Medium 336–676.9 303.2–559.2 100–187.4 261.3–399.4 148.3–217.8 High 676.9>559.2>187.4>399.4>217.8> Overall, n Low 1100 772 1542 1051 790 Medium 1098 772 1436 1064 790 High 1099 772 1489 1057 790 Overall, PCa death risk HR (95% CI) HR (95% CI) HR (95% CI) HR (95% CI) HR (95% CI) Low 1.16 (0.93–1.45) 0.89 (0.67–1.18) 1.27 (1.04–1.55) 1.18 (0.94–1.48) 1.44 (1.12–1.84) Medium 1.06 (0.84–1.33) 0.81 (0.6–1.09) 1.29 (1.05–1.6) 0.93 (0.73–1.19) 1.09 (0.82–1.45) High 0.92 (0.72–1.19) 0.63 (0.45–0.88) 0.97 (0.78–1.21) 1.08 (0.84–1.4) 1.32 (1.02–1.7) Gleason 7, n Low 302 201 465 379 240 Medium 337 255 228 408 215 High 351 238 462 315 241 Gleason 7, PCa death risk HR (95% CI) HR (95% CI) HR (95% CI) HR (95% CI) HR (95% CI) Low 1.15 (0.75–1.78) 0.99 (0.6–1.64) 1.04 (0.71–1.55) 1.11 (0.74–1.65) 1.92 (1.27–2.91) Medium 1.28 (0.84–1.96) 0.76 (0.44–1.33) 0.92 (0.6–1.42) 1.15 (0.75–1.75) 1.3 (0.78–2.15) High 1.67 (1.09–2.57) 0.69 (0.37–1.26) 1.17 (0.78–1.74) 0.92 (0.55–1.55) 1.28 (0.79–2.08) Gleason 8–10, n Low 168 134 256 288 104 Mediate 178 102 229 226 132 High 164 116 220 116 119 Gleason 8–10, PCa death risk HR (95% CI) HR (95% CI) HR (95% CI) HR (95% CI) HR (95% CI) Low 1.06 (0.75–1.48) 0.94 (0.63–1.41) 1.58 (1.18–2.12) 1.38 (0.97–1.97) 1.21 (0.81–1.81) Medium 0.89 (0.63–1.25) 0.85 (0.55–1.31) 1.5 (1.11–2.02) 0.95 (0.65–1.38) 1.02 (0.67–1.55) High 0.69 (0.47–1.02) 0.58 (0.36–0.95) 0.85 (0.61–1.2) 1.15 (0.81–1.65) 1.24 (0.84–1.83) Risk group 2, n Low 287 201 417 476 207 Medium 301 183 394 369 220 High 289 176 400 231 193 Risk group 2, PCa death risk HR (95% CI) HR (95% CI) HR (95% CI) HR (95% CI) HR (95% CI) Low 1.23 (0.94–1.61) 0.9 (0.64–1.27) 1.28 (1–1.62) 1.17 (0.89–1.54) 1.27 (0.93–1.74) Medium 1.06 (0.81–1.41) 0.77 (0.53–1.13) 1.25 (0.97–1.62) 0.87 (0.64–1.18) 1.09 (0.78–1.53) High 1.01 (0.75–1.35) 0.62 (0.41–0.94) 0.91 (0.7–1.19) 1.15 (0.85–1.55) 1.25 (0.91–1.71) Metastatic cancer, n Low 77 33 104 154 43 Medium 69 39 91 78 47 High 62 27 82 27 48 Metastatic cancer, PCa death risk HR (95% CI) HR (95% CI) HR (95% CI) HR (95% CI) HR (95% CI) Low 1.26 (0.86–1.85) 0.91 (0.52–1.61) 1.02 (0.72–1.44) 1.37 (0.93–2.03) 0.79 (0.47–1.33) Medium 1.24 (0.84–1.83) 0.9 (0.52–1.56) 1.4 (0.98–2) 0.75 (0.46–1.21) 0.83 (0.5–1.38) High 1.02 (0.67–1.55) 0.42 (0.2–0.88) 0.62 (0.42–0.91) 1.55 (1.02–2.33) 1.29 (0.81–2.07) https://doi.org/10.1371/journal.pone.0234269.t004 PLOS ONE Antihypertensive drugs and prostate cancer-specific mortality PLOS ONE | https://doi.org/10.1371/journal.pone.0234269 June 29, 2020 9 / 15