New study from Finland [1]. This topic has been raised before.
"Antihypertensive drug use overall was associated with an increased risk of PCa-specific death (Pre-PCa: 1.21...).
"With respect to the separate drug groups, angiotensin II type 1 receptor (ATr) blockers, were associated with improved survival (Post-PCa: 0.81 ...)
"and diuretics with an increased risk (Post-PCa: 1.25 ...)."
-Patrick
[1] journals.plos.org/plosone/a...
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Discussion
We evaluated prostate cancer-specific and all-cause mortality by pre- and post-diagnostic antihypertensive drug use in a Finnish cohort study consisting of men living in metropolitan areas 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 failures as compared to non-users. However, the study consisted only of 62 patients and the mean follow-up time was 29 months. Alashkham et al. [26] showed that biochemical recurrence was decreased after curative-intent radiotherapy with hormone treatment among users of RAS-inhibiting drugs as compared to non-users. Our study supports these findings, although we did not see any reduction in the risk of initiation of ADT therapy among users of RAS-inhibiting drugs.
Results from analysis of pre-diagnostic use of antihypertensive drugs and PCa-specific survival was in line with the results of post-diagnostic use: overall antihypertensive drug use was associated with an increased risk for PCa-specific death, with decreased mortality among users of ATr blockers and an increase in users of diuretics. Furthermore, pre-diagnostic use of antihypertensive drugs was associated with increased all-cause mortality. This was also seen with several different drug groups: ACE inhibitors, beta-blockers, and calcium channel blockers, but not simply ATr blockers. These results underline that, in general, users of antihypertensive drugs are at an increased risk of death as compared to non-users, but the association is different for users of ATr blockers. A similar trend was evident when the association of antihypertensive drugs and CVD-specific deaths was analyzed. The results were similar when deaths due to CVD were taken into account using competing risk analysis, suggesting that the risk association with PCa survival was not affected by the higher risk for CVD death among antihypertensive drug users compared to non-users.
The reason why specifically it is the use of ATr blockers that may improve PCa-specific survival is not clear. In our study, users of ATr blockers had a smaller proportion of metastatic cancer cases, a lower likelihood of initiation of ADT therapy, and lower PCa mortality as compared to patients in the other groups. This could be due to selective prescribing of this drug group to healthier men than other antihypertensive drugs, or due to genuine effects of ATr blockers on PCa. Our results are in line with a recently published study, where the use of ATr blockers increased PCa-specific survival after radical prostatectomy [18]. ATr blockers are antagonists of angiotensin II receptor type 1, which mediates the classical angiotensin II-related effects; vasoconstriction, fluid volume homeostasis, cell proliferation, and fibrosis [27]. Other RAS-inhibiting drugs, ACE inhibitors, inhibit the main angiotensin II forming enzyme, thus both drug groups block angiotensin II-mediated functions, albeit at different sites in the pathway. ATr blockers may have some yet unknown mechanism of action impacting on PCa development and progression. Nevertheless, the possible role of RAS in development and progression of cancer is under investigation [7,28,29].
Diuretics are commonly used in management of edema, which is common in advanced cancer. Thus, loop diuretics (furosemide) and spironolactone, which are used in management of edema rather than hypertension, were excluded from this analysis. Still, the use of diuretics was associated with an increased risk for PCa death despite lack of association with a higher stage cancer, such metastatic or risk group 2 cases, which might be expected if increased the association could be explained by the treatment of end-stage cancer-related problems. In agreement, Holmes et al. [11] reported an increased risk for PCa-specific deaths among thiazide diuretics users. In our study, we did not evaluate the role of separate diuretic classes.
We did not find any association of pre- and post-diagnostic use of beta-blockers with prostate cancer-specific mortality. Previous studies have reported controversial results [14–17]. However, in analyses based on time-dependent variables, as in our study, no association has been found [30, 31]. However, the use of beta-blockers was associated with a slightly increased risk for ADT initiation, pointing to some association with tumor progression. In contrast to our findings, in a Norwegian population-based cohort, Grytli et al. [16] showed that the use of beta-blockers during ADT-therapy seemed to decrease the risk of PCa-specific death. However, that study was analyzed without time-dependent variables. Nevertheless, the link between beta-blockers and PCa outcomes remains unclear.
A recently published study [32] investigated the role of antihypertensive drug use on PCa-specific mortality in gonadotropin-releasing hormone agonist users. They showed a slightly increased PCa mortality in users of blood pressure lowering drugs. We did not have information on blood pressure levels and were thus unable to evaluate the role of hypertension in this risk association.
Our study has several strengths. The Finnish prescription database is comprehensive and accurate; for example, all reimbursements for purchases of antihypertensive drugs are recorded, and thus we had nearly complete coverage of our subjects’ drug purchases. Our follow-up time was long enough to enable modeling cumulative simultaneous use of multiple drugs. We also had comprehensive information of clinical features of prostate cancer, such as Gleason grade and TNM stage. In addition, information on PCa deaths was collected from an accurate and reliable nationwide, population-based database that has been validated by an independent cause of death committee; the validity of information of PCa-specific deaths between cause of death registry and recording in patients’ medical files was compared and 97.7% agreement (kappa = 0.95) between them was found [33]. Furthermore, statistical power in our cohort is sufficient to detect clinically meaningful survival differences as our sample size was sufficient to detect 3.5% survival difference between medication users and non-users with 80% power and risk for type I error being 0.05.
Our study also has some limitations. We did not have information on blood pressure levels of the subjects or indication for antihypertensive drugs. In addition, data of some background information, which might be shared risk factors for prostate cancer death and hypertension, such as smoking habits, were missing. However, we were able to adjust the analysis for the use of other drugs which might have impacted on the development and progression of PCa, such as statins [34]. Our drug use data is based on reimbursement for drug purchases. Thus, we do not know whether the subject actually used the purchased drugs. It should be noted that most likely the users of antihypertensive drugs have more comorbidities and are at increased risk of death in general as compared to non-users, possibly affecting also PCa-specific mortality. Furthermore, different antihypertensive drugs are described based on comorbidities and the health status of the patients which might bias the results.
In conclusion, the use of antihypertensive drugs was associated with an increased risk for prostate cancer-specific and all-cause mortality. When the analysis was done separately for different drug groups, both pre- and post- diagnostic use of RAS inhibiting drugs, especially ATr blockers, associated with improved PCa survival in a dose-dependent manner, whereas the use of diuretics associated with poorer survival. The results might be affected by systematic differences between the users and non-users. Nevertheless, our findings support previous reports about the beneficial effects of RAS-inhibition on PCa progression. The role and potential benefits of RAS inhibition in PCa should be examined further.
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