α₁-Adrenoceptor blockers (α1Bs) are most commonly indicated for the treatment of benign prostatic hyperplasia (BPH) but can also be used for the treatment of hypertension because of their ability to decrease blood pressure. These drugs are divided into two groups, depending on whether they display selectivity for α₁-adrenoceptor subtypes (Table 1). The guidelines of the Japanese Society of Hypertension (JSH) [1] [2] [3] recommend that non-selective α1Bs are preferably used for hypertensive patients with BPH; however, the indications of α1Bs for the treatment of hypertension are becoming more restricted [4] [5] . In contrast, selective α1Bs are used as first-line therapies for BPH [6] . α₁-Adrenoceptors are classified into three subtypes. The α_1A subtype primarily regulates the smooth muscle tone and is expressed in the bladder neck and prostate gland [7] [8] ; the α_1B subtype regulates arterial smooth muscles which mediate blood pressure; and the α_1D subtype is expressed in the detrusor muscle and sacral spinal cord, both involved in bladder filling [7] [8] [9] . Since selective α1Bs can only target the prostate gland or bladder smooth muscle, they are expected to generate fewer adverse drug events, such as dizziness, hypotension, and syncope, than do non-selective α1Bs.

Syncope is defined as “a transient loss of consciousness due to transient global cerebral hypoperfusion characterized by rapid onset, short duration, and spontaneous complete recovery” [10] . A fall in systolic blood pressure to 60 mmHg or lower is associated with syncope in the absence of compensatory mechanisms and inadequate automatic regulation of systemic or cerebral blood flow [11] . Syncope leads to falls, which can cause minor injuries or major morbidities. Indeed, 17% of the patients with syncope visited an emergency department with bruises or lacerations on the head and face [12] ; fractures and motor vehicle accidents due to syncope have also been reported [13] [14] .

Adverse event databases are repositories of information, overseen by regulatory authorities of each country and used to quickly find adverse events caused by marketed drugs. The Japanese Adverse Drug Event Report (JADER) database, managed by the Pharmaceutical and Medical Devices Agency (PMDA), which is the regulatory authority in Japan, is a publicly available database, suitable for analyzing adverse events.

Depending on circumstances, spasmodic loss of consciousness can cause substantial injuries, such as bone fractures, hospitalizations, and fatalities. As reported previously [15] [16] [17] [18] , if an adverse event (e.g., syncope) is attributable to a drug, knowing in advance the approximate onset time and tendency

for occurrence of such an event would allow the patient to be alerted and avoid or minimize the potential injury. Therefore, to evaluate the onset time of syncope due to α1B usage, a disproportionality analysis was performed in this study to examine the association between α1B use and syncope in males. Furthermore, for each drug for which statistical significance was detected, its onset time profile was evaluated using the time information available in the JADER database.

Knowing in advance the approximate onset times of adverse events would be useful information to avoid those. In the present study, we evaluated the onset time profiles of syncope due to the use of individual α1Bs.

For more than 10 years since the JSH published its first guidelines on the management of hypertension in 2000 (JSH2000), α1Bs had been preferably indicated for hypertensive patients with BPH. However, the guidelines were updated in 2014 to recommend that caution be exercised when treating elderly hypertensive patients [4] . Moreover, the 2015 guidelines for medical treatment and safety in the elderly [5] recommended that α1Bs be maximally avoided for elderly patients with hypertension. Thus, the recent indications of α1Bs for hypertension are so few that the small numbers of reports remaining in the JADER database are likely to represent the background.

Tamsulosin, naftopidil, and silodosin were shown to be selective for the α_1B-adrenoceptor subtype, with 15.3-, 5.4-, and 583-fold higher affinity than that for the α_1A-adrenoceptor subtype and 4.6-, 16.7-, and 10.5-fold higher affinity than that for the α_1D-adrenoceptor subtype, respectively [25] [26] . However, in the present study, using adverse event data from clinical reports, significant signals were detected for the three selective α1Bs, but no significance was found for the non-selective α1Bs, including doxazosin, despite a sufficient number of reports. The reasons for these findings are unclear, but one of the likely explanations may be differences in the numbers of reports in the JADER database. As described above, there are relatively few reports on the non-selective α1Bs in the JADER database, as compared with those on the selective α1Bs. The differences may be due to some reporting biases because it is worth reporting severe adverse events, such as syncope, that are attributable to selective α1Bs, whereas orthostatic hypotension, an adverse event caused by non-selective α1Bs, is too common to be reported. Furthermore, concomitant medications coadministered for hypertension may be responsible for the findings. Lai et al. [27] [28] have reported that during an early period after treatment initiation, α1B therapy in patients not taking antihypertensive medications was associated with an increased risk of ischemic stroke and hip/femur fracture, which are severe adverse effects due to α1Bs. The non-selective α1Bs examined in the present study were supposedly indicated for hypertensive BPH patients. Therefore, it would be unlikely for patients taking antihypertensive medications to experience severe adverse events sequential to orthostatic hypotension.

The median values (with interquartile ranges) of the onset times of syncopewere close for naftopidil and silodosin, 37 (4 - 184) and 26 (4 - 391) days, respectively (Figure 2). Tamsulosin showed a later onset, 108 (15 - 341) days, than did the other two drugs (Figure 2); however, based on the expression profiles of the adverse event, all three α1Bs were of the early failure type (Table 4). Therefore, patients treated with α1Bs should be closely monitored for syncope for 100 days, especially in the first 20 to 40 days after initiation of naftopidil or silodosin.

According to the Weibull shape parameter test, there was anincrease in adverse events at an early stage, indicating that syncope was likely caused by hypotension-related adverse events due to the α₁-adrenoceptor-blocking activity. We also calculated the onset times of orthostatic hypotension-related adverse events, using PTs for orthostatic hypotension (PT 10031127), dizziness (PT 10013573), and dizziness postural (PT 10013578), and the median values (with interquartile ranges) were 8 (1 - 149) for naftopidil, 3 (1 - 11) for silodosin, and 71 (15 - 730) days for tamsulosin (data not shown).Considering the median onsettimes of syncope, one of the precursor symptoms would have preceded the occurrence of syncope. In the clinic, patients with these precursor symptoms can be routinely treated to avoid inadequate regulation of systemic or cerebral blood flow.

There are several limitations in this study. First, the reports examined in this study may have included syncope due to factors other than orthostatic hypotension since syncope is classified into three types, namely, syncope due to orthostatic hypotension, neurallymediated syncope, and cardiac syncope [10] . There is a possibility that we included α1Bs that were administered to patients with cardiac arrhythmias, coronary artery disease, or myocardial infarction. In addition, owing to the background α1B indications, only reports for males were extracted and analyzed. Moreover, spontaneous reporting systems have limitations, including the lack of details needed to assess causal associations, generalized underreporting bias, dependence of the reporting rate on the time of the presence of each drug on the market, exclusion of healthy individuals, and the lack of denominators [19] [29] . We excluded some data because of the missing dates, making it impossible to calculate the onset time. However, despite the unique limitations of spontaneous adverse event reporting systems, our study revealed typical onset times of adverse events.

In conclusion, in the present study, we found, using the information from the JADER database, that the use of selective α1Bs was associated with syncope, and the onset time profiles for syncope were similar among the drugs. Therefore, patients treated with selective α1Bs should be closely monitored for 100 days, especially in the first 20 to 40 days after initiation of silodosin or naftopidil. We hope that this information will be useful for patients and healthcare professionals in preventing syncope due to the use of selective α1Bs.

The authors declare no conflicts of interest regarding the publication of this paper.

Ohyama, K., Furumoto, M. and Sugiura, M. (2018) Onset Time Profiles for Syncope Associated with α₁-Adrenoceptor Blockers in Males: Analysis of a Spontaneous Adverse Drug Event Database. Pharmacology & Pharmacy, 9, 515-526. https://doi.org/10.4236/pp.2018.912040