Cardiovascular safety of antimuscarinic add‐on therapy in patients with overactive bladder who had a suboptimal response to mirabegron monotherapy: A post hoc analysis from the Japanese MILAI II study

Abstract Objective This analysis was conducted to investigate the cardiovascular (CV) safety outcomes from the MILAI II study. MILAI II was conducted to evaluate the long‐term safety and efficacy of antimuscarinic add‐on therapy to mirabegron over 52 weeks in patients with overactive bladder (OAB) symptoms. Methods MILAI II consisted of a 2‐week screening period (patients received mirabegron 50 mg once daily) plus a 52‐week treatment period (patients were randomized to receive a combination of mirabegron 50 mg/d plus solifenacin 5 mg/d, propiverine 20 mg/d, imidafenacin 0.2 mg/d, or tolterodine 4 mg/d). CV safety was assessed using treatment‐emergent adverse events (TEAEs), vital signs, and 12‐lead electrocardiograms (ECGs). Vital signs and ECG data were evaluated for each patient using worst post‐baseline values reported. Results Of 647 patients, 570 (88.1%) were female with a mean age of 65 years. CV history at baseline and CV‐related concomitant medication use throughout the study were balanced between groups. The incidences of overall and drug‐related CV TEAEs were ≤8.1% and ≤6.2%, respectively, for all groups. The most common TEAEs were ECG T wave amplitude decreased, ECG QT prolonged, and ventricular extrasystoles. Overall, 36 TEAEs of interest related to the CV system that were possibly/probably related to treatment were reported with similar incidences for each group. For the worst post‐baseline vital signs and ECGs, no relationships were noted in terms of either timing or treatment group. Conclusion A favorable CV safety profile was observed following long‐term combination treatment with mirabegron and an antimuscarinic in patients with OAB symptoms.


| INTRODUCTION
Overactive bladder (OAB) syndrome is a prevalent condition and an estimated 12.4% of the Japanese population who are ≥40 years of age experience symptoms of OAB. 1 Real-world studies have indicated that substantially more patients with OAB present with concomitant cardiovascular (CV) comorbidities compared with age-and gendermatched controls. 2,3 This finding emphasizes the importance of evaluating the CV safety of potential and existing OAB pharmacotherapies.
Antimuscarinic medications currently form the mainstay of pharmacotherapy approaches for treating patients with OAB symptoms. 4 These medications are believed to act by inhibiting the binding of acetylcholine to the muscarinic receptors M2 and M3 that are found on detrusor smooth muscle cells and other bladder wall components. 5 A further medication that is used in clinical practice for treating patients with OAB symptoms is the β3-adrenoreceptor agonist, mirabegron, which may act through various mechanisms, including relaxation of the detrusor muscle by cyclic adenosine monophosphate (cAMP) generation and inhibition of spontaneous contractile activity in the bladder. 6 As well as in the bladder, preclinical studies have shown that M2 and M3 receptors and the β-adrenoreceptors (β1, β2, and β3) are also expressed in the CV system. 7,8 Antagonism of the M2 receptor (which plays a functional role in mediating heart rate) 9 and the M3 receptor (which mediates vasodilation) 10 could possibly increase heart rate, prolong the QT interval, and induce potentially fatal ventricular tachyarrhythmias, such as torsade de pointes. 9 Further investigations have discovered that the β1-adrenoreceptor mediates increased heart rate and contractility and the β2-adrenoreceptor mediates vasodilation in the vascular smooth muscle. 11 The role of the β3-adrenoreceptor in the physiology of the human CV system is currently less clear, although activation of the β3-adrenoreceptor is known to induce positive inotropic effects in human atrial tissue and negative inotropic effects in ventricular tissue. 12 Several clinical studies have also assessed the CV safety of mirabegron or antimuscarinic monotherapy. Antimuscarinic agents appear to have a favorable CV safety profile and CV-related treatment-emergent adverse events (TEAEs) are rarely reported. 13 However, the most commonly reported events of increases in heart rate and QT interval need to be taken into account when prescribing these medications. Furthermore, in a pooled analysis of 12-week mirabegron monotherapy studies, no trends across treatment groups (placebo, mirabegron, tolterodine) were observed in the frequencies of abnormal electrocardiogram (ECG) findings. 14 Although mirabegron and antimuscarinics are effective monotherapies for patients with OAB symptoms, poor responses to treatment have been noted. 15,16 These patients may achieve an improved outcome if they subsequently receive combination therapy involving mirabegron plus an antimuscarinic. However, there is a concern that combining mirabegron with antimuscarinics may result in synergistic effects on the CV system. Several international phase II-IV clinical trials (Symphony, 17 BESIDE, 18 MILAI, 19 SYNERGY, 20 and SYNERGY II 21 ) have been conducted to assess the efficacy and safety of mirabegron with the antimuscarinic, solifenacin. The combination of mirabegron with solifenacin resulted in improved efficacy over the monotherapies 17,18,20,21 and no synergistic CV effects were reported in subanalyses from the BESIDE and SYNERGY trials. 22,23 However, both of these trials were conducted in Western countries and therefore it is important to assess the CV safety of mirabegron and antimuscarinic combination therapy in Asian patients.
MILAI II was a 52-week study involving 649 Japanese patients with residual OAB symptoms. 24 The results of the study showed that antimuscarinic add-on therapy (solifenacin, propiverine, imidafenacin, or tolterodine) was well tolerated and effective following ≥6 weeks of initial treatment with mirabegron. Herein, we report the findings of a post hoc analysis that evaluated the CV safety outcomes from the MILAI II study. In addition, using the vital sign data, we examined whether there are any timing factors that need to be taken into account after commencing combination therapy.

| METHODS
The overall methodology has been previously published. 24      safety, and demographic data were evaluated using the safety analysis set (SAF), which was defined as patients who had received ≥1 dose of study drug.

| Patient characteristics
Out of 649 randomized patients, 647 were included in the SAF; one patient from the mirabegron and solifenacin group did not complete a second informed consent form, and one patient from the mirabegron and tolterodine group did not take any study medication. 24

| CV events
The overall safety and efficacy results from the MILAI II study have been previously presented. 24 In total, 519 (80.2%) patients experienced ≥1 TEAE and 303 (46.8%) patients experienced ≥1 drug-related TEAE. In addition, 28 (4.3%) patients reported ≥1 serious TEAE. Two serious TEAEs were considered to be possibly drug-related by the investigator, one of which was a CV-related event in a patient from the mirabegron and propiverine group who experienced atrial fibrillation; this event resolved 10 days after treatment withdrawal.
The incidence of CV-related TEAEs was similar between groups ( Figure 1 and Table 2). The overall and drug-related incidence rates were ≤8.1% and ≤6.2%, respectively, for all treatment groups. The overall and drug-related incidences of ECG QT prolonged were slightly higher in the mirabegron and imidafenacin group compared with the other three groups.
In total, 36 TEAEs of interest related to the CV system that were possibly or probably related to mirabegron and/or the combination antimuscarinic drug were reported during the MILAI II study (Table 3).
Of these, seven, 11, nine, and nine TEAEs were reported by the patients from the mirabegron and solifenacin, mirabegron and propiverine, mirabegron and imidafenacin, and mirabegron and tolterodine groups, respectively. The events occurred between 21 and 364 days after the start of combination treatment and no discernible differences in time of onset were noted between groups.     The results of this study add to the wealth of CV-related data that have been amassed during the clinical development of mirabegron.

| DISCUSSION
For example, low incidences of CV-related events have been noted in phase III trials with mirabegron monotherapy, 25 although small, statistically significant increases in pulse rate of approximately 1 bpm have also been observed. 14,26,27 However, these increases in pulse rate were reversed once treatment was discontinued 27 and were considered to be clinically acceptable. An analysis of pooled data from mirabegron clinical trials that included almost 13 400 patients who had received ≥1 dose of mirabegron, comparator antimuscarinics (solifenacin or tolterodine), or placebo found no evidence of increased CV risk for mirabegron or antimuscarinics in comparison with placebo. 28 The authors of this analysis concluded that the CV-related TEAEs reported appeared to be related to patients' pre-existing conditions, rather than OAB treatment. Importantly, there was also no evidence that OAB treatment or associated blood pressure increases augmented the risk of CV-related TEAEs. Additional studies have also investigated the effect of mirabegron treatment on ECG parameters.
In a thorough QT study involving 352 healthy subjects, mirabegron was associated with QT interval prolongation at the supratherapeutic dose of 200 mg in women. 29 However, at the therapeutic daily dose of 50 mg, the use of mirabegron was not associated with significant prolongation of QT/QTc interval in either sex. Despite the above F I G U R E 2 Scatter plot of day of worst cases in vital signs and QTcF at clinical site. Data shown for the safety analysis set (patients who received ≥1 dose of study drug). The data are displayed according to the day when each patient experienced the largest change in each parameter (only increases from baseline were included in the analyses). DBP, diastolic blood pressure; IMI, imidafenacin; MIRA, mirabegron; PRO, propiverine; QTcF, QT interval corrected for heart rate by Fridericia's formula; SBP, systolic blood pressure; SOLI, solifenacin; TOL, tolterodine findings, Japanese authorities currently recommend caution in administering mirabegron to patients with known CV disease. 30 Cardiac risk factors may be included as exclusion criteria for clinical trials or may make patients less likely to be included in these studies following assessment by the investigator. For example, trials of mirabegron typically exclude patients with a prolonged QT interval or those taking drugs that are likely to prolong the QT interval. 25 Specific exclusion criteria in the MILAI II study included long QT syndrome, an abnormal ECG, or a QTcF of ≥450 ms. 24 One of the limitations of this study is therefore that the incidence of severe CV disease was potentially lower than that in a real-world population. However, an observational, post-marketing study has been conducted to investigate the CV safety of mirabegron in 236 Japanese patients with OAB and concomitant CV disease (mean age: 74.5 years). 31 In the study, 3.4% of the patient population were taking other medication that could cause QT prolongation and 7.5% had a baseline QTcF >450 ms. Although mean heart rate increased by 1.24 bpm after 4 weeks of treatment, this change was not considered to be clinically significant. Furthermore, no significant changes in PR, QRS (ventricular depolarization), or QTcF intervals were noted during the investigation.
In addition, the present study examined vital sign and ECG fluctuations throughout the treatment period. Previous clinical studies have examined average vital sign results over time, [32][33][34] although we believe that this is the first mirabegron study to examine the most variable values obtained for each patient. The results of the present study showed that no relationships were apparent in the increases in vital signs or QTcF values observed and either the timing of the increase or the treatment administered.
In conclusion, the results of this subanalysis demonstrate the favorable CV safety profile of long-term treatment with mirabegron in combination with the antimuscarinics, solifenacin, propiverine, imidafenacin, or tolterodine. Physicians can therefore be reassured about the CV safety of these combination therapies when treating patients with OAB within their clinical practice.