mirabegron and Cardiovascular-Diseases

Overactive bladder (OAB) syndrome is common in the general population, particularly in elderly patients. Antimuscarinic drugs (AMs) are considered the mainstay pharmaceutical treatment of OAB whereas β3-adrenoceptor agonists, such as mirabegron, represent a good alternative. Owing to the important role of muscarinic and β3 receptors in cardiovascular (CV) tissue and to the fact that OAB patients often have CV comorbidities, the safety-profile of these drugs constitute an important challenge.. The aim of this review is to evaluate the CV effects of AMs and mirabegron in OAB. A systematic literature search from inception until December 2017 was performed on PubMed and Medline.. AMs are generally considered to have good CV safety profile but, however, they may cause undesirable adverse events, such as dry mouth, constipation. CV AEs are rare but noteworthy, the most common CV consequences related to the use of these drugs are constituted by an increase in HR and QT interval. Mirabegron has similar efficacy and tolerability to AMs but causes less adverse events, with either modest hypertension and modest increase in HR (<5 bpm) being the most commonly reported.

Topics: Acetanilides; Adrenergic beta-3 Receptor Agonists; Aged; Cardiovascular Diseases; Heart Rate; Humans; Hypertension; Muscarinic Antagonists; Thiazoles; Urinary Bladder, Overactive

Mirabegron, the first β3-adrenoceptor agonist in clinical practice, is approved for treatment of overactive bladder (OAB) syndrome symptoms. Because β3-adrenoceptors are expressed in cardiovascular (CV) tissues, there are concerns that OAB treatment with β3-adrenoceptor agonists may affect the heart and vasculature.. To provide a summary of CV effects of β3-adrenoceptor agonists in clinical studies.. A systematic literature search from inception until November 2014 was performed on studies in PubMed and Medline.. Twenty papers, published between 1994 and 2014, were identified: mirabegron (16), solabegron (2), AK-677 (1), and BRL35135 (1). More detailed CV data from mirabegron studies were available in online regulatory documents filed with the US Food and Drug Administration and the UK National Institute for Health and Care Excellence.. The CV safety of mirabegron appears to be acceptable at therapeutic doses and comparable with that of antimuscarinic agents, currently first-line therapy for OAB.. In this review we looked at the cardiovascular (CV) effects of β3-adrenoceptor agonists used for the treatment of overactive bladder (OAB). The CV safety of mirabegron (the only clinically approved β3-adrenoceptor agonist) appears to be acceptable at therapeutic doses and comparable with that of antimuscarinic agents, the current first-line therapy for OAB.

Topics: Acetanilides; Adrenergic beta-3 Receptor Agonists; Aniline Compounds; Benzoates; Biphenyl Compounds; Blood Pressure; Cardiovascular Diseases; Electrocardiography; Heart Rate; Humans; Thiazoles; Urinary Bladder, Overactive

To investigate the cardiovascular safety of mirabegron add-on treatment to tamsulosin in male patients with residual overactive bladder symptoms.. This was a post hoc analysis of MATCH, the first double-blind, placebo-controlled study comparing mirabegron and placebo as add-on therapy to tamsulosin for treatment of overactive bladder in men with lower urinary tract symptoms. The analysis focused on treatment-emergent adverse events relating to the cardiovascular system or blood pressure, and changes in vital signs during 12 weeks of follow-up.. Cardiovascular-related treatment-emergent adverse events were reported by 6/566 patients, although only one serious treatment-emergent adverse event was related to treatment (unstable angina in the tamsulosin + placebo group). Hypertension (two patients) and increased blood pressure (one patient) were reported in the tamsulosin + placebo group, but there were no blood pressure-related treatment-emergent adverse events among tamsulosin + mirabegron patients. There were no clinically meaningful changes from baseline in blood pressure, and changes in pulse rate were small (+1.2 bpm in the tamsulosin + mirabegron group). Increased pulse rate was more frequent with tamsulosin + mirabegron than with tamsulosin + placebo in older patients, although within the normal range.. Cardiovascular-related adverse events were uncommon in both treatment groups. Mirabegron is a well-tolerated add-on therapy to tamsulosin in Japanese and Korean males with residual overactive bladder symptoms.

Topics: Acetanilides; Age Factors; Aged; Cardiovascular Diseases; Double-Blind Method; Drug Therapy, Combination; Humans; Lower Urinary Tract Symptoms; Male; Middle Aged; Tamsulosin; Thiazoles; Urinary Bladder, Overactive

To analyze cardiovascular safety of mirabegron in patients with spinal cord injury (SCI)- and multiple sclerosis (MS)-induced neurogenic detrusor overactivity (NDO) in a prospective, randomized, double-blind, placebo-controlled study.. Seventy-eight patients were enrolled into the study, and 66 of them were included into the final analysis. In 49 (74.2%), NDO developed due to suprasacral SCI, 17 (25.8%) suffered from NDO due to MS. Eleven patients were previously treated for hypertension and one for arrhythmia. All study participants received placebo for 2 weeks run-in period. Subsequently, eligible subjects were randomized for 4 weeks of active treatment with mirabegron 50 mg once daily (Group A; n = 32) or placebo (Group B; n = 34). Data from resting electrocardiography (ECG), 24-h ECG and blood pressure monitoring, and echocardiographic examination, were used for cardiovascular safety assessment. All reported variables were evaluated at time of randomization and at the end of the study. Longitudinal changes of variables within the groups and differences between the groups were assessed using nonparametric Kruskal-Wallis test, and p ≤ 0.05 was considered statistically significant.. No statistically significant longitudinal changes were found in safety variables, except for prolongation of QT interval in placebo group (p = 0.0328) recorded by resting ECG. No significant difference between the Groups A and B, in any of the variables, was observed. A single cardiovascular study drug-related adverse event was recorded in a patient with cervical SCI (3.13%).. Our results suggest that mirabegron can be safely used in the treatment of patients with SCI- and MS-induced NDO.

Topics: Acetanilides; Adolescent; Adrenergic beta-3 Receptor Agonists; Adult; Aged; Cardiovascular Diseases; Double-Blind Method; Female; Humans; Male; Middle Aged; Multiple Sclerosis; Prospective Studies; Spinal Cord Injuries; Thiazoles; Urinary Bladder, Overactive; Young Adult

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.. 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.. 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.. A favorable CV safety profile was observed following long-term combination treatment with mirabegron and an antimuscarinic in patients with OAB symptoms.

Topics: Acetanilides; Aged; Aged, 80 and over; Benzilates; Cardiovascular Diseases; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Imidazoles; Japan; Male; Middle Aged; Muscarinic Antagonists; Solifenacin Succinate; Thiazoles; Tolterodine Tartrate; Treatment Outcome; Urinary Bladder, Overactive; Urological Agents

In the BESIDE study, combination therapy (antimuscarinic [solifenacin] and β. OAB patients remaining incontinent despite daily solifenacin 5 mg during 4-week single-blind run-in, were randomised 1:1:1 to double-blind daily combination (solifenacin 5 mg/mirabegron 25 mg, increasing to 50 mg after week 4), solifenacin 5 or 10 mg for 12 weeks. CV safety assessments included frequency of CV-related treatment-emergent adverse events (TEAEs), change from baseline in vital signs (systolic blood pressure [SBP], diastolic blood pressure [DBP], pulse rate) and electrocardiogram (ECG) parameters.. The frequency of hypertension, tachycardia and ECG QT prolongation, respectively, was low and comparable across combination (1.1%, 0.3%, 0.1%), solifenacin 5 mg (0.7%, 0.1%, 0.1%), and solifenacin 10 mg groups (0.8%, 0%, 0.1%). Adjusted mean (SE) change from baseline to end of treatment (EoT) in SBP, DBP, and pulse rate with combination (0.07 mm Hg [0.38], -0.35 mm Hg [0.26], 0.47 bpm [0.28]), solifenacin 5 mg (-0.93 mm Hg [0.38], -0.45 mm Hg [0.26], 0.43 bpm [0.28]) and solifenacin 10 mg (-1.28 mm Hg [0.38], -0.48 mm Hg [0.26], 0.27 bpm [0.28]) was generally comparable, with the exception of a mean treatment difference of ~1 mm Hg in SBP between combination and solifenacin monotherapy; SBP was unchanged with combination and decreased with solifenacin monotherapy. Mean changes from baseline to EoT in ECG parameters were generally similar across treatment groups, except for QT interval corrected using Fridericia's formula, which was higher with solifenacin 10 mg (3.30 mseconds) vs. combination (0.49 mseconds) and solifenacin 5 mg (0.77 mseconds).. The comparable frequency of CV-related TEAEs, changes in vital signs and ECG parameters indicates no synergistic effect on CV safety outcomes when mirabegron and solifenacin are combined.

Topics: Acetanilides; Adrenergic beta-3 Receptor Agonists; Adult; Aged; Aged, 80 and over; Cardiovascular Diseases; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Male; Middle Aged; Muscarinic Antagonists; Single-Blind Method; Solifenacin Succinate; Thiazoles; Treatment Outcome; Urinary Bladder, Overactive

To assess the effect of 25 or 50 mg mirabegron on cardiovascular end-points and adverse drug reactions in real-world Japanese patients with overactive bladder and cardiovascular disease.. Participants had overactive bladder, a history of/coexisting cardiovascular disease and a 12-lead electrocardiogram carried out ≤7 days before initiating 4 weeks of mirabegron treatment. Patients with "serious cardiovascular disease" (class III or IV on the New York Heart Association functional classification and further confirmed by expert analysis) were excluded. Patient demographics, physical characteristics and cardiovascular history were recorded. After 4 weeks, patients underwent another electrocardiogram. Incidence of cardiovascular adverse drug reactions and change from baseline in electrocardiogram parameters (RR, PR, QRS intervals, Fridericia's corrected QT and heart rate) were assessed.. Of 316 patients registered, 236 met criteria and had baseline/post-dose electrocardiograms: 61.9% male; 60.2% aged ≥75 years; 93.6% with coexisting cardiovascular disease, notably, arrhythmia (67.8%) and angina pectoris (19.1%). Starting mirabegron daily doses were 25 mg (19.9%) or 50 mg (80.1%). The incidence of cardiovascular adverse drug reactions was 5.51%. After 4 weeks, the mean heart rate increased by 1.24 b.p.m. (statistically significant, but clinically acceptable as per previous trials). No significant changes were observed in PR, QRS or Fridericia's corrected QT. No significant correlations in the total population or age-/sex-segregated subgroups were observed between baseline Fridericia's corrected QT and change at 4 weeks. No correlation for heart rate versus change from baseline heart rate with treatment was observed.. Mirabegron was well tolerated in real-world Japanese patients with overactive bladder and coexisting cardiovascular disease. No unexpected cardiovascular safety concerns were observed.

Topics: Acetanilides; Adrenergic beta-3 Receptor Agonists; Aged; Cardiovascular Diseases; Female; Humans; Male; Marketing; Thiazoles; Urinary Bladder, Overactive; Urological Agents

During clinical trials, mirabegron, a β3-adrenoreceptor agonist, was associated with increased vital signs vs placebo in patients with overactive bladder.. The purpose of this study was to compare incidence rates of adverse cardiovascular (CV) outcomes following mirabegron or antimuscarinic use.. We conducted an observational post-marketing safety study utilising real-world data. The study population was identified within five sources: Danish and Swedish National Registers, Clinical Practice Research Datalink (UK), Optum (USA) and Humana (USA). Episodes of time when patients were new users of mirabegron or antimuscarinics (October 2012-December 2018) were sourced from prescriptions and matched on propensity scores. Occurrences of major adverse cardiovascular events (MACE), acute myocardial infarction (AMI), stroke, CV mortality and all-cause mortality were identified. Outcome incidence rates and hazard ratios from Cox models were estimated.. Overall, 152,026 mirabegron and 152,026 antimuscarinic episodes were matched. The population consisted of 63.1% women and 72.6% were ≥ 65 years old. There were no appreciable differences in the incidence rates of MACE, AMI or stroke between users of mirabegron and antimuscarinics. Incidence rates of CV mortality (hazard ratio 0.83, 95% confidence interval 0.73-0.95) and all-cause mortality (hazard ratio 0.80, 95% confidence interval 0.76-0.84) were no higher with mirabegron vs antimuscarinics. Results restricted to episodes at high risk for CV events or stratified by age (< 65 years, ≥ 65 years) or prior overactive bladder medication use were consistent with overall findings.. This large, multinational study found no higher risk of MACE, AMI, stroke, CV mortality or all-cause mortality among users of mirabegron relative to users of antimuscarinics.. During clinical trials, mirabegron, which is a treatment for overactive bladder, was associated with small increases in heart rate and blood pressure. This study was conducted to compare the frequency of cardiac events following the use of mirabegron or antimuscarinics, a group of treatments also used to treat overactive bladder. We obtained the data for this study from four countries: Denmark, Sweden, the UK and the USA. We identified people who were new users of mirabegron or antimuscarinics from 2012 to 2018 using prescription or dispensing records. Occurrences of major cardiac events, heart attack, stroke, death due to cardiac events and death from any cause were evaluated. Overall, we identified 152,026 times when mirabegron or antimuscarinics were each used as new treatments. Most of the people in the study were women (63.1%) and at least 65 years old (72.6%). There were no notable differences between the treatment groups with regard to how often major cardiac events, heart attack or stroke occurred. Further, death due to cardiac events and death from any cause were no higher with mirabegron compared with antimuscarinics. We obtained similar results when the data were assessed for patients who were at high risk for cardiac events or split by age (less than 65 years or at least 65 years) or a history of overactive bladder medication use. In conclusion, this large study involving data from several countries found no higher risk of major cardiac events, heart attack, stroke or death among people prescribed mirabegron compared with antimuscarinics.

Topics: Acetanilides; Aged; Cardiovascular Diseases; Cohort Studies; Female; Heart Disease Risk Factors; Humans; Male; Muscarinic Antagonists; Risk Factors; Stroke; Thiazoles; Treatment Outcome; Urinary Bladder, Overactive

For managing overactive bladder (OAB), mirabegron, a β3 adrenergic receptor agonist, is typically used as second-line pharmacotherapy after antimuscarinics. Therefore, patients initiating treatment with mirabegron and antimuscarinics may differ, potentially impacting associated clinical outcomes. When using observational data to evaluate real-world safety and effectiveness of OAB treatments, residual bias due to unmeasured confounding and/or confounding by indication are important considerations. Falsification analysis, in which clinically irrelevant endpoints are tested as a reference, can be used to assess residual bias. The objective in this study was to compare baseline cardiovascular risk among OAB patients by treatment, and assess the presence of residual bias via falsification analysis of OAB patients treated with mirabegron or antimuscarinics, to determine whether clinically relevant comparisons across groups would be feasible. Linked electronic health record and claims data (Optum/Humedica) for OAB patients in the United States from 2011-2015 were available, with index defined as first date of OAB treatment during this period. Unadjusted characteristics were compared across groups at index and propensity-matching conducted. Falsification endpoints (hepatitis C, shingles, community-acquired pneumonia) were compared between groups using odds ratios (ORs) and 95% confidence intervals (CI). The study identified 10,311 antimuscarinic- and 408 mirabegron-treated patients. Mirabegron patients were predominantly older males, with more comorbidities. The analytic sample included 1,188 antimuscarinic patients propensity-matched to 396 mirabegron patients; after matching, no significant baseline differences remained. Estimates of falsification ORs were 0.7 (CI:0.3-1.7) for shingles, 1.5 (CI:0.3-8.2) for hepatitis C, 0.8 (CI:0.4-1.8) and 0.9 (CI:0.6-1.4) for pneumonia. While propensity matching successfully balanced observed covariates, wide CIs prevented definitive conclusions regarding residual bias. Accordingly, further observational comparisons by treatment group were not pursued. In real-world analysis, bias-detection methods could not confirm that differences in cardiovascular risk in patients receiving mirabegron versus antimuscarinics were fully adjusted for, precluding clinically relevant comparisons across treatment groups.

Topics: Acetanilides; Adolescent; Adult; Aged; Aged, 80 and over; Cardiovascular Diseases; Comorbidity; Data Interpretation, Statistical; Databases, Factual; Electronic Health Records; Female; Humans; Male; Middle Aged; Muscarinic Antagonists; Propensity Score; Retrospective Studies; Risk Factors; Thiazoles; United States; Urinary Bladder, Overactive; Urological Agents; Young Adult

To determine risks associated with prescribing mirabegron, the first-in-class β3-adrenoreceptor agonist, to non-selected female patients with overactive bladder.. Routine female patients seeking treatment for overactive bladder (n=221) in a urology/gynecology outpatient clinic. Data on adverse events, cardiovascular outcomes, condition specific symptoms and drug discontinuation was collected at two months follow-up (FU). Non-parametric statistics was used as appropriate. Odds ratios (ORs) with 95% confidence intervals (CIs) for outcome association analyses using logistic regression.. 16 patients (7.2%) discontinued treatment because of side effects. There were no significant associations between cardiovascular adverse events and pre-existing cardiovascular disease (OR 0.3, 95% CI 0.3-2.6), or pre-existing ECG abnormalities (OR 2.3, 95% CI 0.3-16.3). At FU ECGs there were no de novo cases of tachyarrhythmias and no significant difference in mean QTc between baseline (403ms, SD 21.7) and the 2 months follow-up ECG (403ms, SD 20.3) (p=0.75). There was a significant decrease in the mean systolic blood pressure (p=0.03) but no significant change in mean diastolic pressure (p=0.8) or heart rates (p=0.2) from baseline to FU. Overactive bladder specific symptoms and quality of life improved significantly (p<0.001 respectively).. Mirabegron treatment is associated with a satisfactory cardiovascular safety profile, as well as, significant symptomatic improvement also in a heterogeneous population of non-selected women with overactive bladder presenting in everyday clinical practice.

Topics: Acetanilides; Adrenergic beta-3 Receptor Agonists; Aged; Cardiovascular Diseases; Cohort Studies; Drug Monitoring; Female; Follow-Up Studies; Humans; Medication Adherence; Middle Aged; Outpatient Clinics, Hospital; Prospective Studies; Quality of Life; Risk; Self Report; Severity of Illness Index; Sweden; Thiazoles; Urinary Bladder, Overactive; Urological Agents