The bioequivalence of fixed-dose combination tablets of bisoprolol and ramipril and its drug-drug interaction potential.

Chronic antihypertensive treatment often includes combination of two or more therapies with complementary mechanism of action targeting different blood pressure (BP) control system. If available, these components are recommended to be administered as a fixed-dose combination (FDC) to reduce tablet burden, improve adherence and thus BP control. A combination of ramipril (RAMI) and bisoprolol (BISO) is one of the options used in clinical practice and is supported by therapeutic guidelines. The clinical program for a novel BISO/RAMI FDC consisted of two randomized, open-label, bioequivalence (BE) studies and one drug-drug interaction (DDI) study. The BE was examined between two FDC strengths of BISO/RAMI (10/10 and 10/5 mg) and the individual reference products administered concomitantly at respective doses after a single oral dose under fasting conditions. In both BE studies, 64 healthy subjects were randomized according to a two-way crossover design. The DDI study evaluated a potential pharmacokinetic (PK) interaction between BISO 10 mg and RAMI 10 mg following their single or concomitant administrations in 30 healthy subjects under fasting condition. BE for BISO/RAMI 10/5 mg and absence of a clinically relevant PK DDI between BISO and RAMI was demonstrated as the 90% confidence intervals (CIs) of the geometric mean ratios (GMRs) for area under the concentration time curve (AUC) and maximum concentration (Cmax ) remained within the acceptance range of 80.00 to 125.00%. However, BE for BISO/RAMI 10/10 mg was not demonstrated, as the lower bound of the 90% CI of Cmax for RAMI was outside the acceptance range of BE. Both drugs administered alone or combined were well-tolerated. No PK interaction was observed between BISO and RAMI/ramiprilat, since the co-administration of BISO and RAMI 10 mg single doses resulted in comparable rate and extent of absorption for BISO and RAMI when compared to their individual products.

Effects of short-term bisoprolol on perioperative myocardial injury in patients undergoing non-cardiac surgery: a randomized control study.

The protective role of preoperative beta-blocker in patients undergoing non-cardiac surgery is unknown. We aimed to evaluate the effects of beta-blocker on perioperative myocardial injury in patients undergoing non-cardiac surgery. We consecutively enrolled 112 patients undergoing non-cardiac surgery. They were randomly allocated to receive bisoprolol or placebo given at least 2 days preoperatively and continued until 30 days after surgery. The primary outcome was incidence of perioperative myocardial injury defined by a rise of high-sensitive troponin-T (hs-TnT) more than 99th percentile of upper reference limit or a rise of hs-TnT more than 20% if baseline level is abnormal. Baseline characteristics were comparable between bisoprolol and placebo in randomized cohort Mean age was 62.5 ± 11.8 years and 76 (67.8%) of 112 patients were male. Among 112 patients, 49 (43.8%) underwent vascular surgery and 63 (56.2%) underwent thoracic surgery. The median duration of assigned treatment prior to surgery was 4 days (2-6 days). We did not demonstrate the significant difference in the incidence of perioperative myocardial injury [52.6% (30 of 57 patients) vs. 49.1% (27 of 55 patients), P = 0.706]. In addition, the incidence of intraoperative hypotension was higher in bisoprolol group than placebo group in patients undergoing non-cardiac surgery [70.2% (40 of 57 patients) vs. 47.3% (26 of 55 patients), P = 0.017]. We demonstrated that there was no statistically significant difference in perioperative myocardial injury observed between patients receiving bisoprolol and placebo who had undergone non-cardiac surgery.

Initial treatment with a single pill containing quadruple combination of quarter doses of blood pressure medicines versus standard dose monotherapy in patients with hypertension (QUARTET): a phase 3, randomised, double-blind, active-controlled trial.

BACKGROUND: Treatment inertia is a recognised barrier to blood pressure control, and simpler, more effective treatment strategies are needed. We hypothesised that a hypertension management strategy starting with a single pill containing ultra-low-dose quadruple combination therapy would be more effective than a strategy of starting with monotherapy. METHODS: QUARTET was a multicentre, double-blind, parallel-group, randomised, phase 3 trial among Australian adults (≥18 years) with hypertension, who were untreated or receiving monotherapy. Participants were randomly assigned to either treatment, that started with the quadpill (containing irbesartan at 37·5 mg, amlodipine at 1·25 mg, indapamide at 0·625 mg, and bisoprolol at 2·5 mg) or an indistinguishable monotherapy control (irbesartan 150 mg). If blood pressure was not at target, additional medications could be added in both groups, starting with amlodipine at 5 mg. Participants were randomly assigned using an online central randomisation service. There was a 1:1 allocation, stratified by site. Allocation was masked to all participants and study team members (including investigators and those assessing outcomes) except the manufacturer of the investigational product and one unmasked statistician. The primary outcome was difference in unattended office systolic blood pressure at 12 weeks. Secondary outcomes included blood pressure control (standard office blood pressure <140/90 mm Hg), safety, and tolerability. A subgroup continued randomly assigned allocation to 12 months to assess long-term effects. Analyses were per intention to treat. This trial was prospectively registered with the Australian New Zealand Clinical Trials Registry, ACTRN12616001144404, and is now complete. FINDINGS: From June 8, 2017, to Aug 31, 2020, 591 participants were recruited, with 743 assessed for eligibility, 152 ineligible or declined, 300 participants randomly assigned to intervention of initial quadpill treatment, and 291 to control of initial standard dose monotherapy treatment. The mean age of the 591 participants was 59 years (SD 12); 356 (60%) were male and 235 (40%) were female; 483 (82%) were White, 70 (12%) were Asian, and 38 (6%) reported as other ethnicity; and baseline mean unattended office blood pressure was 141 mm Hg (SD 13)/85 mm Hg (SD 10). By 12 weeks, 44 (15%) of 300 participants had additional blood pressure medications in the intervention group compared with 115 (40%) of 291 participants in the control group. Systolic blood pressure was lower by 6·9 mm Hg (95% CI 4·9-8·9; p<0·0001) and blood pressure control rates were higher in the intervention group (76%) versus control group (58%; relative risk [RR] 1·30, 95% CI 1·15-1·47; p<0·0001). There was no difference in adverse event-related treatment withdrawals at 12 weeks (intervention 4·0% vs control 2·4%; p=0·27). Among the 417 patients who continued, uptitration occurred more frequently among control participants than intervention participants (p<0·0001). However, at 52 weeks mean unattended systolic blood pressure remained lower by 7·7 mm Hg (95% CI 5·2-10·3) and blood pressure control rates higher in the intervention group (81%) versus control group (62%; RR 1·32, 95% CI 1·16-1·50). In all randomly assigned participants up to 12 weeks, there were seven (3%) serious adverse events in the intervention group and three (1%) serious adverse events in the control group. INTERPRETATION: A strategy with early treatment of a fixed-dose quadruple quarter-dose combination achieved and maintained greater blood pressure lowering compared with the common strategy of starting monotherapy. This trial demonstrated the efficacy, tolerability, and simplicity of a quadpill-based strategy. FUNDING: National Health and Medical Research Council, Australia.

The influence of edema on the bisoprolol blood concentration after bisoprolol dermal patch application: A case-control study.

BACKGROUND: Beta-blocking is important for critically ill patients. Although some patients are required to continue taking beta-blockers after they no longer need critical care, some of these patients have impaired swallowing abilities. Bisoprolol dermal patches have recently been introduced and appear to be a good alternative to oral bisoprolol tablets. However, it is still unclear whether the pharmacodynamics of such patches are affected by edema in patients who have experienced critical care. This study aimed to clarify the effects of systemic edema on beta-blocker absorption from dermal patches in critically ill patients. METHOD: Patients who exhibited tachycardia and impaired swallowing function after critical care were included in this study. They were assigned to either the edema group (n = 6) or no edema group (n = 6) depending on the presence/absence of edema in the lower extremities. A bisoprolol dermal patch was pasted onto each subject, and the blood bisoprolol concentration was checked at 8 timepoints over the next 24 hours. The area under the serum concentration time curve, maximum concentration observed (Cmax), and time of maximum concentration observed were also examined. RESULT: The mean blood bisoprolol concentrations of the 2 groups were not significantly different at 2, 4, 6, 8, 10, 12, 16, or 24 hours after the patch application. The area under the serum concentration time curve and maximum concentration observed were not different between the groups. The mean heart rates of the 2 groups were not significantly different at 6, 12, or 24 hours after the patch application (Student t test, P = .0588, P = .1080, and P = .2322, respectively). CONCLUSION: In this study, the blood concentration of bisoprolol and its heart rate-reducing effects after bisoprolol dermal patch application might not be affected by systemic edema in the lower extremities.

Impact of the COVID-19 pandemic on the management of chronic heart failure.

The coronavirus disease 2019 (COVID-19) pandemic is an unprecedented challenge. Meeting this has resulted in changes to working practices and the impact on the management of patients with heart failure with reduced ejection fraction (HFrEF) is largely unknown. We performed a retrospective, observational study contrasting patients diagnosed with HFrEF attending specialist heart failure clinics at a UK hospital, whose subsequent period of optimisation of medical therapy was during the COVID-19 pandemic, with patients diagnosed the previous year. The primary outcome was the change in equivalent dosing of ramipril and bisoprolol at 6-months. Secondary outcomes were the number and type of follow-up consultations, hospitalisation for heart failure and all-cause mortality. In total, 60 patients were diagnosed with HFrEF between 1 December 2019 and 30 April 2020, compared to 54 during the same period of the previous year. The absolute number of consultations was higher (390 vs 270; p = 0.69), driven by increases in telephone consultations, with a reduction in appointments with hospital nurse specialists. After 6-months, we observed lower equivalent dosing of ramipril (3.1 ± 3.0 mg vs 4.4 ± 0.5 mg; p = 0.035) and similar dosing of bisoprolol (4.1 ± 0.5 mg vs 4.9 ± 0.5 mg; p = 0.27), which persisted for ramipril (mean difference 1.0 mg, 95% CI 0.018-2.09; p = 0.046) and bisoprolol (mean difference 0.52 mg, 95% CI -0.23-1.28; p = 0.17) after adjustment for baseline dosing. We observed no differences in the proportion of patients who died (5.0% vs 7.4%; p = 0.59) or were hospitalised with heart failure (13.3% vs 9.3%; p = 0.49). Our study suggests the transition to telephone appointments and re-deployment of heart failure nurse specialists was associated with less successful optimisation of medical therapy, especially renin-angiotensin inhibitors, compared with usual care.

Application of physiologically based biopharmaceutics modeling to understand the impact of dissolution differences on in vivo performance of immediate release products: The case of bisoprolol.

Merck KGaA observed slight differences in the dissolution of Concor® (bisoprolol) batches over the years. The purpose of this work was to assess the impact of in vitro dissolution on the simulated pharmacokinetics of bisoprolol using in vitro-in vivo relationship established with available in vitro dissolution and corresponding plasma concentrations-time data for several bisoprolol batches. A mechanistic absorption model/physiologically based pharmacokinetics model linked with a biopharmaceutics tool such as dissolution testing, namely, physiologically based biopharmaceutics modeling (PBBM), can be valuable in determining a dissolution "safe space." A PBBM for bisoprolol was built using in vitro, in silico, and clinical data. We evaluated potential influences of variability in dissolution of bisoprolol batches on its clinical performance through PBBM and virtual bioequivalence (BE) trials. We demonstrated that in vitro dissolution was not critical for the clinical performance of bisoprolol over a wide range of tested values. Based on virtual BE trials, safe space expansion was explored using hypothetical dissolution data. A formulation with in vitro dissolution reaching 70% dissolved in 15 min and 79.5% in 30 min was shown to be BE to classical fast dissolution of bisoprolol (>85% within 15 min), as point estimates and 90% confidence intervals of the maximum plasma concentration and area under the concentration-time curve were within the BE limits (0.8-1.25).

Myocarditis After SARS-CoV-2 Vaccination: A Vaccine-Induced Reaction?

Vaccination plays an important role in the fight against SARS-CoV-2 to minimie the spread of coronavirus disease 2019 (COVID-19) and its life-threatening complications. Myocarditis has been reported as a possible and rare adverse consequence of different vaccines, and its clinical presentation can range from influenza-like symptoms to acute heart failure. We report a case of a 30-year-old man who presented progressive dyspnea and constrictive retrosternal pain after receiving SARS-CoV-2 vaccine. Cardiac magnetic resonance and laboratory data revealed typical findings of acute myopericarditis.

Comprehensive Exploration of Medications That Affect the Bleeding Risk of Oral Anticoagulant Users.

Oral anticoagulants (OACs) pose a major bleeding risk, which may be increased or decreased by concomitant medications. To explore medications that affect the bleeding risk of OACs, we conducted a nested case-control study including 554 bleeding cases (warfarin, n = 327; direct OACs [DOACs], n = 227) and 1337 non-bleeding controls (warfarin, n = 814; DOACs, n = 523), using a Japanese health insurance database from January 2005 to June 2017. Major bleeding risk associated with exposure to concomitant medications within 30 d of the event/index date was evaluated, and adjusted odds ratios (aORs) were calculated using logistic regression analysis. Several antihypertensive drugs, such as amlodipine and bisoprolol, were associated with a decreased risk of bleeding (warfarin + amlodipine [aOR, 0.64; 95% confidence interval (CI): 0.41-0.98], DOACs + bisoprolol [aOR, 0.51; 95% CI, 0.33-0.80]). As hypertension is considered a significant risk factor for intracranial bleeding in antithrombotic therapy, antihypertensive drugs may suppress intracranial bleeding. In contrast, telmisartan, a widely used antihypertensive drug, was associated with an increased risk of bleeding [DOACs + telmisartan (aOR, 4.87; 95% CI, 1.84-12.91)]. Since telmisartan is an inhibitor of P-glycoprotein (P-gp), the elimination of rivaroxaban and apixaban, which are substrates of P-gp, is hindered, resulting in increased blood levels of both drugs, thereby increasing the risk of hemorrhage. In conclusion, antihypertensive drugs may improve the safety of OACs, and the pharmacokinetic-based drug interactions of DOACs must be considered.

Effects of trimetazidine in combination with bisoprolol in patients with chronic heart failure and concomitant chronic obstructive pulmonary disease: A protocol for systematic review and meta-analysis.

BACKGROUND: To the best of our knowledge, there is no study that has conducted a review investigating the clinical efficacy and safety of bisoprolol combined with trimetazidine on chronic heart failure (CHF) patients with chronic obstructive pulmonary disease (COPD). Therefore, in order to provide new evidence-based medical evidence for clinical treatment, we undertook a systematic review and meta-analysis to assess the effectiveness and safety of bisoprolol combined with trimetazidine on CHF patients with COPD. METHODS: Seven electronic databases including Web of Science, Embase, PubMed, Wanfang Data, Scopus, Science Direct, Cochrane Library will be searched in April 2021 by 2 independent reviewers. For search on PubMed, the following search terms will be used: "trimetazidine, bisoprolol, chronic heart failure, chronic obstructive pulmonary disease." In order to achieve a consistency of extracted items, the data extractors will extract data from a sample of eligible studies. The outcomes include all-cause mortality and hospitalization for cardiac or/and respiratory causes; left ventricular structure and function; and functional scores. Review Manager software (v 5.4; Cochrane Collaboration) will be used for the meta-analysis. Two independent reviewers will assess the risk of bias of the included studies at study level. Any disagreements will be discussed and resolved in discussion with a third reviewer. RESULTS: The results of our review will be reported strictly following the PRISMA criteria. CONCLUSIONS: The review will add to the existing literature by showing compelling evidence and improved guidance in clinic settings. OSF REGISTRATION NUMBER: 10.17605/OSF.IO/ZWPRB.

Do beta-adrenergic blocking agents increase asthma exacerbation? A network meta-analysis of randomized controlled trials.

Beta-adrenergic blocking agents (abbreviated as beta-blockers) have been used for treating various cardiovascular diseases. However, the potential for asthma exacerbation is one of the major adverse effects of beta-blockers. This study aimed to compare the level of risk for an asthma attack in patients receiving various beta-blockers. We searched for randomized controlled trials (RCTs) of either placebo-controlled or active-controlled design. The current network meta-analysis (NMA) was conducted under a frequentist model. The primary outcome was the incidence of asthmatic attack. A total of 24 RCTs were included. Overall NMA revealed that only oral timolol [risk ratio (RR) = 3.35 (95% confidence interval (CI) 1.04-10.85)] and infusion of propranolol [RR = 10.19 (95% CI 1.29-80.41)] were associated with significantly higher incidences of asthma attack than the placebo, whereas oral celiprolol [RR = 0.39 (95% CI 0.04-4.11)], oral celiprolol and propranolol [RR = 0.46 (95% CI 0.02-11.65)], oral bisoprolol [RR = 0.46 (95% CI 0.02-11.65)], oral atenolol [RR = 0.51 (95% CI 0.20-1.28)], infusion of practolol [RR = 0.80 (95% CI 0.03-25.14)], and infusion of sotalol [RR = 0.91 (95% CI 0.08-10.65)] were associated with relatively lower incidences of asthma attack than the placebo. In participants with a baseline asthma history, in addition to oral timolol and infusion of propranolol, oral labetalol, oxprenolol, propranolol, and metoprolol exhibited significantly higher incidences of asthma attack than did the placebo. In conclusion, oral timolol and infusion of propranolol were associated with a significantly higher risk of developing an asthma attack in patients, especially in those with a baseline asthma history, and should be avoided in patients who present a risk of asthma.Trial registration: PROSPERO CRD42020190540.

Achieving Optimal Medical Therapy: Insights From the ORBITA Trial.

Background In stable coronary artery disease, medications are used for 2 purposes: cardiovascular risk reduction and symptom improvement. In clinical trials and clinical practice, medication use is often not optimal. The ORBITA (Objective Randomised Blinded Investigation With Optimal Medical Therapy of Angioplasty in Stable Angina) trial was the first placebo-controlled trial of percutaneous coronary intervention. A key component of the ORBITA trial design was the inclusion of a medical optimization phase, aimed at ensuring that all patients were treated with guideline-directed truly optimal medical therapy. In this study, we report the medical therapy that was achieved. Methods and Results After enrollment into the ORBITA trial, all 200 patients entered a 6-week period of intensive medical therapy optimization, with initiation and uptitration of risk reduction and antianginal therapy. At the prerandomization stage, the median number of antianginals established was 3 (interquartile range, 2-4). A total of 195 patients (97.5%) reached the prespecified target of ≥2 antianginals; 136 (68.0%) did not stop any antianginals because of adverse effects, and the median number of antianginals stopped for adverse effects per patient was 0 (interquartile range, 0-1). Amlodipine and bisoprolol were well tolerated (stopped for adverse effects in 4/175 [2.3%] and 9/167 [5.4%], respectively). Ranolazine and ivabradine were also well tolerated (stopped for adverse effects in 1/20 [5.0%] and 1/18 [5.6%], respectively). Isosorbide mononitrate and nicorandil were stopped for adverse effects in 36 of 172 (20.9%) and 32 of 141 (22.7%) of patients, respectively. Statins were well tolerated and taken by 191 of 200 (95.5%) patients. Conclusions In the 12-week ORBITA trial period, medical therapy was successfully optimized and well tolerated, with few drug adverse effects leading to therapy cessation. Truly optimal medical therapy can be achieved in clinical trials, and translating this into longer-term clinical practice should be a focus of future study. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT02062593.

An attempt at administering a transdermal formulation of bisoprolol in patients with acute cardiac symptoms.

BACKGROUND: Bisono® is the world's first transdermal formulation of a bisoprolol, which is approved for the treatment of hypertension in Japan. We aimed to investigate the usefulness of this formulation in patients who were admitted to our hospital with cardiac symptoms suggestive of acute coronary syndrome or an acute exacerbation of heart failure. METHODS: This study involved a retrospective survey of medical records from September 1, 2017 to April 30, 2018 obtained from the Cardiovascular Center of Kyoto Katsura Hospital. The clinical data of patients on admission who had received a transdermal formula of bisoprolol (Bisono® tape) were retrieved; their blood pressure and heart rate data were analyzed in relation to the doses of Bisono® tape administered. RESULTS: Sixty-three patients received the Bisono® tape. Their final diagnoses included acute myocardial infarction, an exacerbation of heart failure, and atrial fibrillation. While there was no significant correlation observed between the administered doses of the drug and reduction in blood pressure achieved within 24 h after admission, there was a significant (p < 0.05) correlation between the doses of Bisono®tnd reduction in the heart rate within 24 h after admission (ΔHR0-24 h). Only one patient who received 8 mg of Bisono® exhibited temporal bradycardia (heart rate < 50 bpm). CONCLUSION: The transdermal formulation of bisoprolol may be useful for the early introduction of ß-blockers in patients admitted with cardiac symptoms associated with myocardial ischemia or heart failure. However, caution should be exercised because of the possible risk of hypotension.

Ultra-low-dose quadruple combination blood pressure-lowering therapy in patients with hypertension: The QUARTET randomized controlled trial protocol.

High blood pressure is the leading cause of preventable morbidity and mortality globally. Many patients remain on single-drug treatment with poor control, although guidelines recognize that most require combination therapy for blood pressure control. Our hypothesis is that a single-pill combination of 4 blood pressure-lowering agents each at a quarter dose may provide a simple, safe, and effective blood pressure-lowering solution which may also improve long-term adherence. The Quadruple UltrA-low-dose tReaTment for hypErTension (QUARTET) double-blind, active-controlled, randomized clinical trial will examine whether ultra-low-dose quadruple combination therapy is more effective than guideline-recommended standard care in lowering blood pressure. QUARTET will enroll 650 participants with high blood pressure either on no treatment or on monotherapy. Participants will be randomized 1:1 and allocated to intervention therapy of a single pill (quadpill) containing irbesartan 37.5 mg, amlodipine 1.25 mg, indapamide 0.625 mg, and bisoprolol 2.5 mg or to control therapy of a single identical-appearing pill containing irbesartan 150 mg. In both arms, step-up therapy of open-label amlodipine 5 mg will be provided if blood pressure is >140/90 at 6 weeks. The primary outcome is the difference between groups in the change from baseline in mean unattended automated office systolic blood pressure at 12-week follow-up. The primary outcome and some secondary outcomes will be assessed at 12 weeks; there is an optional 12-month extension phase to assess longer-term efficacy and tolerability. Our secondary aims are to assess if this approach is safe, has fewer adverse effects, and has better tolerability compared to standard care control. QUARTET will therefore provide evidence for the effectiveness and safety of a new paradigm in the management of high blood pressure.

Association Between Dose and Plasma Concentration of Bisoprolol in Patients with Heart Failure (CVI ARO 6).

Although bisoprolol is used widely to treat patients with heart failure (HF), little information is available regarding the association between the dose of bisoprolol administered and the bisoprolol plasma concentration (Bis-PC) in real-world clinical practice.This was a single-center, observational study in 114 patients with HF receiving once-daily bisoprolol. After determination of trough Bis-PC, the relationship between the dose of bisoprolol and Bis-PC was analyzed. In a multiple linear regression model, the dose of bisoprolol and estimated creatinine clearance (reciprocal number) were identified as independent predictors. HF severity and hepatic function were not associated with Bis-PC.Bis-PC was increased by renal dysfunction, which explained most of the discrepancy between the dose of bisoprolol administered and Bis-PC.