Doses Of Metoprolol Research Articles

Women are started on a lower daily dose of metoprolol than men irrespective of dose recommendations: A potential source of confounding by contraindication in pharmacoepidemiology.

PurposeCurrent guidelines have no sex‐specific dosage advice for metoprolol. To evaluate whether women and men are prescribed the same dose a cohort analysis was performed in the population‐based Rotterdam Study (RS). Results were replicated in the Integrated Primary Care Information (IPCI) database of automated general practice data.MethodsThe mean daily starting doses of metoprolol in both sexes were compared with independent‐samples t‐tests and a linear regression analysis was used to adjust in the RS for co‐variables, notably, cardiovascular comorbidity, migraine, age, SBP, DBP, BMI, socioeconomic status, use of other antihypertensive drugs, smoking, and alcohol. In the IPCI‐database, adjustment was for age only.ResultsThe mean daily starting dose was statistically significantly lower in women than in men in both the RS and IPCI database, with a mean difference of 4.8 mg (95%CI −7.8, −1.8) and 4.6 mg (95%CI −5.3,‐4.0), respectively. Statistical significance remained after adjustment in both databases.ConclusionsWomen received lower starting doses of metoprolol than men in two independent data collections despite non‐sex specific cardiovascular guideline recommendations. This example of real‐life pharmacotherapy can lead to a form of confounding by contraindication in pharmacoepidemiology.

Diurnal QT analysis in patients with sotalol after cardioversion of atrial fibrillation.

BackgroundThe risk of ventricular arrhythmias in patients on QT prolonging drugs is indicated to be increased early after cardioversion (CV) of atrial fibrillation (AF) to sinus rhythm (SR). Sotalol, used to prevent AF relapse, prolongs cardiac repolarization and corrected QT interval (QTc). A pronounced QTc prolongation is an established marker of pro‐arrhythmias. Our objective was to use novel technique to quantify and evaluate the diurnal variation of the QTc interval after elective CV to SR in patients on sotalol or metoprolol.MethodsFifty patients underwent twelve‐lead Holter recording for 24 hr after elective CV for persistent AF. All patients had the highest tolerable stable dose of sotalol (n = 27) or metoprolol (n = 23). Measurements of QT and RR intervals were performed on all valid beats.ResultsA clear diurnal variation of both HR and QTc was seen in both groups, more pronounced in patients on sotalol, where a high percentage of heartbeats with QTc >500 ms was observed, especially at night. Six patients (22%) on sotalol but none on metoprolol had >20% of all heart beats within the 24‐hour recording with QTc >500 ms.ConclusionTwenty‐four‐hour Holter recordings with QT‐measurement immediately after CV demonstrated that one in five patients on sotalol had >20% of all heart beats with prolonged QTc >500 ms, especially during night‐time. The QTc diurnal variation was retained in patients on β‐blockade or a potent class III anti‐arrhythmic drug with β‐blocking properties.

Speeding up beta-blockade prior to coronary CT angiography: can we predict the dose of intravenous metoprolol required to achieve target heart rate in a given patient?

To evaluate the use and safety of intravenous (IV) metoprolol in a cohort of patients undergoing coronary computed tomographic angiography (CCTA) at a university hospital, and in particular, to establish if the minimum dose required to achieve the target heart rate (HR) in a given patient can be predicted from the baseline HR. Patients undergoing CCTA at a tertiary centre between January 2015 and May 2018, with baseline HR ≥60 bpm requiring IV metoprolol, were identified retrospectively from the database. Patients with a contraindication to beta-blockade or an indication for CCTA other than coronary disease were excluded. HR at baseline and at the time of scanning were recorded, together with the total dose of IV metoprolol administered. Of 625 patients identified, 330 (52.8%) achieved HR ≤60 with IV metoprolol. Patients who achieved target HR had lower baseline HR. They received a lower radiation exposure due to tight prospective gating and a lower tube voltage. The lower quartile dose of metoprolol administered was 5 mg for patients with baseline HR <65 beats per minute (bpm), but 10 mg for HR 65-74 bpm, and ≥20 mg for higher HRs. There were no cases of symptomatic bradycardia/hypotension. Patients with a resting HR of ≥60 bpm can reasonably be given an initial minimum dose of 5-20 mg metoprolol IV before CCTA, with additional doses as required.

Evaluation of metoprolol versus diltiazem for rate control of atrial fibrillation in the emergency department.

The purpose of this study was to compare the effectiveness and safety of the metoprolol and diltiazem administration in the Emergency Department (ED) for rate control of supraventricular tachycardia. This was a retrospective cohort study of adult patients who presented to the ED with ventricular rates ≥120 beats per minute (bpm) and who received bolus doses of either intravenous metoprolol or intravenous diltiazem. The primary outcome was achievement of rate control, defined as heart rate < 110bpm, at two hours after administration of the last bolus dose of metoprolol or diltiazem. Safety outcomes included occurrence of hypotension, defined as systolic blood pressure<90mmHg or diastolic blood pressure<60mmHg, and bradycardia, defined as heart rate<60bpm. There were 166 patients receiving metoprolol and 183 patients receiving diltiazem included in the study. The primary outcome, rate control at two hours after the last bolus dose of metoprolol or diltiazem was similar between the two groups (45.8% vs 42.6%, p=0.590, respectively). The percentage of patients achieving rate control was also similar (47.0% vs 41.6%, p=0.333) at one hour. At 0.5h HR had a significantly greater numerical (diltiazem: 29.3±23.1bpm vs metoprolol: 21.8±18.9bpm, p=0.012) and percent decrease (21.1% vs 15.94%, p=0.014) in the diltiazem group compared to metoprolol. There was no significant difference in occurrence of bradycardia in the two groups (diltiazem: 3.83% vs metoprolol: 1.2%, p=0.179). More patients in the diltiazem group compared to the metoprolol group experienced hypotension (39.3% vs 23.5%, p=0.002). The difference in systolic hypotension events was not significantly different (9.29% vs 5.42%, p=0.221), while the difference in diastolic hypotension events was significantly different (37.7% vs 22.3%, p=0.002). There was no difference in acute rate control effectiveness two hours after the last bolus dose of diltiazem and metoprolol for supraventricular tachycardias. There was a significantly higher occurrence of hypotension in the diltiazem group which was driven by higher rates of diastolic blood pressures less than 60mmHg.

Metoprolol Impairs β1-Adrenergic Receptor-Mediated Vasodilation in Rat Cerebral Arteries: Implications for β-Blocker Therapy.

The practice of prescribing β-blockers to lower blood pressure and mitigate perioperative cardiovascular events has been questioned because of reports of an increased risk of stroke. The benefit of β-blocker therapy primarily relies on preventing activation of cardiac β1-adrenergic receptors (ARs). However, we reported that β1ARs also mediate vasodilator responses of rat cerebral arteries (CAs), implying that β-blockers may impair cerebral blood flow under some conditions. Here, we defined the impact of metoprolol (MET), a widely prescribed β1AR-selective antagonist, on adrenergic-elicited diameter responses of rat CAs ex vivo and in vivo. MET (1-10 µmol/l) prevented β1AR-mediated increases in diameter elicited by dobutamine in cannulated rat CAs. The β1AR-mediated dilation elicited by the endogenous adrenergic agonist norepinephrine (NE) was reversed to a sustained constriction by MET. Acute oral administration of MET (30 mg/kg) to rats in doses that attenuated resting heart rate and dobutamine-induced tachycardia also blunted β1AR-mediated dilation of CAs. In the same animals, NE-induced dilation of CAs was reversed to sustained constriction. Administration of MET for 2 weeks in drinking water (2 mg/ml) or subcutaneously (15 mg/kg per day) also resulted in NE-induced constriction of CAs in vivo. Thus, doses of MET that protect the heart from adrenergic stimulation also prevent β1AR-mediated dilation of CAs and favor anomalous adrenergic constriction. Our findings raise the possibility that the increased risk of ischemic stroke in patients on β-blockers relates in part to adrenergic dysregulation of cerebrovascular tone. SIGNIFICANCE STATEMENT: β-Blocker therapy using second-generation, cardioselective β-blockers is associated with an increased risk of stroke, but the responsible mechanisms are unclear. Here, we report that either acute or chronic systemic administration of a cardioselective β-blocker, metoprolol, mitigates adrenergic stimulation of the heart as an intended beneficial action. However, metoprolol concomitantly eliminates vasodilator responses to adrenergic stimuli of rat cerebral arteries in vivo as a potential cause of dysregulated cerebral blood flow predisposing to ischemic stroke.

Impact of Plasmodium vivax malaria and antimalarial treatment on cytochrome P450 activity in Brazilian patients.

To investigate the impact of Plasmodium vivax malaria and chloroquine-primaquine chemotherapy on CYP2D6 and CYP2C19 activity in patients from the Brazilian Amazon. Adult patients (n = 30) were given subtherapeutic doses of CYP2D6 and CYP2C19 phenotypic probes metoprolol (10 mg) and omeprazole (2 mg) in three different stages of vivax malaria illness: acute disease (study phase 1), post chemotherapy (phase 2) and convalescence (stage 3). Plasma concentrations of probes and CYP-hydroxylated metabolites (α-OH metoprolol and 5-OH omeprazole) were measured using LC/MS/MS. Two pharmacokinetic metrics were used to estimate CYP activity: (a) ratio of plasma concentrations of probe/metabolite at 240 minutes after administration of the probes and (b) ratio of areas under the time-concentration curves for probe/metabolite (AUC0-12h ). For statistical analysis, the pharmacokinetic metrics were normalized to the respective values in phase 3. Taqman assays were used for CYP2D6 and CYP2C19 genotyping. Cytokines levels were measured using cytometric bead array. Both pharmacokinetic metrics for metoprolol and omeprazole, and plasma concentrations of cytokines IL-6, IL-8 and IL-10 varied significantly across the three study phases (ANOVA P < 0.0001). Post hoc tests showed greater metoprolol:α-OH metoprolol ratios in phases 1 and 2 compared to phase 3, larger omeprazole:5-OH omeprazole ratios in phase 1 than in phases 2 and 3, and higher circulating IL-6, IL-8 and IL-10 in phase 1 than in phases 2 and 3. P. vivax malaria and treatment altered CYP2D6 and CYP2C19 metabolic phenotypes. CYP2C19 inhibition is attributed to a higher level of circulating proinflammatory cytokines, while suppression of CYP2D6 is ascribed mainly to chloroquine exposure.

ANGINA AND ATRIAL FIBRILLATION IN MELOXICAM USE

SESSION TITLE: Medical Student/Resident Cardiovascular Disease Posters SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: October 18-21, 2020 INTRODUCTION: Atrial fibrillation is the most common arrhythmia that affects patients worldwide. Risk factors that contribute to the development of atrial fibrillation include advanced age > 65, hypertension, thyroid disorders, and alcoholic heart disease. We present a case of a male patient who developed atrial fibrillation and angina from meloxicam use. CASE PRESENTATION: A 55-year-old male with history of arthritis, morbid obesity and recent diagnosis of obstructive sleep apnea and hypertension, presented to the ED with intermittent episodes of 5/10 non-radiating retrosternal chest pain. 10-point review of systems was significant for shortness of breath and palpitations. Patient has history of small hand joint arthritis and body pain for which he was taking meloxicam for 3 weeks. Family history was significant for coronary artery disease in father and brother. He consumed 6 beers daily but denied other substance use. Vitals showed blood pressure was 157/104 mm Hg and heart rate in 109 bpm, with a SpO2 96% on room air. EKG showed atrial fibrillation with rapid ventricular response without acute ST-T changes. Troponin was <0.03. Patient was initially managed with loading dose aspirin and heparin drip. Rate control was achieved with two doses of metoprolol 5 mg IV push. The patient was subsequently started on metoprolol 25 mg PO BID and converted to sinus rhythm in 24 hours. Laboratory results showed unremarkable complete blood count, electrolytes, TSH, and lipid panel. Transthoracic echocardiogram demonstrated left ventricular ejection fraction of 55-60% with no signs of left atrial dilation. Nuclear stress test showed likely physiologic fixed apical thinning without any signs of ischemia. Thus, coronary causes of chest pain were ruled out. Patient was subsequently discharged home with metoprolol 25 mg PO BID for rate control and full dose aspirin for CHADS2-VASc of 1. DISCUSSION: Significant risk factors for atrial fibrillation include age > 65, prolonged history of hypertension, and ischemic heart disease. Additional risk factors for atrial fibrillation such as thyroid disorders, pulmonary hypertension, and alcoholic heart disease were ruled out. While APPROVE, APC, and VIGOR trials reported increased cardiovascular risks associated with selective COX-2 inhibitors such as celecoxib, rofecoxib, vedolicoxib, data is limited on adverse cardiovascular effects of meloxicam use (1,2). Our case report elicits the need for heightened awareness of adverse cardiovascular effects of meloxicam. CONCLUSIONS: Given the negative work up and resolution following discontinuation of the agent, the patient’s angina and atrial fibrillation were likely associated with meloxicam use. Further prospective studies should be performed to assess association of non selective COX inhibitors in development of acute cardiac events and long term cardiovascular mortality. Reference #1: Psaty, B. M., & Furberg, C. D. (2005). COX-2 inhibitors--lessons in drug safety. New England journal of medicine, 352(11), 1133-1134. Reference #2: Schmidt, M., Christiansen, C. F., Mehnert, F., Rothman, K. J., & Sørensen, H. T. (2011). Non-steroidal anti-inflammatory drug use and risk of atrial fibrillation or flutter: population based case-control study. Bmj, 343, d3450. DISCLOSURES: No relevant relationships by Mohammad Al-Akchar, source=Web Response No relevant relationships by Abhishek Kalidas Kulkarni, source=Web Response No relevant relationships by Ruby Maini, source=Web Response No relevant relationships by Zurain Niaz, source=Web Response No relevant relationships by Tharani Sundararajan, source=Web Response No relevant relationships by Nitin Tandan, source=Web Response

Rate-related Left Bundle Branch Block Causing Cardiomyopathy

Background Rate-related left bundle branch block (LBBB) has not been well implicated as a cause of cardiomyopathy and its management remains controversial. Case presentation 52-year-old female presented with acute heart failure; EKG showed sinus tachycardia at 115 bpm with LBBB; an echocardiogram revealed left ventricle ejection fraction (LVEF) of 20%. Her cardiac catheterization showed no coronary disease, cardiac magnetic Resonance showed no late-gadolinium scaring or active inflammation. Heart Failure guideline directed medical therapy was started, including metoprolol succinate, Lisinopril and spironolactone. Follow-up echocardiogram at 4 months showed LVEF 25%. Clinical decision making Plan was to implant cardiac resynchronization therapy (CRT) with defibrillator (ICD); however, at time of implant, EKG showed sinus rhythm at 80 bpm with resolution of LBBB, hence, she underwent an ICD implantation instead. At 6 months, her symptoms improved and her LVEF noted to be 50%. We suspected rate-related LBBB as a cause for her cardiomyopathy. Serial EKGs while using her ICD atrial lead to pace at incremental rates, showed a predictable and reproducible LBBB at a ventricular rate of 110 bpm (Figure 1). ICD histogram showed her heart rate with current dose of metoprolol was predominantly under 110 bpm, which means minimal time in LBBB, which in turn likely resulted in resolution of cardiomyopathy. Conclusion Rate-related LBBB should be recognized as a potential cause of cardiomyopathy; management is to decrease the “time spent” in LBBB; if this is achieved by rate control alone, CRT can be avoided.

Effectiveness of Metoprolol in Improving Cardiac and Motor Functions in Patients with Chronic Heart Failure: A Prospective Study.

PurposeTo assess gender-, age-, and the dose-related influence of metoprolol on cardiac function, motor function, quality-of-life (QoL), and mental status in Chinese chronic heart failure (CHF) patients.Patients and MethodsThis single-center, prospective study enrolled CHF patients with resting heart rate (HR) >80 bpm and used metoprolol continuous release tablets. Patients were initiated with 12.5-mg metoprolol. All patients were assessed for change in cardiac function, motor function, QoL, and mental status according to gender (men vs women), age (<60 vs ≥60 years), and metoprolol dose administered (47.5 mg [n=37], 71.25 mg [n=7], 118.75 [n=74], and 142.5 mg [n=19]).ResultsOverall, 154 CHF patients (101 men and 53 women), with median age 66.39 years, were enrolled. In total, 116 and 38 patients were aged ≥60 and <60 years, respectively. We observed a slight decrease in systolic blood pressure (SBP) in women compared with men. HR had increased with an increase in ejection fraction (EF) from baseline to 1 month (35.24±6.15 and 34.79±6.25) and increased to 50.00±4.45 and 50.72±4.09 among both the genders. Cardiac index (CI) and motor function had improved along with better QoL after metoprolol treatment in both the genders. In both age groups (<60 and ≥60 years), improvement in cardiac function, motor function, and QoL was observed; however, there was a difference in mental status. The dose effect of metoprolol on cardiac function, motor function, QoL, and mental status showed a gradual decrease in EF with dose increments, with no change in CI. Motor function, QoL, and mental status did not show much difference with uptitration of metoprolol dose.ConclusionPsychological responses to metoprolol treatment differ with gender, with no age-related changes in terms of cardiac function, motor function, QoL, or mental status, except increases in depression, burnout, and anxiety.

Abstract 217: Are Discharge Rate Control Medications Adequate for Future Atrial Fibrillation Needs?

Background: Rate control medications (RCM) for atrial fibrillation (AF) usually prescribed are diltiazem (DTZ) and beta blockers. Patients entering the Emergency Department (ED) with AF often convert to a normal sinus rhythm (NSR) by means of spontaneous conversion to normal sinus rhythm (SCNSR), electrical cardioversion, or medications. However, recurrent AF often leads to repeat ED visits and frequent hospitalizations within one year. Goals: To evaluate admission and discharge metoprolol (MTP) and DTZ doses for patients presenting to the ED with rapid AF. Methods: Retrospective, single center chart review of MTP and DTZ doses on admission and discharge for patients admitted with a primary diagnosis of AF. Patients who received new or an increase of other RCMs, or antiarrhythmic medications with RCM properties were excluded. Results: Of 402 patients, 310 (77%) had a heart rate ≥110 bpm on admission. Of those with a rapid rate, 235 (76%) converted to NSR after admission predominantly due to SCNSR. The mean daily dose of MTP was 61mg on admission and 65mg at discharge. The mean DTZ dose on admission was 188mg and 157mg at discharge. Discussion: The discharge doses of 65mg of MTP and 157mg of DTZ were well below the recommended doses of RCMs for AF. The RATAF trial demonstrated adequate rate and symptom control with MTP 100mg/day and DTZ up to 360mg/day. The current study demonstrated significant under dosing of RCMs to manage future rapid ventricular rate. It is possible patients with rapid ventricular rates who convert to NSR, which by itself, results in rate control, would not have attention by the provider focused on the rapid admission rate. Most patients who convert to NSR do not have the substrate leading to AF corrected. Thus, it is not surprising recurrence of AF, regardless of the method of cardioversion, occurs in approximately 70% of patients within one year. It is likely when AF recurs it will have the same rapid rate unless RCMs are increased before discharge from the first initial admission dose. It is possible at discharge an order set may lead to a more logical assessment of targeted RCMs. Lack of long term follow-up to address outcome of apparent under dosing of RCM is a limitation. Conclusion: This single center study found no significant increases in MTP and DTZ dosing at the time of discharge for patients with rapid AF who reverted to NSR after admission. It is possible that modification of RCMs before hospital discharge may decrease future ED admission for symptomatic AF.

CYP2D6 polymorphism and its impact on the clinical response to metoprolol: A systematic review and meta-analysis.

CYP2D6 genetic polymorphisms are associated with metoprolol pharmacokinetics. Whether the clinical response to metoprolol is also affected remains uncertain. We conducted a systematic review on the effects of CYP2D6 polymorphism on the clinical response to metoprolol. Searches were conducted using MEDLINE. Meta-analyses were performed on the impact of CYP2D6-inferred phenotypes on heart rate (HR) reduction, diastolic (DBP) and systolic (SBP) blood pressure reduction, average daily doses, all-type adverse events and bradycardia. Our qualitative assessment indicated inconsistent results in individual studies and endpoints, but CYP2D6 poor metabolizers (PM) generally presented a greater reduction in HR. The meta-analysis of 15 studies, including a total of 1146 individuals, found a reduction in HR of 3 beats/min (P = .017), and of SBP and DBP by 3 mmHg (P = .0048) for PM compared to non-PM individuals using similar metoprolol doses. Bradycardia appeared more frequent by 4-fold for PM, although significant heterogeneity was observed regarding bradycardia, which limits the scope of this finding. Patients without any CYP2D6 metabolic capacities appear to have increased reduction in DBP, HR and SBP during metoprolol treatment and may be at a higher risk of bradycardia compared to patients with active CYP2D6 phenotypes. Further prospective data are required to determine whether CYP2D6 is associated with clinical events in patients treated with metoprolol, as well as to demonstrate the clinical utility of an individualized approach of prescribing metoprolol using CYP2D6-inferred phenotypes.

Role of Metoprolol Succinate in the Treatment of Heart Failure and Atrial Fibrillation: A Systematic Review.

Beta-blockers are one of the most important classes of cardiovascular agents and have been considered a cornerstone therapy in heart diseases, such as heart failure (HF) and atrial fibrillation (AF). Among different beta-blockers, metoprolol is a selective beta1-adrenergic antagonist, which has been extensively used since the 1970s. Although current guidelines include recommendations for the use of controlled-release metoprolol succinate in specific HF and AF indications, and despite extensive clinical experience with metoprolol, comparative evidence on the use of metoprolol succinate compared with other beta-blockers in these indications is limited. We systematically reviewed the data from head-to-head studies directly comparing this compound with other beta-blockers in the treatment of HF or AF. Only clinical trials and observational studies were considered; no other limits were applied. The quality and relevance of retrieved articles were reviewed. A total of 18 articles of the 353 articles identified were selected for inclusion; 12 HF articles and 6 for AF. Additional references were identified from the bibliographies of retrieved articles. The studies show that oral prophylaxis with an appropriate dose of metoprolol may reduce new incidents of AF in high-risk patients. Furthermore, metoprolol succinate is associated with significant mortality and morbidity benefits in the treatment of HF. Despite the introduction of newer beta-blockers with differing clinical characteristics since its introduction, metoprolol succinate remains a useful drug in both HF and AF.

Impact of genotype-predicted CYP2D6 metabolism on clinical effects and tolerability of metoprolol in patients after myocardial infarction - a prospective observational study.

The β-1 adrenergic receptor blocker metoprolol is primarily metabolized by the polymorphic enzyme cytochrome P 450 2D6 (CYP2D6), an enzyme with substantial genetic heterogeneity. Our purpose was to investigate the impact of CYP2D6 metabolism on clinical effects and tolerability of metoprolol in patients after myocardial infarction (MI). We included 136 patients with MI discharged on treatment with metoprolol with a recommendation to the general practitioner (GP) to increase the metoprolol dose up to 200mg/day within 2months if possible. At follow-up, metoprolol dosage after up-titration, metoprolol steady-state trough plasma concentrations, hemodynamic parameters, potential metoprolol-induced adverse drug reactions and number of visits to the GP were measured. CYP2D6 genotyping including the reduced-function variant alleles CYP2D6*9, CYP2D6*10 and CYP2D6*41 was performed after end of follow-up. According to the genotype-defined CYP2D6 phenotypes, 30% of the patients were metoprolol extensive metabolizers (EMs), 55% intermediate metabolizers (IMs) and 13% poor metabolizers (PMs; carriers of non-coding and reduced-function variant included). Dose-adjusted metoprolol trough concentrations were significantly higher in IM (2-fold) and PM (6.2-fold) groups vs. the EM group (p< 0.001). Only 35% of patients in the PM group achieved the primary end point, i.e. reaching at least 85% of the expected maximum heart rate (HR) during exercise, compared with 78% in the EM group (p< 0.01), and maximum observed HR at exercise was significantly lower in the PM group vs. the EM group (129 ± 5 vs. 142 ± 2bpm, p< 0.007). In contrast, metoprolol maintenance dose, blood pressure, exercise capacity, number of visits at the GP and frequency and severity of self-reported potential metoprolol-related adverse drug reactions were not significantly different between the groups. Using a comprehensive CYP2D6 genotyping panel, the present study demonstrates a > 6-fold increase of dose-adjusted plasma metoprolol trough concentration in CYP2D6 PMs vs. EMs with a parallel lower increase in achieved maximum HR during exercise but without association between genotype and frequency or severity of self-reported adverse drug effects. This may indicate that CYP2D6 PMs potentially could benefit of the increased plasma concentration per dose in a naturalistic setting.

The effect of metoprolol and aspirin on cardiovascular risk in bereavement: A randomized controlled trial

Bereavement is associated with an increased risk of cardiovascular disease; however, no reports exist of interventions to reduce risk. In a randomized, double-blind, placebo-controlled trial of 85 recently bereaved participants, we determined whether β-blocker (metoprolol 25 mg) and aspirin (100 mg) reduce cardiovascular risk markers and anxiety, without adversely affecting bereavement intensity. Participants were spouses (n = 73) or parents (n = 12) of deceased from 5 hospitals in Sydney, Australia, 55 females, 30 males, aged 66.1 ± 9.4 years. After assessment within 2 weeks of bereavement, subjects were randomized to 6 weeks of daily treatment or placebo, and the effect evaluated using ANCOVA, adjusted for baseline values (primary analysis). Participants on metoprolol and aspirin had lower levels of home systolic pressure (P = .03), 24-hour average heart rate (P < .001) and anxiety (P = .01) platelet response to arachidonic acid (P < .001) and depression symptoms (P = .046) than placebo with no difference in standard deviation of NN intervals index (SDNNi), von Willebrand Factor antigen, platelet-granulocyte aggregates or bereavement intensity. No significant adverse safety impact was observed. In early bereavement, low dose metoprolol and aspirin for 6 weeks reduces physiological and psychological surrogate measures of cardiovascular risk. Although further research is needed, results suggest a potential preventive benefit of this approach during heightened cardiovascular risk associated with early bereavement.

The effect of the CYP2D6 genotype on the maintenance dose of metoprolol in a chronic Dutch patient population.

Metoprolol is among the most frequently prescribed β-blockers for the treatment of various cardiovascular diseases. Genetic polymorphism within CYP2D6 has been shown to affect the rate of metabolism of metoprolol. Whether metoprolol dose adjustments are indicated in CYP2D6 poor metabolizers (PMs) has thus far not well been studied. The aim of this study was to determine the effect of the CYP2D6 genotype on the metoprolol maintenance dose in a chronic Dutch patient population. Patients were included if they were treated with metoprolol and in whom CYP2D6 genotype status was known. Patient and treatment characteristics were obtained retrospectively from the electronic healthcare records. Metoprolol maintenance dose was the primary endpoint and was defined as the last known dose that the patients had been treated with. Genotype data were categorized into four phenotypes, that is, PMs, intermediate metabolizers, extensive metabolizers, and ultra-rapid metabolizers (UMs). The endpoints were analyzed as PM versus non-PM. A total of 105 patients were included. The mean ± SD maintenance dose in PMs (n = 12) was significantly lower compared with non-PMs (n = 93), that is, 48 ± 20 versus 84 ± 53 mg, respectively (P = 0.019). No association of the CYP2D6 genotype with the incidence of side effects was observed, although there was a trend for increased risk of drowsiness (P = 0.053). The results of this study show that the CYP2D6 genotype is associated with the maintenance dose of metoprolol. Patients with the CYP2D6 PM phenotype may benefit from a lower metoprolol starting dose, followed by further dose titration to provide patient-tailored therapy and thereby increase the effectiveness of treatment.

Evaluation of potential herbal-drug interactions of a standardized propolis extract (EPP-AF®) using an in vivo cocktail approach

Ethnopharmacological relevancePropolis has been employed extensively in many cultures since ancient times as antiseptic, wound healing, anti-pyretic and others due to its biological and pharmacological properties, such as immunomodulatory, antitumor, anti-inflammatory, antioxidant, antibacterial, antiviral, antifungal, antiparasite activities. But despite its broad and traditional use, there is little knowledge about its potential interaction with prescription drugs. Aim of the studyThe main objective of this work was to study the potential herbal-drug interactions (HDIs) of EPP-AF® using an in vivo assay with a cocktail approach. Materials and methodsSubtherapeutic doses of caffeine, losartan, omeprazole, metoprolol, midazolam and fexofenadine were used. Sixteen healthy adult volunteers were investigated before and after exposure to orally administered 125 mg/8 h (375 mg/day) EPP-AF® for 15 days. Pharmacokinetic parameters were calculated based on plasma concentration versus time (AUC) curves. ResultsAfter exposure to EPP-AF®, it was observed decrease in the AUC0−∞ of fexofenadine, caffeine and losartan of approximately 18% (62.20 × 51.00 h.ng/mL), 8% (1085 × 999 h.ng/mL) and 13% (9.01 × 7.86 h.ng/mL), respectively, with all 90% CIs within the equivalence range of 0.80–1.25. On the other hand, omeprazole and midazolam exhibited an increase in AUC0-∞ of, respectively, approximately 18% (18.90 × 22.30 h.ng/mL) and 14% (1.25 × 1.43 h.ng/mL), with the upper bounds of 90% CIs slightly above 1.25. Changes in pharmacokinetics of metoprolol or its metabolite α-hydroxymetoprolol were not statistically significant and their 90% CIs were within the equivalence range of 0.80–1.25. ConclusionsIn conclusion, our study shows that EPP-AF® does not clinically change CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A activities, once, despite statistical significant, the magnitude of the changes in AUC values after EPP-AF® were all below 20% and therefore may be considered safe regarding potential interactions involving these enzymes. Besides, to the best of our knowledge this is the first study to assess potential HDIs with propolis.

The cardioprotective effects of icariin on the isoprenaline-induced takotsubo-like rat model: Involvement of reactive oxygen species and the TLR4/NF-κB signaling pathway

IntroductionTakotsubo syndrome (TS) is an acute cardiac syndrome that mimics acute coronary syndrome (ACS) but lacks coronary obstruction and is associated with sudden physical or psychiatric episodes. Several hypotheses have been proposed for the TS mechanism, but the precise cause of this syndrome remains poorly known. Recent studies noted TS patients with acute endogenous catecholamine discharge, which could trigger an oxidative stress response and inflammatory action. MethodsA single dose of the selective β-adrenergic agonist isoprenaline (ISO) was used to induce a takotsubo-like (TS-like) model. Different icariin or metoprolol doses were supplied as cardioprotective agents by intragastric administration (IG), and lipopolysaccharides (LPS) were assessed to investigate the possible mechanism of action of icariin. Transthoracic echocardiography was used to study cardiac function and morphology. The amounts of intracellular lipids and myocardial fibrosis, which represent the degree of cardiac impairment, were assessed by histological analysis. Real-time polymerase chain reaction (RT-PCR) was performed to analyze a variety of anti-oxidant elements and inflammatory factors, and Western blotting was conducted to analyze the expression of signaling pathway proteins involved in the development of TS. ResultsThe TS-like incidence in rats was lowest with icariin precondition at 2-h post-ISO administration, and both the left ventricular ejection fraction (LVEF) and ejection volume per minute were higher than those of the other groups. However, LPS administration increased the incidence of TS and aggravated cardiac impairment. Moreover, ISO significantly increased the levels of both reactive oxygen species (ROS) and TLR4/NF-κB signaling pathway proteins compared to those of the Sha-group, whereas icariin remarkably decreased the ROS levels and increased anti-oxidant element expression while reducing pro-inflammatory factor secretion and suppressing TLR4/NF-κB signaling pathway protein expression. However, the cardioprotective effect of icariin was significantly weakened by combining treatment with LPS. ConclusionIcariin prevented ISO-induced TS-like cardiac dysfunction in rats. The effects were induced mainly through maintenance of the dynamic balance of the ROS system, promotion of anti-oxidant element activity, and suppression of TLR4/NF-κB signaling pathway protein expression. Furthermore, the ability of icariin to increase anti-inflammatory and reduce pro-inflammatory factor secretion may be involved in the protective process.

Factors influencing long-term heart failure mortality in patients with obstructive hypertrophic cardiomyopathy in Western Sweden: probable dose-related protection from beta-blocker therapy

ObjectiveIn order to avoid effects of referral bias, we assessed risk factors for disease-related mortality in a geographical cohort of patients with hypertrophic obstructive cardiomyopathy (HOCM), and any therapy effect...

SAT-591 Heart Failure Increases Likelihood of Asystolic Cardiac Arrest in Acute Hyperthyroidism

Introduction: Thyrotoxicosis produces multiple catabolic effects including arrhythmias and heart failure. Rapid treatment of overt hyperthyroidism is important to prevent permanent end-organ damage. Clinical Case: A 55yo M with no prior past medical history presents to the ED with 2 weeks of progressive dyspnea on exertion and bilateral lower extremity and scrotal edema, with unintentional 40lb weight gain in 6 months. N-terminal pro-BNP was elevated to 3965pg/mL (normal 5-125pg/mL), with cardiomegaly and right-sided pleural effusion on chest x-ray, concerning for new-onset heart failure. While in the ED, the patient went into rapid atrial fibrillation. He was given 30mg IV Diltiazem bolus, and started on a Diltiazem infusion @ 15cc/h. His new onset heart failure was treated with 60mg IV Lasix. One day later, heart rates remained elevated to 120s, so he was started on metoprolol succinate 25mg in order to optimize rate control. TSH was noted to be less than 0.01mIU/L (normal 0.27 -4.20 mIU/L), with free T4 greater than 7.77ng/dL (normal 0.80 - 1.90 ng/dL). Endocrine was consulted for hyperthyroidism. On Day 2 of hospitalization, metoprolol was switched to propranolol 80mg TID. Methimazole 30mg daily was also started. The patient received a dose of Metoprolol at approximately 830AM. His first dose of propranolol was given at approximately 4PM. Diltiazem infusion and Lasix infusions were continuing at this time as well. After receiving first dose of propranolol, the patient became bradycardiac, hypotensive to 80s/50s within 30 minutes. Poison control was contacted. Diltiazem infusion and Lasix were discontinued. Propranolol was decreased to 40mg TID, although beta blocker toxicity less likely given rapid onset of symptoms. One hour later, the patient went into asystolic cardiac arrest. Conclusion: In the absence of heart failure, symptoms of thyrotoxicosis improve with use of beta-blockers. However, patients with heart failure and thyroid crisis depend on the inotropic effects of excess T3 to maintain their cardiac output and support hemodynamics. Rate controlling medications in these scenarios further reduces inotropic function and predisposes to cardiac arrest. There are prior case reports demonstrating circulatory collapse after administration of non-selective beta blockers, in patients with thyroid storm. However, although prompt treatment of thyrotoxicosis is important, increased caution should be taken when treating hyperthyroidism with associated heart failure to avoid increased risk of circulatory collapse and cardiac arrest.

Effect of Roux-en-Y gastric bypass on the bioavailability of metoprolol from immediate and controlled release tablets: a single oral dose study before and after surgery

ObjectiveRoux-en-Y gastric bypass (RYGB) surgery induces major changes in the gastrointestinal tract that may alter the pharmacokinetics of orally administered drugs. Results from pharmacokinetic studies are sparse. This study aimed...