Concomitant Beta-blocker Research Articles

The effect of concomitant beta-blocker use on survival in patients with metastatic renal cell carcinoma treated with a vascular endothelial growth factor receptor inhibitors in the first line.

Vascular endothelial growth factor (VEGF) inhibition is one of the cornerstones of treatment in the treatment of metastatic renal cell carcinoma (mRCC). Since RCC is a disease of advanced age and hypertension as a side effect of VEGF receptor inhibitors, beta-blocker use is common in these patients. We aimed to compare the treatment efficacy and survival results in case of concomitant use of these two drugs due to the inhibition of VEGF in beta-blockers. A total of 121 patients with a diagnosis of mRCC who used sunitinib or pazopanib in first-line therapy were included in the study. These patients were divided into two groups as those using concomitant beta-blockers and those not using them. The median overall survival (mOS) of the patient using sunitinib or pazopanib and concomitant beta-blocker was 47 (95% CI 29.0-65.0) months, and the mOS of those not using concomitant beta-blocker was 18 (95% CI 8.9-27.1) months (p < 0.001). The median progression-free survival (mPFS) of the patients using sunitinib or pazopanib and concomitant beta-blocker was 20.4 (95% CI 4.5-40.1) months, and the mPFS of those not using it was 11.4 (95% CI 5.9-16.9) months (p = 0.042). Concomitant beta-blocker use was found to be a good prognostic factor for OS in the multivariate analysis (p = 0.029). In the multivariate analysis, concomitant beta-blocker use had a trend towards statistical significance for PFS (p = 0.062). Concomitant use of betablockers with sunitinib or pazopanib is associated with longer overall survial and progression free survival.

Executive Summary of Clinical Practice Guideline on Immunotherapy for Inhalant Allergy.

Allergen immunotherapy (AIT) is the therapeutic exposure to an allergen or allergens selected by clinical assessment and allergy testing to decrease allergic symptoms and induce immunologic tolerance. Inhalant AITis administered to millions of patients for allergic rhinitis (AR) and allergic asthma (AA) and is most commonly delivered as subcutaneous immunotherapy (SCIT) or sublingual immunotherapy (SLIT). Despite its widespread use, there is variability in the initiation and delivery of safe and effective immunotherapy, and there are opportunities for evidence-based recommendations for improved patient care. The purpose of this clinical practice guideline is to identify quality improvement opportunities and provide clinicians trustworthy, evidence-based recommendations regarding the management of inhaled allergies with immunotherapy. Specific goals of the guideline are to optimize patient care, promote safe and effective therapy, reduce unjustified variations in care, and reduce risk of harm. The target patients for the guideline are any individuals aged 5 years and older with AR, with or without AA, who are either candidates for immunotherapy or treated with immunotherapy for their inhalant allergies. The target audience is all clinicians involved in the administration of immunotherapy. This guideline is intended to focus on evidence-based quality improvement opportunities judged most important by the guideline development group. It is not intended to be a comprehensive, general guide regarding the management of inhaled allergies with immunotherapy. The statements in this guideline are not intended to limit or restrict care provided by clinicians based on their experience and assessment of individual patients. The guideline development group made a strong recommendation that (Key Action Statement [KAS] 10) the clinician performing allergy skin testing or administering AIT must be able to diagnose and manage anaphylaxis. The guideline development group made recommendations for the following KASs: (KAS 1) Clinicians should offer or refer to a clinician who can offer immunotherapy for patients with AR with or without AA if their patients' symptoms are inadequately controlled with medical therapy, allergen avoidance, or both, or have a preference for immunomodulation. (KAS 2A) Clinicians should not initiate AIT for patients who are pregnant, have uncontrolled asthma, or are unable to tolerate injectable epinephrine. (KAS 3) Clinicians should evaluate the patient or refer the patient to a clinician who can evaluate for signs and symptoms of asthma before initiating AIT and for signs and symptoms of uncontrolled asthma before administering subsequent AIT. (KAS 4) Clinicians should educate patients who are immunotherapy candidates regarding the differences between SCIT and SLIT (aqueous and tablet) including risks, benefits, convenience, and costs. (KAS 5) Clinicians should educate patients about the potential benefits of AIT in (1) preventing new allergen sensitization, (2)reducing the risk of developing AA, and (3) altering the natural history of the disease with continued benefit after discontinuation of therapy. (KAS 6) Clinicians who administer SLIT to patients with seasonal AR should offer pre- and co-seasonal immunotherapy. (KAS 7) Clinicians prescribing AIT should limit treatment to only those clinically relevant allergens that correlate with the patient's history and are confirmed by testing. (KAS 9) Clinicians administering AIT should continue escalation or maintenance dosing when patients have local reactions to AIT. (KAS 11) Clinicians should avoid repeat allergy testing as an assessment of the efficacy of ongoing AIT unless there is a change in environmental exposures or a loss of control of symptoms. (KAS 12) For patients who are experiencing symptomatic control from AIT, clinicians should treat for a minimum duration of 3 years, with ongoing treatment duration based on patient response to treatment. The guideline development group offered the following KASs as options: (KAS 2B) Clinicians may choose not to initiate AIT for patients who use concomitant beta-blockers, have a history of anaphylaxis, have systemic immunosuppression, or have eosinophilic esophagitis (SLIT only). (KAS 8) Clinicians may treat polysensitized patients with a limited number of allergens.

Clinical Practice Guideline: Immunotherapy for Inhalant Allergy.

Allergen immunotherapy (AIT) is the therapeutic exposure to an allergen or allergens selected by clinical assessment and allergy testing to decrease allergic symptoms and induce immunologic tolerance. Inhalant AITis administered to millions of patients for allergic rhinitis (AR) and allergic asthma (AA) and is most commonly delivered as subcutaneous immunotherapy (SCIT) or sublingual immunotherapy (SLIT). Despite its widespread use, there is variability in the initiation and delivery of safe and effective immunotherapy, and there are opportunities for evidence-based recommendations for improved patient care. The purpose of this clinical practice guideline (CPG) is to identify quality improvement opportunities and provide clinicians trustworthy, evidence-based recommendations regarding the management of inhaled allergies with immunotherapy. Specific goals of the guideline are to optimize patient care, promote safe and effective therapy, reduce unjustified variations in care, and reduce the risk of harm.The target patients for the guideline are any individuals aged 5 years and older with AR, with or without AA, who are either candidates for immunotherapy or treated with immunotherapy for their inhalant allergies. The target audience is all clinicians involved in the administration of immunotherapy. This guideline is intended to focus on evidence-based quality improvement opportunities judged most important by the guideline development group (GDG). It is not intended to be a comprehensive, general guide regarding the management of inhaled allergies with immunotherapy. The statements in this guideline are not intended to limit or restrict care provided by clinicians based on their experience and assessment of individual patients. The GDG made a strong recommendation that (Key Action Statement [KAS] 10) the clinician performing allergy skin testing or administering AIT must be able to diagnose and manage anaphylaxis. The GDG made recommendations for the following KASs: (KAS 1) Clinicians should offer or refer to a clinician who can offer immunotherapy for patients with AR with or without AA if their patients'symptoms are inadequately controlled with medical therapy, allergen avoidance, or both, or have a preference for immunomodulation. (KAS 2A) Clinicians should not initiate AIT for patients who are pregnant, have uncontrolled asthma, or are unable to tolerate injectable epinephrine. (KAS 3) Clinicians should evaluate the patient or refer the patient to a clinician who can evaluate for signs and symptoms of asthma before initiating AIT and for signs and symptoms of uncontrolled asthma before administering subsequent AIT. (KAS 4) Clinicians should educate patients who are immunotherapy candidates regarding the differences between SCIT and SLIT (aqueous and tablet) including risks, benefits, convenience, and costs. (KAS 5) Clinicians should educate patients about the potential benefits of AIT in (1) preventing new allergen sensitizations, (2) reducing the risk of developing AA, and (3) altering the natural history of the disease with continued benefit after discontinuation of therapy. (KAS 6) Clinicians who administer SLIT to patients with seasonal AR should offer pre- and co-seasonal immunotherapy. (KAS 7) Clinicians prescribing AIT should limit treatment to only those clinically relevant allergens that correlate with the patient's history and are confirmed by testing. (KAS 9) Clinicians administering AIT should continue escalation or maintenance dosing when patients have local reactions (LRs) to AIT. (KAS 11) Clinicians should avoid repeat allergy testing as an assessment of the efficacy of ongoing AIT unless there is a change in environmental exposures or a loss of control of symptoms. (KAS 12) For patients who are experiencing symptomatic control from AIT, clinicians should treat for a minimum duration of 3 years, with ongoing treatment duration based on patient response to treatment. The GDG offered the following KASs as options: (KAS 2B) Clinicians may choose not to initiate AIT for patients who use concomitant beta-blockers, have a history of anaphylaxis, have systemic immunosuppression, or have eosinophilic esophagitis (SLIT only). (KAS 8) Clinicians may treat polysensitized patients with a limited number of allergens.

Could the concomitant use of beta blockers with bevacizumab improve survival in metastatic colon cancer?

Drug-drug interactions are sometimes neglected in oncology practice. Due to drug pharmacokinetic and pharmacodynamic interactions, clinically increased or decreased drug effects and increased or decreased adverse effects may occur. Considering that the concomitant use of these two drugs that affect vascular endothelial growth factor receptor (VEGFR) may cause pharmacological potentiation or additive interaction, we aimed to evaluate the survival outcomes of concomitant use of bevacizumab and beta blockers in patients with metastatic colorectal cancer (mCRC). In total, 181 patients with mCRC administered with bevacizumab plus cytotoxic chemotherapy regimen in a first-line setting were divided into two groups: concomitant beta-blocker user and nonuser. The median overall survival (mOS) was 35.9 (95% CI: 27.9-43.9) months in the beta-blocker-using group and 29.6 (95% CI: 27.9-43.9) months in the beta-blocker-non-using group (p = 0.054). The median progression-free survival (mPFS) was 16.1 (95% CI: 12.4-19.9) months in the beta-blocker-using group and 12.8 (95% CI: 10.6-15.0) months in the beta-blocker-non-using group (p = 0.006). The multivariate analysis revealed that beta-blocker use was an independent predictor of mPFS (HR: 0.66, 95% CI: 0.46-0.93, p = 0.018) and mOS (HR: 0.57, 95% CI: 0.36-0.91, p = 0.02). This study demonstrated that concomitant usage of beta blockers improved both survival outcomes, irrespective of the kind of beta blocker.

The Usage of Concomitant Beta-Blockers with Vasopressors and Inotropes in Cardiogenic Shock.

Vasopressors and inotropes (Vs/Is) are widely used in the treatment of cardiogenic shock (CS). Despite improvements in hemodynamic variables and end-organ perfusion, these agents have been associated with an increase in mortality, potentially due to the increased risk of tachyarrhythmias-which we hypothesize may be mitigated by beta-blockers (BBs). We conducted a retrospective chart review of patients who received a V/I (dobutamine, milrinone, dopamine, and norepinephrine) for CS. The primary objective was to assess the effect of BB in patients receiving Vs/Is for CS. In our final analysis of 227 patients, those in the BB group were younger, were more likely to have acute coronary syndrome as the reason for admission, had more reduced left ventricular ejection fraction, were more likely to have coronary artery disease and atrial fibrillation as pre-existing co-morbidities, and had a lower rate of in-hospital mortality. Nevertheless, in our multivariable logistic regression analysis, concurrent BB usage with a V/I was not associated with a reduction in in-hospital mortality. Our present study sheds light on the importance and urgency of large, carefully designed clinical studies to optimize inpatient medical therapy, particularly evaluating the combination of V/I and BB, in this high-risk patient population.

A Single Center Experience of Concomitant Administration of Sofosbuvir/Velpatasvir and Amiodarone After Heart or Lung Transplantation

<h3>Purpose</h3> There is a shortage of donor hearts and lungs available for transplantation. The development of sofosbuvir/velpatasvir (SOF/VEL), an antiviral against the hepatitis C virus (HCV), created an opportunity to expand the donor pool through the use of HCV viremic donors. Atrial fibrillation (AF) is a frequent complication after transplantation. SOF/VEL contains a warning against the concomitant usage of amiodarone and SOF/VEL due to symptomatic bradycardia. We sought to describe our experience with the co-administration of these agents after heart/lung transplantation. <h3>Methods</h3> Retrospective review of patients enrolled in a clinical trial of SOF/VEL after transplantation from HCV viremic donors to seronegative recipients and that received at least a dose of amiodarone. SOF/VEL was initiated on post-operative day 1. The use of amiodarone was at the discretion of the treatment team. We defined bradycardia as a heart rate < 60 bpm. <h3>Results</h3> A total of 11 (8 lung, 3 heart) patients received SOF/VEL and amiodarone. Three (27%) had a history of AF and 7 patients (64%) were on treatment prior to transplant. The median time from SOF/VEL to start of amiodarone was 1.2 days. The median cumulative dose of amiodarone was 9086mg (IQR: 2195 - 10952) over a median duration of concomitant administration of 25 days. While the number of documented bradycardic heart rates was low, 1.2% (90/7573), the majority of patients (64%) experienced at least one bradycardic episode. Of those patients, six (86%) required intervention and five (83%) had received concomitant beta blocker (BB) therapy during their episode, Table 1. All cases of bradycardia resolved after intervention. <h3>Conclusion</h3> The use of amiodarone in patients receiving SOF/VEL frequently resulted in bradycardic episodes; however, these occurred with the addition of BB. In patients requiring the combination of SOF/VEL and amiodarone, consideration is warranted before the addition of other bradycardia inducing medications.

Implication of Ivabradine Therapy in Up-Titrating Beta-Blocker Dose in Patients with Systolic Dysfunction.

Ivabradine, which reduces heart rate (HR) without affecting sympathetic nerve activity, improves mortality and morbidity in patients with systolic dysfunction. However, its impact on up-titrating a concomitant beta-blocker dose in such a cohort, via increasing cardiac output and blood pressure and improving tolerability to beta-blockers, remains unknown. In this single-center, prospective, randomized control trial, patients with systolic dysfunction, defined as left ventricular ejection fraction < 50%, sinus rhythm, heart rate > 75 bpm, systolic blood pressure between 90 and 110 mmHg, and New York Heart Association functional class III or IV, who are refractory to up-titration of a beta-blocker due to symptomatic hypotension, dizziness, or worsening heart failure, were assigned to the 20 ivabradine arm or the 20 conventional therapy arm and followed-up for 6 months. The primary outcome is the daily dose of beta-blocker at 6-months follow-up. The secondary outcomes are echocardiographic parameters including overlap between E-wave and A-wave in transmitral diastolic filling flow, plasma B-type natriuretic peptide level, 6-minute walk distance, and heart failure readmission rate. By conducting this study, we hope to demonstrate the clinical benefit of ivabradine therapy in up-titrating beta-blockers and improving clinical outcomes in patients with systolic dysfunction.

Long-acting antimuscarinic therapy in patients with chronic obstructive pulmonary disease receiving beta-blockers

BackgroundBeta-blocker therapies for cardiovascular comorbidities are often withheld in patients with chronic obstructive pulmonary disease (COPD) due to potential adverse effects on airway obstruction. We carried out a post hoc analysis to determine the efficacy and safety of aclidinium in patients with moderate-to-very severe COPD and increased cardiovascular risk receiving beta-blockers at baseline versus non-users.MethodsASCENT-COPD was a Phase 4, multicenter, double-blind, randomized, placebo-controlled, parallel-group study. Patients were randomized 1:1 to aclidinium or placebo twice-daily for up to 3 years. Outcomes included risk of (time to first) major adverse cardiovascular events (MACE), all-cause mortality, and lung function over 3 years, and exacerbations over 1 year.ResultsOf 3589 patients, 1269 (35.4%) used beta-blockers and 2320 (64.6%) were non-users at baseline. Aclidinium did not statistically increase the risk of MACE (beta-blocker user: hazard ratio 1.01 [95% CI 0.62–1.64]; non-user: 0.80 [0.51–1.24]; interaction P = 0.48) or all-cause mortality (beta-blocker user: 1.13 [0.78–1.64]; non-user: 0.89 [0.62–1.26]; interaction P = 0.35), in patients using beta-blockers. Aclidinium reduced annualized rate of moderate-to-severe COPD exacerbation (beta-blocker user: rate ratio 0.75 [95% CI 0.60–0.94, P = 0.013]; non-user: 0.79 [0.67–0.93, P = 0.005]), delayed time to first exacerbation, and improved lung function versus placebo. There was greater trough FEV1 benefit in beta-blocker users versus non-users (least squares mean difference at 52 weeks: 111 mL [95% CI 74 mL–147 mL] versus 69 mL [42 mL–97 mL]; interaction P = 0.041).ConclusionsThis post hoc analysis supports long-acting anti-muscarinic use with concomitant beta-blockers in patients with moderate-to-very severe COPD and cardiovascular comorbidity.Trial registration: ClinicalTrials.gov, NCT01966107, Registered 16 October 2013, https://clinicaltrials.gov/ct2/show/NCT01966107.

Concomitant beta-blocker use is associated with a reduced rate of remission in patients with rheumatoid arthritis treated with disease-modifying anti-rheumatic drugs: a post hoc multicohort analysis.

Background:Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease associated with increased risk of cardiovascular disease (CVD). Treatment for CVD may involve pharmacological agents that antagonise beta adrenergic receptors. These receptors may play an important role in immunology, and the effects of beta-blockers (BB) in RA is unknown. The aim of this study was to investigate the association between BB use and remission in patients with RA initiating tocilizumab +/− conventional synthetic (cs-) DMARD therapy.Methods:Data was pooled from five randomised trials investigating tocilizumab and/or csDMARD treatment in RA (primarily methotrexate). The association between BB use and remission according to the Simplified Disease Activity Index (SDAI) and Clinical Disease Activity Index (CDAI) was assessed by Cox proportional hazard analysis. Sensitivity analysis in patients with pre-existing CVD and an exploratory analysis of the impact of other CVD drugs were conducted.Results:Data were available from 5502 participants, 594 (10.8%) of whom were using systemic BB. BB use was associated with less frequent SDAI remission in the total [adjusted hazard ratio (HR) 0.70, 95% confidence interval (CI) 0.57–0.87, p = 0.001] and CVD cohort [adjusted HR 0.72 (0.57–0.90, p = 0.005)]. The association was consistent between trials (interaction p = 0.44) and treatment arms (interaction p = 0.06). No significant association between remission and β1-receptor selectivity was identified (p = 0.16), and the association was independent from other cardiovascular drug use. Similar associations between BB use and CDAI remission were observed.Conclusion:In a large, pooled cohort of RA patients initiating csDMARDs and/or tocilizumab, BB use was independently associated with less frequent remission.

P3120Prevention of heart failure in treatments with trastuzumab and anthracyclines: a meta-analysis

Abstract Background Trastuzumab and anthracyclines are conventional chemotherapies used in breast cancer. Unfortunately, they are associated with a decrease in left ventricular function potentially leading to heart failure (HF). In order to prevent this, randomised controlled trials (RCTs) assess the preventive effect of concomitant beta-blocker (BB), angiotensin receptor blocker (ARB) and angiotensin converting enzyme inhibitor (ACEI) therapy during chemotherapy. Purpose To assess the preventive effect of BB, ARB or ACEIs on left ventricular ejection fraction (LVEF) during trastuzumab and anthracycline treatment in patients without HF. Methods Our primary outcomes were the effect of BBs or ARB/ACEIs during 1) trastuzumab and 2) anthracycline treatment. Secondary outcomes were the distinct effects of 1) BBs and 2) ARB/ACEIs in either trastuzumab or anthracycline treatments. Through the search term “(RCTs), prevention, cancer chemotherapy and cardiotoxicity” in PubMed, studies were selected, excluding those without randomising to a BB, ARB/ACEI and a placebo control group during chemotherapy. Means of the LVEF and the standard deviation (SD) post-chemotherapy were applied. Meta-analyses estimated the standardised mean difference (SMD) in the LVEF. Heterogeneity was calculated as the I2. Results A total of 7 studies (Table 1) were included in the analysis. Between 93 and 100% were woman. Age varied from 41 to 51 years. Treatment time varied from 12 to 52 weeks. Concomitant BB or ARB/ACEI therapy during trastuzumab treatment was not associated with the LVEF, significantly (Fig. 1A; p=0.07). Oppositely, in the anthracycline regime the LVEF remained significant higher in the concomitant BB and ARB/ACEI groups as compared to controls (Fig. 1B). BB and ARB/ACEI separation in the analysis showed both to influence the LVEF positively independent of chemotherapy (P=0.03 &amp; p=0.005). Table 1 Study reference Year Chemotherapies Preventive drugs Pituskin et al., “Multidisciplinary Approach to Novel Therapies in Cardio-Oncology Research (MANTICORE 101-Breast): A Randomized Trial for the Prevention of Trastuzumab-Associated Cardiotoxicity.” 2017 Trastuzumab Perindopril. bisoprolol Gulati et al., “Prevention of Cardiac Dysfunction during Adjuvant Breast Cancer Therapy (PRADA).” 2016 Trastuzumab Candesartan, metoprolol Boekhout et al., “Angiotensin II-Receptor Inhibition With Candesartan to Prevent Trastuzumab-Related Cardiotoxic Effects in Patients With Early Breast Cancer: A Randomized Clinical Trial.” 2016 Trastuzumab Candesartan Janbabai et al., “Effect of Enalapril on Preventing Anthracycline-Induced Cardiomyopathy.” 2017 Anthracycline Enalapril Nabati et al., “Cardioprotective Effects of Carvedilol in Inhibiting Doxorubicin-Induced Cardiotoxicity.” 2017 Anthracycline Carvedilol Tashakori Beheshti et al., “Carvedilol Administration Can Prevent Doxorubicin-Induced Cardiotoxicity: A Double-Blind Randomized Trial.” 2016 Anthracycline Carvedilol Kaya et al., “Protective Effects of Nebivolol against Anthracycline-Induced Cardiomyopathy: A Randomized Control Study.” 2013 Anthracycline Nebivolol Figure 1 Conclusions Concomitant BB and ARB/ACEI therapy both favoured maintenance of the LVEF during trastuzumab and anthracyclines regimens as compared to controls.

Incidence of drug-induced torsades de pointes with intravenous amiodarone

AimTo define the incidence, presentation, and outcomes of drug-induced Torsades de Pointes (TdP) with intravenous (IV) amiodarone. MethodsFrom January 2014 to August 2016 a total of 268 patients received IV amiodarone, 142 for ventricular tachycardia, 104 for atrial flutter/fibrillation, and 22 for incessant atrial tachycardia. A uniform dosing of amiodarone to yield 1gm/day was used in all patients. ResultsFour of the 268 patients (M:F 1:3) with mean age of 51.25+9.17years developed pause dependent TdP degenerating to VF, after a mean dose of 690+176.63mg, infused over 12+5.88h. The QTc that was 505+9.02ms at the time of TdP normalized to 433.75+6.13ms 48–72h after stopping amiodarone. There was no immediate or late mortality, and patients are well at 5–10 months of follow-up. None of the patients tested positive for LQTS genes. ConclusionThe incidence of drug-induced TdP with IV amiodarone is about 1.5%. Risk factors include female sex, left ventricular dysfunction, electrolyte abnormalities, baseline prolonged QTc, concomitant beta-blocker, and digoxin therapy. Amiodarone induced TdP has favorable prognosis if recognized and treated promptly, and these patients should not receive amiodarone by any route in future.

Long-term treatment with ivabradine over 12 months in patients with chronic heart failure in clinical practice: Effect on symptoms, quality of life and hospitalizations

BackgroundIvabradine is indicated to control heart rate in otherwise optimally treated patients with chronic heart failure (CHF) and reduced ejection fraction. However, data on its effectiveness outside clinical trials and longer-term effects are scarce. MethodsWe performed a prospective cohort study involving 249 German resident cardiologists and analyzed the 1-year effectiveness and safety of ivabradine used in CHF outpatients. Data on symptoms, quality of life, and hospitalizations were collected. ResultsIn total, 767 CHF patients were enrolled to receive ivabradine twice daily, of whom 684 (90%) were still on ivabradine at study end (mean treatment duration 11.2months). The cohort was representative of CHF patients seen in clinical practice in terms of age, risk factor profile, and comorbidities. Concomitant beta-blocker therapy was prescribed in 497 patients (65%). After one year, compared to baseline, heart rate in ivabradine-treated patients was 16bpm lower. This reduction was associated with a significant improvement in NYHA class, and less frequent signs of decompensation (36% to 8%). The proportion of hospitalized patients within 1year decreased from 23% before treatment, to 5% with ivabradine therapy. These improvements in clinical status were accompanied by a reduction in BNP and an increase in LVEF (+5.1% at 1year). Quality of life was significantly improved in all measured dimensions. Adverse drug reactions were noted in 26 patients (3%), and were in line with the known safety profile of ivabradine. ConclusionsIvabradine was effective and well-tolerated in CHF patients seen in clinical practice throughout 1year of treatment.

Sinus Bradycardia in Habitual Cocaine Users

Common physiological manifestations of cocaine are related to its adrenergic effects, due to inhibition of dopamine and norepinephrine uptake at the postsynaptic terminal. Few studies have documented bradycardia secondary to cocaine use, representing the antithesis of its adrenergic effects. We assessed the prevalence of sinus bradycardia (SB) in habitual cocaine users and postulated a mechanism for this effect. One hundred sixty-two patients with a history of cocaine use were analyzed and compared with age- and gender-matched controls. SB was defined as a rate of <60 beats/min and habitual cocaine use as 2 or more documented uses >30days apart. Propensity score-matching analysis was applied to balance covariates between cocaine users and nonusers and reduce selection bias. Patients with a history of bradycardia, hypothyroidism, or concomitant beta-blocker use were excluded. Mean age of study patients was 44 ± 8years. SB was observed in 43 of 162 (27%) cocaine users and in 9 of 149 (6%) nonusers (p= 0.0001). Propensity score-matching analysis matched 218 patients from both groups. Among matched patients SB was observed in 25 of 109 (23%) cocaine users and in 5 of 109 (5%) nonusers (p= 0.0001). Habitual cocaine use was an independent predictor of SB and associated with a sevenfold increase in the risk of SB (95% CI 2.52 to 19.74, p= 0.0002). In conclusion, habitual cocaine use is a strong predictor of SB and was unrelated to recency of use. A potential mechanism for SB may be related to cocaine-induced desensitization of the beta-adrenergic receptor secondary to continuous exposure. Symptomatic SB was not observed; thus, pacemaker therapy was not indicated.

Effectiveness and Tolerability of Ivabradine with or Without Concomitant Beta-Blocker Therapy in Patients with Chronic Stable Angina in Routine Clinical Practice.

IntroductionIn the prospective, open-label, non-interventional, multicenter RESPONSIfVE study, the effectiveness, response rates and tolerability of ivabradine with or without beta blocker (BB) were evaluated in patients with chronic stable angina pectoris (AP) in daily clinical practice.MethodsIn patients with AP, ivabradine was given twice daily in flexible doses for 4 months. Resting heart rate (HR), number of angina attacks, short-acting nitrate use, severity of symptoms [by Canadian Cardiovascular Society (CCS) score] and tolerability with or without existing BB therapy were documented and analyzed using descriptive statistical methods.ResultsIn total, 1250 patients with AP (mean age 66.0 ± 10.9 years, 59.6% male, 31.9% previous myocardial infarction) and an indication for ivabradine were included. Sixty-five percent of all patients received BB. Further concomitant standard medication included aspirin (74.2%), statins (69.3%), angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (84.2%), diuretics (40.0%), long-acting nitrates (15.7%), and calcium antagonists (21.4%). After 4 months of ivabradine treatment (mean daily dose 11.0 ± 2.7 mg), mean HR was reduced from 82.4 ± 11.8 beats per minute (bpm) to 67.1 ± 8.4 bpm. The average number of angina attacks/week decreased from 1.2 ± 1.9 to 0.1 ± 0.6 and the average use of short-acting nitrates/week from 1.5 ± 2.8 units to 0.2 ± 1.0 units. CCS classification of patients improved from 76% classified in CCS grades II or III and 24% in CCS grade I to 66% classified in CCS grade I and only 35% remaining in CCS grades II or III at study end. Response rate to ivabradine (defined as HR <70 bpm or HR reduction ≥10 bpm) reached 87%. HR reduction, symptomatic improvement and response rates were comparable in patients with or without BB. Adverse drug reactions were reported for 2.2% of patients.ConclusionIn this prospective study over a four-month period in clinical practice, ivabradine effectively reduced HR, angina attacks, and nitrate consumption in patients with AP with or without concomitant BB therapy. Ivabradine improved CCS scores and achieved a high treatment response rate with good general tolerability.FundingServier.Trial registrationControlled-trials.com identifier, ISRCTN73861224.

Effectiveness of Ivabradine Treatment in Different Subpopulations with Stable Angina in Clinical Practice: A Pooled Analysis of Observational Studies

Objectives: The efficacy of ivabradine has been demonstrated in different subpopulations of stable angina patients in randomized clinical trials. This study explored its effectiveness in subpopulations seen in clinical practice as they often differ from those of randomized trials. Methods: Data were pooled from three German observational studies with similar inclusion criteria (stable angina and heart rate ≥60 bpm). All patients received 2.5, 5, or 7.5 mg b.i.d. of ivabradine for 4 months, with or without concomitant beta-blocker. Antianginal effectiveness was analyzed in subpopulations defined by gender, age, heart rate, angina severity, use of concomitant beta-blocker, previous percutaneous coronary intervention procedure, and comorbidities (including previous myocardial infarction and diabetes). Results: Treatment data were available on 8,555 patients, where therapy with ivabradine was associated with a significant reduction in the frequency of angina attacks and consumption of short-acting nitrates of 87%. Effectiveness was maintained in all investigated subpopulations, with a reduction in antianginal parameters of 82-90%. Clinical status (Canadian Cardiovascular Society class) and quality of life were also improved. Ivabradine was well tolerated in all subgroups. Conclusions: Ivabradine is effective and safe in all subpopulations of angina patients seen in clinical practice, independent of age, comorbidities, and use of beta-blocker.

Baseline medical comorbidities in adults randomized in the STRIDE trial for psychostimulant use disorders.

Rates of medical illnesses may be higher among individuals with substance use disorders, complicating their care. This study aimed to expand the understanding of other medical conditions in treatment-seeking adults with stimulant use disorder (SUD) using data from Stimulant Reduction Intervention using Dose Exercise (STRIDE), a randomized, multisite trial investigating exercise augmentation of treatment as usual. Utilizing STRIDE baseline data, we examined demographic and clinical characteristics based on the number of self-reported diagnosed medical conditions among participants meeting eligibility criteria (passing medical screening exam and maximal exercise test, non-opioid dependent, no concomitant beta blocker, or opioid replacement therapy). The majority (59%) of study participants (N = 302, mean age all participants = 39 years) did not report any history of other medical problems. Those with two or more conditions were older (mean age 46 years), reported more pain and worse physical functioning, and more psychiatric disorders (average 1.44). Hypertension was more common among participants with cocaine use disorders only (present in 16%) and liver disease was more common in those with cocaine plus other stimulant use disorders (present in 7%). In this sample, patients with SUD were in surprisingly good health. A subpopulation had an overall higher burden of illness with worsened physical and psychiatric functioning. Provision of coordinated care may optimize treatment outcomes for patients based on medical comorbidity burden as well as type of drug abused, although these conclusions should be considered preliminary as they are based on self-reported data.

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Introduction: Dexmedetomidine is frequently used for sedation of critically ill patients. It is effective, however bradycardia can complicate its use. Trauma patients were not included in the major randomized, controlled trials; therefore, data on adverse events in this specific patient population are limited. The objective of this study was to evaluate the incidence of bradycardia in trauma ICU patients receiving dexmedetomidine, and we hypothesize the rate will be lower than previously reported. Methods: Critically-ill trauma patients receiving dexmedetomidine between 2008 and 2011 were included in this single-center, retrospective, cohort study. Data collected included demographics and heart rate measurements during dexmedetomidine therapy. Demographic and hemodynamic data were analyzed using descriptive statistics and an additional logistic regression analysis was used to determine factors associated with bradycardia (defined as heart rate <60 bpm). Results: Sixty-five patients were included with demographics as follows: average age 39.4 years, 80% female, average BMI 29.8 kg/m2, mean ICU length of stay 21.3 days, and mean ventilator days 15.8. None had a history of arrhythmia and 17 subjects (26.2%) received concomitant beta-blocker therapy. Mean dose was 0.65 ± 0.12 mcg/kg/hr with a mean duration of therapy of 102.10 ± 2.82 hours. Only 37% of subjects had an episode of bradycardia, with a mean of 9.9 episodes among those with bradycardia and an overall mean heart rate of 87.5 ± 13.9 bpm. Regression analyses using dichotomized bradycardia (yes/no) or number of episodes of bradycardia as outcome variables were not significant (R2=21.3%, p=0.085 and R2=18.54%, p=0.57, respectively). Average heart rate was predicted by a logistic regression model where average dose, beta-blocker use, and age were significant (R2=27.3%, p=0.018). Conclusions: The rate of bradycardia among trauma patients appears similar to rates in previously published studies, which were as high as 42%. Heart rate during dexmedetomidine therapy is predicted by dose and beta-blocker use. Overall, however the occurrence of bradycardia appears to be an idiosyncratic reaction that is not dose-dependent.

Immunotherapy Safety: What Have We Learned from Surveillance Surveys?

Subcutaneous allergen immunotherapy (SCIT) is beneficial for the treatment of allergic rhinitis, asthma, and in preventing stinging insect anaphylaxis, but is not without risks. Four retrospective surveillance surveys and one on-going national prospective study have attempted to characterize the incidence and risk factors for fatal and non-fatal SCIT reactions. These studies have contributed significantly to currently recommended SCIT safety guidelines. Recent surveillance studies indicate stable SR rates, and a possible decline in the incidence of fatal reactions since the implementation of evidence-based safety guidelines. This review will provide a detailed summary of the evidence from surveillance studies for risk factors associated with SCIT reactions, including: uncontrolled asthma, prior systemic reactions, dosing during peak pollen seasons, epinephrine being delayed or not given, dosing or administration errors, inadequate waiting times, reactions occurring more than 30 min after injections, injections given in medically unsupervised settings, concomitant beta-blocker and angiotensin-converting enzyme inhibitor (ACEi) use, and accelerated build-up regimens.

Efficacy and Limitations of Oral Inotropic Agents for the Treatment of Chronic Heart Failure

The heart failure guideline in Japan has stated the necessity of investigating the role of oral inotropic agents in patients with chronic heart failure (CHF), which are clinically available only in Japan. A total of 1,846 consecutive patients with heart failure (mean: 69.5 years old, 1,279 males) treated at our institute from November 2009 to August 2010 were investigated retrospectively. Thirty-one patients (1.84%) who had taken oral inotropic agents (pimobendan 27, docarpamine 6, and denopamine 4) were extracted for this study, and the efficacy and limitations of the treatments were analyzed. Following the oral inotropic treatment, the NYHA functional class (P = 0.017), cardiothoracic ratio (P = 0.002) and B-type natriuretic peptide levels (P = 0.011) were significantly improved, and the number of emergency room (ER) visits (P < 0.001) and hospitalizations (P < 0.001) were significantly reduced. The nonsurviving patients (n = 7/31, 22.6%) were significantly older (P = 0.02) and tended to have a larger cardiothoracic ratio (P = 0.084) compared with the survivors. An absence of concomitant beta-blocker therapy was significantly associated with a worse prognosis (oneyear mortality 2/21 versus 5/10, log rank, P = 0.011). Oral inotropic agents brought about improvements in the clinical parameters of CHF and a reduction in ER visits and hospitalizations. However, concomitant beta-blocker therapy should be considered for patients receiving oral inotropic treatment.

Ivabradine for the prevention of inappropriate shocks due to sinus tachycardia in patients with an implanted cardioverter defibrillator

Ivabradine is a specific blocker of the pacemaker current (I(f)) used to decrease the sinus rate. Several clinical trials have shown that it is beneficial, with or without concomitant beta-blocker therapy, in patients with stable angina or heart failure. We sought to take advantage of ivabradine's ability to decrease the maximal obtainable sinus rate in order to prevent inappropriate shocks due to sinus tachycardia in patients with an implanted cardioverter defibrillator (ICD). Prospective open-label series including all our patients with an implanted ICD who, during the course of 2010-2011, received ivabradine with the only purpose of preventing inappropriate ICD shocks for sinus tachycardia. These are patients who received one or more inappropriate shocks for sinus tachycardia or were conceived to be at very high risk for developing such complication. Our series includes five patients who received ivabradine (5-10 mg/day) in addition to their usual beta-blocker therapy. During a follow-up of 14 months no inappropriate shocks due to sinus tachycardia were recorded. It is sensible to recommend ivabradine for the prevention of inappropriate ICD shocks due to sinus tachycardia in carefully selected patients.