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β-Blockers
Abstract
Beta-blockers, which exhibit sympathoinhibitory, cardioprotective and antioxidant actions, have been demonstrated as a drug class that can improve life prognosis in a number of large-scale studies. However, since most of these studies were conducted using oral drugs, injectable drugs have not been investigated sufficiently. It has been reported that injectable β-blockers are effective for tachyarrhythmia in emergency situations because sympathetic hyperactivity is often observed after invasive treatment, such as surgery. We report the current status of injectable β blockers in this article.
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Prevention of postoperative arrhythmias in patients undergoing general thoracic surgery is desirable to prevent morbidity.
A randomized, double-blind, placebo controlled trial of propranolol (10 mg every 6 hours) for 5 days was undertaken in patients undergoing major thoracic operations to determine whether arrhythmias requiring treatment could be reduced. Secondary outcomes included overall arrhythmia rate, adverse events, and length of stay. Arrhythmias were assessed by 72-hour Holter monitoring. Patients with a history of heart failure, asthma, advanced heart block, preexisting arrhythmias, sensitivity to propranolol, or use of antiarrhythmic drugs were excluded.
Using the intention-to-treat principle there was a 70% relative risk reduction from 20% to 6% in the rate of treated arrhythmias with propranolol (p = 0.071, 95% confidence interval 0.6% to 27.2%). Overall arrhythmias were common but usually benign. Adverse effects were common, although generally mild with hypotension and bradycardia being reported more often in the propranolol group. Length of stay was not different.
There was a trend to a reduction in the risk of perioperative arrhythmias with propranolol. Moreover, propranolol was well tolerated showing a slight increase in minor adverse events.
Background:
A rapid heart rate (HR) during atrial fibrillation (AF) and atrial flutter (AFL) in left ventricular (LV) dysfunction often impairs cardiac performance. The J-Land study was conducted to compare the efficacy and safety of landiolol, an ultra-short-acting β-blocker, with those of digoxin for swift control of tachycardia in AF/AFL in patients with LV dysfunction.
Methods and results:
The 200 patients with AF/AFL, HR ≥120beats/min, and LV ejection fraction 25-50% were randomized to receive either landiolol (n=93) or digoxin (n=107). Successful HR control was defined as ≥20% reduction in HR together with HR <110beats/min at 2h after starting intravenous administration of landiolol or digoxin. The dose of landiolol was adjusted in the range of 1-10µg·kg(-1)·min(-1) according to the patient's condition. The mean HR at baseline was 138.2±15.7 and 138.0±15.0beats/min in the landiolol and digoxin groups, respectively. Successful HR control was achieved in 48.0% of patients treated with landiolol and in 13.9% of patients treated with digoxin (P<0.0001). Serious adverse events were reported in 2 and 3 patients in each group, respectively.
Conclusions:
Landiolol was more effective for controlling rapid HR than digoxin in AF/AFL patients with LV dysfunction, and could be considered as a therapeutic option in this clinical setting.
We previously performed a trial of intravenous landiolol hydrochloride during and after cardiac surgery (the PASCAL trial) and demonstrated a preventive effect on postoperative atrial fibrillation (AF). In the present study, we investigated the efficacy of increasing the dose and administration period of landiolol for prevention of postoperative AF, as well as the effect of oral bisoprolol in the early postoperative period.
A total of 105 patients who underwent coronary artery bypass grafting were randomized to 3 groups: a group receiving intravenous landiolol perioperatively at 5 μg/kg/min for 3 days (group L), a group receiving oral bisoprolol postoperatively together with landiolol (group LB), and a control group without beta-blocker therapy (group C). The primary end point was the presence/absence of postoperative AF. Secondary end points were (1) the early clinical outcome, (2) hemodynamics, (3) cardiac enzymes (creatine kinase isoenzyme MB, troponin-I, and human heart fatty acid-binding protein), (4) high-sensitivity C-reactive protein (hs-CRP) and pentraxin-3, (5) asymmetric dimethylarginine (ADMA), and (6) brain natriuretic peptide.
Postoperative AF occurred in 14.5% of group L, 9.1% of group LB, and 35.3% of group C. A significant difference was observed between groups LB and C. Significantly higher levels of troponin-I, human heart fatty acid-binding protein, hs-CRP, pentraxin-3, and ADMA were noted in group C than in groups L and LB.
Landiolol and bisoprolol prevented postoperative AF. The anti-ischemic, anti-inflammatory, and anti-oxidant effects of these beta-blockers presumably inhibited the onset of AF.
Recent studies have suggested that esmolol is the first choice for rate control in patients with postoperative atrial fibrillation (AF) after coronary artery bypass surgery, but side-effects of esmolol such as hypotension are problematic. To overcome this problem, landiolol, an ultra-short-acting β(1)-blocker with a less negative inotropic effect than esmolol, has been developed. The aim of the present study was to investigate whether landiolol was effective for both rate control and conversion to normal sinus rhythm (NSR).
A prospective, randomized, open-label comparison between i.v. landiolol and diltiazem in patients with postoperative AF was undertaken between January 2008 and June 2009 in Japan. Of 335 patients included in the analysis, 71 patients went into AF. Among these 71 patients, conversion to NSR within 8h after onset of AF occurred in 19 of 35 patients (54.3%) in the landiolol group vs. 11 of 36 patients (30.6%) in the diltiazem group (P<0.05). The incidence of hypotension was lower in the landiolol group (4/35, 11.4%) compared with the diltiazem group (11/36, 30.6%; P<0.05). The incidence of bradycardia was also lower in the landiolol group (0%) compared with the diltiazem group (4/36, 11.1%; P<0.05).
Landiolol is more effective and safer than diltiazem for patients with postoperative AF after open heart surgery.
Atrial fibrillation occurs frequently after cardiac surgery and not only prolongs hospitalization but also influences the prognosis. We investigated whether landiolol hydrochloride, an ultrashort-acting beta-blocker, could reduce postoperative atrial fibrillation in a randomized controlled trial.
The subjects were 140 patients undergoing coronary artery bypass grafting at the Nihon University School of Medicine. The primary end point was occurrence/non-occurrence of atrial fibrillation up to 1 week postoperatively. Logistic regression analysis was performed to investigate risk factors for atrial fibrillation among preoperative, perioperative, and postoperative variables.
Atrial fibrillation occurred in 7 patients (10%) in the landiolol group versus 24 patients (34.3%) in the placebo group; the landiolol group had a significantly lower incidence (P = .0006). Postoperative heart rate was significantly lower in the landiolol group than in the placebo group. On returning to the intensive care unit, the landiolol group had significantly lower inflammatory and ischemic parameters. Medical costs were also significantly lower in the landiolol group. Multivariate analysis revealed that significant risk factors for atrial fibrillation were a European System for Cardiac Operative Risk Evaluation of 10 or more, preoperative non-use of angiotensin receptor blockers, and non-use of landiolol.
Postoperative atrial fibrillation was reduced by treatment with landiolol hydrochloride. Amelioration of ischemia, an anti-inflammatory effect, and inhibition of sympathetic hypertonia by landiolol presumably reduced the occurrence of atrial fibrillation. Hypotension or bradycardia did not develop in any of the patients, indicating the safety of this beta-blocker. These findings suggest that landiolol hydrochloride could be useful in the perioperative management of patients undergoing cardiac surgery.
Atrial fibrillation after cardiac surgery is a frequent complication. In this study we studied various factors in addition to trying to identify a marker that would predict the potential for atrial fibrillation before surgical intervention to prevent its occurrence.
We targeted 234 cases in which isolated coronary artery bypass grafting had been performed. The items for study included age, EuroSCORE, and maximum values of creatine phosphokinase-MB, troponin I, and angiotensin II after surgical intervention and preoperative values of atrial natriuretic peptide, brain natriuretic peptide, and C-reactive protein. As fibrotic markers, we measured levels of the sialylated carbohydrate antigen KL-6 in the blood, hyaluronic acid, and pyridinoline cross-linked carboxyterminal telepeptide of type I collagen C. At the time of surgical intervention, a section of the right atrium was extracted, and atrial natriuretic peptide, the sialylated carbohydrate antigen KL-6, hyaluronic acid, and pyridinoline cross-linked telopeptide of type I collagen levels were measured.
Atrial fibrillation was observed in 73 (31.2%) cases, and preoperative factors that showed statistically significant differences in the occurrence of atrial fibrillation included age, EuroSCORE, and preoperative values of atrial natriuretic peptide, angiotensin II, the sialylated carbohydrate antigen KL-6, hyaluronic acid, and pyridinoline cross-linked telopeptide of type I collagen in the blood. As for intraoperative and postoperative factors, statistically significant differences were observed in the postoperative maximum of angiotensin II, atrial natriuretic peptide of the right atrium, the sialylated carbohydrate antigen KL-6, hyaluronic acid, and pyridinoline cross-linked telopeptide of type I collagen levels.
The fibrosis of tissue associated with age is believed to be closely related to the occurrence of atrial fibrillation after coronary artery bypass grafting. This study suggests that the preoperative values of atrial natriuretic peptide, angiotensin II, the sialylated carbohydrate antigen KL-6, hyaluronic acid, and pyridinoline cross-linked telopeptide of type I collagen in the blood are useful as a new index for the occurrence of atrial fibrillation after coronary artery bypass grafting.
To compare the cardiovascular and sympathetic effects of a new ultra-short-acting, highly cardioselective beta- blocker, landiolol, with esmolol, using an in vivo rabbit model.
Different bolus doses of landiolol (0.3, 1.0, 3.0 and 10.0 mg*kg(-1)) or esmolol (0.5, 1.5 and 5.0 mg*kg(-1)) were given intravenously, and the effects on heart rate (HR) mean arterial pressure (MAP) and renal sympathetic nerve activity (RSNA) were compared.
Both landiolol and esmolol produced a dose-dependent decrease in HR. The maximum percent reductions of HR were similar with landiolol 3 mg*kg(-1) and esmolol 5 mg*kg(-1) (-14.0 +/- 0.9% and -13.9 +/- 1.4%, mean +/- SE, respectively). HR decreased more rapidly with landiolol than with esmolol. Esmolol produced a dose-dependent decrease in MAP that was not observed with landiolol. The percent maximum reduction of MAP was -38.2 +/- 3.2% with esmolol 5 mg*kg(-1). RSNA increased in a dose-dependent fashion with esmolol, but no changes were noted with landiolol.
These results suggest that, in rabbits, landiolol has slightly more potent negative chronotropic action than esmolol with significantly less effects on blood pressure.
Despite previous randomised trials of early beta-blocker therapy in the emergency treatment of myocardial infarction (MI), uncertainty has persisted about the value of adding it to current standard interventions (eg, aspirin and fibrinolytic therapy), and the balance of potential benefits and hazards is still unclear in high-risk patients.
45,852 patients admitted to 1250 hospitals within 24 h of suspected acute MI onset were randomly allocated metoprolol (up to 15 mg intravenous then 200 mg oral daily; n=22,929) or matching placebo (n=22,923). 93% had ST-segment elevation or bundle branch block, and 7% had ST-segment depression. Treatment was to continue until discharge or up to 4 weeks in hospital (mean 15 days in survivors) and 89% completed it. The two prespecified co-primary outcomes were: (1) composite of death, reinfarction, or cardiac arrest; and (2) death from any cause during the scheduled treatment period. Comparisons were by intention to treat, and used the log-rank method. This study is registered with ClinicalTrials.gov, number NCT 00222573.
Neither of the co-primary outcomes was significantly reduced by allocation to metoprolol. For death, reinfarction, or cardiac arrest, 2166 (9.4%) patients allocated metoprolol had at least one such event compared with 2261 (9.9%) allocated placebo (odds ratio [OR] 0.96, 95% CI 0.90-1.01; p=0.1). For death alone, there were 1774 (7.7%) deaths in the metoprolol group versus 1797 (7.8%) in the placebo group (OR 0.99, 0.92-1.05; p=0.69). Allocation to metoprolol was associated with five fewer people having reinfarction (464 [2.0%] metoprolol vs 568 [2.5%] placebo; OR 0.82, 0.72-0.92; p=0.001) and five fewer having ventricular fibrillation (581 [2.5%] vs 698 [3.0%]; OR 0.83, 0.75-0.93; p=0.001) per 1000 treated. Overall, these reductions were counterbalanced by 11 more per 1000 developing cardiogenic shock (1141 [5.0%] vs 885 [3.9%]; OR 1.30, 1.19-1.41; p<0.00001). This excess of cardiogenic shock was mainly during days 0-1 after admission, whereas the reductions in reinfarction and ventricular fibrillation emerged more gradually. Consequently, the overall effect on death, reinfarction, arrest, or shock was significantly adverse during days 0-1 and significantly beneficial thereafter. There was substantial net hazard in haemodynamically unstable patients, and moderate net benefit in those who were relatively stable (particularly after days 0-1).
The use of early beta-blocker therapy in acute MI reduces the risks of reinfarction and ventricular fibrillation, but increases the risk of cardiogenic shock, especially during the first day or so after admission. Consequently, it might generally be prudent to consider starting beta-blocker therapy in hospital only when the haemodynamic condition after MI has stabilised.
rapid heart rate in patients with atrial fibrillation/flutter and left ventricular dysfunction: comparison of the ultrashort-acting β1-selective blocker landiolol with digoxin (J-Land Study)
rapid heart rate in patients with atrial fibrillation/flutter
and left ventricular dysfunction: comparison of the ultrashort-acting β1-selective blocker landiolol with digoxin
(J-Land Study). Circ J 2013; 77: 908-913.