Search

Background : Post-operative AF (POAF) is the most common complication following cardiac surgery, occurring in 30% to 60% of patients undergoing bypass and/or valve surgery. POAF is associated with longer intensive care unit/hospital stays, increased healthcare utilization, and increased morbidity and mortality. Injection of botulinum toxin type A into the epicardial fat pads resulted in reduction of AF in animal models, and in 2 clinical studies of cardiac surgery patients, without new safety observations. Methods : The objective of NOVA is to assess the use of AGN-151607 (botulinum toxin type A) for prevention of POAF in cardiac surgery patients. This randomized, multi-site, placebo-controlled trial will study one-time injections of AGN-151607 125 U (25 U / fat pad) and 250 U (50 U / fat pad) or placebo during cardiac surgery in ∼330 participants. Primary endpoint: % of patients with continuous AF ≥ 30 s. Secondary endpoints include several measures of AF frequency, duration, and burden. Additional endpoints include clinically important tachycardia during AF, time to AF termination, and healthcare utilization. Primary and secondary efficacy endpoints will be assessed using continuous ECG monitoring for 30 days following surgery. All patients will be followed for up to 1 year for safety. Conclusion : The NOVA Study will test the hypothesis that injections of AGN-151607 will reduce the incidence of POAF and associated resource utilization. If demonstrated to be safe and effective, the availability of a one-time therapy for the prevention of POAF would represent an important treatment option for patients undergoing cardiac surgery.

BACKGROUND: Frequent hospital attendances in patients with implantable cardioverter-defibrillators (ICDs) result in significant morbidity and health care costs. Current drugs to reduce ICD shocks and hospital visits have limited efficacy and considerable toxicity. We evaluated the efficacy and safety of azimilide, a novel oral class III antiarrhythmic, for use in ICD patients. METHODS: A total of 240 patients were enrolled in a prospective, randomized, double-blind, placebo-controlled trial to evaluate the effect of oral azimilide 75 mg daily in ICD patients with previously documented ventricular tachycardia or ventricular fibrillation, and a left ventricular ejection fraction ≤40%. The primary outcome metric was the adjudicated time-to-first unplanned cardiovascular (CV) hospitalization, or CV emergency department (ED) visit, or CV death. The trial was prematurely discontinued due to withdrawal of study sponsorship. RESULTS: Azimilide demonstrated numerical but statistically nonsignificant reductions in the primary composite outcome (odds ratio [OR] 0.79, 95% CI 0.44-1.44), unplanned CV hospitalizations (OR 0.75, 95% CI 0.41-1.38), ED visits (OR 0.68, 95% CI 0.35-1.31), and all-cause shocks (OR 0.58, 95% CI 0.32-1.05). The incidence of adverse events was lower in the azimilide group. Neutropenia was not observed (absolute neutrophil count Carina Blomström-Lundqvist ingår i SHIELD-2 Investigators.

Antihypertensive efficacy of single‐pill combinations (SPCs) consisting of a β1‐selective adrenergic blocker with vasodilatory properties via β3‐agonism (nebivolol) and an angiotensin II receptor blocker (valsartan) was demonstrated in an 8‐week phase 3 trial (NCT01508026). In this post hoc analysis, seated blood pressure, heart rate, 24‐hour ambulatory blood pressure monitoring, plasma aldosterone, estimated glomerular filtration rate, and safety measures were assessed in obese (body mass index >32 kg/m2; n=1823) and nonobese (body mass index

After demonstration of the antihypertensive efficacy of the combination of the beta-blocker nebivolol and the angiotensin receptor blocker valsartan in an 8-week, randomized, placebo-controlled trial (N = 4161), we now report the effects of this treatment on the renin-angiotensin-aldosterone system in a substudy (n = 805). Plasma renin activity increased with valsartan (54%–73%) and decreased with nebivolol (51%–65%) and the combination treatment (17%–39%). Plasma aldosterone decreased with individual treatments (valsartan, 11%–22%; nebivolol, 20%–26%), with the largest reduction (35%) observed with maximum combination dose (20 mg nebivolol/320 mg valsartan). Baseline ln(plasma renin activity) correlated with the 8-week reductions in 24-hour systolic and diastolic BP following treatments with the combination (all doses combined, P = .003 and P

The fixed-dose combination of any two antihypertensive drugs from different drug classes is typically more effective in reducing blood pressure than a dose increase of component monotherapy. We assessed the efficacy and safety of a fixed-dose combination of a vasodilating β blocker (nebivolol) and an angiotensin II receptor blocker (valsartan) in adults with hypertension.We did an 8-week, phase 3, multicentre, randomised, double-blind, placebo-controlled, parallel-group trial at 401 US sites. Participants (age ≥18 years) with hypertension but with blood pressure less than 180/110 mm Hg were randomly assigned (2:2:2:2:2:2:2:1) by a 24-h interactive web response system in blocks of 15 to 4 weeks of double-blind treatment with nebivolol and valsartan fixed-dose combination (5 and 80 mg/day, 5 and 160 mg/day, or 10 and 160 mg/day), nebivolol (5 mg/day or 20 mg/day), valsartan (80 mg/day or 160 mg/day), or placebo. Doses were doubled in weeks 5-8; results are reported according to the final dose. Participants and research staff were masked to treatment allocation. The primary and key secondary endpoints were changes from baseline to week 8 in diastolic and systolic blood pressure, respectively. The primary statistical comparison was between the highest fixed-dose combination dose and the highest monotherapy doses; lower doses were then compared if this comparison was positive (Hochberg method for multiple testing). Efficacy analyses were by intention to treat. Safety assessments included monitoring of adverse events. Continuous efficacy parameters were analysed using an ANCOVA model; binary outcomes were analysed using a logistic regression model. This study is registered with ClinicalTrials.gov, NCT01508026.Between Jan 6, 2012, and March 15, 2013, 4161 patients were randomly assigned (277 to placebo and 554-555 to each active comparator group), 4118 of whom were included in the primary analysis. At week 8, the fixed-dose combination 20 and 320 mg/day group had significantly greater reductions in diastolic blood pressure from baseline than both nebivolol 40 mg/day (least-squares mean difference -1·2 mm Hg, 95% CI -2·3 to -0·1; p=0·030) and valsartan 320 mg/day (-4·4 mm Hg, -5·4 to -3·3; p0·0001); all other comparisons were also significant, favouring the fixed-dose combinations (all p0·0001). All systolic blood pressure comparisons were also significant (all p0·01). At least one treatment-emergent adverse event was experienced by 30-36% of participants in each group.Nebivolol and valsartan fixed-dose combination is an effective and well-tolerated treatment option for patients with hypertension.Forest Research Institute.

Background and Purpose— The DIAS-2 study was the only large, randomized, intravenous, thrombolytic trial that selected patients based on the presence of ischemic penumbra. However, DIAS-2 did not confirm the positive findings of the smaller DEDAS and DIAS trials, which also used penumbral selection. Therefore, a reevaluation of the penumbra selection strategy is warranted. Methods— In post hoc analyses we assessed the relationships of magnetic resonance imaging–measured lesion volumes with clinical measures in DIAS-2, and the relationships of the presence and size of the diffusion-perfusion mismatch with the clinical effect of desmoteplase in DIAS-2 and in pooled data from DIAS, DEDAS, and DIAS-2. Results— In DIAS-2, lesion volumes correlated with National Institutes of Health Stroke Scale (NIHSS) at both baseline and final time points ( P P =0.004). In the pooled analysis, desmoteplase was associated with 47% clinical response rate (n=143) vs 34% in placebo (n=73; P =0.08). For both the pooled sample and for DIAS-2, increasing the minimum baseline mismatch volume (MMV) for inclusion increased the desmoteplase effect size. The odds ratio for good clinical response between desmoteplase and placebo treatment was 2.83 (95% confidence interval, 1.16–6.94; P =0.023) for MMV >60 mL. Increasing the minimum NIHSS score for inclusion did not affect treatment effect size. Conclusions— Pooled across all desmoteplase trials, desmoteplase appears beneficial in patients with large MMV and ineffective in patients with small MMV. These results support a modified diffusion-perfusion mismatch hypothesis for patient selection in later time-window thrombolytic trials. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique Identifiers: NCT00638781, NCT00638248, NCT00111852.

Background —Delayed rectifier K + currents are critical to action potential (AP) repolarization. The present study examines the effects of left ventricular hypertrophy (LVH) on delayed rectifier K + currents and their contribution to AP repolarization in both epicardial (Epi) and endocardial (Endo) myocytes. Methods and Results —LVH was induced in rabbits by a 1-kidney removal, 1-kidney vascular clamping method. Slowly ( I Ks ) and rapidly ( I Kr ) activating delayed rectifier K + currents were recorded by the whole-cell patch-clamp technique, and APs were recorded by the microelectrode technique. In normal rabbit left ventricular myocytes, I Ks densities were larger in Epi than in Endo (1.1±0.1 versus 0.43±0.07 pA/pF), whereas I Kr density was similar between Epi and Endo (0.31±0.05 versus 0.36±0.07 pA/pF) at 20 mV. LVH reduced I Ks density to a similar extent (≈40%) in both Epi and Endo but had no significant effect on I Kr in either Epi or Endo. Consequently, I Kr was expected to contribute more to AP repolarization in LVH than in control. This was confirmed by specific I Kr block with dofetilide, which prolonged AP significantly more in LVH than in control (31±3% versus 18±2% in Epi; 53±6% versus 32±4% in Endo at 2 Hz). In contrast, L-768,673 (a specific I Ks blocker) prolonged AP less in LVH than in control. The very small I Ks density in Endo with LVH is consistent with the greater incidence of early afterdepolarizations induced in this region by dofetilide. Conclusions —LVH induces a decrease in I Ks density and increases the propensity to develop early afterdepolarizations, especially in Endo.

Atrial fibrillation will present the most significant arrhythmia management challenge for clinicians in the new millennium, particularly as the percentage of elderly patients and longevity increase worldwide. The clinical manifestations of the arrhythmia are wide ranging: paroxysmal to permanent modes of occurrence and asymptomatic to severely symptomatic presentations. Perhaps most important, the major risks of atrial fibrillation are stroke and death. Current therapies remain heavily focused on pharma-cologic efforts to reduce the severity of primary symptoms and to prevent stroke and other thromboembolic complications by means of anticoagulation. It has not yet been proven that prevention of atrial fibrillation will prolong survival, however. Nonphar-macologic therapies remain under intense basic and clinical investigation as promising means to improve outcome further for patients suffering from atrial fibrillation.

Ventricular tachycardia, which causes hemodynamic instability, and ventricular fibrillation do not occur frequently in any hospital. However, they usually occur in patients who have severe underlying cardiovascular disease such as myocardial ischemia/infarction or congestive heart failure, and they are associated with high mortality. Most of those deaths are due to an intractable arrhythmia, not suppressible with even the most potent antiarrhythmic drugs. Fortunately, during the last few years, our ability to suppress highly lethal ventricular arrhythmia has been enhanced by the approval of intravenous amiodarone. When used in appropriate patient populations, intravenous amiodarone has been successful in suppressing the most malignant arrhythmia, thus permitting aggressive and successful treatment of severe underlying cardiac conditions. This article reviews data on the use of parenteral antiarrhythmic drugs for the control of ventricular arrhythmia in patients in hospital, and will attempt to provide some guidance as to how these antiarrhythmic drugs may be used in specific patient populations to maximize their efficacy and safety. We will also make recommendations on the sequence of therapy for specific arrhythmias to optimize the chances of patient survival.

Atrial fibrillation (AF) has captured the imagination of clinical investigators who have initiated trials to examine several aspects of this multifaceted arrhythmia. We will review the protocol designs of ongoing trials that are examining the relative value of rhythm versus rate control, new methods for pharmacologic restoration and maintenance of sinus rhythm (including prophylaxis after cardiac surgery), and nonpharmacologic interventions such as pacing and atrial defibrillation. We antic ipate that the results of these studies will have a major impact on the care of patients with AF in the new millennium.

Cardiac arrhythmias frequently respond only to drugs that have as their predominant electrophysiologic effect the prolongation of repolarization and refractoriness. According to the Singh–Vaughan Williams classification, these drugs are known as class III agents. In the last few years, interest has increased in the development of class III antiarrhythmic drugs as alternatives to sodium channel blocking agents, which mainly affect cardiac conduction. Much of this interest results from a perceived danger of using drugs with sodium channel blocking properties, particularly in patients with ischemic heart disease, based on the results of the Cardiac Arrhythmia Suppression Trial (CAST) and several other trials. This article is a review of the pharmacology, including the pharmacokinetics and pharmacodynamics, of the most commonly used and investigated class III antiarrhythmic drugs. As will be seen from the discussion, each of these drugs has novel pharmacology that makes it applicable in specific clinical situations. Their putative effects on various arrhythmogenic mechanisms and their efficacy in treating specific target arrhythmias will be addressed.

The DIAS-2 study was the only large, randomized intravenous thrombolytic trial that selected patients based on the presence of ischemic penumbra. However, DIAS-2 did not confirm the positive findings of the smaller DEDAS and DIAS trials, which also used penumbral selection. Therefore a reevaluation of the penumbra selection strategy is warranted. In post-hoc analyses we assessed the relationships of MRI-measured lesion volumes to clinical measures in DIAS-2, and the relationships of the presence and size of the diffusion-perfusion mismatch to the clinical effect of desmoteplase in DIAS-2 (MRI-selected patients) and in pooled data from MRI-selected 90- and 125-μg/kg dose groups in DIAS, DEDAS, and DIAS-2. In DIAS-2, lesion volumes correlated with NIHSS at both baseline and final time points (P60 mL baseline mismatch subgroups (P=0.083). The odds ratio for good clinical response between desmoteplase and placebo treatment was 2.83 (95% CI, 1.16-6.94, P=0.023) for a MMV >60 mL. Increasing the minimum NIHSS for inclusion did not affect treatment effect size. Pooled across all desmoteplase trials, penumbral selection by MRI diffusion-perfusion mismatch favored desmoteplase clinical benefit, especially for larger MMV. Based on these results, a three-fold reduction in future trial sample size requirements would be achieved using a criterion of baseline MMV >60 mL over any visible mismatch. These results support a modified diffusion-perfusion mismatch hypothesis for patient selection in later-time-window thrombolytic trials.

Thrombolytic therapy with recombinant tissue plasminogen activator (rt-PA) is effective in treating acute ischemic stroke (AIS) within the first 3 hours after symptom onset. Desmoteplase, or rDSPAα...

Despite the emergence of several forms of nonpharmacologic therapy for cardiac arrhythmias, antiarrhythmic drugs continue to play an important role in the management of patients with this common clinical problem. The key to the proper use of antiarrhythmic drugs is a thorough knowledge of their mode of action and pharmacology. The pharmacology of antiarrhythmic drugs is particularly important because patients with cardiac arrhythmias frequently have multiorgan disease, which may influence the metabolism and elimination of antiarrhythmic drugs. The accumulation of toxic amounts of these agents can lead to dire effects including, but not limited to, ventricular proarrhythmia and malignant bradycardia. The goals of pharmacologic therapy of cardiac arrhythmia are to provide the maximum benefit in terms of arrhythmia suppression while maintaining patient safety. To accomplish these goals, a knowledge of the pharmacology of several antiarrhythmic drugs is mandatory.

Atrial arrhythmias occur frequently after cardiac surgery. This article discusses the incidence of postoperative atrial arrhythmia as well as its prognosis, potential mechanisms of pathogenesis, and management. Prophylactic therapy for postoperative atrial arrhythmia is recommended because of the frequency of occurrence and the ease with which therapies can often be implemented. Treatments with pharmacologic and nonpharmacologic modalities are described. Management strategies for atrial arrhythmias that occur postoperatively, including pharmacologic and nonpharmacologic measures as well as anticoagulation recommendations, are discussed.