Abstract Resting heart rate is central to cardiac output and is influenced by changes occurring in numerous diseases. It predicts longevity and cardiovascular diseases, and current evidence suggests ...that it is also an important marker of outcome in cardiovascular disease, including heart failure. Beta-blockers improve outcomes in heart failure; however, they have effects outside reducing heart rate. Ivabradine has demonstrated efficacy in reducing rehospitalizations and mortality in heart failure and in improving exercise tolerance and reducing angina attacks in patients with coronary artery disease, whereas selective heart rate reduction may also prove to be beneficial in therapeutic areas outside those in which ivabradine has already demonstrated clinical efficacy. This review provides an update on the associations between heart rate and cardiovascular outcomes in various conditions, the experimental effects of heart rate reduction with ivabradine, and the potential new indications in cardiovascular disease.
Hypertrophic cardiomyopathy (HCM) is an inherited disease of the heart muscle characterized by otherwise unexplained thickening of the left ventricle. Left ventricular outflow tract (LVOT) ...obstruction is present in approximately two-thirds of patients and substantially increases the risk of disease complications. Invasive treatment with septal myectomy or alcohol septal ablation can improve symptoms and functional status, but currently available drugs for reducing obstruction have pleiotropic effects and variable therapeutic responses. New medical treatments with more targeted pharmacology are needed, but the lack of preclinical animal models for HCM with LVOT obstruction has limited their development. HCM is a common cause of heart failure in cats, and a subset exhibit systolic anterior motion of the mitral valve leading to LVOT obstruction. MYK-461 is a recently-described, mechanistically novel small molecule that acts at the sarcomere to specifically inhibit contractility that has been proposed as a treatment for HCM. Here, we use MYK-461 to test whether direct reduction in contractility is sufficient to relieve LVOT obstruction in feline HCM. We evaluated mixed-breed cats in a research colony derived from a Maine Coon/mixed-breed founder with naturally-occurring HCM. By echocardiography, we identified five cats that developed systolic anterior motion of the mitral valve and LVOT obstruction both at rest and under anesthesia when provoked with an adrenergic agonist. An IV MYK-461 infusion and echocardiography protocol was developed to serially assess contractility and LVOT gradient at multiple MYK-461 concentrations. Treatment with MYK-461 reduced contractility, eliminated systolic anterior motion of the mitral valve and relieved LVOT pressure gradients in an exposure-dependent manner. Our findings provide proof of principle that acute reduction in contractility with MYK-461 is sufficient to relieve LVOT obstruction. Further, these studies suggest that feline HCM will be a valuable translational model for the study of disease pathology, particularly LVOT obstruction.
We investigate how XBRL adoption affects smaller institutions' access to financial statement information relative to their larger counterparts. We examine three aspects of trading responsiveness: ...abnormal trading volume, response speed to 10-K information, and decision to trade immediately following the 10-K filing. With regard to all three aspects of trading responsiveness, we find that small institutions' responsiveness to 10-K news increases significantly more relative to the change experienced by large institutions from the pre- to post-XBRL periods. We further document that small institutions' stock picking skills in the 10-K filing period increase more compared to those of large institutions following the regulation. Our results are robust to a battery of falsification and sensitivity tests. Collectively, our results suggest that the informational playing field between small and large institutions has become more even following the SEC's XBRL mandate.
Summary Background Proprotein convertase subtilisin/kexin type 9 (PCSK9) increases serum LDL-cholesterol (LDL-C) concentrations. We assessed the effects of AMG 145, a human monoclonal antibody ...against PCSK9, in patients with hypercholesterolaemia in the absence of concurrent lipid-lowering treatment. Methods In a phase 2 trial done at 52 centres in Europe, the USA, Canada, and Australia, patients (aged 18–75 years) with serum LDL-C concentrations of 2·6 mmol/L or greater but less than 4·9 mmol/L were randomly assigned equally through an interactive voice response system to subcutaneous injections of AMG 145 70 mg, 105 mg, or 140 mg, or placebo every 2 weeks; subcutaneous AMG 145 280 mg, 350 mg, or 420 mg or placebo every 4 weeks; or oral ezetimibe 10 mg/day. The primary endpoint was percentage change from baseline in LDL-C concentration at week 12. Analysis was by modified intention to treat. Study personnel and patients were masked to treatment assignment of AMG 145 or placebo. Ezetimibe assignment was open label. This trial is registered with ClinicalTrials.gov , number NCT01375777. Findings 406 patients were assigned to AMG 145 70 mg (n=45), 105 mg (n=46), or 140 mg (n=45) every 2 weeks; AMG 145 280 mg (n=45), 350 mg (n=45), or 420 mg (n=45) every 4 weeks; placebo every 2 weeks (n=45) or every 4 weeks (n=45); or ezetimibe (n=45). AMG 145 significantly reduced LDL-C concentrations in all dose groups (mean baseline LDL-C concentration 3·7 mmol/L SD 0·6; changes from baseline with every 2 weeks AMG 145 70 mg −41·0% 95% CI −46·2 to −35·8; 105 mg −43·9% –49·0 to −38·7; 140 mg −50·9% –56·2 to −45·7; every 4 weeks AMG 145 280 mg −39·0% –44·1 to −34·0; 350 mg −43·2% –48·3 to −38·1; 420 mg −48·0% –53·1 to −42·9; placebo every 2 weeks −3·7% –9·0 to 1·6; placebo every 4 weeks 4·5% –0·7 to 9·8; and ezetimibe −14·7% –18·6 to −10·8; p<0·0001 for all doses vs placebo or ezetimibe). Treatment-emergent adverse events occurred in 136 (50%) of 271 patients in the AMG 145 groups, 41 (46%) of 90 patients in the placebo groups, and 26 (58%) of 45 patients in the ezetimibe group; no deaths or serious treatment-related adverse events were reported. Interpretation The results of our study support the further assessment of AMG 145 in long-term studies with larger and more diverse populations including patients with documented statin intolerance. Funding Amgen.
Induction of delta aminolevulinic acid synthase 1 ( ALAS1) gene expression and accumulation of neurotoxic intermediates result in neurovisceral attacks and disease manifestations in patients with ...acute intermittent porphyria, a rare inherited disease of heme biosynthesis. Givosiran is an investigational RNA interference therapeutic agent that inhibits hepatic ALAS1 synthesis.
We conducted a phase 1 trial of givosiran in patients with acute intermittent porphyria. In part A of the trial, patients without recent porphyria attacks (i.e., no attacks in the 6 months before baseline) were randomly assigned to receive a single subcutaneous injection of one of five ascending doses of givosiran (0.035, 0.10, 0.35, 1.0, or 2.5 mg per kilogram of body weight) or placebo. In part B, patients without recent attacks were randomly assigned to receive once-monthly injections of one of two doses of givosiran (0.35 or 1.0 mg per kilogram) or placebo (total of two injections 28 days apart). In part C, patients who had recurrent attacks were randomly assigned to receive injections of one of two doses of givosiran (2.5 or 5.0 mg per kilogram) or placebo once monthly (total of four injections) or once quarterly (total of two injections) during a 12-week period, starting on day 0. Safety, pharmacokinetic, pharmacodynamic, and exploratory efficacy outcomes were evaluated.
A total of 23 patients in parts A and B and 17 patients in part C underwent randomization. Common adverse events included nasopharyngitis, abdominal pain, and diarrhea. Serious adverse events occurred in 6 patients who received givosiran in parts A through C combined. In part C, all 6 patients who were assigned to receive once-monthly injections of givosiran had sustained reductions in ALAS1 messenger RNA (mRNA), delta aminolevulinic acid, and porphobilinogen levels to near normal. These reductions were associated with a 79% lower mean annualized attack rate than that observed with placebo (exploratory efficacy end point).
Once-monthly injections of givosiran in patients who had recurrent porphyria attacks resulted in mainly low-grade adverse events, reductions in induced ALAS1 mRNA levels, nearly normalized levels of the neurotoxic intermediates delta aminolevulinic acid and porphobilinogen, and a lower attack rate than that observed with placebo. (Funded by Alnylam Pharmaceuticals; ClinicalTrials.gov number, NCT02452372 .).
In this study, we examine whether internal control over financial reporting affects firm operational efficiency. We find that operational efficiency, derived from frontier analysis, is significantly ...lower among firms with material weaknesses in internal control relative to firms without such weaknesses. We also find that the remediation of material weaknesses leads to an improvement in operational efficiency. Additional analyses indicate that the negative effect of material weaknesses on operational efficiency is stronger for firms with a greater demand for higher quality information for decision making, for weaknesses that are deemed to be more severe, and to a certain extent, for smaller firms. Overall, our study extends the literature by presenting systematic evidence on the effect of effective internal control on operational efficiency and informs the debate over the costs and benefits of the internal control reporting requirements under the Sarbanes‐Oxley Act of 2002.
Contrôle interne et efficience de l'exploitation
Les auteurs se demandent si le contrôle interne exercé sur l'information financière influe sur l'efficience de l'exploitation de l'entreprise. Ils constatent que l'efficience de l'exploitation, évaluée selon la méthode de l'analyse des frontières, est sensiblement moins élevée chez les entreprises dont le contrôle interne présente d'importantes déficiences par rapport à celles qui ne présentent pas ces déficiences. Ils observent également que le fait de remédier aux déficiences importantes engendre une amélioration de l'efficience de l'exploitation. Des analyses supplémentaires indiquent que l'incidence négative des déficiences importantes sur l'efficience de l'exploitation est plus marquée dans le cas des entreprises à l'égard desquelles l'exigence d'information de qualité supérieure à des fins décisionnelles est plus élevée, dans celui de déficiences jugées plus sérieuses et, dans une certaine mesure, chez les entreprises plus petites. De façon générale, l'étude enrichit la documentation en établissant un lien systématique entre l'efficacité du contrôle interne et l'efficience de l'exploitation, et elle alimente la réflexion sur les coûts et les avantages des obligations d'information sur le contrôle interne auxquelles la Loi Sarbanes‐Oxley de 2002 assujettit les entreprises.
Evolocumab, a monoclonal antibody that inhibits proprotein convertase subtilisin/kexin type 9 (PCSK9), significantly reduced low-density lipoprotein (LDL) cholesterol levels in phase 2 studies. We ...conducted a phase 3 trial to evaluate the safety and efficacy of 52 weeks of treatment with evolocumab.
We stratified patients with hyperlipidemia according to the risk categories outlined by the Adult Treatment Panel III of the National Cholesterol Education Program. On the basis of this classification, patients were started on background lipid-lowering therapy with diet alone or diet plus atorvastatin at a dose of 10 mg daily, atorvastatin at a dose of 80 mg daily, or atorvastatin at a dose of 80 mg daily plus ezetimibe at a dose of 10 mg daily, for a run-in period of 4 to 12 weeks. Patients with an LDL cholesterol level of 75 mg per deciliter (1.9 mmol per liter) or higher were then randomly assigned in a 2:1 ratio to receive either evolocumab (420 mg) or placebo every 4 weeks. The primary end point was the percent change from baseline in LDL cholesterol, as measured by means of ultracentrifugation, at week 52.
Among the 901 patients included in the primary analysis, the overall least-squares mean (±SE) reduction in LDL cholesterol from baseline in the evolocumab group, taking into account the change in the placebo group, was 57.0±2.1% (P<0.001). The mean reduction was 55.7±4.2% among patients who underwent background therapy with diet alone, 61.6±2.6% among those who received 10 mg of atorvastatin, 56.8±5.3% among those who received 80 mg of atorvastatin, and 48.5±5.2% among those who received a combination of 80 mg of atorvastatin and 10 mg of ezetimibe (P<0.001 for all comparisons). Evolocumab treatment also significantly reduced levels of apolipoprotein B, non-high-density lipoprotein cholesterol, lipoprotein(a), and triglycerides. The most common adverse events were nasopharyngitis, upper respiratory tract infection, influenza, and back pain.
At 52 weeks, evolocumab added to diet alone, to low-dose atorvastatin, or to high-dose atorvastatin with or without ezetimibe significantly reduced LDL cholesterol levels in patients with a range of cardiovascular risks. (Funded by Amgen; DESCARTES ClinicalTrials.gov number, NCT01516879.).
The aim of this study was to compare biweekly and monthly evolocumab with placebo and oral ezetimibe in patients with hypercholesterolemia in a phase III trial.
Evolocumab, a fully human monoclonal ...antibody against proprotein convertase subtilisin/kexin type 9 (PCSK9), significantly reduced LDL-C in phase II trials.
Patients 18 to 80 years of age with fasting low-density lipoprotein cholesterol (LDL-C) ≥100 and <190 mg/dl and Framingham risk scores ≤10% were randomized (1:1:1:1:2:2) to oral placebo and subcutaneous (SC) placebo biweekly; oral placebo and SC placebo monthly; ezetimibe and SC placebo biweekly; ezetimibe and SC placebo monthly; oral placebo and evolocumab 140 mg biweekly; or oral placebo and evolocumab 420 mg monthly.
A total of 614 patients were randomized and administered doses. Evolocumab treatment reduced LDL-C from baseline, on average, by 55% to 57% more than placebo and 38% to 40% more than ezetimibe (p < 0.001 for all comparisons). Evolocumab treatment also favorably altered other lipoprotein levels. Treatment-emergent adverse events (AEs), muscle-related AEs, and laboratory abnormalities were comparable across treatment groups.
In the largest monotherapy trial using a PCSK9 inhibitor to date, evolocumab yielded significant LDL-C reductions compared with placebo or ezetimibe and was well tolerated in patients with hypercholesterolemia. (Monoclonal Antibody Against PCSK9 to Reduce Elevated LDL-C in Subjects Currently Not Receiving Drug Therapy for Easing Lipid Levels-2 MENDEL-2; NCT01763827).
An estimated 10% to 20% of patients cannot tolerate statins or adequate doses to achieve treatment goals. Plasma proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to low-density lipoprotein ...(LDL) receptors, promoting their degradation and increasing LDL cholesterol levels. In phase 1 studies, a human monoclonal antibody to PCSK9, AMG145, was well tolerated and reduced LDL cholesterol levels.
To assess the efficacy and tolerability of AMG145 in patients with statin intolerance due to muscle-related side effects.
A 12-week, randomized, double-blind, placebo- and ezetimibe-controlled, dose-ranging study conducted between July 2011 and May 2012 in statin-intolerant adult patients at 33 international sites.
Patients were randomized equally to 1 of 5 groups: AMG145 alone at doses of 280 mg, 350 mg, or 420 mg; AMG145 at 420 mg plus 10 mg of ezetimibe; or 10 mg of ezetimibe plus placebo. AMG145 or placebo was administered subcutaneously every 4 weeks.
The primary end point was percentage change from baseline to week 12 in ultracentrifugation-measured LDL cholesterol. Other end points included measures of safety and tolerability of different doses of AMG145 and AMG145 plus ezetimibe.
Of 236 patients screened, 160 were randomized (mean age, 62 years; 64% female; mean baseline LDL cholesterol, 193 mg/dL); all patients had intolerance to 1 or more statins because of muscle-related events. At week 12, mean changes in LDL cholesterol levels were -67 mg/dL (-41%; 95% CI, -49% to -33%) for the AMG145, 280-mg, group; -70 mg/dL (-43%; 95% CI, -51% to -35%) for the 350-mg group; -91 mg/dL (-51%; 95% CI, -59% to -43%) for the 420-mg group; and -110 mg/dL (-63%; 95% CI, -71% to -55%) for the 420-mg/ezetimibe group compared with -14 mg/dL (-15%; 95% CI, -23% to -7.0%) for the placebo/ezetimibe group (P < .001). Four serious adverse events were reported with AMG145 (coronary artery disease, acute pancreatitis, hip fracture, syncope). Myalgia was the most common treatment-emergent adverse event during the study, occurring in 5 patients (15.6%) in the 280-mg group (n = 32); 1 patient (3.2%) in the 350-mg group (n = 31), 1 patient (3.1%) in the 420-mg group (n = 32), 6 patients (20.0%) receiving 420-mg AMG145/ezetimibe, and 1 patient (3.1%) receiving placebo/ezetimibe.
In this phase 2 study in statin-intolerant patients, subcutaneous administration of a monoclonal antibody to PCSK9 significantly reduced LDL cholesterol levels and was associated with short-term tolerability. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01375764.
We investigate how the availability of traded credit default swaps (CDSs) affects the referenced firms' voluntary disclosure choices. CDSs enable lenders to hedge their credit risk exposure, ...weakening their incentives to monitor borrowers. We predict that reduced lender monitoring in turn leads shareholders to intensify their monitoring and demand increased voluntary disclosure from managers. Consistent with this expectation, we find that managers are more likely to issue earnings forecasts and forecast more frequently when traded CDSs reference their firms. We further find a stronger impact of CDS availability on firm disclosure when (1) lenders have higher ability and propensity to hedge credit risk using CDSs, and (2) lender monitoring incentives and monitoring strength are weaker. Consistent with an increase in shareholder demand for public information disclosure induced by a reduction in lender monitoring, we find a stronger effect of CDSs on voluntary disclosure for firms with higher institutional ownership and stronger corporate governance. Overall, our findings suggest that firms with traded CDS contracts enhance their voluntary disclosure to offset the effect of reduced monitoring by CDS-protected lenders.
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