Clinical trial update: focus on the ONTARGET study

The renin angiotensin system (RAAS) plays an important role in the pathophysiology of cardiovascular (CV) disease. Modulation of RAAS with angiotensin-converting enzyme inhibitors (ACEi), angiotensin receptor blockers (ARB), and aldosterone inhibitors reduces a range of adverse CV outcomes in patients with or at risk of CV disease. Currently, there is incomplete evidence to show all RAAS modulators provide vascular protection by reducing the incidence of myocardial infarction (MI), stroke and CV death. In patients at high risk for CV events, studies with ACEi designed to test for long-term vascular protection, showed benefit. In contrast, studies of ARBs in patients with hypertension, heart failure, and renal disease have not consistently shown a reduction of CV outcomes. However, none of these studies was specifically designed to examine the impact of ARBs on the vascular protective outcomes of CV death, non-fatal MI, and stroke. The ONTARGET and TRANSCEND studies are designed to determine whether the ARB telmisartan is similar (or non-inferior) or superior to the ACEi ramipril in the reduction of CV events in patients with established CV disease or diabetes with target organ damage. The ONTARGET study has enrolled 25,620, and TRANSCEND 5,776 subjects. The subjects in both trials are similar to those studied in the HOPE study, yet there is greater ethnic diversity, a higher proportion of patients with cerebro-vascular disease, and a greater use of beta blockers and lipid-lowering treatment. The studies completed recruitment in 2004, and are due to complete follow-up and report the results in 2008. The ONTARGET and TRANSCEND studies will provide valuable comparative data on the efficacy of telmisartan and ramipril and their combination in patients at high risk for CV events. Although it is possible that enhanced benefits will be observed with dual therapy, the outcomes with ARB monotherapy remain uncertain

Empagliflozin is associated with improvements in liver enzymes potentially consistent with reductions in liver fat: results from randomised trials including the EMPA-REG OUTCOME® trial

Aims/hypothesis: In addition to beneficial effects on glycaemia and cardiovascular death, empagliflozin improves adiposity indices. We investigated the effect of empagliflozin on aminotransferases (correlates of liver fat) in individuals with type 2 diabetes. Methods: Changes from baseline alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were assessed in the EMPA-REG OUTCOME® trial (n = 7020), pooled data from four 24-week placebo-controlled trials (n = 2477) and a trial of empagliflozin vs glimepiride over 104 weeks (n = 1545). Analyses were performed using data from all participants and by tertiles of baseline aminotransferases. Results: In the EMPA-REG OUTCOME® trial, mean ± SE changes from baseline ALT at week 28 were −2.96 ± 0.18 and −0.73 ± 0.25 U/l with empagliflozin and placebo, respectively (adjusted mean difference: −2.22 [95% CI −2.83, −1.62]; p < 0.0001). Reductions in ALT were greatest in the highest ALT tertile (placebo-adjusted mean difference at week 28: −4.36 U/l [95% CI −5.51, −3.21]; p < 0.0001). The adjusted mean difference in change in ALT was −3.15 U/l (95% CI −4.11, −2.18) with empagliflozin vs placebo at week 24 in pooled 24-week data, and −4.88 U/l (95% CI −6.68, −3.09) with empagliflozin vs glimepiride at week 28. ALT reductions were largely independent of changes in weight or HbA1c. AST changes showed similar patterns to ALT, but the reductions were considerably lower. Conclusions/interpretation: These highly consistent results suggest that empagliflozin reduces aminotransferases in individuals with type 2 diabetes, in a pattern (reductions in ALT>AST) that is potentially consistent with a reduction in liver fat, especially when ALT levels are high

Consequences of gravitational radiation recoil

Coalescing binary black holes experience an impulsive kick due to anisotropic emission of gravitational waves. We discuss the dynamical consequences of the recoil accompanying massive black hole mergers. Recoil velocities are sufficient to eject most coalescing black holes from dwarf galaxies and globular clusters, which may explain the apparent absence of massive black holes in these systems. Ejection from giant elliptical galaxies would be rare, but coalescing black holes are displaced from the center and fall back on a time scale of order the half-mass crossing time. Displacement of the black holes transfers energy to the stars in the nucleus and can convert a steep density cusp into a core. Radiation recoil calls into question models that grow supermassive black holes from hierarchical mergers of stellar-mass precursors.Comment: 5 pages, 4 figures, emulateapj style; minor changes made; accepted to ApJ Letter

Perturbed disks get shocked. Binary black hole merger effects on accretion disks

The merger process of a binary black hole system can have a strong impact on a circumbinary disk. In the present work we study the effect of both central mass reduction (due to the energy loss through gravitational waves) and a possible black hole recoil (due to asymmetric emission of gravitational radiation). For the mass reduction case and recoil directed along the disk's angular momentum, oscillations are induced in the disk which then modulate the internal energy and bremsstrahlung luminosities. On the other hand, when the recoil direction has a component orthogonal to the disk's angular momentum, the disk's dynamics are strongly impacted, giving rise to relativistic shocks. The shock heating leaves its signature in our proxies for radiation, the total internal energy and bremsstrahlung luminosity. Interestingly, for cases where the kick velocity is below the smallest orbital velocity in the disk (a likely scenario in real AGN), we observe a common, characteristic pattern in the internal energy of the disk. Variations in kick velocity simply provide a phase offset in the characteristic pattern implying that observations of such a signature could yield a measure of the kick velocity through electromagnetic signals alone.Comment: 10 pages, 13 figures. v2: Minor changes, version to be published in PR

Momentum flow in black-hole binaries: II. Numerical simulations of equal-mass, head-on mergers with antiparallel spins

Research on extracting science from binary-black-hole (BBH) simulations has often adopted a "scattering matrix" perspective: given the binary's initial parameters, what are the final hole's parameters and the emitted gravitational waveform? In contrast, we are using BBH simulations to explore the nonlinear dynamics of curved spacetime. Focusing on the head-on plunge, merger, and ringdown of a BBH with transverse, antiparallel spins, we explore numerically the momentum flow between the holes and the surrounding spacetime. We use the Landau-Lifshitz field-theory-in-flat-spacetime formulation of general relativity to define and compute the density of field energy and field momentum outside horizons and the energy and momentum contained within horizons, and we define the effective velocity of each apparent and event horizon as the ratio of its enclosed momentum to its enclosed mass-energy. We find surprisingly good agreement between the horizons' effective and coordinate velocities. To investigate the gauge dependence of our results, we compare pseudospectral and moving-puncture evolutions of physically similar initial data; although spectral and puncture simulations use different gauge conditions, we find remarkably good agreement for our results in these two cases. We also compare our simulations with the post-Newtonian trajectories and near-field energy-momentum. [Abstract abbreviated; full abstract also mentions additional results.]Comment: Submitted to Phys. Rev.

Ejection of Supermassive Black Holes from Galaxy Cores

[Abridged] Recent numerical relativity simulations have shown that the emission of gravitational waves during the merger of two supermassive black holes (SMBHs) delivers a kick to the final hole, with a magnitude as large as 4000 km/s. We study the motion of SMBHs ejected from galaxy cores by such kicks and the effects on the stellar distribution using high-accuracy direct N-body simulations. Following the kick, the motion of the SMBH exhibits three distinct phases. (1) The SMBH oscillates with decreasing amplitude, losing energy via dynamical friction each time it passes through the core. Chandrasekhar's theory accurately reproduces the motion of the SMBH in this regime if 2 < ln Lambda < 3 and if the changing core density is taken into account. (2) When the amplitude of the motion has fallen to roughly the core radius, the SMBH and core begin to exhibit oscillations about their common center of mass. These oscillations decay with a time constant that is at least 10 times longer than would be predicted by naive application of the dynamical friction formula. (3) Eventually, the SMBH reaches thermal equilibrium with the stars. We estimate the time for the SMBH's oscillations to damp to the Brownian level in real galaxies and infer times as long as 1 Gyr in the brightest galaxies. Ejection of SMBHs also results in a lowered density of stars near the galaxy center; mass deficits as large as five times the SMBH mass are produced for kick velocities near the escape velocity. We compare the N-body density profiles with luminosity profiles of early-type galaxies in Virgo and show that even the largest observed cores can be reproduced by the kicks, without the need to postulate hypermassive binary SMBHs. Implications for displaced AGNs and helical radio structures are discussed.Comment: 18 pages, The Astrophysical Journal, in press. Replaced with revised versio

Heart failure outcomes with empagliflozin in patients with type 2 diabetes at high cardiovascular risk: results of the EMPA-REG OUTCOME® trial.

AIMS: We previously reported that in the EMPA-REG OUTCOME(®) trial, empagliflozin added to standard of care reduced the risk of 3-point major adverse cardiovascular events, cardiovascular and all-cause death, and hospitalization for heart failure in patients with type 2 diabetes and high cardiovascular risk. We have now further investigated heart failure outcomes in all patients and in subgroups, including patients with or without baseline heart failure. METHODS AND RESULTS: Patients were randomized to receive empagliflozin 10 mg, empagliflozin 25 mg, or placebo. Seven thousand and twenty patients were treated; 706 (10.1%) had heart failure at baseline. Heart failure hospitalization or cardiovascular death occurred in a significantly lower percentage of patients treated with empagliflozin [265/4687 patients (5.7%)] than with placebo [198/2333 patients (8.5%)] [hazard ratio, HR: 0.66 (95% confidence interval: 0.55-0.79); P \u3c 0.001], corresponding to a number needed to treat to prevent one heart failure hospitalization or cardiovascular death of 35 over 3 years. Consistent effects of empagliflozin were observed across subgroups defined by baseline characteristics, including patients with vs. without heart failure, and across categories of medications to treat diabetes and/or heart failure. Empagliflozin improved other heart failure outcomes, including hospitalization for or death from heart failure [2.8 vs. 4.5%; HR: 0.61 (0.47-0.79); P \u3c 0.001] and was associated with a reduction in all-cause hospitalization [36.8 vs. 39.6%; HR: 0.89 (0.82-0.96); P = 0.003]. Serious adverse events and adverse events leading to discontinuation were reported by a higher proportion of patients with vs. without heart failure at baseline in both treatment groups, but were no more common with empagliflozin than with placebo. CONCLUSION: In patients with type 2 diabetes and high cardiovascular risk, empagliflozin reduced heart failure hospitalization and cardiovascular death, with a consistent benefit in patients with and without baseline heart failure