Overcoming thrombolytic resistance Rationale and initial clinical experience combining thrombolytic therapy and glycoprotein IIb/IIIa receptor inhibition for acute myocardial infarction

AbstractOBJECTIVESWe sought to review the emerging data and the clinical rationale for combining glycoprotein (GP) IIb/IIIa inhibitors with thrombolytic therapy for acute myocardial infarction (AMI).BACKGROUNDAlthough thrombolytic therapy has been a major advance in the treatment of acute ST segment elevation MI, new single-bolus thrombolytic agents have been unable to break the “thrombolytic ceiling” in infarct-related artery (IRA) patency.METHODSRecent literature on GPIIb/IIIa inhibitors in acute coronary syndromes was reviewed.RESULTSA new approach toward improving current thrombolytic–antithrombotic regimens focuses on “targeted therapy” for each component of the occlusive coronary thrombus: fibrin, thrombin and platelets. For the fibrin component, front-loading and/or bolus dosing of plasminogen activators (PAs) has identified the currently available doses of tissue-type plasminogen activator (t-PA) and recombinant tissue-type plasminogen activator (r-PA). For the thrombin component, several recent trials have shown that lower doses of heparin improve the safety profile of the thrombolytic-antithrombotic regimen. For the platelet component, aspirin has been shown to be effective, but the GPIIb/IIIa inhibitors offer the potential for more effective platelet inhibition and improved clinical efficacy. The benefits of GPIIb/IIIa inhibition in reducing death, MI or urgent revascularization in the setting of percutaneous coronary intervention are well established. Emerging experimental and clinical data now suggest that combining GPIIb/IIIa inhibition with reduced-dose thrombolytic therapy may improve early IRA patency without increasing bleeding risk.CONCLUSIONSGiven the strong clinical and physiologic rationale, clinical investigation in acute ST segment elevation MI is currently focused on combining the potent GPIIb/IIIa receptor inhibitors with reduced-dose fibrinolytic agents in acute MI, with the goal of overcoming “thrombolytic resistance.

The Potential Relevance of the Multiple Lipid-Independent (Pleiotropic) Effects of Statins in the Management of Acute Coronary Syndromes

Emerging data suggest that acute presentations of coronary artery disease may involve a complex interplay between the vessel wall, inflammatory cells, and the coagulation cascade. Although a culprit thrombotic lesion may be treated effectively by antithrombotic therapy and revascularization, this will have little effect on the global processes that determine recurrent events at non-culprit sites. Thus, additional systemic treatment is required to modulate the adverse biological features that are the hallmark of acute coronary syndromes (ACS). Statins possess multiple beneficial effects that are independent of low-density-lipoprotein cholesterol (LDL-C) lowering and that have favorable effects on inflammation, the endothelium, and the coagulation cascade. In the Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis In Myocardial Infarction 22 (PROVE IT-TIMI 22) trial, differences were seen based on achieved LDL-C that could be further discriminated by the achieved C-reactive protein level. Studies of non-vascular disease such as multiple sclerosis have shown that statins reduce inflammation, supporting the presence of lipid-independent effects of statins. This review focuses on the potential importance of these effects in the management of ACS

Parameter estimation on gravitational waves from neutron-star binaries with spinning components

Inspiraling binary neutron stars are expected to be one of the most significant sources of gravitational-wave signals for the new generation of advanced ground-based detectors. We investigate how well we could hope to measure properties of these binaries using the Advanced LIGO detectors, which began operation in September 2015. We study an astrophysically motivated population of sources (binary components with masses $1.2~\mathrm{M}_\odot$--$1.6~\mathrm{M}_\odot$ and spins of less than $0.05$) using the full LIGO analysis pipeline. While this simulated population covers the observed range of potential binary neutron-star sources, we do not exclude the possibility of sources with parameters outside these ranges; given the existing uncertainty in distributions of mass and spin, it is critical that analyses account for the full range of possible mass and spin configurations. We find that conservative prior assumptions on neutron-star mass and spin lead to average fractional uncertainties in component masses of $\sim 16\%$, with little constraint on spins (the median $90\%$ upper limit on the spin of the more massive component is $\sim 0.7$). Stronger prior constraints on neutron-star spins can further constrain mass estimates, but only marginally. However, we find that the sky position and luminosity distance for these sources are not influenced by the inclusion of spin; therefore, if LIGO detects a low-spin population of BNS sources, less computationally expensive results calculated neglecting spin will be sufficient for guiding electromagnetic follow-up.Comment: 10 pages, 9 figure

Safety and efficacy of double vs. triple antithrombotic therapy in patients with atrial fibrillation with or without acute coronary syndrome undergoing percutaneous coronary intervention: a collaborative meta-analysis of non-vitamin K antagonist oral anticoagulant-based randomized clinical trials.

AIMS Safety and efficacy of antithrombotic regimens in patients with atrial fibrillation (AF) undergoing percutaneous coronary intervention (PCI) may differ based on clinical presentation. We sought to compare double vs. triple antithrombotic therapy (DAT vs. TAT) in AF patients with or without acute coronary syndrome (ACS) undergoing PCI. METHODS AND RESULTS A systematic review and meta-analysis was performed using PubMed to search for non-vitamin K antagonist oral anticoagulant (NOAC)-based randomized clinical trials. Data on subgroups of ACS or elective PCI were obtained by published reports or trial investigators. A total of 10 193 patients from four NOAC trials were analysed, of whom 5675 presenting with ACS (DAT = 3063 vs. TAT = 2612) and 4518 with stable coronary artery disease (SCAD; DAT = 2421 vs. TAT = 2097). The primary safety endpoint of ISTH major bleeding or clinically relevant non-major bleeding was reduced with DAT compared with TAT in both ACS (12.2% vs. 19.4%; RR 0.63, 95% CI 0.56-0.71; P < 0.0001; I2 = 0%) and SCAD (14.6% vs. 22.0%; RR 0.68, 95% CI 0.55-0.85; P = 0.0008; I2 = 66%), without interaction (P-int = 0.54). Findings were consistent for secondary bleeding endpoints, including intra-cranial haemorrhage. In both subgroups, there was no difference between DAT and TAT for all-cause death, major adverse cardiovascular events, or stroke. Myocardial infarction and stent thrombosis were numerically higher with DAT vs. TAT consistently in ACS and SCAD (P-int = 0.60 and 0.86, respectively). Findings were confirmed by multiple sensitivity analyses, including a separate analysis on dabigatran regimens and a restriction to PCI population. CONCLUSIONS DAT, compared with TAT, is associated with lower bleeding risks, including intra-cranial haemorrhage, and a small non-significant excess of cardiac ischaemic events in both patients with or without ACS

Constraining Disk Parameters of Be Stars using Narrowband H-alpha Interferometry with the NPOI

Interferometric observations of two well-known Be stars, gamma Cas and phi Per, were collected and analyzed to determine the spatial characteristics of their circumstellar regions. The observations were obtained using the Navy Prototype Optical Interferometer equipped with custom-made narrowband filters. The filters isolate the H-alpha emission line from the nearby continuum radiation, which results in an increased contrast between the interferometric signature due to the H-alpha-emitting circumstellar region and the central star. Because the narrowband filters do not significantly attenuate the continuum radiation at wavelengths 50 nm or more away from the line, the interferometric signal in the H-alpha channel is calibrated with respect to the continuum channels. The observations used in this study represent the highest spatial resolution measurements of the H-alpha-emitting regions of Be stars obtained to date. These observations allow us to demonstrate for the first time that the intensity distribution in the circumstellar region of a Be star cannot be represented by uniform disk or ring-like structures, whereas a Gaussian intensity distribution appears to be fully consistent with our observations.Comment: 23 pages, 14 figures, accepted for publication in A

Antiplatelet Therapy and Platelet Function Testing

No Abstract.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/58558/1/20370_ftp.pd

Relationship between alirocumab, PCSK9, and LDL-C levels in four phase 3 ODYSSEY trials using 75 and 150 mg doses

BACKGROUND: Alirocumab is a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 (PCSK9). OBJECTIVE: Changes in PCSK9, alirocumab, and low-density lipoprotein cholesterol (LDL-C) levels were assessed after treatment with alirocumab at doses of 75 or 150 mg every 2 weeks (Q2W). METHODS: Data were analyzed from 4 phase 3 trials (MONO; COMBO II; FH I; LONG TERM); all but MONO enrolled patients on statins. Three trials evaluated alirocumab 75 mg Q2W, with possible dose increase to 150 mg Q2W at week 12 based on week 8 LDL-C; LONG TERM studied alirocumab 150 mg Q2W. RESULTS: Patients on background statin therapy had higher mean baseline free PCSK9 concentrations vs patients not on statin. After alirocumab administration, increased alirocumab concentrations were associated with dramatic reductions in circulating free PCSK9, resulting in significant LDL-C reductions and a corresponding increase in inactive PCSK9:alirocumab complex. Alirocumab dose increase was associated with a further lowering of PCSK9 and LDL-C. Patients with higher baseline LDL-C levels (>160 mg/dL) were more likely to have their dose increased. LDL-C reductions with alirocumab were consistent between patients with baseline PCSK9 levels above or below the median when the dose increase strategy was used. When started as alirocumab 150 mg Q2W, patients with PCSK9 levels above vs below the median had a greater LDL-C reduction. CONCLUSIONS: Alirocumab-induced changes in PCSK9 and LDL-C levels were consistent with the known physiologic relationship between PCSK9, LDL receptor, and LDL-C levels, as well as statin-induced increases in PCSK9 production. (C) 2019 National Lipid Association. Published by Elsevier Inc.Peer reviewe