Exploring Meaningful Patient Engagement in ADAPTABLE (Aspirin Dosing: A Patient-centric Trial Assessing Benefits and Long-term Effectiveness).

BackgroundGenuine patient engagement can improve research relevance, impact and is required for studies using the National Patient-Centered Clinical Research Network including major multicenter research projects. It is unclear, however, how best to integrate patients into governance of such projects.MethodsADAPTABLE (Aspirin Dosing: A Patient-centric Trial Assessing Benefits and Long-term Effectiveness) is the first major multicenter research project to be conducted in National Patient-Centered Clinical Research Network. Here, we provide a description of how we implemented patient engagement in ADAPTABLE thus far, including a description of committee structures and composition, first-hand patient testimonials, specific contributions, and lessons learned during the planning and early implementation of ADAPTABLE.ResultsWe recruited 1 patient leader from 6 of the 7 enrolling networks to serve on a Patient Review Board for ADAPTABLE, supported the Board with an experienced patient engagement team including an "investigator-advocate" not otherwise involved in the trial, and facilitated bidirectional communication between the Board and ADAPTABLE Coordinating Center. The Board has reviewed and provided substantial input on the informed consent procedure, recruitment materials, patient portal design, and study policy including compensation of participants. Although it was "too late" for some suggested modifications, most modifications suggested by the patient leaders have been implemented, and they are enthusiastic about the study and their role. The patient leaders also attend Steering and Executive Committee calls; these experiences have been somewhat less productive.ConclusionsWith adequate support, a cadre of committed patient leaders can provide substantial value to design and implementation of a major multicenter clinical trial

Total Cardiovascular and Limb Events and the Impact of Polyvascular Disease in Chronic Symptomatic Peripheral Artery Disease.

Background Peripheral artery disease (PAD) is associated with heightened risk for major adverse cardiovascular and limb events, but data on the burden of risk for total (first and potentially subsequent) events, and the association with polyvascular disease, are limited. This post hoc analysis of the EUCLID (Examining Use of Ticagrelor in Peripheral Artery Disease) trial evaluated total cardiovascular and limb events among patients with symptomatic PAD, overall and by number of symptomatic vascular territories. Methods and Results In the EUCLID trial, patients with symptomatic PAD (lower extremity revascularization >30 days before randomization or ankle-brachial index ≤0.80) were randomized to treatment with ticagrelor or clopidogrel. Relative effects on total events (cardiovascular death; nonfatal myocardial infarction and ischemic stroke; acute limb ischemia, unstable angina, and transient ischemic attack requiring hospitalization; coronary, carotid, and peripheral revascularization procedures; and amputation for symptomatic PAD) were summarized by hazard ratios (HRs), whereas absolute risks were estimated by incidence rates and mean cumulative functions. Among 13 885 randomized patients, 7600 total cardiovascular and limb events occurred during a median 2.7 years of follow-up, translating to 60.0 and 62.5 events per 100 patients through 3 years for the ticagrelor and clopidogrel groups, respectively (HR, 0.96; 95% CI, 0.89-1.03; P=0.27). Among 1393 patients with disease in 3 vascular territories, event accrual rates through 3 years for the ticagrelor and clopidogrel groups were 87.3 and 97.7 events per 100 patients, respectively. Absolute risk reductions for ticagrelor relative to clopidogrel at 3 years were -0.2, 6.7, and 10.3 events per 100 patients for 1, 2, and 3 affected vascular territories, respectively (Pinteraction=0.09). Conclusions Patients with symptomatic PAD have nearly double the number of total events than first events, with rates reflecting the number of affected vascular territories. These findings highlight the clinical relevance of quantifying disease burden in terms of total events and the need for long-term preventive treatments in high-risk patient populations. Registration URL: https://clinicaltrials.gov/; Unique identifier: NCT01732822

Association of Heart Failure With Outcomes Among Patients With Peripheral Artery Disease: Insights From EUCLID.

Background Peripheral artery disease (PAD) and heart failure (HF) are each independently associated with poor outcomes. Risk factors associated with new-onset HF in patients with primary PAD are unknown. Furthermore, how the presence of HF is associated with outcomes in patients with PAD is unknown. Methods and Results This analysis examined risk relationships of HF on outcomes in patients with symptomatic PAD randomized to ticagrelor or clopidogrel as part of the EUCLID (Examining Use of Ticagrelor in Peripheral Arterial Disease) trial. Patients were stratified based on presence of HF at enrollment. Cox models were used to determine the association of HF with outcomes. A separate Cox model was used to identify risk factors associated with development of HF during follow-up. Patients with PAD and HF had over twice the rate of concomitant coronary artery disease as those without HF. Patients with PAD and HF had significantly increased risk of major adverse cardiovascular events (hazard ratio [HR], 1.31; 95% CI, 1.13-1.51) and all-cause mortality (HR, 1.39; 95% CI, 1.19-1.63). In patients with PAD, the presence of HF was associated with significantly less bleeding (HR, 0.65; 95% CI, 0.45-0.96). Characteristics associated with HF development included age ≥66 (HR, 1.29; 95% CI, 1.18-1.40 per 5 years), diabetes mellitus (HR, 1.85; 95% CI, 1.41-2.43), and weight (bidirectionally associated, ≥76 kg, HR, 0.77; 95% CI, 0.64-0.93; <76 kg, HR, 1.12; 95% CI, 1.07-1.16). Conclusions Patients with PAD and HF have a high rate of coronary artery disease with a high risk for major adverse cardiovascular events and death. These data support the possible need for aggressive treatment of (recurrent) atherosclerotic disease in PAD, especially patients with HF

Type Ia Supernova Rate Measurements To Redshift 2.5 From CANDELS: Searching For Prompt Explosions In The Early Universe

dThe Cosmic Assembly Near-infrared Deep Extragalactic Legacy Survey (CANDELS) was a multi-cycle treasury program on the Hubble Space Telescope (HST) that surveyed a total area of -0.25 deg2 with -900 HST orbits spread across five fields over three years. Within these survey images we discovered 65 supernovae (SNe) of all types, out to z 2.5. We classify -24 of these as Type Ia SNe (SNe Ia) based on host galaxy redshifts and SN photometry (supplemented by grism spectroscopy of six SNe). Here we present a measurement of the volumetric SN Ia rate as a function of redshift, reaching for the first time beyond z =- 2 and putting new constraints on SN Ia progenitor models. Our highest redshift bin includes detections of SNe that exploded when the universe was only -3 Gyr old and near the peak of the cosmic star formation history. This gives the CANDELS high redshift sample unique leverage for evaluating the fraction of SNe Ia that explode promptly after formation ( 40 Myr. However, mild tension is apparent between ground-based low-z surveys and space-based high-z surveys. In both CANDELS and the sister HST program CLASH (Cluster Lensing And Supernova Survey with Hubble), we find a low rate of SNe Ia at z > 1. This could be a hint that prompt progenitors are in fact relatively rare, accounting for only 20% of all SN Ia explosions-though further analysis and larger samples will be needed to examine that suggestion. Key words: infrared: general - supernovae:Astronom

Type Ia Supernova Distances at z > 1.5 from the Hubble Space Telescope Multi-Cycle Treasury Programs: The Early Expansion Rate

We present an analysis of 15 Type Ia supernovae (SNe Ia) at redshift z > 1 (9 at 1.5 < z < 2.3) recently discovered in the CANDELS and CLASH Multi-Cycle Treasury programs using WFC3 on the Hubble Space Telescope. We combine these SNe Ia with a new compilation of 1050 SNe Ia, jointly calibrated and corrected for simulated survey biases to produce accurate distance measurements. We present unbiased constraints on the expansion rate at six redshifts in the range 0.07 < z < 1.5 based only on this combined SN Ia sample. The added leverage of our new sample at z > 1.5 leads to a factor of ~3 improvement in the determination of the expansion rate at z = 1.5, reducing its uncertainty to ~20%, a measurement of H(z=1.5)/H0=2.67 (+0.83,-0.52). We then demonstrate that these six measurements alone provide a nearly identical characterization of dark energy as the full SN sample, making them an efficient compression of the SN Ia data. The new sample of SNe Ia at z > 1 usefully distinguishes between alternative cosmological models and unmodeled evolution of the SN Ia distance indicators, placing empirical limits on the latter. Finally, employing a realistic simulation of a potential WFIRST SN survey observing strategy, we forecast optimistic future constraints on the expansion rate from SNe Ia.Comment: 14 pages, 5 figures, 7 tables; submitted to Ap

Nonuniform sampling and maximum entropy reconstruction in multidimensional NMR

NMR spectroscopy is one of the most powerful and versatile analytic tools available to chemists. The discrete Fourier transform (DFT) played a seminal role in the development of modern NMR, including the multidimensional methods that are essential for characterizing complex biomolecules. However, it suffers from well-known limitations: chiefly the difficulty in obtaining high-resolution spectral estimates from short data records. Because the time required to perform an experiment is proportional to the number of data samples, this problem imposes a sampling burden for multidimensional NMR experiments. At high magnetic field, where spectral dispersion is greatest, the problem becomes particularly acute. Consequently multidimensional NMR experiments that rely on the DFT must either sacrifice resolution in order to be completed in reasonable time or use inordinate amounts of time to achieve the potential resolution afforded by high-field magnets.Maximum entropy (MaxEnt) reconstruction is a non-Fourier method of spectrum analysis that can provide high-resolution spectral estimates from short data records. It can also be used with nonuniformly sampled data sets. Since resolution is substantially determined by the largest evolution time sampled, nonuniform sampling enables high resolution while avoiding the need to uniformly sample at large numbers of evolution times. The Nyquist sampling theorem does not apply to nonuniformly sampled data, and artifacts that occur with the use of nonuniform sampling can be viewed as frequency-aliased signals. Strategies for suppressing nonuniform sampling artifacts include the careful design of the sampling scheme and special methods for computing the spectrum. Researchers now routinely report that they can complete an N-dimensional NMR experiment 3 times faster (a 3D experiment in one ninth of the time). As a result, high-resolution three- and four-dimensional experiments that were prohibitively time consuming are now practical. Conversely, tailored sampling in the indirect dimensions has led to improved sensitivity.Further advances in nonuniform sampling strategies could enable further reductions in sampling requirements for high resolution NMR spectra, and the combination of these strategies with robust non-Fourier methods of spectrum analysis (such as MaxEnt) represent a profound change in the way researchers conduct multidimensional experiments. The potential benefits will enable more advanced applications of multidimensional NMR spectroscopy to study biological macromolecules, metabolomics, natural products, dynamic systems, and other areas where resolution, sensitivity, or experiment time are limiting. Just as the development of multidimensional NMR methods presaged multidimensional methods in other areas of spectroscopy, we anticipate that nonuniform sampling approaches will find applications in other forms of spectroscopy

Empagliflozin in patients post myocardial infarction rationale and design of the EMPACT-MI trial

Background : Patients with acute myocardial infarction (MI) are at risk for developing heart failure (HF) and subsequently are at an increased risk of mortality. Sodium-glucose cotransporter-2 inhibitors have been proven to improve outcomes in patients with HF with reduced ejection fraction, and, in the case of empagliflozin, in HF with preserved ejection fraction even without diabetes, but their efficacy and safety in the post-MI population has not yet been evaluated. Methods : The EMPACT-MI trial will evaluate the safety and efficacy of empagliflozin compared with placebo in patients hospitalized for MI with or at high risk of new onset HF, in addition to standard care. EMPACT-MI is a streamlined, multinational, randomized, double-blind, placebo-controlled trial randomizing 5,000 participants at approximately 480 centers in 22 countries. Eligible patients presenting with spontaneous MI must have new signs or symptoms of pulmonary congestion requiring treatment or new left ventricular dysfunction (LVEF&lt;45%), and at least one additional risk factor for development of future HF. Eligible and consenting patients are randomized to empagliflozin 10mg or placebo daily in addition to standard of care within 14 days of hospital admission for MI. The primary composite endpoint is time to first hospitalization for HF or all-cause mortality. Conclusions : EMPACT-MI will inform clinical practice regarding the role of empagliflozin in patients after an MI with high risk for the development of future HF and mortality

Total Cardiovascular and Limb Events and the Impact of Polyvascular Disease in Chronic Symptomatic Peripheral Artery Disease

BACKGROUND: Peripheral artery disease (PAD) is associated with heightened risk for major adverse cardiovascular and limb events, but data on the burden of risk for total (first and potentially subsequent) events, and the association with polyvascular disease, are limited. This post hoc analysis of the EUCLID (Examining Use of Ticagrelor in Peripheral Artery Disease) trial evaluated total cardiovascular and limb events among patients with symptomatic PAD, overall and by number of symptomatic vascular territories.METHODS AND RESULTS: In the EUCLID trial, patients with symptomatic PAD (lower extremity revascularization >30 days before randomization or ankle-brachial index CONCLUSIONS: Patients with symptomatic PAD have nearly double the number of total events than first events, with rates reflecting the number of affected vascular territories. These findings highlight the clinical relevance of quantifying disease burden in terms of total events and the need for long-term preventive treatments in high-risk patient populations.</p

Baseline characteristics of patients enrolled in the EMPACT‐MI trial

Aims: Empagliflozin has been shown to reduce the risk of adverse cardiovascular outcomes in patients with type 2 diabetes and in those with heart failure. The impact of empagliflozin in post-acute myocardial infarction (AMI) patients is unknown. Methods and results: The Study to Test the Effect of Empagliflozin on Hospitalization for Heart Failure and Mortality in Patients with Acute Myocardial Infarction (EMPACT-MI) trial screened 6610 participants with AMI and randomized 6522 to empagliflozin or placebo in addition to standard of care. The median (interquartile) age was 64 (56–71) years and 75.1% of patients were male. Major comorbidities included hypertension (69.1%), type 2 diabetes (31.7%), prior myocardial infarction (13.0%), and atrial fibrillation (10.9%). The majority (74.3%) of patients presented with an ST-elevation myocardial infarction. Overall, 56.9% of patients had acute signs or symptoms of congestion requiring treatment and 78.3% had left ventricular systolic dysfunction with ejection fraction &lt;45%. Clinical characteristics, including baseline demographics, rates of revascularization, and cardiovascular medications at discharge were largely comparable to recent trials of the post-AMI population. Conclusion: The EMPACT-MI trial will establish the benefit and risks of empagliflozin treatment in patients with AMI