Karen Chiswell

Clinical outcomes of fractional flow reserve by computed tomographic angiography-guided diagnostic strategies vs. usual care in patients with suspected coronary artery disease: the prospective longitudinal trial of FFRCT: outcome and resource impacts study

Aims In symptomatic patients with suspected coronary artery disease (CAD), computed tomographic angiography (CTA) improves patient selection for invasive coronary angiography (ICA) compared with functional testing. The impact of measuring fractional flow reserve by CTA (FFRCT) is unknown. Methods and results At 11 sites, 584 patients with new onset chest pain were prospectively assigned to receive either usual testing (n = 287) or CTA/FFRCT (n = 297). Test interpretation and care decisions were made by the clinical care team. The primary endpoint was the percentage of those with planned ICA in whom no significant obstructive CAD (no stenosis ≥50% by core laboratory quantitative analysis or invasive FFR < 0.80) was found at ICA within 90 days. Secondary endpoints including death, myocardial infarction, and unplanned revascularization were independently and blindly adjudicated. Subjects averaged 61 ± 11 years of age, 40% were female, and the mean pre-test probability of obstructive CAD was 49 ± 17%. Among those with intended ICA (FFRCT-guided = 193; usual care = 187), no obstructive CAD was found at ICA in 24 (12%) in the CTA/FFRCT arm and 137 (73%) in the usual care arm (risk difference 61%, 95% confidence interval 53–69, P< 0.0001), with similar mean cumulative radiation exposure (9.9 vs. 9.4 mSv, P = 0.20). Invasive coronary angiography was cancelled in 61% after receiving CTA/FFRCT results. Among those with intended non-invasive testing, the rates of finding no obstructive CAD at ICA were 13% (CTA/FFRCT) and 6% (usual care; P = 0.95). Clinical event rates within 90 days were low in usual care and CTA/FFRCT arms. Conclusions Computed tomographic angiography/fractional flow reserve by CTA was a feasible and safe alternative to ICA and was associated with a significantly lower rate of invasive angiography showing no obstructive CAD.

Compliance with Results Reporting at ClinicalTrials.gov

BACKGROUND The Food and Drug Administration Amendments Act (FDAAA) mandates timely reporting of results of applicable clinical trials to ClinicalTrials.gov. We characterized the proportion of applicable clinical trials with publicly available results and determined independent factors associated with the reporting of results. METHODS Using an algorithm based on input from the National Library of Medicine, we identified trials that were likely to be subject to FDAAA provisions (highly likely applicable clinical trials, or HLACTs) from 2008 through 2013. We determined the proportion of HLACTs that reported results within the 12-month interval mandated by the FDAAA or at any time during the 5-year study period. We used regression models to examine characteristics associated with reporting at 12 months and throughout the 5-year study period. RESULTS From all the trials at ClinicalTrials.gov, we identified 13,327 HLACTs that were terminated or completed from January 1, 2008, through August 31, 2012. Of these trials, 77.4% were classified as drug trials. A total of 36.9% of the trials were phase 2 studies, and 23.4% were phase 3 studies; 65.6% were funded by industry. Only 13.4% of trials reported summary results within 12 months after trial completion, whereas 38.3% reported results at any time up to September 27, 2013. Timely reporting was independently associated with factors such as FDA oversight, a later trial phase, and industry funding. A sample review suggested that 45% of industry-funded trials were not required to report results, as compared with 6% of trials funded by the National Institutes of Health (NIH) and 9% of trials that were funded by other government or academic institutions. CONCLUSIONS Despite ethical and legal obligations to disclose findings promptly, most HLACTs did not report results to ClinicalTrials.gov in a timely fashion during the study period. Industry-funded trials adhered to legal obligations more often than did trials funded by the NIH or other government or academic institutions. (Funded by the Clinical Trials Transformation Initiative and the NIH.).

The PROTECT in-hospital risk model: 7-day outcome in patients hospitalized with acute heart failure and renal dysfunction

In patients with acute heart failure (AHF), early worsening heart failure (WHF) predicts a significant proportion of post‐discharge readmissions and mortality. We aimed to identify the predictors of 7‐day heart failure events or death in patients hospitalized with AHF.

Characteristics of Oncology Clinical Trials: Insights From a Systematic Analysis of ClinicalTrials.gov

IMPORTANCE Clinical trials are essential to cancer care, and data about the current state of research in oncology are needed to develop benchmarks and set the stage for improvement. OBJECTIVE To perform a comprehensive analysis of the national oncology clinical research portfolio. DESIGN All interventional clinical studies registered on ClinicalTrials.gov between October 2007 and September 2010 were identified using Medical Subject Heading terms and submitted conditions. They were reviewed to validate classification, subcategorized by cancer type, and stratified by design characteristics to facilitate comparison across cancer types and with other specialties. RESULTS Of 40 970 interventional studies registered between October 2007 and September 2010, a total of 8942 (21.8%) focused on oncology. Compared with other specialties, oncology trials were more likely to be single arm (62.3% vs 23.8%; P < .001), open label (87.8% vs 47.3%; P < .001), and nonrandomized (63.9% vs 22.7%; P < .001). There was moderate but significant correlation between number of trials conducted by cancer type and associated incidence and mortality (Spearman rank correlation coefficient, 0.56 [P = .04] and 0.77 [P = .001], respectively). More than one-third of all oncology trials were conducted solely outside North America. CONCLUSIONS AND RELEVANCE There are significant variations between clinical trials in oncology and other diseases, as well as among trials within oncology. The differences must be better understood to improve both the impact of cancer research on clinical practice and the use of constrained resources.

Predictors of Postdischarge Outcomes From Information Acquired Shortly After Admission for Acute Heart Failure A Report From the Placebo-Controlled Randomized Study of the Selective A1 Adenosine Receptor Antagonist Rolofylline for Patients Hospitalized With Acute Decompensated Heart Failure and Volume Overload to Assess Treatment Effect on Congestion and Renal Function (PROTECT) Study

Background —Acute heart failure (AHF) is a common reason for admission and outcome is often poor. Improved prognostic risk stratification may assist in the design of future trials and in patient management. Using data from a large randomized trial, we explored the prognostic value of clinical variables, measured at hospital admission for AHF, to determine whether a few selected variables were inferior to an extended data-set. Methods and Results —The prognostic model included 37 clinical characteristics collected at baseline in PROTECT, a study comparing rolofylline and placebo in 2,033 patients admitted with AHF. Pre-specified outcomes at 30 days were death or re-hospitalization for any reason, death or re-hospitalization for cardiovascular or renal reasons and, at both 30 and 180 days, all-cause mortality. No variable had a c-index >0.70 and few had values >0.60; c-indices were lower for composite outcomes than for mortality. Blood urea was generally the strongest single predictor. Eighteen variables contributed independent prognostic information but a reduced model using only eight items (age, prior heart failure hospitalization, peripheral edema, systolic blood pressure, serum sodium, urea, creatinine and albumin) performed similarly. For all-cause mortality at 180-days, the model C-index using all variables was 0.72 and for the simplified model, also 0.72. Conclusions —A few simple clinical variables measured on admission in patients with AHF predict a variety of adverse outcomes with similar accuracy to more complex models. However, predictive models were of only moderate accuracy, especially for outcomes that included non-fatal events. Better methods of risk-stratification are required. Clinical Trial Registration —URL: http://www.clinicaltrials.gov. Unique identifiers: [NCT00328692][1] and [NCT00354458][2]. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00328692&atom=%2Fcirchf%2Fearly%2F2013%2F11%2F26%2FCIRCHEARTFAILURE.113.000284.atom [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00354458&atom=%2Fcirchf%2Fearly%2F2013%2F11%2F26%2FCIRCHEARTFAILURE.113.000284.atom

The Relative Activity of 'Function Sparing' HIV-1 Entry Inhibitors on Viral Entry and CCR5 Internalization: Is Allosteric Functional Selectivity a Valuable Therapeutic Property?

Six allosteric HIV-1 entry inhibitor modulators of the chemokine (C-C motif) receptor 5 (CCR5) receptor are compared for their potency as inhibitors of HIV-1 entry [infection of human osteosarcoma (HOS) cells and peripheral blood mononuclear cells (PBMC)] and antagonists of chemokine (C-C motif) ligand 3-like 1 [CCL3L1]-mediated internalization of CCR5. This latter activity has been identified as a beneficial action of CCL3L1 in prolonging survival after HIV-1 infection ( Science307:1434-1440, 2005 ). The allosteric nature of these modulators was further confirmed with the finding of a 58-fold (HOS cells) and 282-fold (PBMC) difference in relative potency for blockade of CCL3L1-mediated internalization versus HIV-1 entry. For the CCR5 modulators, statistically significant differences in this ratio were found for maraviroc, vicriviroc, aplaviroc, Sch-C, TAK652, and TAK779. For instance, although TAK652 is 13-fold more potent as an HIV-1 inhibitor (over blockade of CCL3L1-mediated CCR5 internalization), this ratio of potency is reversed for Sch-C (22-fold more potent for CCR5-mediated internalization over HIV-1 entry). Quantitative analyses of the insurmountable antagonism of CCR5 internalization by these ligands suggest that all of them reduce the efficacy of CCL3L1 for CCR5 internalization. The relatively small magnitude of dextral displacement accompanying the depression of maximal responses for aplaviroc, maraviroc and vicriviroc suggests that these modulators have minimal effects on CCL3L1 affinity, although possible receptor reserve effects obscure complete interpretation of this effect. These data are discussed in terms of the possible benefits of sparing natural CCR5 chemokine function in HIV-1 entry inhibition treatment for AIDS involving allosteric inhibitors.

Clinical characteristics and outcomes of hospitalized heart failure patients with systolic dysfunction and chronic obstructive pulmonary disease: findings from OPTIMIZE‐HF

Chronic obstructive pulmonary disease (COPD) is common in heart failure (HF) patients, yet the population is poorly characterized and associated with conflicting outcomes data. We aimed to evaluate the clinical characteristics and outcomes of HF patients with systolic dysfunction and COPD in a large acute HF registry.

International differences in clinical characteristics, management, and outcomes in acute heart failure patients: better short-term outcomes in patients enrolled in Eastern Europe and Russia in the PROTECT trial

The implications of geographical variation are unknown following adjustment for hospital length of stay (LOS) in heart failure (HF) trials that included patients whether or not they had systolic dysfunction. We investigated regional differences in an international acute HF trial.

Predictors of Postdischarge Outcomes From Information Acquired Shortly After Admission for Acute Heart FailureClinical Perspective

Background —Acute heart failure (AHF) is a common reason for admission and outcome is often poor. Improved prognostic risk stratification may assist in the design of future trials and in patient management. Using data from a large randomized trial, we explored the prognostic value of clinical variables, measured at hospital admission for AHF, to determine whether a few selected variables were inferior to an extended data-set. Methods and Results —The prognostic model included 37 clinical characteristics collected at baseline in PROTECT, a study comparing rolofylline and placebo in 2,033 patients admitted with AHF. Pre-specified outcomes at 30 days were death or re-hospitalization for any reason, death or re-hospitalization for cardiovascular or renal reasons and, at both 30 and 180 days, all-cause mortality. No variable had a c-index >0.70 and few had values >0.60; c-indices were lower for composite outcomes than for mortality. Blood urea was generally the strongest single predictor. Eighteen variables contributed independent prognostic information but a reduced model using only eight items (age, prior heart failure hospitalization, peripheral edema, systolic blood pressure, serum sodium, urea, creatinine and albumin) performed similarly. For all-cause mortality at 180-days, the model C-index using all variables was 0.72 and for the simplified model, also 0.72. Conclusions —A few simple clinical variables measured on admission in patients with AHF predict a variety of adverse outcomes with similar accuracy to more complex models. However, predictive models were of only moderate accuracy, especially for outcomes that included non-fatal events. Better methods of risk-stratification are required. Clinical Trial Registration —URL: http://www.clinicaltrials.gov. Unique identifiers: [NCT00328692][1] and [NCT00354458][2]. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00328692&atom=%2Fcirchf%2Fearly%2F2013%2F11%2F26%2FCIRCHEARTFAILURE.113.000284.atom [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00354458&atom=%2Fcirchf%2Fearly%2F2013%2F11%2F26%2FCIRCHEARTFAILURE.113.000284.atom

The Database for Aggregate Analysis of ClinicalTrials.gov (AACT) and Subsequent Regrouping by Clinical Specialty

Background The ClinicalTrials.gov registry provides information regarding characteristics of past, current, and planned clinical studies to patients, clinicians, and researchers; in addition, registry data are available for bulk download. However, issues related to data structure, nomenclature, and changes in data collection over time present challenges to the aggregate analysis and interpretation of these data in general and to the analysis of trials according to clinical specialty in particular. Improving usability of these data could enhance the utility of ClinicalTrials.gov as a research resource. Methods/Principal Results The purpose of our project was twofold. First, we sought to extend the usability of ClinicalTrials.gov for research purposes by developing a database for aggregate analysis of ClinicalTrials.gov (AACT) that contains data from the 96,346 clinical trials registered as of September 27, 2010. Second, we developed and validated a methodology for annotating studies by clinical specialty, using a custom taxonomy employing Medical Subject Heading (MeSH) terms applied by an NLM algorithm, as well as MeSH terms and other disease condition terms provided by study sponsors. Clinical specialists reviewed and annotated MeSH and non-MeSH disease condition terms, and an algorithm was created to classify studies into clinical specialties based on both MeSH and non-MeSH annotations. False positives and false negatives were evaluated by comparing algorithmic classification with manual classification for three specialties. Conclusions/Significance The resulting AACT database features study design attributes parsed into discrete fields, integrated metadata, and an integrated MeSH thesaurus, and is available for download as Oracle extracts (.dmp file and text format). This publicly-accessible dataset will facilitate analysis of studies and permit detailed characterization and analysis of the U.S. clinical trials enterprise as a whole. In addition, the methodology we present for creating specialty datasets may facilitate other efforts to analyze studies by specialty groups.