Why do not we talk about MIS fellowship? A short review of the short literature.

BACKGROUND: The minimally invasive surgery (MIS) fellowship has existed for three decades and has steadily grown in both number of positions available and variety of techniques practiced. Despite continued popularity, growth, and wide breadth of surgical techniques of the MIS fellowship, publication rates in medical journals regarding these fellowships have not been as robust as one may expect. Our goal was to review the available literature on MIS fellowship. METHODS: We reviewed PubMed to search for articles pertinent for MIS fellowship. The initial search included "MIS fellowship" "minimally invasive surgery fellowship" and "laparoscopy fellowship." Articles pertaining to MIS fellowship were then reviewed by title and abstract for content. Articles were excluded from subsequent analysis if they focused on disciplines that were not direct extensions of general surgery (such as urology, gynecology, oncology). Using similar search techniques, we tabulated unfiltered publications rates specific to other major surgical fellowship disciplines. The metric articles per position was created by dividing the total number articles for each discipline by the annual fellowship positions RESULTS: An initial review of available literature produced 134 articles pertinent to MIS fellowship. Further analysis for direct relevance to MIS yielded only 58 published articles. MIS had the fewest number of publications and smallest APP, 0.7, of any of the major fellowship disciplines. CONCLUSIONS: There is a surprising dearth of material on MIS fellowship. While, MIS fellowship is a one-year experience, we have the opportunity to build on three decades of clinical experience to continue optimize the fellow experience and improve subspecialized surgical training and patient outcomes. This could be facilitated through broadened focus of inquiry and publication of findings.

Society for cardiovascular magnetic resonance recommendations for training and competency of CMR technologists.

The Society for Cardiovascular Magnetic Resonance (SCMR) recommendations for training and competency of cardiovascular magnetic resonance (CMR) technologists document will define the knowledge, experiences and skills required for a technologist to be competent in CMR imaging. By providing a framework for CMR training and competency the overarching goal is to promote the performance of high-quality CMR and to foster the increased adoption of CMR into clinical care.

Society for Cardiovascular Magnetic Resonance (SCMR) guidance for the practice of cardiovascular magnetic resonance during the COVID-19 pandemic.

The aim of this document is to provide general guidance and specific recommendations on the practice of cardiovascular magnetic resonance (CMR) in the era of the COVID-19 pandemic. There are two major considerations. First, continued urgent and semi-urgent care for the patients who have no known active COVID-19 should be provided in a safe manner for both patients and staff. Second, when necessary, CMR on patients with confirmed or suspected active COVID-19 should focus on the specific clinical question with an emphasis on myocardial function and tissue characterization while optimizing patient and staff safety.

Aminophylline shortage and current recommendations for reversal of vasodilator stress: An ASNC information statement endorsed by SCMR.

Pharmacologic reversal of serious or intolerable side effects (SISEs) from vasodilator stress is an important safety and comfort measure for patients experiencing such effects. While typically performed using intravenous aminophylline, recurrent shortages of this agent have led to a greater need to limit its use and consider alternative agents. This information statement provides background and recommendations addressing indications for vasodilator reversal, timing of a reversal agent, incidence of observed SISE with vasodilator stress, clinical and logistical considerations for aminophylline-based reversal, and alternative non-aminophylline based reversal protocols.

Aminophylline shortage and current recommendations for reversal of vasodilator stress: an ASNC information statement endorsed by SCMR.

Pharmacologic reversal of serious or intolerable side effects (SISE) from vasodilator stress is an important safety and comfort measure for patients experiencing such effects. While typically performed using intravenous aminophylline, recurrent shortages of this agent have led to a greater need to limit its use and consider alternative agents. This information statement provides background and recommendations addressing indications for vasodilator reversal, timing of a reversal agent, incidence of observed SISE with vasodilator stress, clinical and logistical considerations for aminophylline-based reversal, and alternative non-aminophylline based reversal protocols.

Prevalence and prognosis of unrecognized myocardial infarction determined by cardiac magnetic resonance in older adults.

CONTEXT: Unrecognized myocardial infarction (MI) is prognostically important. Electrocardiography (ECG) has limited sensitivity for detecting unrecognized MI (UMI). OBJECTIVE: Determine prevalence and mortality risk for UMI detected by cardiac magnetic resonance (CMR) imaging or ECG among older individuals. DESIGN, SETTING, AND PARTICIPANTS: ICELAND MI is a cohort substudy of the Age, Gene/Environment Susceptibility-Reykjavik Study (enrollment January 2004-January 2007) using ECG or CMR to detect UMI. From a community-dwelling cohort of older individuals in Iceland, data for 936 participants aged 67 to 93 years were analyzed, including 670 who were randomly selected and 266 with diabetes. MAIN OUTCOME MEASURES: Prevalence and mortality of MI through September 1, 2011. Results reported with 95% confidence limits and net reclassification improvement (NRI). RESULTS: Of 936 participants, 91 had recognized MI (RMI) (9.7%; 95% CI, 8% to 12%), and 157 had UMI detected by CMR (17%; 95% CI, 14% to 19%), which was more prevalent than the 46 UMI detected by ECG (5%; 95% CI, 4% to 6%; P < .001). Participants with diabetes (n = 337) had more UMI detected by CMR than by ECG (n = 72; 21%; 95% CI, 17% to 26%, vs n = 15; 4%; 95% CI, 2% to 7%; P < .001). Unrecognized MI by CMR was associated with atherosclerosis risk factors, coronary calcium, coronary revascularization, and peripheral vascular disease. Over a median of 6.4 years, 30 of 91 participants (33%; 95% CI, 23% to 43%) with RMI died, and 44 of 157 participants (28%; 95% CI, 21% to 35%) with UMI died, both higher rates than the 119 of 688 participants (17%; 95% CI, 15% to 20%) with no MI who died. Unrecognized MI by CMR improved risk stratification for mortality over RMI (NRI, 0.34; 95% CI, 0.16 to 0.53). Adjusting for age, sex, diabetes, and RMI, UMI by CMR remained associated with mortality (hazard ratio [HR], 1.45; 95% CI, 1.02 to 2.06, absolute risk increase [ARI], 8%) and significantly improved risk stratification for mortality (NRI, 0.16; 95% CI, 0.01 to 0.31), but UMI by ECG did not (HR, 0.88; 95% CI, 0.45 to 1.73; ARI, -2%; NRI, -0.05; 95% CI, -0.17 to 0.05). Compared with those with RMI, participants with UMI by CMR used cardiac medications such as statins less often (36%; 95% CI, 28% to 43%, or 56/157, vs 73%; 95% CI, 63% to 82%, or 66/91; P < .001). CONCLUSIONS: In a community-based cohort of older individuals, the prevalence of UMI by CMR was higher than the prevalence of RMI and was associated with increased mortality risk. In contrast, UMI by ECG prevalence was lower than that of RMI and was not associated with increased mortality risk. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01322568.

The Future of Cardiac Magnetic Resonance Clinical Trials.

Over the past 2 decades, cardiac magnetic resonance (CMR) has become an essential component of cardiovascular clinical care and contributed to imaging-guided diagnosis and management of coronary artery disease, cardiomyopathy, congenital heart disease, cardio-oncology, valvular, and vascular disease, amongst others. The widespread availability, safety, and capability of CMR to provide corresponding anatomical, physiological, and functional data in 1 imaging session can improve the design and conduct of clinical trials through both a reduction of sample size and provision of important mechanistic data that may augment clinical trial findings. Moreover, prospective imaging-guided strategies using CMR can enhance safety, efficacy, and cost-effectiveness of cardiovascular pathways in clinical practice around the world. As the future of large-scale clinical trial design evolves to integrate personalized medicine, cost-effectiveness, and mechanistic insights of novel therapies, the integration of CMR will continue to play a critical role. In this document, the attributes, limitations, and challenges of CMR's integration into the future design and conduct of clinical trials will also be covered, and recommendations for trialists will be explored. Several prominent examples of clinical trials that test the efficacy of CMR-imaging guided pathways will also be discussed.

Early implementation of Fundamentals of Endoscopic Surgery training using a simulation-based mastery learning curriculum.

BACKGROUND: After the American Board of Surgery announcement of the Flexible Endoscopy Curriculum requirement in 2014, we implemented a dedicated endoscopy rotation at the post graduate year (PGY)2 level including a simulation curriculum for Fundamentals of Endoscopic Surgery skills. Here we evaluate the outcomes of this implementation. METHODS: Beginning in 2015, we developed a clinical endoscopy and simulation-based rotation to prepare for Fundamentals of Endoscopic Surgery testing. Originally, our curriculum was based on the published Texas Association of Surgical Skills Laboratories curriculum using the GI Mentor and transitioned to a mastery learning curriculum using the Endoscopy Training System in 2016. We evaluated the success of the curriculum in terms of first-time pass rates, training time required, and comparison to previously published benchmarks based on clinical experience. RESULTS: Since 2015, a total of 37 general surgery residents in our program were Fundamentals of Endoscopic Surgery tested (PGY2 = 24, PGY3 = 4, PGY5 = 9); 84% (31) completed the Endoscopy Training System curriculum. At the time of testing, 73% (27) had performed <25 esophagogastroduodenoscopies, and 46% had performed <25 colonoscopies. Ninety-two percent (34) spent 10 hours or less completing the curriculum. The first-time pass rate for those completing the Endoscopy Training System curriculum was 97% vs 67% for those not completing the Endoscopy Training System curriculum (P = .01). For residents completing the Endoscopy Training System curriculum, total Fundamentals of Endoscopic Surgery scores were discernibly higher (472 vs 389, P < .01), as were 3/5 task scores (Nav1 80 vs 67, P = .02; Loop2 36 vs 8, P = .02; Retro3 89 vs 71, P = .02). Despite clinical inexperience (<25 esophagogastroduodenoscopies and <50 colonoscopies), PGY2s yielded a mean score of 454 and a pass rate of 92%. This was similar to PGY5s (427, 89%; P = .3) and compares to benchmark data of endoscopists with >300 cases. CONCLUSION: Early implementation of flexible endoscopy training with a simulation-based curriculum results in Fundamentals of Endoscopic Surgery performance equal to a clinical experience not often gained during surgical residency. Often requiring <10 hours, this represents a fantastic return on investment for this training.

Piloting the FIRE: A Novel Error Management Training Simulation Curriculum for Fasciotomy Instruction.

BACKGROUND: Multiple studies have demonstrated poor performance of lower extremity fasciotomy (LEF), highlighted by missed and/or inadequately released compartments. Incorporating error management training (EMT) into surgical simulation has been promoted as a way to gain deeper understanding of procedural errors and overall performance. The purpose of this study was to evaluate LEF performance using a Fasciotomy Improvement through Recognition of Errors (FIRE) simulation training curriculum to train novice surgical trainees. METHODS: A mastery learning-based EMT curriculum was developed, and surgical residents were enrolled and pretested with a multiple-choice question (MCQ) written test, and a simulated fasciotomy using a lower leg model. Each trainee then watched a 15-minute narrated presentation followed by 2 rounds of fasciotomy error recognition and management training exercises to a mastery standard. During each round, trainees performed hands-on assessment of unique premade fasciotomy leg models containing a variable number of procedural errors. They were required to identify and propose corrective action for all errors. Serial rounds of remediation were implemented until the mastery standard was attained on both error identification rounds. All trainees were post-tested with the same MCQ and another simulated fasciotomy. RESULTS: All 14 residents had minimal experience with only 0.3 ± 0.6 fasciotomies performed prior to instruction. There were 3 ± 1.6 missed or inadequately released compartments on the pretest. Residents examined 14 ± 2.5 legs, including 2 ± 2.5 legs during remediation to attain mastery. All residents demonstrated significant improvement following the FIRE of Error curriculum for the MCQ (57% ± 16% vs 78% ± 13%; p = 0.01; Cohen's d = 1.4), fasciotomy score (10 ± 7.1 vs 28 ± 1.9; p < 0.001; Cohen's d = 3.6), and achieving a complete fasciotomy (14% ± 36% vs 93% ± 27%; p < 0.001; Cohen's d = 2.5). Only a single cumulative compartment was missed on post-testing. CONCLUSIONS: Implementation of a mastery learning-based EMT curriculum for fasciotomy simulation training results in significant improvement in fasciotomy technique without reliance on repeated procedure performance nor clinical fasciotomy exposure. This curriculum is a highly effective option for surgical trainees lacking fasciotomy training during residency.

Fact or Fiction? Practice on a Simulator is Not Required to Pass the Fundamentals of Endoscopic Surgery (FES)TM Skills Exam.

PURPOSE: Initial work on the validity evidence used to support the Fundamentals of Endoscopic Surgery (FES) performance exam as a measure of technical competency showed a strong relationship to clinical experience. Despite this evidence, there is a perception among some program directors that the exam cannot be successfully passed without practice on a simulator. We assess the validity of this perception. METHODS: Deidentified data from the initial FES skills examination (prior to the 2014 FEC requirement) was reviewed, and 335 unique participants with reported simulation experience demographics were identified. Self reported data analyzed included gender, total clinical endoscopy procedure experience (1-150, 151-300, >300), and endoscopy simulator training hours (0, 1-5, 6-10, 11-20, >20). Final FES skills exam scores, and pass/fail designations for each participant were reported by the FES program staff. Continuous variables were compared between groups using one-way analysis of variance with post-hoc analysis where appropriate. Categorical variables were compared using Pearson Chi-Squared. The effect of variables on pass rate was assessed using univariate and multivariate logistic regression. RESULTS: Simulation training experience (SE) was categorically reported in hours(n,%): 0 (98, 29%), 1-5 (135, 40%), 6-10 (52, 16%), 11-20 (24, 7%), and >20 (26, 8%). Clinical endoscopy experience (CE), reported categorically as total cases performed (n,%), was available for 323 of 355 identified participants: 1-150 (126, 39%), 151-300 (99, 31%), >300 (98, 30%). There was no statistically discernible differences in mean FES total or task scores across the SE groups (total score 0:72 ± 15, 1-5:72 ± 13, 6-10:71 ± 14, 11-20:71 ± 16, 20:78 ± 13; p = 0.28), while both total score and task scores were discernibly higher in the more experienced CE groups (>151) compared to the least experienced group (total score; <150:67 ± 15, 151-300:75 ± 1, >300:77 ± 14; p < 0.01). Similarly, there was no statistically discernible difference in FES skills exam pass rates between SE groups (0: 80%, 1-5: 82%, 6-10: 79%, 11-20: 75%, >20: 85%; x2 = 2.5, p = 0.6), but there was a strong relationship between clinical experience and pass rate (<150: 70%, 151-300: 87%, >300: 89%; x2 = 15.8, p < 0.001). Finally, on both univariate and multivariate logistic regression, CE remained a discernible predictor of passing, even when controlling for SE (odds ratio = 2, 95% confidence interval 1.4-2.9, p < 0.001). CONCLUSIONS: FES skills examination data collected on participants completing the examination before the FEC requirement shows no demonstrable relationship with self-reported training experience on a simulator but confirms a strong relationship with clinical endoscopy experience. This lends further evidence to the validity of the FES exam as a marker of clinical endoscopic skill.

Incisional hernia incidence following laparotomy for combat trauma: Investigating 15 years of US war surgery.

BACKGROUND: While the incidence of incisional hernia (IH) following elective laparotomy has been well described, incidence following emergent laparotomy for combat trauma has been much less studied. This retrospective cohort investigates the latter to better describe the burden IH represents for the injured warfighter. METHODS: Data were obtained from the Expeditionary Medical Encounter Database for service members who survived a combat-related injury between January 2002 and December 2016 and underwent abdominal surgery in the first 30 days after injury. Incisional hernia diagnosis at least 30 days after injury was determined from inpatient and outpatient records in the Military Health System's Medical Data Repository.Means and SDs were reported for age and continuous Injury Severity Score, and frequency and percentages were reported for sex, branch of service, paygrade, mechanism of injury, Injury Severity Score, and maximum abdominal Abbreviated Injury Scale. Service members with and without a hernia diagnosis were compared using t test for continuous variables and χ or Fisher exact test (depending on cell size) for categorical variables.Multivariate logistic regression models were used to examine relationships between IH diagnosis and the covariates previously mentioned. Data analysis was completed using SAS software version 9.4 (SAS Institute Inc., Cary, NC). RESULTS: Of the 570 laparotomy patients, 109 (19.1%) developed IH. Of these, 58 (53%) were diagnosed within the first year after injury. An additional 21 (19%) were diagnosed within the following year, and 30 (28%) were diagnosed more than 2 years after injury. Presence of gastrointestinal injury, Abbreviated Injury Scale score of 4 and 5, and 5-year increments of age were positively associated with hernia formation. CONCLUSION: The incidence of postlaparotomy IH in combat trauma is 19.1%, a considerable source of disability for injured warfighters. Further investigation into hernia-preventive closure strategies is warranted. LEVEL OF EVIDENCE: Therapeutic study, level IV.

Fundamentals of Anorectal Technical Skills: A Concise Surgical Skills Course.

INTRODUCTION: Anorectal diseases, among the most common surgical conditions, are underrepresented in medical training. The Fundamentals of Anorectal Technical Skills course was developed to provide cost-effective formal training in diagnosis of common anorectal conditions and in commonly performed anorectal procedures using the theories of deliberative practice and perceptual and adaptive learning. MATERIALS AND METHODS: First- through third-year general surgery and internal medicine residents and third- and fourth-year medical students participated in a course consisting of didactic instruction and hands on skills stations. The course covered common anorectal conditions, including internal and external hemorrhoids, fissures, condylomata, abscesses, fistula-in-ano, rectal prolapse, pilonidal disease, pruritis ani, and anal and rectal cancer, as well as common procedures such as anoscopy, excision of thrombosed external hemorrhoids, banding of internal hemorrhoids, rigid proctoscopy, incision and drainage of an abscess, administration of local anesthesia, and reduction of rectal prolapse. Before the course, participants completed a questionnaire consisting of demographics; previous anorectal experience, as measured by procedural case volume; confidence diagnosing and treating anorectal conditions; and a clinical knowledge multiple-choice quiz. Immediately following the course, participants took an additional survey reassessing their confidence and testing their clinical knowledge. This study was granted an educational exception by the Institutional Review Board at Walter Reed National Military Medical Center. RESULTS: Forty-three learners participated in this course. Forty-six percent of participants had not participated in any anorectal cases, 26% had participated in 1 to 5 cases, 17% had participated in 6 to 10 cases, 6% had been involved with 11 to15 cases, and 6% had been involved with more than 15 cases. For learners who had no prior experience, 1 to 5 prior cases, or 6 to 10 cases, there were statistically and educationally significant increases in confidence for all diagnoses and procedures. Additionally, there were statistically and educationally significant increases between pre-course and post-course quiz scores for learners who had no prior experience (7.8 ± 2.0 vs. 11.8 ± 2.5, P < 0.01, Cohen's d = 1.8) and for those who had only participated in 1 to 5 cases (11.0 ± 3.7 vs. 14.2 ± 2.0, P = 0.04, Cohen's d = 1.1). The changes in quiz scores for learners who previously had been involved with six or more cases were not statistically significant. CONCLUSION: This course provides a cost-effective training that significantly boosts learners' confidence in diagnosis of common anorectal procedures and confidence in performance of common anorectal procedures, in addition to improving objectively measured anorectal clinical knowledge.

Phase 1b randomized study of antidote-controlled modulation of factor IXa activity in patients with stable coronary artery disease.

BACKGROUND: Whether selective factor IXa inhibition produces an appropriate anticoagulant effect when combined with platelet-directed therapy in patients with stable coronary artery disease is unknown. REG1 consists of RB006 (drug), an injectable RNA aptamer that specifically binds and inhibits factor IXa, and RB007 (antidote), the complementary oligonucleotide that neutralizes its anti-IXa activity. METHODS AND RESULTS: We evaluated the safety, tolerability, and pharmacodynamic profile of REG1 in a randomized, double-blind, placebo-controlled study, assigning 50 subjects with coronary artery disease taking aspirin and/or clopidogrel to 4 dose levels of RB006 (15, 30, 50, and 75 mg) and RB007 (30, 60, 100, and 150 mg). The median age was 61 years (25th and 75th percentiles, 56 and 68 years), and 80% of patients were male. RB006 increased the activated partial thromboplastin time dose dependently; the median activated partial thromboplastin time at 10 minutes after a single intravenous bolus of 15, 30, 50, and 75 mg RB006 was 29.2 seconds (25th and 75th percentiles, 28.1 and 29.8 seconds), 34.6 seconds (25th and 75th percentiles, 30.9 and 40.0 seconds), 46.9 seconds (25th and 75th percentiles, 40.3 and 51.1 seconds), and 52.2 seconds (25th and 75th percentiles, 46.3 and 58.6) (P<0.0001; normal 25th and 75th percentiles, 27 and 40 seconds). RB007 reversed the activated partial thromboplastin time to baseline levels within a median of 1 minute (25th and 75th percentiles, 1 and 2 minutes) with no rebound increase through 7 days. No major bleeding or other serious adverse events occurred. CONCLUSIONS: This is the first experience of an RNA aptamer drug-antidote pair achieving inhibition and active restoration of factor IXa activity in combination with platelet-directed therapy in stable coronary artery disease. The preliminary clinical safety and predictable pharmacodynamic effects form the basis for ongoing studies in patients undergoing elective revascularization procedures.

Association of Unrecognized Myocardial Infarction With Long-term Outcomes in Community-Dwelling Older Adults: The ICELAND MI Study.

Importance: Cardiac magnetic resonance (CMR) imaging can identify unrecognized myocardial infarction (UMI) in the general population. Unrecognized myocardial infarction by CMR portends poor prognosis in the short term but, to our knowledge, long-term outcomes are not known. Objective: To determine the long-term outcomes of UMI by CMR compared with clinically recognized myocardial infarction (RMI) and no myocardial infarction (MI). Design, Setting, and Participants: Participants of the population-based, prospectively enrolled ICELAND MI cohort study (aged 67-93 years) were characterized with CMR at baseline (from January 2004-January 2007) and followed up for up to 13.3 years. Kaplan-Meier time-to-event analyses and a Cox regression were used to assess the association of UMI at baseline with death and future cardiovascular events. Main Outcomes and Measures: The primary outcome was all-cause mortality. Secondary outcomes were a composite of major adverse cardiac events (MACE: death, nonfatal MI, and heart failure). Results: Of 935 participants, 452 (48.3%) were men; the mean (SD) age of participants with no MI, UMI, and RMI was 75.6 (5.3) years, 76.8 (5.2) years, and 76.8 (4.7) years, respectively. At 3 years, UMI and no MI mortality rates were similar (3%) and lower than RMI rates (9%). At 5 years, UMI mortality rates (13%) increased and were higher than no MI rates (8%) but still lower than RMI rates (19%). By 10 years, UMI and RMI mortality rates (49% and 51%, respectively) were not statistically different; both were significantly higher than no MI (30%) (P < .001). After adjusting for age, sex, and diabetes, UMI by CMR had an increased risk of death (hazard ratio [HR], 1.61; 95% CI, 1.27-2.04), MACE (HR, 1.56; 95% CI, 1.26-1.93), MI (HR, 2.09; 95% CI, 1.45-3.03), and heart failure (HR, 1.52; 95% CI, 1.09-2.14) compared with no MI and statistically nondifferent risk of death (HR, 0.99; 95% CI, 0.71-1.38) and MACE (HR, 1.23; 95% CI, 0.91-1.66) vs RMI. Conclusions and Relevance: In this study, all-cause mortality of UMI was higher than no MI, but within 10 years from baseline evaluation was equivalent with RMI. Unrecognized MI was also associated with an elevated risk of nonfatal MI and heart failure. Whether secondary prevention can alter the prognosis of UMI will require prospective testing.

First-in-human experience of an antidote-controlled anticoagulant using RNA aptamer technology: a phase 1a pharmacodynamic evaluation of a drug-antidote pair for the controlled regulation of factor IXa activity.

BACKGROUND: Selectivity, titratability, rapidity of onset, and active reversibility are desirable pharmacological properties of anticoagulant therapy administered for acute indications and collectively represent an attractive platform to maximize patient safety. A novel anticoagulation system (REG1, Regado Biosciences), developed using a protein-binding oligonucleotide to factor IXa (drug, RB006) and its complementary oligonucleotide antidote (RB007), was evaluated in healthy volunteers. The primary objective was to determine the safety profile and to characterize the pharmacodynamic responses in this first-in-human study. METHODS AND RESULTS: Regado 1a was a subject-blinded, dose-escalation, placebo-controlled study that randomized 85 healthy volunteers to receive a bolus of drug or placebo followed 3 hours later by a bolus of antidote or placebo. Pharmacodynamic samples were collected serially. Subject characteristics were the following: median age, 32 years (interquartile range, 23 to 39 years); female gender, 35%; and median weight, 79 kg (interquartile range, 70 to 87 kg). No significant differences were found in median hemoglobin, platelet, creatinine, or liver function studies. There were no significant bleeding signals associated with RB006, and overall, both drug and antidote were well tolerated. One serious adverse event, an episode of transient encephalopathy, occurred in a subject receiving the low intermediate dose of RB006. The subject's symptoms resolved rapidly, and no further sequelae occurred. A predictable dose-pharmacodynamic response, reflected in activated partial thromboplastin time measurements, was seen after administration of the bolus of drug, with a clear correlation between the peak posttreatment activated partial thromboplastin time and post hoc weight-adjusted dose of drug (correlation coefficient, 0.725; P<0.001). In subjects treated with drug, antidote administration reversed the pharmacological activity of the drug, with a rapid (mean time, 1 to 5 minutes across all dose levels) and sustained return of activated partial thromboplastin time to within the normal range. The activated clotting time followed a similar anticoagulant response and reversal pattern. As anticipated, prothrombin time remained unchanged compared with baseline. CONCLUSIONS: These observations represent a first-in-human experience of an RNA aptamer and its complementary oligonucleotide antidote used as an anticoagulant system. The findings contribute to an emerging platform of selective, actively reversible anticoagulant drugs for use among patients with thrombotic disorders of the venous and arterial circulations.

Age-related vascular stiffness and left ventricular size after myocardial infarction.

Aortic stiffness increases with age and may contribute to adverse remodeling after myocardial infarction (MI). The authors examined whether vascular stiffness affects left ventricular (LV) size after MI using contrast-enhanced cardiac magnetic resonance imaging. Despite similar infarct sizes, patients aged 60 years or older (n=30) had a lower ejection fraction (42+/-15 vs 53+/-11%, P<.01) and greater end-systolic volume index (75+/-47 vs 44+/-18 mL/m(2), P<.01) than younger patients (n=19). As infarct size increased, LV end-systolic volumes (P<.0001) and ejection fraction (P<.0001) in the older participants were progressively greater. Participants with greater aortic stiffness had greater end-systolic volume indices (P<.0001) and lower ejection fraction (P<.0001) with increasing infarct size. Using multivariate analysis, MI size (P<.001) and aortic distensibility (P=.02) were significant predictors of end-systolic volume index. Older patients have increased LV size after MI compared with younger patients, possibly related to age-related decreases in aortic distensibility affecting LV remodeling.

First experience with direct factor Xa inhibition in patients with stable coronary disease: a pharmacokinetic and pharmacodynamic evaluation.

BACKGROUND: Thrombin generation is critical to the formation of an arterial thrombus after rupture of an atherosclerotic plaque. In patients with stable coronary disease receiving standard medical therapy, we evaluated the pharmacokinetics, pharmacodynamics, and safety profile of DX-9065a, a novel small-molecule anticoagulant that directly, selectively, and reversibly inhibits factor Xa. METHODS AND RESULTS: In a double-blind trial, 73 patients (median age, 63 years; 29% women) were randomly assigned to receive a fixed-dose intravenous bolus, followed by a 72-hour infusion of placebo or 1 of 4 weight-adjusted regimens of DX-9065a. Plasma samples were collected during infusion and a 24-hour elimination period. Only minor bleeding occurred, predominantly ecchymoses at infusion sites, and its incidence did not differ significantly among the groups, including placebo. Median hemoglobin, platelet count, serum creatinine level, and liver function tests did not change significantly from baseline during infusion or elimination. Significant predictors of pharmacokinetic response included infusion dose and weight. At 60 hours into the DX-9065a infusion, plasma drug levels correlated strongly with anti-factor Xa activity (r=0.97), prothrombin time (r=0.77), and international normalized ratio (r=0.72) but less so with activated partial thromboplastin time (r=0.56; all P<0.001). CONCLUSIONS: This is the first study of a selective, reversible, and direct small-molecule factor Xa inhibitor in patients with stable coronary disease. These data lay the foundation for further investigation of factor Xa inhibitors in the treatment of patients with coronary atherothrombosis.

Misreporting of myocardial infarction end points: results of adjudication by a central clinical events committee in the PARAGON-B trial. Second Platelet IIb/IIIa Antagonist for the Reduction of Acute Coronary Syndrome Events in a Global Organization Network Trial.

BACKGROUND: Myocardial (re)infarction (MI), a common trial end point, can be difficult to identify because of inconclusive signs and symptoms. We examined disagreement between investigator and clinical events committee (CEC) reporting of MIs in an international, randomized trial. METHODS: The primary end point of the PARAGON-B trial was a 30-day composite of death, MI (CEC adjudicated), or ischemia-driven intervention. If CEC and investigator determinations of MI differed, we sent investigators event summaries and rationales for CEC decisions and asked whether they now agreed with the CEC assessment. If they still disagreed, they were to provide a rationale and supporting data. Such cases were reviewed, and a final decision was made. RESULTS: Overall, 1736 of 5225 (33%) patients had suspected MIs; the CEC adjudicated 483 of 1736 (28%) as MIs. In 404 patients (23%), investigator and CEC assessments of MI differed; 270 MIs were identified by the CEC but not investigators, and 134 were identified by investigators but not the CEC. Most disagreements concerned periprocedural MIs, but some reflected clinical ischemia and enzyme elevations. Letters for 382 disagreements were sent and returned by investigators, and investigators came to agree with CEC assessments in 307 cases (80%). For the other 75 cases (20%), after review the investigators' assessments were confirmed in 10 cases, and the original CEC decisions were supported in the other 65 cases. CONCLUSIONS: Investigators misreport MI end points, but most later agree with CEC assessments. These data support standard, independent adjudication of suspected MIs for accurate reporting, which may affect evaluations of therapies, sample-size calculations, and event-rate comparisons across trials.

Promise of combined low-molecular-weight heparin and platelet glycoprotein IIb/IIIa inhibition: results from Platelet IIb/IIIa Antagonist for the Reduction of Acute coronary syndrome events in a Global Organization Network B (PARAGON B).

BACKGROUND: Low-molecular-weight heparin (LMWH) has a more predictable anticoagulant effect than unfractionated heparin (UFH), is easier to administer, and does not require monitoring. Minimal data are available on LMWH combined with platelet glycoprotein (GP) IIb/IIIa inhibitors. METHODS: In the Platelet IIb/IIIa Antagonist for the Reduction of Acute Coronary Syndrome Events in a Global Organization Network B (PARAGON B) trial, patients with an acute coronary syndrome were randomized to receive the IIb/IIIa inhibitor lamifiban or a placebo. To rigorously explore the potential benefits of LWMH and GP IIb/IIIa inhibition, we analyzed the rates of ischemic complications and safety outcomes in PARAGON B. RESULTS: Approximately one fifth of the patients received LMWH (805 vs 4395 UFH). For the overall cohort, the incidence of death/myocardial infarction (MI)/severe recurrent ischemia (SRI) was 12.2%, and this composite end point was numerically lowest in the lamifiban with LMWH group (10.2%). Similarly, the incidence of death/MI was 11.0% for the entire cohort and lowest in the lamifiban and LMWH group (9.0%). The lower event rate for patients taking LMWH in the lamifiban group was sustained at 6 months, with a lower revascularization rate (51.5% vs 42.8%) and a lower composite of death/MI (13.8% vs 11.9%). Bleeding was comparable in the 2 heparin groups (1.4% with UFH vs 0.9% with LMWH). The propensity adjusted odds ratio for 30-day revascularization was significantly lower with LMWH (odds ratio 0.67, 95% CI 0.57-0.79, P <.001). There were no significant differences in death/MI/SRI at 30 days (P =.465), death/MI at 30 days (P =.264), and stroke at 30 days with the type of heparin use (P =.201) after propensity risk adjustment. CONCLUSIONS: In the PARAGON B trial, use of LMWH in conjunction with a GP IIb/IIIa inhibitor was safe and associated with a lower revascularization rate. These findings support the rationale and promise for combining GP IIb/IIIa blockers and LMWH for future management of acute coronary syndrome.