Debra Egan

Roles of Infectious Agents in Atherosclerosis and Restenosis An Assessment of the Evidence and Need for Future Research

The past few years have witnessed a resurgence of interest in the possibility that infectious processes may contribute to arterial diseases, including atherosclerosis and restenosis after arterial intervention. The recent recognition that Helicobacter pylori contributes to peptic ulcers illustrates how a disease previously believed to result primarily from excessive gastric acid production often involves a microbial pathogen. Although hypercholesterolemia clearly predisposes to development of coronary heart disease, many patients with arterial pathology have serum cholesterol levels within or below the average range. Coronary heart disease frequently affects individuals who lack other traditional risk factors as well. These findings suggest that heretofore unrecognized risk factors may also contribute to the pathogenesis of coronary heart disease. At a recent Special Emphasis Panel convened by the National Heart, Lung, and Blood Institute, a number of experts reviewed the evidence for links between infectious processes and atherosclerosis and restenosis. This report will summarize and examine critically the evidence for involvement of infectious agents in arterial diseases based on the deliberations of this expert panel. It will also highlight some of the unanswered questions in this area that may warrant further investigation. Many reports of associations between a wide variety of infectious agents and atherosclerosis have recently appeared. An exhaustive evaluation of each of these purported associations lies beyond the scope of this survey. Rather, we will concentrate particularly on two particular infectious agents, one viral and one bacterial, currently linked with atherogenesis and supported by emerging evidence. Specifically, this report will focus primarily on herpesviruses, particularly cytomegalovirus (CMV), as an example of a viral agent and Chlamydia pneumoniae ( C pneumoniae , also known as the TWAR strain on the basis of its original laboratory designation) as an example of a bacterial pathogen. Although the preponderance of recent studies have examined CMV and Chlamydia , …

The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT): clinical center recruitment experience.

The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) is a randomized clinical outcome trial of antihypertensive and lipid-lowering therapy in a diverse population (including substantial numbers of women and minorities) of 42,419 high-risk hypertensives aged > or = 55 years with a planned mean follow-up of 6 years. In this paper, we describe our experience in the identification, recruitment, and selection of clinical centers for this large simple trial capable of meeting the recruitment goals outlined for ALLHAT, and we highlight factors associated with clinical center performance. Over 135,000 recruitment brochures were mailed to physicians. Requests for information and application packets were received from 9351 (6.8%) interested investigators. A total of 1053 completed applications were received and 909 sites (86%) were eventually approved to join the trial. Of the approved sites, 278 either later declined participation or were never activated, and 8 were closed within a year for lack of enrollment. The final 623 randomizing centers exceeded the trials recruitment goal to enroll at least 40,000 participants into the trial, although the recruitment period was extended 1.5 years longer than planned. Fewer than a quarter of the sites (22.6%) were recruited from academic medical centers or Department of Veterans Affairs Medical Centers. More than half of the sites (54.7%) were private solo or group practices, which contributed 53% of randomized participants. Community health centers comprised about 8% of the ALLHAT sites and 2.9% were part of health maintenance organizations. More than 22% of the principal investigators reported that they had no previous clinical research experience. In summary, ALLHAT was successful in recruiting a diverse group of clinical centers to achieve its patient recruitment goals.

Trial of Continuous or Interrupted Chest Compressions during CPR

BACKGROUND During cardiopulmonary resuscitation (CPR) in patients with out-of-hospital cardiac arrest, the interruption of manual chest compressions for rescue breathing reduces blood flow and possibly survival. We assessed whether outcomes after continuous compressions with positive-pressure ventilation differed from those after compressions that were interrupted for ventilations at a ratio of 30 compressions to two ventilations. METHODS This cluster-randomized trial with crossover included 114 emergency medical service (EMS) agencies. Adults with non-trauma-related cardiac arrest who were treated by EMS providers received continuous chest compressions (intervention group) or interrupted chest compressions (control group). The primary outcome was the rate of survival to hospital discharge. Secondary outcomes included the modified Rankin scale score (on a scale from 0 to 6, with a score of ≤3 indicating favorable neurologic function). CPR process was measured to assess compliance. RESULTS Of 23,711 patients included in the primary analysis, 12,653 were assigned to the intervention group and 11,058 to the control group. A total of 1129 of 12,613 patients with available data (9.0%) in the intervention group and 1072 of 11,035 with available data (9.7%) in the control group survived until discharge (difference, -0.7 percentage points; 95% confidence interval [CI], -1.5 to 0.1; P=0.07); 7.0% of the patients in the intervention group and 7.7% of those in the control group survived with favorable neurologic function at discharge (difference, -0.6 percentage points; 95% CI, -1.4 to 0.1, P=0.09). Hospital-free survival was significantly shorter in the intervention group than in the control group (mean difference, -0.2 days; 95% CI, -0.3 to -0.1; P=0.004). CONCLUSIONS In patients with out-of-hospital cardiac arrest, continuous chest compressions during CPR performed by EMS providers did not result in significantly higher rates of survival or favorable neurologic function than did interrupted chest compressions. (Funded by the National Heart, Lung, and Blood Institute and others; ROC CCC ClinicalTrials.gov number, NCT01372748.).

Amiodarone, Lidocaine, or Placebo in Out-of-Hospital Cardiac Arrest

BACKGROUND Antiarrhythmic drugs are used commonly in out-of-hospital cardiac arrest for shock-refractory ventricular fibrillation or pulseless ventricular tachycardia, but without proven survival benefit. METHODS In this randomized, double-blind trial, we compared parenteral amiodarone, lidocaine, and saline placebo, along with standard care, in adults who had nontraumatic out-of-hospital cardiac arrest, shock-refractory ventricular fibrillation or pulseless ventricular tachycardia after at least one shock, and vascular access. Paramedics enrolled patients at 10 North American sites. The primary outcome was survival to hospital discharge; the secondary outcome was favorable neurologic function at discharge. The per-protocol (primary analysis) population included all randomly assigned participants who met eligibility criteria and received any dose of a trial drug and whose initial cardiac-arrest rhythm of ventricular fibrillation or pulseless ventricular tachycardia was refractory to shock. RESULTS In the per-protocol population, 3026 patients were randomly assigned to amiodarone (974), lidocaine (993), or placebo (1059); of those, 24.4%, 23.7%, and 21.0%, respectively, survived to hospital discharge. The difference in survival rate for amiodarone versus placebo was 3.2 percentage points (95% confidence interval [CI], -0.4 to 7.0; P=0.08); for lidocaine versus placebo, 2.6 percentage points (95% CI, -1.0 to 6.3; P=0.16); and for amiodarone versus lidocaine, 0.7 percentage points (95% CI, -3.2 to 4.7; P=0.70). Neurologic outcome at discharge was similar in the three groups. There was heterogeneity of treatment effect with respect to whether the arrest was witnessed (P=0.05); active drugs were associated with a survival rate that was significantly higher than the rate with placebo among patients with bystander-witnessed arrest but not among those with unwitnessed arrest. More amiodarone recipients required temporary cardiac pacing than did recipients of lidocaine or placebo. CONCLUSIONS Overall, neither amiodarone nor lidocaine resulted in a significantly higher rate of survival or favorable neurologic outcome than the rate with placebo among patients with out-of-hospital cardiac arrest due to initial shock-refractory ventricular fibrillation or pulseless ventricular tachycardia. (Funded by the National Heart, Lung, and Blood Institute and others; ClinicalTrials.gov number, NCT01401647.).

Pulseless electric activity: Definition, causes, mechanisms, management, and research priorities for the next decade: Report from a national heart, lung, and blood institute workshop

Sudden cardiac arrest (SCA) remains an important public health challenge. Despite a dramatic decrease in the age-adjusted risk of SCA, the cumulative number of fatal SCAs in the United States remains large. Estimates range from 450 000 fatal SCAs per year; a figure in the range of 300 000 to 370 000 per year is likely the best current estimate.1 SCA appears to account for ≈50% of all cardiovascular deaths,2 and it is estimated that 50% of the SCAs are the first clinical expression of previously undiagnosed heart disease.2,3 Most out-of-hospital cardiac arrests (80%) occur in private homes or other living facilities.4 Electric mechanisms associated with SCA are broadly classified into tachyarrhythmic and nontachyarrhythmic categories, the latter including pulseless electric activity (PEA; formerly referred to as electromechanical dissociation), asystole, extreme bradycardia, and other mechanisms often associated with noncardiac factors (Table). The first approaches to the problem of SCA focused on ventricular fibrillation (VF) and pulseless ventricular tachycardia (VT). An early impact on the prevention and treatment of VF and VT was realized in patients with acute coronary syndromes >50 years ago,5 followed by the development of strategies for responding to out-of-hospital cardiac arrest, implantable cardioverter-defibrillators, and defibrillation by lay responders. View this table: Table. Tachyarrhythmic and Nontachyarrhythmic Cardiac Arrest Data from the Seattle emergency rescue system6 and elsewhere7–9 have identified progressive reductions in the number of responses to SCA over 2 to 3 decades. This change was due primarily to a reduction in the number of ventricular tachyarrhythmic events identified by emergency medical services responders. In the Seattle data, the incidences of PEA and asystole had not changed over the 3 decades of observation and therefore have emerged as proportionately more frequent mechanisms than VT/VF. Whether this also reflects the …

A controlled resuscitation strategy is feasible and safe in hypotensive trauma patients: results of a prospective randomized pilot trial.

BACKGROUND Optimal resuscitation of hypotensive trauma patients has not been defined. This trial was performed to assess the feasibility and safety of controlled resuscitation (CR) versus standard resuscitation (SR) in hypotensive trauma patients. METHODS Patients were enrolled and randomized in the out-of-hospital setting. Nineteen emergency medical services (EMS) systems in the Resuscitation Outcome Consortium participated. Eligible patients had an out-of-hospital systolic blood pressure (SBP) of 90 mm Hg or lower. CR patients received 250 mL of fluid if they had no radial pulse or an SBP lower than 70 mm Hg and additional 250-mL boluses to maintain a radial pulse or an SBP of 70 mm Hg or greater. The SR group patients received 2 L initially and additional fluid as needed to maintain an SBP of 110 mm Hg or greater. The crystalloid protocol was maintained until hemorrhage control or 2 hours after hospital arrival. RESULTS A total of 192 patients were randomized (97 CR and 95 SR). The CR and SR groups were similar at baseline. The mean (SD) crystalloid volume administered during the study period was 1.0 L (1.5) in the CR group and 2.0 L (1.4) in the SR group, a difference of 1.0 L (95% confidence interval [CI], 0.6–1.4). Intensive care unit–free days, ventilator-free days, renal injury, and renal failure did not differ between the groups. At 24 hours after admission, there were 5 deaths (5%) in the CR group and 14 (15%) in the SR group (adjusted odds ratio, 0.39; 95% CI, 0.12–1.26). Among patients with blunt trauma, 24-hour mortality was 3% (CR) and 18% (SR) with an adjusted odds ratio of 0.17 (0.03–0.92). There was no difference among patients with penetrating trauma (9% vs. 9%; adjusted odds ratio, 1.93; 95% CI, 0.19–19.17). CONCLUSION CR is achievable in out-of-hospital and hospital settings and may offer an early survival advantage in blunt trauma. A large-scale, Phase III trial to examine its effects on survival and other clinical outcomes is warranted. LEVEL OF EVIDENCE Therapeutic study, level I.

NIH Roundtable on Emergency Trauma Research

STUDY OBJECTIVE The National Institutes of Health (NIH) formed an NIH Task Force on Research in Emergency Medicine to enhance NIH support for emergency care research. The NIH Trauma Research Roundtable was convened on June 22 to 23, 2009. The objectives of the roundtable are to identify key research questions essential to advancing the scientific underpinnings of emergency trauma care and to discuss the barriers and best means to advance research by exploring the role of trauma research networks and collaboration between NIH and the emergency trauma care community. METHODS Before the roundtable, the emergency care domains to be discussed were selected and experts in each of the fields were invited to participate in the roundtable. Domain experts were asked to identify research priorities and challenges and separate them into mechanistic, translational, and clinical categories. During and after the conference, the lists were circulated among the participants and revised to reach a consensus. RESULTS Emergency trauma care research is characterized by focus on the timing, sequence, and time sensitivity of disease processes and treatment effects. Rapidly identifying the phenotype of patients on the time spectrum of acuity and severity after injury and the mechanistic reasons for heterogeneity in outcome are important challenges in emergency trauma research. Other research priorities include the need to elucidate the timing, sequence, and duration of causal molecular and cellular events involved in time-critical injuries, and the development of treatments capable of halting or reversing them; the need for novel experimental models of acute injury; the need to assess the effect of development and aging on the postinjury response; and the need to understand why there are regional differences in outcomes after injury. Important barriers to emergency care research include a limited number of trained investigators and experienced mentors, limited research infrastructure and support, and regulatory hurdles. CONCLUSION The science of emergency trauma care may be advanced by facilitating the following: (1) development of an acute injury template for clinical research; (2) developing emergency trauma clinical research networks; (3) integrating emergency trauma research into Clinical and Translational Science Awards; (4) developing emergency care-specific initiatives within the existing structure of NIH institutes and centers; (5) involving acute trauma and emergency specialists in grant review and research advisory processes; (6) supporting learn-phase or small, clinical trials; (7) performing research to address ethical and regulatory issues; and (8) training emergency care investigators with research training programs.

Original articleThe Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT): Clinical Center Recruitment Experience

The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) is a randomized clinical outcome trial of antihypertensive and lipid-lowering therapy in a diverse population (including substantial numbers of women and minorities) of 42,419 high-risk hypertensives aged > or = 55 years with a planned mean follow-up of 6 years. In this paper, we describe our experience in the identification, recruitment, and selection of clinical centers for this large simple trial capable of meeting the recruitment goals outlined for ALLHAT, and we highlight factors associated with clinical center performance. Over 135,000 recruitment brochures were mailed to physicians. Requests for information and application packets were received from 9351 (6.8%) interested investigators. A total of 1053 completed applications were received and 909 sites (86%) were eventually approved to join the trial. Of the approved sites, 278 either later declined participation or were never activated, and 8 were closed within a year for lack of enrollment. The final 623 randomizing centers exceeded the trials recruitment goal to enroll at least 40,000 participants into the trial, although the recruitment period was extended 1.5 years longer than planned. Fewer than a quarter of the sites (22.6%) were recruited from academic medical centers or Department of Veterans Affairs Medical Centers. More than half of the sites (54.7%) were private solo or group practices, which contributed 53% of randomized participants. Community health centers comprised about 8% of the ALLHAT sites and 2.9% were part of health maintenance organizations. More than 22% of the principal investigators reported that they had no previous clinical research experience. In summary, ALLHAT was successful in recruiting a diverse group of clinical centers to achieve its patient recruitment goals.

Summary of NIH Medical-Surgical Emergency Research Roundtable Held on April 30 to May 1, 2009

STUDY OBJECTIVE In 2003, the Institute of Medicine Committee on the Future of Emergency Care in the United States Health System convened and identified a crisis in emergency care in the United States, including a need to enhance the research base for emergency care. As a result, the National Institutes of Health (NIH) formed an NIH Task Force on Research in Emergency Medicine to enhance NIH support for emergency care research. Members of the NIH Task Force and academic leaders in emergency care participated in 3 roundtable discussions to prioritize current opportunities for enhancing and conducting emergency care research. The objectives of these discussions were to identify key research questions essential to advancing the scientific underpinnings of emergency care and to discuss the barriers and best means to advance research by exploring the role of research networks and collaboration between the NIH and the emergency care community. METHODS The Medical-Surgical Research Roundtable was convened on April 30 to May 1, 2009. Before the roundtable, the emergency care domains to be discussed were selected and experts in each of the fields were invited to participate in the roundtable. Domain experts were asked to identify research priorities and challenges and separate them into mechanistic, translational, and clinical categories. After the conference, the lists were circulated among the participants and revised to reach a consensus. RESULTS Emergency care research is characterized by focus on the timing, sequence, and time sensitivity of disease processes and treatment effects. Rapidly identifying the phenotype and genotype of patients manifesting a specific disease process and the mechanistic reasons for heterogeneity in outcome are important challenges in emergency care research. Other research priorities include the need to elucidate the timing, sequence, and duration of causal molecular and cellular events involved in time-critical illnesses and injuries, and the development of treatments capable of halting or reversing them; the need for novel animal models; and the need to understand why there are regional differences in outcome for the same disease processes. Important barriers to emergency care research include a limited number of trained investigators and experienced mentors, limited research infrastructure and support, and regulatory hurdles. The science of emergency care may be advanced by facilitating the following: (1) training emergency care investigators with research training programs; (2) developing emergency care clinical research networks; (3) integrating emergency care research into Clinical and Translational Science Awards; (4) developing emergency care-specific initiatives within the existing structure of NIH institutes and centers; (5) involving emergency specialists in grant review and research advisory processes; (6) supporting learn-phase or small, clinical trials; and (7) performing research to address ethical and regulatory issues. CONCLUSION Enhancing the research base supporting the care of medical and surgical emergencies will require progress in specific mechanistic, translational, and clinical domains; effective collaboration of academic investigators across traditional clinical and scientific boundaries; federal support of research in high-priority areas; and overcoming limitations in available infrastructure, research training, and access to patient populations.

Rationale and design of the arterial disease multiple intervention trial (ADMIT) pilot study

The primary objectives of the pilot study were to: (1) evaluate the feasibility of recruiting patients with peripheral arterial disease (PAD); (2) measure the efficacy and safety of high-density lipoprotein (HDL)-raising treatment, low-density lipoprotein (LDL)-lowering therapy, antioxidant therapy, antithrombotic therapy, and their combinations; and (3) assess adherence to a complex multiple drug regimen. Secondary objectives included measurement of the effect of the interventions on prespecified biochemical markers, maintenance of therapy masking (in particular with niacin), and measurement of the interventions impact on functional status and on quality of life. To date, no secondary prevention trial has been conducted specifically among patients with PAD. Intermittent claudication affects about 0.5% to 1.0% of persons aged >35 years. There is a striking increase in incidence of PAD with age, particularly among those aged >50 years in both sexes, although men are twice as likely as women to develop PAD. The Arterial Disease Multiple Intervention Trial was a double-blind randomized pilot trial of 468 participants with documented PAD. A 2 x 2 x 2 factorial design was used to evaluate the effect of 3 interventions. The pilot incorporated several major novel design features: first, the use of a simple noninvasive method (measurement of ankle brachial index) to identify a population with either symptomatic or asymptomatic PAD; and second, a lipid modifying strategy to increase HDL with nicotinic acid in the intervention group while lowering LDL levels equally with an hydroxymethylglutaryl-coenzyme A reductase inhibitor as needed in the intervention and control group. Two other arms, the antioxidant arm (consisting of beta-carotene and vitamins E and C) and the antithrombotic arm (using warfarin) were also added. Adherence to therapy was measured by pill count, and success in treatment was measured by the proportion of values in target range for HDL, LDL, and the international normalized ratio.