John T. Watson

The REMATCH trial: rationale, design, and end points

BACKGROUND Because left ventricular assist devices have recently been approved by the Food and Drug Administration to support the circulation of patients with end-stage heart failure awaiting cardiac transplantation, these devices are increasingly being considered as a potential alternative to biologic cardiac replacement. The Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure (REMATCH) trial is a multicenter study supported by the National Heart, Lung, and Blood Institute to compare long-term implantation of left ventricular assist devices with optimal medical management for patients with end-stage heart failure who require, but do not qualify to receive cardiac transplantation. METHODS We discuss the rationale for conducting REMATCH, the obstacles to designing this and other randomized surgical trials, the lessons learned in conducting the multicenter pilot study, and the features of the REMATCH study design (objectives, target population, treatments, end points, analysis, and trial organization). CONCLUSIONS We consider what will be learned from REMATCH, expectations for expanding the use of left ventricular assist devices, and future directions for assessing clinical procedures.

2014 MERS-CoV Outbreak in Jeddah — A Link to Health Care Facilities

BACKGROUND A marked increase in the number of cases of Middle East respiratory syndrome coronavirus (MERS-CoV) infection occurred in Jeddah, Saudi Arabia, in early 2014. We evaluated patients with MERS-CoV infection in Jeddah to explore reasons for this increase and to assess the epidemiologic and clinical features of this disease. METHODS We identified all cases of laboratory-confirmed MERS-CoV infection in Jeddah that were reported to the Saudi Arabian Ministry of Health from January 1 through May 16, 2014. We conducted telephone interviews with symptomatic patients who were not health care personnel, and we reviewed hospital records. We identified patients who were reported as being asymptomatic and interviewed them regarding a history of symptoms in the month before testing. Descriptive analyses were performed. RESULTS Of 255 patients with laboratory-confirmed MERS-CoV infection, 93 died (case fatality rate, 36.5%). The median age of all patients was 45 years (interquartile range, 30 to 59), and 174 patients (68.2%) were male. A total of 64 patients (25.1%) were reported to be asymptomatic. Of the 191 symptomatic patients, 40 (20.9%) were health care personnel. Among the 151 symptomatic patients who were not health care personnel, 112 (74.2%) had data that could be assessed, and 109 (97.3%) of these patients had had contact with a health care facility, a person with a confirmed case of MERS-CoV infection, or someone with severe respiratory illness in the 14 days before the onset of illness. The remaining 3 patients (2.7%) reported no such contacts. Of the 64 patients who had been reported as asymptomatic, 33 (52%) were interviewed, and 26 of these 33 (79%) reported at least one symptom that was consistent with a viral respiratory illness. CONCLUSIONS The majority of patients in the Jeddah MERS-CoV outbreak had contact with a health care facility, other patients, or both. This highlights the role of health care-associated transmission. (Supported by the Ministry of Health, Saudi Arabia, and by the U.S. Centers for Disease Control and Prevention.).

Neurological events during long-term mechanical circulatory support for heart failure ; the Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure (REMATCH) experience

Background—Progression of heart failure can lead to cardiac transplantation, but when patients are ineligible, long-term mechanical circulatory support may improve survival. The REMATCH trial showed that left ventricular assist devices (LVADs) prolonged survival in patients with end-stage disease, but with a significant number of adverse events. We report on the neurological outcomes in the REMATCH trial. Methods and Results—We examined new neurological events in the 129 patients randomized to either LVAD placement (n= 68) or medical management (n= 61), classified as stroke, transient ischemic attack, toxic-metabolic encephalopathy, and other. There were 46 neurological events: 42 in 30 LVAD patients and 4 in 4 patients in the medical arm (χ2, 30/68 versus 4/61, P < 0.001). Sixteen percent of the LVAD patients had a stroke, with a rate of 0.19 per year (95% CI, 0.10 to 0.33), many occurring in the postoperative period. The stroke rate in the medical arm was 0.052. A Kaplan-Meier survival analysis showed a 44% reduction in the risk of stroke or death in the LVAD group versus the optimal medical group (P = 0.002). The mean interval from implantation to stroke was 221.8 days (± 70.4 days). History of stroke, age, and sepsis were not stroke risk factors in the LVAD group. Conclusions—Fewer than half of the patients in the LVAD group had a neurological event, and there were few neurological deaths. Survival analysis combining stroke or death demonstrated a significant benefit for long-term circulatory support with an LVAD over medical therapy. Future trials will need to address prospectively all neurological outcomes, including neurocognitive function, and the role of long-term neuroprotection.

Clinical Characteristics and Functional Outcomes of West Nile Fever

Context The frequency of infection with West Nile virus is increasing rapidly in the United States. While the most fatal and closely studied manifestations of the disease are meningitis and encephalitis, little is known about the symptoms and clinical outcomes of West Nile fever. Contribution The authors interviewed 98 people with nonparalytic West Nile fever following recovery. Muscle weakness, fatigue, headache, difficulty concentrating, and fever were common manifestations. Approximately one third of patients required hospitalization. Median time to full recovery was 60 days. Implications Even in the absence of neurologic manifestations, West Nile virus infection is a potentially severe and debilitating illness. The Editors West Nile virus is a mosquito-borne pathogen with a wide geographic distribution in the eastern hemisphere (1). The first documented West Nile virus infections in the United States occurred in 1999 in New York City (2). Since then, the distribution of the virus has expanded rapidly and the number of infections has increased (3-5). In 2002, 4156 cases of West Nile virus disease and 284 deaths were reported throughout the United States (6), compared with 62 cases and 7 deaths in 1999 (2). Illinois had 884 documented cases with 66 deaths in 2002 (7). In 2003, the expansion continued; 9858 cases and 262 deaths were reported nationally (8). Since the initial identification and isolation of West Nile virus in 1937 (9), associated outbreaks have typically been characterized by mild febrile illnesses (10). Starting in the mid-1990s, however, the frequency and severity of outbreaks increased (11). Recent outbreaks in Romania, Russia, and Israel involved hundreds of persons and high rates of severe neurologic disease and fatalities (12-14). Most recent studies on infections caused by West Nile virus have focused on persons with neurologic disease, such as meningitis or encephalitis (10). However, 3 serologic studies of persons in the United States and Romania found that meningitis or encephalitis occurred in only about 1 of 150 infected persons (12, 15, 16). In addition, the serologic study conducted by Mostashari and colleagues (15) during the 1999 New York City outbreak found that most infections are not clinically apparent; only approximately 20% of infected persons developed symptoms that could be attributed to the virus. On the basis of the number of meningitis and encephalitis cases reported in 1999, the authors estimated that 3500 to 13000 West Nile virus infections occurred throughout the greater New York City area that year. West Nile fever is often the term used to describe symptomatic infections without neurologic disease. The typical description is a febrile illness of sudden onset lasting 3 to 6 days and often accompanied by malaise, anorexia, nausea, vomiting, eye pain, headache, myalgias, and rash (17). Clinical characterization of West Nile fever cases, however, is poor (10). Methods Case Finding and Case Definition Human cases of aseptic meningitis and encephalitis are reportable conditions in Illinois. In 2002, the Illinois Department of Public Health tested all cerebrospinal fluid and blood specimens submitted for suspected arboviral infection, regardless of clinical picture. In addition, the Illinois Department of Public Health accepted positive results on laboratory tests for West Nile virus infection from commercial laboratories. Whenever the Illinois Department of Public Health notified a local health authority of a West Nile viruspositive result in a resident of its jurisdiction, the local health authority conducted an epidemiologic investigation of the case. Persons who had positive test results but did not meet the Centers for Disease Control and Prevention definition for meningitis or encephalitis and did not satisfy published criteria for diagnosis of West Nile virusassociated acute flaccid paralysis (18) were considered to have West Nile fever. As part of the West Nile virus outbreak investigation conducted by the Illinois Department of Public Health and the Chicago Department of Public Health, West Nile fever cases were characterized in terms of reported symptoms and illness severity. We classified cases of West Nile virus disease on the basis of the Centers for Disease Control and Prevention case definitions for meningitis and encephalitis due to arboviral disease (19). The laboratory criterion for a confirmed diagnosis of West Nile virus disease was West Nile virus IgM in cerebrospinal fluid or West Nile virus genomic sequences in blood or cerebrospinal fluid. The laboratory criterion for a probable diagnosis of West Nile virus disease was West Nile virus IgM in serum. Cases were then classified on the basis of reported clinical criteria. We excluded patients with meningitis (fever, headache, stiff neck, and pleocytosis) or encephalitis (fever, headache, altered mental status, and pleocytosis). Patients with acute, progressive, asymmetric weakness, with or without the signs and symptoms of meningitis or encephalitis, were excluded because of the possibility of acute flaccid paralysis. The remaining patients were classified as having West Nile fever, defined as West Nile virus IgM or genomic sequences in serum but no symptoms or signs of meningitis, encephalitis, or acute flaccid paralysis. To ensure the exclusion of patients exhibiting more serious neurologic signs, we checked West Nile fever case reports before interviews to confirm that no patients had had lumbar puncture performed or cerebrospinal fluid submitted for laboratory evaluation and that confusion was not listed on the case report as a symptom. We confirmed this information with patients at the time of the interview. In addition, we obtained information from hospital records of selected patients when necessary to verify classification of illness. Data Collection To assess the clinical syndrome and functional outcomes of West Nile fever, we interviewed affected patients by telephone using a standard questionnaire. The questionnaire contained questions about the presence and duration of 18 different symptoms, hospitalization and other medical visits, medications taken or prescribed, the impact of the illness on daily activities, the amount of work or school missed, and underlying medical conditions during the illness (diabetes mellitus, history of cancer of any type, hypertension, heart disease, liver disease, kidney disease, and history of organ transplantation or immunosuppression). We determined duration of illness using self-reported illness information obtained at the time of the interview. Patients who lived in areas under the jurisdiction of participating local health departments and who were able to independently answer questions were eligible for inclusion. Statistical Analysis We used Epi Info (version 6.04b, Centers for Disease Control and Prevention, Atlanta, Georgia) and SAS (version 8.2, SAS Institute, Inc., Cary, North Carolina) to analyze the collected data. Simple proportions and medians were generated to describe the frequencies with which symptoms were reported, symptom duration, and the effects of symptoms on daily activities. We used the t-test to determine the statistical significance of differences in the means of continuous data and the MantelHaenszel chi-square test to determine the statistical significance of differences in proportions. We calculated 95% CIs of proportions using Wald methods. Because some individuals had continuing symptoms at the time of the interview, we examined the relationship between age and duration of illness using proportional hazards modeling; illness durations in persons with continuing symptoms were considered to be censored. We assessed the proportional hazards assumptions by introducing a time-dependent covariatethe interaction between age and timeto test whether there was a systematic increase or decrease in the effect of age across time. We assessed possible confounding due to hospitalization and underlying illness by including terms in the proportional hazards regression model. Results In 2002, 331 West Nile virus infections reported in Illinois residents met the case definition for West Nile fever. Of these, 140 persons (42%) lived in jurisdictions of participating local health departments and were eligible for inclusion in the study. No information was obtained on 191 individuals (58%) who lived in jurisdictions of nonparticipating health departments. Of the 140 persons eligible for inclusion, 29 were not interviewed because of incorrect telephone numbers; 9 could not be reached in at least 3 attempts; 3 were unwilling or unable to participate; and 1, who was 3 years of age, was not evaluated. The remaining 98 patients, who did not report having a lumbar puncture and had no record of submission of cerebrospinal fluid for laboratory testing, were enrolled in the study. Interviews were conducted from 18 December 2002 to 27 April 2003, a median of 168 days (range, 84 to 254 days) after illness onset. Thirty-eight of 98 patients (39%) had ongoing symptoms at the time of the interview. Questionnaire responses were missing for fever duration in 4 patients, for presence of fever in 1 patient, for duration of muscle weakness in 1 patient, and for duration of rash in 2 patients. Patients with missing responses were not included in the calculated proportions. One patient had unclear information about onset of illness, and date of laboratory diagnosis was used in place of illness onset date. In addition, 1 patient had unclear duration information and was excluded from the analysis of illness duration. The respondents were not significantly different in terms of sex and age from nonparticipating Illinois patients with West Nile fever (Table 1). Table 1. Characteristics of Respondents and Nonrespondents Laboratory Confirmation Standard laboratory methods were used to identify evidence of West Nile virus infection in the serum specimens of the 98 enrolled p

Reduced myocardial reflow and increased coronary vascular resistance following prolonged myocardial ischemia in the dog.

Studies were performed to determine whether an alteration in coronary vascular resistance and a reduction in the reflow phenomenon occurred in the blood-perfused, heparinized canine heart after various periods of myocardial ischemia. Regional myocardial blood flow was measured with radioactive microspheres. Proximal left anterior descending coronary artery blood flow was measured with a periarterial flow transducer. Reduced reflow to the ischemic portion of the left ventricle and increased resistance in the left anterior descending coronary artery were present after 120 minutes of myocardial ischemia. The reduction in reflow was specific to the subendocardium of the ischemic area. Saline and isosorbide dinitrate (Isordil) did not prevent the increase in coronary vascular resistance or the significant reduction in reflow to the subendocardial portion of the ischemic area. Hypertonic mannitol given so as to increase serum osmolality 40 mosmoles/kg prevented the increase in coronary vascular resistance and modified the reduction in the reflow phenomenon to the subendocardial portion of the ischemic area. Thus, both an increase in coronary vascular resistance and a significant reduction in reflow to the subendocardial portion of the ischemic area occur in the canine heart after 120 minutes of myocardial ischemia. Moreover, the increase in coronary vascular resistance can be prevented and the reduction in reflow to the subendocardial portion of the ischemic area can be modified by the administration of hypertonic mannitol.

Intraaortic balloon counterpulsation in patients in cardiogenic shock, medically refractory left ventricular failure and/or recurrent ventricular tachycardia

Of the 27 patients described, 23 were in cardiogenic shock, 2 had severe left ventricular failure, and 2 had medically refractory ventricular tachycardia. Utilizing intraaortic counterpulsation, adequate systemic blood pressure was initially restored in 19 patients. Nine of these were subsequently weaned from circulatory assistance, but only three were discharged from the hospital and are currently alive. The remaining 10 patients who derived initial benefit from circulatory assistance were balloon-dependent in that they could not be weaned from circulatory assistance. Eight of these patients subsequently underwent cardiac catheterization; four had inoperable disease. The remaining four patients underwent surgery for either resection of the area of infarction and/or for myocardial revascularization; only one survived to subsequently leave the hospital. Ventricular volumes were abnormal and ejection fractions were below 30 per cent in all the patients in cardiogenic shock except one who underwent cardiac catheterization and ultimately died. Ejection fractions were greater than 30 per cent in the two patients with cardiogenic shock who were weaned from balloon support and survived to leave the hospital without surgery. Both of these patients had inferior myocardial infarction. The data obtained from this experience suggest that intraaortic counterpulsation is a very useful adjunct to currently existing medical measures to treat both cardiogenic shock and medically refractory left ventricular failure but that most patients have such extensive disease that they can neither be weaned from balloon support nor undergo successful infarctectomy or myocardial revascularization.

Left Ventricular Assist Devices as Permanent Heart Failure Therapy The Price of Progress

Summary Background Data: The REMATCH trial evaluated the efficacy and safety of long-term left ventricular assist device (LVAD) support in stage D chronic end-stage heart failure patients. Compared with optimal medical management, LVAD implantation significantly improved the survival and quality of life of these terminally ill patients. To date, however, there have been no analyses of the cost related to the LVAD survival benefit. This paper addresses the cost of hospital resource use, and its predictors, for long-term LVAD patients. Methods: Detailed cost data were available for 52 of 68 REMATCH patients randomized to LVAD therapy. We combined the clinical dataset with Medicare data, standard billing forms (UB-92), and line item bills provided directly by clinical centers. Charges were converted to costs by using the Ratio-of-Cost-to-Charges for each major resource category. Results: The mean cost for the initial implant-related hospitalization was

Influence of dobutamine on regional myocardial blood flow and ventricular performance during acute and chronic myocardial ischemia in dogs.

210,187 ± 193,295. When implantation hospitalization costs are compared between hospital survivors and nonsurvivors, the mean costs increase from

Long-term mechanical circulatory support system reliability recommendation: American Society for Artificial Internal Organs and The Society of Thoracic Surgeons: Long-term mechanical circulatory support system reliability recommendation

159,271 ± 106,423 to

Methicillin-resistant Staphylococcus aureus infections among healthy full-term newborns

315,015 ± 278,713. Sepsis, pump housing infection, and perioperative bleeding are the major drivers of implantation cost, established by regression modeling. In the patients who survived the procedure (n = 35), bypass time, perioperative bleeding, and late bleeding were the drivers of cost. The average annual readmission cost per patient for the overall cohort was