JAMA. 2008;300(13):1532-1543.
Context In 1999, the US Congress directed the Centers for Disease Control and Prevention to conduct a pivotal safety and efficacy study of anthrax vaccine adsorbed (AVA). Objective To determine the effects on serological responses and injection site adverse events (AEs) resulting from changing the route of administration of AVA from subcutaneous (SQ) to intramuscular (IM) and omitting the week 2 dose from the licensed schedule. Design, Setting, and Participants Assessment of the first 1005 enrollees in a multisite, randomized, double-blind, noninferiority, phase 4 human clinical trial (ongoing from May 2002). Intervention Healthy adults received AVA by the SQ (reference group) or IM route at 0, 2, and 4 weeks and 6 months (4-SQ or 4-IM; n = 165-170 per group) or at a reduced 3-dose schedule (3-IM; n = 501). A control group (n = 169) received saline injections at the same time intervals. Main Outcome Measures Noninferiority at week 8 and month 7 of anti–protective antigen IgG geometric mean concentration (GMC), geometric mean titer (GMT), and proportion of responders with a 4-fold rise in titer (%4xR). Reactogenicity outcomes were proportions of injection site and systemic AEs. Results At week 8, the 4-IM group (GMC, 90.8 µg/mL; GMT, 1114.8; %4xR, 97.7) was noninferior to the 4-SQ group (GMC, 105.1 µg/mL; GMT, 1315.4; %4xR, 98.8) for all 3 primary end points. The 3-IM group was noninferior for only the %4xR (GMC, 52.2 µg/mL; GMT, 650.6; %4xR, 94.4). At month 7, all groups were noninferior to the licensed regimen for all end points. Solicited injection site AEs assessed during examinations occurred at lower proportions in the 4-IM group compared with 4-SQ. The odds ratio for ordinal end point pain reported immediately after injection was reduced by 50% for the 4-IM vs 4-SQ groups (P < .001). Route of administration did not significantly influence the occurrence of systemic AEs. Conclusions The 4-IM and 3-IM regimens of AVA provided noninferior immunological priming by month 7 when compared with the 4-SQ licensed regimen. Intramuscular administration significantly reduced the occurrence of injection site AEs. Trial Registration clinicaltrials.gov Identifier: NCT00119067
JAMA. 2002;287:2114-2119.
Objectives The Bethesda 2001 Workshop was convened to evaluate and update the 1991 Bethesda System terminology for reporting the results of cervical cytology. A primary objective was to develop a new approach to broaden participation in the consensus process. Participants Forum groups composed of 6 to 10 individuals were responsible for developing recommendations for discussion at the workshop. Each forum group included at least 1 cytopathologist, cytotechnologist, clinician, and international representative to ensure a broad range of views and interests. More than 400 cytopathologists, cytotechnologists, histopathologists, family practitioners, gynecologists, public health physicians, epidemiologists, patient advocates, and attorneys participated in the workshop, which was convened by the National Cancer Institute and cosponsored by 44 professional societies. More than 20 countries were represented. Evidence Literature review, expert opinion, and input from an Internet bulletin board were all considered in developing recommendations. The strength of evidence of the scientific data was considered of paramount importance. Consensus Process Bethesda 2001 was a year-long iterative review process. An Internet bulletin board was used for discussion of issues and drafts of recommendations. More than 1000 comments were posted to the bulletin board over the course of 6 months. The Bethesda Workshop, held April 30-May 2, 2001, was open to the public. Postworkshop recommendations were posted on the bulletin board for a last round of critical review prior to finalizing the terminology. Conclusions Bethesda 2001 was developed with broad participation in the consensus process. The 2001 Bethesda System terminology reflects important advances in biological understanding of cervical neoplasia and cervical screening technology.
JAMA. 2003;289:3161-3166.
Objective To encourage treatment of depression and prevention of suicide in physicians by calling for a shift in professional attitudes and institutional policies to support physicians seeking help. Participants An American Foundation for Suicide Prevention planning group invited 15 experts on the subject to evaluate the state of knowledge about physician depression and suicide and barriers to treatment. The group assembled for a workshop held October 6-7, 2002, in Philadelphia, Pa. Evidence The planning group worked with each participant on a preworkshop literature review in an assigned area. Abstracts of presentations and key publications were distributed to participants before the workshop. After workshop presentations, participants were assigned to 1 of 2 breakout groups: (1) physicians in their role as patients and (2) medical institutions and professional organizations. The groups identified areas that required further research, barriers to treatment, and recommendations for reform. Consensus Process This consensus statement emerged from a plenary session during which each work group presented its recommendations. The consensus statement was circulated to and approved by all participants. Conclusions The culture of medicine accords low priority to physician mental health despite evidence of untreated mood disorders and an increased burden of suicide. Barriers to physicians' seeking help are often punitive, including discrimination in medical licensing, hospital privileges, and professional advancement. This consensus statement recommends transforming professional attitudes and changing institutional policies to encourage physicians to seek help. As barriers are removed and physicians confront depression and suicidality in their peers, they are more likely to recognize and treat these conditions in patients, including colleagues and medical students.
JAMA. 2002;288:1097-1101.
Since family practice was first recognized as a specialty in the late 1960s, considerable intellectual and organizational change has occurred in medicine, especially during the 1990s. To reflect on and reconsider the role of family practice in US health care, this article reviews the development of family practice as a specialty, provides a current assessment of the status of family medicine in the United States, and comments on issues that are of ongoing importance to family practice.
JAMA. 2000;283:2417-2426.
Objective Assays for drug resistance testing in human immunodeficiency virus type 1 (HIV-1) infection are now available and clinical studies suggest that viral drug resistance is correlated with poor virologic response to new therapy. The International AIDS Society–USA sought to update prior recommendations to provide guidance for clinicians regarding indications for HIV-1 resistance testing. Participants An International AIDS Society–USA 13-member physician panel with expertise in basic science, clinical research, and patient care involving HIV resistance to antiretroviral drugs was reconvened to provide recommendations for the clinical use of drug resistance testing. Evidence and Consensus Process The full panel met regularly between January and October 1999. Resistance and resistance testing data appearing in the last decade through April 2000 and presentations at national and international research conferences were reviewed. Recommendations and considerations were developed by 100% group consensus, acknowledging that definitive data to support final recommendations are not yet available. Conclusions Emerging data indicate that despite limitations, resistance testing should be incorporated into patient management in some settings. Resistance testing is recommended to help guide the choice of new regimens after treatment failure and for guiding therapy for pregnant women. It should be considered in treatment-naive patients with established infection, but cannot be firmly recommended in this setting. Testing also should be considered prior to initiating therapy in patients with acute HIV infection, although therapy should not be delayed pending the results. Expert interpretation is recommended given the complexity of results and assay limitations.
JAMA. 2005;293:1367-1373.
The discovery of RNA interference (RNAi), an endogenous cellular gene-silencing mechanism, has already provided a powerful tool for basic science researchers to study gene function. The subsequent finding that RNAi also operates in mammalian cells has generated excitement regarding potential therapeutic applications. In this article we discuss the basic mechanism of RNAi and the therapeutic opportunities and obstacles for harnessing RNAi for therapy of human disease.
JAMA. 2002;288:1775-1779.
The chronic care model is a guide to higher-quality chronic illness management within primary care. The model predicts that improvement in its 6 interrelated components—self-management support, clinical information systems, delivery system redesign, decision support, health care organization, and community resources—can produce system reform in which informed, activated patients interact with prepared, proactive practice teams. Case studies are provided describing how components of the chronic care model have been implemented in the primary care practices of 4 health care organizations.
JAMA. 1998;280:78-86.
Objective.— To provide recommendations for antiretroviral therapy based on information available in mid-1998. Participants.— An international panel of physicians with expertise in antiretroviral research and care of patients with human immunodeficiency virus (HIV) infection, first convened by the International AIDS Society–USA in December 1995. Evidence. —The panel reviewed available clinical and basic science study results (including phase 3 controlled trials; clinical, virologic, and immunologic end point data; data presented at research conferences; and studies of HIV pathophysiology); opinions of panel members were also considered. Recommendations were limited to drugs available in mid-1998. Consensus Process. —Panel members monitor new clinical research reports and interim results. The full panel meets regularly to discuss how the new information may change treatment recommendations. Updated recommendations are developed through consensus of the entire panel at each stage of development. Conclusions. —Accumulating data from clinical and pathogenesis studies continue to support early institution of potent antiretroviral therapy in patients with HIV infection. A variety of combination regimens show potency, expanding choices for initial regimens for individual patients. Plasma HIV RNA assays with increased sensitivity are important in monitoring therapeutic response; however, more data are needed to determine precisely the HIV RNA levels that define treatment failure. Long-term adverse drug effects are beginning to emerge, requiring ongoing attention. Some issues regarding optimal long-term approaches to antiretroviral management are unresolved. The increased complexity in HIV management requires ongoing monitoring of new data for optimal treatment of HIV infection.
JAMA. 2008;299(20):2413-2422.
Context Based on concerns about the risk of infection, the jugular site is often preferred over the femoral site for short-term dialysis vascular access. Objective To determine whether jugular catheterization decreases the risk of nosocomial complications compared with femoral catheterization. Design, Setting, and Patients A concealed, randomized, multicenter, evaluator-blinded, parallel-group trial (the Cathedia Study) of 750 patients from a network of 9 tertiary care university medical centers and 3 general hospitals in France conducted between May 2004 and May 2007. The severely ill, bed-bound adults had a body mass index (BMI) of less than 45 and required a first catheter insertion for renal replacement therapy. Intervention Patients were randomized to receive jugular or femoral vein catheterization by operators experienced in placement at both sites. Main Outcome Measures Rates of infectious complications, defined as catheter colonization on removal (primary end point), and catheter-related bloodstream infection. Results Patient and catheter characteristics, including duration of catheterization, were similar in both groups. More hematomas occurred in the jugular group than in the femoral group (13/366 patients [3.6%] vs 4/370 patients [1.1%], respectively; P = .03). The risk of catheter colonization at removal did not differ significantly between the femoral and jugular groups (incidence of 40.8 vs 35.7 per 1000 catheter-days; hazard ratio [HR], 0.85; 95% confidence interval [CI], 0.62-1.16; P = .31). A prespecified subgroup analysis demonstrated significant qualitative heterogeneity by BMI (P for the interaction term < .001). Jugular catheterization significantly increased incidence of catheter colonization vs femoral catheterization (45.4 vs 23.7 per 1000 catheter-days; HR, 2.10; 95% CI, 1.13-3.91; P = .017) in the lowest tercile (BMI <24.2), whereas jugular catheterization significantly decreased this incidence (24.5 vs 50.9 per 1000 catheter-days; HR, 0.40; 95% CI, 0.23-0.69; P < .001) in the highest tercile (BMI >28.4). The rate of catheter-related bloodstream infection was similar in both groups (2.3 vs 1.5 per 1000 catheter-days, respectively; P = .42). Conclusion Jugular venous catheterization access does not appear to reduce the risk of infection compared with femoral access, except among adults with a high BMI, and may have a higher risk of hematoma. Trial Registration clinicaltrials.gov Identifier: NCT00277888
JAMA. 2008;299(4):409-416.
Context Approval of drug-eluting coronary stents was based on results of relatively small trials of selected patients; however, in routine practice, stents are used in a broader spectrum of patients. Objective To compare the first 2 commercially available drug-eluting stents—sirolimus-eluting and paclitaxel-eluting—for prevention of symptom-driven clinical end points, using a study design reflecting everyday clinical practice. Design, Setting, and Patients Randomized, blinded trial conducted August 2004 to January 2006 at 5 university hospitals in Denmark. Patients were 2098 men and women (mean [SD] age, 63.6 [10.8] years) treated with percutaneous coronary intervention (PCI) and randomized to receive either sirolimus-eluting (n = 1065) or paclitaxel-eluting (n = 1033) stents. Indications for PCI included ST-segment elevation myocardial infarction (STEMI), non-STEMI or unstable angina pectoris, and stable angina. Main Outcome Measures The primary end point was a composite clinical end point of major adverse cardiac events, defined as either cardiac death, acute myocardial infarction, target lesion revascularization, or target vessel revascularization. Secondary end points included individual components of the composite end point, all-cause mortality, and stent thrombosis. Results The sirolimus- and the paclitaxel-eluting stent groups did not differ significantly in major adverse cardiac events (98 [9.3%] vs 114 [11.2%]; hazard ratio, 0.83 [95% confidence interval, 0.63-1.08]; P = .16) or in any of the secondary end points. The stent thrombosis rates were 27 (2.5%) and 30 (2.9%) (hazard ratio, 0.87 [95% confidence interval, 0.52-1.46]; P = .60), respectively. Conclusion In this practical randomized trial, there were no significant differences in clinical outcomes between patients receiving sirolimus- and paclitaxel-eluting stents. Trial Registration clinicaltrials.gov Identifier: NCT00388934
JAMA. 2007;298(23):2754-2760.
Context Allowing the emergency department physician to activate the cardiac catheterization laboratory is a key strategy to reduce door-to-balloon times in patients with ST-segment elevation myocardial infarction (STEMI). There are limited data on the frequency of "false-positive" catheterization laboratory activation in patients undergoing percutaneous coronary intervention for suspected STEMI. Objective To determine the prevalence, etiology, and outcomes of false-positive cardiac catheterization laboratory activation in patients with a suspected STEMI. Design, Setting, and Patients Prospective registry from a regional system that includes transfer of patients with STEMI from 30 community and rural hospitals with pretransfer catheterization laboratory activation for percutaneous coronary intervention at a tertiary cardiovascular center in Minnesota. A total of 1345 patients were enrolled from March 2003 to November 2006. Main Outcome Measure Prevalence of false-positive catheterization laboratory activation in patients with suspected STEMI by 3 criteria: no culprit coronary artery, no significant coronary artery disease, and negative cardiac biomarker results. Results Of the 1335 patients with suspected STEMI who underwent angiography, 187 (14%; 95% confidence interval [CI], 12.2%-16.0%) had no culprit coronary artery and 127 (9.5%; 95% CI, 8.0%-11.2%) did not have significant coronary artery disease. Cardiac biomarker levels were negative in 11.2% (95% CI, 9.6%-13.0%) of patients. The combination of no culprit artery with negative cardiac biomarker results was present in 9.2% (95% CI, 7.7%-10.9%) of patients. Thirty-day mortality was 2.7% (95% CI, 0.4%-5.0%) without vs 4.6% (95% CI, 3.4%-5.8%) with a culprit coronary artery (P = .33). Conclusions The frequency of false-positive cardiac catheterization laboratory activation for suspected STEMI is relatively common in community practice, depending on the definition of false-positive. Recent emphasis on rapid door-to-balloon times must also consider the consequences of false-positive catheterization laboratory activation.
JAMA. 2004;292:251-265.
Context Substantial changes in the field of human immunodeficiency virus (HIV) treatment have occurred in the last 2 years, prompting revision of the guidelines for antiretroviral management of adults with established HIV infection. Objective To update recommendations for physicians who provide HIV care regarding when to start antiretroviral therapy, what drugs to start with, when to change drug regimens, and what drug regimens to switch to after therapy fails. Data Sources Evidence was identified and reviewed by a 16-member noncompensated panel of physicians with expertise in HIV-related basic science and clinical research, antiretroviral therapy, and HIV patient care. The panel was designed to have broad US and international representation for areas with adequate access to antiretroviral management. Study Selection Evidence considered included published basic science, clinical research, and epidemiological data (identified by experts in the field or extracted through MEDLINE searches using terms relevant to antiretroviral therapy) and abstracts from HIV-oriented scientific conferences between July 2002 and May 2004. Data Extraction Data were reviewed to identify any information that might change previous guidelines. Based on panel discussion, guidelines were drafted by a writing committee and discussed by the panel until consensus was reached. Data Synthesis Four antiretroviral drugs recently have been made available and have broadened the options for initial and subsequent regimens. New data allow more definitive recommendations for specific drugs or regimens to include or avoid, particularly with regard to initial therapy. Recommendations are rated according to 7 evidence categories, ranging from I (data from prospective randomized clinical trials) to VII (expert opinion of the panel). Conclusion Further insights into the roles of drug toxic effects, drug resistance, and pharmacological interactions have resulted in additional guidance for strategic approaches to antiretroviral management.
JAMA. 1998;279:1094-1099.
Objective.— To review the validity of the clinical assessment and diagnostic tests in patients with suspected deep vein thrombosis (DVT). Methods.— A comprehensive review of the literature was conducted by searching MEDLINE from 1966 to April 1997. Results.— Individual symptoms and signs alone do not reliably predict which patients have DVT. Overall, the diagnostic properties of the clinical examination are poor; the sensitivity of the clinical examination ranges from 60% to 96%, and the specificity ranges from 20% to 72%. However, using specific combinations of risk factors, symptoms, and physical signs for DVT, clinicians can reliably stratify patients with suspected DVT into low, moderate, or high pretest probability categories of actually suffering from DVT. This stratification process in combination with noninvasive testing, such as compression ultrasonography, simplifies the management strategies for patients with suspected DVT. Conclusions.— Use of a clinical prediction guide that includes specific factors from both the history and physical examination in combination with noninvasive tests simplifies management strategies for patients with suspected DVT.
JAMA. 2008;299(14):1690-1697.
Context Maintenance therapy for Crohn disease features the use of immunosuppressive drugs, which are associated with an increased risk of infection. Identification of safe and effective maintenance strategies is a priority. Objective To determine whether the oral administration of omega-3 free fatty acids is more effective than placebo for prevention of relapse of Crohn disease. Design, Setting, and Patients Two randomized, double-blind, placebo-controlled studies (Epanova Program in Crohn's Study 1 [EPIC-1] and EPIC-2) conducted between January 2003 and February 2007 at 98 centers in Canada, Europe, Israel, and the United States. Data from 363 and 375 patients with quiescent Crohn disease were evaluated in EPIC-1 and EPIC-2, respectively. Interventions Patients with a Crohn's Disease Activity Index (CDAI) score of less than 150 were randomly assigned to receive either 4 g/d of omega-3 free fatty acids or placebo for up to 58 weeks. No other treatments for Crohn disease were permitted. Main Outcome Measure Clinical relapse, as defined by a CDAI score of 150 points or greater and an increase of more than 70 points from the baseline value, or initiation of treatment for active Crohn disease. Results For EPIC-1, 188 patients were assigned to receive omega-3 free fatty acids and 186 patients to receive placebo. Corresponding numbers for EPIC-2 were 189 and 190 patients, respectively. The rate of relapse at 1 year in EPIC-1 was 31.6% in patients who received omega-3 free fatty acids and 35.7% in those who received placebo (hazard ratio, 0.82; 95% confidence interval, 0.51-1.19; P = .30). Corresponding values for EPIC-2 were 47.8% and 48.8% (hazard ratio, 0.90; 95% confidence interval, 0.67-1.21; P = .48). Serious adverse events were uncommon and mostly related to Crohn disease. Conclusion In these trials, treatment with omega-3 free fatty acids was not effective for the prevention of relapse in Crohn disease. Trial Registration clinicaltrials.gov Identifiers: EPIC-1: NCT00613197, EPIC-2: NCT00074542
JAMA. 2002;288:222-235.
Objective New information warrants updated recommendations for the 4 central issuesin antiretroviral therapy: when to start, what drugs to start with, when tochange, and what to change to. These updated recommendations are intendedto guide practicing physicians actively involved in human immunodeficiencyvirus (HIV)– and acquired immunodeficiency syndrome (AIDS)–relatedcare. Participants In 1995, physicians with specific expertise in HIV-related basic scienceand clinical research, antiretroviral therapy, and HIV patient care were invitedby the International AIDS Society-USA to serve on a volunteer panel. In 1999,others were invited to broaden international representation. The 17-memberpanel met regularly in closed meetings between its last report in 2000 andApril 2002 to review current data. The effort was sponsored and funded bythe International AIDS Society-USA, a not-for-profit physician education organization. Evidence and Consensus Process The full panel was convened in late 2000 and assigned 7 section committees.A section writer and 3 to 5 section committee members (each panel member servedon numerous sections) identified relevant evidence and prepared draft recommendations.Basic science, clinical research, and epidemiologic data from the publishedliterature and abstracts from recent (within 2 years) scientific conferenceswere considered by strength of evidence. Extrapolations from basic sciencedata and expert opinion of the panel members were included as evidence. Draftsections were combined and circulated to the entire panel and discussed ina series of full-panel conference calls until consensus was reached. Finalrecommendations represent full consensus agreement of the panel. Conclusions Because of increased awareness of the activity and toxicity of currentdrugs, the threshold for initiation of therapy has shifted to a later timein the course of HIV disease. However, the optimal time to initiate therapyremains imprecisely defined. Availability of new drugs has broadened optionsfor therapy initiation and management of treatment failure, which remainsa difficult challenge.
JAMA. 2008;300(14):1653-1659.
Context Patients with suspected deep vein thrombosis (DVT) of the lower extremities are usually investigated with ultrasonography either by the proximal veins (2-point ultrasonography) or the entire deep vein system (whole-leg ultrasonography). The latter approach is thought to be better based on its ability to detect isolated calf vein thrombosis; however, it requires skilled operators and is mainly available only during working hours. No randomized comparisons are yet available evaluating the relative values of these 2 strategies. Objective To assess if the 2 diagnostic strategies are equivalent for the management of symptomatic outpatients with suspected DVT of the lower extremities. Design, Setting, and Patients A prospective, randomized, multicenter study of consecutive symptomatic outpatients (n = 2465) with a first episode of suspected DVT of the lower extremities who were randomized to undergo 2-point or whole-leg ultrasonography. Data were taken from ultrasound laboratories of 14 Italian universities or civic hospitals between January 1, 2003, and December 21, 2006. Patients with normal ultrasound findings were followed up for 3 months, with study completion on March 20, 2007. Main Outcome Measure Objectively confirmed 3-month incidence of symptomatic venous thromboembolism in patients with an initially normal diagnostic workup. Results Of 2465 eligible patients, 345 met 1 or more exclusion criteria and 22 refused to participate; therefore, 2098 patients were randomized to either 2-point (n = 1045) or whole-leg (n = 1053) ultrasonography. Symptomatic venous thromboembolism occurred in 7 of 801 patients (incidence, 0.9%; 95% confidence interval [CI], 0.3%-1.8%) in the 2-point strategy group and in 9 of 763 patients (incidence, 1.2%; 95% CI, 0.5%-2.2%) in the whole-leg strategy group. This met the established equivalence criterion (observed difference, 0.3%;95% CI, –1.4% to 0.8%). Conclusion The 2 diagnostic strategies are equivalent when used for the management of symptomatic outpatients with suspected DVT of the lower extremities. Trial Registration clinicaltrials.gov Identifier: NCT00353093
JAMA. 2003;289:1042-1046.
The advanced access model of patient scheduling is based on the core principle that if the capacity to provide patient appointments balances the demand for appointments, patients calling to see their physician are offered an appointment the same day. The accompanying article in the series "Innovations in Primary Care" presents the theory behind advanced access scheduling. In this article we describe 4 case studies of primary care practices that successfully implemented advanced access and 3 examples of practices that were unable to achieve advanced access despite considerable efforts. The lessons of these case studies should be useful for primary care practices desiring to improve timely access to care and wishing to avoid the pitfalls that can derail this innovation.
JAMA. 2004;291:599-604.
The use of complementary and alternative medicine (CAM) has grown dramatically in recent years, as has research on the safety and efficacy of CAM treatments. Minimal attention, however, has been devoted to the ethical issues relating to research on CAM. We argue that public health and safety demand rigorous research evaluating CAM therapies, research on CAM should adhere to the same ethical requirements for all clinical research, and randomized, placebo-controlled clinical trials should be used for assessing the efficacy of CAM treatments whenever feasible and ethically justifiable. In addition, we explore the legitimacy of providing CAM and conventional therapies that have been demonstrated to be effective only by virtue of the placebo effect.
JAMA. 2008;299(18):2164-2171.
Context The arteriovenous fistula is the preferred type of vascular access for hemodialysis because of lower thrombosis and infection rates and lower health care expenditures compared with synthetic grafts or central venous catheters. Early failure of fistulas due to thrombosis or inadequate maturation is a barrier to increasing the prevalence of fistulas among patients treated with hemodialysis. Small, inconclusive trials have suggested that antiplatelet agents may reduce thrombosis of new fistulas. Objective To determine whether clopidogrel reduces early failure of hemodialysis fistulas. Design, Setting, and Participants Randomized, double-blind, placebo-controlled trial conducted at 9 US centers composed of academic and community nephrology practices in 2003-2007. Eight hundred seventy-seven participants with end-stage renal disease or advanced chronic kidney disease were followed up until 150 to 180 days after fistula creation or 30 days after initiation of dialysis, whichever occurred later. Intervention Participants were randomly assigned to receive clopidogrel (300-mg loading dose followed by daily dose of 75 mg; n = 441) or placebo (n = 436) for 6 weeks starting within 1 day after fistula creation. Main Outcome Measures The primary outcome was fistula thrombosis, determined by physical examination at 6 weeks. The secondary outcome was failure of the fistula to become suitable for dialysis. Suitability was defined as use of the fistula at a dialysis machine blood pump rate of 300 mL/min or more during 8 of 12 dialysis sessions. Results Enrollment was stopped after 877 participants were randomized based on a stopping rule for intervention efficacy. Fistula thrombosis occurred in 53 (12.2%) participants assigned to clopidogrel compared with 84 (19.5%) participants assigned to placebo (relative risk, 0.63; 95% confidence interval, 0.46-0.97; P = .018). Failure to attain suitability for dialysis did not differ between the clopidogrel and placebo groups (61.8% vs 59.5%, respectively; relative risk, 1.05; 95% confidence interval, 0.94-1.17; P = .40). Conclusion Clopidogrel reduces the frequency of early thrombosis of new arteriovenous fistulas but does not increase the proportion of fistulas that become suitable for dialysis. Trial Registration clinicaltrials.gov Identifier: NCT00067119
JAMA. 2008;299(9):1019-1026.
Context Among patients with locally advanced metastatic pancreatic adenocarcinoma, gemcitabine has been shown to improve outcomes compared with fluorouracil. Objective To determine if the addition of gemcitabine to adjuvant fluorouracil chemoradiation (chemotherapy plus radiation) improves survival for patients with resected pancreatic adenocarcinoma. Design, Setting, and Participants Randomized controlled phase 3 trial of patients with complete gross total resection of pancreatic adenocarcinoma and no prior radiation or chemotherapy enrolled between July 1998 and July 2002 with follow-up through August 18, 2006, at 164 US and Canadian institutions. Intervention Chemotherapy with either fluorouracil (continuous infusion of 250 mg/m2 per day; n = 230) or gemcitabine (30-minute infusion of 1000 mg/m2 once per week; n = 221) for 3 weeks prior to chemoradiation therapy and for 12 weeks after chemoradiation therapy. Chemoradiation with a continuous infusion of fluorouracil (250 mg/m2 per day) was the same for all patients (50.4 Gy). Main Outcome Measures Survival for all patients and survival for patients with pancreatic head tumors were the primary end points. Secondary end points included toxicity. Results A total of 451 patients were randomized, eligible, and analyzable. Patients with pancreatic head tumors (n = 388) had a median survival of 20.5 months and a 3-year survival of 31% in the gemcitabine group vs a median survival of 16.9 months and a 3-year survival of 22% in the fluorouracil group (hazard ratio, 0.82 [95% confidence interval, 0.65-1.03]; P = .09). The treatment effect was strengthened on multivariate analysis (hazard ratio, 0.80 [95% confidence interval, 0.63-1.00]; P = .05). Grade 4 hematologic toxicity was 1% in the fluorouracil group and 14% in the gemcitabine group (P < .001) without a difference in febrile neutropenia or infection. There were no differences in the ability to complete chemotherapy or radiation therapy (>85%). Conclusions The addition of gemcitabine to adjuvant fluorouracil-based chemoradiation was associated with a survival benefit for patients with resected pancreatic cancer, although this improvement was not statistically significant. Trial Registration clinicaltrials.gov Identifier: NCT00003216