David L. Veenstra

VTE, Thrombophilia, Antithrombotic Therapy, and Pregnancy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines

BACKGROUND The use of anticoagulant therapy during pregnancy is challenging because of the potential for both fetal and maternal complications. This guideline focuses on the management of VTE and thrombophilia as well as the use of antithrombotic agents during pregnancy. METHODS The methods of this guideline follow the Methodology for the Development of Antithrombotic Therapy and Prevention of Thrombosis Guidelines: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines in this supplement. RESULTS We recommend low-molecular-weight heparin for the prevention and treatment of VTE in pregnant women instead of unfractionated heparin (Grade 1B). For pregnant women with acute VTE, we suggest that anticoagulants be continued for at least 6 weeks postpartum (for a minimum duration of therapy of 3 months) compared with shorter durations of treatment (Grade 2C). For women who fulfill the laboratory criteria for antiphospholipid antibody (APLA) syndrome and meet the clinical APLA criteria based on a history of three or more pregnancy losses, we recommend antepartum administration of prophylactic or intermediate-dose unfractionated heparin or prophylactic low-molecular-weight heparin combined with low-dose aspirin (75-100 mg/d) over no treatment (Grade 1B). For women with inherited thrombophilia and a history of pregnancy complications, we suggest not to use antithrombotic prophylaxis (Grade 2C). For women with two or more miscarriages but without APLA or thrombophilia, we recommend against antithrombotic prophylaxis (Grade 1B). CONCLUSIONS Most recommendations in this guideline are based on observational studies and extrapolation from other populations. There is an urgent need for appropriately designed studies in this population.

Chlorhexidine Compared with Povidone-Iodine Solution for Vascular Catheter–Site Care: A Meta-Analysis

Context Intravascular catheterrelated bloodstream infection is an important and potentially avoidable cause of morbidity. Various antiseptic solutions for skin disinfection and catheter-site care may help prevent catheter-related infections. Contribution This article summarizes data from eight randomized trials that compared antiseptic solutions. Approximately 1% of the patients with chlorhexidine gluconate disinfectant developed bloodstream infections from intravascular catheters. In the patients with disinfection by povidone-iodine, the rate was 2% (risk ratio, 0.49 [95% CI, 0.28 to 0.88]). Implications Chlorhexidine gluconate is more effective than povidoneiodine for intravascular catheter-site care. It is also more expensive. The Editors Intravascular catheters are commonly used in caring for hospitalized patients but can lead to serious infectious complications (1). Catheter-related bloodstream infection is associated with increased morbidity, mortality, length of hospitalization, and medical costs (2-6). Use of an antiseptic solution for skin disinfection at the catheter insertion site helps prevent catheter-related infections. Povidone-iodine solution is the most commonly used agent for this purpose (7, 8). Recently, several studies have compared the efficacy of povidone-iodine with that of chlorhexidine gluconate solutions for reducing vascular catheterrelated infections (7, 9-14; Knasinski V, Maki DG. A prospective, randomized, controlled trial of 1% chlorhexidine 75% alcohol vs. 10% povidone iodine for cutaneous disinfection and follow-up site care with central venous and arterial catheters [Presented paper]. San Diego: National Association of Vascular Access Network Conference; 2000). Unfortunately, because few clinical events have been observed in individual studies, it remains unclear which antiseptic solution is best, both statistically and clinically, for reducing the risk for catheter-related bloodstream infection, particularly in patients with central-line catheters. We sought to aid clinical decision making by evaluating the effectiveness of chlorhexidine gluconate versus povidone-iodine as a skin disinfectant for catheter-site care. We performed a meta-analysis of all available published and unpublished studies comparing chlorhexidine gluconate with povidone-iodine solution for vascular catheter-site care. Methods Study Selection We manually searched Index Medicus (1960 to 1965) and electronically searched MEDLINE (1966 to 2001), CINAHL: Nursing and Allied Health (1982 to 2001), Doctoral Dissertation Abstracts (1861 to 2001), International Pharmaceutical Abstracts (1970 to 2001), EMBASE, Lexis-Nexus, Web of Sciences, and Cochrane Library databases for publications in any language. For our search strategy, we used the Medical Subject Headings chlorhexidine and catheterization and the exploded key words chlorhexidine and catheter. We restricted the searches to clinical trials. To ensure that our search would be thorough, we consulted a research librarian at the University of Washington. To identify additional original studies, we reviewed the reference lists of the retrieved articles and any identified review articles. Studies presented at recent scientific meetings in the area of infection control were also identified by reviewing meeting programs and published meeting proceedings and by attending medical meetings on related topics. We contacted the manufacturer of chlorhexidine gluconate solution, the corresponding authors of relevant studies, and experts in the field to inquire about possible additional studies. To be included in the meta-analysis, a study needed 1) to be a randomized trial comparing any type of chlorhexidine gluconate solution with a povidone-iodine solution for vascular catheter-site care and 2) to report the incidence of catheter colonization or catheter-related bloodstream infection with sufficient data to calculate the risk ratio. Outcome Measures The primary outcome was catheter-related bloodstream infection, which we defined as isolation of the same organism (that is, identical species with the same antibiograms) from a peripheral blood culture and a semiquantitative or quantitative culture of a catheter segment. Our secondary outcome, catheter colonization, was defined as significant growth of microorganisms from a catheter segment, according to quantitative (>1000 colony-forming units [CFUs] per mL) or semiquantitative (>15 CFU) culture techniques (15, 16). Data Extraction Using a standardized data form, two investigators independently abstracted data on the size of the study sample, type of patient population, type of vascular catheter used, type of antiseptic used, anatomic site of insertion, use of catheter exchange with guide wire, concurrent use of other interventions, and incidence of catheter colonization and catheter-related bloodstream infection. We also evaluated the following methodologic components of each study: randomization procedure, extent of blinding, and description of eligible participants. The authors of studies that did not contain sufficient data were contacted for additional information. Statistical Analysis We separately analyzed the incidences of catheter colonization and catheter-related bloodstream infection. The summary risk ratios and 95% CIs were calculated by using the DerSimonian and Laird method under a random-effects model (17). A statistical test of heterogeneity was performed by using the Mantel-Haenszel method (18). To explore potential clinical sources of heterogeneity, we conducted sensitivity analyses according to characteristics of the study, the study participants, the types of catheters used, outcome definitions, and concentrations of antiseptics used. We explored publication bias using the funnel-plot method by graphing the effect size of trials on the horizontal axis and the number of participants in each trial on the vertical axis (19); asymmetry in the funnel plot suggested publication bias. Because some studies allowed patients to receive more than one vascular catheter during the study period, the within-patient correlation could underestimate the standard error of the effect measure. To investigate this effect, we inflated the variance of the risk ratio for each study by multiplying it by the average number of catheters per patient (20). To perform all statistical analyses, we used Stata software, version 6.0 (Stata Corp. College Station, Texas), by employing the command METAN. Results Study Selection We located 302 articles from our manual and computerized searches (Figure 1). Reviews of the titles and abstracts from the computerized search, followed by review of the full manuscripts of potentially relevant articles, identified 6 published studies that met our inclusion criteria. Of the 296 remaining studies, 285 were excluded because chlorhexidine gluconate was not used for catheter-site care (n = 268), use of the disinfectants was not determined by random allocation (n = 13), povidone-iodine was not used as a comparator (n = 2), or colonization or catheter-related bloodstream infection was not recorded (n = 2). The other 11 excluded studies were duplicate studies retrieved from different databases. In addition to the 6 studies identified from searches, 1 published abstract (9) and 1 published study (10) were identified from the reference list of a review article (21). Thus, our meta-analysis comprised 8 total studies. Studies were reviewed by two investigators, and there were no discrepancies in the abstracted data. Figure 1. Trial flow depicting the selection process of studies included in the meta-analysis. Study Characteristics Table 1 shows the characteristics of the eight included studies. These trials used 4143 catheters (1493 central venous, 1361 peripheral venous, 704 peripheral arterial, 395 pulmonary arterial, 75 peripherally inserted central venous, 62 introducer sheaths, and 53 hemodialysis). Five studies included only patients from intensive care units (7, 9, 11, 12, 14); three studies included patients from any unit in the hospital (10, 13; Knasinski V, Maki DG [Presented paper]). One study was a multicenter clinical trial (10). Among the included studies that reported patient age, the average age ranged from 50 to 65 years (7, 10-12, 14). The mean duration of catheterization for the chlorhexidine gluconate and povidone-iodine groups was similar in all studies that provided this information, except one in which the chlorhexidine gluconate group was catheterized longer (9.9 vs. 5.9 days) (14). There was no significant difference in the anatomic sites (such as subclavian or femoral) in which catheters were inserted between the chlorhexidine gluconate and povidone-iodine groups. One study allowed catheter exchange via a guide wire (7). Only one study noted adverse effects from the use of either antiseptic solution: Maki and colleagues (7) found erythema at the insertion site in 28.3% of catheters in the povidone-iodine group and in 45.3% of catheters in the chlorhexidine gluconate group (P < 0.001). However, there was no statistically significant difference in erythema among these two groups and patients whose sites were disinfected with alcohol (7). Table 1. Characteristics of Studies Comparing Chlorhexidine Gluconate Solutions with Povidone-Iodine Solutions for Vascular Catheter-Site Care The included studies used several formulations of chlorhexidine gluconate. Five studies (10, 13, 14; Knasinski V, Maki DG [Presented paper]) used an alcoholic solution, and three studies (7, 9, 11) used an aqueous solution. All studies used 10% povidone-iodine solution for the control group. However, only one study specified the sequence of applications of 70% alcohol and 10% povidone-iodine (13). Five studies clearly described their procedures for care of the catheter site (7, 10-12, 14); in these studies, the dressing was changed and the insertion site was typically cleansed every 48 to 72 hours (7). Sterile gau

Global epidemiology of hepatitis B virus.

The burden of hepatitis B virus (HBV) disease and efforts to control infection will determine the future size of the population requiring treatment of HBV infection. To quantify the current prevalence of HBV infection and to reexamine the epidemiology of HBV infection, a structured review was conducted that focused on available primary literature for over 30 countries worldwide. The prevalence of chronic HBV infection continues to be highly variable, ranging over 10% in some Asian and Western Pacific countries to under 0.5% in the United States and northern European countries. The current global estimate of the number of HBV infected individuals is 350 million. Routes of transmission include vertical (mother to child or generation to generation through close contact and sanitary habits), early life horizontal transmission (through bites, lesions, and sanitary habits), and adult horizontal transmission (through sexual contact, intravenous drug use, and medical procedure exposure) and are evident to varying degrees in every country. Younger age at acquisition of infection continues to be the most important predictor of chronic carriage. However, the choice of serologic markers, temporal influences, and representativeness of the study population limit comparability of HBV seroprevalence results. HBV vaccination programs will decrease the future global burden of HBV infection and evidence of reduced burden is mounting in country-specific populations, but vaccination programs have still not been implemented in all countries, thereby maintaining reservoirs of infection and continued HBV transmission. Regardless of vaccination, large numbers of persons are infected with HBVor will become infected. Preventing the most severe HBV disease consequences in infected individuals, such as cirrhosis and hepatocellular carcinoma, will require appropriate therapeutic agents.

Evidence-Based Management of Anticoagulant Therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines

BACKGROUND High-quality anticoagulation management is required to keep these narrow therapeutic index medications as effective and safe as possible. This article focuses on the common important management questions for which, at a minimum, low-quality published evidence is available to guide best practices. METHODS The methods of this guideline follow those described in Methodology for the Development of Antithrombotic Therapy and Prevention of Thrombosis Guidelines: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines in this supplement. RESULTS Most practical clinical questions regarding the management of anticoagulation, both oral and parenteral, have not been adequately addressed by randomized trials. We found sufficient evidence for summaries of recommendations for 23 questions, of which only two are strong rather than weak recommendations. Strong recommendations include targeting an international normalized ratio of 2.0 to 3.0 for patients on vitamin K antagonist therapy (Grade 1B) and not routinely using pharmacogenetic testing for guiding doses of vitamin K antagonist (Grade 1B). Weak recommendations deal with such issues as loading doses, initiation overlap, monitoring frequency, vitamin K supplementation, patient self-management, weight and renal function adjustment of doses, dosing decision support, drug interactions to avoid, and prevention and management of bleeding complications. We also address anticoagulation management services and intensive patient education. CONCLUSIONS We offer guidance for many common anticoagulation-related management problems. Most anticoagulation management questions have not been adequately studied.

A genome-wide scan for common genetic variants with a large influence on warfarin maintenance dose

Warfarin dosing is correlated with polymorphisms in vitamin K epoxide reductase complex 1 (VKORC1) and the cytochrome P450 2C9 (CYP2C9) genes. Recently, the FDA revised warfarin labeling to raise physician awareness about these genetic effects. Randomized clinical trials are underway to test genetically based dosing algorithms. It is thus important to determine whether common single nucleotide polymorphisms (SNPs) in other gene(s) have a large effect on warfarin dosing. A retrospective genome-wide association study was designed to identify polymorphisms that could explain a large fraction of the dose variance. White patients from an index warfarin population (n = 181) and 2 independent replication patient populations (n = 374) were studied. From the approximately 550 000 polymorphisms tested, the most significant independent effect was associated with VKORC1 polymorphisms (P = 6.2 x 10(-13)) in the index patients. CYP2C9 (rs1057910 CYP2C9*3) and rs4917639) was associated with dose at moderate significance levels (P approximately 10(-4)). Replication polymorphisms (355 SNPs) from the index study did not show any significant effects in the replication patient sets. We conclude that common SNPs with large effects on warfarin dose are unlikely to be discovered outside of the CYP2C9 and VKORC1 genes. Randomized clinical trials that account for these 2 genes should therefore produce results that are definitive and broadly applicable.

Incidence and long-term cost of steroid-related side effects after renal transplantation.

Corticosteroids are an essential component of most immunosuppressive regimens currently used in renal transplantation because of their efficacy in reducing acute rejection and improving graft survival. Steroids, however, are associated with numerous side effects that lead to increased patient morbidity and mortality. The incidence and economic cost of steroid-related side effects have not been quantitatively assessed. Thus, based on a systematic review of the published literature, we estimated the incidence of steroid-related hypertension (15%), posttransplantation diabetes mellitus (10%), peripheral fractures (2% per year), avascular necrosis of the hip (8%), and cataracts (22%). In addition, we estimated that approximately 5% of patients who have cataracts or avascular necrosis of the hip require surgery. We used these literature-based estimates in a model to project the costs of treating side effects over a 10-year posttransplantation time frame for a 50-patient cohort that represented an average-sized renal transplant center. Steroid-induced hypertension and its complications were the most expensive side effect (

Linking payment to health outcomes: A taxonomy and examination of performance-based reimbursement schemes between healthcare payers and manufacturers

93,900), followed closely by posttransplantation diabetes (

The clinical and economic consequences of nosocomial central venous catheter-related infection: are antimicrobial catheters useful?

89,700) and avascular necrosis of the hip (

The Role of Cost-Effectiveness Analysis in the Era of Pharmacogenomics

61,700). Cataracts and peripheral bone fractures were less costly (

CYP2C9 haplotype structure in European American warfarin patients and association with clinical outcomes.

16,300 and