Phase I, randomized, double-blind, placebo-controlled, single-dose escalation study of the recombinant factor VIIa variant BAY 86-6150 in hemophilia.

BACKGROUND: BAY 86-6150 is a new human recombinant factor VIIa variant developed for high procoagulant activity and longer action in people with hemophilia with inhibitors. OBJECTIVES: To investigate the safety, tolerability, pharmacodynamics, pharmacokinetics and immunogenicity of BAY 86-6150 in non-bleeding hemophilia subjects. METHODS: The study included non-bleeding men (18-65 years of age) with moderate or severe hemophilia A or B with or without inhibitors. Sixteen subjects were randomized 3 : 1 to four cohorts of escalating doses of BAY 86-6150 (6.5, 20, 50 or 90 µg kg(-1) [n = 3 per cohort]) or placebo (n = 1 per cohort); an independent data-monitoring committee reviewed previous cohort data before the next dose escalation. Blood sampling was performed predose and postdose; subjects were monitored for 50 days postdose. RESULTS: At the tested doses, BAY 86-6150 was not associated with clinically significant adverse events or dose-limiting toxicities. BAY 86-6150 pharmacokinetics exhibited a linear dose response, with a half-life of 5-7 h. Subjects demonstrated consistent, dose-dependent thrombin generation ex vivo in platelet-poor plasma (PPP) (mean peak effect, 26-237 nm thrombin from 6.5 to 90 µg kg(-1)). Peak thrombin levels over time paralleled BAY 86-6150, with thrombin kinetics appearing to be slightly shorter; thus, circulating BAY 86-6150 retained activity. There were corresponding decreases in activated partial thromboplastin and prothrombin times. No subject developed de novo anti-BAY 86-6150 neutralizing antibodies during the 50-day follow-up. CONCLUSIONS: In this first-in-human, multicenter, randomized, double-blind, placebo-controlled, single-dose escalation study, BAY 86-6150 was tolerated at the highest dose (90 µg kg(-1)), with no safety concerns. Safety and efficacy will be further evaluated in phase II/III studies.

Menorrhagia from a haematologist's point of view. Part II: management.

The management of menorrhagia has until recently been the domain of the gynaecologist. As haematologists, we are now addressing the issue of optimal management of menorrhagia in our patients with bleeding disorders. Addressing three life periods, the menarche, reproductive years, and postchildbearing years, this review will discuss the use of oral contraceptive agents, antifibrinolytics, non-steroidal anti-inflammatory drugs, intranasal DDAVP and the new levonorgestrel-impregnated IUD. Management of specific bleeding disorders will also be reviewed for von Willebrand disease, haemophilia A and B carriers, women with factor XI deficiency and PAI-1 deficiency.

Recent evidence on the effectiveness of prenatal care.

OBJECTIVE: To assess the evidence of effectiveness of prenatal care. DESIGN: A 2-day conference with commissioned papers with summary at the Agency for Healthcare Research and Quality. OUTCOME MEASURES: Effectiveness of prenatal care in preventing prematurity, intrauterine growth restriction, and birth defects and in improving women's health. CONCLUSIONS: Current technology provides limited ability to prevent adverse fetal outcomes but may do much to ameliorate morbidity. However, the latter is not well assessed in data systems. In contrast, the opportunity to improve women's health appears much greater, but doing so is hampered by a number of structural and attitudinal barriers.

Health and health care status of African-born residents of Metropolitan Washington, DC.

This study examines health status, health behaviors, and health care access and utilization among African-born residents of the metropolitan Washington, DC area. A telephone survey was administered to a random sample of 525 African-born adults. Results are compared to those for the general local and regional population. Twenty-nine percent of respondents were uninsured; 24% lacked a usual, appropriate source of primary care. Among female respondents, 44% and 34% reported never having had a mammogram or pap smear, respectively. Most health status indicators demonstrated relatively good health, but 15% of respondents reported one of the infectious diseases we investigated. Consumption of alcohol and tobacco was relatively low. African-born residents are generally at risk regarding access to health care, and certain segments (the uninsured, recent arrivals) face critical access barriers. Infectious diseases are a notable feature of health status, and use of some preventive and dental services is considerably lower than for the general population.

Multiple arterial thromboembolisms in a patient with the 20210 A prothrombin gene mutation.

The most recently characterized genetic defect contributing to venous thrombophilia is the 20210 A prothrombin gene mutation. We describe a patient with this defect who had arterial thrombosis resulting in considerable mesenteric ischemia. Several environmental factors, which might otherwise be considered of low thrombotic risk, may also have contributed to her condition. The recognition of the potential for novel presentations of hypercoagulable states may contribute to a reduction in the morbidity associated with acute mesenteric ischemia.

Hematologic management of gastrointestinal bleeding.

The hematologic management of gastrointestinal (GI) bleeding requires evaluation of the underlying cause of bleeding, associated diseases that can exacerbate the bleeding, and identification of related and unrelated coagulation abnormalities. Erythrocyte transfusions are given to increase oxygen carrying capacity; however, there is limited information on the level of anemia that places a patient at increased risk of adverse events after a GI bleed and when patients should receive erythrocyte transfusion. Isolated thrombocytopenia is uncommon in patients with GI bleeding, and there is little evidence documenting the degree of thrombocytopenia associated with an increased risk of bleeding. Platelets are often administered when the count is 50,000 per cu/mL in a bleeding patient. The coagulopathy of liver disease is the most common abnormality seen in the setting of GI bleeding. Fresh-frozen plasma (FFP) should be given in a dose equivalent to the underlying abnormality and the common practice of administering 2 units of FFP is often insufficient in a bleeding patient.

Distress, personality, and mammography utilization among women with a family history of breast cancer.

The authors examined the impact of psychological distress and the personality construct of conscientiousness (as measured by the Neuroticism, Extraversion, and Openness-Five Factor Inventory) on mammography utilization among women who were at increased risk for breast cancer. Participants were 200 women who had at least 1 first degree relative with breast cancer. Overall, 80% of the participants had obtained a mammogram in the previous year. Analyses controlling for potential confounders (perceived risk, decisional balance, and physician recommendation for mammography), revealed that distress was negatively associated with mammography utilization among participants who were low in conscientiousness. Distress was not significantly related to mammography utilization among highly conscientious women. The results are discussed in terms of their implications regarding interventions designed to increase mammography utilization in this population.

Antithrombin activity during the period of percutaneous coronary revascularization: relation to heparin use, thrombotic complications and restenosis.

OBJECTIVES: This study evaluated changes in antithrombin (AT) activity around the time of percutaneous transluminal coronary revascularization (PTCR) with unfractionated heparin anticoagulation and the effects these changes had on major thrombotic complications of PTCR. BACKGROUND: Heparin is used during PTCR to prevent thrombosis. However, heparin, a cofactor for AT, causes AT activity to fall. AT activity <70% is associated with thrombosis. There is a prothrombotic state after heparin discontinuation that has not been well explained. METHODS: Antithrombin activity was sampled at the start and end of PTCR and the next two mornings in 250 consecutive patients. We recorded occurrence of major thrombotic events, defined as 1) major thrombotic complications of PTCR; 2) major in-lab thrombus formation; or 3) subacute occlusion. Discriminant analysis was employed to evaluate the relationship of AT activity to these events. Change in AT activity and its relationship to heparin was evaluated. Evidence of restenosis at six months was obtained. RESULTS: There were 14 major thrombotic events. Antithrombin activity <70% was strongly (p = 0.006) associated with these events. The AT activity fell significantly through the morning after PTCR when 21% of patients had AT activity <70%; AT activity did not normalize until >20 h after heparin discontinuation. Pre-PTCR use of heparin led to lower AT activity in proportion to duration of heparin use. There was no relationship between AT activity and restenosis. CONCLUSIONS: Low AT activity may contribute to major thrombotic complications of PTCR. The way heparin is used before and after PTCR is important to development of low AT activity.

Monitoring heparin therapy: APTT results from partial- vs full-draw tubes.

Results of the activated partial thromboplastin time (APTT) test can be influenced by biologic, preanalytic, and analytic variables. When a patient is being treated with unfractionated heparin, the correct interpretation of the APTT test result is essential. Laboratories should evaluate all variables influencing this result, particularly when determining the "therapeutic" range for heparin treatment. This study compared the APTT results assayed on specimens drawn into 2 different types of evacuated blood collection tubes. A statistically significant difference was seen in the results when the APTT was outside the reference interval, including results in the therapeutic range for unfractionated heparin. When the therapeutic range is determined by the laboratory, the evacuated blood collection tube system must be standardized.

Effect (or lack of it) of severe anemia on PT and APTT results.

Whether it is necessary to adjust the citrate volume in blood collection tubes for patients with anemia is unknown; however, the standard of care is not to adjust the volume. We compared the prothrombin time (PT) and activated partial thromboplastin time (APTT) test results of nonadjusted and adjusted citrate amounts in specimens from patients who are severely anemic. Samples were drawn into a 3.8% citrate volume, and if the hematocrit was less than 25% (0.25), additional samples were drawn into adjusted citrate tubes. The PT and APTT were run on 78 pairs of specimens, and the correlation coefficient was 0.98 for both assays. A statistically significant difference was noted between sample results collected in evacuated tubes in which the citrate volumes were adjusted to the hematocrit vs those in which it was not. However, when the difference between sets of values was plotted against the hematocrit, there was no correlation. There seems to be no need to change the standard practice for obtaining coagulation specimens into 3.8% citrate for patients who are anemic.

Whose blood is safer? The effect of the stage of the epidemic on screening for HIV.

BACKGROUND: With improvements in HIV antibody test (ELISA) performance, the window of time between infection and seroconversion becomes a major source of error in HIV screening. The authors examined its impact on the false-reassurance rate (FRR). METHODS: Test sensitivity was modeled as the product of two factors: the inherent sensitivity (sensitivity when antibody is present) and the probability that antibody is present in infected blood. A model of HIV and AIDS incidence was used to derive an estimate of the probability of remaining in the seronegative window (pw) among those who are infected. With plausible assumptions, this probability approaches 0.03. The FRR was then estimated as a function of the probability of remaining in the seronegative window, the prevalence of HIV, and the inherent sensitivity of the ELISA test were estimated. RESULTS: The FRRs for two blood donor groups, one with an HIV prevalence of 0.004 and a typical probability of remaining in the seronegative window (pw = 0.03) and the other with a higher prevalence of 0.017 but fewer donors in the window (pw = 0.003), are equal (140 per million donors) if the blood is negative on a single ELISA test. After two negative tests or a single test that can detect antibody more reliably, however, the FRR is much higher in the group with the higher pw (= 120 per million compared with 50 per million), because the greater numbers of donors in the window more than offsets the lower prevalence. CONCLUSION: With improvements in inherent sensitivity of ELISA by virtue of technical progress or retesting, the prevalence of HIV infection may no longer play the critical role in degrading the results of blood screening. As inherent test performance improves, tests are increasingly likely to miss infected blood because of the seronegative-window error rather than because of measurement error. Window error plays a proportionally greater role during the early stages of HIV dissemination in a population where the incidence of new HIV infection is high relative to the incidence of AIDS. These findings may explain, in part, the recent observation that cases of transfusion of contaminated blood often take place in areas where AIDS epidemics have started recently. They also suggest that the traditional strategy of soliciting blood donors from low-prevalence populations may not always be optimal, unless such populations are truly low-risk.

Expected hemoglobin decrease following percutaneous transluminal coronary angioplasty.

To establish expected changes in hemoglobin during and after percutaneous transluminal coronary angioplasty (PTCA), we measured hemoglobin before, at the end of, and on the 2 mornings after PTCA in 177 consecutive patients without obvious out-of-laboratory blood loss. From these data, we calculated confidence intervals that can be used to compare group data, possibly to identify excessive blood loss with new devices or antithrombotic agents, and prediction intervals to identify unexpected blood loss in an individual patient.

Guidelines for pharmacoeconomic studies. Recommendations from the panel on cost effectiveness in health and medicine. Panel on cost Effectiveness in Health and Medicine.

This article reports the recommendations of the Panel on Cost Effectiveness in Health and Medicine, sponsored by the US Public Health Service, on standardised methods for conducting cost-effectiveness analyses. Although not expressly directed at analyses of pharmaceutical agents, the Panel's recommendations are relevant to pharmacoeconomic studies. The Panel outlines a 'Reference Case' set of methodological practices to improve quality and comparability of analyses. Designed for studies that inform resource-allocation decisions, the Reference Case includes recommendations for study framing and scope, components of the numerator and denominator of cost-effectiveness ratios, discounting, handling uncertainty and reporting. The Reference Case analysis is conducted from the societal perspective, and includes all effects of interventions on resource use and health. Resource use includes 'time' resources, such as for caregiving or undergoing an intervention. The quality-adjusted life-year (QALY) is the common measure of health effect across Reference Case studies. Although the Panel does not endorse a measure for obtaining quality-of-life weights, several recommendations address the QALY. The Panel recommends a 3% discount rate for costs and health effects. Pharmacoeconomic studies have burgeoned in recent years. The Reference Case analysis will improve study quality and usability, and permit comparison of pharmaceuticals with other health interventions.

The role of cost-effectiveness analysis in health and medicine. Panel on Cost-Effectiveness in Health and Medicine.

OBJECTIVE: To develop consensus-based recommendations guiding the conduct of cost-effectiveness analysis (CEA) to improve the comparability and quality of studies. The recommendations apply to analyses intended to inform the allocation of health care resources across a broad range of conditions and interventions. This article, first in a 3-part series, discusses how this goal affects the conduct and use of analyses. The remaining articles will outline methodological and reporting recommendations, respectively. PARTICIPANTS: The Panel on Cost-Effectiveness in Health and Medicine, a nonfederal panel with expertise in CEA, clinical medicine, ethics, and health outcomes measurement, was convened by the US Public Health Service (PHS). EVIDENCE: The panel reviewed the theoretical foundations of CEA, current practices, and alternative procedures for measuring and assigning values to resource use and health outcomes. CONSENSUS PROCESS: The panel met 11 times during 2 1/2 years with PHS staff and methodologists from federal agencies. Working groups brought issues and preliminary recommendations to the full panel for discussion. Draft recommendations were circulated to outside experts and the federal agencies prior to finalization. CONCLUSIONS: The panel's recommendations define a "reference case" cost-effectiveness analysis, a standard set of methods to serve as a point of comparison across studies. The reference case analysis is conducted from the societal perspective and accounts for benefits, harms, and costs to all parties. Although CEA does not reflect every element of importance in health care decisions, the information it provides is critical to informing decisions about the allocation of health care resources.

Recommendations for reporting cost-effectiveness analyses. Panel on Cost-Effectiveness in Health and Medicine.

OBJECTIVE: This article, the third in a 3-part series, describes recommendations for the reporting of cost-effective analyses (CEAs) intended to improve the quality and accessibility of CEA reports. PARTICIPANTS: The Panel on Cost-Effectiveness in Health and Medicine, a nonfederal panel with expertise in CEA, clinical medicine, ethics, and health outcomes measurement, convened by the US Public Health Service. EVIDENCE: The panel reviewed the theoretical foundations of CEA, current practices, alternative methods, published critiques of CEAs, and criticisms of general CEA methods and reporting practices. CONSENSUS PROCESS: The panel developed recommendations through 2 1/2 years of discussions. Comments on preliminary drafts were solicited from federal government methodologists, health agency officials, and academic methodologists. CONCLUSIONS: These recommendations are proposed to enhance the transparency of study methods, assist analysts in providing complete information, and facilitate the presentation of comparable cost-effectiveness results across studies. Adherence to reporting conventions and attention to providing information required to understand and interpret study results will improve the relevance and accessibility of CEAs.

Recommendations of the Panel on Cost-effectiveness in Health and Medicine.

OBJECTIVE: To develop consensus-based recommendations for the conduct of cost-effectiveness analysis (CEA). This article, the second in a 3-part series, describes the basis for recommendations constituting the reference case analysis, the set of practices developed to guide CEAs that inform societal resource allocation decisions, and the content of these recommendations. PARTICIPANTS: The Panel on Cost-Effectiveness in Health and Medicine, a nonfederal panel with expertise in CEA, clinical medicine, ethics, and health outcomes measurement, was convened by the US Public Health Service (PHS). EVIDENCE: The panel reviewed the theoretical foundations of CEA, current practices, and alternative methods used in analyses. Recommendations were developed on the basis of theory where possible, but tempered by ethical and pragmatic considerations, as well as the needs of users. CONSENSUS PROCESS: The panel developed recommendations through 2 1/2 years of discussions. Comments on preliminary drafts prepared by panel working groups were solicited from federal government methodologists, health agency officials, and academic methodologists. CONCLUSIONS: The panel's methodological recommendations address (1) components belonging in the numerator and denominator of a cost-effectiveness (C/E) ratio; (2) measuring resource use in the numerator of a C/E ratio; (3) valuing health consequences in the denominator of a C/E ratio; (4) estimating effectiveness of interventions; (5) incorporating time preference and discounting; and (6) handling uncertainty. Recommendations are subject to the ¿rule of reason,¿ balancing the burden engendered by a practice with its importance to a study. If researchers follow a standard set of methods in CEA, the quality and comparability of studies, and their ultimate utility, can be much improved.