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1.  Code development of the national hemovigilance system and expansion strategies for hospital blood banks 
Objectives:
The aims of this study were to develop reportable event codes that are applicable to the national hemovigilance systems for hospital blood banks, and to present expansion strategies for the blood banks.
Materials and Methods:
The data were obtained from a literature review and expert consultation, followed by adding to and revising the established hemovigilance code system and guidelines to develop reportable event codes for hospital blood banks. The Medical Error Reporting System-Transfusion Medicine developed in the US and other codes of reportable events were added to the Korean version of the Biologic Products Deviation Report (BPDR) developed by the Korean Red Cross Blood Safety Administration, then using these codes, mapping work was conducted. We deduced outcomes suitable for practice, referred to the results of the advisory councils, and conducted a survey with experts and blood banks practitioners.
Results:
We developed reportable event codes that were applicable to hospital blood banks and could cover blood safety - from blood product safety to blood transfusion safety - and also presented expansion strategies for hospital blood banks.
Conclusion:
It was necessary to add 10 major categories to the blood transfusion safety stage and 97 reportable event codes to the blood safety stage. Contextualized solutions were presented on 9 categories of expansion strategies of hemovigilance system for the hospital blood banks.
doi:10.4103/0973-6247.98916
PMCID: PMC3439753  PMID: 22988379
Biologic products deviation report; hemovigilance; medical error reporting system-transfusion medicine; reportable event code
2.  Retrospective evaluation of adverse transfusion reactions following blood product transfusion from a tertiary care hospital: A preliminary step towards hemovigilance 
Background:
The goal of hemovigilance is to increase the safety and quality of blood transfusion. Identification of the adverse reactions will help in taking appropriate steps to reduce their incidence and make blood transfusion process as safe as possible.
Aims:
To determine the frequency and type of transfusion reactions (TRs) occurring in patients, reported to the blood bank at our institute.
Materials and Methods:
A retrospective review of all TRs reported to the blood bank at the All India Institute of Medical Sciences, between December 2007 and April 2012 was done. All the TRs were evaluated in the blood bank and classified using standard definitions.
Results:
During the study period a total of 380,658 bloods and blood components were issued by our blood bank. Out of the total 196 adverse reactions reported under the hemovigilance system, the most common type of reaction observed was allergic 55.1% (n = 108), followed by febrile non-hemolytic transfusion reaction (FNHTR) 35.7% (n = 70). Other less frequently observed reactions were Anaphylactoid reactions 5.1% (n = 10), Acute non-immune HTRs 2.6% (n = 5), Circulatory overload 0.5% (n = 1), Transfusion related acute lung injury 0.5% (n = 1), Delayed HTRs 0.5% (n = 1). Not a single case of bacterial contamination was observed.
Conclusion:
The frequency of TRs in our patients was found to be 0.05% (196 out of 380,658). This can be an underestimation of the true incidence because of under reporting. It should be the responsibility of the blood transfusion consultant to create awareness amongst their clinical counterpart about safe transfusion practices so that proper hemovigilance system can be achieved to provide better patient care.
doi:10.4103/0973-6247.115564
PMCID: PMC3757769  PMID: 24014939
Adverse transfusion reactions; blood transfusion; hemovigilance
3.  Hemovigilance Program–India 
A centralized hemovigilance program to assure patient safety and to promote public health has been launched for the first time in India on Dec 10, 2012 in 60 medical colleges in the first phase along with a well-structured program for monitoring adverse reactions associated with blood transfusion and blood product administration. National Institute of Biologicals (NIB) will be the National Coordinating Centre for Hemovigilance. This program will be implemented under overall ambit of Pharmacovigilance Program of India (PvPI), which is being coordinated by Indian Pharmacopoeia Commission (IPC). All medical colleges of the country will be enrolled in this program by the year 2016 in order to have a National Centre of Excellence for Hemovigilance at NIB, which will act as a global knowledge platform.
doi:10.4103/0973-6247.106744
PMCID: PMC3613669  PMID: 23559771
Hemovigilance; India; Medical colleges; Transfusion Reaction Reporting Form
4.  French Haemovigilance Data on Platelet Transfusion 
Summary
The Agence Française de Securite Sanitaire des Produits de Santé (Afssaps; French Health Products Safety Agency) is responsible, through its hemovigilance unit, for the organization and the functioning of the national hemovigilance network. In accordance with the French law, it receives all data on adverse transfusion reactions regardless of their severity. With the aim of evaluating the tolerance of two kinds of labile blood products (LBP), pooled platelet concentrates (PP) and apheresis platelet concentrates (APC), we screened the French national database from January 1, 2000 to December 31, 2006. We observed that the number of transfusion incident reports is more than twice as high with APC (8.61:1,000 LBP) than with PP (4.21:1,000 LBP). The difference between these two ratios is statistically significant as shown by chi-square test (e = 21.00 with α = 5%). The risk to suffer adverse reactions of any type, except for alloimmunization, is higher with APC, and the major type of diagnosis related to APC is allergic reaction (1:200 APC issued) even if those allergic reactions are rarely serious. The new French National Hemovigilance Commission should impel a working group evaluating this topic and above all the impact of additive solutions which have been used since 2005 to put forward preventives measures.
doi:10.1159/000118887
PMCID: PMC3076346  PMID: 21512639
French hemovigilance; Apheresis platelet concentratece; Pooled platelet concentrate; Adverse reaction
5.  Pathogen Inactivation of Platelet and Plasma Blood Components for Transfusion Using the INTERCEPT Blood System™ 
Summary
Background
The transmission of pathogens via blood transfusion is still a major threat. Expert conferences established the need for a pro-active approach and concluded that the introduction of a pathogen inactivation/reduction technology requires a thorough safety profile, a comprehensive pre-clinical and clinical development and an ongoing hemovigilance program.
Material and Methods
The INTERCEPT Blood System utilizes amotosalen and UVA light and enables for the treatment of platelets and plasma in the same device. Preclinical studies of pathogen inactivation and toxicology and a thorough program of clinical studies have been conducted and an active he-movigilance-program established.
Results
INTERCEPT shows robust efficacy of inactivation for viruses, bacteria (including spirochetes), protozoa and leukocytes as well as large safety margins. Furthermore, it integrates well into routine blood center operations. The clinical study program demonstrates the successful use for very diverse patient groups. The hemovigilance program shows safety and tolerability in routine use. Approximately 700,000 INTERCEPT-treated products have been transfused worldwide. The system is in clinical use since class III CE-mark registration in 2002. The safety and efficacy has been shown in routine use and during an epidemic.
Conclusion
The INTERCEPT Blood System for platelets and plasma offers enhanced safety for the patient and protection against transfusion-transmitted infections.
doi:10.1159/000323937
PMCID: PMC3132977  PMID: 21779203
Pathogen inactivation; Platelets; Plasma; Amotosalen
6.  Normative evaluation of blood banks in the Brazilian Amazon region in respect to the prevention of transfusion-transmitted malaria 
Objective
To evaluate blood banks in the Brazilian Amazon region with regard to structure and procedures directed toward the prevention of transfusion-transmitted malaria (TTM).
Methods
This was a normative evaluation based on the Brazilian National Health Surveillance Agency (ANVISA) Resolution RDC No. 153/2004. Ten blood banks were included in the study and classified as ‘adequate’ (≥80 points), ‘partially adequate’ (from 50 to 80 points), or ‘inadequate’ (<50 points). The following components were evaluated: ‘donor education’ (5 points), ‘clinical screening’ (40 points), ‘laboratory screening’ (40 points) and ‘hemovigilance’ (15 points).
Results
The overall median score was 49.8 (minimum = 16; maximum = 78). Five blood banks were classified as ‘inadequate’ and five as ‘partially adequate’. The median clinical screening score was 26 (minimum = 16; maximum = 32). The median laboratory screening score was 20 (minimum = 0; maximum = 32). Eight blood banks performed laboratory tests for malaria; six tested all donations. Seven used thick smears, but only one performed this procedure in accordance with Ministry of Health requirements. One service had a Program of External Quality Evaluation for malaria testing. With regard to hemovigilance, two institutions reported having procedures to detect cases of transfusion-transmitted malaria.
Conclusion
Malaria is neglected as a blood–borne disease in the blood banks of the Brazilian Amazon region. None of the institutions were classified as ‘adequate’ in the overall classification or with regard to clinical screening and laboratory screening. Blood bank professionals, the Ministry of Health and Health Surveillance service managers need to pay more attention to this matter so that the safety procedures required by law are complied with.
doi:10.1016/j.bjhh.2014.09.002
PMCID: PMC4318476  PMID: 25453648
Health evaluation; Malaria; Blood banks; Donor selection; Blood safety
7.  Pathogen Inactivation Technologies for Cellular Blood Components: an Update 
Summary
Nowadays patients receiving blood components are exposed to much less transfusion-transmitted infectious diseases than three decades before when among others HIV was identified as causative agent for the acquired immunodeficiency syndrome and the transmission by blood or coagulation factors became evident. Since that time the implementation of measures for risk prevention and safety precaution was socially and politically accepted. Currently emerging pathogens like arboviruses and the well-known bacterial contamination of platelet concentrates still remain major concerns of blood safety with important clinical consequences, but very rarely with fatal outcome for the blood recipient. In contrast to the well-established pathogen inactivation strategies for fresh frozen plasma using the solvent-detergent procedure or methylene blue and visible light, the bench-to-bedside translation of novel pathogen inactivation technologies for cell-containing blood components such as platelets and red blood cells are still underway. This review summarizes the pharmacological/toxicological assessment and the inactivation efficacy against viruses, bacteria, and protozoa of each of the currently available pathogen inactivation technologies and highlights the impact of the results obtained from several randomized clinical trials and hemovigilance data. Until now in some European countries pathogen inactivation technologies are in in routine use for single-donor plasma and platelets. The invention and adaption of pathogen inactivation technologies for red blood cell units and whole blood donations suggest the universal applicability of these technologies and foster a paradigm shift in the manufacturing of safe blood.
doi:10.1159/000365646
PMCID: PMC4164100  PMID: 25254027
Pathogen inactivation; Blood safety; Dengue virus; Chikungunya virus; West Nile virus; Bacteria; Protozoa; Platelet concentrates; Red blood cells; Randomized clinical trial; Hemovigilance
8.  Teaching transfusion medicine: current situation and proposals for proper medical training 
The current curricula in medical schools and hospital residence worldwide lack exposure to blood transfusion medicine, and require the reformulation of academic programs. In many countries, training in blood transfusion is not currently offered to medical students or during residency. Clinical evidence indicates that blood transfusions occur more frequently than recommended, contributing to increased risk due to this procedure. Therefore, the rational use of blood and its components is essential, due to the frequent undesirable reactions, to the increasing demand of blood products and the cost of the process. Significant improvements in knowledge of and skills in transfusion medicine are needed by both students and residents. Improvements are needed in both background knowledge and the practical application of this knowledge to improve safety. Studies prove that hemovigilance has an impact on transfusion safety and helps to prevent the occurrence of transfusion-related adverse effects. To ensure that all these aspects of blood transfusion are being properly addressed, many countries have instituted hospital transfusion committees. From this perspective, the interventions performed during the formation of medical students and residents, even the simplest, have proven effective in the acquisition of knowledge and medical training, thereby leading to a reduction in inappropriate use of blood. Therefore, we would like to emphasize the importance of the exposure of medical students and residents to blood services and transfusion medicine in order for them to acquire adequate medical training, as well as to discuss some changes in the current medical curricula regarding transfusion medicine that we judge critical.
doi:10.1016/j.bjhh.2014.11.004
PMCID: PMC4318849  PMID: 25638770
Blood transfusion; Advisory committees; Blood safety
9.  The importance of hemovigilance in the transmission of infectious diseases 
Background
Hemovigilance is an organized system of surveillance throughout the transfusion chain intended to evaluate information in order to prevent the appearance or recurrence of adverse reactions related to the use of blood products.
Objective
The aims of this study were to assess the late reporting of incidents related to possible seroconversion in respect to age, marital status and ethnical background, annual variations in late reporting, the number of reports opened and closed, seroconversion of donors and transfusions of blood products within the window period.
Methods
This retrospective, descriptive study used data on blood donations in the blood bank in Uberaba during the period from 2004 to 2011. Some socio-epidemiological characteristics of the donors and serology test results of donors and recipients were analyzed in respect to the late reporting of incidents related to possible seroconversion. The Chi-square test, odds ratio and a regression model were used for statistical analysis.
Results
From 2004 to 2011, the blood bank in Uberaba collected 117,857 blood bags, 284 (0.24%) of which were investigated for late reported incidents. The profile of the donors was less than 29 years old, unmarried and non-Whites. Differences in age (p-value < 0.0001), marital status (p-value = 0.0002) and ethnical background (p-value < 0.0001) were found to be statistically significant. There was no statistical difference between men and women (0.24% and 0.23% respectively; p-value = 0.951). The number of late reported incidents increased until 2008 followed by a downward trend until 2011. There were twelve cases of seroconversion in subsequent donations (seven human immunodeficiency virus, four hepatitis B and one hepatitis C) with proven human immunodeficiency virus infection after screening of only one recipient.
Conclusion
The twelve cases of seroconversion in donors with subsequent infection proven in one recipient underscores the importance of this tool to increase transfusion safety.
doi:10.5581/1516-8484.20130040
PMCID: PMC3728130  PMID: 23904807
Blood safety; Serology; Blood donors; Blood transfusion/adverse effects; Communicable diseases/transmission; Quality assurance, health care; Retrospective studies
10.  Epidemiological Data – an Important Part of the Hemovigilance System 
Summary
Epidemiological data are essential for monitoring trends and outbreaks of infectious diseases in the general population. The reporting system pursuant to the Infection Protection Act in Germany results in a very good quality of timely nationwide data on all reportable diseases including those relevant for the blood supply: HIV, hepatitis C, hepatitis B and syphilis. Notifications of acute hepatitis B and first-time diagnosed hepatitis C infections in the general population showed a declining trend in the past years, but the number of reports of HIV and syphilis infections increased until 2007 especially among men who have sex with men. New preventive strategies should also address changes in sexual behavior. The specific surveillance of blood donors is an important part of the hemovigilance system. The highly effective donor selection process results in a small number of confirmed infections among donors in Germany. The surveillance data enable us to identify specific trends that might challenge blood safety like the increase in HIV infections among repeat donors. Specific evaluations are performed when needed. These additional studies can be used to modify guidelines or recommendations and to (re)evaluate the need for or the effect of further testing.
doi:10.1159/000314212
PMCID: PMC2889626  PMID: 20577601
Blood donation; HBV; HCV; Hemovigilance; HIV; Epidemiology
11.  Viral inactivation in hemotherapy: systematic review on inactivators with action on nucleic acids 
The aim of this study was to conduct a systematic review on the photoinactivators used in hemotherapy, with action on viral genomes. The SciELO, Science Direct, PubMed and Lilacs databases were searched for articles. The inclusion criterion was that these should be articles on inactivators with action on genetic material that had been published between 2000 and 2010. The key words used in identifying such articles were "hemovigilance", "viral inactivation", "photodynamics", "chemoprevention" and "transfusion safety". Twenty-four articles on viral photoinactivation were found with the main photoinactivators covered being: methylene blue, amotosalen HCl, S-303 frangible anchor linker effector (FRALE), riboflavin and inactin. The results showed that methylene blue has currently been studied least, because it diminishes coagulation factors and fibrinogen. Riboflavin has been studied most because it is a photoinactivator of endogenous origin and has few collateral effects. Amotosalen HCl is effective for platelets and is also used on plasma, but may cause changes both to plasma and to platelets, although these are not significant for hemostasis. S-303 FRALE may lead to neoantigens in erythrocytes and is less indicated for red-cell treatment; in such cases, PEN 110 is recommended. Thus, none of the methods for pathogen reduction is effective for all classes of agents and for all blood components, but despite the high cost, these photoinactivators may diminish the risk of blood-transmitted diseases.
doi:10.5581/1516-8484.20120056
PMCID: PMC3459627  PMID: 23049426
Blood safety; Virus inactivation; Chemoprevention; Nucleic acids
12.  ‘Sterility Testing of Blood Components and Advanced Therapy Medicinal Products’ (Munich, April 29, 2010) Organized by the DGTI Section ‘Safety in Hemotherapy’ - Meeting Report 
Neither screening method completely detects all clinically relevant bacterial contaminations. The effect of sampling time and volume as well as standardization of the assay applied has also to be taken into account. Therefore, minimizing the risk of contamination during manufacture by measures such as donor selection, skin disinfection, division, and processing within closed systems remains crucial. In this context new concepts in sterility testing, especially with instable advanced therapy medicinal products (ATMPs), are needed as well as reassessment of pathogen inactivation techniques. At present hemovigilance data indicate that shortening the shelf life of platelet concentrates as introduced in Germany 2008 reduced the risk of transfusion-transmitted bacterial infections to the same extent as bacterial screening as done in Canada or the Netherlands. The evolving methodological progress, e.g. by standardizing culture methods or enhancing detection systems, requires careful follow-up in parallel to hemovigilance data in order to ensure optimal bacterial safety in hemotherapy.
doi:10.1159/000331397
PMCID: PMC3364095  PMID: 22670121
Sterility testing; Bacterial contamination; Blood components; Advanced therapy medicinal products; Hemovigilance
13.  Pulmonary Transfusion Reactions 
Summary
Background
In recent years, pulmonary transfusion reactions have gained increasing importance as serious adverse transfusion events.
Methods
Review of the literature.
Results
Pulmonary transfusion reactions are not extremely rare and, according to hemovigilance data, important causes of transfusion-induced major morbidity and death. They can be classified as primary with predominant pulmonary injury and secondary as part of another transfusion reaction. Primary reactions include transfusion-related acute lung injury (TRALI), transfusion-associated circulatory overload (TACO) and transfusion-associated dyspnea (TAD). Secondary pulmonary reactions are often observed in the wake of hemolytic transfusion reactions, hypotensive/anaphylactic reactions, and transfusion-transmitted bacterial infections.
Conclusion
Knowledge and careful management of cases of pulmonary transfusion reactions are essential for correct reporting to blood services and hemovigilance systems. Careful differentiation between TRALI and TACO is important for taking adequate preventive measures.
doi:10.1159/000151349
PMCID: PMC3076325  PMID: 21512622
Acute lung injury; Transfusion reaction; Transfusion risks
14.  Prevalence of Acute Blood Transfusion Reactions in Mazandaran Heart Center, Sari, Iran, 2010-2012 
Medical Archives  2014;68(2):137-139.
ABSTRACT
Introduction:
Although blood transfusion is life saving for patients, it is responsible for a series of complications and exposes the patients to a variety of risks. Therefore knowing different adverse effects of blood transfusion represents a great issue in managing recipient patients.
Aim:
The aim of the present work was to study the prevalence of blood transfusion complications among patients in the Mazandaran Heart Center, Sari, Iran, during a period of 2 years.
Material and Methods:
A retrospective review of all reported and evaluated acute transfusion reactions during a 2 years period in Mazandaran Heart Center was performed. Associated clinical signs and symptoms were evaluated.
Results:
In 9193 transfused blood products, there was 34 (0.4%) acute transfusion reactions. The commonest were discomfort and restlessness(0.16%), dyspnea(0.16%), rigors (0.13%), fever (0.08%), chest pain(0.06%), rash or urticaria (0.04%), nausea and vomiting(0.03%), palpitation(0.03%), hypertension(0.03%)flashing(0.02%), hypotension(0.02%).
Conclusion:
Acute transfusion reaction is seen in %0.4 of transfused patients therefore, we recommend a well-structured program for monitoring adverse reactions associated with blood transfusion and blood product administration (Hemovigilance program).
doi:10.5455/medarh.2014.68.137-139
PMCID: PMC4272498  PMID: 24937941
Blood transfusion; acute transfusion reactions; hemovigilance
15.  An association between decreased cardiopulmonary complications (TRALI and TACO) and implementation of universal leukoreduction of blood transfusions 
Transfusion  2010;50(12):2738-2744.
Background
Cardiopulmonary adverse events after transfusion include acute lung injury (TRALI) and circulatory overload (TACO), which are potentially lethal and incompletely understood.
Study Design and Methods
To determine whether the incidence of TRALI and TACO was affected by leukoreduction we conducted a retrospective, before and after study of acute transfusion reactions for the seven years prior to and after introduction of universal leukoreduction in 2000, involving 778,559 blood components.
Results
Substantial decreases occurred in the rates of TRALI (−83%; from 2.8 cases per 100,000 components pre- to 0.48 post-universal leukoreduction; p=0.01), TACO (−49%; 7.4 to 3.8 cases per 100,000; p=0.03) and febrile reactions (−35%; 11.4 to 7.4 cases per 10,000; p<0.0001). The incidence of allergic reactions remained unchanged (7.0 per 100,000 pre- and post-universal leukoreduction). These outcomes were primarily attributable to decreased TRALI/TACO associated with RBC and platelet transfusions (−64%) with notably smaller decreases associated with FFP or cryoprecipitate transfusions (−29%). The incidence of TRALI/TACO after 28,120 washed red cell and 69,325 platelet transfusions was zero.
Conclusion
These data suggest novel hypotheses for further testing in animal models, in prospective clinical trials, and via the new US Hemovigilance System : (1) Is TACO or TRALI mitigated by leukoreduction? (2) Is the mechanism of TACO more complex than excessive blood volume? (3) Does washing mitigate TRALI and TACO due to platelet and RBC transfusions?
doi:10.1111/j.1537-2995.2010.02748.x
PMCID: PMC2944002  PMID: 20561296
16.  Epidemiology of Transfusion Related Acute Lung Injury in France: Preliminary Results 
Summary
The French Hemovigilance Network has been established in 1994 and records all adverse events associated with the transfusion of a labile blood products (LBP) regardless of their severity. From 1994 to 2006 35,423,172 LBP were issued, 85,812 adverse transfusion reactions notified, and 139 cases of transfusion related acute lung injury (TRALI) observed. The LBP most at risk is fresh frozen plasma (FFP), followed by platelets concentrates (PC) and packed red cells (PRC). However, because the use of FFP is not frequent in France, it only accounts for about 10% of TRALI, whereas PRC and PC are involved in the remaining cases. In no case, pooled FFP treated with solvent-detergent were involved. Patients’ profiles are peculiar with a high disease burden. Therefore, targeting a prevention policy only on FFP would result in a marginal reduction of TRALI in France.
doi:10.1159/000117812
PMCID: PMC3076340  PMID: 21512633
TRALI; Hemovigilance; Blood transfusion; Sickle cell disease; Public health
17.  A Randomized, Double-Blind, Placebo-Controlled Trial of Lessertia frutescens in Healthy Adults 
PLoS Clinical Trials  2007;2(4):e16.
Objectives:
Indigenous medicines are widely used throughout Africa, despite a lack of scientific evidence for their safety or efficacy. The aims of this study were: (a) to conduct a pilot study of the safety of a common indigenous South African phytotherapy, Lessertia frutescens (Sutherlandia), in healthy adults; and (b) to contribute to establishing procedures for ethical and scientifically rigorous clinical trials of African indigenous medicines.
Design:
A randomized, double-blind, placebo-controlled trial of Sutherlandia leaf powder in healthy adults.
Setting:
Tiervlei Trial Centre, Karl Bremer Hospital, Bellville, South Africa.
Participants:
25 adults who provided informed consent and had no known significant diseases or allergic conditions nor clinically abnormal laboratory blood profiles during screening.
Intervention:
12 participants randomized to a treatment arm consumed 400 mg capsules of Sutherlandia leaf powder twice daily (800 mg/d). 13 individuals randomized to the control arm consumed a placebo capsule. Each participant received 180 capsules for the trial duration of 3 mo.
Outcome Measures:
The primary endpoint was frequency of adverse events; secondary endpoints were changes in physical, vital, blood, and biomarker indices.
Results:
There were no significant differences in general adverse events or physical, vital, blood, and biomarker indices between the treatment and placebo groups (p > 0.05). However, participants consuming Sutherlandia reported improved appetite compared to those in the placebo group (p = 0.01). Although the treatment group exhibited a lower respiration rate (p < 0.04) and higher platelet count (p = 0.03), MCH (p = 0.01), MCHC (p = 0.02), total protein (p = 0.03), and albumin (p = 0.03), than the placebo group, these differences remained within the normal physiological range, and were not clinically relevant. The Sutherlandia biomarker canavanine was undetectable in participant plasma.
Conclusion:
Consumption of 800 mg/d Sutherlandia leaf powder capsules for 3 mo was tolerated by healthy adults.
Editorial Commentary
Background: In Africa, traditional herbal medicines are given for many illnesses. In particular, one herbal medicine, Sutherlandia (Lessertia frutescens) is commonly given in the belief that this herb will treat some of the symptoms associated with HIV/AIDS, such as nausea and lack of appetite, amongst others. However, there is very little evidence relating to the safety and none to the efficacy of this herb. Generally, when new drugs are developed, the first stage of human testing involves a Phase 1 trial. This type of trial would typically involve small numbers of healthy individuals, who would receive progressively increasing doses of the drug under study, and would be closely monitored for any sign of side effects. Phase 1 trials would typically also collect data from blood samples to find out how the drug is handled in the body and broken down and eliminated. Therefore, the researchers here carried out a preliminary study to assess just the safety of Sutherlandia. 25 healthy adults were randomized to receive either tablets containing a fixed dose of Sutherlandia leaf powder daily for three months, or matched placebo tablets containing lettuce leaf powder, for the same period of time. The main aim of the trial was to assess safety, so the primary outcomes were adverse events experienced by the participants. The researchers also measured standard outcomes such as blood pressure, heart rate, body weight, urine glucose, protein, and many others, at one-month intervals over the three-month period.
What the trial shows: Adverse events experienced by trial participants over the three months of this trial included those that might be expected in a group of otherwise healthy individuals, such as headaches, insomnia, allergies, malaise, palpitations, nosebleeds, and so on. The researchers did not see statistically significant differences between treatment and placebo groups in any of the major categories of these events. Most physical and laboratory measurements also showed no statistically significant differences between the study groups. However, there were statistically significant, but small, differences between groups in respiratory rate and in various basic blood tests. The researchers did not think these differences were clinically important. Overall, this trial suggested that Sutherlandia use was not associated with side effects at this dosage and over this time scale.
Strengths and limitations: Strengths of this study include the use of randomization to distribute individuals to either the Sutherlandia or control groups, and in the use of a placebo control group, which therefore allowed the researchers to compare the frequencies of adverse events in the Sutherlandia group with what might be expected among healthy individuals over the course of three months. An important limitation is the small sample size of the trial. This size limits the sensitivity of the trial to detect rare adverse events to the herb under study, and therefore one cannot say conclusively that the herb is safe, based on this data. Additionally, the study looked only at the participants' response to one dosage level of Sutherlandia. A strategy using progressively increasing doses would have allowed the researchers to see if there was a maximum tolerated dose to this herb. A further limitation in this study is the lack of data relating to how the herb is broken down in the body; these data are normally an important part of Phase 1 trials and, combined with safety data, are crucial to finding out whether a compound is safe when given at a dosage that allows it to be available to the appropriate tissues.
Contribution to the evidence: Data from previous studies in nonhuman primates have shown that Sutherlandia is not associated with toxic or other side effects at approximately equivalent or higher doses than that normally taken by people with HIV/AIDS. This study adds safety data relating to Sutherlandia consumption in healthy humans, which confirm the primate data. However, it is crucial to collect more data relating to how the probable active ingredients of Sutherlandia are absorbed and broken down, and to assess safety at different dosages, before studies are even considered for the next stage, which is to see whether Sutherlandia has any efficacy in people with HIV/AIDS.
doi:10.1371/journal.pctr.0020016
PMCID: PMC1863514  PMID: 17476314
18.  Safety Events during an Automated Telephone Self-Management Support Intervention 
Background
Interactive health information technology (HIT) can support the complex self-management tasks for diabetes. However, less is known about between-visit interactions and patient safety among chronic illness patients treated in the outpatient setting.
Methods
We classified 13 categories for safety events and potential safety events within a larger trial evaluating a multilingual automated telephone self-management support system for diabetes using interactive voice response. Participants could trigger safety concerns by reporting hyperglycemia or hypoglycemia, inability to obtain medications, medication nonadherence and side effects, and needing appointments and/or supplies. We then examined these triggers across patient demographic and health characteristics to determine which patients were most likely to experience safety events.
Results
Overall, there were 360 safety triggers that occurred among 155 participants, which represented 53% of individuals and 7.6% of all automated calls over the 27-week intervention. The most common triggers were for pain or medication side effects (22%) and not checking blood sugars (13%). In adjusted models, race/ethnicity and language were related to safety triggers; Spanish-speaking participants were significantly (p = .02) more likely than English-speaking participants to experience a safety trigger, and black participants were marginally more likely (p =.09) than white participants to experience a safety trigger.
Conclusion
About half of patients enrolled in a self-management technology intervention triggered at least one potential safety event over the course of the trial, and this was more frequent among some patients. Systems implementing HIT strategies to improve self-care and remote monitoring should consider specific program design elements to address these potential safety events.
PMCID: PMC3869126  PMID: 23759391
diabetes self-care; interactive voice response intervention; patient safety
19.  Intermittent Preventive Treatment of Malaria in Pregnancy with Mefloquine in HIV-Negative Women: A Multicentre Randomized Controlled Trial 
PLoS Medicine  2014;11(9):e1001733.
Clara Menéndez and colleagues conducted an open-label randomized controlled trial in HIV-negative pregnant women in Benin, Gabon, Mozambique, and Tanzania to evaluate the safety and efficacy of mefloquine compared to sulfadoxine-pyrimethamine for intermittent preventative therapy for malaria.
Please see later in the article for the Editors' Summary
Background
Intermittent preventive treatment in pregnancy (IPTp) with sulfadoxine-pyrimethamine (SP) is recommended by WHO to prevent malaria in African pregnant women. The spread of SP parasite resistance has raised concerns regarding long-term use for IPT. Mefloquine (MQ) is the most promising of available alternatives to SP based on safety profile, long half-life, and high efficacy in Africa. We evaluated the safety and efficacy of MQ for IPTp compared to those of SP in HIV-negative women.
Methods and Findings
A total of 4,749 pregnant women were enrolled in an open-label randomized clinical trial conducted in Benin, Gabon, Mozambique, and Tanzania comparing two-dose MQ or SP for IPTp and MQ tolerability of two different regimens. The study arms were: (1) SP, (2) single dose MQ (15 mg/kg), and (3) split-dose MQ in the context of long lasting insecticide treated nets. There was no difference on low birth weight prevalence (primary study outcome) between groups (360/2,778 [13.0%]) for MQ group and 177/1,398 (12.7%) for SP group; risk ratio [RR], 1.02 (95% CI 0.86–1.22; p = 0.80 in the ITT analysis). Women receiving MQ had reduced risks of parasitemia (63/1,372 [4.6%] in the SP group and 88/2,737 [3.2%] in the MQ group; RR, 0.70 [95% CI 0.51–0.96]; p = 0.03) and anemia at delivery (609/1,380 [44.1%] in the SP group and 1,110/2743 [40.5%] in the MQ group; RR, 0.92 [95% CI 0.85–0.99]; p = 0.03), and reduced incidence of clinical malaria (96/551.8 malaria episodes person/year [PYAR] in the SP group and 130/1,103.2 episodes PYAR in the MQ group; RR, 0.67 [95% CI 0.52–0.88]; p = 0.004) and all-cause outpatient attendances during pregnancy (850/557.8 outpatients visits PYAR in the SP group and 1,480/1,110.1 visits PYAR in the MQ group; RR, 0.86 [0.78–0.95]; p = 0.003). There were no differences in the prevalence of placental infection and adverse pregnancy outcomes between groups. Tolerability was poorer in the two MQ groups compared to SP. The most frequently reported related adverse events were dizziness (ranging from 33.9% to 35.5% after dose 1; and 16.0% to 20.8% after dose 2) and vomiting (30.2% to 31.7%, after dose 1 and 15.3% to 17.4% after dose 2) with similar proportions in the full and split MQ arms. The open-label design is a limitation of the study that affects mainly the safety assessment.
Conclusions
Women taking MQ IPTp (15 mg/kg) in the context of long lasting insecticide treated nets had similar prevalence rates of low birth weight as those taking SP IPTp. MQ recipients had less clinical malaria than SP recipients, and the pregnancy outcomes and safety profile were similar. MQ had poorer tolerability even when splitting the dose over two days. These results do not support a change in the current IPTp policy.
Trial registration
ClinicalTrials.gov NCT 00811421; Pan African Clinical Trials Registry PACTR 2010020001429343
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Half the world's population is at risk of malaria, a mosquito-borne parasitic disease that kills about 600,000 people every year. Most of these deaths occur among young children in sub-Saharan Africa but pregnant women and their unborn children living in Africa are also very vulnerable to malaria. Infection with malaria during pregnancy can cause severe maternal anemia (reduced red blood cell numbers), stillbirths, and pre-term and low-birthweight babies, and is responsible for the deaths of many African babies and women. To prevent this loss of life, the World Health Organization (WHO) recommends a three-pronged approach—the delivery to pregnant women of the antimalarial drug sulfadoxine-pyrimethamine (SP) at each scheduled antenatal care visit given at least one month apart (intermittent preventive treatment in pregnancy; IPTp), the use of insecticide treated bed nets to protect pregnant women from the bites of infected mosquitoes, and effective case management of pregnant women with malarial illness.
Why Was This Study Done?
IPTp with SP reduces the delivery of low-birth-weight babies and neonatal deaths but malaria parasites are becoming resistant to SP. Thus, other antimalarial drugs need to be evaluated for use in IPTp. Suitable drugs need to remain in the body for a long time to maximize their prophylactic (preventative) effect, they need to be given as a single dose at antenatal clinic visits to ensure compliance, and they must not harm the unborn child. In this open-label, randomized controlled trial (RCT), the researchers compare the efficacy and safety of IPTp with SP and mefloquine (MQ, an antimalarial drug that matches these criteria) in HIV-negative women living in Africa. The study also compares the tolerability of two MQ regimens. RCTs compare outcomes in groups of people chosen to receive different interventions through the play of chance; in open-label RCTs, both the researchers and the study participants know which treatment is being administered. IPTp with SP is only recommended for HIV-negative women because SP interacts with cotrimoxazole, which is routinely given to HIV-positive individuals to prevent infections.
What Did the Researchers Do and Find?
The researchers assigned 4,749 pregnant women in Benin, Gabon, Mozambique, and Tanzania to one of three study groups. Participants in the SP and MQ groups received two doses of SP or MQ, respectively, administered at least one month apart. Participants in the split-dose MQ group received each MQ dose as half doses given on consecutive days. The prevalence of low-birth-weight deliveries (the study's primary outcome; the prevalence of a condition is the proportion of a population with that condition) was similar in the SP group and in the combined MQ groups. However, compared to women who received SP, women who received MQ had a lower risk of parasitemia (parasites in the blood), a lower risk of anemia at delivery, fewer episodes of clinical malaria, and fewer outpatient attendances. The prevalence of placental infection with malaria parasites and of adverse pregnancy outcomes such as stillbirth was similar in all the study groups. Finally, the tolerability of IPTp was poorer in the two MQ intervention groups than in the SP group, but similar proportions of adverse events (mainly dizziness and vomiting) were reported for the two MQ dosing regimens.
What Do These Findings Mean?
These findings indicate that HIV-negative African women taking MQ for IPTp had a similar risk of a low-birth-weight delivery (the study's primary outcome) and lower risk of malaria illness during pregnancy than women taking SP for IPTp. Because the study did not have a no-IPTp arm (for ethical reasons), these findings provide no information about the efficacy or safety or either MQ or SP per se; these findings only indicate that MQ is no more efficacious than SP in the prevention of low-birth-weight babies. Moreover, because the study was open-label, the accuracy of the findings related to the tolerability and safety of MQ compared to SP may be limited because of biases in the assessment of safety outcomes. Given that the MQ dose used here for IPTp was associated with poorer tolerability than that of SP, these findings do not support the use of MQ instead of SP for IPTp.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001733.
A related PLOS Medicine Research Article by Raquel González and colleagues examines IPTp-MQ in HIV-infected women receiving cotrimoxazole prophylaxis
This study is further discussed in a PLOS Medicine Perspective by Richard Steketee.
Information is available from the World Health Organization on malaria (in several languages) and on malaria in pregnancy; information on IPTp and the updated WHO policy recommendation on IPTp with SP are available; the 2013 World Malaria Report provides details of the current global malaria situation
The US Centers for Disease Control and Prevention also provides information on malaria; a personal story about malaria in pregnancy is available
Information is available from the Roll Back Malaria Partnership on all aspects of global malaria control, including information on malaria in pregnancy
The Malaria in Pregnancy Consortium is undertaking research into the prevention and treatment of malaria in pregnancy
MedlinePlus provides links to additional information on malaria (in English and Spanish)
doi:10.1371/journal.pmed.1001733
PMCID: PMC4172436  PMID: 25247709
20.  Tenofovir Disoproxil Fumarate for Prevention of HIV Infection in Women: A Phase 2, Double-Blind, Randomized, Placebo-Controlled Trial 
PLoS Clinical Trials  2007;2(5):e27.
Objectives:
The objective of this trial was to investigate the safety and preliminary effectiveness of a daily dose of 300 mg of tenofovir disoproxil fumarate (TDF) versus placebo in preventing HIV infection in women.
Design:
This was a phase 2, randomized, double-blind, placebo-controlled trial.
Setting:
The study was conducted between June 2004 and March 2006 in Tema, Ghana; Douala, Cameroon; and Ibadan, Nigeria.
Participants:
We enrolled 936 HIV-negative women at high risk of HIV infection into this study.
Intervention:
Participants were randomized 1:1 to once daily use of 300 mg of TDF or placebo.
Outcome measures:
The primary safety endpoints were grade 2 or higher serum creatinine elevations (>2.0 mg/dl) for renal function, grade 3 or 4 aspartate aminotransferase or alanine aminotransferase elevations (>170 U/l) for hepatic function, and grade 3 or 4 phosphorus abnormalities (<1.5 mg/dl). The effectiveness endpoint was infection with HIV-1 or HIV-2.
Results:
Study participants contributed 428 person-years of laboratory testing to the primary safety analysis. No significant differences emerged between treatment groups in clinical or laboratory safety outcomes. Study participants contributed 476 person-years of HIV testing to the primary effectiveness analysis, during which time eight seroconversions occurred. Two were diagnosed in participants randomized to TDF (0.86 per 100 person-years) and six in participants receiving placebo (2.48 per 100 person-years), yielding a rate ratio of 0.35 (95% confidence interval = 0.03–1.93), which did not achieve statistical significance. Owing to premature closures of the Cameroon and Nigeria study sites, the planned person-years of follow-up and study power could not be achieved.
Conclusion:
Daily oral use of TDF in HIV-uninfected women was not associated with increased clinical or laboratory adverse events. Effectiveness could not be conclusively evaluated because of the small number of HIV infections observed during the study.
Editorial Commentary
Background: The World Health Organization has estimated that in 2006 around 4.3 million people were newly infected with HIV. Infection rates seem to be increasing in some countries, and there is an urgent need to find safe and effective ways of preventing HIV from being transmitted from one person to another. Many strategies for the prevention of HIV transmission between adults, such as use of condoms or changes to behavior, are not completely reliable, and women, in particular, may not always be able to negotiate condom use. Additional strategies for reducing the risk of HIV transmission are needed. One of these strategies is called “pre-exposure prophylaxis.” This strategy involves individuals who are at high risk of becoming infected with HIV taking antiviral drugs to prevent HIV infection. One particular drug, tenofovir disoproxil fumarate, is currently approved as a treatment for HIV infection, and is also being investigated as a strong candidate for pre-exposure prophylaxis. The research presented here reports on results of a trial carried out at three different sites in Ghana, Cameroon, and Nigeria. In the trial, 936 women who were not infected with HIV but who were at high risk of becoming infected, were randomized to take tenofovir tablets daily or, alternatively, placebo tablets. The researchers planned to follow up with the women for 12 months, and the primary analysis for efficacy would focus on a comparison of the rate of new HIV infections between the two arms of the trial. Primary safety analyses included specific laboratory tests carried out on blood samples that might point to abnormalities in liver or kidney function. Safety data were also collected throughout the trial, and health problems that arose were classified as adverse events or serious adverse events.
What this trial shows: Unfortunately, this trial was not completed as planned. Two sites (Nigeria and Cameroon) were closed either before the planned number of participants had been recruited or before all participants had completed full follow-up. Therefore, not enough data were available from this trial to determine whether tenofovir reduced the risk of HIV infection. Only two sites contributed data for the primary safety analyses, which looked at liver and kidney function. The researchers did not see any statistically significant differences in these safety endpoints between participants taking tenofovir and those taking placebo. There were also no statistically significant differences between the treatment groups in the number of adverse events. The main efficacy analysis found two new HIV infections in the tenofovir group and six in the placebo group. Because only eight effectiveness endpoints were observed during this study, the difference in HIV incidence between these groups was not statistically significant.
Strengths and limitations: A strength of this trial is that it was correctly designed to address the original objectives of the study, involving appropriate concealment of randomization and blinding of participants and study staff to treatment assignment. The main limitation of this study was the closure of two study sites, which meant that the study did not have sufficient power to assess differences between trial arms in the primary efficacy analysis.
Contribution to the evidence: At the time this trial was completed, there was no other evidence from randomized studies that evaluated antiretroviral drugs for prevention of HIV infection. This trial cannot, however, definitively address whether tenofovir reduces the risk of HIV infection among at-risk women or not. Ongoing and future trials are essential in order to answer this question. The trial reported here provides important data on the safety of daily tenofovir among high-risk HIV-uninfected women; the safety data are encouraging and suggest that tenofovir use is not associated with increased adverse events as compared to placebo.
doi:10.1371/journal.pctr.0020027
PMCID: PMC1876601  PMID: 17525796
21.  Limit Allogeneic Blood Use with Routine Re-use of Patient's Own Blood: A Prospective, Randomized, Controlled Trial in Total Hip Surgery 
PLoS ONE  2012;7(9):e44503.
Background
There are risks related to blood incompatibility and blood-borne diseases when using allogeneic blood transfusion. Several alternatives exist today, one of which, used for autologous blood salvage perioperatively, is the Sangvia Blood Management System. This study was designed to investigate the efficacy of the system and to add data to previously reported safety results.
Methodology/Principal Findings
Two hundred sixteen patients undergoing primary or revision total hip arthroplasty (THA) were enrolled in this randomized, controlled, assessor-blinded multicenter study. Randomization was either autologous blood transfusion (Sangvia group) or no use of autologous blood (Control group), both in combination with a transfusion protocol for allogeneic transfusion. Patients were followed during hospital stay and at two months after discharge. The primary outcome was allogeneic blood transfusion frequency. Data on blood loss, postoperative hemoglobin/hematocrit, safety and quality of life were also collected. The effectiveness analysis including all patients showed an allogeneic blood transfusion rate of 14% in both groups. The efficacy analysis included 197 patients and showed a transfusion rate of 9% in the Sangvia group as compared to 13% in the Control group (95%CI −0.05–0.12, p = 0.5016). A mean of 522 mL autologous blood was returned in the Sangvia group and lower calculated blood loss was seen. 1095 mL vs 1285 mL in the Control group (95%CI 31–346, p = 0.0175). No differences in postoperative hemoglobin was detected but a lower hematocrit reduction after surgery was seen among patients receiving autologous blood. No relevant differences were found for safety parameters or quality of life.
Conclusions/Significance
General low use of allogeneic blood in THA is seen in the current study of the Sangvia system used together with a transfusion protocol. The trial setting is under-powered due to premature termination and therefore not able to verify efficacy for the system itself but contributes with descriptive data on safety.
Trial Registration
Clinicaltrials.gov NCT00822588
doi:10.1371/journal.pone.0044503
PMCID: PMC3441549  PMID: 23028549
22.  Blood transfer devices for malaria rapid diagnostic tests: evaluation of accuracy, safety and ease of use 
Malaria Journal  2011;10:30.
Background
Malaria rapid diagnostic tests (RDTs) are increasingly used by remote health personnel with minimal training in laboratory techniques. RDTs must, therefore, be as simple, safe and reliable as possible. Transfer of blood from the patient to the RDT is critical to safety and accuracy, and poses a significant challenge to many users. Blood transfer devices were evaluated for accuracy and precision of volume transferred, safety and ease of use, to identify the most appropriate devices for use with RDTs in routine clinical care.
Methods
Five devices, a loop, straw-pipette, calibrated pipette, glass capillary tube, and a new inverted cup device, were evaluated in Nigeria, the Philippines and Uganda. The 227 participating health workers used each device to transfer blood from a simulated finger-prick site to filter paper. For each transfer, the number of attempts required to collect and deposit blood and any spilling of blood during transfer were recorded. Perceptions of ease of use and safety of each device were recorded for each participant. Blood volume transferred was calculated from the area of blood spots deposited on filter paper.
Results
The overall mean volumes transferred by devices differed significantly from the target volume of 5 microliters (p < 0.001). The inverted cup (4.6 microliters) most closely approximated the target volume. The glass capillary was excluded from volume analysis as the estimation method used is not compatible with this device. The calibrated pipette accounted for the largest proportion of blood exposures (23/225, 10%); exposures ranged from 2% to 6% for the other four devices. The inverted cup was considered easiest to use in blood collection (206/226, 91%); the straw-pipette and calibrated pipette were rated lowest (143/225 [64%] and 135/225 [60%] respectively). Overall, the inverted cup was the most preferred device (72%, 163/227), followed by the loop (61%, 138/227).
Conclusions
The performance of blood transfer devices varied in this evaluation of accuracy, blood safety, ease of use, and user preference. The inverted cup design achieved the highest overall performance, while the loop also performed well. These findings have relevance for any point-of-care diagnostics that require blood sampling.
doi:10.1186/1475-2875-10-30
PMCID: PMC3041722  PMID: 21303528
23.  Performance review of the National Blood Safety Improvement Project in Korea (2004-2009) 
Blood research  2013;48(2):139-144.
Background
In 2004, the Korean government and blood transfusion community deliberated on the issue of a national blood system reform and agreed to implement a 5-year project (2004-2009) to further improve safety measures. Our study delineates the basis of the current national blood program and analyzes the performance of this 5-year project initiated by the Korean government.
Methods
A performance review of the 5-year project was conducted from May 2009 to February 2010 using various approaches. Numerous data and documentation were collected from the Korean Red Cross and the Korean Centers for Disease Control and Prevention and reviewed by experts. Approximately 20 interviews with representatives of stakeholder groups were conducted to gather information, opinions, and perceptions. We conducted a nationwide field survey on a total of 144 blood donor centers.
Results
Among the 5 major categories of the 5-year project, blood donor recruitment, laboratory testing, and product manufacturing were improved in terms of quality performance. Specifically, government's financial support ensured that the infrastructure of blood donor centers and blood laboratory centers improved. The pivotal role of the government contributed to improvements in the national blood program and enhanced national surveillance for blood safety.
Conclusion
Korea has made a tremendous effort with positive outcomes to provide safety measures for blood products for transfusion in its citizens. In all areas of blood management, from blood donations to transfusions, continuous developments in monitoring safety standards and practices are paramount.
doi:10.5045/br.2013.48.2.139
PMCID: PMC3698400  PMID: 23826584
Blood safety; Improvement project; Quality performance
24.  Artist® Tablets (Carvedilol) for Hypertensive Patients in Japan 
Drugs in R&D  2012;11(2):191-205.
Background: In Japan, when pharmaceutical companies launch a new drug, they are obligated to conduct a post-marketing survey to evaluate the safety and efficacy of the drug in accordance with Good Post-Marketing Surveillance Practice under Article 14-4 (re-examination) of the Pharmaceutical Affairs Law at contracted medical institutions. We report the results of a long-term special survey that we conducted as a post-marketing survey.
Objective: The results of a prospective post-marketing survey that was conducted to assess the safety and efficacy of the b-adrenergic receptor antagonist (β-blocker) Artist® tablets 10 mg, 20mg (carvedilol) in patients with hypertension in Japan, were investigated in order to examine the safety and efficacy of the drug during long-term treatment (18 months).
Patients: Patients were carvedilol-naive and had essential hypertension or renal parenchymal hypertension.
Methods: We performed this survey as a prospective cohort study (special survey) utilizing a centralized registration method over 3 years (starting from April 1994), for an observation period of 18 months of carvedilol treatment.
Results: Sixty-one medical institutions across Japan collected 380 case report forms of patients who received long-term administration of carvedilol, with 363 and 341 cases evaluated for safety and efficacy, respectively. The discontinuation rate was 7.2% and the incidence of adverse drug reactions was 5.23% (19 of 363) in the safety population. There was no significant change in fasting plasma glucose levels from baseline (118.1 ± 46.5mg/dL) to after carvedilol treatment (114.6 ± 43.3 mg/dL) [n = 141; p = 0.310].
In 341 evaluable patients in the efficacy population, decreases in both blood pressure and pulse rate were statistically significant at all assessment points in comparison with baseline data (p < 0.001). Similarly, in hypertensive patients with diabetes mellitus, decreases in blood pressure were statistically significant at all assessment points in comparison with baseline data (p < 0.001).
Conclusions: The results of this study show that carvedilol exerted stable antihypertensive effects leading to favorable blood pressure control throughout long-term treatment, without showing any safety concerns. It was concluded that there were no clinically significant issues in terms of safety or efficacy with the long-term treatment of carvedilol in patients with hypertension.
doi:10.2165/11592460-000000000-00000
PMCID: PMC3585767  PMID: 21679008
25.  Artist® Tablets (Carvedilol) for Hypertensive Patients in Japan 
Drugs in R&d  2012;11(2):191-205.
Background: In Japan, when pharmaceutical companies launch a new drug, they are obligated to conduct a post-marketing survey to evaluate the safety and efficacy of the drug in accordance with Good Post-Marketing Surveillance Practice under Article 14-4 (re-examination) of the Pharmaceutical Affairs Law at contracted medical institutions. We report the results of a long-term special survey that we conducted as a post-marketing survey.
Objective: The results of a prospective post-marketing survey that was conducted to assess the safety and efficacy of the b-adrenergic receptor antagonist (β-blocker) Artist® tablets 10 mg, 20mg (carvedilol) in patients with hypertension in Japan, were investigated in order to examine the safety and efficacy of the drug during long-term treatment (18 months).
Patients: Patients were carvedilol-naive and had essential hypertension or renal parenchymal hypertension.
Methods: We performed this survey as a prospective cohort study (special survey) utilizing a centralized registration method over 3 years (starting from April 1994), for an observation period of 18 months of carvedilol treatment.
Results: Sixty-one medical institutions across Japan collected 380 case report forms of patients who received long-term administration of carvedilol, with 363 and 341 cases evaluated for safety and efficacy, respectively. The discontinuation rate was 7.2% and the incidence of adverse drug reactions was 5.23% (19 of 363) in the safety population. There was no significant change in fasting plasma glucose levels from baseline (118.1 ± 46.5mg/dL) to after carvedilol treatment (114.6 ± 43.3 mg/dL) [n = 141; p = 0.310].
In 341 evaluable patients in the efficacy population, decreases in both blood pressure and pulse rate were statistically significant at all assessment points in comparison with baseline data (p < 0.001). Similarly, in hypertensive patients with diabetes mellitus, decreases in blood pressure were statistically significant at all assessment points in comparison with baseline data (p < 0.001).
Conclusions: The results of this study show that carvedilol exerted stable antihypertensive effects leading to favorable blood pressure control throughout long-term treatment, without showing any safety concerns. It was concluded that there were no clinically significant issues in terms of safety or efficacy with the long-term treatment of carvedilol in patients with hypertension.
doi:10.2165/11592460-000000000-00000
PMCID: PMC3585767  PMID: 21679008

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