Michael V. Tatley

Randomised controlled trial of self-supervised and directly observed treatment of tuberculosis

BACKGROUND Tuberculosis is a major public-health problem in South Africa, made worse by poor adherence to and frequent interruption of treatment. Direct observation (DO) of tuberculosis patients taking their drugs is supposed to improve treatment completion and outcome. We compared DO with self-supervision, in which patients on the same drug regimen are not observed taking their pills, to assess the effect of each on the success of tuberculosis treatment. METHODS We undertook an unblinded randomised controlled trial in two communities with large tuberculosis caseloads. The trial included 216 adults who started pulmonary tuberculosis treatment for the first time, or who had a second course of treatment (retreatment patients). No changes to existing treatment delivery were made other than randomisation. Analysis was by intention to treat. Individual patient data from the two communities were combined. FINDINGS Treatment for tuberculosis was more successful among self-supervised patients (60% of patients) than among those on DO (54% of patients, difference between groups 6% [90% CI -5.1 to 17.0]). Retreatment patients had significantly more successful treatment outcomes if self-supervised (74% of patients) than on DO (42% of patients, difference between groups 32% [11%-52%]). INTERPRETATION At high rates of treatment interruption, self-supervision achieved equivalent outcomes to clinic DO at lower cost. Self-supervision achieved better outcomes for retreatment patients. Supportive patient-carer relations, rather than the authoritarian surveillance implicit in DO, may improve treatment outcomes and help to control tuberculosis.

Vaccines against meningococcal serogroup B disease containing outer membrane vesicles (OMV): Lessons from past programs and implications for the future

The utility of wild-type outer membrane vesicle (wtOMV) vaccines against serogroup B (MenB) meningococcal disease has been explored since the 1970s. Public health interventions in Cuba, Norway and New Zealand have demonstrated that these protein-based vaccines can prevent MenB disease. Data from large clinical studies and retrospective statistical analyses in New Zealand give effectiveness estimates of at least 70%. A consistent pattern of moderately reactogenic and safe vaccines has been seen with the use of approximately 60 million doses of three different wtOMV vaccine formulations. The key limitation of conventional wtOMV vaccines is their lack of broad protective activity against the large diversity of MenB strains circulating globally. The public health intervention in New Zealand (between 2004–2008) when MeNZB was used to control a clonal MenB epidemic, provided a number of new insights regarding international and public-private collaboration, vaccine safety surveillance, vaccine effectiveness estimates and communication to the public. The experience with wtOMV vaccines also provide important information for the next generation of MenB vaccines designed to give more comprehensive protection against multiple strains.

Psychiatric adverse reactions with statins, fibrates and ezetimibe: implications for the use of lipid-lowering agents.

The HMG-CoA reductase inhibitors (‘statins’) have come into widespread use internationally. There has been a long history of their use in New Zealand and this use has increased in recent years. There has also been an increase in the number of reports to the New Zealand Centre for Adverse Reactions Monitoring (CARM) of suspected psychiatric adverse reactions associated with statins. The reactions mentioned in these reports include depression, memory loss, confusion and aggressive reactions. Convincing reports to CARM of recurrence of these reactions upon rechallenge add weight to recent studies reporting serious psychiatric disturbances in association with statin treatment. Aggressive reactions associated with statins are poorly documented in the literature. These observations emphasise the need to be vigilant in looking for these reactions as they can have a significant personal impact on a patient. The observation that other lipid-lowering agents have similar adverse effects supports the hypothesis that decreased brain cell membrane cholesterol may be important in the aetiology of these psychiatric reactions.

Post-Marketing Safety Monitoring of a New Group B Meningococcal Vaccine in New Zealand, 2004-2006

New Zealand introduced a new outer membrane vesicle vaccine in 2004 to combat an epidemic of group B meningococcal disease. An Independent Safety Monitoring Board oversaw intensive safety monitoring, which included hospital surveillance, health professional reporting (passive and active) and mortality monitoring. With over three million doses administered to individuals aged under 20 years, the monitoring results provide consistent evidence supporting the vaccine’s safety.

The Intensive Vaccines Monitoring Programme (IVMP) : An electronic system to monitor vaccine safety in New Zealand

New Zealand introduced a tailor-made vaccine (MeNZB) for epidemic control of Group B meningococcal disease. The Intensives Vaccine Monitoring Programme (IVMP), which prospectively collected data electronically on a cohort of children receiving vaccinations in sentinel practices across NZ, was developed as part of a national multi-faceted safety strategy. The main aim of the IVMP was to identify the presence of unexpected adverse events occurring with MeNZB vaccination. We describe the methodology and success factors plus consider the limitations encountered in this system which shows potential as a means for post-marketing vaccine and medicine surveillance in the future.

Detecting Medication Errors in the New Zealand Pharmacovigilance Database A Retrospective Analysis

AbstractBackground: Despite the traditional focus being adverse drug reactions (ADRs), pharmacovigilance centres have recently been identified as a potentially rich and important source of medication error data. Objective: To identify medication errors in the New Zealand Pharmacovigilance database (Centre for Adverse Reactions Monitoring [CARM]), and to describe the frequency and characteristics of these events. Methods: A retrospective analysis of the CARM pharmacovigilance database operated by the New Zealand Pharmacovigilance Centre was undertaken for the year 1 January–31 December 2007. All reports, excluding those relating to vaccines, clinical trials and pharmaceutical company reports, underwent a preventability assessment using predetermined criteria. Those events deemed preventable were subsequently classified to identify the degree of patient harm, type of error, stage of medication use process where the error occurred and origin of the error. Results: A total of 1412 reports met the inclusion criteria and were reviewed, of which 4.3% (61/1412) were deemed preventable. Not all errors resulted in patient harm: 29.5% (18/61) were ‘no harm’ errors but 65.5% (40/61) of errors were deemed to have been associated with some degree of patient harm (preventable adverse drug events [ADEs]). For 5.0% (3/61) of events, the degree of patient harm was unable to be determined as the patient outcome was unknown. The majority of preventable ADEs (62.5% [25/40]) occurred in adults aged 65 years and older. The medication classes most involved in preventable ADEs were antibacterials for systemic use and anti-inflammatory agents, with gastrointestinal and respiratory system disorders the most common adverse events reported. For both preventable ADEs and ‘no harm’ events, most errors were incorrect dose and drug therapy monitoring problems consisting of failures in detection of significant drug interactions, past allergies or lack of necessary clinical monitoring. Preventable events were mostly related to the prescribing and administration stages of the medication use process, with the majority of errors 82.0% (50/61) deemed to have originated in the community setting. Conclusions: The CARM pharmacovigilance database includes medication errors, many of which were found to originate in the community setting and reported as ADRs. Error-prone situations were able to be identified, providing greater opportunity to improve patient safety. However, to enhance detection of medication errors by pharmacovigilance centres, reports should be prospectively reviewed for preventability and the reporting form revised to facilitate capture of important information that will provide meaningful insight into the nature of the underlying systems defects that caused the error.

International Reports of Unexpected Low Plasma Concentrations of Dabigatran Suggest That More Frequent Measurements Will Add Value

We were interested to read the report by Chin1 recently published in this journal, suggesting that some patients may benefit from dose adjustment of non–vitamin K antagonist oral anticoagulants (NOACs), otherwise referred to as direct oral anticoagulants (DOACs). We would like to report a small case series that provides evidence for selective dose adjustment and/ormeasurement of NOACs, in particular dabigatran. The World Health Organization (WHO) Global Database of Individual Case Safety Reports (“VigiBase”) holds reports of suspected adverse drug reactions collected worldwide throughtheWHOProgramfor InternationalDrugMonitoring.2 A previous investigation of reports of thromboembolic events associated with dabigatran in VigiBase3 included a literature search, which identified four published case reports of dabigatran plasma concentrations below the expected “within therapy range” (representing the generally reported range of values identified in patients on such therapy in clinical trials). VigiBase was therefore searched for similar reports of low plasma concentrations. It is acknowledged, however, that the information provided in VigiBase is heterogeneous (i.e., it originates frommultiple sources [different countries and types of reporters] and the amount of information given, as well as the likelihood that the medicine caused the adverse reaction, may vary from case to case). Two of the published reports and 12additional reports of this unexpectedeffectwere identified, originating from five countries. While specific target therapeutic ranges for dabigatran plasma concentrations have not been validated, “within therapy” ranges identifying values that are typically seen in treated patients have been described. Thus, “expected” trough and peak dabigatran plasma levels after intake of approved dosages for atrial fibrillation are around 61 to 143 and 117 to 275 ng/mL, respectively, for 150 mg twice a day and 43 to 102 and 85 to 200 ng/mL, respectively, for 110 mg twice a day.4 Chin calculated an optimal trough range of 30 to 130 ng/mL after constructing a combined risk versus trough concentration model for a typical patient based on data from the RE-LY (Randomized Evaluation of Long-term anticoagulant therapY) trial.1 ►Table 1 shows the details of the four published case reports. Patients 1 and 2 had embolic stroke while taking dabigatran.5,6 Peak and trough plasma concentrations were measured thereafter using Hemoclot, a commercially available dilute thrombin time (dTT) assay, following witnessed intake. Patients 3 and 4 did not have thromboembolic events.7,8 Patient 3 had a lower than expected activated partial thromboplastin time (aPTT) shortly after starting dabigatran, so that peak concentrations at two dose levels were quantified, usingHemoclot, following confirmed intake after 31 days of treatment. Patient 4, who had undergone gastric bypass surgery, had trough concentrations quantified because another patient with gastric bypass developed a cardioembolic stroke on dabigatran and was found to have lower than expected aPTT values. The doses of dabigatran administered were appropriate for all four patients, especially after the dose increase in patient 3 who had normal

Active surveillance of serious adverse drug reactions in New Zealand children

Children are at risk of developing adverse drug reactions (ADRs),1 yet few are reported through postmarketing surveillance schemes monitoring safety in this vulnerable population.2 We therefore developed an active surveillance system targeting New Zealand paediatricians to enhance serious ADR notifications in children aged <16 years. A priori, paediatricians were given written case definitions of serious ADRs, which …