Pessary or progesterone to prevent preterm birth in women with short cervical length.: Protocol of the 4–6 year follow-up of a randomised controlled trial (Quadruple-P)

INTRODUCTION: Vaginal progesterone and a cervical pessary are both interventions that are investigated for the prevention of preterm birth (PTB). Thus far, beneficial or harmful effects of these interventions on long-term child health and development are described, but evidence is not robust enough to draw firm conclusions. With this follow-up study, we intent to investigate if progesterone or a pessary is superior for the prevention of PTB considering the child's health at 4-6 years of corrected age. METHODS AND ANALYSIS: This study is a follow-up study of the Quadruple-P trial; a multicentre, randomised clinical trial (NL42926.018.13, Eudractnumber 2013-002884-24) which randomises women with an asymptomatic midtrimester short cervix to daily progesterone or a pessary for the prevention of PTB. All children born to mothers who participated in the Quadruple-P study (n=628 singletons and n=332 multiples) will be eligible for follow-up at 4-6 years of corrected age. Children will be assessed using parental questionnaires. Main outcomes are child (neuro)development and behaviour. Other outcomes include child mortality, growth and general health. A composite of adverse child outcomes will be compared between the progesterone and pessary groups reporting OR and the corresponding 95% CI. Analyses will be performed separately for singletons and multiples and using the intention-to-treat approach. ETHICS AND DISSEMINATION: The Medical Research Ethics Committee from Amsterdam UMC confirmed that de Medical Research Involving Human Subjects Act (WMO) did not apply to our study (W20_481 #20.531). Results will be published in a peer-reviewed journal and shared with stakeholders and participants. This protocol is published before analysis of the results. TRIAL REGISTRATION NUMBER: Dutch Trial Register (NL9646)

Acetylsalicylic acid use is associated with reduced risk of out-of-hospital cardiac arrest in the general population: Real-world data from a population-based study

AIM: Activated blood platelet products facilitate myocardial intracellular Ca2+ overload, thereby provoking afterdepolarizations and increasing susceptibility of ischemic myocardium to ventricular fibrillation (VF). These effects are counteracted in vitro by acetylsalicylic acid (ASA), but no prior study investigated whether ASA is associated with decreased out-of-hospital cardiac arrest (OHCA) risk on a population level. Therefore, we studied whether ASA and other antiplatelet drugs (carbasalate calcium, clopidogrel) are associated with decreased risk of OHCA. METHODS: We conducted a population-based case-control study among individuals (772 OHCA-cases with documented VT/VF, 2444 non-OHCA-controls) who had used antiplatelet drugs in the year before index-date (OHCA-date), and studied the association between current antiplatelet drug use and OHCA-risk with multivariable logistic regression analysis. RESULTS: ASA use was associated with reduced OHCA-risk (adjusted odds ratio (ORadj) 0.6 [0.5-0.8]), and more so in women (ORadj 0.3 [0.2-0.6]) than in men (ORadj 0.7 [0.5-0.95], Pinteraction 0.021). Carbasalate calcium was associated with decreased OHCA-risk in women (ORadj 0.5 [0.3-0.9]), but not in men (ORadj 1.3 [0.96-1.7], Pinteraction 0.005). Clopidogrel was not associated with reduction in OHCA-risk. Risk reduction associated with ASA in patients with OHCA was similar in the presence of acute myocardial infarction (AMI) (ORadj 0.6 [0.4-0.9]) and in the absence of AMI (ORadj 0.7 [0.4-1.2]). CONCLUSION: ASA use was associated with reduced OHCA-risk in both sexes, and more so in women, while carbasalate calcium only protected women. Clopidogrel was not associated with reduced OHCA-risk

Understanding access to medicines in low- and middle-income countries through the use of price and availability indicators

Objectives: While it is generally understood that large sections of the population in low- and middle-income countries (LMICs) lack access to medicines, the concept of access is difficult to define and measure.Data on medicine prices and availability obtained through national facility-based surveys were examined through a variety of approaches to determine their usefulness in informing a global understanding of access to medicines. Methods: National and sub-national data on medicine price and availability were obtained from a database containing results of surveys conducted using a standard methodology (developed through a collaboration between the World Health Organization (WHO) and Health Action International (HAI)). In the surveys, the prices and availability of approximately 50 medicines are collected in a sample of facilities in the public and private sectors. Data are also collected on public procurement prices as well as the add-on costs applied through the supply and distribution chain. WHO/HAI data for 15 commonly-surveyed medicines were aggregated on a global level, taking several steps to improve the comparability of results. Similar analyses were also conducted for individual disease areas, namely cardiovascular disease and epilepsy. The availability of medicines used for acute and chronic conditions, respectively, were then compared. To further explore treatment affordability, medicine price data was used to quantify the impoverishment effects of medicine purchases in a subset of 17 countries. Finally, medicine prices were used in combination with consumption data to estimate potential savings which could arise from switching consumption from originator brands to generics. Findings: The secondary analysis of survey results for commonly-available medicines showed that medicine availability is generally low: 38.4% and 64.2% in the public and private sectors, respectively. Analyses for individual disease areas showed similar results: availability of generics medicines was only 26.3% for cardiovascular medicines and <50% for nearly all antiepileptics. When the availability of medicines for acute and chronic conditions was compared, it was found that medicines for chronic conditions were substantially less available than those for acute conditions (36.0% availability versus 53.5% in the public sector). Overall, private sector patient prices ranged from 9-25 times international reference prices for lowest-priced generic medicines. This was found to translate into poor affordability: for example, purchasing a month’s supply of the antidiabetic glibenclamide in generic form would push an additional 6% of populations below the international poverty line (US $1.25/day). Originator brand medicines were found to be consistently less affordable than their lowest-priced generic equivalents, which was illustrated in an analysis which showed that approximately 60% of private sector spending on medicines could be achieved by switching consumption from originators to lowest-priced generics. Conclusions: These analyses show that national-level data on medicine price and availability can be used to improve our understanding of access to medicines in low- and middle-income countries. While results vary across countries, global and regional trends raise concerns regarding access to medicines in these contexts. Given their role in informing advocacy efforts, investments, and policy and programmatic support related to access to medicines, ongoing efforts are needed to collect and report on medicine prices and availability

Evaluating pharmaceutical policies using cross-national comparisons and time series analysis

The aim of this thesis was to evaluate the effects of different pharmaceutical policies on the use of medicines (e.g. antibiotics). These policies were evaluated using diverse data sources from the public and private sector in countries in Africa, Latin America, and Western Europe. In addition, the studies contained in this thesis explore and strengthen methods for policy evaluation, with a focus on time series analysis. The importance of cross-national comparisons is addressed together with the next steps to improve their reporting by adequate and detailed descriptions of data coverage and country characteristics such as marketing status of medicines and reimbursement policies to increase the validity and reliability of comparisons. Subsequently, the use of interrupted time series analysis (ITSA) and the application of this method in the evaluation of pharmaceutical policies is discussed. As an example of a pharmaceutical policy evaluation, the intended and unintended effects of the over-the-counter antibiotic sales restriction in Mexico and Brazil were assessed. Firstly, the size of the effect of the policy was measured using ITSA. Next, changes in the seasonal variation of penicillins were estimated as a proxy of appropriateness of penicillin use. Subsequently, unintended effects of the policy were assessed by measuring the changes in the use of therapeutic groups that can be perceived as substitutes of antibiotics to relieve cold symptoms (NSAIDs, analgesics, and cough and cold medicines). It was found that the usage level of antibiotics decreased in both countries by about 1 defined daily dose per 1,000 inhabitants per day (DDD/TID), with a decreasing trend in Mexico and an increasing trend in Brazil. The seasonal variation in penicillins decreased in Mexico by 0.4 DDD/TID after the restriction mainly due to changes in seasonal variation of amoxicillin and ampicillin, whereas changes in seasonal variation were not found in Brazil. Lastly, in the two countries, NSAIDs-analgesics usage changes were related with antibiotic usage changes, while only in Mexico cough and cold medicines usage changes had a relation with the antibiotics usage changes. These results showed a substitution effect on the use of other medicines, especially NSAIDs and analgesics, after the reinforcement of OTC antibiotics sales restrictions which might have unintended clinical consequences. It was concluded that although after the regulations the level of antibiotics decreased in both countries, interventions to improve the appropriateness of antibiotics are required. Furthermore, this type of policies should be comprehensive and take into account the potential substitution effects on the use of other medicines. Although ITSA has been one of the most used methodologies for the evaluation of pharmaceutical policies, further development and improvement of methodologies used in such studies is of great importance to guarantee evidence-based and effective policy-making. Applying other statistical tests in time series can improve the evaluation of policies by examining unintended effects and forecasting possible outcomes. The studies in this thesis show that the effects of interventions in the pharmaceutical sector need to be adequately quantified, and provide new approaches to do so which strengthens evidence-based policy making

Instructies voor monitoren van klinische parameters in de registratieteksten van psychofarmaca: Overzicht en toepasbaarheid voor de klinische praktijk

background The Summary of Product Characteristics (SmPC) for psychotropic drugs includes instructions for clinical and biomarker monitoring intended to optimise effectiveness and minimise harm. aim To evaluate which monitoring instructions are given in the SmPC and to assess the applicability in clinical practice. method The reasons and requirements for monitoring in Smpcs for psychotropic drugs were assessed and somatic parameters were distinguished from non-somatic parameters, thereby the applicability was assessed. results An average of 3.3 instructions per drug label was found. Monitoring was primarily for safety reasons (78%). Requirement was predominantly mandatory (71%). Somatic parameters were most often mentioned (80%). Only 34% of the instructions were determined applicable. conclusion Monitoring instructions for psychotropic drugs are aimed at improving safe use. However, most instructions on monitoring do not provide sufficient information to be applicable in clinical practice

Instructies voor monitoren van klinische parameters in de registratieteksten van psychofarmaca: Overzicht en toepasbaarheid voor de klinische praktijk

background The Summary of Product Characteristics (SmPC) for psychotropic drugs includes instructions for clinical and biomarker monitoring intended to optimise effectiveness and minimise harm. aim To evaluate which monitoring instructions are given in the SmPC and to assess the applicability in clinical practice. method The reasons and requirements for monitoring in Smpcs for psychotropic drugs were assessed and somatic parameters were distinguished from non-somatic parameters, thereby the applicability was assessed. results An average of 3.3 instructions per drug label was found. Monitoring was primarily for safety reasons (78%). Requirement was predominantly mandatory (71%). Somatic parameters were most often mentioned (80%). Only 34% of the instructions were determined applicable. conclusion Monitoring instructions for psychotropic drugs are aimed at improving safe use. However, most instructions on monitoring do not provide sufficient information to be applicable in clinical practice

Instructions for clinical and biomarker monitoring in the Summary of Product Characteristics (SmPC) for psychotropic drugs: Overview and applicability in clinical practice

The Summary of Product Characteristics (SmPC) for psychotropic drugs includes instructions for clinical and biomarker monitoring intended to optimise effectiveness and minimise harm. The present study evaluated which monitoring instructions are given in the SmPCs, and assessed whether instructions are informative enough to be applicable in clinical practice. Monitoring instructions were collected from complete SmPCs for psychotropic drugs (n=70). Reasons and requirements for monitoring were assessed and somatic parameters were distinguished from non-somatic parameters. Instructions were evaluated using the Systematic Information for Monitoring (SIM) score and considered applicable when a SIM score of ⩾3 was found. An average of 3.3 (range 0-13) instructions per drug label was found. Monitoring was primarily for safety reasons (78%). Requirement was predominantly mandatory (71%). Somatic parameters were most often mentioned (80%). Only 34% of the instructions were determined applicable. Overall, an average SIM score of 2.0 (SD=1.7) was found (out of a maximum possible score of 6). In conclusion, prescribing of psychotropic drugs is accompanied by diverse instructions aimed at improving safe use. However, most instructions on monitoring do not provide sufficient information to be applicable in clinical practice

Occurrence and clinical management of moderate-to-severe adverse events during drug-resistant tuberculosis treatment: a retrospective cohort study

OBJECTIVES: To determine the incidence of symptomatic moderate-to-severe adverse events during treatment of drug-resistant tuberculosis, and to compare their risk and outcomes by patients' human immunodeficiency virus (HIV) co-infection status. METHODS: We conducted a retrospective cohort analysis of patients treated for drug-resistant tuberculosis between January 2008 and February 2010. Routinely, clinicians monitored and managed patients' response to treatment until its completion. Any symptomatic adverse event observed by the clinician or reported by the patient was recorded in the standard patient treatment booklet of the National Tuberculosis and Leprosy Programme. There were 18 symptomatic adverse events routinely monitored. Depending on the nature of the medical intervention needed, each was graded as mild, moderate or severe. Data were extracted from the patient treatment booklet using a structured form, then descriptive, bivariate and Cox proportional hazard analysis performed, stratified by patients' HIV infection status. Statistical associations were done at the 5% level of significance and reported with 95% confidence intervals. RESULTS: Fifty seven (57) patients with drug-resistant tuberculosis were identified, 31 (53%) of whom were HIV co-infected. The cumulative incidence of moderate-to-severe adverse events was 46 events in 100 patients. HIV co-infected patients experienced more moderate-to-severe adverse events compared with the HIV uninfected patients (median 3 versus 1 events, p = 0.01). They had a four-fold increase in the cumulative hazard of moderate-to-severe adverse events compared with the HIV uninfected patients (HR = 4.0, 95% CI 1.5 - 10.5). Moderate-to-severe adverse events were the main determinant of a clinician's decision to reduce the dose or to stop the suspected offending medicine (RR = 3.8, 95% 1.2-11.8). CONCLUSIONS: Moderate-to-severe adverse events are common during drug-resistant tuberculosis therapy. They are more likely to occur and to persist in HIV co-infected patients than in HIV uninfected patients. Clinicians should employ various strategies for preventing drug-induced patient discomfort and harm, such as reducing the dose or stopping the suspected offending medicine. Managers of tuberculosis control programmes should strengthen pharmacovigilance systems. We recommend a more powered study for conclusive risk-factor analysis

Discontinuation of somatic medication during psychiatric hospitalization

BACKGROUND: Psychiatric hospitalization can increase the risk of discontinuation of pharmacotherapy, which may negatively influence patients' health. OBJECTIVE: To investigate the association between psychiatric hospitalization and discontinuation of somatic medication. METHODS: A retrospective crossover study was performed in patients admitted to a psychiatric hospital (index date), who had got somatic medication dispensed during the 3 months prior to hospitalization. Discontinuation of somatic medication was investigated at the following time points: index date and 3, 6, and 9 months before the index date. Relative risks (RR) with 95% confidence intervals (95% CIs) of discontinuing somatic medication at the index date versus the time points before the index date were estimated using Cox regression. RESULTS: In all, 471 hospitalized patients were included in the study; 38.9% of the patients were discontinuers on the index date. RR for discontinuation of ≥1 somatic medication was 1.88 (95% CI=1.55-2.27) at the index date compared with the other time points and highest for patients<45 years (RR=2.83; 95% CI=1.92-4.18). CONCLUSIONS: Psychiatric hospitalization was associated with an almost doubled risk of discontinuation of somatic medication. Future studies should address the influence of discontinuation of care on patients' health

Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers and risk of depression among older people with hypertension

BACKGROUND: Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), commonly used antihypertensive drugs, may have a protective effect against depression in older individuals, but evidence in humans is limited. AIMS: We evaluated the risk of depression, among older individuals with hypertension, comparing ACE or ARB initiators to thiazide(-like) diuretic initiators. Thiazide(-like) diuretics were used as control because these drugs are not associated with mood disorders. METHODS: We used a propensity score-matched new user cohort design with routinely collected data from general practices in England from the Clinical Practice Research Datalink database. We matched 12,938 pairs of new users of ACEIs/ARBs and thiazide(-like) diuretics with hypertension (mean age 67.6 years; 54.7% women). Follow-up time started on the date of drug initiation and ended on the date of treatment discontinuation plus 30 days, or switch to a comparator, occurrence of a study event, death, date of patient's transfer out of practice, or end of the study period. The primary outcome was a composite endpoint of treated depression and nonfatal and fatal self-harm. RESULTS/OUTCOMES: Compared to the thiazide(-like) diuretic group, ACEIs/ARBs use was not associated with a lower risk of the primary outcome (hazard ratio 0.96 (95% confidence interval: 0.79; 1.15)). Results did not differ according to lipophilicity, duration of use, and average daily dose, or class (ACEIs or ARBs). CONCLUSIONS/INTERPRETATION: New use of ACEIs or ARBs is not associated with a lower risk of depression among individuals with hypertension