R. Vander Stichele

Measurement of patient compliance and the interpretation of randomized clinical trials.

SummaryThe aim of this review is to demonstrate why the management of compliance, although not an explicit feature of the rules of Good Clinical Practice, is essential to the successful conduct of clinical trials and in correct interpretation of the results. Methods to measure compliance in randomized clinical trials are also described. The relevant literature was retrieved by a manual search of the Cumulated Index Medicus 1975–1989 and a MEDLINE computer search of publications in 1990 using the Medical Subject Headings “patient compliance” and “clinical trials”. All retrieved articles are discussed. Research into patient compliance has stagnated because of the lack of a “gold” standard of measurement. Nevertheless, management of compliance at the different stages of clinical trials is necessary; at trial design, compliance should be taken into account in sample size calculations; during the conduct of a trial, compliance should be monitored in order to safeguard the power of the study; and in interpretation of trial results, compliance data are helpful both in order to avoid erroneous conclusions and to enrich the value of the data. Compliance should be measured in all limbs of randomized trials, including the placebo limb, without breaking trial blinding. A classification of compliance behaviour into six types (complier, partial complier, overuser, erratic user, partial dropout and dropout) is proposed, based on the changes in the risk-benefit ratio produced by non-compliance. The use of deuterium oxide, low dose phenobarbitone (2 mg per day), digoxin (2,2 μg per day) and the new electronic monitoring devices are suitable methods for measurement in clinical trials.

Indicators of prescribing quality in drug utilisation research: report of a European meeting (DURQUIM, 13-15 May 2004)

An invitational expert meeting on indicators of prescribing quality was held on 13–15 May 2004, bringing together—from 19 European countries, the US, Canada, and Australia—40 researchers specialized in the development and application of indicators. The meeting was organized by the European Drug Utilization Research Group (EuroDURG), the Belgian National Health Insurance Institute (RIZIV-INAMI), and the World Health Organisation Regional Office for Europe (WHO-Euro). The field of prescribing quality was defined and delineated from the medical error field. A conceptual grid for classifying quality indicators was discussed, combining two axes (a drug/disease/patient axis and a structure/process/outcome axis). In addition, available databases were listed for continuous monitoring of drug utilization in Europe, with a description of the content and the richness of the collected data, as well as the impact on the potential and limitations to develop quality indicators. The importance of the origin of data for validity assessment was stressed, as data on drug utilization may originate from physician sources (prescribing data), from pharmacist or health insurer sources (distribution data), or directly from patient sources (compliance data). The different aspects of validity and their methods of assessment were listed. An overview of the (in)appropriate uses of indicators was given. The state of the art of the development and application of prescribing quality indicators in all represented countries was made, together with a first draft of a database of prescribing quality indicators, already subjected to validation procedures.

Attitudes, Sociodemographic Characteristics, and Actual End-of-Life Decisions of Physicians in Flanders, Belgium

Aim. To study the effect of sociodemographic and attitudinal determinants of physicians making end-of-life decisions (ELDs). Methods. The physicians having signed 489 consecutive death certificates in the city of Hasselt (Belgium) were sent an anonymous questionnaire regarding their ELDs and another on their attitudes toward voluntary euthanasia (EUTH) and physician-assisted suicide (PAS).Results.55% response rate. Nontreatment decisions occurred in 16.7% of all death cases; in 16%, there was potentially life-shortening use of drugs to alleviate pain and symptoms; in 4.8% of cases,death was deliberately induced by lethal drugs, including EUTH, PAS, and life termination without explicit request by the patient. In their attitudes toward EUTH and PAS, the 92 responding physicians clustered into 3 groups: positive and rule oriented, positive rule-adverse, and opposed. Cluster groupmembership, commitment to life stance, years of professional experience, and gender were each associated with specific ELD-making patterns.

Naftidrofuryl for intermittent claudication: meta-analysis based on individual patient data

Objective To assess the efficacy of naftidrofuryl compared with placebo in treating the symptoms of intermittent claudication. Design Meta-analysis based on individual patient data. Data sources Medline, International Pharmaceutical Abstracts, Embase, Science Citation Index, and the Cochrane trial registers. Reference lists of retrieved articles were checked. Authors and companies were approached for additional information and individual patient data. Inclusion criteria Double blind, randomised controlled trials in patients with intermittent claudication receiving oral naftidrofuryl or placebo and with pain-free walking distance as primary outcome. Data collection Individual patient data were collected from electronic data or from case report forms and checked for integrity. Analysis All randomised patients were analysed following the intention to treat principle. Efficacy was assessed by the ratio of geometric mean of the relative improvement in pain-free walking distance after use of naftidrofuryl compared with placebo. In the analysis of responders, therapeutic success was defined as an improvement of walking distance at baseline by at least 50%. Results In total, 1266 patients were randomised (1083 in the main analysis). The ratio of relative improvement in pain-free walking distance after use of naftidrofuryl compared with placebo was 1.37 (95% confidence interval 1.27 to 1.49). The difference in response rate was 22.3% (95% confidence interval 17.1% to 27.6%) and the number needed to treat for relief of symptoms during six months of treatment was 4.48 (95% confidence interval 3.62 to 5.85). Conclusion This meta-analysis of individual patient data provides evidence that naftidrofuryl has a clinically meaningful effect compared with placebo in improving walking distance in patients with intermittent claudication.

Oral vasoactive medication in intermittent claudication: utile or futile?

AbstractObjective: To evaluate the role of orally administered vasoactive medication in the management of intermittent claudication. Setting: We limited our study to the products on the market in Belgium: cinnarizine, cyclandelate, isoxsuprine, naftidrofuryl, pentoxifylline, xanthinol nicotinate and buflomedil. Data sources: We conducted a systematic literature search involving Medline, International Pharmaceutical Abstracts, the Cochrane Library, direct contact with marketing companies and key authors, snowballing and Science Citation Index search. We looked for randomised placebo-controlled trials (RCTs) in patients with Fontaine stage II, in which pain-free and/or maximal walking distance were measured using a standardised exercise test. For isoxsuprine and xanthinol nicotinate, no trials conforming to these criteria were found. Thirty-six trials on cinnarizine, cyclandelate, buflomedil, naftidrofuryl and pentoxifylline met our inclusion criteria. Study selection: After quality assessment, 26 trials were excluded, mainly because of short trial duration (less than 12 weeks), small sample size (less than 30 patients) and/or failure to report details on variability (standard deviation or confidence limits). For cinnarizine and cyclandelate, none of the three selected RCTs was included. Data extraction: For buflomedil, of six published RCTs, two were included after quality assessment, each showing a marginally positive effect of buflomedil versus placebo. For naftidrofuryl, nine RCTs were selected; six were included of which five showed a significant positive result. The likelihood of publication bias and the heterogeneity of the results within and between trials precluded a meta-analysis. For pentoxifylline, of the 18 selected RCTs, only two could be included, both with inconclusive results. Conclusion: A national consensus conference, based on this review, concluded that health resources should be allocated to prevention and rehabilitation of intermittent claudication rather than to reimbursement of these products with doubtful efficacy.

Use of laxatives in institutions for the mentally retarded

AbstractObjective: To study, in institutionalized mentally retarded patients, the prevalence of regular laxative use, and to identify its correlates. Methods: Twenty-one of the 22 institutions for the mentally retarded in Flanders (Belgium) provided the setting for the study, which included a population of 3712 residents with an IQ of <50. This was a descriptive cross-sectional study of a random sample of 20 patients per institution, consisting of a structured interview of the personnel responsible for daily care of the selected patients. The study population consisted of 420 mentally retarded patients. Their median age was 29 years (range 2–72 years). Twenty-six percent of patients had an IQ of 35–49, 40% an IQ of 20–34 and 34% an IQ of <20. Sixteen percent of the patients were non-ambulant. Results: Regular laxative use was found in 26.4% (111/420) of the residents. In addition, occasional laxative use was found in 2% (10/420) of the residents. Oral laxatives were used daily by 13% (56/420) and oral laxatives daily in combination with enemas were used by 9% (39/420). Enemas but no oral laxatives were used by 3% (11/420); manual evacuation in combination with oral laxatives and enemas was used by 1% (5/420). Seventy-eight percent (78/100) of the oral laxative users used them for more than 1 year. Seventy-one percent (71/100) used one laxative, 23% two and 6% three. Thirty different brands of oral laxatives were used. Sixty-seven percent (67/100) used osmotic laxatives alone or in combination, 30% used stimulant laxatives, 19% used bulk forming laxatives and 19% mineral oil. Oral laxatives were always prescribed by attending physicians, while enemas were also initiated by nurses in 35% (18/52). Laxative use was positively and independently correlated with female gender, with being non-ambulant, with oral motor dysfunction and with the use of medication other than laxatives. It did not correlate with age. Within the institutions, laxative use varied from one to 15 users out of the 20 randomly selected patients (median 4/20). Conclusion: Laxative use is frequent in institutions for the mentally retarded, with a large inter-institution variation, indicating that constipation is an important problem and underlining the need for research into cost-effective treatment.

Attitude of physicians toward patient package inserts for medication information in Belgium.

In Belgium, the distribution of medications to outpatients in community pharmacies is almost exclusively by branded unit-of-use packages, with a package insert inside every package. At the time of the study (spring 1990), the implementation of legislation that mandated a shift from highly technical documents to patient package inserts (PPIs), understandable by the lay person, had begun. This study explores the attitude of practising physicians toward written medication information for patients. A mail questionnaire was sent to 1500 (8% random sample) Belgian general practitioners and to 500 (22% random sample) internal medicine specialists. A total of 543 usable questionnaires were returned (27.5% return rate). Ninety-two percent of the physicians stated that their patients seldom or never requested additional information on drug efficacy or side effects, during routine consultation; 30% estimated that more than half of their patients read the PPI; 75% expect that a patient would experience side effects after reading about them in the PPI; 59% agreed that the PPI could help the patient react more adequately in unforeseen situations. It was possible to cluster the respondents in a stable segmentation of three clusters: moderately positive physicians (20%), ambiguous to neutral physicians (44%), physicians overtly negative to written drug information (36%). The low response rate to this extensive postal questionnaire limits the conclusions to a qualitative description of relevant clusters of respondents. In contrast with the opinion of physicians about patient readership, results from other studies indicate that the vast majority of patients read the package inserts.

Analysing policy interventions to prohibit over-the-counter antibiotic sales in four Latin American countries.

To describe and evaluate policies implemented in Chile, Colombia, Venezuela and Mexico (1995–2009) to prohibit antibiotic OTC sales and explore limitations in available data.

The effects of abrupt antipsychotic discontinuation in cognitively impaired older persons: a pilot study

Background: Antipsychotic use for behavioural and psychological symptoms of dementia (BPSD) is controversial. Guidelines advise to reduce antipsychotics given the adverse effects and limited efficacy, to limit dose and treatment duration as well as to undertake discontinuation. Methods: A pilot study with 40 hospitalised geriatric cognitively impaired patients, in which the effects of abrupt antipsychotic discontinuation were investigated, using neuropsychiatric inventory (NPI) scores before and one month after discontinuation. Withdrawal symptoms were monitored thrice a day with a checklist during five consecutive days. Results: Participants (n = 40) had a mean age of 84 years (range 67–95) and 53% were male. The total mean baseline NPI score was 21 (SD 12) with predominantly behavioural rather than psychological disturbances. After abrupt discontinuation, mild withdrawal symptoms were observed in 72% of the patients, with frequencies of symptoms peaking on day 2 (53%) and day 3 (48%). After one month, 31 patients (85%) were still off antipsychotics and improved on the majority of NPI domains, with a total mean NPI score decreasing from 18 (SD 13) to 12 (SD 8, p = 0.003). In the relapse group, there was no deterioration associated with the abrupt discontinuation and subsequent resumption of therapy with a total mean NPI score decreasing from 31 (SD 12) at baseline to 27 (SD 8) at one-month follow-up (p = 0.345). Conclusion: Abrupt antipsychotic discontinuation appears to be feasible in older individuals with BPSD. Systematically performed discontinuation efforts in clinical practice are needed to differentiate between patients where antipsychotics have no added value and patients where the benefits outweigh the risks.

Package inserts for antihypertensive drugs : use by the patients and impact on adverse drug reactions

SummaryIn Belgium, all dispensed drugs are provided with package inserts. Traditional physician-orientated inserts are gradually being replaced by patient package inserts (PPIs). The present survey is focused on the use of inserts for antihypertensive drugs and their impact on the reported occurrence and attribution of adverse drug reactions (ADRs). A group of 28 general practitioners (GPs) from the Flemish part of Belgium collected data from 702 hypertensive patients. Each participating GP submitted a consecutive sample of his patients to an interview in the Spring 1989, when 25% of the antihypertensive specialties carried a PPI-version.1049 prescriptions for antihypertensive drugs had been dispensed. Two thirds of the patients, mostly those with a higher educational level, had read the package inserts. PPIs accounted for 16% of the inserts, and they had not been read significantly more than the traditional inserts.Reporting by the patients of possible drug-related health problems (spontaneously + after having heard the items on a check-list) was not affected by reading the insert or by the type of insert. However, the PPI did bring about spontaneous reporting, especially by patients with a low educational level. Attribution of at least one health problem to the medication was not affected by reading in itself but by the type of insert.Attribution was higher when the patient had received a PPI, except in the case of highly educated patients. Spontaneous reporting and attribution of health problems to the medications prescribed was found more frequently among patients with higher education, who did not seem to need a PPI to recognize problems as being drug-related.