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Objective: To develop a comprehensive and easily applicable prognostic model predicting mortality risk in patients with moderate to severe heart failure. Design: Prospective follow up study. Setting: Seven general hospitals [...]

In patients with multiple sclerosis (MS), disability and autoinflammatory processes may result in an increased risk of venous thromboembolism (VTE)

Long-term risk of venous thromboembolism (VTE) following total hip or knee replacement (THR/TKR) compared with controls has not been studied extensively, and the long-term influence of outpatient anticoagulant use on VTE risk remains unknown. The objectives were to evaluate long-term VTE risk following THR/TKR compared with matched controls, and to investigate effect modification by prolonged outpatient vitamin K antagonist use.

Background:Anticoagulation control is often summarized using the percentage of time spent in a therapeutic range (TTR). This method does not describe the timing and severity of fluctuations in the International Normalised Ratio (INR).Objective:To evaluate whether the TTR method can be improved by considering the patterns of INR over time.Methods:The cohort included adults aged 40+ years with atrial fibrillation (AF) and laboratory records of INR as recorded in the UK Clinical Practice Research Datalink. Statistical clustering techniques based on simple INR measures were used to describe the patterns of INR. Nested case–control studies calculated the odds ratios (ORs) for the risk of stroke, bleeding and mortality with TTR and different INR patterns. It was also evaluated whether cluster analyses improved the prediction of outcomes over TTR.Results:A number of 27 381 patients were studied with a mean age of 73 years. The OR for mortality was 3.76 (95% confidence interval [CI] 3.03–4.68) in patients with < 30% TTR compared with patients with 100% TTR. INR patterns were found to be best described by six different clusters. The cluster with the most unstable pattern was associated with the largest risk of mortality (OR 10.7, 95% CI 8.27–13.85) and stroke (OR 3.42, 95% CI 2.08–5.63). INR measures that predicted death independent of the TTR‐included absolute difference between two subsequent INR measurements and change relative to the mean over time.Conclusion:Cluster analysis of INR patterns improved the prediction of clinical outcomes over TTR and may help to identify warfarin users who need additional anticoagulation monitoring.

To examine the risk of fracture in patients with multiple sclerosis (MS) compared with population-based controls.

Background & Aims: This study was performed to quantify the risk of renal disease in patients using aminosalicylates (5-ASA). Methods: Data from the United Kingdom General Practice Research Database were used to estimate the incidence of renal disease in adult patients with inflammatory bowel disease (IBD) or prescription for 5-ASA and in patients without IBD. In a nested case-control analysis, each case of renal disease was matched to 5 controls. Results: Among the 19,025 5-ASA users with IBD, 130 patients developed renal disease (incidence rate of 0.17 cases per 100 patients per year). The incidence among patients with IBD but without 5-ASA use was 0.25 and among patients without IBD was 0.08. In the case-control analysis, the crude odds ratio (OR) for renal disease in current 5-ASA users was 1.60 (95% confidence interval [95% CI]: 1.14-2.26); the adjusted OR was 0.86 (95% CI: 0.53-1.41). For recent users, the crude OR was 4.18 (95% CI: 2.59-6.76) and adjusted OR 2.48 (95% CI: 1.33-4.61); for past users (last prescription more than 12 months before), 1.71 (95% CI: 1.09-2.70) and 0.99 (95% CI: 0.55-1.76), respectively. Although the numbers were small, mesalazine and sulfasalazine users had comparable risks (crude OR for current and recent users of OR 2.08 [95% CI: 1.44-3.01] and 1.84 [95% CI: 1.20-2.82], respectively). In only a few records was renal disease attributed to interstitial nephritis or 5-ASA use. Conclusions: Users of 5-ASA have an increased risk of renal disease that may be partly attributable to the underlying disease. Although renal disease is a recognized adverse effect of 5-ASA, the incidence appears to be low and does not appear to be related to either the dose or type of 5-ASA used.

The aim of this study was to assess whether use of selective serotonin reuptake inhibitors (SSRIs) is associated with extrapyramidal syndromes (EPS). We analysed the spontaneous reports of adverse drug reactions (ADRs) collected by The Netherlands Pharmacovigilance Foundation Lareb in the period 1985–99 (n24 263). The study population comprised all patients using an antidepressant drug at the time the ADR occurred. We calculated ADR-reporting odds ratios (ADR-OR) to estimate the association between SSRI-use and EPS, relative to other antidepressants. We identified 61 patients with EPS. SSRI-use was associated with spontaneous reporting of EPS compared to other antidepressants (adjusted ADR-OR 2.2; 95 confidence interval 1.2–3.9). This risk estimate appeared to be higher in patients concurrently using antipsychotic medication (6.9, 0.7–68.0), although the confidence interval was very wide. In conclusion, SSRI-use seems only to be moderately associated with EPS compared to other antidepressants. However, those concurrently using antipsychotic drugs or presenting with other risk factors may be more susceptible and should be closely monitored.

Background:Proton pump inhibitors (PPI) demonstrate high healing rates of 85‐98% in clinical trials. Due to the limited knowledge regarding response and non‐response to lansoprazole in daily practice and for the reason that resistance to PPIs is scarce, we investigated factors possibly associated with non‐response. Methods:Data were used from a prospective, open label, observational follow‐up study in which 10,008 lansoprazole users were followed over time. The study was designed according to the SAMM guidelines. A matched nested case‐control design was used to compare non‐responding (cases) and responding (controls) lansoprazole users. Non‐response was defined as worsening or non‐improvement of symptoms at the first evaluation after at least 8 weeks of use, response as disappearance or improvement of symptoms within 8 weeks of use. Controls were matched for the evaluating physician.Results:A total of 186 non‐responders and 372 responders to PPI treatment were identified as cases and controls. Age of over 60 years, heavy smoking and previous use of PPIs were significantly more common in non‐responding patients compared with responding patients. There were no differences found between the reported diagnosis regarding response. Conclusion:In daily clinical practice, previous use of PPIs, heavy smoking and an age > 60 years were significantly associated with non‐response to treatment with lansoprazole. Previous use of PPIs in non‐responding patients might suggest resistance to PPIs. The knowledge that non‐response drives non‐response may encourage physicians to follow PPI users with previous PPI use more closely.

Aim of study:The role of pharmacists in today's healthcare is changing rapidly. As they are close to the prescribing process, pharmacists are in the position to identify and adjust prescribing errors before dispensing. The objective of this study was to identify relevant determinants of interventions directly linked to prescription processing in community pharmacy. Methods:As part of a yearly continuing education programme, all community pharmacies in the region of 'Zeeland' (N=23) in the south‐west of The Netherlands kept detailed records of all interventions directly linked to prescription processing during one week in May 1998. For every patient involved in an intervention, a control‐patient was matched on pharmacy practice, date, gender and age. Results:A total of 39,357 prescriptions were evaluated by the 23 pharmacies during the one‐week intervention programme. Out of these, one out of 10 resulted into an intervention. Being a first prescription in a new treatment episode was found to be a significant determinant (OR 1.75, 95 CI% 1.18‐2.33). Variables reflecting drug therapy complexity (> 3 prescribers, > 15 prescriptions in 3 months before, > 3 different medications) showed all ORs higher than 1.00, but not significant. When looking at the individual drug categories, anti‐infectives, respiratory drugs and cardiovascular medicines came out as important drug classes for intervention risk. We could not find any association between the number of signals per pharmacy and the number of interventions. Conclusion:The 'whistle‐blower'‐ model of pharmacy based interventions is a valid one but needs a targeted and integral way of implemented thinking and use of information technology. In such an environment, interventions are a logical step of in‐process quality control in the drug usage system.

Introduction:Shortly after their introduction, fluoroquinolones were associated with reports of tendinitis and tendon rupture. During the past years, the number of reports has risen, possibly because of an increased use of fluoroquinolones. In this study, we describe the use of fluoroquinolones in the Dutch community and the possible public health effects of an association between fluoroquinolone use and tendon ruptures. Methods:In the PHARMO drug database we identified all prescriptions for fluoroquinolones in the period 1991‐1996. The incidence of fluoroquinolone use was expressed as the number of fluoroquinolone episodes per 1000 inhabitants in one year, and extrapolated to the Dutch population after standardisation on age and gender. The annual incidence of non‐traumatic tendon ruptures in the period 1991‐1996 was calculated with data from the nation‐wide hospital registry. The expected number of fluoroquinolone attributable tendon ruptures was calculated on the basis of the use of fluoroquinolones, the number of non‐traumatic tendon ruptures and an assumed relative risk of 1.5‐10. Results:In 1996, approximately 251,000 patients experienced 318,000 episodes of fluoroquinolone use in the Netherlands. Females used more often fluoroquinolones than males, and the number of episodes increased exponentially with age. In the period 1991 through 1996, the absolute number of fluoroquinolone episodes increased by 160%, from 122,000 to 318,000. The absolute number of hospitalised tendon ruptures increased with 28%, from 768 in 1991 to 984 in 1996. Assuming a relative risk of 1.5 to 10.0, 1 to 15 tendon ruptures could be attributed to fluoroquinolone use in 1996. Only 7 % of the observed increase could be attributed to the increased use of fluoroquinolones. If the total increase of hospitalised non‐traumatic tendon ruptures would be attributable to the increase in fluoroquinolone use, this would mean that the risk of non traumatic tendon ruptures to fluoroquinolones would be more than 250 times the risk during non‐use. Conclusion:In the Netherlands, a large simultaneous increase in non‐traumatic tendon ruptures and fluoroquinolone use was observed in the period between 1991 to 1996. Assuming a relative risk of 1.5 to 10.0 for tendon ruptures during fluoroquinolone use, only 0.5 to 7% of the increase in non‐traumatic tendon ruptures could be attributed to the increased fluoroquinolone use. The increase in the incidence of non‐traumatic hospitalised tendon ruptures in the Netherlands is not likely to be explained solely by the increased use of fluoroquinolones.

Adverse drug events in hospitalized patients lead to increased morbidity, mortality and costs. Early detection of adverse drug events could aid in the prevention of these adverse outcomes. A cost‐effective system for the early detection of adverse drug events should focus on high risk patients. A study was set up with the primary aim to identify characteristics that are associated with the development of adverse drug events (ADEs) in hospitalized patients.ADE reports were gathered from physicians and nurses (spontaneous reports) and from patients after intensive ward interviews by hospital pharmacists. All patients admitted to the internal medicine wards of two Dutch hospitals, during a two month period, were included.The following characteristics were analyzed for their potential relationship to the occurence of ADEs: age (categorized), gender, number of drugs prescribed during hospital stay, types of drugs used and changes in drug use on admission.Age was found to be inversely associated with the development of ADEs (OR 0.36, CI 0.21‐0.61 for age category > 80 years; OR 0.56; CI 0.31‐1.02 for age category 75‐80 years and OR 0.69; CI 0.42‐1.11 for age category 60‐74 years). Furthermore, statistically significant associations were found for the number of drugs prescribed per hospitalized patient (for the class of 4‐6 drugs per patient OR 2.61, CI 1.32‐5.18), for newly prescribed drugs (OR 6.65, CI 2.63‐16.81) and for the cessation of drugs on hospital admission (OR 1.50, CI 1.02‐2.20). The use of gastrointestinal drugs (OR 2.13, CI 1.32‐3.45), central nervous system drugs (OR 1.66, CI 1.07‐2.57) and antibiotics (OR 2.44, CI 1.65‐3.60) were associated with the development of ADEs, when compared to all other drugs taken by the patients.In this study, the most important risk factors are the number of drugs used per patient and the starting of a new drug during hospitalization. As most hospitalized patients start new drug therapies while in hospital, this seems an inappropriate focus. However, careful monitoring of patients using more than 7 drugs at a time may be possible in a cost‐effective system for the early detection of ADEs.

Administration of oral corticosteroids is associated with the development of osteoporosis and an increased risk of fractures. However, the size of the treated sub‐population who would benefit from preventive therapy remains uncertain. The objective of this study was to investigate the usage pattern of oral corticosteroids in a large sample representative of the general population in England and Wales. Information was obtained from the General Practice Research Database (GPRD) which contains medical records of general practitioners. Oral corticosteroid users were patients aged 18 years or older who received one or more prescriptions for oral corticosteroids. Over 1.6 million oral corticosteroid prescriptions were issued to the cohort of 244 235 oral corticosteroid users. At any point in time, oral corticosteroids were being used by 0.9% of the total adult GPRD population. The highest use (2.5%) was by people between 70 and 79 years of age. Respiratory disease was the most frequently recorded indication for oral corticosteroid treatment (40%). Patients with arthropathies were most likely to use long‐term, continuous treatment, and patients with chronic obstructive pulmonary disease least likely (19.3% and 6.1%, respectively, used oral corticosteroids for more than 2 years). The overall use of bone‐active medication (oestrogens, bisphosphonates, vitamin D, and calcitonin) during oral corticosteroid treatment was low (between 4.0% and 5.5%). The current population in the UK at risk of developing corticosteroid‐induced fractures might be as large as 350 000. Identification of these patients will be important for implementing preventive strategies in a cost‐effective manner.

Long acting β2‐agonists (LBA) have become an important therapeutic strategy in the treatment of asthma. There is, however, debate whether LBA increase the risk of asthma exacerbations (AE). We studied whether the risk of AE was increased in patients starting LBA therapy and whether the risk was associated with severity. Patients, aged 5‐49 years, who were firstly prescribed LBA between 1992 and 1995, and who had at least two consecutive prescriptions of LBA, were selected from the PHARMO‐RLS database. The exposure period was the interval between the first and last dispensing of the first exposure episode. The year before the onset was the control period. Single short courses of oral glucocorticosteroids or antibiotics were used as proxy indicators for AE. Severity indicators, assessed in the 6 months before initiation of LBA, were used to classify patients' severity. A total of 788 patients met the inclusion criteria (men: 45.1%, median age: 35). The incidence rate of AE increased significantly (p<0.001) with severity from 1.7 to 2.4 and 1.1 to 2.7 AE per person year in index and control period, respectively. The risk was merely elevated among patients who start LBA therapy without being treated with other anti‐asthma drugs before (RR 1.4, 95% CI 1.0‐2.2). First starters of LBA showed no overall change in incidence of AE when compared with the year before starting treatment. A total of 6.9% of patients used LBA as step‐one therapy. These patients suffer, in contrast to the whole population, a 40% increased risk of having AE. Although this could be due to confounding, we recommend being reluctant to prescribe LBA to patients who have not been treated before with other anti‐asthma drugs.

Objective:The objective of this study was to determine whether pharmacy records of nitrate prescriptions could be used as a marker of angina pectoris.Method:This study was conducted within the Rotterdam Study, a prospective follow-up study which started in 1991 and included 7983 elderly subjects. During follow-up, 1601 subjects filled a first prescription for a nitrate and later filled at least one other prescription for nitrates according to pharmacy records. After excluding subjects who started using nitrates in 1991 and who had less than one year of medication history, we took a random sample of 78 subjects (10%). We studied discharge and outpatient cardiologist letters and files from general practitioners for additional information on angina pectoris in these subjects, and allocated patients to one of three categories according to the possibility of the initial diagnosis of angina being correct.Results:From the random sample of 78, additional information was available on 75 subjects. Definite angina pectoris was present in 33, probable angina pectoris in 18, and possible angina pectoris in 19 subjects. Five subjects had no angina pectoris. Therefore, 93% had at least a possible diagnosis while 68% had at least a probable diagnosis of angina pectoris. The positive predictive value of 2 nitrate prescriptions of which at least one was for rescue therapy was 94%.Conclusions:We conclude that the use of more than one nitrate prescription can be used as a marker for angina pectoris. This marker may be useful in epidemiological studies.

Background: Simple tools are needed to identify patients at high risk of fracture. Aim: To develop a simple clinical tool for assessing 5-year risk of fracture. Design: Cohort study. Methods: The study population consisted of all women aged 50+ included in the THIN Research Database (containing computerized medical records of UK general practices). Using Cox proportional hazards models, a risk score was initially estimated from age, body mass index, and clinical risk factors. The 5-year risk of fracture (survival function) was estimated for each score. Results: The study population included 366 104 women aged 50 years (mean follow-up 5.8 years). Of these, 6453 suffered a hip fracture. Several characteristics independently contributed to the fracture risk score (age, body mass index, fracture and fall history, previous diagnoses and use of medication). The 5-year risks for hip fracture for patients with total scores of 10, 30 and 50 were 0.3% (95%CI 0.3–0.4%), 2.2% (95%CI 2.1–2.2%), and 13.1% (95%CI 12.5–13.7%), respectively. A woman aged 65 years with low BMI and a history of both fracture and falling would have a hip fracture risk score of 37, with a corresponding 5-year risk for a hip fracture of 4.1% (4.0–4.2%). The risk score was validated and tested in another population (from GPRD), with a good concurrence between predicted and observed risks of fracture. Discussion: This risk score predicts the long-term risk of fracture, and could be used for targeting patients for further investigation, such as bone densitometry.

Background: Previous analyses of risk factors for glucocorticoid (GC)-induced osteoporosis have focused on the estimation of relative rather than absolute fracture probability. Aim: To estimate risk scores for the individual probability of fracture in GC users. Design: Retrospective data analysis. Methods: We evaluated all patients aged 40 years or older with a prescription for oral GCs in the General Practice Research Database (GPRD), which comprises the computerized medical records of around 7 million UK subjects. Individual risk factors for osteoporotic fractures were identified, and combined in a predictive model for 10-year absolute fracture risk. Results: Of 191 752 oral GC users aged ≥40 years, 7412 experienced an osteoporotic fracture. Several characteristics independently contributed to the fracture risk score (GC therapy, age, gender, fall history, fracture history, body mass index, smoking, previous diagnoses, use of medication, recent hospitalization and indication for GC treatment). Scores of 30, 40 and 50 corresponded to absolute 5-year fracture risks of 6.2%, 15.3% and 35.2%, respectively. A woman aged 65 years with RA, low BMI, and a previous history of fracture and falls, who used 15 mg GC daily (total risk score 54) would have a 5-year fracture risk of 47% (a man with similar history, 30.1%). Short-term use of high-dose GC therapy (≥30 mg) was associated with only a small increased risk of osteoporotic fracture (RR 1.21, 95%CI 1.04–1.42) in patients with a history of GC use. Discussion: This risk score helps to predict an individual's risk of fracture during GC use. Decisions about bone protection treatment could be based on long-term risks of fracture.