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Excitement about the dramatic increase in potential successful anticancer medicines in recent years is hampered by the high costs involved as well as the length of time traditional pathways take for regulatory approval. The translation of experimental clinical data into real-world evidence is also problematic. While the randomised controlled trial remains the gold standard for assessing efficacy and safety, there is increasing interest in the use of observational data to enable more rapid, informed and widespread availability and access to important anticancer medicines. Taking real-world evidence into account in regulatory and health technology assessment in a thoughtful and balanced fashion will enrich and justify sound decision-making. [ABSTRACT FROM AUTHOR]

With the anticipated health challenges brought by demographic and technological changes, ensuring capacity in underlying workforce in place is essential for addressing patients' needs. Therefore, a timely identification of important drivers facilitating capacity building is important for strategic decisions and workforce planning. In 2020, internationally renowned pharmaceutical scientists (N = 92), largely from the academia and pharmaceutical industry, with mostly pharmacy and pharmaceutical sciences educational background were approached (through a questionnaire) for their considerations on influencing drivers to facilitate meeting current capacity in pharmaceutical sciences research. From a global view, based on the results of the questionnaire, the top drivers were better alignment with patient needs as well as strengthening education – both through continuous learning and deeper specialisation. The study also showed that capacity building is more than simply increasing the influx of graduates. Pharmaceutical sciences are being influenced by other disciplines, and we can expect more diversity in scientific background and training. Capacity building of pharmaceutical scientists should allow flexibility for rapid change driven by the clinic and need for specialised science and it should be underpinned by lifelong learning. [ABSTRACT FROM AUTHOR]

Medical diagnosis can be studied using various sources of information, such as medical and hospital discharge records and laboratory measurements. These sources do not always concur. The objective of the present study was to assess the sensitivity, specificity, and positive and negative predictive values of hospital discharge diagnosis compared with clinical laboratory data for the identification of hyponatremia. Patients with hyponatremia were selected from a hospital information system determined by the International Classification of Diseases, 9th edition (ICD-9). The validity parameters for hyponatremia (ICD code 276.1) were estimated by comparison with accurate serum sodium (Na+) levels. A total of 2632 cases of hyponatremia were identified using laboratory measurements (Na+≤135 mmol/L). The sensitivity of ICD coding for hyponatremia was maximally about 30% for patients with very severe hyponatremia (Na+≤115 mmol/L). Corresponding specificities were high (>99%). In 87% of the cases with severe hyponatremia (Na+≤125 mmol/L), other discharge ICD codes reflecting severe morbidity were found. This study suggests that ICD codes for hyponatremia represent only one third of the patients admitted to the hospital and experiencing hyponatremia. About two thirds of the patients with hyponatremia were classified as hospitalized for other reasons. To assess the validity of case finding of patients with hyponatremia, the use of analytical techniques, such as certain laboratory measurements, is advisable. [Copyright &y& Elsevier]

Preventive strategies against osteoporotic fracture depend, in part, on the availability of simple risk prediction tools whereby pharmacological therapy may be targeted to those at greatest risk. The objective of this study was to evaluate the performance of a series of risk factors routinely listed in primary care records for the prediction of future fracture. Information was obtained from the UK General Practice Research Database, which contains the general practitioner medical records of around 6% of the UK population. We performed a case-control study of all 231,778 adult patients with a recorded fracture between 1988 and 1999 and an equal number of controls, individually matched by age, gender, and medical practice to the cases. In addition to a previous history of fracture, 11 items were identified that independently predicted fracture risk (history of anemia, dementia, cerebrovascular disease, and chronic obstructive pulmonary disease; recent use of oral corticosteroids, anticonvulsants, nonsteroidal anti-inflammatory drugs [NSAIDs], antiarrythmics, hypnotics/anxiolytics, antidepressants, and anti-Parkinson drugs). Three or more of these medical risk factors increased the risk of a vertebral fracture 8.1 times (95% confidence interval [CI] 7.0–9.4) and of hip fracture by 4.6 times (95% CI 4.3–5.0), when compared with subjects without these attributes. The optimum screening characteristics of the risk factors for prediction of vertebral fracture revealed a sensitivity 66%, and specificity 89%. These values were 61% and 68%, respectively, for hip fracture. The positive predictive value (PPV) for fracture over a 5 year period improved with the addition of age and previous fracture history to the number of medical risk factors. PPV rose from 8.4% for women aged 65 years without risk factors or fracture history, compared with 26.8% if women had sustained a previous fracture and had three or more risk factors recorded. The data suggest that routinely recorded medical risk factors permit identification of groups of patients with a substantial increase in future risk of fracture. Further investigations, such as bone densitometry, might be conveniently targeted at this group of patients. [ABSTRACT FROM AUTHOR]

Objective: To investigate differences in attitudes, knowledge and actual use of economic evaluations in different groups of decision-makers, and to compare the results from the Netherlands with the overall European results of the European Network on Methodology and Application of Economic Evaluation Techniques (EUROMET) project.Design and Setting: Members of the EUROMET group conducted interviews and surveys with politicians, regulators, hospital pharmacists and physicians in The Netherlands. Three approaches of investigation could be adopted: (i) a postal questionnaire survey, (ii) semi-structured interviews, and (iii) a focus-group approach.Main Outcome Measures and Results: In the Netherlands, decision-makers generally have a positive attitude towards economic evaluations. Nevertheless, their actual use and knowledge of economic evaluations are still limited. Hospital pharmacists and regulators are more objective than physicians and politicians, who also base their judgements on other societal values. Hospital pharmacists and regulators have a greater knowledge of economic evaluations, and they use them more often than the other groups. Most decision-makers do not want to base their decisions strictly on a cost-effectiveness ranking alone. Our findings were similar to the findings in other European countries.Conclusions: Decision-makers prefer to make their own broad comparisons of advantages and disadvantages, and do not base their decisions solely on a single summary measure. [ABSTRACT FROM AUTHOR]

Historical antecedents of pharmaceutical sciences are sound on product orientation based on (analytical) chemistry, drug delivery and basic pharmacology. Over the last decades we have seen a transition towards a stronger disease orientation. This raises questions on whether, how and to what extent unmet medical need (UMN) is important in priority setting, funding and impact in pharmaceutical sciences. An online survey in 2020 collected perspectives of internationally recognised pharmaceutical scientists (N = 92), mainly from academia and industry, on drivers and influencing factors in pharmaceutical sciences. The study offers a unique global perspective, demonstrating a solid command of the global needs in pharmaceutical sciences. The survey revealed that UMN is currently seen as one of the three most important drivers, also in addition to emerging trends in science and opportunities driven by collaboration. There are expectations that UMN's impact becomes more influential. This was consistent for both industry and academic respondents. The majority of respondents also indicated that anticipated lessons learned from COVID-19 will strengthen the impact of UMN on science and leadership. This is important as prioritisation of research towards UMN can address the clinical needs where needed the most. [ABSTRACT FROM AUTHOR]

Abstract: Objective: We investigated the validity of hospital discharge diagnosis regarding ventricular arrhythmias and cardiac arrest. Methods: We identified patients whose record in the PHARMO record linkage system database showed a code for ventricular or unspecified cardiac arrhythmias according to codes of the International Classification of Diseases, 9th revision, clinical modification (ICD-9-CM). The validity of ICD codes for ventricular arrhythmias and cardiac arrest (427.1, 427.4, 427.41, 427.42, 427.5, 427.69) and ICD codes for unspecified cardiac arrhythmias (427.2, 427.60, 427.8, 427.89, 427.9) was ascertained through manual review of hospital clinical records. The positive predictive value (PPV) was calculated, and differences between characteristics of true and false positives were evaluated. Results: The PPV of ICD codes for ventricular arrhythmias and cardiac arrest was 82% (95% confidence interval CI = 72–92). True positive results were associated with male gender (P = .09) and younger age (P = .05). Of the unspecified cardiac arrhythmias 10% (95% CI = 2–18) were identified as ventricular arrhythmias or cardiac arrest. Conclusion: Hospitalizations for ventricular cardiac arrhythmias and cardiac arrest (coded according to ICD-9-CM as paroxysmal ventricular tachycardia, ventricular fibrillation, ventricular flutter, ventricular premature beats, or cardiac arrest) have a high PPV and are useful for selecting events in epidemiological studies on drug-induced arrhythmias. [Copyright &y& Elsevier]

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 the Netherlands. Patients: 152 outpatients with heart failure or patients admitted to hospital because of heart failure, who were included in a randomised trial to assess the impact of a pharmacist led intervention to improve drug compliance. Duration of follow up was at least 18 months. Main outcome measures: Multivariable logistic regression modelling was used to evaluate information from history, physical examination (for example, blood pressure), drug use, and quality of life questionnaires that independently contributed to the prediction of death. The area under receiver operating characteristic curves (AUC) was used to estimate the predictive ability of the prognostic models. Results: During the 18 months of follow up, 51 patients (34%) died. Independent predictors of mortality were diabetes mellitus, a history of renal dysfunction (or higher creatinine), New York Heart Association (NYHA) functional class III or IV, lower weight or body mass index, lower blood pressure, ankle oedema, and higher scores on a disease specific quality of life questionnaire. The use of β blockers was predictive of a better prognosis. These factors were used to derive various prediction formulas. A model based on medical history, weight, presence of oedema, and lower blood pressure had an AUC of 0.77. Addition of use of β blockers to this model improved the AUC to 0.80. Addition of NYHA class increased the AUC to 0.84. Data on quality of life did not improve the AUC further (AUC 0.85). Conclusions: A prognostic model produced on the basis of easily obtainable information from medical history and physical examination can adequately stratify heart failure patients according to their short term risk of death. [ABSTRACT FROM AUTHOR]

Abstract "Non-biological complex drugs" (NBCDs), such as liposomal formulations, iron-carbohydrate complexes and glatiramoids, gained increased interest from a regulatory perspective in recent years. Similar to biologics, the quality of NBCD products is highly dependent on a robust and well-controlled manufacturing process. This provides challenges for generic drug developers to replicate NBCD products once market exclusivity of the originator product is expired. However, unlike biologics for which a consistent regulatory framework was established with the biosimilars pathway, NBCDs are not recognised as a distinct category of medicines and hence no formal regulatory pathway for their approval is defined. Currently, a "case-by-case" approach is applied for regulating NBCD follow-on products in the EU. Furthermore, NBCDs can follow a non-centralised authorisation procedure, leaving regulatory approvals to national competent authorities. This can lead to heterogeneity in the regulatory approach and outcomes when assessing NBCD follow-on products throughout the EU, which for some product classes has already resulted in some safety and efficacy implications. Here, we explore the regulatory landscape of NBCDs and their follow on products. This study shows that almost all of the 85 NBCD follow-on products available in the EU in 2018 have been approved via various non-centralised procedures. Although most NBCD follow-on products followed an Article 10(1) procedure, we clearly see a recent increase of the use of the hybrid pathway via Article 10(3). This study shows the heterogeneity in the regulatory approach taken for many NBCD follow on products. To what extent this may have consequences for their safety and efficacy evaluations is unknown and needs to be further investigated. The present study should stimulate the rethinking to design prudent regulatory pathways for NBCD follow-on products. Graphical abstract Unlabelled Image [ABSTRACT FROM AUTHOR]

There is a widely held expectation of clinical advance with the development of gene and cell-based therapies (GCTs). Yet, establishing benefits and risks is highly uncertain. We examine differences in decision-making for GCT approval between jurisdictions by comparing regulatory assessment procedures in the United States (US), European Union (EU) and Japan. A cohort of 18 assessment procedures was analyzed by comparing product characteristics, evidentiary and non-evidentiary factors considered for approval and post-marketing risk management. Product characteristics are very heterogeneous and only three products are marketed in multiple jurisdictions. Almost half of all approved GCTs received an orphan designation. Overall, confirmatory evidence or indications of clinical benefit were evident in US and EU applications, whereas in Japan approval was solely granted based on non-confirmatory evidence. Due to scientific uncertainties and safety risks, substantial post-marketing risk management activities were requested in the EU and Japan. EU and Japanese authorities often took unmet medical needs into consideration in decision-making for approval. These observations underline the effects of implemented legislation in these two jurisdictions that facilitate an adaptive approach to licensing. In the US, the recent assessments of two chimeric antigen receptor-T cell (CAR-T) products are suggestive of a trend toward a more permissive approach for GCT approval under recent reforms, in contrast to a more binary decision-making approach for previous approvals. It indicates that all three regulatory agencies are currently willing to take risks by approving GCTs with scientific uncertainties and safety risks, urging them to pay accurate attention to post-marketing risk management. [ABSTRACT FROM AUTHOR]

Net Gain Analysis (NGA) is proposed as an alternative to Responders Analysis (RA) as a more comprehensive method to tap clinical relevance of the effect of treatment. NGA is the group difference in responders minus the group difference in deteriorators; while RA is the group difference in responders. We examined the performance of these two methods in a dataset consisting of individual patient data from 10 randomized controlled trials (N = 2666) of five different antipsychotics in patients with acute mania by comparing the rank ordering of the five compounds according to both systems (NGA and RA). The rank order did not differ between the 2 systems but the inferiority of one compound was revealed more evidently by the NGA in comparison to the RA. [ABSTRACT FROM AUTHOR]

We examined the role of placebo response in acute mania trials. Specifically, whether placebo response: (1) predicts treatment effect, (2) can be predicted by patient and study characteristics, and (3) can be predicted by a parsimonious model. We performed a meta-analysis of individual patient data from 10 registration studies ( n =1019) for the indication acute manic episode of bipolar disorder. We assessed the effect of 14 determinants on placebo response. Primary outcome measures were mean symptom change score (MCS) on the Young Mania Rating Scale (YMRS) and response rate (RR), defined as ≥50% YMRS symptom improvement from baseline to endpoint. The overall placebo response was 8.5 points improvement on the YMRS (=27.9%) with a RR of 32.8%. Placebo response was significantly associated with the overall treatment response. Five determinants significantly ( p <0.05) predicted the placebo response. The multivariate prediction model, which consisted of baseline severity, psychotic features at baseline, number of geographic regions, and region, explained 10.4% and 5.5% of the variance in MSC and RR, respectively. Our findings showed that the placebo response in efficacy trials of antipsychotics for acute mania is substantial and an important determinant of treatment effect. Placebo response is influenced by patient characteristics (illness severity and presence of psychotic features) and by study characteristics (study year, number of geographic regions and region). However, the prediction model could only explain the placebo response to a limited extent. Therefore, limiting trials to certain patients in certain geographic regions seems not a viable strategy to improve assay sensitivity. [ABSTRACT FROM AUTHOR]

New use of third generation oral contraceptives is associated with a four-fold increased risk of venous thromboembolism compared with users of second generation oral contraceptives, particularly among young, healthy women. [ABSTRACT FROM AUTHOR]

Highlights: [•] We compare marketing authorisation reviews of orphan and non-orphan drugs. [•] Deficits in clinical development plans and outcomes are related to non-approval. [•] Similarity exists in orphan and non-orphan review and marketing approval decisions. [•] Regulatory standards are equally high for orphan as for non-orphan drugs. [ABSTRACT FROM AUTHOR]

The main objective of this study was to evaluate the risk of renal toxicity in patients using aminosalicylates 5-ASA). The medico records of GPs in the UK (from the Genera Practice Research Database) were used to estimate the incidence rates of renal toxicity of adult patients with either a record of inflammatory bowel disease (IBD) or prescription for 5-ASA (eg mesalazine or sulfasalazine) and that of control patients. Each case of renal toxicity was subsequently matched by age, sex, practice, and calendar time to one patient without renal toxicity. 37 984 adult patients with a record of BD or 5-ASA prescription and a similar number of control patients were included n the patients without a history of arthropathy we found that IBD patients using 5-ASA had an increased risk of renal toxicity: the overall incidence was about 1 case per 1000 person-years of treatment (double compared to non-users). The case control analysis revealed the risk of renal disease was related to indicators of IBD severity. It was also increased in current and recent users (ie their last prescription in the 3 to 12 months before the index date of 5-ASA. Compared to non-users, the odds ratio (OR for renal events was 1.80 (95% CI 1.22 to 2.60) in current 5-ASA users. This excess risk markedly reduced in current users after adjustment for concomitant disease and drug use (adjusted OR 1.22 [0.69-2.16]). For recent users, the crude OR was 3.96 (2.20-7.13) and adjusted OR 2.80 (1.33-5.91). Users of mesalazine and sulfasalazine had comparable risks (crude ORs 1.66 [0.94-2.96] and 1.93 [1.18-3.14], and adjusted ORs 1.05 [0.472.31] and 1.34 [0.68-2.62], respectively). There was no relationship between 5-ASA dose and risk of renal disease. Numbers were too small to compare individual 5-ASA compounds. Users of 5-ASA hod an increased risk of renal disease which may be influenced by the underlying disease severity. There were no differences in risk of renal disease between mesalazine and sulfasalazine. [ABSTRACT FROM AUTHOR]

Abstract: Objectives:: To assess and compare the risk of prostatic surgery in (subsets of) patients with a diagnosis of BPH. We sought to expand on data of an earlier pharmacy-based study by obtaining more information on BPH disease parameters by using a Dutch GP-based research database. Methods:: A retrospective cohort study (1994–mid-year 2002) was conducted among 1430 men aged ≥45 years with ≥6 months of registration with the GP. BPH case identification was based on review of medical records. Results:: Overall, we found that there was no difference in the risk of prostatic surgery between patients on medical treatment and watchful waiting. Patients using 5α-reductase inhibitors (5-ARIs) at any stage had a statistically significant reduced risk of surgery compared to patients using α-blockers only: adjusted hazard ratio 0.35 (95%CI: 0.13-0.96). The routine collection of BPH parameters were insufficient to be useful in the analysis. Conclusion:: Patients using 5-ARIs seemed to have a reduced risk of prostatic surgery compared to patients using α-blockers. However, it was unknown whether the disease profile of 5-ARI users is different compare to non-5-ARI-treated and untreated patients with BPH, as detailed medical information necessary to characterise patients according to the BPH disease severity and development of disease parameters is not routinely recorded by GPs. [Copyright &y& Elsevier]

The driving performance is easily impaired as a consequence of the use of alcohol and/or licit and illicit drugs. However, the role of drugs other than alcohol in motor vehicle accidents has not been well established. The objective of this study was to estimate the association between psychoactive drug use and motor vehicle accidents requiring hospitalisation.A prospective observational case-control study was conducted in the Tilburg region of The Netherlands from May 2000 to August 2001. Cases were car or van drivers involved in road crashes needing hospitalisation. Demographic and trauma related data was collected from hospital and ambulance records. Urine and/or blood samples were collected on admission.Controls were drivers recruited at random while driving on public roads. Sampling was conducted by researchers, in close collaboration with the Tilburg police, covering different days of the week and times of the day. Respondents were interviewed and asked for a urine sample. If no urine sample could be collected, a blood sample was requested.All blood and urine samples were tested for alcohol and a number of licit and illicit drugs. The main outcome measures were odds ratios (OR) for injury crash associated with single or multiple use of several drugs by drivers.The risk for road trauma was increased for single use of benzodiazepines (adjusted OR 5.1 (95% Cl: 1.8–14.0)) and alcohol (blood alcohol concentrations of 0.50–0.79 g/l, adjusted OR 5.5 (95% Cl: 1.3–23.2) and ≥0.8 g/l, adjusted OR 15.5 (95% Cl: 7.1–33.9)). High relative risks were estimated for drivers using combinations of drugs (adjusted OR 6.1 (95% Cl: 2.6–14.1)) and those using a combination of drugs and alcohol (OR 112.2 (95% Cl: 14.1–892)). Increased risks, although not statistically significantly, were assessed for drivers using amphetamines, cocaine, or opiates. No increased risk for road trauma was found for drivers exposed to cannabis.The study concludes that drug use, especially alcohol, benzodiazepines and multiple drug use and drug–alcohol combinations, among vehicle drivers increases the risk for a road trauma accident requiring hospitalisation. [Copyright &y& Elsevier]

Souverein PC, Van Staa TP, Egberts ACG, De la Rosette JJMCH, Cooper C, Leufkens HGM. (Utrecht Institute for Pharmaceutical Sciences, Utrecht, The Netherlands; Southampton University Hospital, Southampton, UK; and Academic Medical Centre, Amsterdam, The Netherlands). Use of α-blockers and the risk of hip/femur fractures. J Intern Med 2003; 254: 548–554. To study the association between use of α-blockers and risk of hip/femur fractures. Population-based case–control study. General Practice Research Database. Cases were defined as men, aged 40 years and older with a first diagnosis for hip/femur fracture. Controls were matched 1 : 1 on gender, year of birth and general practitioner-practice. In all, 4571 cases and an equal number of controls were identified. Current use of α-blockers (prazosin, doxazosin, indoramin, terazosin, alfuzosin and tamsulosin) was compared with non-use of α-blockers. Current use of α-blockers on the index date was associated with an increased risk of hip/femur fracture [adjusted odds ratio (OR) 1.9, 95% confidence interval (CI): 1.1–3.0] in the overall analysis. The effect was particularly strong for first prescriptions within a treatment episode (adjusted OR 5.1, 95% CI: 1.0–31.7) and during the first month of treatment (adjusted OR 4.1, 95% CI: 0.7–23.9). Stratification according to indication of use showed that current use of α-blockers was not associated with hip/femur fracture in men with a diagnosis of benign prostatic hyperplasia (adjusted OR 1.0, 95% CI: 0.4–2.5), but was associated in men who used α-blockers for cardiovascular disease (adjusted OR 2.8, 95% CI: 1.4–5.4). Current use of α-blockers was associated with an increased risk of hip/femur fracture and with the start of a new treatment episode. The effect seemed to be confined to patients who used α-blockers for cardiovascular disease. Caution with respect to first-dose effects related to the initiation of a new episode of α-blocker treatment is advised. [ABSTRACT FROM AUTHOR]

Objective: To investigate whether there is a difference in the risk of progressing to BPH-related prostatic surgery between patients using alpha-blockers and patients using the 5-alpha-reductase inhibitors (5-ARIs).Methods: A population-based cohort study was conducted, using data from the PHARMO Record Linkage System. We identified 5671 patients (≥50 years old, no history of using both alpha-blockers and 5-ARIs, more than one year of database history prior to the first date of BPH drug-dispensing), who filled at least one prescription for either alpha-blockers (alfuzosin, tamsulosin, terazosin) or 5-ARIs (finasteride). The incidence of BPH-related surgery was compared between patients treated with alpha-blockers and patients treated with 5-ARIs.Results: The cumulative incidence of BPH-related prostatic surgery was 15.2% and mainly involved transurethral resection of the prostate (TURP) (13.4%). Patients using alpha-blockers had a significantly increased risk of BPH-related prostatic surgery compared to patients using 5-ARIs, which remained after adjusting for age, calendar time, type of prescriber and chronic disease score (adjusted HR: 1.52, 95% CI: 1.24–1.88). The difference between alpha-blockers and 5-ARIs was sustained after stratification of time period (<1995, ≥1995) and exclusion of patients with prostatic surgery within one month of treatment initiation.Conclusions: It is concluded that alpha-blocker treated patients had a higher risk of BPH-related surgery compared to 5-ARI treated patients. Additional research on the long-term outcomes and risk factors for the natural progression of BPH is necessary to identify the optimal medical treatment for BPH patients according to their baseline characteristics. [Copyright &y& Elsevier]

The association between the use of calcium channel blockers (CCB) and cancer has received ample attention, but is still controversial. In this study, we have tested the hypothesis that the observed association between CCB and cancer in earlier studies could be explained by residual confounding or by misclassification of exposure because of the use of cross-sectional data on drug use. Data from the Rotterdam Study, a prospective population-based cohort study in the municipal area Ommoord, were used. The study population consisted of a cohort of 3204 participants aged 71 years or older who were followed from a baseline interview in the period 1991–1993 for the occurrence of incident cancer. Data on drug use were gathered at baseline and through the seven community pharmacies which served the Ommoord region during the study period between 1 January 1991 and 1 January 1999. Incident cancer events were gathered from a nationwide registry of hospitalisation data and from a specialised cancer centre in the Rotterdam region. We performed three analyses. First, we followed the method, and adjusted for the same risk factors, as in the earlier studies. In the second analysis, we included all risk factors that were univariately associated with cancer in the Rotterdam Study. In the third analysis, we included exposure to CCBs as time-varying co-variates, while adjusting for potential confounders. The relative risk (RR) of cancer associated with CCB was 1.4 (95% Confidence Interval (CI): 0.9–2.0) in the first analysis and lowered to 1.2 (95% CI: 0.8–1.8) upon adjustment for the different co-variates in the second. In both analyses, however, verapamil was significantly associated with cancer with RRs of 2.1 (95% CI: 1.1–4.0) and 2.0 (1.01–3.9), respectively, whereas no associations were found with the other CCB in this study, i.e. diltiazem and nifedipine. A significantly increased risk of cancer was found for intermediate daily doses of verapamil and diltiazem. Intake of other antihypertensives such as β-blocking agents, diuretics and ACE-inhibitors was not associated with cancer. In the third analysis with exposure to CCB as time-varying co-variates, the risk increase was non-significant for use of 2 years or less, 1.0 (95% CI: 0.7–1.5), and for use for a cumulative period of more than 2 years, 1.3 (95% CI: 0.8–2.0). However, in all models the hazard ratio was statistically significantly increased for verapamil, but not for diltiazem and nifedipine. On the basis of these analyses, we found no increase in cancer in users of diltiazem and nifedipine, nor in users of other antihypertensives. In line with earlier studies, however, we found an increased risk of cancer in users of verapamil. At variance with the conclusions from several other studies, we think that it is too early to conclude that CCB are not associated with cancer. [Copyright &y& Elsevier]

Objective: Given the high possibility of co-occurrence of benign prostatic hyperplasia (BPH) and cardiovascular disease, we evaluated whether patients using BPH drugs are at an increased risk of acute hospital admission for ischemic heart disease (IHD).Methods: A nested case control study within a cohort of 4414 men (aged ≥30 years) who had a history of using BPH products between 1992 and 1998 was conducted. Cases were defined as men with a first record of an acute hospital admission for IHD during the study period; three controls were matched to each case on year of birth, pharmacy and calendar time (index date).Results: The study population comprised 220 cases and 515 controls. Current use of alpha-blockers (adjusted odds ratio 1.0, 95% confidence interval: 0.5–2.2) or finasteride (adjusted odds ratio 0.3, 95% CI: 0.1–1.4) was not associated with hospital admission for IHD. Furthermore, current use of BPH drugs was not associated with IHD in patient subgroups (age, history of cardiovascular disease, diabetes), nor with duration of use prior to hospitalization.Conclusion: Although the power of the study was low, we found no evidence for an association between current use of BPH drugs and hospital admission for IHD. Therefore, our study seems to confirm the good cardiovascular safety profile of modern BPH drugs. [ABSTRACT FROM AUTHOR]

Sildenafil utilization was prospectively evaluated among 1.53 men with a history of erectile dysfunction (ED)-prescription drug use prior to starting sildenafil and 164 men who were new starters of ED-prescription drugs. Further, some determinants of sildenafil discontinuation were identified. During a median follow-up period of 18 months 45% of all patients discontinued sildenafil treatment, regardless of earlier treatment history. However, patients with a history of drug treatment for ED were nearly eight times as likely to switch or re-start another EDprescription drug after discontinuing sildenafil compared to previously untreated users. Age > 60 y, diabetes medication, nitrate use, and use of incontinence pads (a proxy for disease/surgery in the pelvic region) were associated with an increased likelihood of discontinuing sildenafil. Although the introduction of sildenafil reduced the barrier to seek medical help for erectile problems, sildenafil treatment failure in previously untreated patients results in a high dropout rate from further ED drug treatment of any kind. [ABSTRACT FROM AUTHOR]

Discusses the use of spontaneous reports of adverse events to estimate the risk for developing cardiac arrhythmias due to the systemic use of nonsedating antihistamine drugs in the Netherlands. Risk estimate before and after the regulatory action to recall the over-the-counter status of some of these drugs; Indication that nonsedating antihistamines might have an increased risk for inducing arrhythmias.

Objective: During proton pump inhibitor (PPI) use, in clinical trials, headache is one of the most frequently reported adverse events (frequency 1.3 to 8.8%), while results of one observational study indicate that headache is the fifth most frequently reported adverse event (incidence densities 2.5 to 4.6 per 1000 patient-months of exposure). However, there are no observational studies performed regarding the occurrence and features of headache during use of PPIs in daily practice. For this reason this study was set up with the aim to assess the incidence and characteristics of headache and to investigate possible associated co-factors in PPI users in daily practice.Design: Data were used from a prospective, observational study in which 10 008 lansoprazole users were followed over time. The study was designed according to the Safety Assessment of Marketed Medicines guidelines. A nested case-control design was used to compare PPI users reporting headache or not.Results: The frequency of headache was 2.5% in users of lansoprazole and the incidence density was 7.2 per 1000 patient-months of PPI lansoprazole use. Two-thirds of patients with headache had tension headache and one-third had migraine. The analysis of co-factors revealed that women, patients with previous use of analgesics and patients reporting several adverse events, were at risk to develop headache during PPI use. Patients with headache also, significantly more often, reported diarrhoea, nausea and dizziness. A discontinuation of PPI therapy resulted in a cessation or reduction of the headache in 80.0% (20 of 25).Conclusions: As can be expected, headache was reported less frequently in this study compared with clinical trials with lansoprazole. The incidence density was comparable with other observational data of lansoprazole and omeprazole users. Besides several commonly accepted co-factors such as female gender and a history of analgesic use, we also found the reporting of other adverse events to be associated with the reporting of headache during lansoprazole use. The cessation of headache after a discontinuation of use of the PPI and the observed dose relationship suggested that headache was indeed an adverse effect of lansoprazole use. [ABSTRACT FROM AUTHOR]

Objective To identify a Dutch cohort of sildenafil users and describe their baseline characteristics. Patients and methods Each pharmacy in The Netherlands (n = 1571) was asked to identify prospectively the first 20 sildenafil prescriptions in their pharmacy over 1 year, and to complete and return a registration form. The collected data included patient characteristics, the details of the sildenafil prescription (date, prescriber, number of prescriptions, dosing), and the use of co-medication by the patient in the year preceding the sildenafil prescription. Results Data were collected from 4460 sildenafil prescriptions during the year under study, relating to 3477 individual patients. Most of the cohort had cardiovascular morbidity or diabetes. Sildenafil seems to have been used by a new, previously untreated population of patients with erectile dysfunction. In addition, 69 men were identified who could have been using nitrates and sildenafil concomitantly. Conclusion A cohort of patients using sildenafil was identified and characterized; they appeared to be representative of sildenafil users in The Netherlands. This cohort will be followed prospectively to evaluate the medical status (particularly cardiovascular) of the patients with time. [ABSTRACT FROM AUTHOR]

Patients with inflammatory bowel disease (IBD) have an increased risk of Iow bone mass, the pathogenesis of which is multifactorial. There are limited data on fracture. We therefore conducted a primary care based case-control study to determine the risk and major risk factors of fracture in IBD patients. 231 778 patients with a fracture and 231 778 age and sex matched controls were recruited from the General Practice Research Database. The database has been previously demonstrated to be a representative sample of the general population of England and Wales. Adjusted odds ratios (OR) were estimated from conditional logistic regression. The mean age of cases and controis was 51 years and 52.5% were women. A history of IBD was found in 1134 fracture cases, compared with 896 of the controls (adjusted OR 1.21; 95% CI 1.10 to 1.32). The OR was 1.72 (1.132.61) for vertebral fracture and 1.59 (1.14 to 2.23) for hip fracture. The risk of fracture was greater in patients with a history of Crohn's disease (OR 1.32 (1.13-1.53)) than in patients with ulcerative colitis (OR 1.13 (1.02-1.27)). The risk of fracture in patients with a history of IBD was significantly related to disease severity as assessed by the number of symptoms (OR in IBD patients without symptoms, 1.02 (090-1.17) 1 symptom, 1.66 (1.41-1.96); and ≥2 symptoms, 1.74 (1.43-12.12)). Similarly, severity assessed by medication demonstrated increasing fracture risks compared with untreated patients: aminosalicylates use 1.32 (1.14-1.54), oral corticosteroids 1.46 (1.18-1.82), and steroid sparing agents 1.86 (1.15-3.02). IBD patients with a history of bowel surgery did not have an increased risk of fracture (OR 1.03 (0.84-1.28)). Use of oral corticosteroids increased with severity of disease; after adjustment for oral corticosteroid use the risk of hip fracture remained elevated (OR 1.46 (1.04-2.04)). In conclusion, IBD patients have a higher risk of fractures, which is due to a combination of disease activity... [ABSTRACT FROM AUTHOR]

Examines the effects of antihypertensive drug therapies on plasma lipid levels. Treatment of hypertensive; Cholesterol levels of antihypertensive; Prevalence of hypertension in women.

Evaluates whether adverse drug reactions (ADR) to selective serotonin reuptake inhibitors (SSRI) were associated with extrapyramidal syndrome in the Netherlands. Calculation of ADR reporting odds ratios; Other drugs associated with extrapyramidal syndrome; Risk of extrapyramidal syndrome on patients under SSRI and other antidepressant drugs.