Analysing duration of treatment episodes has become a standard task in many pharmacoepidemiological studies. However, such analyses are often carried out in a rather simplistic manner and more subtle issues are often ignored. In this paper, methods of analysing duration treatment episodes beyond simple analyses allowing investigation of the risk for certain events over time are demonstrated. In particular, the use of cumulative incidence functions, cause-specific hazard functions, hazard rate models and expected mortality in analysing duration of episodes is presented. We used these statistical techniques in analysing the early treatment history of patients who started a regular treatment with antidepressant drugs in the primary health care sector in Denmark. We have extracted some important features: The risk of discontinuing and switching treatment was very high around 10 weeks after starting treatment. After discontinuing the first treatment period, many patients soon started a second treatment period depending on the duration of the first treatment period with highest risk around 10 weeks. The mortality rate among the patients in treatment was about three times higher than the expected mortality. The risk of dying immediately after stopping treatment was about twice the expected mortality. The analysis suggests that: (1) there is a critical period for a first discontinuing, switching and restarting treatment around 10 weeks, (2) the GPs prescribing habits have more influence on the patterns than patient or drug characteristics, (3) over time Danish GPs tend to prolong the duration of first treatment period and avoid longer treatment breaks.
GOAL: The factors underlying the choice of opioids for cancer patients in primary care are largely unknown. Our aim was to describe cancer patients' first treatment episode with opioids in relation to disease characteristics and clinical course. PATIENTS AND METHODS: During 1997 and 1998, a population-based cohort of 4,006 incident cancer patients from a Danish county was identified. The patients were followed up from diagnosis to death or until 31 December 2003, and data on their use of opioids were obtained from a prescription database. MAIN RESULTS: Eventually, 54% of the cancer patients became incident users of opioids. Opioid treatment was initiated close to the diagnosis date in 20% of the patients. Most incident users (57%) were not terminal when they began using opioids, and 44% survived the first treatment episode. Of those who died, 70% received opioids in their terminal phase. The incidence rates of new opioid users were inversely related to the 5-year cancer survival period. A weak opioid was the first choice in 64% of the non-terminal users and in 43% of the terminal ones. No statistically significant differences in opioid use were found between men and women. CONCLUSIONS: Opioid use in cancer patients was not confined to the terminal course. Treatment with opioids should be viewed as a dynamic condition, with patients shifting between periods of use and non-use. The aggressiveness of the cancer and the presence of metastases were characteristics found to be strong determinants of opioid use.
BACKGROUND: Inhibitors of histone deacetylases (HDAC) have shown promise as targeted cancer therapy. Valproate, an older anticonvulsant, has been shown to possess HDAC inhibitory activity. We undertook this case-control study to clarify whether long-term users of valproate had a reduced cancer incidence. If so, it would support HDAC inhibition as a pharmacologic principle in chemoprevention. METHODS: We identified 149,417 incident cancer cases in Denmark during the study period 2000 through 2005, and 597,668 age- and gender-matched controls. Data on history of cancer, past hospital admission diagnoses, and prescription history were obtained from the Danish Cancer Registry, the Danish National Patient Registry, and the Danish Prescription Registry. Primary exposure to valproate was defined as a cumulative dose of minimum 1,500 g within the past 5 years. Confounders were controlled by conditional logistic regression. RESULTS: Among the cases and controls, 81 (0.05%) and 260 (0.04%), respectively, were long-term users of valproate. For cancer overall, the crude and adjusted odds ratios were 1.25 [95% confidence interval (95% CI), 0.97-1.60] and 1.21 (95% CI, 0.95-1.56), respectively. Subgroup analyses revealed no dose or duration effect for overall cancer incidence, and no specific cancer site was found to be inversely associated with long-term use of valproate. For lung cancer, we found a positive but imprecise association (adjusted odds ratio, 2.32; 95% CI, 1.12-4.79). CONCLUSION: Long-term valproate use is not associated with a reduced cancer risk. Our study does not support HDAC inhibition as a pharmacologic principle for general chemoprevention.
OBJECTIVE: During the past 30 years, various cardiovascular drugs have been implicated as causes of depression or suicide. Although the evidence for causal relationships has generally been conflicting, both beta-blockers and angiotensin-converting-enzyme inhibitors (ACE-inhibitors) have been related to depression. Lipid-lowering therapies and calcium-channel blockers have also been linked to an increased risk of suicide. In this study, we investigated the possible association between the use of cardiovascular drugs and suicide using population-based register data. METHODS: We performed a nested case-control study in the county of Funen, Denmark, that consisted of 743 cases of completed suicide identified in a Death Registry for the period 1991-1998 and 14,860 age- and sex-matched controls. Information on previous drug use was retrieved from prescription data and the association between suicide and use of cardiovascular drugs was analysed by conditional logistic regression. Previous exposures to other drugs were used as proxies for potential confounding co-morbidities, including the use of psychotropic drugs to indicate psychiatric illness. RESULTS: The risk of suicide was not associated with current exposure to lipid-lowering drugs [odds ratio (OR): 1.21; 95% confidence interval (95% CI): 0.45-3.28), calcium-channel blockers (OR: 0.96; 95% CI: 0.63-1.48), beta-blockers (OR: 0.76; 95% CI: 0.47-1.25) or ACE-inhibitors (OR: 1.11; 95% CI: 0.68-1.83). Suicide risk was associated with current angiotensin-receptor antagonist use (OR: 3.52; 95% CI: 1.33-9.30) based on five of the cases exposed. CONCLUSION: With the exception of the imprecise risk associated with current use of angiotensin-receptor antagonists, the results from our study do not support the hypothesis that other cardiovascular drugs are associated with an increased the risk of suicide.
ABSTRACT: BACKGROUND: Diabetes prevalence increases globally with severe consequences for afflicted individuals and societies. Data on diabetes incidence and diabetes related mortality on a population level are, however, scarce. As an alternative to dedicated studies it has been suggested to use pharmacoepidemiological databases that are readily available, at least in the Nordic countries. METHODS: For all 470,000 inhabitants in Funen County, Denmark, in the period 1992-2003, data on gender, date of birth, death and migration to and from the county, and any filled prescriptions of an anti-diabetic medication was obtained from the Odense Pharmaco-Epidemiological Database. RESULTS: Prevalence odds for use of an anti-diabetic medication rose annually 3.5% (95% confidence interval: 3.1%, 3.9%) for females, 4.5% (4.0%, 4.9%) for males. Corresponding incidence rates annually rose 4.8% (3.8%, 5.8%) for females, 4.5% (3.5%, 5.4%) for males. Mortality rates among treated annually declined 2.8% (1.4%, 4.1%) among females, 2.2% (0.9%, 3.5%) among males. The disequilibrium in absolute numbers between incidence and mortality among treated was the main driver for the increasing prevalence, while concurrent trends in incidence and diabetes related mortality only marginally affected prevalence trends. Trend estimates were insensitive to varying the length of the run-in period used for determining treatment status, except when using the naive and methodologically flawed run-in period of variable length. CONCLUSION: While pharmacoepidemiological databases provide a useful tool for monitoring pharmacologically treated diabetes, a dedicated diabetes database covering all prevalents and incidents is needed for a more detailed analysis of underlying causes and trends.
AIMS: Recently, an apparent protective effect of statins against upper gastrointestinal bleeding (UGB) was postulated in a post hoc analysis of a randomized trial. We aimed to evaluate the effect of statin use on acute nonvariceal UGB alone or in combinations with low-dose aspirin and other antithrombotic drugs. METHODS: A population-based case-control study was conducted in the County of Funen, Denmark. Cases (n = 3652) were all subjects with a first discharge diagnosis of serious UGB from a hospital during the period 1995 to 2006. Age- and gender-matched controls (10 for each case) (n = 36 502) were selected by a risk set sampling. Data on all subjects' drug exposure and past medical history were retrieved from a prescription database and from the County's patient register. Confounders were controlled by conditional logistic regression. RESULTS: The adjusted odds ratios (ORs) associating use of statins with UGB were 0.94 (0.78-1.12) for current use, 1.40 (0.89-2.20) for recent use and 1.42 (0.96-2.10) for past use. The lack of effect was consistent across most patient subgroups, different cumulative or current statin doses and different statin substances. In explorative analyses, a borderline significant protective effect was observed for concurrent users of low-dose aspirin [OR 0.43 (0.18-1.05)]. CONCLUSION: Statins do not prevent UGB, except possibly in users of low-dose aspirin.
AIMS: To investigate the driving forces behind increasing utilization of cardiovascular drugs. METHODS: Using register data, all Danish residents as of 1 January 1996 were followed until 2006. Cohort members were censored at death or emigration. Cardiovascular drug utilization on the individual level was traced, applying registered out-of-hospital dispensing. The impact of population ageing on cardiovascular drug utilization was investigated using standardized intensities and prevalences. Based on a three-state (untreated, treated and dead) semi-Markov model, we explored to what extent increasing treatment prevalence was driven by changing incidence, discontinuation and mortality. Expected treatment prevalences were modelled, applying stratum-specific cohort prevalence in 1996 along with incidence, discontinuation and drug user mortality either throughout 1996-2004 or at fixed 1996 levels. RESULTS: Treatment prevalence (ages > or =20 years) with cardiovascular drugs increased by 39% during 1996-2005 from 192.4 to 256.9 per 1000 inhabitants (95% confidence interval 256.5, 257.3). Treatment intensity grew by 109% from 272 to 569 defined daily doses 1000(-1) day(-1). Population 'middle-ageing' accounted for 11.5 and 20.3%, respectively. Increasing treatment incidence was the main driver of the rising treatment prevalence in most drug categories. Declining discontinuation drove some of the growth, declining drug user mortality less. Even with fixed incidence in the model, treatment prevalence continued to increase. CONCLUSIONS: Age-related increases in treatment intensity and prevalence, rather than population ageing, drove the increasing treatment intensity with cardiovascular drugs. Increasing treatment prevalence in subgroups was primarily caused by increasing incidence. Due to pharmacoepidemiological disequilibrium, treatment prevalence will continue to grow even with unchanged incidence.
Objective. To explore how GPs choose between drugs in a therapeutic drug group. Design. A qualitative study based on semi-structured ethnographic interviews. Setting and subjects. General practitioners from the counties of both Funen and West Zealand in Denmark. A total of 15 general practitioners (GPs) were selected with reference to variation in organizational structure, age, and gender. Main outcome measures. GPs' description of drug choice in relation to specific patient encounters involving a prescription. Results. All informants appeared to consider drug price important as it was a recurring theme during all interviews. External factors outside the GP's control such as governmental regulation on prescribing and the pharmaceutical industry influenced most GPs. Internal factors related to the actual consultation included characteristics of the GP and the patient, drug characteristics, and repeat prescriptions. These factors interact in a non-linear and unpredictable way similar to complex adaptive systems. Conclusion. GPs balance both internal and external factors when choosing between analogues. Drug choice is a regulated process in the realm of complex prescribing behaviour with drug costs as a major factor.
CONTEXT: General practitioners are frequently involved in clinical trials sponsored by pharmaceutical companies but the effects of participation on their prescribing patterns have not been evaluated. OBJECTIVE: To determine how conducting a company-sponsored clinical trial influenced physicians' adherence to international treatment recommendations and their prescribing of the pharmaceutical company's drugs. DESIGN, SETTING, AND PATIENTS: Observational cohort study in Funen County, Denmark, comparing 10 practices that were conducting a trial on asthma medicine with 165 control (non-trial-conducting) practices. The study population included 5439 patients treated with asthma drugs from the trial-conducting practices and 59,574 patients from the control practices. Practices conducted the trial between April 26, 2001, and October 7, 2002. MAIN OUTCOME MEASURES: Adherence to guidelines measured as use of inhaled corticosteroids among asthma patients. Prevalence of use of the company's drugs and the trial sponsor's share of the total volume of asthma drugs prescribed. RESULTS: The baseline proportion of asthma patients using inhaled corticosteroids was 68.5% in trial-conducting and 69.1% in control practices. Conducting the trial did not influence guideline adherence (odds ratio [OR] after 2 years, 1.00; 95% confidence interval [CI], 0.84-1.19). In trial-conducting practices, the sponsoring company's share of the total prescribed volume of asthma drugs increased compared with control practices (6.7%; 95% CI, 3.0%-11.7%). This could be attributed to a significantly higher preference for the company's inhaled corticosteroids (OR, 1.26; 95% CI, 1.04-1.54) and trends toward increased prescribing of the company's other asthma drugs. CONCLUSION: Conducting a trial sponsored by a pharmaceutical company had no significant impact on physicians' adherence to international treatment recommendations but increased their use of the trial sponsor's drugs.
Comment In: JAMA. 2006 Jun 21;295(23):2787-9016788134
ReprintIn: Ugeskr Laeger. 2006 Nov 13;168(46):3987-9117125649
BACKGROUND: Pharmaceutical representative visits are believed to have substantial impact, but the effects on prescribing patterns have not been systematically evaluated. OBJECTIVE: This study investigates how pharmaceutical sales representative visits influenced physicians' company-specific drug preferences and prevalence of steroid prescribing. METHODS: Observational cohort study in Funen County, Denmark, including 165 general practices visited 832 times by pharmaceutical representatives and 54 080 patients treated with asthma drugs. Visits were conducted from 2001 to 2003. Our main outcome measures were (i) company-specific drug preferences measured as the proportion of dispensings of the promoted drug among all dispensings of fixed combinations of inhaled corticosteroid and long-acting beta2-agonists and (ii) the proportion of patients receiving repeated beta2-agonist dispensings who were treated with inhaled steroids. RESULTS: The first visit had a statistically significant effect on the GPs' drug preference in favour of the marketed drug [odds ratio (OR), 2.39; 95% confidence interval (CI), 1.72-3.32]. The effect on drug preference increased further after the second visit (OR, 1.51; 95% CI, 1.19-1.93), while there was no significant change after the third visit (OR, 1.06; 95% CI, 0.94-1.20). Pharmaceutical sales representative visits did not influence the overall treatment pattern with inhaled steroids (OR, 1.01; 95% CI, 0.97-1.06). CONCLUSIONS: Pharmaceutical sales representative visits markedly increased the market share of the promoted drug, but only the two first visits had significant impact. Visits had no significant impact on GPs' overall prescribing of inhaled steroids.