Jane Møller Hansen

Use of single and combined antithrombotic therapy and risk of serious upper gastrointestinal bleeding: population based case-control study

Abstract Objectives To assess the risk of serious upper gastrointestinal bleeding associated with the newer antithrombotic agents used alone or in combination with other antithrombotic drugs; to describe the trends in use of antithrombotic drugs in the background population. Design Population based case-control study. Setting Funen County, Denmark (population 470 000). Subjects 1443 cases of serious upper gastrointestinal bleeding identified during 2000-4; 57 720 age and sex matched controls. Main outcome measure Exposure to low dose aspirin, clopidogrel, dipyridamole, vitamin K antagonists, and combined antithrombotic treatment. Results Adjusted odds ratios associating drug use with upper gastrointestinal bleeding were 1.8 (95% confidence interval 1.5 to 2.1) for low dose aspirin, 1.1 (0.6 to 2.1) for clopidogrel, 1.9 (1.3 to 2.8) for dipyridamole, and 1.8 (1.3 to 2.4) for vitamin K antagonists. Corresponding figures for combined use were 7.4 (3.5 to 15) for clopidogrel and aspirin, 5.3 (2.9 to 9.5) for vitamin K antagonists and aspirin, and 2.3 (1.7 to 3.3) for dipyridamole and aspirin. Other combinations were used too infrequently to allow estimation. The number of treatment years needed to produce one excess case varied from 124 for the clopidogrel-aspirin combination to 8800 for clopidogrel alone. During the study period, exposure to combined antithrombotic regimens increased by 425% in the background population. Conclusion Antithrombotic treatment is becoming increasingly aggressive. Combined antithrombotic treatment confers particular risk and is associated with high incidence of gastrointestinal bleeding.

Non-Steroidal Anti-Inflammatory Drugs and Ulcer Complications: a Risk Factor Analysis for Clinical Decision-Making

BACKGROUND Use of non-steroidal anti-inflammatory drugs (NSAIDs) is recognized as an important cause of peptic ulcer complications. The aim of this nested case-control study was to identify risk factors for NSAID-related ulcer complications. METHODS Cases were consecutive NSAID users admitted with an ulcer complication (n = 118), and controls were a random sample of all NSAID users without ulcer complication identified by a pharmacoepidemiologic database (n = 540). RESULTS Ninety-four of 118 cases were interviewed, and 324 of 540 controls answered the questionnaire. Analysis showed no difference between included and non-included subjects. Risk factors for patients at start of NSAID therapy were high age: 60-75 years (odds ratio (OR), 3.5 (95% confidence interval (Cl), 1.8-7.1); > 75 years (OR, 8.9 (4.3-18.3)); male sex (OR 1.7 (1.0-3.0)); ulcer history (OR 2.5 (1.2-5.1)); steroid treatment (OR 2.0 (0.8-4.6)); smoking (OR 1.6 (0.9-2.7)); and alcohol use (OR 1.8 (0.9-3.6)). Risk factors for patients receiving NSAID therapy were high age, male sex, ulcer history, smoking and, furthermore, dyspepsia (OR 2.0 (1.0-4.2)), especially NSAID-related dyspepsia (OR 8.7 (4.0-18.9)). Risk was lower for patients treated more than 3 months. CONCLUSION Risk measured from this design can be shown to correlate strongly with the rate difference, a measure that is more clinically relevant than conventional relative risk estimates. Strong risk factors for NSAID-related ulcer complication are high age, male sex, ulcer history, and dyspepsia related to the NSAID therapy. Avoiding NSAID therapy in these high-risk patients, whenever possible, might prevent many adverse events.

An Association Between Selective Serotonin Reuptake Inhibitor Use and Serious Upper Gastrointestinal Bleeding

BACKGROUND & AIMS In vitro studies have shown that selective serotonin reuptake inhibitors (SSRIs) inhibit platelet aggregation. It is controversial whether use of SSRIs is a cause of clinically important bleeding; results from observational studies have been equivocal. METHODS A population-based case-control study was conducted in Denmark. The 3652 cases all had a first discharge diagnosis of serious upper gastrointestinal bleeding (UGB) from 1995 to 2006. Controls (n = 36,502), matched for age and sex, were selected by risk-set sampling. Data on drug exposure and medical history were retrieved from a prescription database and the countys patient register. Confounders were controlled for by conditional logistic regression and the case-crossover design. RESULTS The adjusted odds ratio (OR) of UGB among current, recent, and past users of SSRIs was 1.67 (95% confidence interval [CI], 1.46-1.92), 1.88 (95% CI, 1.42-2.5), and 1.22 (95% CI, 1.07-1.39). The adjusted OR for concurrent use of SSRI and nonsteroidal anti-inflammatory drugs (NSAIDs) was 8.0 (95% CI, 4.8-13). The adjusted OR for the concurrent use of NSAID, aspirin, and SSRI was 28 (95% CI, 7.6-103). Of the UGB cases, 377 were current users of SSRI; the adjusted OR for UGB in the case crossover analysis was 2.8 (95% CI, 2.2-3.6). The adjusted OR among users of proton pump inhibitors was 0.96 (95% CI, 0.50-1.82). CONCLUSIONS Use of SSRI was associated with UGB, consistent with its antiplatelet effects. SSRIs should be prescribed with caution for patients at high risk for UGB.

Rates of Dyspepsia One Year After Helicobacter pylori Screening and Eradication in a Danish Population

BACKGROUND & AIMS Helicobacter pylori (Hp) is strongly correlated with peptic ulcer and is a risk factor for gastric cancer. The aim of this study was to assess whether screening and eradication of Hp in a general population would reduce the prevalence of dyspepsia and the incidence of peptic ulcer and thus save health care resources and improve quality of life. METHODS Twenty thousand individuals aged 40 to 65 years were randomized to screening and eradication for Hp or to the control group. Hp status was assessed by a whole blood Hp test, a positive result confirmed by a (13)C-urea breath test. Hp-positive individuals were offered Hp eradication therapy. The prevalence of dyspepsia and the quality of life were assessed through a mailed questionnaire. Information on the use of endoscopies and the use of prescription medication was obtained from registers. RESULTS The response rate was 62.6%. The prevalence of Hp was 17.5%. The Hp eradication rate was 95%. In the intervention group, the prevalence of dyspepsia decreased from 24.3% at inclusion to 20.5% at 1-year follow-up. The reduction was similar in Hp-negative and Hp-positive persons. In the control group, dyspepsia increased from 20.3% to 21.5%. Gastroesophageal reflux symptoms improved slightly in Hp-eradicated participants. Except for a decreased consultation rate for dyspepsia, there were no visible savings in health care. CONCLUSIONS Dyspepsia was modestly reduced after the screening and treatment procedure, and the result was not sufficiently extensive to have an effect on the use of health care or to improve quality of life.

Placebo-controlled trial of cisapride and nizatidine in unselected Patients with functional dyspepsia

Objective:Patients in most trials of pharmacotherapy for nonorganic dyspepsia have been groups referred selectively for endoscopy, which could have led to a selection bias of nonresponders, explaining the negative outcome of most controlled treatment trials in nonorganic dyspepsia. The aim of this study was to evaluate the effects of cisapride and nizatidine in patients with nonorganic dyspepsia who were recruited directly from primary care settings, and to evaluate the therapeutic implications of dyspepsia subgrouping.Methods:A consecutive series of patients who consulted their general practitioner with dyspepsia were invited to an interview and endoscopy. Before endoscopy, symptoms were classified as reflux-like, dysmotility-like, ulcer-like, or unclassifiable. A total of 330 patients with either minor or no abnormalities at endoscopy were randomized to double blind treatment with cisapride 10 mg t.i.d., nizatidine 300 mg at night, or placebo for 2 wk.Results:A symptomatic response was found in 62% of patients on cisapride (therapeutic gain cisapride vs placebo: 0.1% [95% confidence interval –14% to 14%]) and in 54% of patients on nizatidine (therapeutic gain nizatidine vs placebo: –8% [95% confidence interval –22% to 7%]). Response to treatment was independent of symptom classification.Conclusions:The effects of a 2-wk course of cisapride or nizatidine in unselected patients with dyspepsia recruited from primary care were not superior to those of placebo. Symptom subgrouping was not predictive of response to therapy.

Risk factors for dyspepsia in a general population: Non-steroidal anti-inflammatory drugs, cigarette smoking and unemployment are more important than Helicobacter pylori infection

Objective. Dyspepsia, a common condition in the community, affects quality of life and imposes costs on both the individual and the community. Several factors including Helicobacter pylori, acetylic salicylic acid (ASA)/non-steroidal anti-inflammatory drugs (NSAIDs) use, low-dose ASA use, alcohol consumption, cigarette smoking and social status might be responsible. Material and methods. A cross-sectional study from the inclusion (intervention group) of a general population study evaluating rates of dyspepsia after H. pylori screening and eradication was carried out. A total of 10,007 individuals aged 40–64 years received questionnaires and an invitation to take part in H. pylori screening. Information on dyspepsia (the gastrointestinal symptom rating scale (GSRS) and “most bothersome symptom”), use of ASA/NSAIDs, use of low-dose ASA, lifestyle factors and level of education and employment status was obtained from the questionnaire. Dyspepsia was defined as a score of ≥2 in the GSRS dimension abdominal pain syndrome (aps), allowing for a maximum of one light problem score in any of the 3 items in the dimension to be overlooked. Results. In all, 5749/10,007 individuals participated in the study; 24.9% reported dyspepsia. In a multiple logistic regression analysis H. pylori infection was found to be a risk factor for dyspepsia, odds ratio (OR) 1.21 (CI; 1.03–1.42). However, the highest ORs for dyspepsia were: for daily use of ASA/NSAIDs 2.33 (CI; 1.72–3.15), unemployment 2.18 (CI; 2.86–2.56) and cigarette smoking ≥20 g/day 1.55 (CI; 1.29–1.86). Conclusions. H. pylori infection is a significant risk factor for dyspepsia although of less importance than ASA/NSAIDs use, unemployment and heavy smoking.

Strategies for discontinuation of proton pump inhibitors: a systematic review

PURPOSE Proton pump inhibitors (PPIs) are considered to be overprescribed. Consensus on how to attempt discontinuation is, however, lacking. We therefore conducted a systematic review of clinical studies on discontinuation of PPIs. METHODS Systematic review based on clinical studies investigating discontinuation strategies and discontinuation rates for users of antisecretory medication judged eligible for withdrawal. The databases Medline, Embase and Cochrane Library were searched to December 2013 using the terms antisecretory, anti-ulcer, PPI, acid suppressant, discontinuation, step-down, step down, cessation, tapering, withdrawal and withhold. Search terms were used either singularly or in combination. Papers written in English or Scandinavian were included. Concurrent hand searching was undertaken to pursue references of references. The website ClinicalTrials.gov was searched for unpublished results and ongoing studies. A total of 371 abstracts were scrutinized to determine relevancy. RESULTS The thorough search resulted in six clinical studies on strategies for discontinuation of PPIs. All discontinuation regimens used in the studies differed, and several interventions have been tested in order to decrease use of PPIs. Discontinuations were reported across all studies ranging from 14% to 64% without deteriorating symptom control. Tapering seems to be a more effective discontinuation strategy than abrupt discontinuation. CONCLUSION Discontinuation of PPIs is feasible in a clinical setting, and a substantial number of the patients treated without a clear indication can safely reduce or discontinue treatment. Tapering seems to be the most effective way of doing this.

Risk Factors on the Development of New-Onset Gastroesophageal Reflux Symptoms. A Population-Based Prospective Cohort Study: The HUNT Study

Objectives:Gastroesophageal reflux disease (GERD) is a highly prevalent disorder. This study assessed the risk factors of new-onset gastroesophageal reflux symptoms (GERS).Methods:The study was based on the HUNT study, a prospective population-based cohort study conducted in 1995–1997 and 2006–2009 in Nord-Trøndelag County, Norway. All inhabitants from 20 years of age were invited. Risk factors of new-onset heartburn or acid regurgitation were examined using logistic regression, providing odds ratios (OR) and 95% confidence intervals (CI).Results:A total of 29,610 individuals were included (61% response rate). Participants reporting no GERS at baseline and severe GERS at follow-up (new-onset GERS; n=510) were compared with participants reporting no complaints at both times (n=14,406). Increasing age (OR 1.01 per year, 95% CI 1.00–1.02) was positively associated, whereas male sex (OR 0.81, 95% CI 0.66–0.98) and higher education (OR 0.69, 95% CI 0.56–0.86) were negatively associated with new-onset GERS. Gain in body mass index (BMI) was dose-dependently associated with new-onset GERS (OR 1.30 per unit increase in BMI, 95% CI 1.25–1.35), irrespective of baseline BMI. Previous and current tobacco smoking were associated with new-onset GERS (OR 1.37, 95% CI 1.07–1.76 and OR 1.29, 95% CI 1.00–1.67, respectively). Tobacco smoking cessation was associated with new-onset GERS among those with gain in BMI upon quitting (OR 2.03, 95% CI 1.31–3.16, with >3.5 BMI units increase).Conclusions:New-onset GERS were associated with increasing age, female sex, lower education, gain in BMI, and ever tobacco smoking. Tobacco smoking cessation was associated with new-onset GERS among those who gained weight upon quitting.

Gastroesophageal Reflux Symptoms in a Danish Population: A Prospective Follow-Up Analysis of Symptoms, Quality of Life, and Health-Care Use

OBJECTIVES:The prevalence of gastroesophageal reflux symptoms (GERS) in the population is high; however, data on long-term follow-up and incidence of GERS in the population are sparse. This study describes the long-term natural history of GERS, the related health-care use, and quality of life in a population followed up for 5 years.METHODS:A total of 10,000 randomly selected inhabitants, 40–65 years old, received, as a part of a controlled trial of Helicobacter pylori screening and treatment (control group), a mailed questionnaire regarding demographic data, gastrointestinal symptoms (the Gastrointestinal Symptom Rating Scale (GSRS)), and quality of life (the Short-Form 36-Item Health Survey (SF-36)) at inclusion and after 5 years. GERS was defined as a mean score ≥2 in the reflux dimension in the GSRS. Information on use of health-care resources was drawn from the questionnaires and registers.RESULTS:In all, 6,781 individuals answered the first questionnaire and 5-year symptom data were complete for 5,578 (82.3%) of them. The mean age at inclusion was 52.4 years, 48% were men. At inclusion, 22% reported GERS. During follow-up, symptoms resolved in 43%, of whom 10% received acid inhibitory treatment at 5-year follow-up. The incidence of GERS was 2.2% per year. Health-care use during follow-up was significantly higher in individuals with GERS at baseline than in individuals without GERS. Quality of life at 5-year follow-up was lower in individuals with GERS at inclusion than in individuals without GERS at inclusion.CONCLUSIONS:GERS are prevalent, long lasting, and associated with an impaired quality of life and substantial health-care use.

Rapidly increasing prescribing of proton pump inhibitors in primary care despite interventions: A nationwide observational study

Abstract Background: Guideline and reimbursement modifications have been introduced to optimize prescribing of antisecretory medication in Danish general practice. Impacts of the interventions have not been evaluated. Objectives: To analyse developments in prescribing of antisecretory medication in Denmark 2001–2011 and to assess the impacts of interventions on prescribing of antisecretory medication. Methods: Register-based cohort study covering the entire Danish population of currently 5.5 million inhabitants. Developments in the prescribing of antisecretory medication over time in Denmark between 2001 and 2011 and association with age and gender of users along with the impact of interventions on the prescribing of drug subgroups are analysed. Results: 96.8% of all antisecretory drugs sold are proton pump inhibitors (PPIs) and 94.4% of the PPIs are prescribed in primary care. Prescribing of PPIs has increased substantially during the past decade. Both number of users and the average individual use have increased. The prescribing of ulcerogenic drugs to the elderly has stagnated in the same time range. Reimbursement modifications and scientific guidelines do not seem to have had a substantial influence on the steadily increasing prescribing of PPIs. Conclusion: Use of PPIs has increased substantially during the past decade, without a change in indications for use of PPIs in the same time range. Interventions to enhance adherence to guidelines and promote rational use of PPIs do not seem to have had a substantial influence on the overall prescribing rate.