Commentary: statins and fracture risk--unresolved questions.
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Case-Control Studies↗
Biomedical subjects
Christoph R Meier
Publications and source records attributed to Christoph R Meier.
Drug interactions and risk of acute bleeding leading to hospitalisation or death in patients with chronic atrial fibrillation treated with warfarin.
Although drug interactions with warfarin are an important cause of excessive anticoagulation, their impact on the risk of serious bleeding is unknown. We therefore performed a cohort study and a nested case-control analysis to determine the risk of serious bleeding in 4152 patients (aged 40-84 years) with nonvalvular atrial fibrillation (AF) taking long-term warfarin (> 3 months). The study population was drawn from the UK General Practice Research Database. More than half (58%) of eligible patients used potentially interacting drugs during continuous warfarin treatment. Among 45 identified cases of incident idiopathic bleeds (resulting in hospitalisation within 30 days or death within 7 days) and 143 matched controls, more cases than controls took > or = 1 potentially interacting drug within the preceding 30 days (62.2% vs. 35.7%) and used > 4 drugs (polypharmacy) within the preceding 90 days (80.0% vs. 66.4%). Conditional logistic regression analysis yielded an odds ratio (OR) of 3.4 (95% confidence interval [CI]: 1.4-8.5) for the risk of serious bleeding in patients treated with warfarin and > or = 1 drugs potentially increasing the effect of warfarin vs. warfarin alone adjusted for polypharmacy, diabetes, hypertension, heart failure, and thyroid disease; the adjusted OR for the combined use of warfarin and aspirin vs. warfarin alone was 4.5 (95% CI: 1.1-18.1). We conclude that concurrent use of potentially interacting drugs with warfarin is associated with a 3 to 4.5-fold increased risk of serious bleeding in long-term warfarin users.
Adult↗
Current use of nonsteroidal antiinflammatory drugs and the risk of acute myocardial infarction.
STUDY OBJECTIVE: To evaluate the risk of acute myocardial infarction during current exposure to nonsteroidal antiinflammatory drugs (NSAIDs). DESIGN: Retrospective case-control analysis. SETTING: General practice offices. SUBJECTS: A total of 8688 case patients, aged 89 years or younger, with a first-time acute myocardial infarction and 33,923 control subjects matched on age, sex, calendar time, and general practice attended. INTERVENTION: The United Kingdom General Practice Research Database was searched for potential cases of first-time acute myocardial infarction between January 1995 and April 2001. Control subjects without acute myocardial infarction were identified at random. MEASUREMENTS AND MAIN RESULTS: Exposure to NSAIDs was assessed, and 650 case patients and 2339 control subjects were found to be currently taking NSAIDs. After adjusting for various risk factors for acute myocardial infarction (e.g., hypertension, hyperlipidemia, diabetes mellitus, ischemic heart disease, body mass index, smoking), the relative risk (expressed as odds ratio [OR]) of acute myocardial infarction was 1.07 (95% confidence interval [CI] 0.96-1.19) for subjects with current NSAID exposure compared with those not taking NSAIDs. The adjusted OR for current diclofenac use was 1.23 (95% CI 1.00-1.51), for current ibuprofen use 1.16 (95% CI 0.92-1.46), and for current naproxen use 0.96 (95% CI 0.66-1.38) compared with those not taking NSAIDs. Current aspirin use combined with current NSAID use was associated with a statistically significant risk reduction (adjusted OR 0.74, 95% CI 0.57-0.97), compared with nonuse of NSAIDs and aspirin. Current use of aspirin together with current use of ibuprofen yielded an adjusted OR of 0.69 (95% CI 0.42-1.15). CONCLUSIONS: Our results provide additional evidence that the risk of first-time acute myocardial infarction during current use of NSAIDs is not materially altered. We found no evidence for a reduced cardioprotective effect of aspirin with concomitant NSAID use.
Adult↗
Use of beta-blockers and risk of fractures.
CONTEXT: Animal studies suggest that the beta-blocker propranolol increases bone formation, but data on whether use of beta-blockers (with or without concomitant use of thiazide diuretics) is associated with reduced fracture risk in humans are limited. OBJECTIVE: To determine whether use of beta-blockers alone or in combination with thiazides is associated with a decreased risk of fracture in adults. DESIGN, SETTING, AND PARTICIPANTS: Case-control analysis using the UK General Practice Research Database (GPRD). The study included 30,601 case patients aged 30 to 79 years with an incident fracture diagnosis between 1993 and 1999 and 120,819 controls, matched to cases on age, sex, calendar time, and general practice attended. MAIN OUTCOME MEASURES: Odds ratios (ORs) of having a fracture in association with use of beta-blockers or a combination of beta-blockers with thiazides. RESULTS: The most frequent fractures were of the hand/lower arm (n = 12,837 [42.0%]) and of the foot (n = 4627 [15.1%]). Compared with patients who did not use either beta-blockers or thiazide diuretics, the OR for current use of beta-blockers only (> or =3 prescriptions) was 0.77 (95% confidence interval [CI], 0.72-0.83); for current use of thiazides only (> or =3 prescriptions), 0.80 (95% CI, 0.74-0.86); and for combined current use of beta-blockers and thiazides, 0.71 (95% CI, 0.64-0.79). Data were adjusted for smoking; body mass index; number of practice visits; and use of calcium channel blockers, angiotensin-converting enzyme inhibitors, antipsychotics, antidepressants, statins, antiepileptics, benzodiazepines, corticosteroids, and estrogens. CONCLUSIONS: Our data suggest that current use of beta-blockers is associated with a reduced risk of fractures, taken alone as well as in combination with thiazide diuretics. Many elderly patients with hypertension who are at risk of developing osteoporosis may potentially benefit from combined therapy with beta-blockers and thiazides.
Adrenergic beta-Antagonists↗
Effect of rheumatoid arthritis or systemic lupus erythematosus on the risk of first-time acute myocardial infarction.
We explored the association between diagnosed rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE) and the risk of developing a first-time acute myocardial infarction (AMI) by conducting a population-based, case-control analysis using data from the United Kingdom-based General Practice Research Database (GPRD). Among 8,688 patients with AMI and 33,329 matched controls, the adjusted odds ratio (ORs) of AMI for subjects with RA was 1.47 (95% confidence interval [CI] 1.23 to 1.76), and in subjects with both RA and diagnosed hyperlipidemia, the OR was 7.12 (95% CI 4.16 to 12.18). The risk associated with SLE was 2.67 (95% CI 1.34 to 5.34). These results underline that RA and SLE increase the risk of AMI.
Aged↗
Inhaled corticosteroids and the risk of fractures in children and adolescents.
OBJECTIVE: To determine whether children or adolescents who are exposed to inhaled corticosteroids (ie, beclomethasone, budesonide, fluticasone) are at a higher risk of having bone fractures compared with nonexposed individuals. METHODS: We performed a population-based nested case-control analysis using data from the United Kingdom-based General Practice Research Database. Within a base population of 273,456 individuals aged 5 to 79 years, we identified by International Classification of Diseases codes children or adolescents who were aged 5 to 17 years with a fracture diagnosis and up to 6 control subjects per case matched to cases on age, gender, general practice attended, calendar time, and years of history in the GPRD. We compared use of inhaled steroids before the index date between fracture cases and control patients. RESULTS: We identified 3744 cases and 21,757 matched control subjects aged 5 to 17 years. Current exposure to inhaled steroids did not reveal a substantially altered fracture risk compared with nonusers, even in individuals with current longer term exposure (ie, > or =20 prescriptions; adjusted odds ratio 1.15; 95% confidence interval: 0.89-1.48). In individuals with current or previous exposure to oral steroids, the adjusted odds ratio for current long-term inhaled steroid use compared with nonusers was 1.21 (95% confidence interval: 0.99-1.49). CONCLUSIONS: Exposure to inhaled steroids does not materially increase the fracture risk in children or adolescents compared with nonexposed individuals.
Administration, Inhalation↗
The risk of severe depression, psychosis or panic attacks with prophylactic antimalarials.
INTRODUCTION/OBJECTIVE: Experimental and observational studies have linked mefloquine use to an increased risk of developing neuropsychiatric adverse effects such as depression or psychoses. Most of these reports relied on interview-based information from travellers. We conducted a population-based observational study using a database of medical records to quantify and compare the risk of psychiatric disorders during or after use of mefloquine with the risk during use of proguanil and/or chloroquine, or doxycycline. STUDY DESIGN/METHODS: The study population was drawn from the large UK-based General Practice Research Database (GPRD). Subjects were aged from 17-79 years and were exposed to mefloquine, proguanil, chloroquine or doxycycline (or a combination of these drugs) at some time between 1990 and 1999. We performed a person-time and a nested case-control analysis to assess the risk of developing a first-time diagnosis of depression, psychosis or panic attack during or after use of these antimalarial drugs. RESULTS: Within the study population of 35 370 subjects (45.2% males), we identified 580 subjects with a first-time diagnosis of depression (n = 505), psychosis (n = 16) or panic attack (n = 57) and two subjects committed suicide. The incidence rates of first-time diagnoses of depression during current use of mefloquine, proguanil and/or chloroquine, or doxycycline, adjusted for age, gender and calendar year, were 6.9 (95% CI 4.5-10.6), 7.6 (95% CI 5.5-10.5) and 9.5 (95% CI 3.7-24.1)/1000 person-years, respectively. The incidence rates of psychosis or panic attacks during current mefloquine exposure were 1.0/1000 person-years (95% CI 0.3-2.9) and 3.0/1000 person-years (95% CI 1.6-5.7), respectively, approximately 2-fold higher (statistically nonsignificant) than during current use of proguanil and/or chloroquine, or doxycycline. The nested case-control analysis encompassed 505 cases with depression and 3026 controls, 16 cases with psychosis and 96 controls, and 57 cases with a panic attack and 342 controls. Current use of mefloquine was not associated with an elevated risk of developing depression. In a comparison between patients currently using mefloquine with all past users of antimalarials combined, the risk estimate was elevated for current users of mefloquine for both psychosis (odds ratio [OR] 8.0, 95% CI 1.0-62.7; p < 0.05) and panic attacks (OR 2.7, 95% CI 1.1-6.5; p < 0.05). CONCLUSION: The absolute risk of developing psychosis or panic attack appears low with all the antimalarials tested. No evidence was found in this large observational study that mefloquine use increased the risk of first-time diagnosis of depression when compared with the use of other antimalarials investigated in this study.
Adolescent↗
Current use of selective serotonin reuptake inhibitors and risk of acute myocardial infarction.
BACKGROUND: It has been suggested that increased platelet activation increases the risk of acute myocardial infarction (AMI) in patients with depression. Selective serotonin reuptake inhibitors (SSRIs) may attenuate platelet activation by serotonin depletion in platelets. Observational studies have shown discrepant results of AMI risk associated with the use of SSRIs. OBJECTIVE: The aim of this study was to evaluate the association of exposure to different groups of antidepressants, including SSRIs, and the risk of AMI. The study also assessed in more detail the influence of timing of the exposure to antidepressants in a general adult population (<90 years of age), with or without diagnosed risk factors for AMI. STUDY DESIGN/METHODS: We conducted a population-based case-control analysis on the UK General Practice Research Database (GPRD). The study included 8688 patients (<90 years of age), with a first-time AMI between 1995 and 2001, and 33 923 controls, who were matched by age, sex, calendar time, and general practice. Conditional logistic regression was used to estimate odds ratios (ORs). RESULTS: Current use of an antidepressant was defined as a supply of the last prescription for an antidepressant that lasted up to the index date or beyond. Recent past use was defined as a supply of the last prescription for an antidepressant that ended 1-29 days before the index date. SSRIs investigated were citalopram, fluoxetine, fluvoxamine, paroxetine, sertraline and venlafaxine. Non-SSRIs investigated were amitriptyline, clomipramine, dosulepin, doxepin, imipramine, lofepramine, nefazodone, trazodone and trimipramine. Other antidepressants included were amoxapine, desipramine, lithium, maprotiline, mianserin, moclobemide, nortriptyline and protriptyline. Adjusted ORs (with 95% CI) for the current use of SSRIs, non-SSRIs, or other antidepressants, compared with non-use of antidepressants, were 0.63 (95% CI 0.43, 0.91; p=0.02), 0.92 (95% CI 0.77, 1.09; p=0.32) and 0.59 (95% CI 0.29, 1.20; p=0.14), respectively. The adjusted OR of recent past use of SSRIs compared with non-use of SSRIs was 1.42 (95% CI 1.02, 1.97; p=0.04). CONCLUSION: The present analysis provides further evidence that the current use of SSRIs is associated with a slightly decreased risk for AMI.
Age Distribution↗
Validity of the general practice research database.
The United Kingdom General Practice Research Database (GPRD) is an office-based, computer-generated, medical resource designed from its inception to be used for epidemiologic research. A distinct version of the GPRD is maintained by the Boston Collaborative Drug Surveillance Program and has been the source of more than 130 scientific articles primarily addressing drug safety issues. We reviewed evidence related to the validity of the GPRD. Specifically, with our extensive experience with this automated database, we evaluated the quality and completeness of the data that it contains.
Databases, Factual↗
HMG-CoA reductase inhibitors in osteoporosis: do they reduce the risk of fracture?
Osteoporosis affects a large number of people in industrialised countries. It has clinical and public-health impacts, most importantly due to subsequent fractures. Osteoporotic fractures are one of the most common causes of disability and are associated with enormous healthcare expenditure. The majority of existing treatment options for osteoporosis only inhibit bone resorption and prevent excessive bone loss but are not capable of stimulating bone formation. However, several recent in vitro and in vivo studies in animals demonstrated that HMG-CoA reductase inhibitors stimulate the production of bone morphogenetic protein (BMP-2), which is a potent regulating protein in osteoblast differentiation and activity. This suggests that HMG-CoA reductase inhibitors may have an anabolic effect on bones, making them a potentially interesting treatment option for osteoporosis. Additionally, several studies in humans showed that some HMG-CoA reductase inhibitors may have a beneficial effect on bone turnover and may lead to an increase in bone mineral density. Consequently, several observational studies tried to evaluate whether use of HMG-CoA reductase inhibitors is associated with a decreased risk of fractures. Even though not all results of these epidemiological studies, using different designs in different study populations, were entirely consistent, they provided substantial evidence that HMG-CoA reductase inhibitor use may decrease the bone fracture risk by approximately 50%. On the other hand, reanalysis of two randomised controlled trials of HMG-CoA reductase inhibitor therapy, designed to assess cardiovascular outcomes, could not show that patients treated with HMG-CoA reductase inhibitors had a lower fracture risk in comparison with placebo-treated patients. Therefore, to conclusively assess the potential of HMG-CoA reductase inhibitors in the prevention and treatment of osteoporosis, randomised controlled trials need to be performed to address this conflicting issue. Until the results of such trials are available, practitioners should prescribe the drugs that have been proven to reduce the risk of osteoporotic fractures.
Animals↗
Effect of selective serotonin reuptake inhibitors on platelet activation: can they prevent acute myocardial infarction?
In recent years a large body of evidence from several longitudinal studies has emerged suggesting that depression is an independent risk factor for cardiovascular disease (CVD) and that the association between depression and increased CVD risk is not merely due to negative mood-driven behavior related with depression. Even though the underlying mechanisms are not well understood, several hypotheses and explanations have been proposed such as increased activation of the hypothalamic-pituitary-adrenal axis, abnormalities in the sympathoadrenal system, or abnormalities in platelet function. Platelet function abnormalities, including increased platelet reactivity, may predispose patients with depressive disorders to clotting diatheses and may explain their vulnerability to CVD. Serotonin secreted by platelets induces both platelet aggregation and coronary vasoconstriction. Even though serotonin itself is only a weak platelet agonist, it markedly enhances platelet reactions to a variety of other agonists. Several studies have shown that selective serotonin reuptake inhibitors (SSRIs) reduce platelet and whole blood serotonin concentrations after repeated doses, and could therefore exert an inhibitory effect on platelet activation. For that reason, it was hypothesized that SSRIs could have a protective effect against myocardial infarction (MI). Results from three currently available epidemiological studies assessing the risk of MI in patients treated with antidepressants, including SSRIs, are controversial with respect to a potential beneficial effect of SSRIs on CVD risk in depressed patients. However, there is evidence that exposure to SSRIs does not substantially increase the risk of CVD in patients. A recent randomized, double-blind, placebo-controlled, multicenter trial that evaluated the safety and efficacy of the SSRI sertraline in patients with major depression and acute MI or unstable angina suggested that sertraline is well tolerated and effective. Further epidemiological studies or longer-term clinical trials may shed more light on this issue, and answer the question conclusively, whether the effect of SSRIs on platelets or another mechanism translates into a decreased risk of CVD in depressed patients.
Cardiovascular Diseases↗
Association between body mass index and liver disorders: an epidemiological study.
BACKGROUND/AIMS: Cross-sectional studies showed an association between obesity and liver disorders. Information on incidence rates from epidemiological studies is scarce. METHODS: To explore the association between body mass index (BMI) and incident liver disorders, we conducted a follow-up study with a nested case-control analysis using the UK-based General Practice Research Database. The study population encompassed normal weight (BMI <25 kg/m(2)), pre-obese (BMI 25-29.9 kg/m(2)) or obese (BMI > or =30 kg/m(2)) subjects aged 20-79 years, matched on age, sex and general practice attended. RESULTS: Within the study population of 207,630 subjects, we identified 2718 cases of newly diagnosed liver disorder, of whom 1524 (56.1%) had known predisposing conditions. The incidence rates were 2.48 (95% CI 2.31-2.66)/1000 person-years (py) in normal weight, 2.91 (95% CI 2.72-3.11)/1000 py in pre-obese, and 3.83 (95% CI 3.62-4.07)/1000 py in obese subjects. In the nested case-control analysis, the adjusted odds ratio (OR) for obese, as compared to normal weight subjects, was 1.2 (95% CI 1.1-1.4). The OR for idiopathic cases (without known risk factors for liver disorders) was 1.3 (95% CI 1.1-1.6). CONCLUSIONS: The study indicates that obesity is associated with a modest increase in the incidence of newly diagnosed liver disorder.
Adult↗
Use of nonsteroidal anti-inflammatory drugs and the risk of first-time acute myocardial infarction.
AIMS: Aspirin decreases the risk of clinical manifestations of atherothrombosis. This effect is mainly due to inhibition of platelet aggregation and potentially due to anti-inflammatory properties of aspirin. To evaluate whether use of non-aspirin non-steroidal anti-inflammatory drugs (NSAIDs) may also be associated with a decreased risk of first-time acute myocardial infarction (AMI), we performed a population-based case-control analysis using the United Kingdom-based General Practice Research Database (GPRD) METHODS: We identified first-time AMI-patients free of preexisting diagnosed cardiovascular or metabolic diseases. We compared use of NSAIDs prior to the index date between cases and control patients who were matched to cases on age, gender, practice and calendar time. RESULTS: A total of 3319 cases ( or=30 prescriptions) yielded an adjusted odds ratio (OR) of 1.20 (95% CI 0.94, 1.55). Stratification by age (<65 years vs>or=65 years) and sex did not materially change the results. CONCLUSIONS: Our findings indicate that current NSAID exposure in patients free of diagnosed cardiovascular or metabolic conditions predisposing to cardiovascular diseases does not decrease the risk of AMI.
Adult↗
Association between acetaminophen or nonsteroidal antiinflammatory drugs and risk of developing ovarian, breast, or colon cancer.
STUDY OBJECTIVE: To explore the association between exposure to acetaminophen (paracetamol) or nonsteroidal antiinflammatory drugs (NSAIDs) and risk of developing ovarian, breast, or colon cancer. DESIGN: Retrospective case-control study SETTING: General practice offices. SUBJECTS: Four hundred eighty-three women with ovarian cancer and 1877 women matched for age, years of medical history in computer record, general practice attended, and calendar time; 3706 women with breast cancer and 14,155 matched control subjects; and 635 women with colon cancer and 2434 matched control subjects. INTERVENTION: United Kingdom-based General Practice Research Database was searched for women aged 50-89 years with a first-time diagnosis of ovarian, breast, or colon cancer and for matched controls to assess prescription analgesic exposure. MEASUREMENTS AND MAIN RESULTS: Regular acetaminophen exposure (> or = 30 prescriptions) was associated with a slightly decreased risk of developing breast (odds ratio [OR] 0.8, 95% confidence interval [CI] 0.7-1.0) but not ovarian (OR 1.0, 95% CI 0.6-1.5) or colon (OR 1.0, 95% Cl 0.7-1.4) cancer. Regular NSAID exposure was associated with a reduced risk of colon (OR 0.5, 95% CI 0.3-0.9) but not ovarian or breast cancer. CONCLUSION: We found no evidence for a decreased ovarian cancer risk for women with regular acetaminophen or NSAID exposure.
Acetaminophen↗
Discontinuation of nonsteroidal anti-inflammatory drug therapy and risk of acute myocardial infarction.
BACKGROUND: Systemic inflammation has been shown to be associated with an increased risk of acute myocardial infarction (AMI). However, the effect of the use of nonsteroidal anti-inflammatory drugs (NSAIDs) on the risk of AMI has not yet been well defined. We therefore studied the risk of AMI during NSAID exposure and after the cessation of NSAID therapy. METHODS: We conducted a large case-control analysis on the British General Practice Research Database. The study included 8688 cases with a first-time AMI between 1995 and 2001 and 33 923 controls, matched to cases on age, sex, calendar time, and general practice attended. RESULTS: After adjusting for hypertension, hyperlipidemia, diabetes mellitus, ischemic heart disease, rheumatoid arthritis, systemic lupus erythematosus, acute chest infection, body mass index, smoking, and aspirin use, the risk of AMI was 1.52 (95% confidence interval [CI], 1.33-1.74) for subjects who stopped taking NSAIDs 1 to 29 days prior to the index date, compared with nonusers. The risk was highest in subjects with rheumatoid arthritis or systemic lupus erythematosus (adjusted OR, 3.68 [95% CI, 2.36-5.74]) and for subjects who discontinued therapy with NSAIDs after previous long-term use (adjusted OR, 2.60 [95% CI, 1.84-3.68]). Current and past NSAID use (discontinued therapy >/=60 days prior to the index date) were not associated with an increased risk of AMI (adjusted OR, 1.07 [95% CI, 0.96-1.19] and 1.05 [95% CI, 0.99-1.12], respectively). CONCLUSION: Our findings suggest that the risk of AMI is increased during several weeks after the cessation of NSAID therapy.
Aged↗