Central nervous system-active medications and risk for falls in older women

OBJECTIVES: To determine whether current use of central nervous system (CNS)-active medications, including benzodiazepines, antidepressants, anticonvulsants, and narcotics, increases the risk for subsequent falls. DESIGN: Prospective cohort study. SETTING: Four clinical centers in Baltimore, Maryland; Portland, Oregon; Minneapolis, Minnesota; and the Monongahela Valley, Pennsylvania. PARTICIPANTS: Eight thousand one hundred twenty-seven women aged 65 and older participating in the fourth examination of the Study of Osteoporotic Fractures between 1992 and 1994. MEASUREMENTS: Current use of CNS-active medications was assessed with an interviewer-administered questionnaire with verification of use from medication containers. A computerized dictionary was used to categorize type of medication from product brand and generic names. Incident falls were reported every 4 months for 1 year after the fourth examination. RESULTS: During an average follow-up of 12 months, 2,241 women (28%) reported falling at least once, including 917 women (11%) who experienced two or more (frequent) falls. Compared with nonusers, women using benzodiazepines (multivariate odds ratio (MOR) = 1.51, 95% confidence interval (CI) = 1.14-2.01), those taking antidepressants (MOR = 1.54, 95% CI = 1.14-2.07), and those using anticonvulsants (MOR = 2.56, 95% CI = 1.49-4.41) were at increased risk of experiencing frequent falls during the subsequent year. We found no evidence of an independent association between narcotic use and falls (MOR = 0.99 for frequent falling, 95% CI = 0.68-1.43). Among benzodiazepine users, both women using short-acting benzodiazepines (MOR = 1.42, 95% CI = 0.98-2.04) and those using long-acting benzodiazepines (MOR = 1.56, 95% CI = 1.00-2.43) appeared to be at greater risk of frequent falls than nonusers, although the CIs overlapped 1.0. We found no evidence to suggest that women using selective serotonin-reuptake inhibitors (MOR = 3.45, 95% CI = 1.89-6.30) had a lower risk of frequent falls than those using tricyclic antidepressants (MOR 1.28, 95% CI = 0.90-1.84). CONCLUSIONS: Community-dwelling older women taking CNS-active medications, including those taking benzodiazepines, antidepressants, and anticonvulsants, are at increased risk of frequent falls. Minimizing use of these CNS-active medications may decrease risk of future falls. Our results suggest that fall risk in women taking benzodiazepines is at best marginally decreased by use of short-acting preparations. Similarly, our findings indicate that preferential use of selective serotonin-reuptake inhibitors is unlikely to reduce fall risk in older women taking antidepressants.     

Atypical antipsychotic medications and risk of falls in residents of aged care facilities

OBJECTIVES: To determine whether use of atypical antipsychotics (olanzapine and risperidone) is associated with lower risk of falls than use of typical antipsychotics. DESIGN: Prospective cohort study with 1-month follow-up. SETTING: Residential aged care facilities in Sydney, Australia. PARTICIPANTS: Two thousand five people aged 65 to 104 (mean age 86). MEASUREMENTS: Medication use at baseline was collected from medical records. Data on potential confounders were collected at interview and physical examination and from medical records. The outcome was accidental falls (one or more). RESULTS: One thousand one hundred seven subjects (55%) used at least one type of psychotropic medication, with 289 (14%) using an antipsychotic. There were 82 olanzapine users, 38 risperidone users, and 181 users of typical antipsychotics. Eleven percent of subjects (n=226) had at least one fall during follow-up. After adjusting for a comprehensive range of falls risk factors, hazard ratios (HRs) for falls were 1.35 (95% confidence interval (CI)=0.87-2.09) for typical antipsychotics, 1.32 (95% CI=0.57-3.06) for risperidone, and 1.74 (95% CI=1.04-2.90) for olanzapine. Antidepressants were also associated with falls (adjusted HR=1.45, 95% CI=1.09-1.93). CONCLUSION: Despite fewer extrapyramidal side effects, atypical antipsychotic medications are not associated with fewer falls than the older, more-established antipsychotics.     

Venous thromboembolism among elderly patients treated with atypical and conventional antipsychotic agents

BACKGROUND: Some antipsychotic agents have been indicated as a possible risk factor for venous thromboembolism (VTE) in adult patients with psychiatric disorders. The aim of this study was to estimate the effect of atypical and conventional antipsychotic agents on the risk of hospitalization for VTE among elderly patients. METHODS: We conducted a retrospective cohort study on nursing home residents in 5 states. We used data from the Minimum Data Set to identify 19 940 new users of antipsychotic agents and 112 078 nonusers. Hospitalization with VTE as primary discharge diagnosis was determined during a 6-month follow-up period using Medicare inpatient claims. Cox proportional hazards models provided estimates of effect adjusted for confounders. RESULTS: The rate of hospitalization for VTE was 0.91 per 100 person-years. Venous thrombosis accounted for 77.6% of events and 22.4% were pulmonary embolisms. Relative to nonusers, the rate of hospitalization for VTE was increased for users of atypical antipsychotic agents, including risperidone (adjusted hazard ratio [HR], 1.98; 95% confidence interval [CI], 1.40-2.78), olanzapine (adjusted HR, 1.87; 95% CI, 1.06-3.27), and clozapine and quetiapine fumarate (adjusted HR, 2.68; 95% CI, 1.15-6.28). No increased rate was associated with phenothiazines (adjusted HR, 1.03; 95% CI, 0.60-1.77) or other conventional agents (adjusted HR, 0.98; 95% CI, 0.52-1.87). CONCLUSIONS: Atypical antipsychotic agents appear to increase the risk of VTE. However, these events are rare, and in clinical practice the absolute risk should be weighed against the effectiveness of these medications in the elderly population.     

Benzodiazepines and the risk of falls in nursing home residents

CONTEXT: For nursing home residents who require a benzodiazepine, short-acting agents are recommended, primarily to avoid increased risk of falls and other injuries associated with the long-acting agents. However, much of the data for the clinical outcomes of falls and injuries comes from community-dwelling older people. OBJECTIVE: To quantify the rate of falls among nursing home residents taking benzodiazepines and how this varies with drug elimination half-life. DESIGN: Historical cohort study. POPULATION: A total of 2510 residents of 53 Tennessee nursing homes, classified according to benzodiazepine use on each day of follow-up. OUTCOME MEASURES: Falls occurring during study follow-up. RESULTS: After adjustment for differences in resident characteristics, benzodiazepine users had a 44% increased rate of falls (adjusted rate ratio 1.44 [95% confidence interval, 1.33-1.56]). The adjusted rate ratio increased from 1.30 (1.12-1.52) for a dose equivalent to < or = 2 mg of diazepam, to 2.21 (1.89-2.60, P < .001) for a dose of > 8 mg. The rate of falls was greatest in the 7 days after the benzodiazepine was started (rate ratio of 2.96 [2.33-3.75]) but remained elevated (1.30 [1.17-1.44]) after the first 30 days of therapy. Drugs with elimination half-lives of <12, 12-23, and > or = 24 hours had adjusted rate ratios of 1.15 (0.94-1.40), 1.45 (1.33-1.59), and 1.73 (1.40-2.14), respectively. Users of hypnotics with elimination half-lives <12 hours had an increased rate of falls occurring during the night (adjusted rate ratio 2.82 [2.02-3.94]). CONCLUSIONS: Although the risk of falls among nursing home residents receiving short-acting benzodiazepines is less than that for the long-acting agents, these drugs are associated with a materially increased risk of nocturnal falls.     

Risk factors for adverse drug events among nursing home residents.

BACKGROUND: In a prospective study of nursing home residents, we found adverse drug events (ADEs) to be common, serious, and often preventable. To direct prevention efforts at high-risk residents, information is needed on resident-level risk factors. METHODS: Case-control study nested within a prospective study of ADEs among residents in 18 nursing homes. For each ADE, we randomly selected a control from the same home. Data were abstracted from medical records on functional status, medical conditions, and medication use. RESULTS: Adverse drug events were identified in 410 nursing home residents. Independent risk factors included being a new resident (odds ratio [OR], 2.8; 95% confidence interval [CI], 1.5-5.2) and taking anti-infective medications (OR, 4.0; CI, 2.5-6.2), antipsychotics (OR, 3.2; CI, 2.1-4.9), or antidepressants (OR, 1.5; CI, 1.1-2.3). The number of regularly scheduled medications was associated with increased risk of ADEs; the OR associated with taking 5 to 6 medications was 2.0 (CI, 1.2-3.2); 7 to 8 medications, 2.8 (CI, 1.7-4.7); and 9 or more, 3.3 (CI, 1.9-5.6). Taking supplements or nutrients was associated with lower risk (OR, 0.42; CI, 0.27-0.63). Preventable ADEs occurred in 226 residents. Independent risk factors included taking opioid medications (OR, 6.6; CI, 2.3-19.3), antipsychotics (OR, 4.0; CI, 2.2-7.3), anti-infectives (OR, 3.0; CI, 1.6-5.8), antiepileptics (OR, 2.2; CI, 1.1-4.5), or antidepressants (OR, 2.0; CI, 1.1-3.5). Scores of 5 or higher on the Charlson Comorbidity Index were associated with increased risk of ADEs (OR, 2.6; CI, 1.1-6.0). The number of regularly scheduled medications was also a risk factor: the OR for 7 to 8 medications was 3.2 (CI, 1.4-6.9) and for 9 or more, 2.9 (CI, 1.3-6.8). Residents taking nutrients or supplements were at lower risk (OR, 0.27; CI, 0.14-0.50). CONCLUSIONS: It is possible to identify nursing home residents at high risk of having an ADE. Particular attention should be directed at new residents, those with multiple medical conditions, those taking multiple medications, and those taking psychoactive medications, opioids, or anti-infective drugs.     

Blood pressure destabilization and edema among 8538 users of celecoxib, rofecoxib, and nonselective nonsteroidal antiinflammatory drugs (NSAID) and nonusers of NSAID receiving ordinary clinical care

OBJECTIVE: To investigate the relationship between nonselective nonsteroidal antiinflammatory drugs (NS NSAID), rofecoxib, celecoxib, and risk of edema and blood pressure destabilization in patients with rheumatoid arthritis (RA) and osteoarthritis (OA) receiving ordinary clinic care. METHODS: Patients participating in a longterm outcome study reported drug use, as well as the presence of edema and blood pressure increases occurring during the previous 6 months. To measure pure drug effect, analyses were restricted to 8538 patients who exclusively used a NS NSAID, rofecoxib, or celecoxib, and compared to nonusers of NS NSAID, rofecoxib, or celecoxib. We evaluated blood pressure destabilization using patient-reported increases in blood pressure and/or difficulty in controlling blood pressure. RESULTS: Compared with nonusers, after adjusting for age, sex, presence of RA, and history of heart disease and hypertension, patients using rofecoxib, but not celecoxib or NS NSAID, had an increased rate of edema (23.3% vs 18.0%), while the rates for celecoxib and NS NSAID were 17.5% and 18.2%, respectively. The adjusted risk of edema was significantly increased for rofecoxib compared to celecoxib (OR 1.33, 95% CI 1.08-1.64). For blood pressure increases, among patients who did not report having hypertension, no significant increase was noted for NS NSAID and celecoxib compared with nonusers. However a significant increased risk of blood pressure increase was seen for rofecoxib (OR 2.08, 95% CI 1.41-3.06). Among patients who reported having hypertension, patients taking rofecoxib had a significant increased risk of blood pressure increase compared to nonusers (OR 1.55, 95% CI 1.23-1.96), while the risks of blood pressure increase for users of celecoxib and NS NSAID were not significantly different than among nonusers. After controlling for age, sex, RA, and new starts on NSAID, the risk of blood pressure increase was significantly higher for users of rofecoxib than celecoxib (OR 1.21, 95% CI 1.03-1.61) among patients with hypertension, and numerically higher for nonhypertensives (OR 1.42, 95% CI 0.96-2.22). The increased risk for hypertension and edema of rofecoxib compared to celecoxib users was further confirmed by analysis of specific reported side effects during 2 separate 6-month periods (July 1 to December 31, 1999, and January 1 to June 30, 2000). During these 2 periods, rofecoxib-treated patients were 2.16 to 3.82 times more likely to report edema or blood pressure increase side effects compared to celecoxib-treated patients. CONCLUSION: Rofecoxib, but not celecoxib and NS NSAID, is associated with an increased risk of edema and blood pressure increase compared to nonusers of NSAID.     

Central nervous system active medications and risk for fractures in older women

BACKGROUND: Use of central nervous system (CNS) active medications may increase the risk for fractures. Prior studies are limited by incomplete control of confounders. METHODS: To determine whether use of CNS active medications, including benzodiazepines, antidepressants, anticonvulsants, and narcotics, increases fracture risk in elderly, community-dwelling women, we examined use of these 4 categories of medications in a cohort of 8127 older women and followed the participants prospectively for incident nonspine fractures, including hip fractures. Current use of CNS active medications was assessed by interview with verification of use from containers between 1992 and 1994 and between 1995 and 1996. Use was coded as a time-dependent variable. Incident nonspine fractures occurring after the initial medication assessment until May 31, 1999, were confirmed by radiographic reports. RESULTS: During an average follow-up of 4.8 years, 1256 women (15%) experienced at least one nonspine fracture, including 288 (4%) with first hip fractures. Compared with nonusers, women taking narcotics (multivariate hazard ratio [HR], 1.40; 95% confidence interval [CI], 1.06-1.83) and those taking antidepressants (multivariate HR, 1.25; 95% CI, 0.99-1.58) had increases in the risks for any nonspine fractures. Women taking tricyclic antidepressants and those using selective serotonin reuptake inhibitors (SSRIs) had similar fracture rates. There were no independent associations between benzodiazepine use or anticonvulsant use and risk for nonspine fracture. Women taking antidepressants compared with nonusers had a 1.7-fold increase in the risk for hip fracture (multivariate HR, 1.65; 95% CI, 1.05-2.57). We did not observe independent associations between use of any of the other 3 classes of CNS active medications and risk of hip fracture. CONCLUSIONS: Community-dwelling older women taking narcotics have an increased risk for any nonspine fracture, and those taking antidepressants have a greater risk for nonspine fractures, including hip fracture. Rates of fracture were similar in women taking tricyclic antidepressants and those using SSRIs. Benzodiazepine use and anticonvulsant use were not independently associated with an increased risk of nonspine fractures, including hip fracture.     

The impact of legislation on psychotropic drug use in nursing homes: a cross-national perspective

OBJECTIVES: To quantify the impact of legislation on nursing home residents, psychotropic drug use, and the occurrence of falls in the US compared with five countries with no such regulation. DESIGN: A retrospective cross-sectional study SETTING: Nursing homes in five US states and selected nursing homes in Denmark, Iceland, Italy, Japan, and Sweden. PARTICIPANTS: Residents in nursing homes in five US states and the aforementioned countries during 1993-1996. MAIN OUTCOME MEASURES: Using data collected using the Minimum Data Set, logistic regression provided estimates of the legislative effects on the use of antipsychotics and antianxiety/hypnotics while simultaneously adjusting for potential confounders. The occurrence of falls was evaluated similarly. RESULTS: Prevalence of antipsychotic and/or antianxiety/ hypnotic use varied substantially across countries. After adjustment for differences in age, gender, presence of psychiatric/neurologic conditions, and physical and cognitive functioning, residents in Denmark, Italy, and Sweden were at least twice as likely to receive these drugs (Denmark Odds Ratio (OR)=2.32; 95% Confidence Intervals (CI), 2.15-2.51; Italy OR=2.05; 95% CI, 1.78-2.34; Sweden OR=2.50; 95% CI, 2.16-2.90); in Iceland, the risk was increased to greater than 6 times (OR=6.54; 95% CI, 5.75-7.44) that of the US. Residents were less likely to fall in Italy, Iceland, and Japan compared with the US, despite more extensive use of psychotropic medication, whereas residents in Sweden and Denmark were more likely to fall. CONCLUSIONS: Policy has had an impact on the prescribing of psychotropic medication in US nursing homes compared with other countries, but it is unclear if this is translated into better outcomes for residents.     

Medication and falls: risk and optimization

The association between drugs and falls has been widely studied in the past 3 decades, with increasingly robust evidence of a causal link. Both specific classes of drugs and the total number of drugs taken are associated with falls. This review examines some of the reasons why older people are at greater risk of drug-related adverse events such as falls. We discuss the role of drugs in general and polypharmacy (the concurrent use of multiple drugs) on the risk of falling, with a focus on community-dwelling older people. We critically appraise the evidence that specific classes of drugs, such as benzodiazepines and antidepressants, increase the risk of falling and that falls can be prevented through interventions that target medications.     

Psychotropic medication withdrawal and a home-based exercise program to prevent falls: a randomized, controlled trial.

OBJECTIVE: To assess the effectiveness of psychotropic medication withdrawal and a home-based exercise program in reducing falls in older people. DESIGN: A randomized controlled trial with a two by two factorial design. SETTING: Seventeen general practices in Dunedin, New Zealand. PARTICIPANTS: Women and men aged 65 years registered with a general practitioner and currently taking psychotropic medication (n = 93). INTERVENTIONS: Two interventions: (1) gradual withdrawal of psychotropic medication versus continuing to take psychotropic medication (double blind) and (2) a home-based exercise program versus no exercise program (single blind). MEASUREMENTS: Number of falls and falls risk during 44 weeks of follow-up. Analysis was on an intent to treat basis. RESULTS: After 44 weeks, the relative hazard for falls in the medication withdrawal group compared with the group taking their original medication was .34 (95% CI, .16-.74). The risk of falling for the exercise program group compared with those not receiving the exercise program was not significantly reduced. CONCLUSIONS: Withdrawal of psychotropic medication significantly reduced the risk of falling, but permanent withdrawal is very difficult to achieve.     

Bone mineral density in subjects using central nervous system-active medications

Purpose

Decreased bone mineral density defines osteoporosis according to the World Health Organization and is an important predictor of future fractures. The use of several types of central nervous system-active drugs, including benzodiazepines, anticonvulsants, antidepressants, and opioids, have all been associated with increased risk of fracture. However, it is unclear whether such an increase in risk is related to an effect of bone mineral density or to other factors, such as increased risk of falls. We sought to examine the relationship between bone mineral density and the use of benzodiazepines, anticonvulsants, antidepressants, and opioids in a representative US population-based sample.

Subjects and methods

We analyzed data on adults aged 17 years and older from the Third National Health and Nutrition Examination Survey (NHANES III, 1988-1994). Total femoral bone mineral density of 7114 male and 7532 female participants was measured by dual-energy x-ray absorptiometry. Multivariable linear regression models were used to quantify the relation between central nervous system medication exposure and total femoral bone mineral density. Models controlled for relevant covariates, including age, sex, and body mass index.

Results

In linear regression models, significantly reduced bone mineral density was found in subjects taking anticonvulsants (0.92 g/cm²; 95% confidence interval [CI]: 0.89 to 0.94) and opioids (0.92 g/cm²; 95% CI: 0.88 to 0.95) compared with nonusers (0.95 g/cm²; 95% CI: 0.95 to 0.95) after adjusting for several potential confounders. The other central nervous system-active drugs—benzodiazepines or antidepressants—were not associated with significantly reduced bone mineral density.

Conclusion

In cross-sectional analysis of NHANES III, anticonvulsants and opioids (but not benzodiazepines or antidepressants) were associated with significantly reduced bone mineral density. These findings have implications for fracture-prevention strategies.     

Medication as a risk factor for falls: critical systematic review

BACKGROUND: Falls in older people are associated with poor prognosis. Medication use is a potential cause of falls. Our aim was to systemically review all original articles examining medication use as a risk factor for falls or fall-related fractures in people aged >/=60 years. METHODS: We searched English articles in Medline (1996-2004) indexed under "falls" or "accidental falls" and "pharmaceutical preparations" or specific groups of drugs. We excluded studies not meeting the age criterion, not controlled with nonusers of target medicines or nonfallers, or with no clear definition of target medication. RESULTS: Twenty-eight observational studies and one randomized controlled trial met the inclusion criteria. The number of participants ranged from 70 to 132,873. The outcome measure was a fall in 22 studies and a fracture in 7 studies. The main group of drugs associated with an increased risk of falling was psychotropics: benzodiazepines, antidepressants, and antipsychotics. Antiepileptics and drugs that lower blood pressure were weakly associated with falls. CONCLUSIONS: Central nervous system drugs, especially psychotropics, seem to be associated with an increased risk of falls. The quality of observational studies needs to be improved, for many appear to lack even a clear definition of a fall, target medicines, or prospective follow-up. Many drugs commonly used by older persons are not systematically studied as risk factors for falls.     

Consequences of falling in older men and women and risk factors for health service use and functional decline

OBJECTIVES: (1) to examine consequences of falls in older men and women and (2) to examine risk factors for health service use and functional decline among older fallers. METHODS: the study was performed within the Longitudinal Aging Study Amsterdam. In 1998/1999, potential risk factors were assessed during the third data collection. In 1999/2000, 204 community-dwelling persons (> or =65 years) who reported at least one fall in the year before the interview, were asked about consequences of their last fall, including physical injury, health service use, treatment and functional decline (i.e. decline in functional status, social and physical activities). RESULTS: as a consequence of falling, respondents reported physical injury (68.1%), major injury (5.9%), health service use (23.5%), treatment (17.2%), and decline in functional status (35.3%), and social (16.7%) and physical activities (15.2%). Using multivariate logistic regression, specific risk factors for health service use after falling could not be identified. Female gender (OR = 2.8, 95% CI = 1.5-5.1), higher medication use (OR = 1.5, 95% CI = 1.0-2.2) and depressive symptoms (OR = 1.9, 95% CI = 1.3-2.8) were independently associated with functional decline after falling. Depressive symptoms (OR = 2.0, 95% CI = 1.2-3.3) and falls inside (OR = 2.6, 95% CI = 1.1-6.5) were risk factors for decline in social activities, while female gender (OR = 2.7, 95% CI = 1.1-7.0) and depressive symptoms (OR = 1.9, 95% CI = 1.2-3.0) were risk factors for decline in physical activities after falling. CONCLUSIONS: almost 70% of the respondents suffered physical injury, almost one-quarter used health services and more than one-third suffered functional decline after falling. No risk factors were found for health service use needed after falling. Female gender, higher medication use, depressive symptoms and falls inside were risk factors for functional decline after falling.     

Angiotensin-converting enzyme inhibitors, calcium channel blockers, and breast cancer

BACKGROUND: The use of angiotensin-converting enzyme (ACE) inhibitors has been linked to a decreased risk of developing cancer, and longer-term use of calcium channel blockers (CCBs) has been associated with an increased risk of developing cancer in general and breast cancer in particular. METHODS: Using data from the General Practice Research Database, we conducted a large case-control analysis. Previous exposure to ACE inhibitors, CCBs, and beta-blockers was compared between 3706 postmenopausal women who were diagnosed with incident breast cancer between 1992 and 1997 and 14155 matched-control women. RESULTS: Compared with nonusers of antihypertensive drugs, women who used ACE inhibitors (odds ratio [OR], 1.0; 95% confidence interval [CI], 0.7-1.5), CCBs (OR, 0.9; 95% CI, 0.7-1.2), or beta-blockers (OR, 1.0; 95% CI, 0.8-1.2) for 5 or more years were not at an increased or decreased risk of developing breast cancer (adjusted for smoking and body mass index [calculated as weight in kilograms divided by the square of height in meters]). The risk of breast cancer did not differ between users of different ACE inhibitors or different CCBs (dihydropyridines, diltiazem hydrochloride, and verapamil hydrochloride) or between users of short-acting (OR, 1.0; 95% CI, 0.7-1.4) or sustained-release (OR, 1.0; 95% CI, 0.8-1.3) nifedipine preparations. CONCLUSION: The findings of this large case-control analysis do not support the hypothesis that longer-term use of ACE inhibitors or CCBs affects the risk of developing breast cancer.     

Increased bleeding risk with concurrent use of selective serotonin reuptake inhibitors and coumarins

BACKGROUND: Treatment with vitamin K antagonists (coumarins) is associated with an increased risk of bleeding. Because use of selective serotonin reuptake inhibitors (SSRIs) is also associated with an increased risk of bleeding, we assessed the odds ratio (OR) of abnormal bleeding associated with SSRI use in users of the coumarins acenocoumarol or phenprocoumon and compared this with the OR of bleeding as a result of use of nonsteroidal anti-inflammatory drugs. METHODS: We used data from a Dutch linkage system including pharmacy and linked hospitalization records for approximately 2 million subjects to conduct a case-control study in a cohort of new users of coumarins. Cases were patients who were hospitalized having a primary diagnosis of abnormal major bleeding while taking a coumarin and were matched with up to 4 control subjects. Conditional logistic regression analysis was used to determine ORs and 95% confidence intervals (CIs) for the risk of hospitalization because of abnormal bleeding associated with concurrent use of SSRIs or nonsteroidal anti-inflammatory drugs. RESULTS: We identified 1848 case patients with abnormal bleeding. Users of SSRIs were at significantly increased risk of hospitalization because of nongastrointestinal tract bleeding (hereafter referred to as "nongastrointestinal bleeding") (adjusted OR, 1.7; 95% CI, 1.1-2.5) but not because of gastrointestinal tract bleeding (hereafter referred to as "gastrointestinal bleeding") (adjusted OR, 0.8; 95% CI, 0.4-1.5). Users of nonsteroidal anti-inflammatory drugs had a similar increased risk of nongastrointestinal bleeding (adjusted OR, 1.7; 95% CI, 1.3-2.2), whereas the risk of gastrointestinal bleeding was higher (adjusted OR, 4.6; 95% CI, 3.3-6.5). CONCLUSION: In users of coumarins, SSRI usage was associated with increased risk of hospitalization because of nongastrointestinal bleeding but not because of gastrointestinal bleeding.