Harvard Publications in Pharmacoepidemiology 1997



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Alonso MP. de Abajo FJ. Martinez JJ. Montero D. Martin-Serrano G. Madurga M.: Evolution of antidepressive drug consumption in Spain. The impact of selective serotonin re-uptake inhibitors. Medicina Clinica. 1997;108(5):161-6.

Avorn J. Putting adverse drug events into perspective [editorial]. JAMA 1997;277(4):341-2.

Choo PW.  Galil K.  Donahue JG.  Walker AM.  Spiegelman D. Platt R. Risk factors for postherpetic neuralgia. Archives of Internal Medicine. 1997;157(11):1217-24.

Gurwitz JH.  Kalish SC.  Bohn RL.  Glynn RJ.  Monane M.  Mogun H.  Avorn J. Thiazide diuretics and the initiation of anti-gout therapy. Journal of Clinical Epidemiology. 1997;50(8):953-9.

Gurwitz JH.  Monette J.  Rochon PA.  Eckler MA.  Avorn J. Atrial fibrillation and stroke prevention with warfarin in the long-term care setting. Archives of Internal Medicine. 1997;157(9):978-84.

Harari D.  Gurwitz JH.  Avorn J.  Bohn R.  Minaker KL. How do older persons define constipation? Implications for therapeutic management. Journal of General Internal Medicine. 1997;12(1):63-6.

Huttin C.  Avorn J. Drug expenditures for hypertension: an empirical test of an economic model in a French population. Cahiers de Sociologie et de Demographie Medicales. 1997;37(1):33-52.

Kalish SC.  Bohn RL.  Avorn J. Policy analysis of the conversion of histamine2 antagonists to over-the-counter use. Medical Care. 1997;35(1):32-48.

Lanes SF.  Birmann B.  Raiford D.  Walker AM. International trends in sales of inhaled fenoterol, all inhaled beta-agonists, and asthma mortality, 1970-1992. Journal of Clinical Epidemiology. 1997;50(3):321-8.

Lanes SF.  Lanza LL.  Radensky PW.  Yood RA.  Meenan RF.   Walker AM.  Dreyer NA. Resource utilization and cost of care for rheumatoid arthritis and osteoarthritis in a managed care setting: the importance of drug and surgery costs. Arthritis & Rheumatism. 1997;40(8):1475-81.

Liese JG. Meschievitz CK. Harzer E. Froeschle J. Hosbach P. Hoppe JE. Porter F. Stojanov S. Niinivaara K. Walker AM. Belohradsky BH. Adisdutschmann B. Busching U. Burk M. Bartels R. Berger S. Berger W. Bergner A. Binder K. Bittmann B. Borgmeyer A. Braun H. Breiner W. Daubuisson CC. Domay J. Enzel U. et al.: Efficay of a Two-Component Acellular Pertussis Vaccine in Infants. Pediatric Infectious Disease Journal. 1997;16(11):1038-1044.

Monane M.  Bohn RL.  Gurwitz JH.  Glynn RJ.  Levin R.  Avorn  J.  The effects of initial drug choice and comorbidity on antihypertensive therapy compliance: results from a population-based study in the elderly. American Journal of Hypertension.  1997;10(7):697-704.

Monane M.  Gurwitz JH.  Bohn RL.  Glynn RJ.  Levin R.  Monette J.  Avorn J. The impact of thiazide diuretics on the initiation of lipid-reducing agents in older people: a population-based analysis. Journal of the American Geriatrics Society. 1997;45(1):71-5.

Monette J.  Gurwitz JH.  Rochon PA.  Avorn J. Physician attitudes concerning warfarin for stroke prevention in atrial fibrillation: results of a survey of long-term care practitioners. Journal of the American Geriatrics Society. 1997;45(9):1060-5.

Monette J.  Mogun H.  Bohn RL.  Avorn J. Concurrent use of antiulcerative agentsJournal of Clinical Gastroenterology 1997;24(4):207-13.

Rothman KJ.  Cann CI.  Walker AM. Epidemiology and the internet [editorial]. Epidemiology. 1997;8(2):123-5.

Schneeweiss S, Stürmer T, MaclureM: Case-Crossover and Case-Time-Control Designs as Alternatives in Pharmacoepidemiologic Research. Pharmacoepidemiology and Drug Safety 1997;6 S3:S51-S59.

Walker AM. Quantitative studies of the risk of serious hepatic injury in persons using nonsteroidal antiinflammatory drugs. Arthritis & Rheumatism. 1997;40(2):201-8.

Walker AM.  Funch DP.  Bianchi L.  Blot WJ. Shop order fracture rate as a risk factor for strut fracture in Bjork-Shiley CC60 degrees heart valves. Journal of Heart Valve Disease. 1997;6(3):264-7; discussion p268.

Walker AM.  Szneke P.  Bianchi LA.  Field LG.  Sutherland LR.  Dreyer NA. 5-Aminosalicylates, sulfa-salazine, steroid use, and complications in patients with ulcerative colitis. American Journal of Gastroenterology. 1997;92(5):816-20.

Zatonski WA.  Lowenfels AB.  Boyle P.  Maisonneuve P.  Bueno de Mesquita HB.  Ghadirian P.  Jain M.  Przewozniak K.  Baghurst P.  Moerman CJ.  Simard A.  Howe GR.  McMichael AJ.  Hsieh CC.  Walker AM. Epidemiologic aspects of gallbladder cancer: a case-control study of the SEARCH Program of the International Agency for Research on Cancer. Journal of the National Cancer Institute. 1997;89(15):1132-8.
 

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Resource utilization and cost of care for rheumatoid arthritis and osteoarthritis in a managed care setting: the importance of drug and surgery costs. Arthritis & Rheumatism. 1997;40(8):1475-81

Abstract:
OBJECTIVE: To describe the frequency and costs of medical services for patients with osteoarthritis (OA) or rheumatoid arthritis (RA) in a managed care setting.
METHODS: Individual utilization records of medical and pharmacy services for OA and RA patients were obtained from a group-model health maintenance organization (HMO). Estimates were made for costs of drugs and medical services for arthritis from July 1, 1993 to June 30, 1994 using Medicare reimbursement schedules and average wholesale drug prices. Calculated rates for each population were expressed as counts of events or as dollars per person-year.
RESULTS: The average individual cost rate of arthritis-related care for 365 RA patients was $2,162 per year, and the total cost of RA care to the HMO was $703,053. Prescription medications accounted for 62% ($436,440) of the total cost of RA care, while ambulatory care accounted for 21% ($150,938), and hospital visits accounted for 16% ($115,674). With regard to 10,101 OA patients, the average individual cost rate was $543 per year, and total cost to the HMO was $4,728,425. Hospital care accounted for 46% ($2,170,890) of the total cost of OA care, medications accounted for 32% ($1,509,637), and ambulatory care accounted for 22% ($1,047,898).
CONCLUSION: RA care, in the setting of this study, was characterized by intensive treatment, especially frequent use of medications that were delivered to most patients. Although the cost of RA care per patient was high, cost to the managed care provider was relatively low, owing to the rarity of RA. OA care tended to be infrequent, and the largest component of cost was hospital care for a small proportion of patients (5%). Owing to the greater prevalence of OA, care of OA was nearly 7 times more costly to the managed care provider than was care of RA.

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Epidemiologic aspects of gallbladder cancer: a case-control study of the SEARCH Program of the International Agency for Research on Cancer. Journal of the National Cancer Institute.  1997;89(15):1132-8.

Abstract
BACKGROUND: There are few previous epidemiologic studies of gallbladder cancer, a rare but nearly always lethal gastrointestinal cancer with a demonstrated greater frequency in adult women and older subjects of both sexes, and also in the members of populations throughout central and eastern Europe and certain racial groups such as native American Indians. Unfortunately, the prospects for the prevention of this form of cancer are poor.
PURPOSE: Our purpose in conducting this study was to investigate possible new risk factors for gallbladder cancer and to strengthen our understanding of established causal agents that may be involved in this disease.
METHODS: A large, collaborative, multicenter, case-control study of cancer of the gallbladder was conducted in five centers located in Australia (Adelaide), Canada (Montreal and Toronto), The Netherlands (Utrecht), and Poland (Opole) from January 1983 through July 1988. Case subjects with gallbladder cancer were accrued by the centers from hospital pathology records and from reports to regional cancer registries. Cancer diagnosis was confirmed by either biopsy, cholecystectomy, or at the time of autopsy. Control subjects were randomly assigned at each center from the population. The pooled analysis included 196 case subjects and 1515 control subjects (who did not report previous cholecystectomy). Ninety-eight percent of the subjects were white. Personal interviews of case subjects, control subjects, and surrogates (spouse or next of kin) were conducted by trained personnel.
RESULTS: After adjusting for potential confounding factors (age, sex, center, type of interview, years of schooling, alcohol intake, and lifetime cigarette smoking), a history of gallbladder symptoms requiring medical attention (e.g., reduced bile secretion from the gallbladder into the small intestine due to obstructions of the common bile or cystic ducts) was the major risk factor associated with this form of cancer (odds ratio [OR] = 4.4; 95% confidence interval [CI] = 2.6-7.5). This association was present even in subjects who had their first gallbladder examination because of symptoms present more than 20 years earlier (OR = 6.2; 95% CI = 2.8-13.4). Other variables associated with gallbladder cancer risk included an elevated body mass index, high total energy intake, high carbohydrate intake (after adjustment for total energy intake), and chronic diarrhea. All of these risk factors have been previously associated with gallstone disease.
CONCLUSIONS: These findings are consistent with a major role of gallstones, or risk factors for gallstones, in the cause of gallbladder cancer. Additional information on whether or not screening high-risk subjects for gallstones or gallbladder cancer is needed.

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Quantitative studies of the risk of serious hepatic injury in persons using nonsteroidal antiinflammatory drugs. Arthritis & Rheumatism. 1997;40(2):201-8.

Abstract
OBJECTIVE: To quantify the risk of symptomatic hepatic injury associated with nonsteroidal antiinflammatory drugs (NSAIDs). METHODS: Five population-based studies were summarized to evaluate information on more than 1,000,000 patients using NSAIDs. RESULTS: The risk of clinically apparent liver injury was approximately 1 case per 10,000 patient-years of NSAID use. Only sulindac, associated with a 5-10-fold higher incidence of hepatic injury, differed significantly from other NSAIDs. Patients using diclofenac showed no higher incidence of serious liver disease than did patients using other NSAIDs.
CONCLUSION: Symptomatic hepatic effects attributable to most NSAIDs are extremely rare and usually mild. [References: 11]

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Risk factors for postherpetic neuralgia. Archives of Internal Medicine. 1997;157(11):1217-24.

Abstract
BACKGROUND: The risk factors for postherpetic neuralgia (PHN), the most common complication of herpes zoster, have not been well established.
OBJECTIVE: To elucidate the risk factors for PHN. METHODS: Automated medical, claims, and pharmacy records of a health maintenance organization were used to identify cases of PHN and obtain data on risk factors. A case-base design was used to assess the impact of various patient, disease, and treatment factors on the prevalence of PHN 1 and 2 months after developing zoster.
RESULTS: There were 821 cases of herpes zoster that met all eligibility criteria. The prevalence of PHN more than 30 days after onset of zoster was 8.0% (95% confidence interval [CI], 6.3%-10.1%) and 4.5% (95% CI, 3.2%-6.2%) after 60 days. Compared with patients younger than 50 years, individuals aged 50 years or older had a 14.7-fold higher prevalence (95% CI, 6.8-32.0) 30 days and a 27.4-fold higher prevalence (95% CI, 8.8-85.4) 60 days after developing zoster. Prodromal sensory symptoms and certain conditions associated with compromised immunity were also associated with PHN. Systemic corticosteroids before zoster and treatment of zoster with acyclovir or corticosteroids did not significantly affect the prevalence of PHN.
CONCLUSIONS: Increased age and prodromal symptoms are associated with higher prevalence of PHN 1 and 2 months after onset of zoster. Overall, systemic acyclovir appears not to confer any protection against PHN, although benefit among elderly patients cannot be excluded.

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International trends in sales of inhaled fenoterol, all in-haled beta-agonists, and asthma mortality, 1970-1992. Journal of Clinical Epidemiology. 1997;50(3):321-8.

Abstract
To evaluate the hypothesis that fenoterol or all inhaled beta-agonists caused an epidemic of asthma mortality in New Zealand from the late 1970s to the mid-1980s, we examined trends from 1970 to 1992 in per capita sales of inhaled fenoterol, inhaled beta-agonists, and asthma mortality in New Zealand and nine other countries that marketed fenoterol. During the last two decades, there has been a large and widespread increase in sales of inhaled beta-agonists, including fenoterol. Asthma mortality in most countries, however, has been relatively stable. Only New Zealand experienced an epidemic of asthma mortality. In addition, sales rates of fenoterol similar in magnitude to those in New Zealand near the peak of the epidemic also occurred in Belgium, Austria, and Germany, while asthma mortality in these countries remained low. Also, sales rates of all beta-agonists in Australia were similar to those in New Zealand, but no epidemic of asthma mortality occurred in Australia. Therefore, the difference between asthma mortality rates in New Zealand and other countries is not explained by differences in per capita sales of fenoterol or all beta-agonists. Within New Zealand, the beginning and end of the epidemic correlated with a rise and fall in sales of all beta-agonists, including fenoterol. From 1980 to 1989, however, sales of fenoterol and all beta-agonists doubled in New Zealand while asthma mortality declined by 40%. International data on medication sales and asthma mortality, therefore, do not point to a relation between asthma mortality and beta-agonists in general nor fenoterol in particular.

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Shop order fracture rate as a risk factor for strut fracture in Bjork-Shiley CC60 degrees heart valves. Journal of Heart Valve Disease. 1997;6(3):264-7; discussion p268.

Abstract
BACKGROUND AND AIMS OF THE STUDY: Previous studies have implicated a number of characteristics that predict strut fracture in Bjork-Shiley convexo-concave heart valves, including valve size and position, opening angle, and weld date. This study examines whether the specific batch (shop order) with which a valve is associated during manufacture is related to the risk of fracture.
MATERIAL AND METHODS: Our case-control study of CC60 degrees valves obtained detailed information on the manufacturing characteristics of 147 case and 1094 control valves used. Shop order fracture rate for each valve (percentage of other valves in the same shop order with a fracture) was obtained from the research database maintained by the valve manufacturer.
RESULTS: Shop order was associated with fracture risk. Valves originating from shop orders with the highest two categories of fracture rate were at approximately twice the risk of fracture as other valves, after accounting for the effect of known risk factors.
CONCLUSIONS: Shop order information may provide additional data for assessing the likelihood of valve fracture in individuals being considered for prophylactic explant of heart valves.

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5-Aminosalicylates, sulfa-salazine, steroid use, and complications in patients with ulcerative colitis. American Journal of Gastroenterology. 1997;92(5):816-20.
Abstract
OBJECTIVES: The choice between sulfasalazine and 5-aminosalicylate (5-ASA) drugs in the management of patients with ulcerative colitis often depends on idiosyncrasies of drug tolerance and control of the disease in individual patients. We sought to evaluate whether there were population differences in the effect of 5-ASA and sulfasalazine on the occurrence of clinically recognized adverse events. We also attempted to determine whether there were differences in the use of concomitant steroids and in the rates of hospitalization.
METHODS: We reviewed a large computerized database drawn from general practices in the United Kingdom. There we found records of 2894 patients in whom general practitioners had diagnosed ulcerative colitis, and who were receiving ongoing medical therapy specific to ulcerative colitis. The period of data availability ran from the beginning of 1990 to the latter part of 1993. The average duration of observation was 2.1 yr per patient. Patient histories were categorized into distinct periods according to the dose of 5-ASAs and sulfasalazine, steroids, and immunosuppressants, and were further separated according to the activity of ulcerative colitis. Within these categories, we examined the initiation and discontinuation of steroids, incidence of new hospitalizations for ulcerative colitis, and clinical mention of adverse events. RESULTS: New clinical mentions of hepatic, pancreatic, renal, and hematological events other than anemia were similar among the 5-ASAs and were very infrequent overall. Hospitalizations for ulcerative colitis occurred with similar frequency (about 15 hospitalizations per 100 patients per year) among users of those drugs. Patients receiving sulfasalazine had lower rates of initiation of prednisolone than did patients receiving 5-ASA, but sulfasalazine was used proportionately less often in patients who had been recently hospitalized, and it may be that sulfasalazine patients were somewhat less sick, overall, than were 5-ASA-using patients. The choice of drug did not affect discontinuation rates for prednisolone among established users.
CONCLUSIONS: In the United Kingdom, during the period of this study, serious adverse reactions to drugs were not an important aspect of the management of patients with ulcerative colitis. Renal and pancreatic complications of sulfasalazine and 5-ASA therapy were extremely rare. Sulfasalazine and 5-ASA drugs have similar steroid-sparing properties. Disease-specific hospitalizations are approximately 100 times more common in ulcerative colitis patients than are serious adverse drug effects. Considerations of drug efficacy should therefore dominate the choice between therapeutic agents.

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Thiazide diuretics and the initiation of anti-gout therapy. Journal of Clinical Epidemiology. 1997;50(8):953-9.

Abstract
While physiologic and epidemiologic evidence link diuretic therapy with hyperuricemia, no previous study has quantified the risk for initiation of treatment specific for hyperuricemia or gout among elderly patients taking thiazide diuretics. We performed a retrospective cohort study of 9249 enrollees aged 65 or older in the New Jersey Medicaid program who were newly started on an antihypertensive medication from November 1981 through February 1989 and who had no prior use of anti-gout therapy (allopurinol, colchicine, or a uricosutic) during the preceding one-year period. We used Cox proportional hazards analysis to determine the risk for the initiation of anti-gout therapy in patients using various antihypertensive treatment regimens relative to no antihypertensive exposure. Patient follow-up extended for up to two years. Antihypertensive exposure was characterized over the entire period of follow-up according to the following categories: thiazide diuretic therapy alone; non-thiazide antihypertensive therapy; thiazide diuretic therapy in combination with any non-thiazide antihypertensive agent(s); and no antihypertensive use. Antihypertensive exposure was entered into the model as a time-varying covariate. Estimates of risk were adjusted for age, sex, race, nursing home residence, number of prescriptions filled, intensity of physician use, hospitalization history, and year of antihypertensive treatment initiation. The adjusted relative risk for the initiation of anti-gout therapy was 1.00 (95% CI, 0.65-1.53) for non-thiazide antihypertensive therapy alone, 1.99 (95%, CI, 1.21-3.26) for thiazide diuretic therapy, and 2.29 (95% CI, 1.55-3.37) for thiazide diuretic therapy in combination with any non-thiazide agent(s). Risk for anti-gout therapy was significantly increased for thiazide doses of > or = 25 mg/day (in hydrochlorothiazide equivalents); no significant increase in risk was seen for lower doses. We conclude that use of thiazide diuretics in doses of 25 mg/day or higher is associated with a significantly increased risk for initiation of anti-gout therapy. Such treatment may reflect the occurrence of clinical sequelae of diuretic-induced hyperuricemia or the inappropriate treatment of asymptomatic hyperuricemia.

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Concurrent use of antiulcerative agents. Journal of Clinical Gastroenterology 1997;24(4):207-13.

Abstract
Many physicians prescribe more than one antiulcerative agent (AUA) simultaneously to the same patient, although there is little evidence to support this practice. The purposes of this study were to (a) determine patient factors associated with the concurrent use of these agents and (b) estimate the excess costs generated by the prescription of multiple rather than a single agent. We conducted a case-control study of concurrent AUA users among New Jersey Medicaid enrollees age 65 years and older. To evaluate the excess cost generated by the ongoing prescription of an additional AUA, we measured the additional drug expenditures associated with each regimen of concurrent use. Nearly 1 in 15 AUA users (6.6%) met our conservative definition of concurrent AUA use. In a multiple logistic regression model, previous gastrointestinal procedure, use of a nonsteroidal anti-inflammatory drugs, nursing home residency, and recent hospitalization for more than 20 days were all predictors of concurrent use of more than one AUA. No association was found with age, sex, or number of pharmacies used. The upper bound estimate of the cost generated by the concurrent prescription of a second AUA was $210 (range: $2-$942) over the 180-day study period, with a lower bound of $151 (range: $1-$449). Annually, such excess cost would range from $301 to $420 per patient. This would account for between $457 million and $637 million per year for the nation's elderly if these patterns are generalizable. Despite the lack of evidence of therapeutic benefit from multiple concurrent AUA use in most patients, this practice is fairly common. Besides introducing the risk of additional costs and side effects in the absence of additional efficacy, the costs of such duplicative prescribing are substantial.

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Physician attitudes concerning warfarin for stroke prevention in atrial fibrillation: results of a survey of long-term care practitioners. Journal of the American Geriatrics Society. 1997;45(9):1060-5.

Abstract
BACKGROUND: The prevalence of atrial fibrillation (AF) increases dramatically with advancing patient age, and, as a result, this condition is common in persons residing in the long-term care setting.
OBJECTIVES: To assess the knowledge and attitudes of physicians regarding the use of warfarin for stroke prevention in patients with atrial fibrillation in long-term care facilities.
METHODS: We surveyed physicians actively providing primary care to older patients in 30 long-term care facilities located in New England, Quebec, and Ontario. Physicians were requested to complete a structured questionnaire about use of warfarin therapy for stroke prevention in patients with AF residing in long-term care facilities. The questionnaire included two clinical scenarios designed to provide substantial contrasts in patient characteristics including underlying comorbidity, functional status, bleeding risk, and stroke risk.
RESULTS: A total of 269 physicians were asked to participate in the survey, and 182 (67.7%) completed the questionnaire between February 1, 1995, and July 31, 1995. Only 47% of respondents indicated that the benefits of warfarin therapy "greatly outweigh the risks" in this setting; the remainder of physicians indicated that benefits only "slightly outweigh the risks" (34%) or that risks "outweigh benefits" (19%). The most frequently cited contraindications to warfarin use were: excessive risk of falls (71%), history of gastrointestinal bleeding (71%), history of other non-central nervous system bleeding (36%), and history of cerebrovascular hemorrhage (25%). Among the 164 physicians who reported using the international normalized ratio to monitor warfarin therapy, 27% indicated a target range with a lower limit less than 2, 71% indicated a target range between 2 and 3, and 2% indicated an upper limit greater than 3. Among respondents who answered questions about the two clinical scenarios, estimates of the risk of a stroke without warfarin therapy and the risk of an intracranial hemorrhage with therapy varied widely.
CONCLUSIONS: Our findings suggest that many uncertainties surround the decision to prescribe warfarin to patients with AF in the long-term care setting, as well as questions about the appropriate intensity of this treatment when it is prescribed. Concerns about the risks of bleeding appear to prevail over stroke prevention when physicians make such prescribing decisions.

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The effects of initial drug choice and comorbidity on antihypertensive therapy compliance: results from a population-based study in the elderly. American Journal of Hypertension.  1997;10(7):697-704.

Abstract
Approximately half of all elderly patients have elevated blood pressure, and proper treatment of this disorder leads to decreased cardiovascular morbidity in patients 65 and older. This study examined the effect of initial drug choice and comorbidity on medication compliance. We conducted a retrospective follow-up of 8643 outpatients aged 65 to 99 with newly prescribed antihypertensive therapy (AHT) from 1982 to 1988 in the New Jersey Medicaid and Medicare programs. Compliance was measured in terms of the number of days in which AHT was available to the patient during the 12 months following the initiation of therapy. Odds ratios (OR) and 95% confidence intervals (CI) for the outcome of good compliance (> or =80%) were calculated. In a logistic regression model, good compliance (> or =80%) was significantly associated with use of newer agents such as angiotensin converting enzyme inhibitors (OR 1.9, 95% CI 1.6 to 2.2) and calcium channel blockers (OR 1.7, 95% CI 1.5 to 2.1) as compared to thiazides, the presence of comorbid cardiac disease (OR 1.2, 95% CI 1.1 to 1.2), and multiple physician visits (OR 2.2, 95% CI 1.8 to 2.5). Good compliance was inversely associated with use of multiple pharmacies (OR 0.4, 95% CI 0.4 to 0.5) and number of medications prescribed overall (OR 0.8, 95% CI 0.7 to 0.9). Drug choice, comorbidity, and health services utilization were significantly associated with AHT compliance and represent important considerations in the management of high blood pressure. Noncompliance may be an important cause of treatment failure in elderly hypertensives.

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How do older persons define constipation? Implications for therapeutic management. Journal of General Internal Medicine. 1997;12(1):63-6.

Abstract
This study examined the relation between bowel-related symptoms and self-report of constipation in 10,875 subjects aged 60 years and over, who participated in the 1989 National Health Interview Survey. Subjects reporting constipation "always" or "mostly" over the past 12 months (n = 594) were compared with those who reported never having the symptom (n = 4,192). Straining (adjusted odds ratio 66.7; 95% confidence interval 31.5, 142.4) and hard bowel movements (25.6; 16.7, 38.7) were most strongly associated with self-report of constipation. These findings suggest that treatment for constipation in the older population should be directed as much or more at facilitating comfortable rectal evacuation, as increasing bowel movement frequency.

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Avorn J. Atrial fibrillation and stroke prevention with warfarin in the long-term care setting. Archives of Internal Medicine. 1997;157(9):978-84.

Abstract
BACKGROUND: While the benefits of warfarin sodium therapy for stroke prevention in patients with atrial fibrillation (AF) have been extensively documented, generalizing clinical trial results to the majority of elderly persons with AF, especially to those who reside in the long-term care setting, remains challenging.
OBJECTIVES: To determine the prevalence of AF in the institutionalized elderly population and the proportion receiving anticoagulation therapy with warfarin: to identify the clinical and functional characteristics of institutionalized elderly persons with AF that are associated with the use of warfarin; and to assess the quality of prescribing and monitoring of warfarin therapy in institutionalized elderly persons with AF.
METHODS: This study involved 30 long-term care facilities (total No. of beds, 6437) located in New England, Quebec, and Ontario. The proportion of patients with AF who were receiving treatment with warfarin was  determined. The association between clinical and functional characteristics and the use of warfarin was examined with crude and multivariable-adjusted analyses. For study subjects with at least 2 weeks of warfarin therapy during the 12-month period preceding the date of medical record abstraction, we assessed the quality of warfarin prescribing based on all international normalized ratio or prothrombin time ratio values during this period.
RESULTS: An electrocardiogram indicating AF was present in the records of 413 of 5500 long-term care residents (7.5%); 32% of such patients were being treated with warfarin. Only a history of stroke was found to be positively associated with the use of warfarin in this setting. Patients with a diagnosis of dementia and those in the oldest age group (> or = 85 years) were less likely to receive warfarin therapy. Warfarin was commonly prescribed to patients with a history of bleeding, substantial comorbidity and functional impairment, a history of falls, or concomitant potentiating drug therapy. Patients were maintained above or below the recommended therapeutic range 60% of the time.
CONCLUSIONS: Atrial fibrillation is common in patients residing in long-term care facilities, but its management with warfarin is highly variable. A more systematic approach to decision making regarding the use of warfarin for stroke prevention in these patients is required. Among patients receiving warfarin, the quality of anticoagulation care warrants improvement.

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Policy analysis of the conversion of histamine2 antagonists to over-the-counter use. Medical Care. 1997;35(1):32-48.

Abstract
OBJECTIVES: The authors assess the costs associated with treatment of dyspepsia with histamine2 antagonists versus without availability of over-the-counter (OTC).
METHODS: A cost analysis was performed using a decision-analysis model. Patients with an initial episode of dyspepsia were studied. The model includes costs associated with consumption of OTC and prescription (Rx) medications for dyspepsia, physician visits and associated diagnostic testing, time spent for physician visits and diagnostic tests, and hospitalization costs.
RESULTS: The model is sensitive to the relative cost of histamine2 antagonists when purchased Rx or OTC, as well as to the efficacy of these drugs in relieving dyspeptic symptoms. For patients with nonulcer dyspepsia (the largest group of likely consumers), the model demonstrates a cost savings if the OTC cost of the medication is slightly less than one third the Rx cost. Costs are similar whether or not histamine2 antagonists are available OTC. If the symptom relief efficacies of histamine2 antagonists are equivalent whether purchased by prescription only or OTC, then the health-care expenditures for a typical patient with dyspepsia are $204 for OTC availability and $203 for Rx-only use. Viewing costs from the perspective of a managed-care organization, expenditures for an episode of dyspepsia are $149 regardless of whether or not histamine2 antagonists are available OTC. Restricting the analysis to patients with underlying nonulcer dyspepsia yields similar results. Variation of numerous assumptions and probabilities other than histamine antagonist cost and efficacy, including costs associated with physician visits and diagnostic tests, and the likelihood of seeking medical care, do not substantially affect the results of the model.
CONCLUSIONS: Health-care costs associated with initial treatment of dyspepsia are similar regardless of the availability of histamine2 antagonists OTC. This is due largely to the similar efficacy of these drugs compared with antacids and the predicted increase in diagnostic testing that may result if a patient visits a physician after failure to achieve symptom relief with OTC use of histamine2 antagonists.

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The impact of thiazide diuretics on the initiation of lipid-reducing agents in older people: a population-based analysis. Journal of the American Geriatrics Society. 1997;45(1):71-5.

Abstract
OBJECTIVE: The objective of this study was to examine how often treatment for hyperlipidemia followed the use of thiazides, compared with the use of other antihypertensive drugs, in older patients.
DESIGN: Retrospective follow-up of all health claims filed over a 12-month period.
SETTING: New Jersey Medicaid and Medicare programs.
PARTICIPANTS: A total of 9274 enrollees, aged 65 to 99, who were newly initiated on antihypertensive medications from 1981-1989.
MEASUREMENTS: We measured rates of lipid-reducing agent (LRA) initiation among patients in the 2 years following antihypertensive initiation (thiazide, non-thiazide drug, or combinations of the two) compared with rates among patients not currently taking antihypertensive agents. We used Cox regression analyses to estimate relative risks (RR), accounting for switching in antihypertensive therapy and for time when drug therapy was not currently available according to pharmacy refill records.
RESULTS: There were 226 patients (2.4%) in the cohort who were started on LRA during the follow-up period. After adjusting for potential confounders, we found no significant relationship between LRA initiation and overall thiazide use (RR 1.47, 95% CI 0.89-2.40), or other antihypertensive use, relative to no current exposure. However, use of high-dose thiazides (> or = 50 mg) was associated significantly with LRA initiation (RR 1.97, 95% CI 1.12-3.45). Factors associated with decreased incidence of LRA use included age > or = 85 (RR 0.59, 95% CI 0.36-0.96), black race (RR 0.58, 95% CI 0.37-0.91), and nursing home residency (RR 0.20, 95% CI 0.11-0.35).
CONCLUSION: Use of low-cost and effective thiazide diuretics in older hypertensives was not associated with more common initiation of lipid-reducing agents, except with high-dose use of thiazides currently seen as inappropriate in most cases. Age and race were important determinants of LRA use.

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Case-Crossover and Case-Time-Control Designs as Alternatives in Pharmacoepidemiologic Research. Pharmacoepidemiology and Drug Safety 1997;6 S3:S51-S59.

Abstract
Standard cohort and case-control designs are suited to the study of cumulative effects of chronic exposures, but they are prone to confounding by indication. Case-crossover and case-time-control studies are especially useful for studying intermittent exposures with transient effects, and are less susceptible to confounding by indication. Each design has its strengths and weaknesses. Despite the increasing availability of automated databases, cohort studies are usually time consuming and expensive, and therefore not preferred for time-critical decisions. In case-control studies, the selection of appropriate controls can be difficult and time consuming, and sometimes impractical when the exposure is rare. Case-crossover studies use the exposure history of each case as his or her own control to examine the effect of transient exposures on acute events. It further allows to study the time relationship of immediate effects to the exposure. This design eliminates between-person confounding by constant characteristics, including chronic indications. Because exposure data for the case and control periods are provided by the same person, the problems of differential recall may be reduced in many but not all case-crossover studies. Bias can result from temporal changes in prescribing or within-person confounding, including transient indication or changes in disease severity. The case-time-control design is an elaboration of the case-crossover design, which uses exposure history data from a traditional control group to estimate and adjust for the bias from temporal changes in prescribing.
This paper will present a structured decision table of when to use which design in pharmacoepidemiologic research.
In conclusion, case-crossover and case-time-control studies are the designs of choice when separating acute effects from chronic effects of transient exposures and if confounding by indication is an outstanding problem.

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Evolution of antidepressive drug consumption in Spain. The impact of selective serotonin reuptake inhibitors. Medicina Clinica. 1997;108(5):161-6.
Abstract
     BACKGROUND: The pattern of use of antidepressive drugs in Spain through 1985-1994 is studied.
     Special emphasis is given to the impact of selective serotonin re-uptake inhibitors introduction at the end of
     the eighties. MATERIAL AND METHODS: Information on drug utilization was obtained from the
     databases of the Ministry of Health which contain the number of packages sold in community pharmacies
     and charged to the National Health System. Data are expressed in defined daily doses (DDD) per 1,000
     inhabitants per day. RESULTS: The use of antidepressants (excluding fixed-dose combinations) increased
     from 2.7 DDD/1,000 inhabitants/day in 1985 to 9.3 DDD/1,000 inhabitants/day in 1994 (247%). All the
     subgroups contributed. Selective serotonin re-uptake inhibitors utilization was 4.71 DDD/1,000
     inhabitants/day in 1994, representing 71% of the overall increase during the study period. The consumption
     of fixed-dose combinations decreased in 17%. Since 1991 fluoxetine is the antidepressant most widely
     used. The consumption through pensioner prescriptions is proportionally higher for second generation
     antidepressants than for the other groups. CONCLUSIONS: Antidepressive drugs consumption in Spain
     increased three times in the last ten years, though it is still below the estimated point prevalence of
     depression. Selective serotonin re-uptake inhibitors introduction has modified the pattern of use of
     antidepressants but their impact on the use of the rest of the group has been apparently low.

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Efficay of a Two-Component Acellular Pertussis Vaccine in Infants. Pediatric Infectious Disease Journal. 1997;16(11):1038-1044.

Abstract
Objective, This case-control study investigated the protective efficacy against pertussis of three doses of a  two-component acellular pertussis vaccine (manufactured by Biken in Japan) combined with diphtheria and tetanus toxoids (manufactured by Connaught Laboratories in the US) in infants.
Methods, A case-control study was performed in 63 pediatric practices in Germany, Prospective recruitment of 16 780 infants ages 6 to 17 weeks took place between February, 1993, and July, 1994. According to parental choice infants received either Biken acellular pertussis vaccine combined with diphtheria and tetanus toxoids (DTacP) (74.6%) at similar to 2, 4 and 6 months of age, or a licensed German diphtheria-tetanus toxoids-whole cell pertussis vaccine (10.9%), diphtheria-tetanus toxoids vaccine (12.5%) or no vaccine (2.0%), Prospective surveillance of pertussis cases between February, 1993, and May, 1995, was accomplished by culturing all infants less than or equal to 2 years of age presenting with cough greater than or equal to 7 days, A pertussis case was defined as any cough of 21 days or longer plus a positive Bordetella pertussis culture or household contact exposure.
Results, We identified 241 pertussis cases prospectively by 11 017 B. pertussis cultures and 949 controls matched for age were selected from the same pediatric practices, Medical history and demographic and vaccine status data were collected from each case and for four controls, Data were analyzed through conditional logistic regression taking into account individual matching and adjusting for potential confounding variables, DTacP combined with diphtheria and tetanus toxoids vaccine was 82% protective (95% confidence interval, 68 to 90), diphtheria-tetanus toxoids whole cell pertussis vaccine was 96% protective (95% confidence interval, 78 to 99). Protection against typical B. pertussis infection characterized by paroxysmal cough lasting greater than or equal to 21 days was 96% (95% confidence interval, 87 to 99) for DTacP and was 97% (95% confidence interval, 79 to 100) for diphtheria-tetanus toxoids-whole cell pertussis vaccine, Adjustment for potentially confounding variables did not change the results significantly.
Conclusions. Three doses of the two-component acellular pertussis vaccine protected infants against pertussis disease during the period before the recommended booster vaccination. For typical pertussis disease as defined by the WHO efficacy was high and similar to that of a licensed German diphtheria-tetanus toxoids-whole cell pertussis vaccine.

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