Three-tiered-copayment drug coverage and use of nonsteroidal anti-inflammatory drugs

BACKGROUND: Previous studies of 3-tier formularies are rare, although the evidence suggests that their cost-sharing structure reduces overall drug spending. However, it is unclear how incentive-based formularies affect the selection of medications with safety advantages, or restrict the access that high-risk populations have to recommended therapies in the higher tiers. This study was designed to determine whether 3-tier formularies influence the use of nonsteroidal anti-inflammatory drugs (NSAIDs) in a population of patients with arthritis. METHODS: This retrospective study used the 2000 MarketScan Research Database, which contains person-level claims data for employer-sponsored health plans. The sample for this study consisted of 20 868 individuals treated for osteoarthritis or rheumatoid arthritis and using NSAIDs while enrolled in tiered drug plans (n = 32). The likelihood of any use of cyclo-oxygenase (COX-2)-selective inhibitors was determined as a function of tiered drug plan coverage, adjusting for other person-level and plan-level covariates. RESULTS: Use of COX-2-selective inhibitors decreased (63.0% vs 53.6% vs 41.6%, respectively) and use of generic NSAIDs increased (37.7% vs 40.7% vs 55.7%, respectively) as formularies incorporated 1, 2, and 3 tiers. Enrollees in 3-tier plans with arthritis and serious gastrointestinal comorbidities (odds ratio, 0.51; 95% confidence interval, 0.40-0.66) were significantly less likely to use COX-2-selective inhibitors compared with patients in 1-tier plans. CONCLUSIONS: Three-tier formularies appear to reduce the use of COX-2-selective inhibitors among all patients with arthritis, even those at risk of experiencing gastrointestinal complications from using nonselective NSAIDs. These findings are among the first to suggest that tiered-copayment drug plans may be influencing the selection of medications beyond generic and branded products.     

Approaches to nonsteroidal anti-inflammatory drug use in the high-risk patient

Nonsteroidal anti-inflammatory drugs (NSAIDs) are probably the most common cause of gastroduodenal injury in the United States today. Approximately half of patients who regularly take NSAIDs have gastric erosions, and 15%-30% have ulcers when they are examined endoscopically. However, the incidence of clinical gastrointestinal (GI) events caused by NSAIDs is much lower. Clinical upper GI events may occur in 3%-4.5% of patients taking NSAIDs, and serious complicated events develop in approximately 1.5%. However, the risk varies widely in relationship to clinical features such as history of ulcers or GI events, age, concomitant anticoagulant or steroid use, and NSAID dose. This review discusses the risks of clinical GI disease in NSAID users, the predictors of increased risk, and strategies for prevention of NSAID-associated GI disease.     

Colorectal cancer after start of nonsteroidal anti-inflammatory drug use

Purpose

Nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin, have been consistently shown to reduce the risk of colorectal cancer (CRC) in non-experimental studies, but little is known of the factors associated with starting and continuing regular NSAID use and their effect on the NSAID and CRC association.

Subjects and methods

We performed a prospective cohort study of 22,071 healthy male physicians aged 40 to 84 years without indications or contraindications to regular NSAID use at baseline. Annual questionnaires assessed quantity of NSAID use, occurrence of cancer, and risk factors for CRC. Propensity for regular NSAID use (>60 days/year) was estimated using generalized estimating equations. We used a time-varying Cox proportional hazards model to estimate the association between duration since initiation of regular NSAID use and risk for CRC.

Results

Regular non-aspirin and any NSAID use increased from 0% to 12% and 1% to 56% over time, respectively and was predicted by age, body mass index, alcohol consumption, medication use, coronary artery disease, gastrointestinal diseases, arthritis, hypertension, and headaches. Over a median follow-up of 18 years, 495 physicians were diagnosed with CRC. There was no trend of CRC risk with increased duration of regular NSAID use. Five or more years of regular use of any NSAID were associated with a relative risk for CRC of 1.0 (95% confidence interval: 0.7-1.5), after adjustment for predictors of regular NSAID use.

Conclusion

Regular NSAID use was not associated with a substantial risk reduction of CRC after controlling for time-varying predictors of both NSAID use and CRC.     

Long-term nonsteroidal anti-inflammatory drug use and gastroduodenal injury: the role of Helicobacter pylori.

To evaluate the association of Helicobacter pylori infection with gastroduodenal ulceration and symptoms in rheumatoid arthritis patients chronically ingesting nonsteroidal anti-inflammatory drugs (NSAIDs), a population-based study was performed. Residents of Olmsted County, Minnesota, and surrounding counties, 40 years of age and over with active rheumatoid arthritis taking therapeutic dose of NSAIDs daily for 6 months or more were evaluated (n = 50). An endoscopic score from 0 to 5 was assigned and independently confirmed. Biopsies were obtained from the antrum and gastric body for the presence of H. pylori. A symptom score based on the frequency and severity of dyspeptic symptoms was calculated. Substantial mucosal injury (greater than or equal to grade 2) was observed at endoscopy in 33 patients (66%); 14 (28%) had chronic ulcers. Eleven of the community patients with rheumatoid arthritis (22%) were H. pylori positive; adjusting for age, the prevalence of H. pylori was not significantly different to that in 67 health controls (25%). One or more upper gastrointestinal symptoms were reported by 19 of the community patients (38%). Adjusting for age, community rheumatoid arthritis patients with H. pylori were not more likely to have visible mucosal damage or dyspepsia, but were significantly more likely to have histological gastritis (P less than 0.01). The results suggest that, in primarily asymptomatic persons from the community with rheumatoid arthritis taking daily NSAIDs for 6 months or more, H. pylori infection is not related to the severity of visible mucosal injury.     

The use of nimesulide in patients with acetylsalicylic acid and nonsteroidal anti-inflammatory drug intolerance.

Intolerance or idiosyncrasy to acetylsalicylic acid (ASA) and other nonsteroidal anti-inflammatory drugs (NSAIDs) is a crucial problem because these drugs are frequently used in medical treatment. In this study, we tested whether nimesulide, a selective cyclooxygenase-2 (COX-2) inhibitor, might be a valid alternative for patients with histories of adverse reaction to ASA or NSAIDs. A single-blind, placebo-controlled oral challenge procedure was applied to 60 adult patients (19 male, 41 female; with a mean age of 40.31 +/- 10.44 years, range 20-68 years) with a reliable history of ASA/NSAIDs-intolerance. According to history, the clinical presentations of intolerance were urticaria/angioedema in 32 patients, anaphylactoid reaction in 2 patients, respiratory reaction in 19 patients, and respiratory and cutaneous reaction in 7 patients. Atopy was confirmed by means of skin prick test with inhalant allergens. Oral challenge protocol was started with 25 mg of nimesulide and the remaining 75 mg was given 1 hr later. During the challenge procedure, blood pressure, pulse, nasoocular, pulmonary, and cutaneous symptoms were monitored. Of the 60 patients tested, 55 (91.7%) tolerated the drug with no adverse reaction. Only five (8.3%) patients demonstrated a positive response to oral challenge. The clinical presentations of intolerance to nimesulide were urticaria/angioedema in three patients, mild rhinitis in one patient, and mild dyspnea in one patient. The atopy prevalence was higher, with a ratio of 41.7%, in patients with ASA/NSAIDs intolerance than that of the healthy adult population in Turkey (p < 0.05). We believe that nimesulide can be used as an alternative drug for patients with ASA/NSAIDs intolerance.     

The relationship between nonsteroidal anti-inflammatory drug use and peptic ulcer disease

It has become increasingly recognized that nonsteroidal anti-inflammatory drug (NSAID) use is associated with serious gastroduodenal mucosal injury that can eventuate in upper gastrointestinal bleeding or perforation. This article discusses the lack of predictive value of studies administering NSAIDs to normal volunteers. The new data concerning prevention and treatment of chronic NSAID ulcers is also discussed.     

Utility of published guidelines on the use of nonsteroidal anti-inflammatory drugs in the elderly

Canadian Consensus guidelines regarding appropriate use of nonsteroidal anti-inflammatory drugs (NSAID) were recently published. This study was done to evaluate the application of these guidelines on NSAID practice patterns in frail elderly patients referred to a specialist Geriatric Assessment Clinic. A retrospective chart review was undertaken of referrals who were currently prescribed NSAIDs. Data were captured on age, sex, weight, diagnoses, medications and dosages, indication for NSAID treatment, lying BP (as assessed in the clinic) and recent serum creatinine result. Creatinine clearance was subsequently calculated use the Cockcroft-Gault equation. Complete data were available on 107 patients (68% women, average age 80.6 years). Thirty percent were on a traditional NSAID, the remainder were on a Coxib. Concomitant aspirin was prescribed in 37%. Cytoprotection was being used in 38% and did not increase appreciably in patients with additional risk factors for GI toxicity, i.e., concomitant aspirin usage(35%), and history of GI toxicity (48%). Sixty-seven were taking anti-hypertensive medications, although more than two thirds of these patients were uncontrolled. Newly diagnosed hypertension was present in 19.6%. Calculated creatinine clearance revealed moderate to severe renal impairment in 79% of subjects, although serum creatinine was only elevated in 18%. In total, 70% of subjects were found to have relative or absolute risk factors for NSAID therapy. Given the high prevalence of potential contraindications to anti-inflammatory drug usage in this study, we advocate the dissemination and application of these guidelines in geriatric patients in an attempt to reduce potential morbidity and mortality.     

Outcome of peptic ulcer bleeding, nonsteroidal anti-inflammatory drug use, and Helicobacter pylori infection.

BACKGROUND & AIMS: NSAIDs and Helicobacter pylori are risk factors for the development of peptic ulcers. A prospective study was conducted to determine prevalence of NSAID use, H pylori infection, and outcome of peptic ulcer bleeding. METHODS: In 2000, data of all 361 patients presenting with peptic ulcer bleeding were prospectively collected in a defined geographical area, including 14 hospitals, and serving a catch area of 1.68 million persons. Follow-up data after a mean of 31 months were obtained from 211 patients. RESULTS: The overall incidence was 21.5 cases per 100,000 persons. Mean age of the group was 70.9 years, 55% were male, and 41% had severe or life-threatening comorbidity. NSAIDs were used by 52%, and in only 17% concomitant acid suppressive therapy was given. H pylori infection was tested in 64%. Of the patients tested for H pylori, 43% were positive. Twenty-three percent were H pylori negative and not using NSAIDs. Rebleeding during initial admission occurred in 19%. Mortality during initial admission was 14%. During follow-up mortality was high, 29%. CONCLUSIONS: Half of all ulcer bleeding was associated with NSAID use. Only a minority of NSAID users used concomitant acid suppressive therapy. H pylori is not assessed systematically in all patients with ulcer bleeding. Almost a quarter of the ulcers were associated with neither H pylori infection nor NSAID use. Mortality, both during hospitalization and follow-up, was substantial.     

Association of chronic non-steroidal anti-inflammatory drugs use and cognitive decline in non-demented elderly patients admitted to a geriatric evaluation and rehabilitation unit

In a geriatric evaluation and rehabilitation unit (GERU), 258 elderly patients (M: 71, F: 187; mean age 77.4 +/- 7.5) scoring 22 or more at Mini-Mental State Examination (MMSE) consecutively admitted were assessed in order to evaluate the effects of non-steroidal anti-inflammatory drugs (NSAID) chronic treatment on cognitive status in non-demented elderly patients. Sixty-six patients (25.6%) were considered chronic NSAID users. Patients chronically assuming NSAADs showed a significantly higher MMSE score than non-users (26.9+/-2.1 vs 25.7+/-2.5, P<0.0005 ). After controlling for potential confounders in a multivariate model, chronic NSAID use remained independently associated with MMSE score. The results support a positive association between chronic NSAID use and cognitive function in non-demented elderly patients. Randomized controlled trials will be needed to definitively prove this beneficial effect.     

Role of Helicobacter pylori infection and nonsteroidal anti-inflammatory drug use in bleeding peptic ulcers in Japan

Background Helicobacter pylori infection and nonsteroidal anti-inflammatory drugs (NSAIDs) are well-known major causes of peptic ulcers. This study aimed to characterize the features of bleeding peptic ulcers in Japan. Methods This prospective study evaluated 116 patients revealed to have bleeding peptic ulcers from January 2000 to December 2002. Results Eighty-eight of the 116 patients (75.9%) had H. pylori infection. Seventy (60.3%) patients were positive for H. pylori with no history of NSAID use (group A), and 18 (15.5%) were positive for H. pylori with a history of NSAID use (group B). Among the H. pylori-negative patients, 15 (12.9%) were associated with NSAID use (group C). Thirteen (11.2%) patients had no H. pylori infection or history of NSAID use (group D). Among the 33 patients with a history of NSAID use, 11 were on-demand NSAID users and 14 took daily low-dose aspirin. The patients in groups B and C were significantly older that those in groups A and D, and they more frequently had coexisting diseases compared with group A. In group D, 11 patients had atrophic changes revealed by endoscopic examination, suggesting a past H. pylori infection, and these atrophic changes remained at the time of bleeding. Many of the patients in group D had serious comorbidity. Compared with healthy control subjects, the concentrations of both phosphatidylcholine and phosphatidylethanolamine were significantly decreased in the antral gastric mucosa in all patient groups. Conclusions NSAID use contributed to bleeding ulcers in 28.4% of patients; thus, low-dose aspirin or on-demand NSAID use may cause bleeding ulcers. There were only two (1.7%) confirmed cases of H. pylori-negative, non-NSAID ulcers.     

A cecal diaphragm associated with the use of nonsteroidal anti-inflammatory drugs.

In the small intestine, strictures and diaphragms causing obstructive symptoms are well known to occur in patients using nonsteroidal anti-inflammatory drugs. Recently, two cases of nonsteroidal anti-inflammatory drug (NSAID)-associated diaphragm-like colonic stricture were reported as unexpected findings in patients being investigated for iron-deficiency anemia. We present a third such case that occurred in the cecum in a 49-year-old woman with rheumatoid arthritis who had been taking NSAIDs for 5 years.     

Congestive heart failure due to nonsteroidal anti-inflammatory drugs in the elderly

Congestive heart failure in the elderly which might be due to treatment with nonsteroidal anti-inflammatory drugs was studied by means of a questionnaire sent to the participants of a postgraduate course on locomotor disease in the elderly, and also by analysis of the hospital records of 600 elderly subjects diagnosed with congestive heart failure. The questionnaire revealed 22 possible cases, reported by 20 physicians (84 physicians out of 243 responded). In the hospital population five probable cases were detected. Details of these patients are presented. In contrast with findings in the literature, solute retention was in no case the result of kidney function impairment. The specific problems regarding the attribution of this adverse effect are discussed. The results of our study provide further evidence that congestive heart failure due to nonsteroidal anti-inflammatory drug treatment is a probable adverse drug reaction in elderly individuals with or without a history of impaired cardiac performance. It may result from drug toxicity following (relative) overdosing in this age group, from reduced effectiveness of concomitant diuretic treatment or from effects on cardiovascular homoeostasis.     

Basophil activation test for the in vitro diagnosis of nonsteroidal anti-inflammatory drug hypersensitivity.

There is need for an in vitro diagnostic test for hypersensitivity to nonsteroidal anti-inflammatory drugs (NSAIDs). The purpose of this study was to assess the reliability of one such diagnostic, the basophil activation test. Forty-three drug hypersensitive patients referring several immediate reactions (anaphylaxis, urticaria, angioedema, asthma, and rhinoconjunctivitis) to one or more NSAIDs and 29 controls participated. Using the Basotest commercial kit, 63 determinations were performed with the drugs implicated in the adverse reactions (ASA, ibuprofen, metamizol, diclofenac, paracetamol, and ketorolac). In 16 patients additional determinations were made with other chemically unrelated NSAIDs. Forty-two determinations were made for controls. The analysis was performed by flow colorimetric cytometry and double staining with the monoclonal antibodies anti-IgE and anti-CD63. A Basophil Activation Index (percentage of activated basophils after allergen stimulation/percentage of basally activated basophils) of two or more was considered a positive result. Specificity of 100% and sensitivity of 42.85% were achieved. The positive predictive value was 100%, and the negative predictive value was 53.84%. In 35.29% of intolerant patients there was a positive reaction to at least two drugs implicated in adverse reactions, and in 27.27% of these patients there was a positive reaction to other chemically unrelated NSAIDs. The basophil activation test is useful for the in vitro diagnosis of NSAID hypersensitivity, providing good specificity and positive predictive value and diagnostic reliability in the assessment of NSAID intolerance.     

Social disengagement and incident cognitive decline in community-dwelling elderly persons.

BACKGROUND: Social engagement, which is defined as the maintenance of many social connections and a high level of participation in social activities, has been thought to prevent cognitive decline in elderly persons. However, few longitudinal studies of this relation have been done. OBJECTIVE: To determine the relation between social disengagement and incident cognitive decline in community-dwelling elderly persons. DESIGN: Cohort study. SETTING: New Haven, Connecticut. PARTICIPANTS: 2812 noninstitutionalized elderly persons (65 years of age or older) who were interviewed in their homes in 1982, 1985, 1988, and 1994. MEASUREMENTS: A global social disengagement scale was constructed from the following indicators: presence of a spouse, monthly visual contact with three or more relatives or friends, yearly nonvisual contact with 10 or more relatives or friends, attendance at religious services, group membership, and regular social activities. Cognitive function was assessed with the Short Portable Mental Status Questionnaire. Response to the questionnaire was scored as high, medium, or low. Cognitive decline was defined as a transition to a lower category. RESULTS: Compared with persons who had five or six social ties, those who had no social ties were at increased risk for incident cognitive decline after adjustment for age, initial cognitive performance, sex, ethnicity, education, income, housing type, physical disability, cardiovascular profile, sensory impairment, symptoms of depression, smoking, alcohol use, and level of physical activity. The 3-year odds ratio was 2.24 (95% CI, 1.40 to 3.58; P < 0.001), the 6-year odds ratio was 1.91 (CI, 1.14 to 3.18; P = 0.01), and the 12-year odds ratio was 2.37 (CI, 1.07 to 4.88; P = 0.03). CONCLUSION: Social disengagement is a risk factor for cognitive impairment among elderly persons.     

Cox-2 inhibitors and other nonsteroidal anti-inflammatory drugs in the treatment of pain in the elderly.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most commonly prescribed therapies for acute and chronic pain in the elderly. NSAIDs are effective in treating many disorders, but their use often is limited by toxicities, especially gastrointestinal and renal toxicity. COX-2 inhibitors are a major therapeutic advance, providing the analgesic and anti-inflammatory activity of NSAIDs, with a significant improvement in gastrointestinal safety. These new agents may be ideal therapies for older patients at risk for NSAID-related gastrointestinal toxicity.