Suicide-related events in patients treated with antiepileptic drugs.

BACKGROUND: A previous meta-analysis of data from clinical trials showed an association between antiepileptic drugs and suicidality (suicidal ideation, behavior, or both). We used observational data to examine the association between the use or nonuse of antiepileptic drugs and suicide-related events (attempted suicides and completed suicides) in patients with epilepsy, depression, or bipolar disorder. METHODS: We used data collected as part of the clinical care of patients who were representative of the general population in the United Kingdom to identify patients with epilepsy, depression, or bipolar disorder and to determine whether they received antiepileptic drugs. We estimated the incidence rate of suicide-related events and used logistic regression to compute odds ratios, controlling for confounding factors. RESULTS: In a cohort of 5,130,795 patients, the incidence of suicide-related events per 100,000 person-years was 15.0 (95% confidence interval [CI], 14.6 to 15.5) among patients without epilepsy, depression, bipolar disorder, or antiepileptic-drug treatment, 38.2 (95% CI, 26.3 to 53.7) among patients with epilepsy who did not receive antiepileptic drugs, and 48.2 (95% CI, 39.4 to 58.5) among patients with epilepsy who received antiepileptic drugs. In adjusted analyses, the use of antiepileptic drugs was not associated with an increased risk of suicide-related events among patients with epilepsy (odds ratio, 0.59; 95% CI, 0.35 to 0.98) or bipolar disorder (1.13; 95% CI, 0.35 to 3.61) but was significantly associated with an increased risk among patients with depression (1.65; 95% CI, 1.24 to 2.19) and those who did not have epilepsy, depression, or bipolar disorder (2.57; 95% CI, 1.78 to 3.71). CONCLUSIONS: The current use of antiepileptic drugs was not associated with an increased risk of suicide-related events among patients with epilepsy, but it was associated with an increased risk of such events among patients with depression and among those who did not have epilepsy, depression, or bipolar disorder.

Prescription patterns for asthma medications in children and adolescents with health care insurance in the United States.

Asthma is the most common chronic condition of childhood, and its prevalence has increased over recent decades. However, many children and adolescents with asthma are not being managed in accordance with guideline recommendations. The objective of this study was to analyze prescribing patterns for asthma medications in 6- to 18-yr-olds, with a focus on those aged 6-11 yr. Data from patients enrolled for ≥6 months in PharMetrics were analyzed between June 1, 1995, and September 30, 2008. PharMetrics contains data from 45 million US patients from 85 health care plans, including standard and mail order prescription records. Prescriptions for asthma medication for each patient were recorded. The overall asthma cohort included 659,169 patients; 34,950 (5%) were classified as having severe asthma. The 6- to 11-yr-old subgroup consisted of 374,068 patients (56.7% of the overall asthma cohort). Almost 40% of the population received no medication (severe asthma 1.0%; non-severe asthma 37.6%), with almost identical findings in the 6- to 11-yr-old subgroup. In patients with non-severe and severe asthma, frequency of medication use was as follows: short-acting ß(2) -agonists (53% and 92%), oral steroids (23% and 64%), leukotriene receptor antagonists (17% and 49%); inhaled corticosteroids alone (15% and 80%) and in combination with long-acting ß(2) -agonists (10% and 22%), respectively. Results for patients in the 6- to 11-yr subgroup were similar to those of the overall cohort. In conclusion, a considerable proportion of children and adolescents with asthma do not receive any asthma medication. Among those who do receive medication, adherence to current guidelines is questionable.

Lymphoma among patients with atopic dermatitis and/or treated with topical immunosuppressants in the United Kingdom.

BACKGROUND: Atopic dermatitis (AD) has been associated with an increased risk of lymphoma. OBJECTIVES: To assess the risk of lymphoma associated with AD and use of topical corticosteroids (TCS) or topical calcineurin inhibitors (TCI) in a database allowing medical record validation. METHODS: We conducted a nested-case control study using the United Kingdom-based The Health Improvement Network (THIN) database. We excluded patients with established risk factors for lymphoma. Cases of lymphoma were identified and classified after review of the medical records and hospital discharge files. RESULTS: In the study population of 3,500,194 individuals, we identified 2738 cases of lymphoma (1722 non-Hodgkin lymphoma [NHL], 466 Hodgkin disease, 550 indeterminate cases; overall, 188 had cutaneous involvement) and 10,949 matched controls. AD was associated with an increased lymphoma risk (odds ratio [OR], 1.83; 95% CI, 1.41-2.36). In patients with AD referred to a dermatologist, the OR further increased (OR, 3.72; 95% CI, 1.40-9.87). We did not find any cases of lymphoma in TCI users; however, the number of patients exposed to TCI was insufficient to study any possible association between lymphoma and these drugs. TCS use was associated with an increased lymphoma risk (OR, 1.46; 95% CI, 1.33-1.61). The risk increase was dependent on TCS potency (OR for high-potency TCS, 1.80; 95% CI, 1.54-2.11). The increased risk involved both Hodgkin disease and NHL, especially NHL with skin involvement (OR for high-potency TCS, 26.24; 95% CI, 13.49-51.07). CONCLUSION: Our results show an association between lymphoma-especially skin lymphoma-and use of TCS. The risk increased with duration of exposure and potency of TCS.

Discontinuation of antihypertensive drugs among newly diagnosed hypertensive patients in UK general practice.

OBJECTIVES: To evaluate antihypertensive drug discontinuation among newly diagnosed hypertensive patients. METHODS: This was a population-based cohort study using the UK General Practice Research Database (GPRD). Patients newly diagnosed with hypertension between 1991 and 2001 and subsequently treated with antihypertensive drugs were included. Overall antihypertensive drug discontinuation was evaluated from a patient's first-ever antihypertensive prescription. Class-specific discontinuations were evaluated from a patient's first-ever prescriptions of angiotensin-converting enzyme (ACE) inhibitors (ACE-I), alpha antagonists, angiotensin-2 antagonists (AIIA), beta blockers, calcium-channel blockers (CCB), miscellaneous, potassium-sparing diuretics, and thiazides. Discontinuation occurred when no antihypertensive prescription was issued within 90 days following the most recent prescription expiration. RESULTS: The study population comprised 109 454 patients, with 223 228 antihypertensive drug-class episodes contributing to the class-specific analysis. Overall antihypertensive drug discontinuation was 20.3% [95% confidence interval (CI): 20.0, 20.5%] at 6 months and 28.5% (95% CI: 28.2, 28.7%) at 1 year, with a median time to discontinuation of 3.07 years. The median time to antihypertensive class discontinuation was longest for AIIAs (2.90 years) followed by ACE-I (2.24), CCB (1.86), beta blockers (1.50), thiazides (1.50), alpha antagonists (1.35), potassium-sparing diuretics (0.40), and miscellaneous (0.39). One-year discontinuation ranged from 29.4% (95% CI: 28.0, 30.7) for AIIAs to 64.1% (95% CI: 62.1, 66.3) for potassium-sparing diuretics. Forty-four percent who discontinue their first-ever antihypertensive drug class failed to switch to a different drug class within 90 days of discontinuation. CONCLUSION: It is important that general practitioners (GPs) monitor patients closely in the first year following antihypertensive drug initiation, due to the high early risk of discontinuation, and the low percentage of patients who switch to a different antihypertensive drug class after a drug-class discontinuation. AIIA, followed by ACE-I and CCB, had the lowest risk of discontinuation among antihypertensive drug classes.

Infliximab paediatric Crohn's disease educational plan: a European, cross-sectional, multicentre evaluation.

BACKGROUND: The infliximab (Remicade; Schering-Plough, Kenilworth, NJ, USA) Risk Management Plan included the development, execution and tracking of an education programme directed towards prescribers of infliximab for patients with paediatric Crohn's disease (the Infliximab Paediatric Crohn's Disease Educational Plan). The programme content consisted of educational materials and communications aimed at educating prescribers on the risks associated with infliximab use. OBJECTIVE: To evaluate the effectiveness of the risk minimization plan. METHODS: Evaluation focused on two components: documentation of training of sponsors' personnel, and evaluation of awareness among prescribing physicians in European countries. Treating physicians, identified both independently of the sponsor (6 countries) and by the sponsor (24 countries), were surveyed using a structured questionnaire. RESULTS: Training of internal staff on the educational programme was performed and completed by every person designated an appropriate candidate for the programme in all European countries. The independent survey conducted in Germany, France, Italy, Spain, Sweden and the UK indicated that around 90% of the physicians were either paediatric gastroenterologists (57%) or paediatricians (33%). The great majority (96%) of the interviewed physicians were currently treating paediatric Crohn's disease, and most were currently using infliximab in their treatment of the disease. More specifically, 82% of gastroentrologists treating paediatric Crohn's disease were using infliximab; among paediatricians, the proportion was lower (42%). Ninety-six percent of paediatric gastroenterologists or gastroenterologists declared themselves aware of the benefits and risks of using infliximab for the treatment of paediatric Crohn's disease; in comparison, fewer paediatricians (82%) declared themselves aware of these benefits and risks. The majority initially gained awareness through congresses and workshops, and at the time of the survey only 25% declared that they were made aware of the benefits and risks through the educational programme. However, the majority of physicians reported that they had been approached by the sponsor's personnel in France (98%), Italy (100%), Spain (83%) and Sweden (70%). In Germany and the UK this proportion was 42%. Almost all physicians were aware of the need to perform tuberculosis (TB) and cancer screening prior to initiating therapy with infliximab, and to screen for hypersensitivity reactions before, during and after treatment. Ninety percent of the physicians were aware of the need to update immunization therapy before initiating therapy and, except in Italy (92% aware), around 50% of the physicians were aware of the need to provide patients with the infliximab Patient Alert Card. In the other European countries where the survey took place among physicians identified by the sponsor, 99% of paediatric gastroenterologists and 90% of gastroenterologists or paediatricians declared themselves aware of the benefits and risks of using infliximab for the treatment of paediatric Crohn's disease, and all of them were aware of the risk of TB and opportunistic infections and the need to perform TB and cancer screening prior to initiating therapy with infliximab. CONCLUSIONS: Overall, the results of the evaluation of the Infliximab Paediatric Crohn's Disease Educational Plan were satisfactory. The objective of education of internal personnel of the pharmaceutical companies distributing infliximab was completely achieved; over 90% of physicians reported being aware of the benefits and risks of infliximab for the treatment of paediatric Crohn's disease. Further work should be carried out across all countries to educate physicians on providing patients with the infliximab Patient Alert Card. In Germany and the UK in particular, where <50% of physicians reported having been approached by the sponsor's personnel, further work is needed to raise awareness of the educational programme.

Dosage, titration, and gaps in treatment with extended release niacin in clinical practice.

OBJECTIVE: To examine the dosage, titration patterns, and gaps in treatment of newly-initiated ER niacin in clinical practice. RESEARCH DESIGN AND METHODS: Historical cohort study using the Ingenix Lab/Rx database. Patients were at least 20 years old, received an initial, index ER niacin prescription between January 1, 2001 and June 30, 2003, and had no ER niacin use in the preceding 12 months. Follow-up data were collected for at least 6 months after the index date. MAIN OUTCOME MEASURES: Average daily dosage (ADD) and titration patterns of ER niacin therapy at defined time points after the index prescription, and the incidence and timing of continuous gaps of >/=30 days in ER niacin therapy. RESULTS: A total of 14 386 patients initiating ER niacin were followed for a mean of 6.5 months after the index prescription. The ADD of the initial ER niacin prescription was 750 mg. Forty percent of patients experienced a >/=30-day gap in therapy immediately after the first prescription. Almost 80% had at least one >/=30-day gap in therapy during the post-index period, and the ADD of the last prescription prior to discontinuation was /=1000 mg and only 7.6% reached the dose of 2000 mg. CONCLUSIONS: A considerable proportion of new ER niacin users failed to reach recommended daily maintenance dosages in clinical practice. The main limitations of the study include its reliance on administrative data, inability to capture over-the-counter niacin use, and evaluation of reasons for suboptimal titration. Future research should determine the extent to which gaps in ER niacin therapy and failure to titrate to optimal dosages are due to poor tolerability, physician practice, or other factors.

The effect of antihypertensive drugs and drug combinations on the incidence of new-onset type-2 diabetes mellitus.

PURPOSE: To evaluate the effect of antihypertensive drugs on new-onset type-2 diabetes. METHODS: This was a cohort study using the UK General Practice Research Database (GPRD). Patients newly diagnosed with hypertension between 1991 and 2001, and treated with antihypertensive drugs, were included. Type-2 diabetes mellitus was identified based on a physician diagnosis or an anti-diabetic drug prescription. Antihypertensive treatments were classified as: ACE inhibitors (ACE-Is), beta blockers, calcium channel blockers (CCB), thiazides, all other drugs, and their combinations. RESULTS: A total of 2706 incident diabetes cases were identified in 98 629 hypertensive patients during 307 356 patient years (8.8/1000 patient years). New-onset diabetes was lower for ACE-I regimens compared with non-ACE inhibitor regimens (HR = 0.90; 95%CI: 0.82-0.99). CCB monotherapy (HR = 1.27; 95%CI: 1.07-1.51) had an increased risk of diabetes compared with ACE-I monotherapy. ACE-I plus thiazide had the lowest risk of diabetes among double combinations, followed by ACE-I plus beta blocker, and ACE-I plus CCB. Double combinations with an ACE-I had 0.79 (95%CI: 0.67-0.92) times the risk compared with non-ACE inhibitor combinations. The risk of new-onset diabetes was significantly higher for beta blocker plus thiazide (HR = 1.37; 1.10-1.70), CCB plus thiazide (HR = 1.44; 95%CI: 1.13-1.83), but not beta blocker plus CCB (HR = 1.30; 95%CI: 0.99-1.70) compared with ACE-I plus thiazide. CONCLUSIONS: Antihypertensive drug combinations including an ACE-I had a significantly lower risk of new-onset diabetes than antihypertensive drug combinations without an ACE-I.

Risk of lymphoma following exposure to calcineurin inhibitors and topical steroids in patients with atopic dermatitis.

Systemic use of immunosuppressant agents increases the risk of lymphoma in transplantation. We performed a nested case-control study in the PharMetrics database to evaluate the association between topical immunosuppressants and lymphoma in a cohort of patients with atopic dermatitis. We identified cases of lymphoma and randomly selected four controls for each case, matched by length of follow-up. We used conditional logistic regression to calculate odds ratio (OR) and 95% confidence intervals (CIs) of the association between topical immunosuppressants and lymphoma. Two hundred and ninety-four cases of lymphoma occurred in 293,253 patients, 81 in patients younger than 20 years. The adjusted analysis yielded the following OR (95%CI) for: severity (OR 2.4; 95% CI 1.5-3.8), oral steroids 1.5 (1.0-2.4), "super potent" topical steroids 1.2 (0.8-1.8) , "low potency" topical steroids OR 1.1 (0.7-1.6); pimecrolimus 0.8(0.4-1.6), tacrolimus OR 0.8 (0.4-1.7), and concomitant topical steroids, pimecrolimus, and tacrolimus 1.0 (0.3-4.1). We did not find an increased risk of lymphoma in patients treated with topical calcineurin inhibitors. It is difficult to disentangle the effects of severity of disease on outcome versus the true effects of drugs. However, in the adjusted analysis, severity of AD was the main factor associated with an increased risk of lymphoma.

Use of cyclo-oxygenase 2 inhibitors (COX-2) and prescription non-steroidal anti-inflammatory drugs (NSAIDS) in UK and USA populations. Implications for COX-2 cardiovascular profile.

BACKGROUND: COX-2 and NSAIDS differ in their gastrointestinal (GI) and cardiovascular (CV) toxicity from pharmacological, clinical and epidemiologic point of views. OBJECTIVE: Describe the patterns of use of NSAIDS and COX-2 in The Health Improvement Network (THIN) database in UK and the PharMetrics database in USA. METHODS: We examined the experience of 10 distinct cohorts of new users of diclofenac, naproxen, ibuprofen, piroxicam, other NSAIDS, meloxicam, celecoxib, etoricoxib, rofecoxib and valdecoxib. The study period was 1 January 1995 through 2004 (31 March in UK and 28 February in USA). We collected information on covariates including history of upper GI disease, CV disease, hepatic disease, dosage, concomitant medication, and visits to a rheumatologist. RESULTS: We identified 486 076 unique patient-drug pairs in UK and 1 533 239 in USA. In UK population 78 201 (16%) were COX-2 users and in PharMetrics 324 206 (21%) were COX-2 users. Diclofenac and ibuprofen (NSAIDS), and celecoxib and rofecoxib (COX-2) were the agents prescribed most frequently. The duration of therapy was longer among celecoxib and rofecoxib users than among other users. More COX-2 users than NSAIDS users received concomitant gastroprotective agents (GPA), corticosteroids and anti-platelet therapy, and had a history of thromboembolic events and hypertension. PharMetrics patients were prescribed higher doses of NSAIDS and COX-2. The use of any single agent for more than 90 days was uncommon, but more frequent in PharMetrics. Switching was uncommon and was generally to a NSAID. DISCUSSION: Our results confirm some previous findings from other authors such as the presence of both GI and CV channelling to COX-2 agents but refute others, such as the frequency of drug switching between these agents. The typical use of COX-2 agents in practice is for shorter duration, and at lower doses, than was employed in randomized clinical trials. This difference may help clarify the apparent discrepancy with respect to CV toxicity between the results from clinical trials, which showed a higher CV risk with these drugs, and non-experimental epidemiologic studies, which showed lower or no increase in risk.

Mortality of cystic fibrosis patients treated with tobramycin solution for inhalation.

BACKGROUND: Tobramycin solution for inhalation (TOBI; TSI) is indicated to treat patients with cystic fibrosis who are infected with Pseudomonas aeruginosa. Preliminary findings from a randomized trial indicate that patients who received TSI had about half the mortality rate of those assigned to placebo. METHODS: We used the Cystic Fibrosis Foundation registry data to conduct a retrospective cohort study of the risk of death among cystic fibrosis patients in 1999 according to their use of TSI during 1998. We controlled for age, lung function, height and infection with; other factors were not important confounders. RESULTS: The crude risk of death among those who received TSI therapy for 4 or more months was 3.5 times greater than that among those who received no TSI (90% confidence interval = 3.0-4.2). In general, increased TSI use was related to progressive increases in the risk of death. Such a relation is expected because TSI is used for those who are close to death, resulting in strong confounding by indication. After control of the previously mentioned confounders, the estimated risk ratio was reduced from 3.5 to 1.2. Unfortunately, it is difficult to remove confounding by indication in its entirety. Using a method that estimates the magnitude of uncontrolled confounding, we show that the actual relation between TSI and the risk of death is likely to be protective, and may well be consistent with the results from the randomized trial. CONCLUSIONS: These data illustrate strong confounding by indication and the extent to which the interpretation of data can rest on assumptions about the data and its residual biases.