Comparative safety of long-acting inhaled bronchodilators: a cohort study using the UK THIN primary care database.

BACKGROUND: Use of a long-acting inhaled bronchodilator, either an anticholinergic or a beta-adrenergic receptor agonist (beta-agonist), is recommended for maintenance treatment of chronic obstructive pulmonary disease (COPD). In COPD, the organ system most frequently requiring medical care, other than the respiratory system, is the cardiac system. OBJECTIVES: To compare the risk of total mortality and certain respiratory and cardiac adverse events among users of the two types of recommended long-acting bronchodilators, we conducted a cohort study. Specifically, the study compared the safety of the only approved long-acting anticholinergic, tiotropium bromide, with the single-ingredient long-acting beta-agonists (LABAs) salmeterol or formoterol in a broad population of users. METHODS: We used automated general practitioner data from the UK THIN (The Health Information Network) database as the data source for this study. We used Cox proportional hazards models to compute hazard ratio (HR) estimates and 95% CI controlling for propensity scores comprising various baseline demographic variables, medical therapies and illnesses. RESULTS: The 1061 tiotropium users and 1801 LABA users were similar with regard to risk of total mortality (HR 0.93; 95% CI 0.59, 1.44) and most cardiac events, including angina (HR 0.77; 95% CI 0.37, 1.59), atrial fibrillation or flutter (HR 0.60; 95% CI 0.25, 1.42), myocardial infarction (HR 1.29; 95% CI 0.45, 3.66) and tachycardia (HR 0.66; 95% CI 0.29, 1.51). Though imprecise, there was evidence of a decreased risk of heart failure (HR 0.65; 95% CI 0.37, 1.12) in tiotropium users. As regards respiratory endpoints, the risk of COPD exacerbation (HR 1.15; 95% CI 0.79, 1.67) and pneumonia (HR 1.11; 95% CI 0.38, 3.26) were similar among users of each type of drug, although there was a decreased risk of asthma exacerbation (HR 0.41; 95% CI 0.26, 0.64) in tiotropium users compared with LABA users. CONCLUSIONS: Users of tiotropium and single-ingredient LABA had similar risk of total mortality and cardiovascular endpoints. The decreased risk of asthma exacerbations with tiotropium may be due to residual confounding by indication. Confidence limits for most events include reduced risks for tiotropium and also small increases in risk. Nevertheless, the point estimates suggest that tiotropium was associated with a lower risk of each cardiac event except myocardial infarction. However, the small number of cases means that further studies are needed to confirm these results.

Pooled clinical trial analysis of tiotropium safety.

BACKGROUND: Marketing approval of pharmaceutical products is often based on data from several thousand subjects or fewer. Evaluation of safety is greatly enhanced by augmenting the safety database with postapproval studies. METHODS: We conducted a pooled analysis of adverse event data from 19 randomized, double-blind, placebo-controlled trials with tiotropium in patients with obstructive lung disease. We computed incidence rates and rate ratios (RRs) for various reported adverse event end points of interest. Patients contributed person-time to the analysis as long as they were in the study until 30 days after treatment (tiotropium, placebo), or until they had the event of interest, whichever came first. Studies were pooled using the Mantel-Haenszel estimator, and we used 95% confidence intervals (CIs) to assess the precision of effect estimates. RESULTS: The pooled trial population includes 4,435 tiotropium patients and 3,384 placebo patients contributing 2,159 person-years of exposure to tiotropium and 1,662 person-years of exposure to placebo. Dyspnea, dry mouth, COPD exacerbation, and upper respiratory tract infection were the most commonly reported events. There was a higher relative risk of dry mouth in the tiotropium group (RR, 3.60; 95% CI, 2.56 to 5.05). There was a lower risk of dyspnea (RR, 0.64; 95% CI, 0.50 to 0.81) and COPD exacerbation (RR, 0.72; 95% CI, 0.64 to 0.82) in patients receiving tiotropium compared to patients receiving placebo. Other results of interest are as follows: (1) all-cause mortality (RR, 0.76; 95% CI, 0.50 to 1.16); (2) cardiovascular mortality (RR, 0.57; 95% CI, 0.26 to 1.26); and (3) respiratory mortality (RR, 0.71; 95% CI, 0.29 to 1.74). The relative risk of urinary retention was 10.93 (95% CI, 1.26 to 94.88). CONCLUSIONS: Pooling of adverse event data from preapproval and postapproval tiotropium clinical trials increase the precision of effect estimates and supports the present safety profile of tiotropium.

Diagnostic evaluation for Creutzfeldt-Jakob disease in Massachusetts, 1991-2001.

BACKGROUND: Surveillance for Creutzfeldt-Jakob disease (CJD) in the United States has become a focus of public health attention due to concerns about disease acquired through exposure to transmissible spongiform encephalopathy in other species. A definitive diagnosis requires neuropathologic examination, yet concerns about the invasiveness of procedures and infection control may be barriers to brain biopsy or autopsy in patients with suspected CJD. METHODS: We reviewed medical records of 50 of the 97 patients identified through the Massachusetts Department of Public Health CJD surveillance system for 1991-2001 and of an additional 21 patients in whom CJD was suspected but later ruled out. RESULTS: Of the 50 patients, brain biopsy was performed on 14 (28%), brain biopsy or autopsy was performed on 27 (54%), and brain biopsy and autopsy were performed on 4 (8%). Brain biopsy or autopsy was declined for an additional 7 patients (14%) by family or health care proxy. The proportion of patients on whom brain biopsy was performed was inversely correlated with age, with only 9 (21%) of the 43 patients >60 years old having brain tissue diagnosis. Brain biopsy was performed on patients in whom CJD was suspected but ruled out somewhat less often than it was for patients with confirmed CJD (4 [19%] of 21 patients vs. 7 [23%] of 30 patients, respectively; P=.71). CONCLUSION: The majority of patients with CJD-related death whose medical records were available had a brain biopsy or autopsy performed or requested (34 [68%] of 50 patients).

Prescriber utilization of dalfampridine extended release tablets in multiple sclerosis: a retrospective pharmacy and medical claims analysis.

PURPOSE: This study aimed to characterize the prescribing of dalfampridine extended release (D-ER) 10 mg tablet treatment in people with multiple sclerosis (MS). METHODS: A retrospective cohort study was performed using Medco pharmacy and medical claims. Medical claims were used to identify MS patients with more than one prescription for D-ER with 1 year of prior continuous enrollment (n=704). These patients were matched 2:1 on age, sex, and health insurance source with a comparison group of MS patients who were treatment naïve for D-ER (n=1,403). Categorical data were analyzed by χ (2) test; ordinal data by Wilcoxon rank sum test; and continuous data by Student's t-test. RESULTS: Most patients were women aged 45-64 years. In the year preceding D-ER initiation, the prevalence of seizure and renal impairment was numerically lower in the D-ER cohort relative to those who were D-ER naïve (seizure: 3.1% versus 4.7%, respectively; renal impairment: 4.3% versus 5.1%, respectively); however, prescriptions for antiepileptic drugs in the two cohorts were comparable. In the year preceding treatment initiation, 62% of the D-ER cohort was prescribed MS-specific disease-modifying therapies relative to 45% who were D-ER naïve. CONCLUSION: Seizure and renal impairment rates among D-ER-naïve patients were consistent with published literature, yet rates among those prescribed D-ER during the year preceding treatment initiation were slightly lower than rates among D-ER-naïve patients. Given that D-ER is contraindicated in patients with history of seizure or moderate or severe renal impairment, lower rates may indicate that risk-minimization strategies contributed to the lower prevalence.

Safety profile of dalfampridine extended release in multiple sclerosis: 5-year postmarketing experience in the United States.

BACKGROUND: Dalfampridine extended release tablets (dalfampridine-ER; prolonged-, modified, or sustained-release fampridine outside the US), 10 mg twice daily, was approved by the US Food and Drug Administration (FDA) in January 2010 to improve walking in people with multiple sclerosis, as determined by an increase in walking speed. OBJECTIVE: To provide a descriptive analysis of reported adverse events (AEs) for commercially available dalfampridine-ER from March 2010 through March 31, 2015. METHODS: Five-year postmarketing data for dalfampridine-ER were available from the exposure of approximately 107,000 patients in the US (103,700 patient-years). Commonly reported AEs (≥2% of all reported AEs) and serious AEs were determined. The incidence of reported seizures was determined and the events were further investigated. RESULTS: Among the 107,000 patients exposed to dalfampridine-ER (70% female; mean age 52.1), the most common AEs were dizziness (3.7%), insomnia (3.2%), balance disorder (3%), fall (2.4%), headache (2.4%), nausea (2.1%), and urinary tract infection (2%). Other common AEs were drug ineffectiveness (5.8%), gait disturbance (4.6%), and inappropriate dosing (3.1%). Serious AEs included rare anaphylactic reactions (five cases) and drug hypersensitivity reactions (eight cases). A total of 657 seizure cases were reported (6.3/1,000 patient-years); of these, 324 were medically confirmed (3.1/1,000 patient-years). Incidence of reported seizures was stable over time. Duration of treatment prior to a seizure ranged from a single dose to >4 years; 12% of the seizures occurred within a week of starting treatment. CONCLUSION: The 5-year US postmarketing safety data of dalfampridine-ER is consistent with the safety profile observed in clinical trials. Incidence of reported seizures remained stable over time. Since commercial availability in March 2010, a warning regarding the risk of anaphylaxis and severe allergic reactions was added to the US prescribing information.

The reliability of passively collected AIDS surveillance data in Massachusetts.

PURPOSE: To determine the reliability of demographic, clinical, and treatment information collected during routine AIDS surveillance. METHODS: Information from the medical records of a random sample of 212 AIDS cases reported to the Massachusetts Department of Public Health between November 1993 and November 1994 was compared with that from the original case reports. We assessed levels of agreement by calculating overall percent agreement and kappa statistics with 95% confidence limits. We used an intraclass correlation coefficient to compare the CD4+ lymphocyte count reported from the two sources. RESULTS: There was excellent agreement for gender (kappa = 0.97) and race (kappa = 0.87). Agreement was lower for transmission mode (kappa = 0.73), CD4+ cell count (ICC = 0.76) and category of AIDS case definition (kappa = 0.59). There was poor agreement for use of antiretrovirals (kappa = 0.23), use of prophylaxis for Pneumocystis carinii pneumonia (kappa = 0.12) and vital status (kappa = 0.22). The month and year of diagnosis agreed in only 55% of cases reviewed. CONCLUSIONS: Routine AIDS surveillance data was reliable for demographic variables, but less reliable for information about clinical events, laboratory findings, or treatment. Future AIDS surveillance efforts should improve the collection of these data by using sources where this information is more reliable.

Dalfampridine extended release tablets: 1 year of postmarketing safety experience in the US.

BACKGROUND: Dalfampridine extended release tablets (dalfampridine-ER; prolonged-, modified, or sustained-release fampridine in some countries) were approved in the US to improve walking in patients with multiple sclerosis, as demonstrated by improvement in walking speed. Postmarketing safety experience is available from exposure of approximately 46,000 patients in the US from product approval through March 2011. OBJECTIVE: To provide a descriptive analysis of all spontaneously reported postmarketing adverse events (AEs) for dalfampridine-ER since product launch. METHODS: AE data were extracted from the safety database from product launch through March 31, 2011; AEs were classified using the Medical Dictionary for Regulatory Activities. Seizure cases were reviewed for patient demographics, time to event from treatment onset, and presence of additional risk factors. RESULTS: THE MOST FREQUENTLY REPORTED POSTMARKETING AES WERE SIMILAR TO THOSE REPORTED DURING CLINICAL DEVELOPMENT: dizziness, insomnia, balance disorder, headache, nausea, urinary tract infection, asthenia, and back pain (all included in US product labeling). New clinically significant findings are related to lack of efficacy and inappropriate dosing. Of the approximately 46,000 patients exposed, 85 seizures were reported (∼5.4/1000 patient-years), of which 82 were reported or confirmed by a health care practitioner (∼5.2/1000 patient-years). Beyond the intrinsic multiple sclerosis-related seizure risk, more than half of the 85 cases (62%) had an additional potential risk factor for seizure including a previous history of convulsions, renal impairment, incorrect dosing, or use of concurrent medications with a labeled seizure risk. Duration of treatment prior to the seizure ranged from one dose to 365 days; 26/85 (31%) patients suffered a seizure within a week of starting treatment. CONCLUSION: Spontaneous safety data from the US postmarketing experience were consistent with the safety profile seen during clinical development. Although first-year seizure incidence was not substantially different from that observed in dalfampridine-ER clinical trials, patients should be monitored for concomitant use of drugs that lower seizure threshold.

A new user cohort study comparing the safety of long-acting inhaled bronchodilators in COPD.

OBJECTIVE: To investigate a possible increased risk observed in tiotropium clinical trials of stroke and other adverse events. DESIGN: New users of long-acting anticholinergic therapy (tiotropium HandiHaler®) were compared with new users of long-acting ß-agonist (LABA) monotherapy, and propensity scores were used to control confounding. SETTING: UK healthcare system general practitioner electronic medical record database. PARTICIPANTS: 10 840 patients newly prescribed tiotropium (n=4767) or LABA (n=6073), at least 40 years old, and not having asthma as their only respiratory illness. PRIMARY AND SECONDARY OUTCOME MEASURES: Incidence rates of total stroke, myocardial infarction, angina and other adverse events. RESULTS: Tiotropium was associated with increased rates of stroke (HR=1.49, 95% CI 0.91 to 2.45), angina (HR=1.38, 95% CI 0.88 to 2.16) and myocardial infarction (HR=1.26, 95% CI 0.72 to 2.21). Groups had similar rates of chronic obstructive pulmonary disease exacerbation (HR=0.95, 95% CI 0.80 to 1.12) and pneumonia (HR=0.96, 95% CI 0.58 to 1.58). Tiotropium was associated with a lower rate of total mortality (HR=0.70, 95% CI 0.56 to 0.89) and asthma exacerbations (HR=0.46, 95% CI 0.36 to 0.57) than users of LABA. CONCLUSION: Small increased risks of serious ischaemic cardiovascular events have been reported with inhaled anticholinergic medication from randomised and nonrandomized studies of ipratropium, tiotropium HandiHaler® and tiotropium Respimat®. Additional research is needed to understand the full extent of cardiovascular effects of inhaled anticholinergic medications and the patients who may be most susceptible.

Estimating effects from randomized trials with discontinuations: the need for intent-to-treat design and G-estimation.

BACKGROUND: Randomized trials provide pivotal evidence for evaluation and approval of therapies. Nonetheless, such trials are often plagued by noncompliance, especially in the form of premature discontinuation of treatment. While intent-to-treat (ITT) analysis can provide valid tests of no-effect hypotheses, some trials may make ITT analysis impossible by ceasing follow-up when patients go off assigned treatment. Furthermore, estimates based on ITT, on-treatment, or per-protocol comparisons can seriously understate harm or benefit. PURPOSE: To show how g-estimation based on randomization status is a natural generalization of ITT null testing to estimating efficacy from trials with important discontinuation or noncompliance. METHODS: We contrast with an analysis of the effect of a tiotropium inhaler on the occurrence of chronic obstructive pulmonary disease (COPD) events in a six-month double-blind placebo-controlled trial of 1829 patients with good but imperfect compliance. RESULTS: The covariate-adjusted point estimates, 95% confidence limits (CL), and null P-values comparing expected COPD event times in placebo versus tiotropium patients were: ITT, 1.21, CL = 1.02, 1.43, P = 0.027; on-treatment, 1.27, CL = 1.06, 1.52, P = 0.009; per-protocol, 1.36, CL = 1.13, 1.63, P = 0.001; and g-estimation, 1.31, CL = 1.03,1.72, P = 0.027. Thus g-estimation preserved the ITT test of the null, but exhibited more uncertainty about the size of the tiotropium effect than the other methods. In particular, it allowed for a much larger potential effect than did ITT analysis, but produced a much larger null P than exhibited by per-protocol analysis. LIMITATIONS: Like ITT analysis, g-estimation requires all patients be followed to the end of the trial protocol, regardless of whether they comply with the protocol. Like on-treatment and per-protocol analyses, it also requires accurate compliance information be recorded. CONCLUSION: G-estimation should become a standard procedure for the analysis of trials with noncompliance. Software to do so is available in major packages, and the procedure is easily coded for other packages.