Occurrence of adverse events among patients with inflammatory bowel disease in the HealthCore Integrated Research Database.

OBJECTIVES: Inflammatory bowel disease (IBD) is a chronic condition commonly requiring lifelong care. Both IBD and IBD-related treatments can cause significant morbidity, and it is often difficult to differentiate their relative etiologic contribution to adverse events (AEs). The objectives of this study were to assess the rates of select AEs among patients with IBD as a function of disease severity and of the use of anti-tumor necrosis factor alpha (anti-TNFα) medications. METHODS: We conducted a retrospective cohort study of IBD patients in the HealthCore Integrated Research Database (HIRD(TM)) between January 2004 and January 2011 to determine rates of AEs in patients with mild and moderate to severe IBD. Key study endpoints were select prespecified malignant neoplasms, infections, and other AEs of interest. RESULTS: A total of 33,386 IBD patients (52.7% ulcerative colitis; 47.3% Crohn's disease) met the inclusion criteria, and 60% had been followed for ≥1 year. Patients with moderate to severe IBD had increased rates of infections, lymphatic and digestive tract cancers, gastrointestinal (GI) perforations, and myocardial infarctions versus patients with mild IBD. Patients with IBD who used anti-TNFα therapies during the study had increased incidence of many types of infections, certain GI cancers (including rectal and anal cancer), intestinal perforations, and kidney stones compared with patients who had never used anti-TNFα therapies. CONCLUSIONS: Results from this large US cohort provide descriptive information on AE rates in a population of IBD patients undergoing routine care, estimating background incidence rates of AEs that are not readily available in the published literature. Our study findings may be limited owing to a lack of generalizability and potential for misclassification due to reliance on medical diagnosis and treatment and procedure codes to identify disease, comorbidities, and treatments. Further research and validation of our findings in other populations and databases are needed.

Lessons learned in the conduct of a global, large simple trial of treatments indicated for schizophrenia.

Large, "practical" or streamlined trials (LSTs) are used to study the effectiveness and/or safety of medicines in real world settings with minimal study imposed interventions. While LSTs have benefits over traditional randomized clinical trials and observational studies, there are inherent challenges to their conduct. Enrollment and follow-up of a large study sample of patients with mental illness pose a particular difficulty. To assist in overcoming operational barriers in future LSTs in psychiatry, this paper describes the recruitment and observational follow-up strategies used for the ZODIAC study, an international, open-label LST, which followed 18,239 persons randomly assigned to one of two treatments indicated for schizophrenia for 1 year. ZODIAC enrolled patients in 18 countries in North America, South America, Europe, and Asia using broad study entry criteria and required minimal clinical care intervention. Recruitment of adequate numbers and continued engagement of both study centers and subjects were significant challenges. Strategies implemented to mitigate these in ZODIAC include global study expansion, study branding, field coordinator and site relations programs, monthly site newsletters, collection of alternate contact information, conduct of national death index (NDI) searches, and frequent sponsor, contract research organization (CRO) and site interaction to share best practices and address recruitment challenges quickly. We conclude that conduct of large LSTs in psychiatric patient populations is feasible, but importantly, realistic site recruitment goals and maintaining site engagement are key factors that need to be considered in early study planning and conduct.

Comparative mortality associated with ziprasidone and olanzapine in real-world use among 18,154 patients with schizophrenia: The Ziprasidone Observational Study of Cardiac Outcomes (ZODIAC).

OBJECTIVE: The authors compared 1-year mortality rates associated with ziprasidone and olanzapine in real-world use. METHOD: The Ziprasidone Observational Study of Cardiac Outcomes (ZODIAC) was an open-label, randomized, postmarketing large simple trial that enrolled patients with schizophrenia (N=18,154) in naturalistic practice in 18 countries. The primary outcome measure was nonsuicide mortality in the year after initiation of assigned treatment. Patients were randomly assigned to receive treatment with either ziprasidone or olanzapine and followed for 1 year by unblinded investigators providing usual care. A physician-administered questionnaire was used to collect baseline demographic information, medical and psychiatric history, and concomitant medication use. Follow-up information on hospitalizations and emergency department visits, patients' vital status, and current antipsychotic drug status was collected and reported by treating psychiatrists. Post hoc analyses of sudden death, a secondary endpoint, were also conducted. RESULTS: The incidence of nonsuicide mortality within 1 year of initiating pharmacotherapy was 0.91 for ziprasidone (N=9,077) and 0.90 for olanzapine (N=9,077). The relative risk was 1.02 (95% CI=0.76-1.39). This finding was confirmed in numerous secondary and sensitivity analyses. CONCLUSIONS: Despite the known risk of QTc prolongation with ziprasidone treatment, the findings of this study failed to show that ziprasidone is associated with an elevated risk of nonsuicidal mortality relative to olanzapine in real-world use; the study excludes a relative risk larger than 1.39 with a high probability. However, the study was neither powered nor designed to examine the risk of rare events like torsade de pointes.

The Ziprasidone Observational Study of Cardiac Outcomes (ZODIAC): design and baseline subject characteristics.

BACKGROUND: Ziprasidone has been used to treat schizophrenia since 2000. It is unknown whether its modest QTc-prolonging effect increases cardiovascular event risk. PURPOSE: To describe the study design of the Ziprasidone Observational Study of Cardiac Outcomes (ZODIAC). METHOD: The study was conducted between February 2002 and February 2006. One-year follow-up for the primary endpoint of nonsuicide death ended in April 2007. ZODIAC is an open-label, randomized, postmarketing study enrolling patients with schizophrenia in naturalistic practice in 18 countries. The primary outcome measure was the rate of nonsuicide mortality in the year after initial recommendation for therapy. Subjects were randomly assigned to either ziprasidone or olanzapine, after which follow-up was conducted by investigators aware of the assigned exposure. A physician-administered questionnaire collected baseline information on patients' demographics, medical and psychiatric history, and concomitant medication use. Data were self-reported by patients or reported by enrolling physicians. RESULTS: ZODIAC enrolled 18,240 patients with schizophrenia. Most (73.0%) were from the United States or Brazil. Patients' baseline mean age was 41.6 years, 55.1% were male, and 60.0% were white. At baseline, approximately 18% had hypertension, 14.8% had hyperlipidemia, 46.5% currently smoked, 28.9% had a body mass index >or= 30 kg/m(2), and 7.7% had diabetes. Mean time from schizophrenia diagnosis to study enrollment was 10.4 years and mean Clinical Global Impressions scale score was 5.2 (range: 1-8). Nearly one third of patients had ever attempted suicide. Seventy-one percent were using antipsychotics at baseline. Almost 80% were using concomitant medications, with 29.5% using antidepressants, 25.4% using anxiolytics, and 19.0% using mood stabilizers. Less than 3% were using antihypertensives or statins. CONCLUSIONS: ZODIAC is a uniquely designed study with an initial randomization to ziprasidone or olanzapine and follow-up largely consistent with usual practice (i.e., many characteristics of a nonexperimental study). Baseline data suggest this study population has a substantial prevalence of cardiovascular risk factors. Concomitant medications were used frequently, although hyperlipidemia and hypertension may be undertreated. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00174447.

Incidence of allergic reactions associated with antibacterial use in a large, managed care organisation.

BACKGROUND: Data on the incidence of serious allergic reactions to fluoroquinolone antibacterials are mainly derived from spontaneous reports that cannot be used to accurately estimate incidence. METHODS: This study estimated the drug-specific incidence of serious allergic reactions after fluoroquinolone, cephalosporin and phenoxymethylpenicillin potassium exposure, using claims for healthcare services with confirmation through medical record abstraction within a large health insurer database. Cohorts exposed to each antibacterial of interest (moxifloxacin, levofloxacin, ciprofloxacin, gatifloxacin, cephalosporins and penicillin) were identified, and followed for 14 days for anaphylaxis (9th revision of the International Classification of Diseases [ICD-9] code 995.0), other allergic drug reactions (ICD-9 995.2, 995.3) or cardiopulmonary resuscitation. RESULTS: The incidence per 10,000 first dispensings of any allergic diagnosis made in the hospital or emergency department was similar for moxifloxacin (4.3; 95% CI 3.5, 5.3), penicillin (4.7; 95% CI 3.8, 5.7) and ciprofloxacin (5.4; 95% CI 4.4, 6.5). The incidence for moxifloxacin was lower than that for levofloxacin (8.7; 95% CI 7.4, 10.0), gatifloxacin (6.7; 95% CI 5.6, 7.9) and the cephalosporins (7.5; 95% CI 6.3, 8.8). The incidence of anaphylaxis/anaphylactoid reactions after first dispensings was similar for the fluoroquinolones: 0.1 (95% CI 0.0, 0.3) for ciprofloxacin, 0.3 (95% CI 0.1, 0.5) for moxifloxacin, 0.3 (95% CI 0.1, 0.6) for gatifloxacin and 0.5 (95% CI 0.3, 0.9) for levofloxacin; and comparable with that of the cephalosporins (0.2; 95% CI 0.0, 0.4) and penicillin (0.1; 95% CI 0.0, 0.3). CONCLUSIONS: Anaphylactic reactions were rare and their incidence did not differ substantially among the drug groups studied. By determining the occurrence of reactions following defined exposures, these results provide a context for the interpretation of spontaneous reports of allergic reactions.

Administration of parenteral iron and mortality among hemodialysis patients.

The objective of this study was to evaluate whether the apparent relationship demonstrated in prior studies between iron dosing and mortality in hemodialysis (HD) patients was confounded by incomplete representation of iron dosing and morbidity over time. A cohort study was conducted among 32,566 patients who received at least 1 yr of HD at the Fresenius Medical Corporation dialysis centers during 1996 to 1997. The outcome measure was all-cause mortality through mid-1998. A total of 19 demographic, comorbidity, and laboratory characteristics were available. By proportional hazards analysis, no adverse effect on 2-year survival was found for baseline iron dose over 6 mo of < or = 1000 mg, but statistically significant elevated mortality was demonstrated for iron doses >1000 mg to 1800 mg (adjusted hazards ratio [HR] = 1.09; 95% confidence interval [CI], 1.01 to 1.17) and >1800 mg (adjusted HR = 1.18; 95% CI, 1.09 to 1.27). However, fitting multivariable models that appropriately account for time-varying measures of iron administration as well as other fixed and time-varying measures of morbidity, the authors found no statistically significant association between any level of iron administration and mortality. This study suggests that previously observed associations between iron administration and higher mortality may have been confounded, and it provides cautious support for the safety of the judicious administration of cumulative iron doses >1000 mg over 6 mo if needed to maintain target hemoglobin levels among patients treated with maintenance HD.

Clinical experience with moxifloxacin in patients with respiratory tract infections.

BACKGROUND: Moxifloxacin is an advanced-generation fluoroquinolone used primarily for the treatment of respiratory tract infections. OBJECTIVE: To further investigate moxifloxacin's general and cardiac safety and evaluate its efficacy in the community practice setting in a large surveillance study. METHODS: A total of 18,409 outpatients with suspected bacterial episodes of acute sinusitis, acute exacerbation of chronic bronchitis, or community-acquired pneumonia of mild to moderate severity were enrolled at 3377 community practice sites. Patients with sinusitis or pneumonia received once-daily oral moxifloxacin 400 mg for 10 days; those with bronchitis received 5 days' treatment. At follow-up, within 48 hours after the end of treatment, adverse event information was collected. An external safety committee assessed possible cardiac-related events. Efficacy was also evaluated at follow-up via the degree of resolution of clinical signs and symptoms. RESULTS: Of 18,374 safety-valid patients, 17.7% experienced adverse events and 14.3% experienced drug-related adverse events. The most common drug-related adverse events were nausea (5.3%), diarrhea (2.2%), and dizziness (2.0%). There was no clinical evidence of increased risk of cardiac arrhythmias with moxifloxacin treatment. Of 17,137 patients included in the efficacy analysis, 92.9% overall experienced clinical cure or improvement (92.8% with sinusitis, 92.9% with bronchitis, 94.1% with pneumonia). CONCLUSIONS: Once-daily oral moxifloxacin 400 mg was shown to be safe and effective in this trial for the treatment of respiratory tract infections of suspected bacterial origin in the clinical practice setting.

Cardiovascular thrombotic events in arthritis trials of the cyclooxygenase-2 inhibitor celecoxib.

To determine whether the cyclooxygenase-2 (COX-2) inhibitor celecoxib affects cardiovascular thrombotic risk, we analyzed the incidence of cardiovascular events for celecoxib, placebo, and nonsteroidal anti-inflammatory drugs (NSAIDs) in the entire controlled, arthritis clinical trial database for celecoxib. The primary analysis used the Antiplatelet Trialists' Collaboration end points, which include: (1) cardiovascular, hemorrhagic, and unknown deaths, (2) nonfatal myocardial infarction, and (3) nonfatal stroke. Other secondary thrombotic events were also examined. Separate analyses were performed for all patients and for those not taking aspirin. Data from all controlled, completed arthritis trials of > or =4 weeks duration, including 13 new drug application studies and 2 large post-marketing trials (CLASS and SUCCESS) were included for analyses. Patients were randomized to celecoxib at doses from 100 to 400 mg twice daily (18,942 patients; 5,668.2 patient-years of exposure), diclofenac 50 to 75 mg twice daily, ibuprofen 800 mg thrice daily, naproxen 500 mg twice daily (combined NSAID exposure of 11,143 patients; 3,612.2 patient-years), or placebo (1,794 subjects; 199.9 subject-years). Data from a long-term uncontrolled trial with 5,209 patients (6,950 patients-years) treated with celecoxib were included in a supplemental analysis. The entire 15-trial database was searched for possible serious thrombotic events as well as to identify all deaths. For these patients, detailed clinical data were obtained and reviewed by 2 of the investigators (WBW and JSB), who were independently and blinded to exposure, to classify the event as primary, secondary, or neither. All analyses were done using the intent-to-treat population, and time-to-event analyses were performed using per-patient data. To examine heterogeneity of results among studies, tests of interaction were performed using the Cox model. Incidences of the primary and secondary events were not significantly different between the celecoxib and placebo groups, nor for the celecoxib group compared with the NSAIDs group, regardless of aspirin use and NSAID type. The relative risks comparing celecoxib with the NSAIDs for the primary events were 1.06 (95% confidence interval 0.70 to 1.61, p = 0.79) for all patients, and 0.86 (95% confidence interval 0.48 to 1.56, p = 0.62) for the subgroup not taking aspirin. Similarly, for secondary cardiovascular end points, all relative risks were < or =1 for celecoxib compared with either placebo or NSAIDs. These comparative analyses demonstrate no evidence of increased risk of cardiovascular thrombotic events associated with celecoxib compared with either conventional NSAIDs or placebo.

Iron administration and clinical outcomes in hemodialysis patients.

To evaluate the impact of parenteral iron administration on the survival and rate of hospitalization of US hemodialysis patients, a nonconcurrent cohort study of 10,169 hemodialysis patients in the United States in 1994 was conducted. The main outcome measures were patient survival and rate of hospitalization. After adjusting for 23 demographic and comorbidity characteristics among 5833 patients included in multivariable analysis, bills for 10 vials showed a statistically significant elevated rate of death (adjusted RR = 1.11; 95% CI, 1.00 to 1.24; P = 0.05). Bills for 10 vials showed statistically significant elevated risk (adjusted RR = 1.12; 95% CI, 1.01 to 1.25; P = 0.03). Prescribing iron in quantities of 10 vials (1000 mg) of iron dextran over a period of 6 mo.

Comparison of thromboembolic events in patients treated with celecoxib, a cyclooxygenase-2 specific inhibitor, versus ibuprofen or diclofenac.

It has been hypothesized that cyclooxygenase 2 specific inhibitors may increase the risk of cardiovascular (CV) thromboembolic events because of their inhibition of vascular prostacyclin synthesis and lack of an effect on platelet thromboxane A(2) production and aggregation. Thus, we analyzed the data for celecoxib and nonsteroidal anti-inflammatory drugs (NSAIDs) from the Celecoxib Long-term Arthritis Safety Study to determine the incidences of serious CV thromboembolic events. This trial included 3,987 persons randomized to celecoxib 400 mg twice daily (2,320 person-years of exposure) and 3,981 persons randomized to either ibuprofen 800 mg 3 times daily or diclofenac 75 mg twice daily (2,203 person-years). Because acetylsalicylic acid (ASA) use for CV risk prophylaxis (< or =325 mg/day) was permitted, separate analyses were performed for all patients and those not taking ASA. The incidences of serious CV thromboembolic events (myocardial infarction, stroke, CV deaths, and peripheral events) were similar, and not significantly different, between celecoxib and NSAID comparators (combined or individually) for all patients as well as the subgroup of patients not taking ASA. This observation was true both for all serious CV thromboembolic events, as well as for individual events. No increase in myocardial infarction was apparent, even in patients not taking ASA who were candidates for secondary prophylaxis for myocardial infarction. The relative risks for celecoxib versus NSAIDs for serious CV thromboembolic events were 1.1 for all patients and 1.1 for the subgroup of patients not taking ASA (95% confidence interval 0.7 to 1.6 and 0.6 to 1.9, respectively). In addition, the incidences of adverse CV events such as hypertension, edema, and congestive heart failure were similar to, or significantly lower than, NSAID comparators regardless of the use of ASA. Thus, these analyses demonstrate no increased risk of serious CV thromboembolic events associated with celecoxib compared with conventional NSAIDs and therefore do not support the hypothesis of a class adverse effect of cyclooxygenase 2 specific inhibitors on the CV system.

Tendencias de la disentería de shiga en el Salvador, 1969-1973 / The rise and fall of shiga dysentery in El Salvador, 1969-1973

En julio de 1969 surgió en el Salvador una gran epidemia de disentería de shiga, que llegó al máximo en julio de 1970 y luego descendió rápidamente a niveles casi endémicos en 1973. Los casos registrados excedieron de 197,000, con unas 11,750 defunciones