Safety of saxagliptin: rationale for and design of a series of postmarketing observational studies.

PURPOSE: To describe the design and rationale of a series of postmarketing studies to examine the safety of saxagliptin, an oral dipeptidyl peptidase-4 inhibitor for the treatment of type 2 diabetes mellitus, in real-world settings. METHODS: We are conducting a series of retrospective cohort studies using two UK (General Practice Research Database, and The Health Improvement Network) and two US (Medicare, HealthCore Integrated Research Database(SM) ) data sources. The primary outcomes of interest will include (i) hospitalization with acute liver failure, (ii) hospitalization for acute kidney injury, (iii) hospitalization for severe hypersensitivity reactions, (iv) hospitalization for severe infections, (v) hospitalization with infections associated with T-lymphocyte dysfunction (i.e., herpes zoster, tuberculosis, or nontuberculous mycobacteria), and (vi) major cardiovascular events. Diagnosis codes for the outcomes of interest will be validated by medical record review within each data source. Projected use and estimated incidence rates of outcomes of interest suggest there will be at least 80% statistical power to detect a minimum hazard ratio of 1.5 for major cardiovascular events, 2.0 for acute kidney injury and severe infections, 2.4 for acute liver failure, and 4.0 for severe hypersensitivity reactions. RESULTS: Forthcoming. CONCLUSIONS: This postmarketing safety assessment will provide important information regarding the safety of saxagliptin and could potentially identify important dipeptidyl peptidase-4 inhibitor class effects. The methods described may be useful to others planning similar evaluations.

Effectiveness of rosuvastatin compared to other statins for the prevention of cardiovascular events-a cohort study in 395 039 patients from clinical practice.

PURPOSE: This study compared the effectiveness of rosuvastatin (RSV) to other statins prescribed in clinical practice in prevention of cardiovascular (CV) events. METHODS: This longitudinal inception cohort study, using Thomson Healthcare's MarketScan databases, included patients aged > or = 18 starting statin therapy during August 2003-December 2005. Patients were followed until 90 days after index statin monotherapy exposure, start of another lipid-lowering therapy, an event, end of eligibility, or end of study. The primary endpoint was a composite of CV death (in-hospital only), myocardial infarction, unstable angina, coronary revascularization, stroke, and carotid revascularization. Adjusted time-to-event analyses incorporating a propensity score covariate were used, and analyses were stratified by duration of statin exposure. RESULTS: Among 395 039 patients who met inclusion/exclusion criteria, 12% initiated RSV, and 9622 (2.4%) of the total patient population experienced an outcome event. The median duration of statin treatment and follow-up was 100 days and 180 days, respectively. No statistically significant difference in CV event rates between RSV and other statins was observed after adjustment for demographics and medical/prescription history (HR = 0.99, 95%CI = 0.93-1.06). However, with longer exposure time, there was a suggestion of increased benefit with RSV compared to other statins. CONCLUSIONS: The primary analysis showed similar incidence rates of CV-related events between the statin cohorts over a median of 180 days of follow-up.

Estimating the Prevalence of Binge Eating Disorder in a Community Sample From the United States: Comparing DSM-IV-TR and DSM-5 Criteria.

OBJECTIVE: To estimate binge eating disorder (BED) prevalence according to DSM-5 and DSM-IV-TR criteria in US adults and to estimate the proportion of individuals meeting DSM-5 BED criteria who reported being formally diagnosed. METHODS: A representative sample of US adults who participated in the National Health and Wellness Survey were asked to respond to an Internet survey (conducted in October 2013). Assessments included 3-month, 12-month, and lifetime BED prevalence based on DSM-5 and DSM-IV-TR criteria and demographics, psychiatric comorbidities, and self-esteem (Rosenberg Self-Esteem Scale). Descriptive statistics are provided. Prevalence estimates were calculated using poststratification sampling weights. RESULTS: Of 22,397 respondents, 344 (women, n = 242; men, n = 102) self-reported symptoms consistent with DSM-5 BED symptom criteria. The 3-month, 12-month, and lifetime DSM-5 prevalence estimates (95% CIs) projected to the US population were 1.19% (1.04%-1.37%), 1.64% (1.45%-1.85%), and 2.03% (1.83%-2.26%), respectively. The 12-month and lifetime projected DSM-IV-TR prevalence estimates were 1.15% (1.00%-1.32%) and 1.52% (1.35%-1.70%), respectively. Of respondents meeting DSM-5 BED criteria in the past 12 months, 3.2% (11/344) reported receiving a formal diagnosis. Compared with non-BED respondents, respondents meeting DSM-5 BED criteria in the past 12 months were younger (mean ± SD age = 46.01 ± 14.32 vs 51.59 ± 15.80 years; P < .001), had a higher body mass index (mean ± SD = 33.71 ± 9.36 vs 27.96 ± 6.68 kg/m²; P < .001), and had lower self-esteem (mean ± SD score = 16.47 ± 6.99 vs 23.33 ± 6.06; P < .001). CONCLUSIONS: DSM-5 BED criteria resulted in higher BED prevalence estimates than with DSM-IV-TR criteria. Most BED respondents did not report being formally diagnosed, indicating an unmet need in BED recognition and diagnosis.

Cardiovascular reactivity to work stress predicts subsequent onset of hypertension: the Air Traffic Controller Health Change Study.

OBJECTIVE: The hypothesis that increased blood pressure reactivity to stress is an early risk marker of hypertension was tested in a 1994 follow-up of the 1974 to 1978 Air Traffic Controller Health Change Study sample. METHODS: Assessments in 1974 to 1978 included physical examinations and recordings (every 20 minutes for 5 hours) of both workload (planes within controller airspace) and blood pressure reactivity. Individual differences in reactivity were used to predict 1994 self-report of ever having been told by a physician to take antihypertensive medication, assessed in a telephone survey of 218 respondents who were normotensive or stage 1 hypertensive in 1974 to 1978. RESULTS: Each SD increase in baseline systolic reactivity was associated with a 1.7 (p <.019) increase in the relative-odds of 1994 hypertension, after controlling for age, body mass index, and clinic systolic and diastolic blood pressure at clinical examination, with effects comparable for baseline normotensives and stage 1 hypertensives. CONCLUSION: A 20-year follow-up of originally normotensive and stage I hypertensive workers suggests that increased systolic blood pressure reactivity to work stress is associated with long-term risk of hypertension.

Incidence and duration of side effects and those rated as bothersome with selective serotonin reuptake inhibitor treatment for depression: patient report versus physician estimate.

BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs) are widely used as the first-line treatment for depression. Information regarding their side effects is mostly based on controlled clinical trials. METHOD: Patients who received an SSRI for a new or recurrent case of depression (ICD-9 code 296.2 or 311) between December 15, 1999, and May 31, 2000 were interviewed by telephone 75 to 105 days after initiation of SSRI therapy. Using closed-ended questions, investigators asked patients if they experienced any of 17 side effects commonly associated with SSRIs, how bothersome they were, and what their duration was. Prescribing physicians completed a written survey providing their estimates about frequency of side effects associated with SSRIs and how bothersome those side effects are. RESULTS: Of 401 patients who completed the phone interview, 344 patients (86%) reported at least 1 side effect, and 219 patients (55%) experienced 1 or more bothersome side effect(s). The most common bothersome side effects were sexual dysfunction and drowsiness (17% each). While most side effects first occurred within the first 2 weeks of treatment, the majority of patients were still experiencing the same side effects at the time of interview, most notably blurred vision (85%) and sexual dysfunction (83%). Overall, physicians (N = 137) significantly underestimated the occurrence of the 17 side effects explored, and they tended to underrate how bothersome those side effects were to their patients. CONCLUSION: Side effects associated with SSRIs are common and bothersome to patients. Treatment-emergent side effects tend to persist during the first 3 months of treatment.

Prevalence of lipid abnormalities in the United States: the National Health and Nutrition Examination Survey 2003-2006.

BACKGROUND: The association between increased low-density lipoprotein cholesterol (LDL-C) and increased risk for cardiovascular events is well established, with treatment focusing on LDL-C lowering. Other lipid abnormalities are also associated with increased cardiovascular risk (eg, low high-density lipoprotein cholesterol [HDL-C], high triglycerides [TG], and high non-HDL-C). Despite national lipid guidelines, the prevalence of these abnormal lipid parameters alone or in combination (mixed dyslipidemia) is not well recognized. OBJECTIVE: We assessed the prevalence of high LDL-C, low HDL-C, high TG, high non-HDL-C, and mixed dyslipidemia by using National Health and Nutrition Examination Survey (NHANES) data to estimate the proportions of U.S. adults not at guideline-recommended lipid goals. METHODS: NHANES 2003-2006 fasting blood serum data were used to categorize adults aged ≥20 years by LDL-C (risk stratum-specific), HDL-C (men, <40 mg/dL; women, <50 mg/dL), non-HDL-C (in subjects with TG ≥200 mg/dL), and TG (≥150 mg/dL) target levels with use of the NCEP ATP III definitions based on coronary heart disease (CHD) risk. RESULTS: An estimated 53% (105.3M) of U.S. adults have lipid abnormalities: 27% (53.5M) have high LDL-C, 23% (46.4M) have low HDL-C, and 30% (58.9M) have high TG. Among patients with serum TG levels ≥200 mg/dL, approximately 13% (25.7M) of adults have non-HDL-C levels ≥130 mg/dL. Also, 21% (42.0M) of U.S. adults have mixed dyslipidemia (high LDL-C with either low HDL-C and/or high TG), with nearly 6% (11.6M) having all three lipid abnormalities. For LDL-C, an estimated 23M adults with CHD or a CHD risk equivalent and 17M with ≥2 risk factors but a Framingham risk ≤20% are not at goals of <100 and <130 mg/dL, respectively. CONCLUSION: Prevalence of dyslipidemia in the United States continues to be high, with the majority of U.S. adults now affected by some form of lipid abnormality. Efforts to promote screening, risk stratification, and initiating appropriate treatment should be intensified.

Pharmacoepidemiology safety study of fibrate and statin concomitant therapy.

Combinations of statins and fibrates may be increasingly prescribed to achieve lipid goals in high-risk patients and those with other cardiovascular risk factors, such as mixed dyslipidemia. The purpose of this retrospective cohort study was to compare rates of hospitalization for specific diagnoses in a cohort of new users of statins or fibrates, using claims data from a large United States health insurer. New users of statin, fibrate, or statin-fibrate therapy from 2004 to 2007 were identified; followed for hospitalization with rhabdomyolysis, renal impairment, hepatic injury, or pancreatitis; and confirmed by medical record review. Incidence rates (IRs) were compared across categories of fibrate or statin use, with adjusted IR ratios estimated using Poisson regression. A total of 584,784 patients initiated statins or fibrates. The IR of rhabdomyolysis in statins was 3.30 per 100,000 patient-years; the adjusted IR ratio for statin-fenofibrate combinations compared to statins alone was 3.75 (95% confidence interval 1.23 to 11.40). The IRs of renal impairment and pancreatitis in statins were 108.87 per 100,000 patient-years and 45.76 per 100,000 patient-years, respectively; the adjusted IR ratios for statin-fenofibrate combinations compared to statins alone were 1.47 (95% confidence interval 1.12 to 1.93) and 2.87 (95% confidence interval 2.05 to 4.02), respectively. The IR of hepatic injury with statins was 8.57 per 100,000 patient-years, with no risk difference between exposure groups. In conclusion, the risk for rhabdomyolysis was low, although higher in patients newly treated with statin-fibrate concurrent therapy than those treated with either as monotherapy. The risk for pancreatitis was higher in patients treated with fenofibrate, whether in combination with statins or alone.

Concomitant use of statins and CYP3A4 inhibitors in administrative claims and electronic medical records databases.

BACKGROUND: Patients may experience increased risk of adverse drug interactions when statins are administered concomitantly with cytochrome P450 3A4 (CYP3A4) inhibitors. OBJECTIVE: To determine patient numbers in routine clinical practice with concomitant exposure to CYP3A4-metabolized statins and CYP3A4 inhibitors and highlight potential risk for adverse drug interaction. METHODS: Exposure to prescription medications over 1 year (2005-2006) was evaluated from patient records: US PharMetrics Integrated Patient-Centric administrative claims database and the US General Electric Medical System (GEMS) database. Rates of concomitant prescribing of statins with CYP3A4 inhibitors (listed in United States of America product labels and all identified potential inhibitors) were examined in the cohort overall, in those aged ≥65 years, and in those receiving higher doses of statins. RESULTS: Overall, 951,166 patient records were included (PharMetrics n = 650,825; GEMS, n = 300,341). Of these, 792,081 (83%) patients used a CYP3A4-metabolized statin as opposed to a non-CYP3A4-metabolized statin (17%). Findings from both databases were consistent. Overall, 25-30% of patients given a CYP3A4-metabolized statin were concomitantly exposed to a CYP3A4 inhibitor, including approximately 9% concomitantly exposed to a labeled inhibitor, findings consistent with those in patients aged ≥65 years, and patients on higher doses of statins. CONCLUSIONS: Clinicians frequently co-prescribe CYP3A4-metabolized statins with CYP3A4 inhibitors. Physician education regarding the impact of these inhibitors on the metabolism of lovastatin, simvastatin, and atrovastatin is needed. Further studies are also needed to determine whether concomitant administration of a non-CYP3A4-metabolized statin (such as fluvastatin, pravastatin, or rosuvastatin) with a CYP3A4 inhibitor, may reduce adverse event rates in routine clinical practice.

Chemotherapy-induced nausea and vomiting: incidence and impact on patient quality of life at community oncology settings.

GOALS OF WORK: The present study sought to determine the prevalence of acute and delayed chemotherapy-induced nausea and vomiting (CINV) across ten community oncology settings. The effect of CINV on quality of life (QOL) was also evaluated. MATERIALS AND METHODS: Cancer patients who were scheduled for their first cycle of a new chemotherapy regimen were recruited from ten community oncology clinics. Study participants recorded occurrence of CINV by completing a daily diary each day for the first 8 days after treatment during each cycle and the Functional Living Index-Emesis (FLIE) before chemotherapy, at the end of day 1 and day 6 after chemotherapy. Mixed model regression analysis was used to explore the association between occurrence of CINV at cycle 1 and subsequent cycles and its impact on patient QOL. MAIN RESULTS: One hundred and fifty-one patients provided information for at least one cycle. During cycle 1, only 33% had neither acute nor delayed CINV. Of the 36% patients who developed acute CINV, 8% developed acute CINV only. Of the 59% who developed delayed CINV, 53% reported delayed only and 47% reported acute and delayed CINV. A similar pattern was seen at cycles 2 and 3. Experience of CINV at cycle 1 was associated with the development of CINV at cycles 2 and 3. Occurrence of CINV significantly interfered with patient QOL as assessed by the FLIE. CONCLUSIONS: CINV remained a substantial problem for patients receiving chemotherapy in this community-based sample, especially delayed CINV. CINV significantly interfered with patient QOL and daily functioning.

The comparative safety of rosuvastatin: a retrospective matched cohort study in over 48,000 initiators of statin therapy.

PURPOSE: The purpose of this study was to compare incidence rates of hospitalization associated with rhabdomyolysis, myopathy, renal, or hepatic dysfunction, and of in-hospital death, between initiators of rosuvastatin and other statins. METHODS: This was a matched cohort study of statin initiators from the administrative database of a large health insurer in the US, during the first 6 months of rosuvastatin availability with up to 18 months of follow-up. All outcome events were verified by medical record review. Incidence rates, risk ratios, and associated 95% confidence intervals were estimated. RESULTS: From an initial pool of 12,217, 11,249 eligible rosuvastatin initiators were matched to 37,282 initiators of other statins. The incidence rate (IR) per 1000 person-years for rhabdomyolysis was 0.10 [0.00, 0.55] for rosuvastatin initiators (n = 1) and 0.06 [0.01, 0.22] for other statin initiators (n = 2), for a hazard ratio (HR) of 1.98 [0.18, 21.90]. The IR for myopathy was 0.20 [0.02, 0.71] for rosuvastatin initiators (n = 2) and 0.00 [0.00, 0.09] for other statin initiators (n = 0). The IR for renal dysfunction was 1.18 [0.61, 2.06] for rosuvastatin initiators (n = 12) and 1.26 [0.91, 1.71] for other statin initiators (n = 42), for a HR of 0.90 [0.47, 1.73]. The IR for hepatic dysfunction was 0.20 (0.02, 0.71) for rosuvastatin initiators (n = 2) and 0.24 (0.10, 0.47) for other statin initiators (n = 8), for a HR of 0.87 (0.18, 4.14). CONCLUSIONS: This study found no difference between rosuvastatin and the other statins in the incidence of hospitalizations associated with renal or hepatic events, or death. The absolute incidence rates of rhabdomyolysis and myopathy were reassuringly low among all statin initiators but remain too small for firm conclusions to be drawn on any difference between the statins.

Rosuvastatin safety: a comprehensive, international pharmacoepidemiology programme.

Results from clinical trials and clinical practice have shown statins to be generally well tolerated with a low frequency of clinically relevant side effects. Nevertheless, there are rare occasions when adverse events (AEs), sometimes serious, may occur. Rosuvastatin is the newest statin to be approved in the USA and many other countries. As part of the continued assessment of the benefit-risk profile of rosuvastatin, AstraZeneca has developed a progressive, comprehensive pharmacoepidemiology programme to complement safety data obtained from randomised clinical trials and spontaneous reporting systems, which have demonstrated that rosuvastatin has a safety profile in line with comparator statins. This programme comprises nine studies conducted in recognised centres of excellence assessing over 50,000 patients treated with rosuvastatin. It consists of three components: patient characteristics studies (four studies), safety evaluation studies (four studies); and review of data generated from the Prescription-Event Monitoring (PEM) study, designed and run by an independent third party. Patient characteristics studies are designed to describe the characteristics and drug utilisation patterns of new users of rosuvastatin compared with new users of other statins in automated databases. Safety evaluation studies will examine the rates of specific AEs in different cohorts of statin users and determine risk factors for these events using data recorded prospectively in automated databases with case adjudication via medical record review. The independent PEM study will monitor any significant events recorded by general practitioners since starting rosuvastatin treatment. This article is an overview of the rationale and methodology of the rosuvastatin pharmacoepidemiology programme.

Discontinuation of use and switching of antidepressants: influence of patient-physician communication.

CONTEXT: Although current depression treatment guidelines recommend continuing antidepressant therapy for at least 4 to 9 months, many patients discontinue treatment prematurely, within 3 months. OBJECTIVES: To investigate the relationship between patient-physician communication and the continuation of treatment with antidepressants and to explore the demographics, adverse effects, therapeutic response, and frequency of follow-up visits. DESIGN, SETTING, AND PATIENTS: A total of 401 telephone interviews of depressed patients being treated with selective serotonin reuptake inhibitor (SSRI) therapy between December 15, 1999, and May 31, 2000, were conducted and 137 prescribing physicians completed written surveys from Northern California Kaiser Permanente health maintenance organization outpatient clinics. MAIN OUTCOME MEASURES: Patient-physician communication about therapy duration and about adverse effects; therapy discontinuation or medication switching within 3 months after start of SSRI therapy. RESULTS: Ninety-nine physicians (72%) reported that they usually ask patients to continue using antidepressants for at least 6 months, but 137 patients (34%) reported that their physicians asked them to continue using antidepressants for this duration and 228 (56%) reported receiving no instructions. Patients who said they were told to take their medication for less than 6 months were 3 times more likely to discontinue therapy (odds ratio [OR], 3.12; 95% confidence interval [CI], 1.21-8.07) compared with patients who said they were told to continue therapy longer. Patients who discussed adverse effects with their physicians were less likely to discontinue therapy than patients who did not discuss them (OR, 0.49; 95% CI, 0.25-0.95). Patients who reported discussing adverse effects with their physicians were more likely to switch medications (OR, 5.60; 95% CI, 2.31-13.60). Fewer than 3 follow-up visits for depression, adverse effects, and lack of therapeutic response to medication were also associated with patients' discontinuing therapy. CONCLUSIONS: Discrepancies exist between instructions that physicians report they communicate to patients and what patients remember being told. Explicit instructions about expected duration of therapy and discussions about medication adverse effects throughout treatment may reduce discontinuation of SSRI use. Our finding that patients with 3 or more follow-up visits were more likely to continue using the initially prescribed antidepressant medication suggests that frequent patient-physician contact may increase the probability that patients will continue therapy.