Unintended pregnancy in users of nomegestrol acetate and 17ß-oestradiol (NOMAC-E2) compared with levonorgestrel-containing combined oral contraceptives: final results from the PRO-E2 study.

OBJECTIVE: To assess and compare the risk of unintended pregnancy in NOMAC-E2 users with levonorgestrel-containing COC (COCLNG) users in clinical practice. STUDY DESIGN: In this observational study, new users1 of NOMAC-E2 and COCLNG were recruited in Europe, Australia, and Latin America and followed for up to 2 years. Unintended pregnancy was expressed by the Pearl Index (contraceptive failures per 100 women-years [WY]), crude hazard ratios (HRcrude) and adjusted hazard ratios (HRadj). RESULTS: Overall, 44,559 and 46,754 users were recruited to the NOMAC-E2 and COCLNG user cohorts, respectively. There were 64 unintended pregnancies in NOMAC-E2 users (0.15 per 100 WY; 95% CI, 0.11-0.19) and 200 in COCLNG users (0.41 per 100 WY; 95% CI, 0.35-0.47). The unintended pregnancy risk was statistically significantly lower in the NOMAC-E2 cohort (p<.0001) compared to the COCLNG user cohort. The HRadj of NOMAC-E2 vs COCLNG was 0.45 (95% CI, 0.34-0.60; adjusted for age, body mass index, gravidity, COC user status, education level). CONCLUSIONS: NOMAC-E2 demonstrated superior contraceptive effectiveness compared to COCLNG, likely due to the comparatively short hormone-free interval and possibly reinforced by the long half-life of NOMAC.

Prospective controlled cohort study on the safety of a monophasic oral contraceptive containing nomegestrol acetate (2.5mg) and 17ß-oestradiol (1.5mg) (PRO-E2 study): risk of venous and arterial thromboembolism.

OBJECTIVE: To assess and compare the risk of venous thromboembolism (VTE) and arterial thromboembolism (ATE) in NOMAC-E2 users with levonorgestrel-containing combined oral contraceptive (COCLNG) users. STUDY DESIGN: This large, prospective, observational active surveillance study used a non-inferiority design. New users of NOMAC-E2 and COCLNG were recruited in 12 countries in Australia, Europe, and Latin America. Women were followed up directly and self-reported outcomes of interest were validated via treating physicians. The main outcome of interest was VTE, specifically deep venous thrombosis of the lower extremities (DVT) and pulmonary embolism (PE). Secondary outcomes included all VTE and ATE. Data on confounders were captured and independent blinded adjudication assessed the classification of events. Incidence rates, crude (HRcrude), and adjusted (HRadj) hazard ratios were calculated. RESULTS: A total of 101,498 women (49,598 NOMAC-E2 users and 51,900 COCLNG users) were enrolled and followed for up to 2 years (144,901 WY of observation). NOMAC-E2 users had a higher mean age (31.0 ± 8.63 years) than COCLNG users (29.3 ± 8.53 years) but other baseline characteristics were similar between the cohorts. The main analysis comparing the risk of DVT of the lower extremities and PE in NOMAC-E2 users versus COCLNG users yielded an HRadj of 0.59 (95% CI, 0.25-1.35) (adjusted for age, BMI, family history of VTE, and current duration of use). The risk of all VTE and ATE was not higher in NOMAC-E2 users compared with COCLNG users. CONCLUSION(S): NOMAC-E2 use was not associated with a higher risk of VTE or ATE compared with COCLNG.

Neuromuscular Blocking Agents and Reversal Agents Among Hospitalized Children: A Cerner Database Study.

Background: Sugammadex (Bridion) was approved by the US Food and Drug Administration (FDA) in December 2015 for the reversal of neuromuscular block (NMB) induced by rocuronium and vecuronium bromide in adults undergoing surgery and approved for use in both adults and children in the European Union in 2008. Sugammadex use in children has been reported in the United States, but to what extent is not clear. Aims: The aim was to describe the utilization pattern of NMB agents and factors associated with the use of reversal agents (neostigmine and sugammadex) in US children. Methods: Cross-sectional study of children with exposure to NMB agents between 2015 and 2017 in the Cerner Health Facts® database, which is an electronic health record (EHR) database across 600 facilities in the United States. Logistic regression estimated factors associated with the use of sugammadex vs neostigmine. Results: A total of 27 094 pediatric clinical encounters were exposed to neuromuscular blocking agents (NMBAs), in which 21 845 were exposed to rocuronium (76%), vecuronium (18%), or both (6%). Among children with exposure to rocuronium and vecuronium, the use of sugammadex was 1.7% in 2016 and 7.6% in 2017. The multivariable logistic model suggested that children who were older (age 12-17 years vs 0-1 year; odds ratio [OR] 1.96; 95% confidence interval [CI], 1.36-2.83), Hispanic or Latino ethnicity and other ethnicities (vs non-Hispanic or Latino; OR 2.03 and 1.56; 95% CI, 1.55-2.67 and 1.15-2.13, respectively), in teaching facilities (OR 1.26; 95% CI, 1.00-1.59), or admitted through emergency departments (OR 1.65; 95% CI, 1.06-2.58) were independently more likely to receive sugammadex than neostigmine after controlling for other covariates. Conclusions: In Cerner Health Facts database 2015 to 2017, among children, rocuronium was more commonly used than vecuronium, and sugammadex use was observed since 2016. Sugammadex and neostigmine users varied by demographic, clinical, and site-level characteristics.

Lipoprotein-Associated Phospholipase A2 and Incident Peripheral Arterial Disease in Older Adults: The Cardiovascular Health Study.

OBJECTIVE: Although prior studies report a relationship between elevated lipoprotein-associated phospholipase A2 (Lp-PLA2) and incident cardiovascular disease, the prospective association of Lp-PLA2 with incident peripheral arterial disease (PAD) has not been studied. We investigated the association between Lp-PLA2 mass and activity and the risk of developing clinical PAD and low ankle-brachial index (ABI). APPROACH AND RESULTS: Among Cardiovascular Health Study participants, a population-based cohort of 5888 adults aged ≥65 years enrolled in 1989 to 1990, Lp-PLA2 mass and activity were measured in 4537 individuals without baseline PAD. Clinical PAD, defined as leg artery revascularization or diagnosed claudication, was ascertained through 2011. Incident low ABI, defined as ABI <0.9 and decline of ≥0.15, was assessed among 3537 individuals who had an ABI >0.9 at baseline and a second ABI measurement 3 or 6 years later. Analyses were adjusted for demographics, cholesterol, smoking, comorbidities, and C-reactive protein. Each standard deviation increment in Lp-PLA2 mass (117 ng/mL) was associated with a higher risk of developing clinical PAD (hazard ratio 1.28; 95% confidence interval 1.13, 1.45) and incident low ABI (odds ratio 1.16; 95% confidence interval 1.00, 1.33). Results per standard deviation increment in Lp-PLA2 activity (13 nmol/min per mL) were similar for clinical PAD (hazard ratio 1.24; 95% confidence interval 1.07, 1.44) and low ABI (odds ratio 1.28; 95% confidence interval 1.09, 1.50). CONCLUSIONS: Higher Lp-PLA2 mass and activity were associated with development of both incident clinical PAD and low ABI. Future studies are needed to determine whether pharmacological inhibition of Lp-PLA2 reduces the incidence of PAD.

Characterization of chronic and acute ESA hyporesponse: a retrospective cohort study of hemodialysis patients.

BACKGROUND: Some patients with chronic kidney disease do not respond adequately to erythropoiesis-stimulating agent (ESA) treatment; these patients are referred to as ESA hyporesponders. There is no widely accepted contemporary definition for chronic ESA hyporesponse. The study objective was to propose and validate an operational definition for chronic ESA hyporesponse. METHODS: This was a retrospective cohort study using electronic health care records. Participants were anemic hemodialysis patients treated during February 2012 and were followed for 15 months. Patients' ESA response (responders) or lack of response (chronic and acute hyporesponders) based on longitudinal patterns of ESA dose and hemoglobin level was assessed. Persistence of hyporesponse, longitudinal iron measures, transfusion rates, and mortality rates were analyzed. Frequency of blood transfusions (monthly) and death rates (quarterly) were calculated. Log normalized serum ferritin concentration was analyzed. RESULTS: Of 97,677 eligible patients, 6632 had acute hyporesponsiveness (ESA responsiveness restituted in ≤ 4 months) and 3086 had chronic hyporesponsiveness (lack of ESA response for > 4 months). Over months 1-4 among chronic hyporesponders, mean serum ferritin (722-785 ng/mL) and transferrin saturation (TSAT; 26.76 %-27.08 %) were constant, while acute hyporesponsive patients experienced increased ferritin (654-760 ng/mL) and TSAT (25.71-30.88 %) levels. Compared to ESA responders (0.19-0.30 %), chronic hyporesponders were transfused 7-times (1.20-2.17 %) more frequently over follow-up. Quarterly mortality was greatest in chronic ESA hyporesponders (2.98-5.48 %), followed by acute ESA hyporesponders (2.17-3.30 %) and ESA responders (1.43-2.49 %). With consistence over the study, chronic hyporesponders died more frequently than patients in the other study cohorts. CONCLUSIONS: Findings indicate that 4 months of continuous ESA hyporesponsiveness can be used to differentiate acute from chronic hyporesponsiveness. This definition of chronic hyporesponsiveness is supported by outcome data showing higher mortality and transfusion rates in chronic hyporesponders compared to acute hyporesponders.

Meta-analysis of clinical trial safety data in a drug development program: answers to frequently asked questions.

BACKGROUND: Meta-analyses of clinical trial safety data have risen in importance beyond regulatory submissions. During drug development, sponsors need to recognize safety signals early and adjust the development program accordingly, so as to facilitate the assessment of causality. Once a product is marketed, sponsors add postapproval clinical trial data to the body of information to help understand existing safety concerns or those that arise from other postapproval data sources, such as spontaneous reports. PURPOSE: This article focuses on common questions encountered when designing and performing a meta-analysis of clinical trial safety data. Although far from an exhaustive set of questions, they touch on some basic and often misunderstood features of conducting such meta-analyses. METHODS: The authors reviewed the current literature and used their combined experience with regulatory and other uses of meta-analysis to answer common questions that arise when performing meta-analyses of safety data. RESULTS: We addressed the following topics: choice of studies to pool, effects of the method of ascertainment, use of patient-level data compared to trial-level data, the need (or not) for multiplicity adjustments, heterogeneity of effects and sources of it, and choice of fixed effects versus random effects. LIMITATIONS: The list of topics is not exhaustive and the opinions offered represent only our perspective; we recognize that there may be other valid perspectives. CONCLUSIONS: Meta-analysis can be a valuable tool for evaluating safety questions, but a number of methodological choices need to be made in designing and conducting any meta-analysis. This article provides advice on some of the more commonly encountered choices.

Pregnancy and pregnancy outcomes in a prospective cohort study: Final results from the Nexplanon Observational Risk Assessment Study (NORA).

OBJECTIVES: To monitor pregnancy occurrence and outcomes among Nexplanon users in the United States during standard clinical practice. STUDY DESIGN: The Nexplanon Observational Risk Assessment (NORA) study was a large prospective cohort study conducted in the United States (US). Study participants with a newly inserted Nexplanon implant were recruited by health care professionals (HCPs) who had completed the Nexplanon clinical training. Via a survey, study participants were followed up at 6-month intervals for 36 months and 6 months after implant removal. Reported unintended pregnancies were validated and classified as noninsertion, preinsertion, during-use, or postremoval. RESULTS: Four hundred and twenty-eight HCPs in 47 states recruited 7364 Nexplanon users. Pregnancies included one noninsertion, eight preinsertion, three during-use, and 14 postremoval pregnancies; of these 26 pregnancies, 22 resulted in the birth of a healthy child, two resulted in an induced abortion, one resulted in a spontaneous abortion, and one resulted in an ectopic pregnancy. Six pregnancies occurred during-use (n = 3) or within 7 days following implant removal (n = 3), yielding a Pearl Index of 0.04 (95% CI, 0.02-0.09). CONCLUSIONS: Nexplanon is an effective contraceptive in real-world users; the Pearl Index was 0.02 (95% CI, 0.00-0.06) for during-use pregnancies, and 0.04 when including pregnancies that occurred within 7 days following implant removal. IMPLICATIONS: This large real-world-use study indicates that Nexplanon is as effective as shown in the preapproval clinical trials.

High coverage and adherence to dose intervals of the national school-based HPV vaccination program in Sweden during 2012-2019.

Background: Close monitoring of vaccination coverage is important for cervical cancer prevention efforts. The study aims to describe the HPV vaccination coverage by dose in girls eligible for HPV vaccination within Sweden's childhood immunization program and provide an estimate on dose timing compliance. Methods: Vaccination records between 2012 and March 2019 were obtained for girls born in 2000-2006 from the vaccination registers in Sweden. The mid-time population counts for the respective birth cohorts were taken as the denominator. Full-dose coverage and coverage with at least one dose of the vaccine were calculated within the two-dose and three-dose regimen, by region. Dose compliance was calculated within the two-dose regimen. Results: Vaccination coverage with at least one dose of the vaccine was >80% within birth cohorts 2001-2006. Full-dose coverage within a two-dose and three-dose regimen were 73.4% in birth cohorts 2004-2005, and 56.3% in birth cohorts 2000-2001, respectively. Little variation was observed in vaccination coverage between regions. Dose completion was 91.8%, and 72.8% in girls that initiated a two-dose and three-dose regimen, respectively. Among girls receiving a two-dose regimen, 93.0% received the second dose 6-12 months after dose one. Discussion: In conclusion, high levels of HPV vaccination coverage were observed with little variation between regions. Dose timing compliance was particularly high in the two-dose regimen. To fully benefit from the impact of HPV vaccination, it will be important to further push the vaccination coverage and reach the girls that do not or partially engage with HPV vaccination.

Real-world impact and effectiveness of the quadrivalent HPV vaccine: an updated systematic literature review.

INTRODUCTION: Human papillomavirus (HPV) infection, which poses significant disease burden, is decreasing following implementation of vaccination programs. Synthesized evidence on HPV vaccine real-world benefit was published in 2016. However, long-term impact of vaccination, and how vaccination programs influence infection rates and disease outcomes, requires further examination. AREAS COVERED: We systematically reviewed observational studies on HPV vaccination within MEDLINE, EMBASE, and Google Scholar from 2016 to 2020, involving 14 years of follow-up data. We identified 138 peer-reviewed publications reporting HPV vaccine impact or effectiveness. Outcomes of interest included rates of infection at different anatomical sites and incidence of several HPV-related disease endpoints. EXPERT OPINION: The expansion of HPV vaccination programs worldwide has led to a reduction in genital infection and significant decreases in incidence of HPV-related disease outcomes. Therefore, the WHO has set goals for the elimination of cervical cancer as a public health concern. To track progress toward this requires an understanding of the effectiveness of different vaccination initiatives. However, the impact on males, and potential benefit of gender-neutral vaccination programs have not been fully explored. To present an accurate commentary on the current outlook of vaccination and to help shape policy therefore requires a systematic review of available data.

Kidney function decline in the elderly: impact of lipoprotein-associated phospholipase A(2).

BACKGROUND: Whether lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) levels are associated with kidney function decline has not been well studied. METHODS: We investigated associations of Lp-PLA(2) antigen and activity with kidney function decline and rapid decline over 5.7 years in the Cardiovascular Health Study (n = 4,359). We estimated kidney function by cystatin C (eGFRcys) in repeated measures, and defined rapid decline as ≥3 ml/min/1.73 m(2) per year. We stratified by baseline preserved GFR (≥60 ml/min/1.73 m(2)). RESULTS: Mean age was 72 ± 5 years. Average eGFRcys decline was -1.79 ml/min/1.73 m(2) (SD = 2.60) per year. Among persons with preserved GFR, compared to the lowest quartile of Lp-PLA(2) antigen, eGFRcys decline was faster among persons in the second, ß -0.31 (95% CI -0.52, -0.10), third -0.19 (-0.41, 0.02) and fourth quartiles -0.26 (-0.48, -0.04) after full adjustment. Persons in the highest quartile of Lp-PLA(2) antigen had increased odds of rapid decline 1.34 (1.03, 1.75), compared to the lowest. There was no significant association between levels of Lp-PLA(2) activity and eGFRcys decline or rapid decline. Associations were not statistically significant among persons with low eGFR (<60 ml/min/1.73 m(2)) at baseline. CONCLUSION: Higher levels of Lp-PLA(2) antigen but not activity were significantly associated with faster rates of kidney function decline. These findings may suggest a novel vascular pathway for kidney disease progression.

Knowledge and Understanding of the Safety and Efficacy Aspects of BRIDION® Among Canadian Anesthesiologists.

BACKGROUND: BRIDION® (sugammadex sodium) is an agent for the reversal of neuromuscular blockade (NMB) induced by rocuronium and vecuronium in general anesthesia. Following the approval of sugammadex in Canada (February 2016), Health Canada required a survey to assess the knowledge and understanding of the safety and efficacy aspects of sugammadex among anesthesiologists in Canada. OBJECTIVE: Our objective was to evaluate how well the anesthesiologists in Canada understood the safety and efficacy aspects of sugammadex. METHODS: A survey was implemented among anesthesiologists in Canada via internet/phone. The survey was organized to test the knowledge of anesthesiologists by utilizing 11 key questions regarding the safety and efficacy of sugammadex. Five additional safety questions that were not considered part of the key messages but were important concepts for anesthesiologists to know when administering sugammadex were also included. RESULTS: A total of 202 completed surveys were collected. Based on an a priori threshold of understanding of 75%, 9 out of 11 key messages scored at or above this threshold. The two messages that scored below this threshold involved (1) knowledge that sugammadex is not indicated for use in children aged < 18 years (71.8%; 95% confidence interval [CI] 65.0-77.9) and (2) that monitoring is required for recurrence of NMB after reversal with sugammadex (73.3%; 95% CI 66.6-79.2). Of the five additional safety questions, four had an understanding rate of ≥ 88.1%. One question scored 60.4%; this question covered the concept that sugammadex is not recommended for use in patients with severe renal impairment (creatinine clearance < 30 mL/min), including those requiring dialysis. CONCLUSION: In general, the survey results suggested that anesthesiologists understood the use, safety, and efficacy of sugammadex for the reversal of moderate to deep NMB induced by rocuronium or vecuronium in adults undergoing surgery.

SGLT2 Inhibitors and the Risk of Hospitalization for Fournier's Gangrene: A Nested Case-Control Study.

INTRODUCTION: Based on post-marketing surveillance, concern has been raised that sodium-glucose cotransporter 2 inhibitors (SGLT2i) may increase the risk of necrotizing fasciitis of the perineum (Fournier's gangrene, FG). As a result of the low incidence of FG, data from clinical trials may be insufficient to robustly assess this issue because of the relatively limited numbers of participants. Real-world evidence may help clarify the association between SGLT2i and FG in the type 2 diabetes (T2D) population. METHODS: A nested case-control study was performed using Truven Health MarketScan™ databases. Each patient with T2D hospitalized for FG between 1 April 2013 (when the first SGLT2i was available) and 31 March 2018 (latest available data) was matched (on the basis of sex, age, and cohort entry date) with six controls from the same cohort. The adjusted odds ratio (OR) of hospitalization for FG was estimated for patients receiving SGLT2i compared with those receiving two or more non-SGLT2i antihyperglycemic agents (AHAs) or insulin alone using conditional logistic regression. RESULTS: The cohort included 1,897,935 patients, with 216 hospitalized for FG (incidence rate, 5.2 events per 100,000 person-years). Patients with FG ranged from 23 to 79 years of age; 201 (93.1%) were men. Among the 216 FG cases, 9 (4.2%) were current SGLT2i users; among the 1296 matched controls, 100 (7.7%) were current SGLT2i users. Approximately 93% of SGLT2i were used in combination. The adjusted OR of FG in patients treated with SGLT2i compared with patients treated with two or more non-SGLT2i AHAs or insulin alone was 0.55 [95% CI 0.25-1.18]. CONCLUSION: The study did not find that treatment with SGLT2i, as compared with treatment with two or more non-SGLT2i AHAs or insulin alone, was statistically significantly associated with an increased risk of hospitalization for FG. Additional studies are needed to corroborate the findings.

Chronic kidney disease among US adults with type 2 diabetes and cardiovascular diseases: A national estimate of prevalence by KDIGO 2012 classification.

AIM: Data on prevalence of chronic kidney disease (CKD) among US adults with type 2 diabetes (T2D) and cardiovascular diseases (CVD) are limited. The aim of this study was to provide such estimates for T2D, both overall and in those with CVD. MATERIALS AND METHODS: Using the NHANES 2007-2014 data, we conducted a cross-sectional analysis of an adult sample with diagnosed and undiagnosed T2D, aged ≥18 years. CVD was defined based on self-reported personal interview data on a broad range of health conditions-congestive heart failure, coronary heart disease, angina, stroke, or heart attack. T2D was defined as diagnosed T2D (self-reported provider diagnosis) and undiagnosed T2D (FPG ≥126 mg/dL or HbA1c ≥ 6.5% without self-reported diagnosis). Participants who started insulin within a year of T2D diagnosis, or were pregnant at the time of health examination were excluded. Appropriate sample weights were used to provide a national estimate. RESULTS: The prevalence of moderate to severe renal impairment based on eGFR below 60 ml/min/1.73 m2 among T2D was 18.0%. The prevalence of mild renal impairment was 36.9%: 28.3% with UACR<30 mg/g, 7.0% with UACR ≥30-300 mg/g and 1.6% with UACR >300 mg/g. For T2D and CVD subgroup, the prevalence was 33.6% for moderate to severe renal impairment and 42.8% for mild renal impairment. CONCLUSIONS: This study confirms the high prevalence of CKD in patients with multiple comorbidities: T2D and CVD. It also provides estimates of the prevalence of CKD categories based on KDIGO 2012 classification for US adults with T2D.

Real world data on Nexplanon® procedure-related events: final results from the Nexplanon Observational Risk Assessment study (NORA).

OBJECTIVES: We conducted this study to characterize the frequency of insertion-, localization- and removal-related events and their clinically significant consequences among Nexplanon® (etonogestrel radiopaque contraceptive implant) users in the United States during standard clinical practice. STUDY DESIGN: The Nexplanon Observational Risk Assessment (NORA) study was a large, prospective cohort study conducted in the United States. A total of 428 Health Care Professionals (HCPs) who had completed the Nexplanon clinical training program recruited women who were newly prescribed Nexplanon. We collected data on insertion-, localization- and removal-related events experienced during routine clinical practice via questionnaires completed by patients and HCPs. Recruitment began in December 2011 and follow-up ended in October 2017. Data analysis characterized the frequency of procedure-related events. RESULTS: We collected data on 7364 insertion procedures. The incidence of incorrect insertion (i.e., initially unrecognized non-insertion, partial insertion or deep insertion) was 12.6 per 1000 insertions (95% CI, 10.2-15.5). Pins and needles/numbness in the arm/hand/fingers was the most common patient-reported event. We obtained data on 5159 removal procedures, of which all were successful but one (due to the location of the implant in deep muscle tissue). No implants were localized outside the arm. The most common challenge reported by HCPs during implant removal was encasement of the implant within fibrotic tissue. CONCLUSIONS: Events associated with the insertion, localization and removal of the Nexplanon contraceptive implant were rare and their clinical consequences were generally not suggestive of serious injury. IMPLICATIONS: This study is the largest prospective evaluation of events associated with insertion and removal of Nexplanon during routine clinical practice. It demonstrates that complications associated with insertion and removal of Nexplanon are rare when performed by trained clinicians.

The risk of myopathy associated with thiazolidinediones and statins in patients with type 2 diabetes: a nested case-control analysis.

BACKGROUND: The implementation of more aggressive goals for low-density lipoprotein cholesterol lowering in subjects with type 2 diabetes (T2D) and the expected increase in the use of statins is likely to increase the concomitant use of thiazolidinediones (TZDs) and statins. OBJECTIVE: This study evaluated whether concomitant use of TZDs and statins is associated with an increased risk of myopathic events in subjects with T2D. METHODS: This was a nested case-control study in subjects with T2D. Cases and controls were identified from a cohort of 125,394 subjects with T2D in the Integrated Healthcare Information Services database. Each case with a myopathic event (rhabdomyolysis, myositis, myopathy, or myalgia) was matched to up to 6 controls by age (+/-5 years), sex, calendar year of diagnosis of a myopathic event, and length of follow-up in the database. Incident cases of myopathy were identified using the following International Classification of Diseases, Ninth Revision codes: 359.x for myopathy, 728.88 for rhabdomyolysis, and 729.1 for unspecified myalgia and myositis. Prescription claims were used as a proxy for drug exposure. Five categories of exposure were employed: statins only, TZDs only, concomitant TZDs and statins, other antidiabetic agents only, and neither statins nor antidiabetic agents. Exposure to statins and/or TZDs within 90 days before the case index date was defined as recent exposure, and exposure at any time before the case index date was defined as ever exposure. Concomitant exposure to TZDs and statins, either recent or ever, was defined by an overlap of at least 30 days in the days supply of TZDs and statins during the exposure period. RESULTS: The 3696 cases of myopathy were matched with 21,871 controls. The adjusted odds ratio (OR) for myopathic events for ever exposure to concomitant TZDs and statins compared with statins alone was 1.03 (95% CI, 0.83-1.26). Compared with neither statins nor antidiabetic agents, ever use of statins alone was associated with an increased likelihood of myopathic events (adjusted OR=1.36; 95% CI, 1.12-1.64). The likelihood of myopathic events was not significantly different for TZDs compared with other antidiabetic agents. CONCLUSION: In this population of subjects with T2D, concomitant use of statins and TZDs was not associated with an increased risk of myopathic events beyond that conferred by statins alone.

An assessment of the effect of thiazolidinedione exposure on the risk of myocardial infarction in type 2 diabetic patients.

PURPOSE: To determine the likelihood of myocardial infarction (MI) in type 2 diabetic patients exposed to rosiglitazone and pioglitazone, separately, compared to other antidiabetic therapies. METHODS: A case-control analysis nested within the cohort of type 2 diabetic subjects from the Integrated Healthcare Information Services (IHCIS) claims database. Incident cases of MI were matched to three controls each on age (+/-5 years), gender, and year of first diabetes diagnosis. Subjects were classified according to their antidiabetic drug exposure in the 3, < 6, 6-12, and > 12 months prior to the index date. The adjusted odds ratios of MI were calculated for subjects exposed to rosiglitazone and pioglitazone, separately, compared to other antidiabetic agents. Risk factors adjusted for are age, ACE inhibitors, beta-blockers, diuretics, nitrates, diagnosis of hyperlipidemia, and hypertension and coronary artery disease (CAD). RESULTS: A total of 891 901 diabetic subjects (9870 cases and 29 610 control) identified from 1999 to 2006 were included in the analysis. The mean age was 63 years for the cases and controls. Compared to those treated with other antidiabetic therapies, the adjusted odds ratio of MI was 1.03 [95%CI: 0.93-1.12] for rosiglitazone and 0.92 [95%CI: 0.83-1.01] for pioglitazone in the 3 months prior to the index date. CONCLUSIONS: The results suggest that the risk of MI in subjects exposed to rosiglitazone or pioglitazone for < or = 12 months is not different from those exposed to other antidiabetic agents but exposure for > 12 months is associated with 15 and 13% increased risk of MI, respectively.

Coronary heart disease outcomes in patients receiving antidiabetic agents in the PharMetrics database 2000-2007.

BACKGROUND: The risk of coronary heart disease (CHD) in users of antidiabetic agents must be quantified to permit reasoned therapeutic choices. OBJECTIVES: To assess the risk of myocardial infarction (MI) and coronary revascularization (CR), in diabetic patients who began rosiglitazone, pioglitazone, metformin, or sulfonylureas. METHODS: We conducted a retrospective cohort study of MI and CR in the PharMetrics database. We performed head-to-head comparisons using propensity-score-stratified Cox proportional hazards models, examining risks both on-treatment and during total follow-up before regimen switches. RESULTS: For the combined outcome (MI and CR), the crude rates per 1000 person years were 9 on monotherapy, 13 on dual therapy, and 21 on therapies combined with insulin. In the absence of insulin, regimens containing thiazolidinediones (TZDs) tended toward lower risk than comparable regimens containing sulfonylureas and higher risk than those containing metformin. The summary hazard ratio for rosiglitazone versus pioglitazone was 1.04 (95%CI: 0.94-1.14) for total follow-up and 1.05 (0.92-1.19) for on-treatment time. For MI, the hazard ratios were 1.07 (0.89-1.27) for total follow-up and 1.21 (0.95-1.54) for on-treatment time. CONCLUSIONS: The present data indicate that the risk of CHD in patients using TZDs appears to lie between the risks associated with sulfonylureas and metformin. Neither the risk of MI and CR together nor the risk of MI alone was significantly different between rosiglitazone and pioglitazone. A nonsignificant observed excess risk of 21% for MI during on-treatment time will require combination with the results of other studies to provide a reliable assessment.

Quantitative Testing of Prescriber Knowledge Regarding the Risks and Safe Use of Albiglutide.

BACKGROUND: The risk of pancreatitis and potential risk of medullary thyroid carcinoma associated with glucagon-like peptide-1 receptor agonists prompted the US Food and Drug Administration to require a Risk Evaluation and Mitigation Strategy for albiglutide, including education for prescribers and subsequent assessment of their knowledge of the risks and safe use of albiglutide via a quantitative survey. OBJECTIVE: The objective of this study was to assess prescribers' knowledge of the risks related to medullary thyroid carcinoma, pancreatitis, and the appropriate patient population for albiglutide. METHODS: Two Risk Evaluation and Mitigation Strategy surveys were conducted 18 months and 3 years after albiglutide was launched. Primary analyses evaluated correct response rates for each question. Secondary analyses evaluated the number of correct responses and the percentage of respondents scoring at/above the target comprehension thresholds (75% at 18 months; 80% at 3 years), which were selected based on discussion with the Food and Drug Administration and current standards for Risk Evaluation and Mitigation Strategy assessments, for each key risk message. RESULTS: The correct response rate for individual questions ranged from 68.2 to 97.9% (18-month survey) and from 69.4 to 98.1% (3-year survey). For the secondary analysis, 79.5, 86.7, and 86.7% of respondents in the 18-month survey answered ≥ 75% of the questions correctly and 70.8, 90.9, and 54.1% of respondents in the 3-year survey answered ≥ 80% of the questions correctly for key risk messages related to medullary thyroid carcinoma, pancreatitis, and appropriate patient population, respectively. CONCLUSIONS: Survey results indicated most, but not all, prescribers are knowledgeable regarding the risks and safe use of albiglutide. Additional education to address gaps in knowledge could further improve risk mitigation.

Does statin therapy initiation increase the risk for myopathy? An observational study of 32,225 diabetic and nondiabetic patients.

BACKGROUND: Estimates of myopathy rates in the literature are based on adverse events reported in clinical trials, which may not be representative of the clinical practice setting. OBJECTIVE: The objective of this study was to estimate the prevalence of myopathic events, particularly myalgia, myositis, and rhabdomyolysis in a community-based practice among a cohort of subjects with or without diabetes, some of whom received statin treatment. METHODS: In this retrospective data analysis, we identified members of a health maintenance organization (HMO) who initiated statin treatment between 1997 and 2004 and classified them into 2 groups: those subjects with diabetes and those without. We matched them to an equal number of health plan members based on age group, diabetes diagnosis, and year of health plan enrollment. We defined 4 levels of myopathic events according to the American College of Cardiology, the American Heart Association, and the National Heart, Lung, and Blood Institute's definitions as follows: myalgia, mild myositis, severe myositis, and rhabdomyolysis. Subjects were observed for approximately 9 years. Prevalence rates were calculated by adjusting for known myopathic risk factors and also by utilizing Cox regression models to identify predictors of time for myopathic events. RESULTS: Of the 35,413 HMO members initially assessed for inclusion, 32,225 were identified and classified into the 2 cohorts: diabetes (n = 10,247) and nondiabetes (n = 21,978). A greater proportion of statin initiators in both the diabetes (7.9% vs 5.5%; P < 0.001) and nondiabetes cohorts (9.0% vs 3.7%; P < 0.001) experienced myopathic events. However, 95% of events were myalgia or mild myositis. The prevalence of severe myositis was 0.4 per 1000 person-years (95% CI, 0.2-0.7) and 0.8 per 1000 person-years (95% CI, 0.6-1.1) among statin initiators with or without diabetes, respectively. By comparison, rates were 0.3 (95% CI, 0.1-0.5) and 0.2 (95% CI, 0.1-0.4) per 1000 person-years among nonstatin users with or without diabetes, respectively. Rates of rhabdomyolysis were 0.1 (95% CI, 0.1-0.3) and 0.2 (95% CI, 0.1-0.5) per 1000 person-years among statin and non-statin users with diabetes, respectively, and 0.2 (95% CI, 0.1-0.4) in both groups without diabetes. CONCLUSIONS: Statin initiation was associated with an approximate doubling of the risk for any myopathic event but did not appear to be associated with an increased risk for rhabdomyolysis in these patients. Because clinically significant elevations of creatine kinase levels were rare, statins appeared to be well tolerated in diabetic and nondiabetic patients who used them.

The independent correlation between high-density lipoprotein cholesterol and subsequent major adverse coronary events.

BACKGROUND: There is substantial evidence from clinical trials that lowering low-density lipoprotein cholesterol (LDL-C) reduces cardiovascular risk. There is less evidence for the salutatory effects of raising high-density lipoprotein cholesterol (HDL-C). The predictive strength of an initial HDL-C measurement and its change over time for major adverse coronary events is not well understood. METHODS: We identified a cohort of all 6928 patients in an urban primary care practice who had two or more lipid measurements between January 1985 and December 1997. We used bivariable and multivariable (Cox proportional hazards) techniques to identify independent predictors of subsequent major adverse coronary events (hospitalization for myocardial infarction or acute coronary syndrome) after the second set of lipid measurements. RESULTS: The time between first and second lipid measurements averaged 2.6 years. During a mean of 5.1 +/- 3.2 years of observation after their second lipid measurements, 2167 (31%) patients had an acute coronary event. Patients having events were significantly older, more often white, male, and smokers and more often had antecedent diabetes, hypertension, coronary heart disease, and myocardial infarctions. Adjusting for covariates, a 10-mg/dL higher initial HDL-C was associated with an 11% (95% CI 7%-14%) lower risk of coronary events. A 10-mg/dL increase in HDL-C between lipid measurements was associated with a 7% (95% CI 3%-10%) lower risk of events. Neither initial or change in triglycerides nor LDL-C predicted subsequent coronary events. CONCLUSION: High-density lipoprotein cholesterol measurements and change in HDL-C predicted major adverse coronary events in this urban practice, which provides support studying interventions targeting HDL-C for cardiovascular risk reduction.