This large study found no increased risk of cardiovascular events in children and young adults using attention deficit–hyperactivity disorder (ADHD) drugs. Although the data are compatible with ...nearly a doubling of risk, the study was underpowered and the absolute event rate was quite low.
Medications that are used to treat attention deficit–hyperactivity disorder (ADHD) are prescribed for more than 2.7 million children in the United States each year
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and have been considered to be relatively safe.
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However, reports of adverse events from Canada and the United States that have included cases of sudden death, myocardial infarction, and stroke in conjunction with the use of these drugs have raised concern about their safety.
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Although case reports from adverse-event reporting systems can be an important source for identifying medication safety signals, they cannot reliably quantify risk. Thus, there is a compelling need to obtain . . .
IMPORTANCE: In 2010, due to a pertussis outbreak and neonatal deaths, the California Department of Health recommended that the tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis ...vaccine (Tdap) be administered during pregnancy. Tdap is now recommended by the Advisory Committee on Immunization Practices for all pregnant women, preferably between 27 and 36 weeks’ gestation. Limited data exist on Tdap safety during pregnancy. OBJECTIVE: To evaluate whether maternal Tdap vaccination during pregnancy is associated with increased risks of adverse obstetric events or adverse birth outcomes. DESIGN AND SETTING: Retrospective, observational cohort study using administrative health care databases from 2 California Vaccine Safety Datalink sites. PARTICIPANTS AND EXPOSURES: Of 123 494 women with singleton pregnancies ending in a live birth between January 1, 2010, and November 15, 2012, 26 229 (21%) received Tdap during pregnancy and 97 265 did not. MAIN OUTCOMES AND MEASURES: Risks of small-for-gestational-age (SGA) births (<10th percentile), chorioamnionitis, preterm birth (<37 weeks’ gestation), and hypertensive disorders of pregnancy were evaluated. Relative risk (RR) estimates were adjusted for site, receipt of another vaccine during pregnancy, and propensity to receive Tdap during pregnancy. Cox regression was used for preterm delivery, and Poisson regression for other outcomes. RESULTS: Vaccination was not associated with increased risks of adverse birth outcomes: crude estimates for preterm delivery were 6.3% of vaccinated and 7.8% of unvaccinated women (adjusted RR, 1.03; 95% CI, 0.97-1.09); 8.4% of vaccinated and 8.3% of unvaccinated had an SGA birth (adjusted RR, 1.00; 95% CI, 0.96-1.06). Receipt of Tdap before 20 weeks was not associated with hypertensive disorder of pregnancy (adjusted RR, 1.09; 95% CI, 0.99-1.20); chorioamnionitis was diagnosed in 6.1% of vaccinated and 5.5% of unvaccinated women (adjusted RR, 1.19; 95% CI, 1.13-1.26). CONCLUSIONS AND RELEVANCE: In this cohort of women with singleton pregnancies that ended in live birth, receipt of Tdap during pregnancy was not associated with increased risk of hypertensive disorders of pregnancy or preterm or SGA birth, although a small but statistically significant increased risk of chorioamnionitis diagnosis was observed.
To compare maternal and infant outcomes with different antihypertensive medications in pregnancy.
Retrospective cohort study.
Kaiser Permanente, a large healthcare system in the United States.
Women ...aged 15-49 years with a singleton birth from 2005-2014 treated for hypertension.
We identified medication exposure from automated pharmacy data based on the earliest dispensing after the first prenatal visit. Using logistic regression, we calculated weighted outcome prevalences, adjusted odds ratios (aORs) and 95% confidence intervals, with inverse probability of treatment weighting to address confounding.
Small for gestational age, preterm delivery, neonatal and maternal intensive care unit (ICU) admission, preeclampsia, and stillbirth or termination at > 20 weeks.
Among 6346 deliveries, 87% with chronic hypertension, the risk of the infant being small for gestational age (birthweight < 10th percentile) was lower with methyldopa than labetalol (prevalence 13.6% vs. 16.6%; aOR 0.77, 95% CI 0.63 to 0.92). For birthweight < 3rd percentile the aOR was 0.57 (0.39 to 0.80). Compared with labetalol (26.0%), risk of preterm delivery was similar for methyldopa (26.5%; aOR 1.10 0.95 to 1.27) and slightly higher for nifedipine (28.5%; aOR 1.25 1.06 to 1.46) and other β-blockers (31.2%; aOR 1.58 1.07 to 2.23). Neonatal ICU admission was more common with nifedipine than labetalol (25.9% vs. 23.3%, aOR 1.21 1.02 to 1.43) but not elevated with methyldopa. Risks of other outcomes did not differ by medication.
Risk of most outcomes was similar comparing labetalol, methyldopa and nifedipine. Risk of the infant being small for gestational age was substantially lower for methyldopa, suggesting this medication may warrant further consideration.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
IMPORTANCE: Controversy exists regarding the safety of testosterone replacement therapy (TRT) following recent reports of an increased risk of adverse cardiovascular events. OBJECTIVE: To investigate ...the association between TRT and cardiovascular outcomes in men with androgen deficiency. DESIGN, SETTING, AND PARTICIPANTS: A retrospective cohort study was conducted within an integrated health care delivery system. Men at least 40 years old with evidence of androgen deficiency either by a coded diagnosis and/or a morning serum total testosterone level of less than 300 ng/dL were included. The eligibility window was January 1, 1999, to December 31, 2010, with follow-up through December 31, 2012. EXPOSURES: Any prescribed TRT given by injection, orally, or topically. MAIN OUTCOMES AND MEASURES: The primary outcome was a composite of cardiovascular end points that included acute myocardial infarction (AMI), coronary revascularization, unstable angina, stroke, transient ischemic attack (TIA), and sudden cardiac death (SCD). Multivariable Cox proportional hazards models were used to investigate the association between TRT and cardiovascular outcomes. An inverse probability of treatment weight, propensity score methodology, was used to balance baseline characteristics. RESULTS: The cohorts consisted of 8808 men (19.8%) ever dispensed testosterone (ever-TRT) (mean age, 58.4 years; 1.4% with prior cardiovascular events) and 35 527 men (80.2%) never dispensed testosterone (never-TRT) (mean age, 59.8 years; 2.0% with prior cardiovascular events). Median follow was 3.2 years (interquartile range IQR, 1.7-6.6 years) in the never-TRT group vs 4.2 (IQR, 2.1-7.8) years in the ever-TRT group. The rates of the composite cardiovascular end point were 23.9 vs 16.9 per 1000 person-years in the never-TRT and ever-TRT groups, respectively. The adjusted hazard ratio (HR) for the composite cardiovascular end point in the ever-TRT group was 0.67 (95% CI, 0.62-0.73. Similar results were seen when the outcome was restricted to combined stroke events (stroke and TIA) (HR, 0.72; 95% CI, 0.62-0.84) and combined cardiac events (AMI, SCD, unstable angina, revascularization procedures) (HR, 0.66; 95% CI, 0.60-0.72). CONCLUSIONS AND RELEVANCE: Among men with androgen deficiency, dispensed testosterone prescriptions were associated with a lower risk of cardiovascular outcomes over a median follow-up of 3.4 years.
Abstract Introduction Since October 2012, the combined tetanus toxoid, reduced diphtheria toxoid, acellular pertussis vaccine (Tdap) has been recommended in the United States during every pregnancy. ...Methods In this observational study from the Vaccine Safety Datalink, we describe receipt of Tdap during pregnancy among insured women with live births across seven health systems. Using a retrospective matched cohort, we evaluated risks for selected medically attended adverse events in pregnant women, occurring within 42 days of vaccination. Using a generalized estimating equation, we calculated adjusted incident rate ratios (AIRR). Results Our vaccine coverage cohort included 438,487 live births between January 1, 2007 and November 15, 2013. Across the coverage cohort, 14% received Tdap during pregnancy. By 2013, Tdap was administered during pregnancy in 41.7% of live births, primarily in the 3rd trimester. Our vaccine safety cohort included 53,885 vaccinated and 109,253 matched unvaccinated pregnant women. There was no increased risk for a composite outcome of medically attended acute adverse events within 3 days of vaccination. Similarly, across the safety cohort, over a 42 day window, incident neurologic events, thrombotic events, and new onset proteinuria did not differ by maternal receipt of Tdap. Among women receiving Tdap at 20 weeks gestation or later, as compared to their matched controls, there was no increased risk for gestational diabetes or cardiac events while venous thromboembolic events and thrombocytopenia were diagnosed within 42 days of vaccination at slightly decreased rates. Conclusion Tdap coverage during pregnancy increased from 2007 through 2013, but was still below 50%. No acute maternal safety signals were detected in this large cohort.
Background Preventing fetal exposure to isotretinoin is widely acknowledged as an important safety issue. The iPLEDGE program is the latest in a series of Food and Drug Administration–mandated risk ...management programs designed to prevent pregnancies in female patients of childbearing potential (FCBP) taking isotretinoin. Objective We sought to evaluate the effect of iPLEDGE relative to the prior risk management program (system to manage Accutane-related teratogenicity SMART) on the risk of isotretinoin fetal exposure in FCBP in a managed care setting. Methods All FCBP at Kaiser Permanente Southern and Northern California who filled at least one prescription for isotretinoin during a 4-year period (March 1, 2004, to February 29, 2008) were included in this retrospective cohort study (n = 8344). Chart review was performed to confirm fetal exposures and outcomes. A Cox proportional hazards model was used to estimate the hazard ratio and 95% confidence intervals. Results There were a total of 29 fetal exposures and 9912 isotretinoin treatment courses. After iPLEDGE was implemented, the unadjusted rate of fetal exposure decreased from 3.11 to 2.67 per 1000 treatment courses ( P = .69). The hazard ratio = 0.76 (95% confidence interval 0.36-1.61) for fetal exposures to isotretinoin during treatment courses filled after iPLEDGE implementation compared with SMART. Limitations Limitations include limited generalizability of results, small sample size (n = 29 total documented fetal exposures), and potential uncontrolled confounders. Conclusion Evaluating the impact of iPLEDGE on isotretinoin fetal exposures is important in understanding the full risks and benefits of isotretinoin treatment. We found no evidence that iPLEDGE significantly decreased the risk of fetal exposure in FCBP compared to the SMART program.
Abstract Background A combined measles, mumps, rubella, varicella live vaccine (MMRV, Merck and Co., Inc., US) was recently licensed in the US. Pre-licensure clinical trial data showed a significant ...increase in fever in days 5–12 following MMRV vaccination as compared to the vaccines given separately (MMR + V). This post-licensure retrospective cohort study was undertaken to assess the incidence of febrile convulsion following MMRV. Methods Children ages 12–60 months who received a first dose of MMRV in February 2006–June 2007 in a managed care organization were included in the study. Subjects were optimally matched on age, sex, and calendar date of vaccination to children who received MMR + V concomitantly in November 2003–January 2006, before MMRV licensure. Potential cases of febrile convulsion were identified through administrative data and adjudicated by expert panel, according to pre-specified criteria. Results During the 30 days post-vaccination, there were 128 and 94 potential convulsion cases among the 31,298 children in the MMRV and MMR + V cohorts, respectively. After review of available medical charts and adjudication, there were 84 cases of confirmed febrile convulsion, 44 (1.41/1000) and 40 (1.28/1000) in the MMRV and MMR + V cohorts, respectively (RR = 1.10, 95% CI = 0.72, 1.69). In days 5–12 following vaccination, a pre-specified period of interest, the respective numbers were 22 (0.70/1000) and 10 (0.32/1000) (RR = 2.20, 95% CI = 1.04, 4.65). Conclusion These data suggest that the risk of febrile convulsion is increased in days 5–12 following vaccination with MMRV as compared to MMR + V given separately during the same visit, when post-vaccination fever and rash are also increased in clinical trials. While there was no evidence of an increase in the overall month following vaccination, the elevated risk during this time period should be communicated and needs to be balanced with the potential benefit of a combined vaccine.
Primary nonadherence occurs when new prescriptions are not dispensed. Little is known about how to reduce primary nonadherence. We performed a randomized controlled trial to evaluate an automated ...system to decrease primary nonadherence to statins for lowering cholesterol.
Adult members of Kaiser Permanente Southern California with no history of statin use within the past year who did not fill a statin prescription after 1 to 2 weeks were passively enrolled. The intervention group received automated telephone calls followed 1 week later by letters for continued nonadherence; the control group received no outreach. The primary outcome was a statin dispensed up to 2 weeks after delivery of the letter. Secondary outcomes included refills at intervals up to 1 year. Intervention effectiveness was determined by intent-to-treat analysis and Fisher exact test. Subgroups were examined using logistic regression.
There were 2606 participants in the intervention group and 2610 in the control group. Statins were dispensed to 42.3% of intervention participants and 26.0% of control participants (absolute difference, 16.3%; P < .001). The relative risk for the intervention vs control group was 1.63 (95% CI, 1.50-1.76). Intervention effectiveness varied slightly by age (P = .045) but was effective across all age strata. Differences in the frequency of statin dispensations persisted up to 1 year (P < .001).
The intervention was effective in reducing primary nonadherence to statin medications. Because of low marginal costs for outreach, this strategy appears feasible for reducing primary nonadherence. This approach may generalize well to other medications and chronic conditions.
To identify modifiable patient and provider factors associated with allopurinol adherence and the achievement of a serum urate acid (SUA) goal in gout.
We identified a retrospective cohort of ...patients with gout, newly treated with allopurinol. All patient data came from administrative datasets at a large integrated health delivery system. Patients were ≥ 18 years old at time of initial allopurinol dispensing, and had 12 months or more of membership and drug eligibility prior to the index date. Allopurinol adherence was defined as a proportion of days covered ≥ 0.80, evaluated during the first 12 months of observation after the initial dispensing. Multivariable logistic regression was used to examine factors associated with allopurinol nonadherence and attaining an SUA concentration < 6.0 mg/dl.
We identified 13,341 patients with gout with incident allopurinol use (mean age 60 yrs, 78% men). Of these, 9581 patients (72%) had SUA measured both at baseline and during followup. Only 3078 patients (32%) attained an SUA target of < 6.0 mg/dl during followup. Potentially modifiable factors associated with treatment adherence and obtaining the SUA goal in the multivariable analysis included concomitant diuretic use, prescriber specialty, and allopurinol dosing practices. Adherent patients were 2.5-fold more likely than nonadherent patients to achieve an SUA < 6.0 mg/dl during observation.
Among patients with gout initiating allopurinol in our study, 68% did not reach the SUA goal and 57% of patients were nonadherent. Modifiable factors, including allopurinol dose escalation, treatment adherence, rheumatology referral, and concomitant medication use, could be important factors to consider in efforts aimed at optimizing gout treatment outcomes.
CONTEXT More than 1.5 million US adults use stimulants and other medications labeled for treatment of attention-deficit/hyperactivity disorder (ADHD). These agents can increase heart rate and blood ...pressure, raising concerns about their cardiovascular safety. OBJECTIVE To examine whether current use of medications prescribed primarily to treat ADHD is associated with increased risk of serious cardiovascular events in young and middle-aged adults. DESIGN, SETTING, AND PARTICIPANTS Retrospective, population-based cohort study using electronic health care records from 4 study sites (OptumInsight Epidemiology, Tennessee Medicaid, Kaiser Permanente California, and the HMO Research Network), starting in 1986 at 1 site and ending in 2005 at all sites, with additional covariate assessment using 2007 survey data. Participants were adults aged 25 through 64 years with dispensed prescriptions for methylphenidate, amphetamine, or atomoxetine at baseline. Each medication user (n = 150 359) was matched to 2 nonusers on study site, birth year, sex, and calendar year (443 198 total users and nonusers). MAIN OUTCOME MEASURES Serious cardiovascular events, including myocardial infarction (MI), sudden cardiac death (SCD), or stroke, with comparison between current or new users and remote users to account for potential healthy-user bias. RESULTS During 806 182 person-years of follow-up (median, 1.3 years per person), 1357 cases of MI, 296 cases of SCD, and 575 cases of stroke occurred. There were 107 322 person-years of current use (median, 0.33 years), with a crude incidence per 1000 person-years of 1.34 (95% CI, 1.14-1.57) for MI, 0.30 (95% CI, 0.20-0.42) for SCD, and 0.56 (95% CI, 0.43-0.72) for stroke. The multivariable-adjusted rate ratio (RR) of serious cardiovascular events for current use vs nonuse of ADHD medications was 0.83 (95% CI, 0.72-0.96). Among new users of ADHD medications, the adjusted RR was 0.77 (95% CI, 0.63-0.94). The adjusted RR for current use vs remote use was 1.03 (95% CI, 0.86-1.24); for new use vs remote use, the adjusted RR was 1.02 (95% CI, 0.82-1.28); the upper limit of 1.28 corresponds to an additional 0.19 events per 1000 person-years at ages 25-44 years and 0.77 events per 1000 person-years at ages 45-64 years. CONCLUSIONS Among young and middle-aged adults, current or new use of ADHD medications, compared with nonuse or remote use, was not associated with an increased risk of serious cardiovascular events. Apparent protective associations likely represent healthy-user bias.
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