ADHD Medications and Risk of Serious Cardiovascular Events in Young and Middle-aged Adults

Original Contribution
ONLINE FIRST
JAMA. 2011;306(24):2673-2683. Published online December 12, 2011. doi: 10.1001/jama.2011.1830

Laurel A. Habel, PhD; William O. Cooper, MD, MPH; Colin M. Sox, MD, MS; K. Arnold Chan, MD, ScD; Bruce H. Fireman, MA; Patrick G. Arbogast, PhD; T. Craig Cheetham, PharmD, MS; Virginia P. Quinn, PhD, MPH; Sascha Dublin, MD, PhD; Denise M. Boudreau, PhD, RPh; Susan E. Andrade, ScD; Pamala A. Pawloski, PharmD; Marsha A. Raebel, PharmD; David H. Smith, RPh, PhD; Ninah Achacoso, MS; Connie Uratsu, RN; Alan S. Go, MD; Steve Sidney, MD, MPH; Mai N. Nguyen-Huynh, MD, MAS; Wayne A. Ray, PhD; Joe V. Selby, MD, MPH
[+] Author Affiliations
Author Affiliations: Division of Research, Kaiser Permanente Northern California, Oakland (Drs Habel, Go, Sidney, Nguyen-Huynh, and Selby, Mr Fireman, and Mss Achacoso and Uratsu); Department of Pediatrics (Dr Cooper), Division of Pharmacoepidemiology, Department of Preventive Medicine (Drs Cooper and Ray), and Department of Biostatistics (Dr Arbogast), Vanderbilt University, Nashville, Tennessee; Harvard Pilgrim Health Care Institute, Department of Population Medicine, Harvard Medical School, Boston, Massachusetts, and Department of Pediatrics, Boston University School of Medicine, Boston (Dr Sox); OptumInsight Epidemiology, Waltham, Massachusetts (Dr Chan); Pharmacy Analytical Service, Kaiser Permanente Southern California, Downy (Dr Cheetham); Research and Evaluation Department, Kaiser Permanente Southern California, Pasadena (Drs Cheetham and Quinn); Group Health Research Institute, Seattle, Washington (Drs Dublin and Boudreau); Departments of Epidemiology (Dr Dublin) and Pharmacy (Dr Boudreau), University of Washington, Seattle; Meyers Primary Care Institute, Worcester, Massachusetts (Dr Andrade); HealthPartners Research Foundation, Bloomington, Minnesota (Dr Pawloski); Institute for Health Research, Kaiser Permanente Colorado, and School of Pharmacy, University of Colorado at Denver (Dr Raebel); Center for Health Research, Kaiser Permanente Northwest, Portland, Oregon (Dr Smith); and Departments of Epidemiology, Biostatistics and Medicine, University of California, San Francisco (Dr Sidney).
ABSTRACT

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.