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

Division of Research, Kaiser Permanente Northern California, 2000 Broadway, Fifth Floor, Oakland, CA 94612,, USA.
JAMA The Journal of the American Medical Association (Impact Factor: 35.29). 12/2011; 306(24):2673-83. DOI: 10.1001/jama.2011.1830
Source: PubMed


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.
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.
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).
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.
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.
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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    • "However, the indications for treatment were not reported, and patients were only followed for 60 days. In a retrospective cohort of >800,000 adults aged 25 to 64 years, Habel et al. (2011) failed to find any increase in cardiovascular risk in users of ADHD medications (methylphenidate, amphetamine and atomoxetine) as compared to matched non-user controls. However, a meta-analysis by Mick et al. (2013) reported a statistically significant increased risk of high (>90 bmp) resting heart rate in adult ADHD patients treated with CNS stimulants, and these findings have been confirmed in recent studies (Vitiello et al. 2012; Ginsberg and Lindefors 2012). "
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    ABSTRACT: Methylphenidate is a piperidine derivative structurally and pharmacologically similar to amphetamine. Methylphenidate is indicated for Attention Deficit Hyperactivity Disorder (ADHD) in children aged 6 years of age and over when remedial measures alone prove insufficient. In adults, its indication, except in narcolepsy, is not defined. Methylphenidate received regulatory approval almost sixty years ago with a first registration in Switzerland in October 1954. To evaluate the off-label use of methylphenidate and its characteristics from a database of spontaneous reports. This study analysed data from the French Pharmacovigilance Database of adverse drug reactions spontaneously reported by health professionals from 1985 to December 2011. Off-label use was evaluated according to age. In the French Pharmacovigilance database, 181 cases of adverse drug reactions were reported with methylphenidate. Neuropsychiatric effects were the most frequent adverse event reported (41%) followed by cardiovascular and cutaneous side effects (14%). 143 reports concerned children (113 boys, 30 girls, mean age 10.6 ± 3.3 years) of which 46 (30%) were off-label uses. There were 38 adults (20 men, 18 women), of which 32 (88%) off-label use. In adults, methylphenidate was prescribed for depression, and this practice was associated with serious adverse events of drug dependence, overdose and suicide attempt. Overall, off-label use was detected in 43% (78/181) of all cases reported. More than 40% of the patients with drug reactions received methylphenidate for off-label indications. Additional long-term exposures and independent clinical studies are necessary to establish the long-term profile safety of methylphenidate.
    Full-text · Article · Jun 2014 · SpringerPlus
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    • "Regarding this normalization, our data rather point to cardio-protective effects of psychostimulants than to an increase in a sudden heart death risk. This influence on basal autonomic activation could be a potential explanation of the very recently published population-based cohort studies, reporting association of psychostimulant medication with reduced incidence of serious cardiovascular events (Cooper et al. 2011; Habel et al. 2011). Due to the limitations of the study design, the reported results have to be considered as preliminary data, which contribute to the actual data on autonomic effects of psychostimulants and channel continuative studies. "

    Full-text · Dataset · May 2014
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    • "Although background rates of serious cardiovascular events in children and adolescents are small [68], evidence of an increased risk of serious cardiac events in adult patients receiving ADHD medications is also limited. A retrospective US study of healthcare records of 443,198 adults aged 25–64 years (150,359 of whom received ADHD medications) found no evidence of sudden cardiac death, myocardial infarction, or stroke associated with the use of ADHD medication compared with no use [71]. Finally, a recent retrospective study of Medicaid and commercial US databases of 43,999 adult (≥18 years of age) new MPH users and 175,955 matched non-users found a small increased risk of sudden death or ventricular arrhythmia (but not stroke, myocardial infarction, or combined stroke/myocardial infarction) among MPH users, although the lack of a dose-response effect argued against a causal relationship [72]. "
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    ABSTRACT: Here we review the safety and tolerability profile of lisdexamfetamine dimesylate (LDX), the first long-acting prodrug stimulant for the treatment of attention-deficit/hyperactivity disorder (ADHD). A PubMed search was conducted for English-language articles published up to 16 September 2013 using the following search terms: (lisdexamfetamine OR lisdexamphetamine OR SPD489 OR Vyvanse OR Venvanse OR NRP104 NOT review [publication type]). In short-term, parallel-group, placebo-controlled, phase III trials, treatment-emergent adverse events (TEAEs) in children, adolescents, and adults receiving LDX were typical for those reported for stimulants in general. Decreased appetite was reported by 25-39 % of patients and insomnia by 11-19 %. The most frequently reported TEAEs in long-term studies were similar to those reported in the short-term trials. Most TEAEs were mild or moderate in severity. Literature relating to four specific safety concerns associated with stimulant medications was evaluated in detail in patients receiving LDX. Gains in weight, height, and body mass index were smaller in children and adolescents receiving LDX than in placebo controls or untreated norms. Insomnia was a frequently reported TEAE in patients with ADHD of all ages receiving LDX, although the available data indicated no overall worsening of sleep quality in adults. Post-marketing survey data suggest that the rate of non-medical use of LDX was lower than that for short-acting stimulants and lower than or equivalent to long-acting stimulant formulations. Small mean increases were seen in blood pressure and pulse rate in patients receiving LDX. The safety and tolerability profile of LDX in individuals with ADHD is similar to that of other stimulants.
    Full-text · Article · May 2014 · CNS Drugs
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