Meta-analysis of increased heart rate and blood pressure associated with CNS stimulant treatment of ADHD in adults

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Abstract

Compared to children, adults with ADHD are at greater risk for developing adverse cardiovascular related outcomes and, if treated, may be likely to carry a greater burden of exposure to stimulant medications. The goal of this report is to critically review the available literature relevant to the cardiovascular safety of CNS stimulants for adult ADHD (aADHD). Twenty potential clinical trials of a CNS stimulant for aADHD have been published between 1979 and 2012. Of these, ten presented sufficient data to estimate the relative change in various cardiovascular parameters associated with ADHD treatment modalities. These trials were predominantly focused on long-acting stimulant preparations for acute symptom reduction (median duration=6 weeks, range: 4–24 weeks) and enrolled relatively young subjects (median age=36 years, range: 22–40). Using random effects meta-analysis, we found that subjects randomized to CNS stimulant treatment demonstrated a statistically significant increased resting heart rate [+5.7 bpm (3.6, 7.8), p<0.001] and systolic blood pressure findings [+2.0 mmHg (0.8, 3.2), p=0.005] compared with subjects randomized to placebo. There was a statistically significant increased risk for a resting heart rate >90 bpm [4.2% (n=50) vs. 1.7% (n=8), OR=2.75 (1.3, 6.7), p=0.006] associated with CNS stimulant treatment. In light of prognostic value of resting heart rate with regard to cardiovascular morbidity in epidemiological studies, future research of adults with ADHD should focus on the potential clinical impact of the increase in heart rate observed in this meta-analysis.

Introduction

Attention-deficit/hyperactivity disorder (ADHD) is a common psychiatric disorder in children with worldwide prevalence estimates of approximately 3–10% (Akinbami et al., 2011, Polanczyk et al., 2007). Follow-up studies of children with this disorder have demonstrated that the symptoms of ADHD and its associated impairment persist into adulthood in approximately 30–50% of persons diagnosed with ADHD (Kessler et al., 2006, Faraone et al., 2006, Simon et al., 2009); it is estimated that 4–5% of American adults have this disorder. As the recognition that ADHD may persist into adulthood has gained greater acceptance, there has been a coincident increase in the use of CNS stimulants in adults with ADHD. For example, nearly 2% of American adults 20–44 years old were using stimulant medications for ADHD in 2010 representing marked increases in use among men (+188%) and women (+265%) over the prior decade (Medco, 2011). Faraone and Glatt (2009) conducted a meta-analysis of aADHD pharmacotherapy and concluded that both short- and long-acting CNS stimulants were effective (effect sizes of 0.96 and 0.73, respectively) in treating the over-activity, impulsivity, and inattention characteristic of patients with ADHD.

Despite their increasing use and documented efficacy, CNS stimulant pharmacotherapy has remained controversial due to safety concerns, including the potential for abuse and adverse cardiovascular side effects. In children, a case-control study suggested that stimulant exposure was associated with a 7-fold increased risk of sudden unexplained death as 1.8% of children with sudden unexplained death compared with 0.4% of children dying in a car accident had been exposed to methylphenidate (Gould et al., 2009). Subsequent studies of large claims databases failed to identify an increased risk for serious cardiovascular events associated with the use of CNS stimulants and concluded that the absolute and relative risks associated with these medications are exceedingly small in children (Winterstein et al., 2007, Mccarthy et al., 2009, Schelleman et al., 2011, Cooper et al., 2011).

Estimates of cardiovascular safety of CNS stimulants in children cannot be directly generalized to adults with ADHD, however. In general, adults have accumulated more cardiovascular disease risk factors with subsequently higher incidence rates in each decade of life. It is also noteworthy that adults with ADHD are at an even greater risk for developing unhealthy lifestyle practices and cardiovascular risk factors, such as obesity, early initiation of tobacco use, and a greater probability of chronic substance misuse (Franke et al., 2011, De Zwaan et al., 2011, Wilens et al., 2011, Matthies et al., 2012). Therefore, pharmacotherapy for aADHD results in exposure to CNS stimulants during a period of greater risk of cardiovascular disease.

The goal of this report is to critically review the available literature relevant to the cardiovascular safety of stimulants for aADHD. In this summary overview, we update previous literature reviews and conduct a formal meta-analysis of the effects of CNS stimulants in adults on several pathophysiologic cardiovascular parameters based on data from placebo-controlled trials conducted in adults with ADHD.

Section snippets

Literature search

Since there have been recent reviews of cardiovascular safety (Hammerness et al., 2011) and meta-analyses of clinical response (Faraone and Glatt, 2009) of the aADHD treatment literature, we conducted a systematic search of literature published since 2010 through PubMed using the search terms ADHD, adult, clinical trial, and stimulant. We extracted the following information from each article: (1) drug name and dose; (2) baseline, endpoint and change values for systolic blood pressure (SBP),

Statistical analysis

We extracted and analyzed the change from baseline values at the time of trial entry in cardiovascular parameters in adults with ADHD randomized to treatment with either an active CNS stimulant or to placebo. We used random-effects meta-analysis to estimate change in these variables pooled within the active and placebo groups and used random-effects meta-analytic regression models to estimate the magnitude and statistical significance of the change scores in the active relative to placebo

Results

The ten randomized, placebo-controlled clinical trials of CNS stimulants for aADHD included in this meta-analysis are listed in Table 1. All studies meeting our inclusion criteria were published after 2005 and focused predominantly on preparations designed to provide day-long coverage with a single dose. The one exception was a study of immediate release methylphenidate (Spencer et al., 2005) that required three daily doses and effectively provided the same coverage as a long-acting preparation

Discussion

In this meta-analysis of published clinical trials, we provide a contemporary estimate of change in blood pressure and pulse findings associated with CNS stimulant use for aADHD. In 2665 patients from 10 trials, we observed that use of CNS stimulants was associated with an increase in heart rate of approximately 5 bpm and an increase in systolic or diastolic blood pressure of 1.2 mmHg. We also noted a low overall risk (≤5%) of clinically significant cardiovascular events, including tachycardia or

Role of the funding source

The authors were supported by the following NIH Grants R01HL035434 (Goldberg, Mick), R01HL105268 (Goldberg, McManus), R01HL69874 (Goldberg, McManus), and P30HD004147 (Mick). The individual NIH institutions represented had no further role in study design; in the collection, analysis or interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.

Contributors

All authors have contributed to and have approved the final manuscript. Dr. Mick designed this study, preformed the literature review and conducted all meta-analyses. Dr. Mick generated the first draft which was edited by Drs. McManus and Goldberg who provided further interpretation of these results.

Conflict of interest

All authors declare that they have no conflicts of interest.

Acknowledgment

None.

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