Attention-Deficit/Hyperactivity Disorder (ADHD) is a common neuropsychiatric condition, characterised by age-inappropriate, pervasive and impairing levels of inattention and/or hyperactivity-impulsivity (American Psychiatric Association, 2013).

Pharmacological treatment is currently considered as an important component of the multimodal treatment of ADHD. Medications are recommended as the first treatment option in several guidelines/practice parameters (e.g., Pliszka S, 2007), at least for severe cases (NICE 2008, Taylor E. et al 2004), or as a treatment strategy for patients who did not respond to non-pharmacological interventions (NICE 2008).

Drugs used to treat ADHD include psychostimulants (e.g., methylphenidate and amphetamine derivatives) and non-psychostimulants (e.g. atomoxetine or guanfacine). As with other medications, and some non-pharmacological interventions, adverse events may and do occur during treatment with psychostimulants. A careful consideration of potential adverse events, balanced against the potential beneficial effects of medications, is crucial in the daily clinical practice. On the one hand, overlooking possible adverse events may result in patients being exposed to harm; on the other hand, overestimating adverse events may result in patients not benefitting from a potentially effective treatment.

One of the most concerning adverse events during treatment with psychostimulants relates to their possible cardiovascular effects. There is large body of evidence showing that psychostimulants may lead to increases in blood pressure and heart rate. A meta-analysis of clinical trial in adults with ADHD showed that psychostimulant treatment was associated with a statistically significant increase in 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] (Mick et al, 2013). In many subjects treated for ADHD, such changes are relatively minor. However, in a subset of patients (5-15%) these increases may be substantive (above 95^th centile) (Hammerness P.G. et al. 2011).

In terms of severe cardiovascular events, a series of large case control epidemiological studies showed no significant association between psychostimulant use and increased risk of myocardial infarction or stroke (Cooper W.O. et al., 2011; Schelleman H. et al., 2011; Winterstein A.G. et al., 2007, 2012). However, it has been pointed out that, since the absolute risk of cardiovascular events is low in the general population, even these large case control studies were underpowered to detect any significant association and were prone to possible confounding factors (Westover A.N. et al., 2012).

In a study recently published in the BMJ, Shin J.Y. et al. (2016) set out to address this issue using a study design, namely self controlled case series analysis, that allowed for the control of possible confounding factors.

Methods

Shin et al (2016) have drawn on the South Korea national health insurance claims database, which contains information on the diagnoses and drugs prescribed in about 50 million Koreans. They focused the analyses on individuals aged ≤17 who had received at least one prescription of methylphenidate and had experienced one of the following cardiovascular events: arrhythmias, hypertension, myocardial infarction, ischaemic stroke, or heart failure in the period January 2008 to 31 December 2011.

The main aim of the study was to determine the incidence of cardiovascular adverse events during periods in which study participants were exposed to methylphenidate, compared with the incidence in periods in which they were not exposed. As such, the study design was suitable to determine if methylphenidate triggers the occurrence of cardiovascular adverse events. An important secondary analysis was conducted to assess if the incidence of cardiovascular adverse events was higher in individuals with, compared to those without, congenital heart disease. Of note, analyses were conducted considering several exposure periods: 1-3 days, 4-7 days, 8-14 days, 15-28 days, 29-56 days, and >56 days after prescription of methylphenidate.

Results

The authors identified 1,224 participants who met study entry criteria (75-80% males; median age at first exposure: 11-13).

• The authors found an increased risk of arrhythmia for all periods combined (adjusted incidence rate ratio 1.61, 95% confidence interval: 1.48 to 1.74)
  • The highest risk (adjusted incidence rate ratio 2.01, 95% CI: 1.74 to 2.31) was found in the first three days of treatment and became not significant after day 56
• The risk of hypertension was higher only in days 4-7
• The risk of myocardial infarction was slightly raised in the first 56 days of treatment
• Use of methylphenidate was not associated with any increased risk, at any time, of ischaemic stroke and heart failure
• Of note, risk for arrhythmia was higher in patients with, than in those without, congenital heart disease (incidence rate ratio 3.49 (95% confidence interval 2.33 to 5.22) although it was still significant in individuals without congenital cardiovascular malformation
• There was no differential risk comparing low (< 27 mg/day) to high (> 27 mg/day) of methylphenidate.

Conclusions

The authors concluded:

The relative risk of myocardial infarction and arrhythmias is increased in the early period after the start of methylphenidate treatment for ADHD in children and young people. Though the absolute risk is likely to be low, the risk-benefit balance of methylphenidate should be carefully considered, particularly in children with mild ADHD.

Strengths and limitations

The main strength of the study is its design, which allowed detecting rare events and controlling for confounding factors. Another strength is the analysis of risk at different time points, which is informative for the clinical practice and management of patients.

A number of limitations should also be mentioned:

• Diagnoses made on the base of claims databases do not fully correlate with actual diagnoses inpatients’ records. However, since a differential rate of misclassification in individuals treated and untreated is unlikely.
• Additionally, although the authors adjusted for comorbidities and co-treatment with other medications, it is possible that unmeasured time varying factors could have affected the results.
• Finally, the authors could not assess non-compliance to prescribed medication, which could have influenced the results.

Summary

• The study showed that methylphenidate is associated with a small, but significantly increased risk of arrhythmias and myocardial infarction.
• This risk is higher in the early period of treatment and is independent from the dose.
• Of note, the risk of arrhythmias was higher in patients with congenital cardiovascular malformations, although it was still significant in those without congenital heart disease.
• There was no significantly increased risk of hypertension, ischaemic stroke, or heart failure.
• Overall, the results suggest that the increased risk might be accounted for by the increased heart rate associated with the use of methylphenidate.

What is the take-home message for prescribers? Should they stop prescribing methylphenidate?

Considering the magnitude (small) of the increased risk and the potential benefits of methylphenidate, at least in individuals without congenital cardiovascular problems, it seems that this should not be interpreted as the take-home message from this study. Rather, this study is a further reminder that the prescriber should be cautious and use methylphenidate when other non pharmacological options are not effective, and only after a careful evaluation of the cardiovascular risk.

As suggested by the European ADHD guidelines group:

There is no evidence available to support decision making with respect to the treatment of children with ADHD and congenital heart disease. In such cases, the EAGG recommends a full and frank discussion between the family, the ADHD specialist and a paediatric cardiologist. It is, however, the case that most children with cardiac problems, once stabilized by the paediatric cardiologist, may be treated with ADHD medications.
– (Cortese S. et al., 2013).

It is hoped that the paper by Shin et al. contributes to implementing a systematic discussion between family, ADHD specialist and paediatric cardiologist in the interest of the patient, rather than systematically preventing patients from receiving potentially beneficial medications.

Links 

Primary paper

Shin JY, Roughead EE, Park BJ, Pratt NL (2016). Cardiovascular safety of methylphenidate among children and young people with attention-deficit/hyperactivity disorder (ADHD): nationwide self controlled case series study. BMJ;353:i2550. doi: 10.1136/bmj.i2550. [PubMed abstract]

Other references

American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, DSM-5. American Psychiatric Publishing ed.; 2013.

Cooper WO, Habel LA, Sox CM, et al. (2011) ADHD drugs and serious cardiovascular events in children and young adults. N Engl J Med ;365:1896-904. doi:10.1056/NEJMoa1110212. [PubMed abstract]

Cortese S, Holtmann M, Banaschewski T, et al. (2013) Practitioner review: current best practice in the management of adverse events during treatment with ADHD medications in children and adolescents. J Child Psychol Psychiatry.;54(3):227–46. [PubMed abstract]

Hammerness, P.G., Perrin, J.M., Shelley-Abrahamson, R., & Wilens, T.E. (2011). Cardiovascular risk of stimulant treatment in pediatric attention-deficit/hyperactivity disorder: Update and clinical recommendations. J Am Acad Child Adol Psychiatry, 50, 978–990. [PubMed abstract]

Mick E, McManus DD, Goldberg RJ (2013). Meta-analysis of increased heart rate and blood pressure associated with CNS stimulant treatment of ADHD in adults. Eur Neuropsychopharmacol; 23(6): 534-41. [PubMed abstract]

National Institute for Health and Care Excellence (2008). Attention deficit hyperactivity disorder CG72.

Pliszka S (2007). Practice parameter for the assessment and treatment of children and adolescents with attention-deficit/hyperactivity disorder. J Am Acad Child Adol Psychiatry;46(7):894-921. [PubMed abstract]

Schelleman H, Bilker WB, Strom BL, et al. (2011) Cardiovascular events and death in children exposed and unexposed to ADHD agents. Pediatrics;127:1102-10. doi:10.1542/peds.2010-3371. [PubMed abstract]

Taylor E, Dopfner M, Sergeant J et al. (2004). European clinical guidelines for hyperkinetic disorder — first upgrade. Eur Child Adolesc Psychiatry;13 Suppl 1:I7-30. [PubMed abstract]

Westover AN, Halm EA (2012). Do prescription stimulants increase the risk of adverse cardiovascular events?: A systematic review. BMC Cardiovasc Disord;12:41. doi:10.1186/1471-2261-12-41. [PubMed abstract]

Winterstein AG, Gerhard T, Kubilis P, et al. (2012) Cardiovascular safety of central nervous system stimulants in children and adolescents: population based cohort study. BMJ;345:e4627. doi:10.1136/ bmj.e4627. [PubMed abstract]

Winterstein AG, Gerhard T, Shuster J, Johnson M, Zito JM, Saidi A (2007). Cardiac safety of central nervous system stimulants in children and adolescents with attention-deficit/hyperactivity disorder. Pediatrics;120:e1494-501. doi:10.1542/peds.2007-0675. [PubMed abstract]

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