New Link Between Stimulant Treatment and Heart Disease
Stimulant treatment for ADHD associated with rare cases of heart disease
Posted Sep 13, 2014
In the current issue of the Journal of Child and Adolescent Psychopharmacology, Soren Dalsgaard and colleagues report a longitudinal study of all Danish children born between 1990 and 1998 that studied the effects of stimulant medication on heart disease (2). Because Denmark has socialized medicine, the medical records of every citizen are entered into registries. This leads to data that are well suited to the study of variables that might be related to illness.
The initial group selected to study was all of the children born in Denmark between 1990 and 1998. This group of 714,258 children was subdivided into those children who were or were not diagnosed with ADHD at age 5 or older. There were 8,300 children diagnosed with ADHD. The children with ADHD were then divided into those treated with stimulants (5482) and those not treated with stimulants (2818). The study ended December 31, 2008. The children were followed for an average of 9.5 years.
The goal of the study was to assess the risk of stimulants for cardiac illness or death in children with ADHD taking stimulant medication. The dose of stimulant medication was also studied. The dose was divided into three levels: (1) more than 30 mg of methylphenidate, (2) between 15 mg and 30 mg of methylphenidate and (3) less than 15mg of methylphenidate.
The risk for heart disease was expressed in the statistical test called the Hazard Ratio (HR). The Hazard Ratio is the ratio of an event in one sample compared to another. For example, if in a study of medication (clinical trial), the death rate in the sample that received the medication was twice that of the sample that didn’t receive the medication, the HR of the medication would be 2 (3http://en.wikipedia.org/wiki/Hazard_ratio).
Among all of the 714,258 children, 5734 individuals had a cardiovascular event. (This is 84 events per 100,000 person years. A person year is a measure of the risk of exposure. One person taking a medication for one year is one person year.) In the total population, there was an increased risk of cardiovascular events in stimulant users compared to non-users (HR 1.83).
In children with ADHD (stimulant users and non stimulant users combined, 8,300 subjects), there were 111 cardiovascular events (170 events per 100,000 person years). The cardiac events and their percent occurrence were hypertension (8%), ischemic heart disease (2%), pulmonary heart disease(1%), arrhythmias (23%), cardiac arrest (1%), cerebrovascular disease (9%), heart disease, not otherwise specified (14%), cardiovascular disease, not otherwise specified (40%).
In children with ADHD, stimulant use compared to non stimulant use was associated with an increased risk for a cardiovascular event ( HR=2.34).
An unexpected finding was that decreasing the dose of stimulant medication toward the end of the study period was associated with increased risk of a cardiovascular event. At the time of the cardiac event, lower doses of stimulant medication in those who had received higher doses in the past were associated with a greater risk of a cardiac event. 57% of children with ADHD on stimulant medication with a dose decrease had a cardiovascular event. In contrast only 30% of children with ADHD on stimulant medication had a dose decrease without a cardiovascular event (p=0.002). At the time of the cardiac event in stimulant treated children, the lower the dose of stimulants the greater the likelihood of a cardiac event. The counterintuitive finding that lower doses of stimulant medication are associated with increased risk of a cardiac event receives support from a study of stimulants in Adult ADHD. Schelleman and colleagues found that doses of methylphenidate less than 20 mg /day in adults with ADHD were associated with twice the death rate compared to adults with ADHD treated with more than 20 mg /day of methylphenidate (3).
Six children died, but none died from cardiovascular causes.
Five children with ADHD had a serious cardiovascular event, but none of these children were treated with stimulants.
To summarize the results of this study, the use of stimulants in children with ADHD was associated with an increased risk of a cardiovascular event. Overall, higher doses of stimulants were associated an increased risk of an event. Unexpectedly, a decrease in dosage was also associated with an increased the risk of a cardiovascular event.
This is the most through study of the relationship between ADHD and cardiovascular events in children. It used the most subjects, ran the longest time, studied the effect of dose, and attempted to control for a number of issues related to the study. Several smaller studies have failed to find a relationship between stimulant medication and cardiovascular events in children. A study by Winterstein, et al (4) did find such a relationship ( HR 1.2), which was somewhat weaker than the current study.
The study is not free from shortcomings. The severity of the ADHD is not reported. This raises the question of whether the ADHD group who received stimulants differed by severity of their ADHD from the group who did not take stimulants. Reasons for not taking stimulants are not reported. 54% of the cardiac events are reported as NOS-not otherwise specified. This designation is not informative. The authors offer a speculative medical biological explanation for low doses of stimulants creating a high risk for a cardiac event. They speculate that lower doses may shorten contractility time for the heart that might lead to a cardiac event. Although this is an interesting possibility, the authors ignore the reduction of blood level to 0 on a daily basis with the use of stimulants. Everyone who takes stimulants has a low level of stimulants at least once a day. For this reason, it might be expected that shortened cardiac contractility time would be more evenly divided between high dose and low dose groups.
Although there is a detectable level of risk between the use of stimulants and a cardiovascular event, the authors note that the events are rare. The authors also note that children with ADHD are at increased risk of a cardiovascular event even if they have not received stimulant medication. Not mentioned by the authors of the study is that weighing the advisability of the use of stimulants in children entails a consideration of the remarkable effectiveness of stimulants for the treatment of ADHD. The ratio between the barely detectable risk of using these medications compared to the benefits afforded to most ADHD patients is a strong argument for their continued use in children and adolescents with ADHD.
- Westover AN, Halm EA: Do prescription stimulants increase the risk of adverse ardiovascular events? A systematic review BMC Cardiovasc Disord 12:41, 2012.
- Dalsgaard S, et al. Cardiovascular safety of stimulants in children with attention-deficit/hyperactivity disorder: a nationwide Prospective cohort study. JCAP 24: pp302-310. 2014
- Schelleman H. et al:Methylphenidate and risk of serious cardiovascular events in adults. Am J Psychiatry 169:178-185,2012
- Winterstein AG et al. Cardiac safety of central nervous system stimulants in children and adolescents with attention-deficit/hyperactivity disorder. Pediatrics 120:e1494-e1501, 2007.
Copyright, Stuart L. Kaplan, M.D., 2014 Stuart L. Kaplan, M.D., is the author of Your Child Does Not Have Bipolar Disorder: How Bad Science and Good Public Relations Created the Diagnosis. Available at Amazon.com.