A study conducted to explore the effects of methylphenidate, a drug used to treat Attention Deficit Hyperactivity Disorder (ADHD), was found to be associated with cardiovascular diseases. The data was collected using nationwide health insurance database from 1st  January 2008 to 31st  December 2011 in South Korea. 1224 participants aged 17 or less, who had a history of cardiovascular disease and had at least one incident prescription ADHD medicine for methylphenidate, took part in the trial.

Heart conditions such as arrhythmias, hypertension, myocardial infarction, ischemic stroke or heart failure were considered and incidence rate ratios were calculated with conditional Poisson regression and adjusted for time varying comorbidity and co-medication. There was an increased risk of arrhythmia during the period of exposure to methylphenidate. The risk was highest in children with congenital heart defect. There was no significant risk of myocardial infarction, hypertension, ischemic stroke or heart failure. While there was an increased relative risk, the possibility of absolute risk was likely to be low.

ADHD Medicine – A Background

Previous observational studies have reported no association between the methylphenidate ADHD medicine used in children and young people, and adverse cardiovascular events. In 2009, one case-controlled study reported a strong association between the use of stimulants in young people and sudden death (1.8% people i.e. 10 users among 564 cases). This was compared with the use of stimulants in people in motor vehicle crashes (0.4% i.e. 2 users among 564 controls), with an odds ratio of 7.4 and 95% confidence interval ranging from 1.4-74.9.

In contrast, detailed studies have shown that there is no link between myocardial infarction and strokes associated with methylphenidate. Extensive studies showed that there were a lot of uncertainties which meant that correlation could not be ruled out.

There were five cases in Sweden that showed a significant link between cardiovascular disease and methylphenidate. Furthermore, small but significant increases in blood pressure were reported in children and adolescents. Despite these significant reports, no studies were conducted to fully explore this connection. The researchers looked at the incidence of each cardiovascular adverse event in children during periods in which they were exposed to methylphenidate, as compared to the times when they were not.

Methodology

The database contains all information on the diagnoses and prescribed drugs for about 50 million Koreans. The data that was used had been submitted by healthcare providers from 1st January 2007 to 31st December.  The database considered all factors such as age, sex, diagnoses and prescription drugs. Information on prescribed drugs included generic name, prescription date, duration as well as route of administration.

The researchers determined the incidence of cardiovascular adverse events in unexposed times before and after exposure. Patients were considered new users of methylphenidate if they had not received a prescription during the preceding year. None of the data was influenced by the participants nor was the data disseminated to the participants. In the case of a patient having multiple diagnoses, only the first diagnosis was considered. This was done to prevent the other diagnoses being influenced by it and potentially biasing the data.

The washout period was also taken into account. This meant that the possibility that patients might not take their medicine strictly according to the prescription instructions and might be exposed to drugs for longer than prescribed, was given due consideration.

Washout periods were defined as 1-3 days, 4-7 days, and 8-14 days after the end date of prescription supply. The day of initiation was also examined separately. Two consecutive 30 days pre-exposure periods of the drug were also taken into account. The purpose of this was to minimize the risk of patients being prescribed methylphenidate as a result of experiencing heart disease.

Results

Out of the 1224 participants, 864 had arrhythmias, 396 had disease, 52 had myocardial infarction, 67 had ischemic strokes and 44 had heart failure. The mean duration of methylphenidate exposure was 0.5 years for all events except heart failure, which was 0.3 years. The median age at first exposure was 11-13 and median age at first event was 11-13. Depression was the most common comorbid disease constituting for 29% in participants with myocardial infarction.

For myocardial infarction, no increased risk was observed overall, although risk was significantly raised for exposure up to 56 days only. No increased risk was observed with methylphenidate exposure for ischaemic stroke or heart failure.

This study found a significantly increased overall risk of arrhythmia associated with treatment with the ADHD medicine, methylphenidate in children and adolescents diagnosed with the disease.

While the risk of myocardial infarction was not significant overall, the researchers found an increased risk after the first week of treatment, which remained significantly high for the first two months of continuous treatment. The risk of arrhythmia was substantially higher in patients with existing congenital heart disease.

Previous research did not find any correlation stroke or myocardial infarction with methylphenidate, which is consistent with the current study’s results. This study, however showed that the risk is higher in the early time periods of prescription (8-14, 15-28, and 29-56 days). This is quite an interesting fact and warrants further research. The lack of increased heart disease risks might be due to discontinuation of the drug treatment or due to the relatively shorter treatment periods.

The risk of arrhythmia was increased for all risk periods up to 56 days. In particular, risk was highest in patients with congenital heart disease. While the risk of arrhythmia was lower in those without congenital heart disease, a significant risk was still present.

Conclusion

The study was quite conclusive since it considered the whole population of South Korea. Previous studies regarding ADHD medicine effects in comparison were quite limited. As cardiovascular diseases are quite rare in young children and adolescents, this study was quite interesting, since it explored the chances of these diseases being developed in such an age group. Antidepressants, antipsychotics, or antiepileptics are often co-prescribed with methylphenidate and could explain some of the association found with adverse cardiovascular events.

It is possible that other unmeasured time-varying confounders could have influenced the results. For instance, the variation in severity of ADHD or substance abuse could have affected the outcome. Hence, like every other study, there is a slight chance for error. There is a chance for error or missing information in the database or even of misdiagnosed or undiagnosed diseases. Therefore, this study should be considered with a grain of salt.

As the number of children and adolescents diagnosed with ADHD increases, the results of the study should be carefully considered and the potential outcomes should be weighed against the need of using the ADHD medicine, methylphenidate for treatment, especially for those with mild cases of the disease