Cardiovascular Events With ADHD Medications
Cooper WO, Habel LA, Sox CM, et al.
New Engl J Med. 2011;365:1896-1904
Background. Many pediatric providers are familiar with the controversy over recommendations to include ECGs before beginning stimulant treatment for patients with attention-deficit hyperactivity disorder (ADHD). These concerns were raised primarily on the basis of case reports and not on population-based data. Cooper and colleagues used data from 4 health plans in the United States, retrospectively reconstructing health histories to assess the association between initiation of ADHD medications and the risk for serious cardiovascular events.
Methods. The data were obtained from Tennessee Medicaid, Washington State Medicaid, Kaiser Permanente of California, and a private insurance health plan data warehouse. The data represented visits from 1986 through the end of 2005. Data included enrollment records, hospital and outpatient claims, and dispensed prescriptions. Participants were 2-24 years old and had continuous enrollment for 365 days prior to the dispensing of their first ADHD medication. The investigators included stimulants as well as atomoxetine or pemoline as ADHD medications. Patients with potentially life-threatening illnesses were excluded, except those with congenital heart disease, who were purposefully included for this study. Each child who received an ADHD medication was matched with 2 children who were not receiving ADHD medication and who did not have a serious illness. Children were matched according to health plan and day of qualifying use. Investigators classified every person-day of the period after the initial ADHD medication was prescribed as either current-use days, former-use days (after the prescribed medication would have run out based on prescription records), and non-use days. Three serious cardiac events were considered primary endpoints: sudden cardiac death, myocardial infarction, or stroke. When a claim for a primary endpoint was identified, additional records were reviewed to establish the validity of the case, including review of death certificate data if needed. The primary comparison between children taking ADHD medications and nonusers was the hazard ratio. The analysis for the hazard ratio included controlling for the study site, medical and psychiatric conditions, the degree to which the child used care, age, and the calendar year.
Findings. The study included 1.2 million children with a mean age of 11 years and a mean length of follow-up of 2.1 years. At baseline, the children who were current users of ADHD medications sought healthcare more often, had a greater prevalence of psychiatric illnesses, and were more likely to have asthma, seizures, and congenital heart defects. In all, 81 children had a serious cardiovascular event: 33 children experienced sudden cardiac death; 39 experienced acute myocardial infarction; and 39 experienced a stroke. For all serious cardiovascular events, there were 3.1 events per 100,000 person-years. In the multivariate regression model, older children, those who were currently using antipsychotic drugs or had a major psychiatric illness, and children with serious cardiovascular conditions or chronic illnesses experienced an increased risk for serious cardiovascular events. When comparing current users of ADHD medication with either former users or nonusers, the hazard ratios were not significantly different. For example, current users had a hazard ratio 0.75 (95% confidence interval [CI], 0.31-1.85) compared with those who had never used ADHD medications. In a similar fashion, risk was not increased for current users compared with former users (hazard ratio, 0.70; 95% CI, 0.29-1.72). When the 3 cardiovascular endpoints were considered separately, no increased risk was found. Equally, there was no increased risk found for children taking methylphenidate, the most frequently used ADHD drug. Alternative analyses were conducted to assess the robustness of these findings. Even when evaluating children who were new users of ADHD drugs and including those with serious underlying cardiac disease, no significant association between ADHD medication use and serious cardiovascular events was found.
The full text of this article includes a review of the timeline of events that led to the American Heart Association's policy that ECGs were reasonable to obtain before beginning children on stimulant therapy for ADHD.
Although these data are not experimental, the rare incidence of serious cardiac events among children would make any sort of prospective trial impossible. As Cooper and colleagues emphasize, this is a very large cohort study, with many person-years of risk contained in the data set. Even when focusing on the highest-risk group (children with existing cardiovascular defects), the authors were unable to demonstrate a significant increased risk. The investigators were careful to state that the upper bound of the 95% CI for the point estimate of the hazard ratio was 1.85, meaning that it was possible that the rate was 85% higher among the children with ADHD treatment. However, the lower bound was 0.31, suggesting the possibility of a reduced risk for sudden cardiac death among children on ADHD medication. Either way, the absolute risk is quite small, a fact that was lost in the debate about whether to do baseline ECGs on children starting ADHD therapy. Perhaps now, future discussions on the topic will refer to this study, which offers a good quantification of that risk.
Abstract
ADHD Drugs and Serious Cardiovascular Events in Children and Young Adults
Cooper WO, Habel LA, Sox CM, et al.
New Engl J Med. 2011;365:1896-1904
Study Summary
Background. Many pediatric providers are familiar with the controversy over recommendations to include ECGs before beginning stimulant treatment for patients with attention-deficit hyperactivity disorder (ADHD). These concerns were raised primarily on the basis of case reports and not on population-based data. Cooper and colleagues used data from 4 health plans in the United States, retrospectively reconstructing health histories to assess the association between initiation of ADHD medications and the risk for serious cardiovascular events.
Methods. The data were obtained from Tennessee Medicaid, Washington State Medicaid, Kaiser Permanente of California, and a private insurance health plan data warehouse. The data represented visits from 1986 through the end of 2005. Data included enrollment records, hospital and outpatient claims, and dispensed prescriptions. Participants were 2-24 years old and had continuous enrollment for 365 days prior to the dispensing of their first ADHD medication. The investigators included stimulants as well as atomoxetine or pemoline as ADHD medications. Patients with potentially life-threatening illnesses were excluded, except those with congenital heart disease, who were purposefully included for this study. Each child who received an ADHD medication was matched with 2 children who were not receiving ADHD medication and who did not have a serious illness. Children were matched according to health plan and day of qualifying use. Investigators classified every person-day of the period after the initial ADHD medication was prescribed as either current-use days, former-use days (after the prescribed medication would have run out based on prescription records), and non-use days. Three serious cardiac events were considered primary endpoints: sudden cardiac death, myocardial infarction, or stroke. When a claim for a primary endpoint was identified, additional records were reviewed to establish the validity of the case, including review of death certificate data if needed. The primary comparison between children taking ADHD medications and nonusers was the hazard ratio. The analysis for the hazard ratio included controlling for the study site, medical and psychiatric conditions, the degree to which the child used care, age, and the calendar year.
Findings. The study included 1.2 million children with a mean age of 11 years and a mean length of follow-up of 2.1 years. At baseline, the children who were current users of ADHD medications sought healthcare more often, had a greater prevalence of psychiatric illnesses, and were more likely to have asthma, seizures, and congenital heart defects. In all, 81 children had a serious cardiovascular event: 33 children experienced sudden cardiac death; 39 experienced acute myocardial infarction; and 39 experienced a stroke. For all serious cardiovascular events, there were 3.1 events per 100,000 person-years. In the multivariate regression model, older children, those who were currently using antipsychotic drugs or had a major psychiatric illness, and children with serious cardiovascular conditions or chronic illnesses experienced an increased risk for serious cardiovascular events. When comparing current users of ADHD medication with either former users or nonusers, the hazard ratios were not significantly different. For example, current users had a hazard ratio 0.75 (95% confidence interval [CI], 0.31-1.85) compared with those who had never used ADHD medications. In a similar fashion, risk was not increased for current users compared with former users (hazard ratio, 0.70; 95% CI, 0.29-1.72). When the 3 cardiovascular endpoints were considered separately, no increased risk was found. Equally, there was no increased risk found for children taking methylphenidate, the most frequently used ADHD drug. Alternative analyses were conducted to assess the robustness of these findings. Even when evaluating children who were new users of ADHD drugs and including those with serious underlying cardiac disease, no significant association between ADHD medication use and serious cardiovascular events was found.
Viewpoint
The full text of this article includes a review of the timeline of events that led to the American Heart Association's policy that ECGs were reasonable to obtain before beginning children on stimulant therapy for ADHD.
Although these data are not experimental, the rare incidence of serious cardiac events among children would make any sort of prospective trial impossible. As Cooper and colleagues emphasize, this is a very large cohort study, with many person-years of risk contained in the data set. Even when focusing on the highest-risk group (children with existing cardiovascular defects), the authors were unable to demonstrate a significant increased risk. The investigators were careful to state that the upper bound of the 95% CI for the point estimate of the hazard ratio was 1.85, meaning that it was possible that the rate was 85% higher among the children with ADHD treatment. However, the lower bound was 0.31, suggesting the possibility of a reduced risk for sudden cardiac death among children on ADHD medication. Either way, the absolute risk is quite small, a fact that was lost in the debate about whether to do baseline ECGs on children starting ADHD therapy. Perhaps now, future discussions on the topic will refer to this study, which offers a good quantification of that risk.
Abstract
Source...