FDA Urges Caution in Interpreting Study Linking Stimulants to Increased Risk for Sudden Death in Children

Barbara Boughton


June 15, 2009

June 15, 2009 — The US Food and Drug Administration (FDA) has urged caution in interpreting the results of a new case-control study that shows that stimulant medications, specifically methylphenidate, are associated with a 6- to 7-times increased risk for sudden death in children and adolescents.

The study is published online June 15 in the American Journal of Psychiatry. The authors emphasized that sudden death is a rare event even among children who take stimulants but concluded that careful assessment is necessary when prescribing these medications.

The work was funded by the FDA and the National Institute of Mental Health, but in a statement released today, the agency said: "Given the limitation of this study's methodology, the FDA is unable to conclude that these data affect the overall risk and benefit profile of stimulant medications used to treat [attention-deficit/hyperactivity disorder] ADHD in children. FDA believes that this study should not serve as a basis for parents to stop a child's stimulant medication."

FDA believes that this study should not serve as a basis for parents to stop a child's stimulant medication.

In an interview with Medscape Psychiatry before the FDA statement was released, lead author Madelyn S. Gould, PhD, professor of psychiatry and public health at Columbia University/New York State Psychiatric Institute, in New York City, essentially agreed with this assessment.

"I don't think this study should be used to preclude the use of stimulants in cases where it is clinically indicated," she said. "You have to consider that the risk [for sudden death] is still quite rare, and untreated ADHD can have serious detrimental impacts on a child's life."

In a press conference, Robert Temple, MD, director of medical policy for the FDA's Center for Drug Evaluation and Research, noted the limitations of the new study. "I don’t think it makes the case that there is real risk here," he said.

The authors relied on parents’ memories of their children’s medications at the time of their death, and that can be subject to recall bias, he noted. While the statistical significance of the study is unquestioned, it also relies on a relatively small number of events, Dr. Temple added.

Careful Clinical and Family History

In the study, the rate of stimulant use among 564 children and adolescents whose sudden deaths were due to unknown causes or cardiac dysrhythmia was 1.8%, compared with 0.4% for a matched group of youths who died as passengers in motor-vehicle accidents (odds ratio, 7.4; 95% CI, 1.4 – 74.9).

All the children — 10 in all — who were taking stimulants and experienced sudden death were taking methylphenidate, while use of stimulants was found in only 2 cases, 1 involving methylphenidate, among those who died as passengers in car accidents. Most, but not all, of the stimulants were prescribed for ADHD.

A careful clinical and family history to rule out heart problems and a history of sudden death, as well as an electrocardiogram, may be indicated before children are prescribed stimulants for ADHD, Dr. Gould noted.

The authors used mortality data from 1985 to 1996 to find 564 cases of sudden death occurring from age 7 years to age 19 years across the United States, along with a matched group of youths who died as passengers in motor-vehicle accidents. The research team also obtained death certificates that were reviewed for eligibility for the study, and parents of the deceased youths were interviewed with a survey that assessed medical history, use of medications, and medical conditions. The researchers also consulted autopsy and toxicology records.

This painstaking research was meant to eliminate any possible sources of bias, Dr. Gould said. The researchers also excluded those with evidence of cardiac disease or abnormal cardiac finding after autopsy; known syndromes that may have caused sudden death, including asthma, seizure, and prolonged-QT interval; as well as a history of sudden death in any first-degree relatives. In addition, they performed a series of sensitivity analyses to eliminate any confounding variables, such as use of tricyclic antidepressants, which may have been associated with sudden death.

You have to consider that the risk is still quite rare, and untreated ADHD can have serious detrimental impacts on a child's life.

"We ruled out as many confounding factors and biases that we could think of," Dr. Gould said. "But in a case-control study such as ours, there's no guarantee that we've ruled out every single one. We really did not anticipate finding this significant association between sudden death and methylphenidate."

According to an FDA press release, limitations of the study also include:

  • A time lag between when the deaths occurred and collection of data.

  • Sudden unexplained death is more likely to trigger a postmortem inquiry into the cause of death than motor-vehicle collision.

  • The difference in the circumstances of death (sudden death vs auto collision) may account for the differences in caregiver recall regarding medication use.

In an interview following the press conference, Dr. Gould acknowledged the limitations of the study but emphasized that the findings do show that sudden death may be a potential risk associated with stimulant use. She also noted that the authors had made every attempt to address the methodological challenges inherent in the study. "The study had enough statistical power to detect an association. My confidence in the results is not diminished, since it has been peer-reviewed," she said.

Dr. Gould noted that the study's findings should be considered in light of the risks known to be associated with untreated ADHD, such as increased accidents, antisocial behavior, and drug use. She added that more research is needed to assess both the risks and benefits of stimulants used to treat ADHD, as well as studies that look at the physiological effects of these medications on young people.

The American Academy of Pediatrics (AAP) and the American Heart Association (AHA) are somewhat at odds on the issue of whether or not to recommend an ECG prior to prescribing stimulant medications for ADHD. In August 2008, the AAP issued a policy statement saying routine ECGs were not warranted after the AHA had released a recommendation that physicians consider ordering an ECG to determine whether underlying heart disease is present before prescribing these medications.

At the FDA press conference, Benedetto Vitiello, MD, from the National Institute of Mental Health, in Bethesda, Maryland, who coauthored the editorial that accompanied the paper by Gould and colleagues, said that the new study could mean that scientists need to reconsider this issue. "The question is: Should the debate be reopened about the use of ECG prior to stimulant treatment?" he said.

Sudden Death Rare, but Stimulants "Not Innocuous"

In an editorial, Dr. Vitiello and Kenneth Towbin, MD, also from the National Institute for Mental Health, noted that although the design of the study was rigorous, its small numbers and case-control design may limit the strength of its conclusion.

Yet they point out, "The report by Gould et al should underscore that stimulants are not innocuous and that their therapeutic use requires careful diagnostic assessment, diligent safety screening, and ongoing monitoring."

Stimulants are not innocuous and their therapeutic use requires careful diagnostic assessment, diligent safety screening, and ongoing monitoring.

At the same time, the authors of the editorial emphasized that sudden death is a rare event and that it is difficult to estimate the risk even in those who take stimulants on a populationwide level, other than saying it is quite small. A prospective study that could reliably provide a more accurate estimate of the risk for this rare event would have to be so large that it would be impractical, Drs. Vitiello and Towbin add.

In its statement, the FDA said it would continue to review the strengths and limitations of the new study and others that have evaluated the risks of using stimulants to treat ADHD in children.

At the FDA press conference, Gerald Dal Pan, MD, director of surveillance and epidemiology for the FDA's Center for Drug Evaluation and Research, said the agency is sponsoring 2 studies — 1 in children and 1 in adults — that will evaluate the risk of stimulants for myocardial infarction, sudden death, and stroke.

The studies will rely on data from a large administrative database, as well as validation from medical records. The results of the study on stimulants and children should be available in the fall of 2009, and the study on adults should be released in early 2010, Dr. Dal Pan added.

In addition, the FDA cautioned that any child who develops cardiovascular symptoms — including chest pain, shortness of breath, or fainting — during treatment with stimulants should be seen immediately by a physician.

Products involved in the FDA review include: dexmethylphenidate HCl (Focalin, Focalin XR, Novartis); dextroamphetamine sulfate (Dexedrine, Dexedrine Spansules, GlaxoSmithKline; Dextroamphetamine ER; Dextrostat, Shire Pharmaceuticals); lisdexamfetamine dimesylate (Vyvanse, Shire Pharmaceuticals); methamphetamine (Desoxyn, Ovation Pharma); methylphenidate (Concerta, McNeil Pediatrics; Daytrana, Shire Pharmaceuticals; Metadate CD, Metadate ER, UCB Pharma; Methylin, Methylin ER, Mallinckrodt; Ritalin, Ritalin-LA, Ritalin-SR, Novartis); mixed salts amphetamine (Adderall, Adderall XR, Shire Pharmaceuticals); pemoline (Cylert, Abbott Laboratories), and generics.

Adverse events related to the use of stimulants, including methylphenidate, should be communicated to the FDA's MedWatch reporting program by telephone at 1-800-FDA-1088, by fax at 1-800-FDA-0178, online at http://www.fda.gov/medwatch, or by mail to 5600 Fishers Lane, Rockville, Maryland 20852-9787.

Drs. Gould, Vitiello, and Towbin reported no relevant financial disclosures.

Am J Psychiatry. Published online June 15.


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