Recent studies show low to no risk for cardiac events with ADHD drugs

The prescription of attention-deficit/hyperactivity disorder medications to children and adults has steadily increased during the past decade, with estimates revealing widespread use among nearly 3 million youth and 1.5 million adults in the United States. The most commonly used medications, including psychostimulants and atomoxetine, have been linked to increases in BP and heart rate, as well as the potential for serious CV events such as sudden cardiac death, MI and stroke.

In the past year, the spotlight has been on adverse cardiac risks in those using attention-deficit/hyperactivity disorder (ADHD) drugs. In November, the FDA issued a statement that medications used to treat ADHD are not associated with an increased incidence of CV events in children and young adults, based on available information. Additionally, three large, retrospective studies sponsored by the FDA and the Agency for Healthcare Research and Quality that examined potential CV risks associated with ADHD medications were released in the past year, each showing no or minimal risks for serious CV events in both children and adults prescribed ADHD drugs.

Timothy K. Knilans, MD, said recent data provide a clearer picture of the link between ADHD drugs and cardiac events. Source: Cincinnati Children’s Hospital Medical Center

“We have known for decades that there is an association between stimulant medications and CV effects,” Timothy K. Knilans, MD, director of clinical cardiac electrophysiology and pacing at Cincinnati Children’s Hospital Medical Center, said in an interview. “However, recent large studies do not seem to be finding a substantial risk for associated life-threatening events.”

Cardiology Today interviewed cardiologists, pediatricians and psychiatrists about the effect that recent statistics, studies and FDA warnings have on the care of patients with ADHD in clinical practice.

Recent evidence

Post-marketing reports of sudden cardiac death, MI and stroke in those who were prescribed ADHD drugs led the FDA and the Agency of Healthcare Research and Quality to sponsor the three observational studies.

The first study, published by William O. Cooper, MD, MPH, and colleagues in The New England Journal of Medicine in November, showed that current ADHD drug use was not associated with increased risk for CV events among more than 1.2 million children and young adults aged 2 to 24 years (HR=0.75; 95% CI, 0.31-1.85). The retrospective cohort study used automated data from four health plans (Tennessee Medicaid, Washington State Medicaid, Kaiser Permanente California and OptumInsight Epidemiology). Researchers identified 81 serious CV events — defined as sudden cardiac death, acute MI and stroke — and an overall rate of 3.1 events per 100,000 person-years. Compared with former users, current users of ADHD drugs were not at increased risk for CV events (HR=0.7; 95% CI, 0.29-1.72).

“The upper limit of the 95% confidence interval indicated that a doubling of the risk could not be ruled out. However, the absolute magnitude of such an increased risk would be low,” the researchers said.

For another study, the same group of researchers, led by Laurel A. Habel, PhD, analyzed serious CV events and ADHD medication use in an older population of adults aged 25 to 64 years. The retrospective, population-based, cohort study included more than 443,000 adults, 150,000 of whom had prescriptions for methylphenidate, amphetamine or atomoxetine. After 806,182 person-years of follow-up (median of 1.3 years per person), 1,357 cases of MI, 575 cases of stroke and 296 cases of sudden cardiac death were reported. Analysis of 107,322 person-years of current drug use yielded a crude incidence of 1.34 per 1,000 person-years for MI, 0.56 per 1,000 person-years for stroke and 0.30 per 1,000 person-years for sudden cardiac death. The researchers calculated a multivariable-adjusted rate ratio (RR) of 0.83 (95% CI, 0.72-0.96) of serious CV events for current users vs. nonusers. The adjusted RR among new users was 0.77 (95% CI, 0.63-0.94).

Although the researchers concluded that the risk for serious CV events in this population is low, they said “a modestly elevated risk cannot be ruled out, given limited power and a lack of complete information on some potentially important risk factors and other factors related to use of these medications.” The data were published online in the Journal of the American Medical Association in December.

“Since adults are more likely to have underlying CV problems than children, it is especially reassuring to learn that FDA-approved medications for ADHD do not likely pose any serious CV risk in adults with ADHD,” Andrew Adesman, MD, chief of developmental and behavioral pediatrics at Steven and Alexandra Cohen Children’s Medical Center of New York, told Cardiology Today. “Since more than 1.5 million adults take ADHD medications, it is comforting to read that a careful study of a very large sample failed to find evidence or suggestion of serious CV risks from these medications.”

A third sponsored study found no elevated risk for stroke in those taking ADHD medications. Cooper, Habel and colleagues identified 150,658 adults aged 25 to 64 years with prescriptions for ADHD medication using computerized health records from four study sites; each user was matched to two nonusers. During more than 835,000 person-years of follow-up, 575 strokes occurred. Among current users, the crude incidence of stroke was 0.69 per 1,000 person-users. The multivariable-adjusted RR for any stroke for current users vs. nonusers was 0.77 (95% CI, 0.59-1.02). RRs for hemorrhagic and ischemic strokes were similar. Among current users, the adjusted RR for stroke comparing current vs. remote use (more than 1 year since last use) was 1.02 (95% CI, 0.71-1.45).

The researchers concluded: “The results of our large, population-based study should be reassuring with respective to the CV safety of relatively short-term use of ADHD medication in young and middle-aged adults.” The findings have not yet been published.

Mark Olfson

Another recent study published in the Journal of the American Academy of Child and Adolescent Psychiatry also found no definitive link between CV events and ADHD medication in children with known CV conditions. According to Mark Olfson, MD, MPH, and colleagues, this is one of the largest studies to date focusing primarily on youth while controlling for pre-existing CV risk factors. The study focused on more than 171,000 privately insured youth aged 6 to 21 years who had previously received ADHD stimulant treatment, were currently receiving treatment, or began or stopped treatment during the study period. Results showed that CV events and symptoms were rare in this cohort and were not associated with stimulant use.

“Most of the studies [on ADHD drugs and CV risks] all seem to be pointing in the direction of safety,” Olfson, professor of clinical psychiatry at Columbia University, said in an interview.

Concerns alleviated

For many, the recent data have helped to alleviate some of the concerns about the potential for serious CV events in those taking ADHD medications.

“In general, the large majority of research does not demonstrate any direct link. There are case reports in the literature, but any attempt at bringing together more systematic evidence has failed to show a real relationship between stimulant medications and serious cardiac events,” James M. Perrin, MD, professor of pediatrics at Harvard Medical School, told Cardiology Today.

With the newer data, “some of the early concerns have been allayed, and that is reassuring,” Olfson. “At the same time, we need to be watchful and vigilant in terms of identifying children and adults who have pre-existing risk factors and need to be particularly cautious of them starting treatment with stimulants.”

For others, the available CV safety data are limited and inconsistent.

“The recent studies do not alleviate my concerns,” said Steven Nissen, MD, chair of the department of CV medicine at Cleveland Clinic and a Cardiology Today Editorial Board member. “We have an absence of high-quality information. The problem is that there haven’t been the right kinds of long-term, randomized safety trials with these drugs.”

Long-term safety

ADHD has traditionally been considered a disorder confined to childhood. However, longitudinal studies that have followed children with ADHD into adulthood have shown that a significant number continue to struggle with some of the same issues of trouble focusing their attention and restlessness, Olfson said.

Almut Winterstein

With research showing no direct link between serious cardiac risks and ADHD medication use, Almut Winterstein, PhD, of the department of pharmaceutical outcomes and policy at the University of Florida, told Cardiology Today that more research is needed on patients prescribed to stimulants, especially on patients prescribed for more than 2 years.

“We do not know what happens to children who have been exposed to stimulants for many years,” Winterstein said. “The follow-up time in most studies to date has been less than 2 years, on average. There are children who are taking stimulants well into adulthood, and we have no evidence right now to look at the effects over a decade or more.”

Increased recognition of ADHD has prompted increased treatment. Use of ADHD medications increased more rapidly in adults than in children between 2001 and 2010, according to America’s State of Mind Report, a Medco Health Solutions analysis of trends in mental health medication usage among approximately 2.5 million insured Americans.

“There are people over the age of 55 who are being diagnosed with ADHD, a disease that used to be defined to children,” Nissen said.

“The longer-term effects of these drugs, especially on a population that has other increasing CV risk factors, remains to be seen,” Knilans said.

Other issues

An FDA Drug Safety Communication issued in November, after the results of the three sponsored studies were released, encouraged health care professionals to note that stimulants and atomoxetine should generally not be used in patients with serious CV problems or for whom an increase in BP or heart rate may be of particular concern. It was also suggested that patients treated with ADHD medications be periodically monitored for changes in BP and heart rate.

The link between adverse cardiac events and ADHD medications has also been the topic of several FDA advisory committee meetings. In 2006, an FDA advisory panel proposed placing a black-box warning concerning CV events on psychostimulants in response to adverse event reports. A final decision was made not to place the black-box warning on medications, but to pursue further research. In 2007, the FDA directed manufacturers of ADHD medications to revise product labeling to reflect concerns about the adverse CV and psychiatric events. Current prescribing label instructions for ADHD medications emphasize a physical exam and a review of personal and family history for relevant cardiac events before initiating stimulant treatments.

As concern over the safety of stimulant medications has grown, so has controversy about the best method to screen for underlying cardiac defects. In 2008, the American Heart Association published a scientific statement suggesting universal electrocardiographic screening for patients prescribed stimulant medications. Significant debate ensued, with organizations such as the American Academy of Pediatrics refuting the need for this. A recommendation was subsequently revised on the basis of input from several pediatric organizations.

“The American Academy of Pediatrics said the evidence to support electrocardiographic evaluations does not exist, and that has been supported by recent evidence as well,” Perrin said.

Despite controversy surrounding whether electrocardiograms are needed before prescribing stimulants, a study by Patricia Elizabeth Thomas, MD, of the department of pediatric cardiology at Ochsner Medical Center for Children in New Orleans, and colleagues published in Archives of Pediatrics and Adolescent Medicine in February 2011 showed that ECG screenings increased fourfold from before the 2008 scientific statement to after.

A 2012 study published in Pediatrics by Laurel K. Leslie, MD, MPH, of Tufts University School of Medicine, and colleagues showed that 18% of physicians recognized in-depth cardiac history and physicals as a barrier to care, and 71% recognized interpreting pediatric ECG as a barrier. Only 15% of 525 physicians reported ordering an ECG.

Major organizations recommend that physicians screen patients for medical and family history of CV risk before stimulant medications are prescribed. Some said they believe that a personal and medical history is enough to determine whether a person is at risk for CV events before prescribing ADHD medications. Others, such as Perrin, disagreed. “We all feel that we can do a better job in identifying children who may have CV risks than we are doing now,” he said.

Increased collaboration

Joint care by cardiologists and other physicians is warranted for patients of all ages with ADHD.

Jeffrey A. Towbin

“An increasing number of pediatricians and general medicine physicians are prescribing ADHD medications and diagnosing ADHD compared with in the past,” Winterstein said.

Jeffrey A. Towbin, MD, executive co-director of The Heart Institute and professor and chief of cardiology at Cincinnati Children’s Hospital, said cardiologists should be included in the prescription of stimulants if the patient has a risk factor such as CVD.

“There are too many children with a diagnosis of ADHD for the small cadre of cardiologists, particularly pediatric cardiologists, to deal with,” Towbin said.

Olfson said particular attention should be paid to premature sudden death, syncope, dizziness, palpitations and chest pains.

“If the family history or physical exam uncovers risk factors, then that child should be seen by a cardiologist before making the decision to start stimulant medication,” Olfson told Cardiology Today. “Cardiologists have an important role to play in the treatment and decisions about initiating stimulants in high-risk children.”

Although psychiatrists and physicians said they believe that collaboration should exist, there is still hesitance on collaboration between psychiatry and general medical services.

“My overall sense is that there are problems throughout our health care system with integrating mental health and general medical services,” Olfson said. “We know that adults with major mental illnesses, such as schizophrenia, tend to end up getting poor general medical care. It wouldn’t surprise me if the same kinds of problems tend to occur in psychiatrically challenged children, particularly in children with serious disruptive behavior disorders and CV risk factors.”

Ongoing research on the link between adverse cardiac events and ADHD medications is expected to continue.

“We’re still unsure, but the evidence, at least with regard to immediate life-threatening events, is becoming clearer,” Knilans said. – by Casey Murphy

For more information:

• Akinbami L. NCHS Data Brief. 2011;70:1-8.
• CDC. Data and statistics. Available at: www.cdc.gov/ncbddd/adhd/data.html. Updated Dec. 12, 2011. Accessed Dec. 30, 2011.
• CDC. Increasing prevalence of parent-reported attention-deficit/hyperactivity disorder among children – United States, 2003 and 2007. Available at: www.cdc.gov/mmwr/preview/mmwrhtml/mm5944a3.htm. Updated Nov. 12, 2010. Accessed Dec. 30, 2011.
• Cooper W. N Engl J Med. 2011;365:1896-1904.
• FDA. ADHD medications and risk of stroke in young and middle-aged adults. Available at: www.fda.gov/downloads/Drugs/DrugSafety/UCM279877.pdf. Accessed Jan. 25, 2012.
• FDA. ADHD: Not just for kids. Available at: www.fda.gov/Drugs/ResourcesForYou/SpecialFeatures/ucm289089.htm. Updated Jan. 25, 2012. Accessed Jan. 25, 2012.
• FDA. FDA directs ADHD drug manufacturers to notify patients about cardiovascular adverse events and psychiatric adverse events. Available at: www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2007/ucm108849.htm. Updated June 18, 2009. Accessed Jan. 24, 2012.
• FDA. Public health advisory for Adderall and Adderall XR. Available at: www.FDA.gov. Updated Jan. 21, 2010. Accessed Jan. 26, 2012.
• Gould M. Am J Psychiatry. 2009;166:992-1001.
• Habel L. JAMA. 2011;306:2673-2683.
• Leslie LK. Pediatrics. 2012;129:222-230.
• Nissen SE. N Engl J Med. 2006;354:1445-1448.
• Olfson M. J Am Acad Child Adolesc Psychiatry. 2012;51:147-156.
• Shaw P. JAMA. 2011;306:2723-2724.
• Thomas PE. Arch Pediatr Adolesc Med. 2011;165:166-170.

Disclosure: Drs. Adesman, Knilans, Nissen, Olfson, Perrin, Towbin and Winterstein report no relevant financial disclosures.