BOCA RATON, FLA. – The use of methylphenidate or mixed amphetamine salts for attention-deficit/hyperactivity disorder can increase heart rate, blood pressure, and the QT interval in children, adolescents, and adults, according to a review of placebo-controlled and open-label extension trials published since 2000.
The magnitude of the effects appears small for most patients, which points to the importance of screening for preexisting cardiovascular disease and asking about any relevant family or patient history, Dr. Raul R. Silva said.
Despite long-term use and the effectiveness of these stimulant medications to reduce core symptoms of ADHD, concerns arose about increased potential for cardiovascular events. The American Heart Association released guidelines for cardiac monitoring of all children with ADHD before treatment (Circulation 2008;117:2407–23). “Some of what they came out with was severe,” said Dr. Silva, vice chair of the department of child and adolescent psychiatry at New York University. For example, he pointed out, the American Academy of Pediatrics said it had to temper its recommendations (Pediatrics 2008;122:451–3).
Ultimately, the two organizations released a clarification statement that recognizes the need for responsible cardiovascular monitoring while not withholding these medications to treat ADHD, Dr. Silva said (J. Dev. Behav. Pediatr. 2008;29:335. Despite the joint clarification, confusion about the actual risks remains, Dr. Silva said.
To determine more, Dr. Silva and his colleagues identified and reviewed five double-blind, placebo-controlled studies and six open-label studies that reported relevant cardiovascular data.
“We looked at 10 years' worth of studies in children and adults that reported heart rate, blood pressure, and EKG changes,” Dr. Silva said in an interview at his poster presentation during the meeting, which was sponsored by the National Institute of Mental Health.
Both types of studies were included because double-blind, placebo-controlled studies “are so short, there is not always a clear picture” and because “long-term studies tend to be open label,” said Dr. Silva, who also has a private practice in Cresskill, N.J.
In the double-blind studies, mean heart rate increased by 1–8.5 beats per minute after 3–6 weeks of treatment. The percentages of patients who experienced predefined, “clinically notable” heart rate events were similar among groups who received methylphenidate (MPH), mixed amphetamine salts (MAS), or placebo. Significant increases of 1.5–4.4 bpm in mean heart rate were reported by most of the long-term, open-label extension studies. A comparison of the short-term and long-term studies does not suggest an accumulative risk, Dr. Silva said. He added that it is unclear whether long-term increases in heart rate associated with these stimulants could increase the risk for stroke, heart attacks, or dysrhythmias.
“It may be reasonable to assume that increases in heart rate with therapeutic doses of stimulants are relatively safe in patients without predisposing or preexisting cardiac risk factors; however, further research and data are required to confirm any potential increased risk for cardiovascular events later in life,” the authors wrote.
In terms of blood pressure changes, most of the double-blind studies demonstrated no significant increases with stimulant treatment, compared with baseline. Again, the percentages of patients who experienced clinically notable increases in blood pressure were similar among groups that received MPH, MAS, or placebo.
In contrast, most of the open-label studies found significant increases in systolic blood pressure (0.6–3.5 mm Hg) and diastolic blood pressure (0.7–2.6 mm Hg), compared with baseline. Despite the disparity in significance, numerically, the changes in blood pressure in both study types were similar, suggesting no accumulative effect.
Researchers have not demonstrated a relationship between such small increases in blood pressure and increased morbidity, Dr. Silva said. It is also unclear whether these increases translate to an increased risk for cardiovascular events in patients with preexisting hypertension.
“In essence, you end up seeing [that] there aren't that many serious changes that occur, and there are some you see in the placebo group as well,” Dr. Silva said. Even so, he added, the rate for these heart rate and blood pressure changes “tends to be a little higher for stimulant drugs, and that is what you want to be most concerned about.”
Acute consequences in children with preexisting cardiac disease and the unknown potential for long-term adverse effects in all children who are exposed to these stimulants are two major concerns. “Personally, I always follow up [with patients]. I take a family history, for example, of arrhythmias, and personal history for syncope and chest pain,” Dr. Silva said.
These are among the recommendations in the 12-item screening recommendations from the American Heart Association (Circulation 2008;117:2407–23 and Circulation 2007;115:1643–55). Also, pay attention to symptoms such as palpitations, near syncope, or syncope that could indicate a cardiac condition. Family history should include hypertrophic cardiomyopathy, long QT syndrome, Wolff-Parkinson-White syndrome, and Marfan syndrome.
Novartis Pharmaceuticals Corp. supported the study. Dr. Silva disclosed that he is a consultant and on the speakers bureau for Novartis.
