Major Findings: Patients' mean heart rate increased significantly from 82 beats per minute at baseline to around 86 beats per minute at week 6 and at 6 months of using the OROS methylphenidate.
Source of Data: An open-label trial of 114 adolescents with ADHD.
Disclosures: The study was sponsored by McNeil, which markets OROS methylphenidate under the brand name Concerta. Dr. Hammerness acknowledged serving as a speaker for, receiving research funds from, or participating in CME activities or professional talks supported by several pharmaceutical companies, including McNeil.
HONOLULU – High-dose OROS methylphenidate was associated with small but statistically significant increases in systolic blood pressure and heart rate in a 6-month, open-label study in adolescents.
The study found that there were no significant long-term increases in diastolic blood pressure or in electrocardiographic measures, Dr. Paul Hammerness said at the annual meeting of the American Academy of Child and Adolescent Psychiatry.
The findings are consistent with other studies involving younger children and lower doses, said Dr. Hammerness of Massachusetts General Hospital and Harvard Medical School, Boston. Because of concerns about possible associations between stimulant medications for attention-deficit/hyperactivity disorder (ADHD) and cardiovascular complications–including sudden cardiac death–the Food and Drug Administration recommended in June 2009 that physicians pay special attention to a child's cardiovascular system when prescribing stimulants.
The study involved 114 adolescents with a mean age of 14 years at baseline (range, 12 to 18 years). All of the subjects were healthy, and all had a diagnosis of ADHD based on full DSM-IV criteria. The trial was intended to evaluate the use of OROS methylphenidate for the prevention of cigarette smoking (J. Pediatr. 2009;155:84–9).
Participants were excluded if they had a history of cardiovascular disease or had untreated mood or anxiety disorders, eating disorders, psychosis, or substance use disorders. Participants who were on stable regimens of benzodiazepines or antidepressants (other than monoamine oxidase inhibitors) could be admitted into the study.
The beginning dose of OROS methylphenidate was 0.5–0.75 mg/kg per day, and that was titrated to a maximum of 1.5 mg/kg per day by week 3. At week 6, the mean total daily dose was 63 mg, and 50% of the participants were taking 72 mg or more.
As expected, OROS methylphenidate was highly effective in treating the participants' ADHD. Their Rating Scale scores declined from a mean of 26.9 at baseline to 9.7 at week 6.
Of the 114 participants who entered the study, 73% were male, and their mean body mass index was 22.6 kg/m
Mean systolic blood pressure at baseline was 113 mm Hg, and that increased to 117 mm Hg at 6 months, a significant increase. Mean diastolic blood pressure began at 63 mm Hg, increased significantly to 65 mm Hg at week 6, but then returned to 64 mm Hg at 6 months. Mean heart rate began at 82 beats per minute, increased significantly to 86 beats per minute at week 6, and remained at about that rate at 6 months.
The investigators found no statistically significant or clinically meaningful changes in ECG variables, including PR, QRS, or QTC.
Reasoning that any adverse cardiovascular effects of OROS methylphenidate might be restricted to certain subsets of adolescents, the investigators separately analyzed those 16 participants who met criteria for prehypertension or hypertension at baseline, based on at least one blood pressure reading above the 90th or 95th percentile. The investigators found no impact of abnormal premedication blood pressure readings on blood pressure changes during treatment.
None of the participants experienced serious adverse events or serious cardiovascular adverse events during the study. Ten of the 114 subjects reported one or more subjective cardiovascular complaints, including palpitations, chest pain, and fast or racing heartbeat. Of those, six had a lifetime diagnosis of comorbid anxiety disorder.
One participant discontinued treatment because of recurrent palpitations. She had a lifetime history of comorbid generalized anxiety disorder and migraines. But she showed no change from baseline in any cardiovascular measurement, and her primary care physician did not find her complaints to be consistent with cardiac disease. She later used a different stimulant medication with no subsequent cardiovascular symptoms.
“The FDA continues to review and still concludes that the overall risk-benefit ratio supports the use of stimulant medications for ADHD,” Dr. Hammerness said. But he did recommend that clinicians carefully evaluate a child's cardiovascular symptoms and family history before prescribing stimulants.