ADHD Drug Overprescribing Raises Concerns Over Future CV Events

Despite evidence that prescription stimulants used to treat attention-deficit/hyperactivity disorder (ADHD) raise blood pressure and resting heart rate, the literature is unclear with regard to the long-term CV risks of using them, according to a review paper. Researchers say prescribing rates of the medications have been climbing in the United States while global rates of ADHD remain relatively stable.

In an interview with TCTMD, a co-author said US physicians and the general public have been “too lackadaisical” about prescription stimulant medications. While there are upsides for many users, such as better concentration in school or work, they are not benign therapies.

“It's a public health message that I think is overdue,” said James H. O’Keefe, MD (Saint Luke’s Mid America Heart Institute, Kansas City, MO). “We need to track this closely and we need to be really careful about doses, about who's getting it, and how long they're taking it.”

In a review of the literature looking at potential cardiovascular toxicity of pharmacotherapies including amphetamine salts, methylphenidate, lisdexamfetamine, atomoxetine, and methamphetamine, O’Keefe and colleagues led by Noel Torres-Acosta, MD (University of Missouri-Kansas City), found a mixed bag of reported CV events in kids and adults alike. These included arrythmias, increased emergency department visits for cardiac complaints, and even sporadic cases of sudden cardiac death in children. But other data, including a large Danish study of over 1.2 million people ages 2 to 24 years, found no heightened risk of MI, sudden cardiac death, or stroke. At 9.5 years, that study’s follow-up is far longer than most of the stimulant data. That’s a problem, Torres-Acosta and colleagues say, because longer follow-up may be required to fully grasp the CV risks of the various medications.

We need to track this closely and we need to be really careful about doses, about who's getting it, and how long they're taking it. James H. O’Keefe

The largest study in adults included more than 400,000 people ages 25 to 64 years who had a median duration of use of ADHD medications of 4 months and a median follow-up of 1.3 years. Overall, CV risk was not increased, but there was a trend toward more adverse CVD events in patients who had recently started taking ADHD medications. However, that study also suggested that current users of ADHD medication had less occurrence of the composite of MI, sudden cardiac death, and stroke compared with nonusers.

Another study that looked at methylphenidate found a greater risk for sudden cardiac death or ventricular arrhythmia and all-cause mortality in users versus nonusers. The follow-up for that study was only a median of 60 days. A similar study of amphetamine and atomoxetine use found no increased risk of sudden cardiac death, ventricular arrhythmia, stroke, MI, or all-cause death, again with short median follow-ups.

As Torres-Acosta and colleagues note, the available studies are disparate, combining different age groups, outcomes, and medications. Future research, they say, will need to include very large cohorts since “the incidence of these events is low and would be very hard to demonstrate on RCTs. Also, study samples should be enhanced with older adults as well as those at a high risk for CV disease,” they write.

Skyrocketing Prescriptions in Adults

An estimated 6.1 million children and adults in the United States take prescription stimulants for ADHD symptoms. Torres-Acosta and colleagues say while the global prevalence of ADHD has remained stable for the last three decades, an increase of 26% was seen in ADHD diagnoses in US children ages 5 to 11 between 2007 and 2016, with an increase of 123% during the same period among US adults. Even more startling, adult women had a 344% increase in prescription filling rate of ADHD medications between 2003 and 2015.

“If you look at the use of these medications in America versus, say, Japan or Europe, or China, it's between five hundred and a thousand percent higher here than there,” O’Keefe said. “Physicians are way too liberal about using them, and parents are too trusting.”

He noted that more education is needed about safe alternatives. The review paper describes a few studies that support exercise therapy for adults and children with ADHD. While the amounts of regular exercise needed to combat symptoms either as a stand-alone therapy or in combination with medication is uncertain, the benefits of exercise therapy should not be ruled out, O’Keefe said.

Additionally, the review paper notes that some research indicates that children with ADHD have lower levels of omega-3 polyunsaturated fatty acids than controls, raising the possibility that supplements may be a reasonable addition to conventional treatment, or an option for people who refuse stimulants for themselves or their children.

“Nutrition is powerful therapy,” O’Keefe said, noting that most physicians in practice today have had “zero training in nutrition.”  

Data show that children taking eicosapentaenoic acid at doses greater than 500 mg/day consistently showed improvements in hyperactivity symptoms, although not improvements in inattention behavior. Still, O’Keefe said for patients and physicians who haven’t discussed this option, “it's harmless, it's inexpensive, and it’s a great substitute.”