Acute and Long-Term Cardiovascular Effects of Stimulant, Guanfacine, and Combination Therapy for Attention-Deficit/Hyperactivity Disorder

J Child Adolesc Psychopharmacol. 2016 Dec;26(10):882-888. doi: 10.1089/cap.2015.0264. Epub 2016 Aug 2.


Objectives: This study examines cardiovascular (CV) effects of guanfacine immediate-release (GUAN-IR), dexmethylphenidate extended-release (DMPH), and their combination (COMB) during acute and long-term treatment of youth with attention-deficit/hyperactivity disorder.

Methods: Two hundred seven participants aged 7-14 years enrolled in an 8-week double-blind randomized trial of GUAN-IR (1-3 milligrams (mg)/day), DMPH (5-20 mg/day), or COMB with fixed-flexible dosing and titrated to optimal behavioral response. Heart rate, systolic blood pressure (BP), diastolic BP, and electrocardiograms were assessed at baseline, end of blinded optimization, and over a 1-year open-label maintenance phase.

Results: During acute titration, GUAN-IR decreased heart rate, systolic BP, and diastolic BP; DMPH increased heart rate, systolic BP, diastolic BP, and corrected QT (QTc) interval; COMB increased diastolic BP, but had no effects on heart rate, systolic BP, or QTc. During maintenance, GUAN-IR-associated decreases in heart rate and DMPH-associated increases in systolic BP returned to baseline values. Other variables across the three groups remained unchanged from the end of blinded titration. There were no discontinuations due to CV adverse events.

Conclusion: GUAN-IR, DMPH, and COMB were well tolerated and safe. Expected changes in CV parameters during acute titration were seen in GUAN-IR and DMPH groups, with COMB values falling intermediately between the two other treatment groups. No serious CV events occurred in any participant. GUAN-IR- and DMPH-associated CV changes generally returned to baseline with sustained therapy. These data suggest that COMB treatment might attenuate long-term CV effects of GUAN-IR and stimulant monotherapy, possibly reducing risk of the small but statistically significant changes associated with either single treatment. Identifier: NCT00429273.

Keywords: ADHD; cardiovascular; guanfacine; safety; stimulant.

Publication types

  • Comparative Study
  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adrenergic alpha-2 Receptor Agonists / administration & dosage
  • Adrenergic alpha-2 Receptor Agonists / adverse effects*
  • Adrenergic alpha-2 Receptor Agonists / therapeutic use
  • Attention Deficit Disorder with Hyperactivity / drug therapy*
  • Blood Pressure / drug effects
  • Central Nervous System Stimulants / administration & dosage
  • Central Nervous System Stimulants / adverse effects*
  • Central Nervous System Stimulants / therapeutic use
  • Child
  • Delayed-Action Preparations
  • Dexmethylphenidate Hydrochloride / administration & dosage
  • Dexmethylphenidate Hydrochloride / adverse effects*
  • Dexmethylphenidate Hydrochloride / therapeutic use
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Drug Therapy, Combination
  • Electrocardiography
  • Female
  • Guanfacine / administration & dosage
  • Guanfacine / adverse effects*
  • Guanfacine / therapeutic use
  • Heart Rate / drug effects
  • Humans
  • Male
  • Time Factors


  • Adrenergic alpha-2 Receptor Agonists
  • Central Nervous System Stimulants
  • Delayed-Action Preparations
  • Dexmethylphenidate Hydrochloride
  • Guanfacine

Associated data