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

Abstract

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. Clinicaltrials.gov Identifier: NCT00429273.

The Association between Low Blood Pressure and Attention-Deficit Hyperactivity Disorder (ADHD) Observed in Children/Adolescents Does Not Persist into Young Adulthood. A Population-Based Ten-Year Follow-Up Study

“…When children with ADHD are treated with stimulants, they often show an increase of their usually low BP concurrently with symptom improvement [ 51 , 52 , 53 , 54 ]. This clinical observation and additional findings from diurnal heart rate, cortisol level and sleep stages suggest a dysregulation of the autonomic nervous system in children with ADHD and leads to the subcortical (low) arousal hypothesis.…”

Viloxazine in the Management of CNS Disorders: A Historical Overview and Current Status

“…However, nonstimulants, which are generally less effective and have a slower onset of effect than stimulants [84], are also not without limitations. For example, they have been associated with minor changes in blood pressure or cardiovascular risk [85][86][87], precipitation of secondary mania [88,89], and suicidal ideation [90], although these events are rare and generally restricted to vulnerable populations with pre-existing conditions.…”

Attention-deficit hyperactivity disorder medication use: factors involved in prescribing, safety aspects and outcomes

“…Indeed, in a comprehensive double-blind, cross-over QT study with 83 healthy adults therapeutic and supra-therapeutic doses (4 mg and 8 mg, respectively) of guanfacine-IR revealed that neither doses of this α2-adrenergic receptor agonist prolonged the QTc interval through 12 h after drug administration [Martin et al 2015]. In addition, a recent double-blind randomized trial assessed the acute and long-term cardiovascular effects of stimulants (d-methylphenidate-XR), guanfacine-IR and their combination in 207 children and adolescents with ADHD, aged 7-14 years [Sayer et al 2016]. The study showed that combination therapy might attenuate the small but statistically significant changes associated with either single treatment.…”

“…However, although commonly mild, time-limited and manageable with dose adjustment, without the need to stop treatment, ADHD pharmacotherapies are not exempt from treatment emergent adverse events (TEAEs), as evidenced in randomized controlled trials [Aagaard and Hansen, 2011; Adler et al 2009; Graham and Coghill, 2008; Upadhyaya et al 2015]. Indeed, treatment discontinuation rates due to adverse events with any of the approved medications for ADHD are generally low [Clavenna and Bonati, 2014; Michelson et al 2003; Sayer et al 2016; Weisler et al 2006].…”

“…The study showed that combination therapy might attenuate the small but statistically significant changes associated with either single treatment. Thus, while guanfacine caused a short-term decrease in HR, systolic BP, and diastolic BP, and dexmethylphenidate a short-term increase in HR, systolic BP, diastolic BP, and QTc interval during acute titration phase, combination of these two medications only was associated with an increase in diastolic BP, but had no effects on HR, systolic BP, or QTc [McCracken et al 2016; Sayer et al 2016].…”