Cardiovascular Effects and Safety of Lisdexamfetamine in Attention-Deficit/Hyperactivity Disorder and Healthy Volunteers: A Systematic Review.

Technical Summary: Cardiovascular Effects and Safety of Lisdexamfetamine in ADHD and Healthy Volunteers

Problem Statement
Lisdexamfetamine dimesylate is a long-acting amphetamine-based prodrug widely utilized for treating Attention-Deficit/Hyperactivity Disorder (ADHD). While its pharmacokinetic profile—characterized by gradual conversion to active dextroamphetamine—offers predictable therapeutic exposure, its sympathomimetic mechanism raises concerns regarding cardiovascular safety. Specifically, increased catecholaminergic neurotransmission may influence heart rate, blood pressure, vascular tone, and myocardial workload. Although clinical evidence suggests generally modest effects, there is a need to synthesize available data across diverse populations (pediatric, adult, and healthy volunteers) and study designs to clarify the extent of these cardiovascular risks, particularly regarding QTc prolongation and serious adverse events. Furthermore, existing literature often excludes individuals with pre-existing cardiovascular conditions, potentially limiting the generalizability of safety findings to higher-risk clinical populations.

Methodology
This study is a systematic review conducted in accordance with the PRISMA 2020 recommendations and prospectively registered in PROSPERO (CRD420261343822).

• Search Strategy: A comprehensive search was performed across PubMed/MEDLINE, Embase, Cochrane Library, Google Scholar, and SciELO for studies published between January 2000 and March 2026.
• Eligibility Criteria: The review included randomized controlled trials, open-label extensions, observational studies, pharmacokinetic/pharmacodynamic studies, case reports, and systematic reviews involving individuals with ADHD or healthy volunteers exposed to lisdexamfetamine. Eligible studies had to report cardiovascular outcomes such as heart rate, blood pressure, electrocardiographic findings (including QTc interval), arrhythmias, or cardiovascular adverse events.
• Selection and Analysis: From an initial pool of 727 records, 20 studies met the inclusion criteria after duplicate removal and screening. Two reviewers independently conducted study selection, data extraction, and risk-of-bias assessment using tools appropriate for each design (RoB 2 for RCTs, Newcastle–Ottawa Scale for observational studies, and AMSTAR 2 for systematic reviews).
• Synthesis: Due to significant heterogeneity in study designs, populations, dosing, and outcome reporting, a quantitative meta-analysis was not performed. Instead, a narrative synthesis was conducted, grouping evidence by population (preschool children, children/adolescents, adults, healthy volunteers) and study type.

Key Results
The synthesis of 20 studies revealed the following cardiovascular profile for lisdexamfetamine:

• Hemodynamic Changes: Across pediatric, adult, and healthy volunteer populations, lisdexamfetamine was consistently associated with small mean increases in heart rate, generally ranging from 4 to 7 beats per minute. Modest increases in systolic and diastolic blood pressure were also observed, typically between 1 and 4 mmHg. These changes align with the drug's sympathomimetic mechanism.
• Electrocardiographic Safety: Available studies did not demonstrate consistent evidence of clinically meaningful QTc prolongation or a significant increase in serious electrocardiographic abnormalities.
• Adverse Events: Serious cardiovascular adverse events were rare within the included studies. However, the authors note that this finding must be interpreted cautiously, as many trials excluded participants with significant cardiovascular disease, uncontrolled hypertension, or relevant ECG abnormalities.
• General Tolerability: The most frequently reported adverse events were non-cardiovascular but systemic in nature, including decreased appetite, weight loss, insomnia, irritability, headache, and nausea.
• Population Variability: While group-level mean changes were modest, individual responses varied. Some patients experienced more noticeable vital sign changes, underscoring the necessity of individualized monitoring rather than reliance solely on aggregate data.

Significance and Claims
The paper concludes that lisdexamfetamine possesses an overall favorable cardiovascular safety profile in selected and clinically monitored populations with ADHD and healthy volunteers. The primary cardiovascular effects are limited to modest increases in heart rate and blood pressure, consistent with its pharmacological mechanism, without evidence of clinically significant QTc prolongation or a marked increase in serious adverse events in the studied cohorts.

However, the authors emphasize that these findings are not without limitations. The exclusion of high-risk patients from many clinical trials means the observed safety profile may not fully apply to individuals with pre-existing cardiovascular risk factors, uncontrolled hypertension, or structural heart disease. Consequently, the paper asserts that while lisdexamfetamine is not a high-risk medication for appropriately selected patients, its use necessitates:

1. Individualized Assessment: Baseline evaluation of cardiovascular history, blood pressure, heart rate, and symptoms (e.g., palpitations, chest pain, syncope).
2. Regular Monitoring: Periodic tracking of vital signs, particularly during dose titration, long-term treatment, and in patients with cardiovascular risk factors.
3. Holistic Management: In pediatric populations, cardiovascular monitoring should be integrated with the assessment of growth, weight, appetite, and sleep.

The review highlights the need for future research involving longer follow-up periods, standardized cardiovascular outcome reporting, and the inclusion of patients with stable cardiovascular risk factors to better understand rare or cumulative cardiovascular events in real-world settings.