Comparative Cardiovascular Safety of Prescription Amphetamine and Methylphenidate Initiation Among Older Adult Medicare Beneficiaries

Background: Prescription stimulant use among the United States’ (US) older adult population is increasing, yet little is known about the cardiovascular safety profiles of the two major prescription stimulant classes, methylphenidate (MPD) and amphetamine (AMP). Objective: To compare the hazard of major adverse cardiovascular (CV) events between new users of prescription MPD and AMP products in US older adults. Methods: We employed a new-user comparative safety study from a 5% random sample of fee-for-service Medicare beneficiaries. Continuously enrolled beneficiaries (Parts A/B/D) aged ≥66 years who initiated MPD or AMP (1/1/17 - 12/31/21) were included. We required a 1-year washout before the first prescription claim (index date) and excluded those with contraindications based on diagnosis codes. The primary outcome was incident 4-P MACE (modified 4-point major adverse CV event, including acute myocardial infarction, stroke or transient ischemic attack, ventricular arrhythmia, and all-cause mortality); secondary outcomes included mortality and CV events (all MACE excluding death). We used a 1-year follow up after index date that was censored at change in insurance coverage, therapeutic switch, addition of the comparator drug, or end of the study (12/31/21). Confounders included demographics, healthcare utilization indicators, comorbidities, and other medications. We used trimmed propensity scores (PS) to create stabilized inverse probability of treatment weights (IPTW) and Cox proportional hazard regression to estimate the effect of MPD vs. AMP initiation on the first occurrence of 4-P MACE. Results: We identified 2526 Medicare beneficiaries initiating MPD (N=1340, mean [SD] age=74.5 [6.4] years, 56.3% female sex) or AMP (N=1186, mean [SD] age=74.7 [6.6] years, 55.7% female sex). After PS trimming and applying IPTW, the groups were well-balanced based on absolute standardized mean differences. During 2021.6 person-years follow up (MPD [1009.9 years] vs. AMP [1011.8 years]), 339 4-P MACE events occurred (MPD [N=280] vs. AMP [N=59]), of which 225 were deaths (MPD [N=192] vs. AMP [N=33]), and 114 were CV events (MPD [N=88] vs. AMP [N=26]). In the primary analysis, MPD vs. AMP initiation was associated with an increased risk of 4-P MACE (HR = 1.73, 95% CI [1.36, 2.19]). The secondary analysis showed a statistically significant increased risk of mortality (HR = 2.20, 95% CI [1.62, 3.00]), but not CV events (HR = 1.14, 95% CI [0.77, 1.67]). Conclusions: Initiation of MPD vs. AMP among older adults was associated with an increase in the hazard of 4-P MACE. Secondary analysis suggested that this increase was driven by mortality as opposed to CV events. Supplementary Material File (pds-25-0667-file001.docx) - Download - 262.90 KB Information & Authors Information Version history Peer review timeline Published Pharmacoepidemiology and Drug Safety Version of Record20 Apr 2026Published Copyright This work is licensed under a Non Exclusive No Reuse License. Collection

Authors Metrics & Citations Metrics Article Usage 260views 178downloads Citations Download citation Noah Smith, Daniel Manion, Emily Slade, et al. Comparative Cardiovascular Safety of Prescription Amphetamine and Methylphenidate Initiation Among Older Adult Medicare Beneficiaries. Authorea. 20 August 2025. DOI: https://doi.org/10.22541/au.175568597.70915237/v1 DOI: https://doi.org/10.22541/au.175568597.70915237/v1 If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download. For more information or tips please see 'Downloading to a citation manager' in the Help menu.