Arthur N. Westover

Do prescription stimulants increase the risk of adverse cardiovascular events?: A systematic review

BackgroundThere is increasing concern that prescription stimulants may be associated with adverse cardiovascular events such as stroke, myocardial infarction, and sudden death. Public health concerns are amplified by increasing use of prescription stimulants among adults.MethodsThe objective of this study was to conduct a systematic review of the evidence of an association between prescription stimulant use and adverse cardiovascular outcomes. PUBMED, MEDLINE, EMBASE and Google Scholar searches were conducted using key words related to these topics (MESH): ADHD; Adults; Amphetamine; Amphetamines; Arrhythmias, Cardiac; Cardiovascular Diseases; Cardiovascular System; Central Nervous Stimulants; Cerebrovascular; Cohort Studies; Case–control Studies; Death; Death, Sudden, Cardiac; Dextroamphetamine; Drug Toxicity; Methamphetamine; Methylphenidate; Myocardial Infarction; Stimulant; Stroke; Safety. Eligible studies were population-based studies of children, adolescents, or adults using prescription stimulant use as the independent variable and a hard cardiovascular outcome as the dependent variable.ResultsTen population-based observational studies which evaluated prescription stimulant use with cardiovascular outcomes were reviewed. Six out of seven studies in children and adolescents did not show an association between stimulant use and adverse cardiovascular outcomes. In contrast, two out of three studies in adults found an association.ConclusionsFindings of an association between prescription stimulant use and adverse cardiovascular outcomes are mixed. Studies of children and adolescents suggest that statistical power is limited in available study populations, and the absolute risk of an event is low. More suggestive of a safety signal, studies of adults found an increased risk for transient ischemic attack and sudden death/ventricular arrhythmia. Interpretation was limited due to differences in population, cardiovascular outcome selection/ascertainment, and methodology. Accounting for confounding and selection biases in these studies is of particular concern. Future studies should address this and other methodological issues.

Acute Myocardial Infarction in Young Adults Who Abuse Amphetamines

BACKGROUND Case reports suggest a link between methamphetamine abuse and acute myocardial infarction (AMI), but no epidemiologic studies have examined this link. Our objective was to test the hypothesis that young adults who abuse amphetamines are at higher risk for AMI. METHODS In this study of 3,148,165 discharges from Texas hospitals in a quality indicators database during 2000-2003, among persons aged 18-44 years we identified 11,011 AMIs, defined according to the Agency for Healthcare Research and Qualitys AMI mortality inpatient quality indicator. RESULTS In a multiple logistic regression analysis - while controlling for cocaine abuse, alcohol abuse, tobacco use, hypertension, diabetes mellitus, lipid disorders, obesity, congenital defects, and coagulation defects - amphetamine abuse was significantly associated with AMI (adjusted odds ratio=1.61; 95% CI=1.24-2.04, p=0.0004). The rate of AMIs among amphetamine abusers increased significantly from 2000 to 2003. The population attributable risk suggests that amphetamine abuse is responsible for 0.2% of AMIs in the state of Texas. The geographical distribution of amphetamine abuse varied by region, with the prevalence being highest in the North Texas and Panhandle regions of Texas. CONCLUSIONS This modest, though statistically robust, association suggests that amphetamine abuse may play a role in AMI.

Aortic dissection in young adults who abuse amphetamines

BACKGROUND Case reports suggest a relationship between amphetamine abuse/dependence and aortic dissection, but no population-based epidemiologic studies have examined this link. Our objective was to test the hypothesis that young adults with a diagnosis of amphetamine abuse/dependence would be at higher risk for aortic dissection after accounting for known risk factors. METHODS In this population-based case-control study of 30,922,098 discharges from the Healthcare Cost and Utilization Project Nationwide Inpatient Sample from 1995 to 2007, among persons aged 18 to 49 years, we identified 3,116 thoracic and thoracoabdominal aortic dissections using International Classification of Disease, Ninth Edition, Clinical Modification codes 441.01 and 441.03. The SURVEYLOGISTIC procedure in SAS 9.2 (SAS Institute, Cary, NC) was used to account for the Nationwide Inpatient Sample sampling methodology. RESULTS In a multiple logistic regression analysis, while controlling for known risk factors, amphetamine abuse/dependence was significantly associated with aortic dissection (adjusted odds ratio = 3.33, 95% CI = 2.37-4.69, P < .0001). CONCLUSIONS This statistically significant association suggests that amphetamine abuse/dependence may play a role in aortic dissection in young adults in the United States.

A systematic approach to subgroup analyses in a smoking cessation trial

Abstract Background: Traditional approaches to subgroup analyses that test each moderating factor as a separate hypothesis can lead to erroneous conclusions due to the problems of multiple comparisons, model misspecification, and multicollinearity. Objective: To demonstrate a novel, systematic approach to subgroup analyses that avoids these pitfalls. Methods: A Best Approximating Model (BAM) approach that identifies multiple moderators and estimates their simultaneous impact on treatment effect sizes was applied to a randomized, controlled, 11-week, double-blind efficacy trial on smoking cessation of adult smokers with attention-deficit/hyperactivity disorder (ADHD), randomized to either OROS-methylphenidate (n = 127) or placebo (n = 128), and treated with nicotine patch. Binary outcomes measures were prolonged smoking abstinence and point prevalence smoking abstinence. Results: Although the original clinical trial data analysis showed no treatment effect on smoking cessation, the BAM analysis showed significant subgroup effects for the primary outcome of prolonged smoking abstinence: (1) lifetime history of substance use disorders (adjusted odds ratio [AOR] 0.27; 95% confidence interval [CI] 0.10–0.74), and (2) more severe ADHD symptoms (baseline score >36; AOR 2.64; 95% CI 1.17–5.96). A significant subgroup effect was also shown for the secondary outcome of point prevalence smoking abstinence – age 18 to 29 years (AOR 0.23; 95% CI 0.07–0.76). Conclusions: The BAM analysis resulted in different conclusions about subgroup effects compared to a hypothesis-driven approach. By examining moderator independence and avoiding multiple testing, BAMs have the potential to better identify and explain how treatment effects vary across subgroups in heterogeneous patient populations, thus providing better guidance to more effectively match individual patients with specific treatments.

Risk of methylphenidate-induced prehypertension in normotensive adult smokers with attention deficit hyperactivity disorder.

The authors studied predictors of methylphenidate‐induced increases in blood pressure (BP). In this secondary analysis of a randomized, double‐blind, placebo‐controlled smoking cessation trial, nonhypertensive adult smokers with attention deficit hyperactivity disorder randomized to osmotic‐release oral system methylphenidate (OROS‐MPH) (n=115) were matched one‐to‐one on baseline systolic BP (SBP) (±5 mm Hg) with participants randomized to placebo (n=115) and followed for 10 weeks. In adjusted mixed linear models of SBP and diastolic BP (DBP), baseline normal SBP (P<.0001) and DBP (P<.0001) were associated with significant OROS‐MPH–induced increases compared with placebo, whereas significant increases were not observed in participants with baseline prehypertensive SBP (P=.27) and DBP (P=.79). Participants randomized to OROS‐MPH with baseline normal BP had increased odds of developing either systolic (odds ratio [OR], 3.32; 95% confidence interval [CI], 1.41–8.37; P=.006) or diastolic prehypertension (OR, 4.32; 95% CI, 1.56–14.0; P=.004) compared with placebo using simple logistic regression. The authors demonstrated an augmented OROS‐MPH–induced BP elevation and risk of prehypertension in adults with baseline normal BP. Significantly increased BP was not observed in adults with baseline prehypertension. J Clin Hypertens (Greenwich). 2012; 00:00–00. ©2012 Wiley Periodicals, Inc.

Risk of Methylphenidate-Induced Prehypertension in Normotensive Adult Smokers with ADHD

The authors studied predictors of methylphenidate‐induced increases in blood pressure (BP). In this secondary analysis of a randomized, double‐blind, placebo‐controlled smoking cessation trial, nonhypertensive adult smokers with attention deficit hyperactivity disorder randomized to osmotic‐release oral system methylphenidate (OROS‐MPH) (n=115) were matched one‐to‐one on baseline systolic BP (SBP) (±5 mm Hg) with participants randomized to placebo (n=115) and followed for 10 weeks. In adjusted mixed linear models of SBP and diastolic BP (DBP), baseline normal SBP (P<.0001) and DBP (P<.0001) were associated with significant OROS‐MPH–induced increases compared with placebo, whereas significant increases were not observed in participants with baseline prehypertensive SBP (P=.27) and DBP (P=.79). Participants randomized to OROS‐MPH with baseline normal BP had increased odds of developing either systolic (odds ratio [OR], 3.32; 95% confidence interval [CI], 1.41–8.37; P=.006) or diastolic prehypertension (OR, 4.32; 95% CI, 1.56–14.0; P=.004) compared with placebo using simple logistic regression. The authors demonstrated an augmented OROS‐MPH–induced BP elevation and risk of prehypertension in adults with baseline normal BP. Significantly increased BP was not observed in adults with baseline prehypertension. J Clin Hypertens (Greenwich). 2012; 00:00–00. ©2012 Wiley Periodicals, Inc.

Heart Rate Recovery and Systolic Blood Pressure Recovery After Maximal Exercise in Prevalent Users of Stimulant Medications.

To the Editors: I ncreasing use of prescribed stimulant medications among adults and a study that linked their use to increased risk of ventricular arrhythmia and sudden death have increased concerns about their cardiovascular safety. Acute methylphenidate use has been shown to increase heart rate (HR) compared with placebo during exercise. However, our recent study found that prevalent use of stimulant medications was associated with decreased peak HR during maximal exercise testing. In addition, stimulant medication users had an increased risk of chronotropic incompetence (defined as an inappropriately lowHR in the face of activity demands), which has been associated with serious cardiovascular events and mortality. This unexpected finding led us to hypothesize that autonomic adjustment immediately after exercise might be abnormal in stimulant users—HR recovery (HRR) and systolic blood pressure (SBP) recovery. After exercise, HR and BP normally decrease to resting levels via reactivation of vagal tone in healthy persons and withdrawal of sympathetic neural drive. However, the autonomic influence of stimulants during recovery from exercise has never been adequately assessed. Two previous studies of stimulant medications have demonstrated delayed HRR after exercise testing. Adults with attentiondeficit/hyperactivity disorder (ADHD) on stimulant medications (n = 29) had a significant 7 beats per minute elevation in 1-minute HRR compared with controls (n = 27) during symptom-limited treadmill exercise testing (P = 0.001). Similarly, in an open-label study of 15 adults who underwent exercise testing before and after 3 to 6months of treatment with lisdexamfetamine, the 1-minute HRR increased by 4.3 beats per minute by study end (P = 0.05). The aim of the present study was to determine, in a large sample, whether stimulant medication users compared with matched nonusers have an increased risk of abnormal HRR and abnormal SBP recovery after a maximal exercise test while matching/adjusting for fitness, obesity, smoking, and other covariates.

Response to letter regarding “A systematic approach to subgroup analyses in a smoking cessation trial”

Sir: We appreciate the questions and are thankful for the opportunity to further clarify our approach. In Westover et al. (1), the pool of expert-specified recoded 50 covariates (including possible...

Family Discord After Completion of an Outpatient Community Treatment Program Predicts Greater Substance Use During Follow-up

ABSTRACT Background: It is reasonable to consider family discord after treatment as a potential target for a next-step intervention, since family discord is often comorbid with substance use disorders. Objective: This study evaluated family discord after completing an initial course of treatment as a predictor of substance use and retention in the community treatment program during follow-up. Method: Patients were from two multisite randomized clinical trials implemented through the Clinical Trials Network of the National Institute on Drug Abuse. There were 315 participants from Study 1 (12-week posttreatment follow-up) and 295 participants from Study 2 (8-week posttreatment follow-up). Negative binomial and logistic regression were used to estimate days of substance use and odds of retention in the community treatment program at follow-up, respectively, from family discord status. Results: Family discord was significantly associated with more days of substance use during the posttreatment follow-up period than those without family discord in both Study 1 (9.12 vs. 2.89 days, p =.0001) and Study 2 (5.58 vs. 2.83 days, p =.0062). Family discord was significantly associated with lower retention in the community treatment program at follow-up than those not reporting family discord in Study 1 (47.6% vs. 60.6%; p =.03), but not in Study 2 (55.3% vs. 64.9%; p =.11). Conclusion: Family discord after an initial course of treatment might be a clinically relevant predictor of substance use. There is mixed support for a conclusion that family discord is associated with lower retention in the community treatment program at follow-up.

Risk of Methylphenidate-Induced Prehypertension in Normotensive Adult Smokers With Attention Deficit Hyperactivity Disorder: Methylphenidate-Induced Prehypertension

The authors studied predictors of methylphenidate‐induced increases in blood pressure (BP). In this secondary analysis of a randomized, double‐blind, placebo‐controlled smoking cessation trial, nonhypertensive adult smokers with attention deficit hyperactivity disorder randomized to osmotic‐release oral system methylphenidate (OROS‐MPH) (n=115) were matched one‐to‐one on baseline systolic BP (SBP) (±5 mm Hg) with participants randomized to placebo (n=115) and followed for 10 weeks. In adjusted mixed linear models of SBP and diastolic BP (DBP), baseline normal SBP (P<.0001) and DBP (P<.0001) were associated with significant OROS‐MPH–induced increases compared with placebo, whereas significant increases were not observed in participants with baseline prehypertensive SBP (P=.27) and DBP (P=.79). Participants randomized to OROS‐MPH with baseline normal BP had increased odds of developing either systolic (odds ratio [OR], 3.32; 95% confidence interval [CI], 1.41–8.37; P=.006) or diastolic prehypertension (OR, 4.32; 95% CI, 1.56–14.0; P=.004) compared with placebo using simple logistic regression. The authors demonstrated an augmented OROS‐MPH–induced BP elevation and risk of prehypertension in adults with baseline normal BP. Significantly increased BP was not observed in adults with baseline prehypertension. J Clin Hypertens (Greenwich). 2012; 00:00–00. ©2012 Wiley Periodicals, Inc.